Text Book of Medicine

(For Medical Students and Practitioners)

Authors
Dr. Siva Rami Reddy E MD, Ph.D.
Professor & Head
Department of Practice of Medicine
S.G.N. Homoeopathic Medical College & Hospital Research Center,
Rajasthan, India

Dr. Tanuja B MDS

Senior Lecturer
Department of Periodontics & Implantology
G. Pulla Reddy Dental College & Hospital, Kurnool, Andhra Pradesh, India

Publication Month and Year: December 2019

Pages: 192
E-BOOK ISBN: 978-81-943354-6-7

Academic Publications
C-11, 169, Sector-3, Rohini, Delhi, India
Website: www.publishbookonline.com
Email: publishbookonline@gmail.com
Phone: +91-9999744933
 Preface

Dear Doctors, Greetings. Practice of Medicine, though difficult, is one of the

crucial subject for post graduate, Ph.D. entrance examinations.
This edition of book has been completely revamped and updated. This e-
book provided with colour pictures to make understanding of the text, lot
easier. This will be quite handy for final year students. It will be adequate for
the final year medicine theory examination and at the same time it will orient
you, exactly towards entrance examinations so that getting a P.G, Ph.D. of
choice immediately after completing internship become a reality!
This text book of medicine is to link recent scientific advances to
disease pathogenesis and therapeutic innovations. After studying this book,
student will be able to answer all the questions and have a through
explanation for each of the answers.
This text book is dedicated to all medical students and practitioners.
We have tried to make this book error free but sincerely apologize for
any mistake that may have escaped my notice.
We will highly appreciate the suggestions and criticisms are most
welcome from our readers for the improvement of the book.

Dr. Siva Rami Reddy E

Dr. Tanuja B
 Contents

Sl. No. Chapters Page No

1. Diseases of the Cardiology 1-27
2. Diseases of the Endocrinology 28-41
3. Diseases of the Gastroenterology 42-56
4. Diseases of the Nephrology 57-71
5. Diseases of the Neurology 72-78
6. Diseases of the Respiratory System 79-98
7. Diseases of the Hepatic System 99-108
8. Diseases of the Connective Tissues 109-127
9. Diseases of the Oncology 128-138
10. Diabetes Mellitus 139-142
11. Infectious Diseases 143-151
12. Diseases of the Blood 152-163
References 164-191
 Chapter - 1
Diseases of the Cardiology

Ischaemic Heart Disease

Ischemic heart disease also called as coronary heart disease. In the India
one in three men and one in four women die from this disease. Chronic
coronary artery disease (CAD) is estimated to affect 16.8 million people in
the United States; of these, 9.8 million have angina pectoris, and nearly.
8 million have had a myocardial infarction (MI). In 2002, out of 57
million deaths worldwide, approximately 16.7 million were due to
cardiovascular disease (as compared with approximately 5 million due to
tuberculosis, human immunodeficiency virus, and malaria combined), and
80% of these cardiovascular deaths were in the developing world. The article
provides a state-of-the-art review of the literature on cardio vascular diseases
for interested medical, dental, ayush physicians; appropriate articles were
identified by searching the international journal database for the following
terms: cardio vascular disease, causes.
Aetiology
Age and Male Sex: Males are more risk when compared to females.
Family history: Family aetiology may be due to genetic factors or the effects
of a shared environment (diet, smoking habits etc.). Hyperlipidaemia,
hyperfibrinogenemia and abnormalities of other coagulation factors are often
geneticallydetermined.
Smoking: Tobacco is probably the most important avoidable cause of
coronary disease.
Hypertension: The incidence of coronary artery disease increase as
blood pressure rises and excess risk is related to both systolic and diastolic
blood pressure.
Hypercholesterolaemia: Patient with familial hyperlipidaemia have a
high incidence of premature coronary disease and many epidemiological
studies have demonstrated a positive correlation between mean population
and plasma cholesterol concentration and morbidity and death from
coronarydisease.

Page | 1
 Diabetes Mellitus: This is associated with a increased incidence of
ischaemic heart disease (IHD) and with a tendency to diffuse coronary
atheroma.
Haemostatic factors, physical inactivity, obesity, alcohol, mental stress
may leads to ischemic heart disease.

Fig 1: The evolution of an atheromatous plaque

Pathophysiology
Mechanisms that account for a minority of fatal coronary thrombosis
include superficial erosion, intraplaque hemorrhage, and the erosion of a
calcified nodule. Thus, physical disruption of the atherosclerotic plaque
accounts for almost all acute coronary thrombosis. Disrupted plaques
provoke thrombosis in several ways. First, contact with collagen in the
plaque’s extracellular matrix can trigger platelet activation. Second, TF
produced by macrophages and SMCs activates the coagulation cascade. The
disrupted plaque thereby represents a “solid-state” stimulus to both
thrombosis and coagulation; these pathways reinforce each other, as
thrombin generation amplifies the activation of platelets and other cells in
the lesion. Conversionof fibrinogen to fibrin and release of von Willebrand
factor from activated platelets can provide the cross-linking molecular
bridges between platelets that yield the dense, 3-dimensional network of
platelets entrapped in fibrin characteristic of the “white” arterial thrombus. In
addition to the solid state of the disrupted plaque, the “fluid phase” of blood
can predispose toward coronary thrombosis. Plasminogen activator inhibitor-
1 (PAI-1) extinguishes the body’s natural fibrinolytic mechanism that
combats the persistence and accumulation of thrombi by inhibiting
urokinase-like and tissue-type plasminogen activators. Circulating levels of
PAI-1 increase in diabetes and obesity, and mediators of hypertension such
as angiotensin II can augment PAI-1 expression by various cell types.

Page | 2
 Furthermore, disrupted plaques can elaborate particulate TF, which can
heighten the thrombogenicity of blood. These fluid-phase changes led to the
concept of the “vulnerable patient,” thus augmenting our appreciation of the
so called “vulnerable plaque”. In the context of ACS, the distal embolization
of TF rch debris spewing in to the blood stream from the core of the
suddenly disrupted plaque may promote distal thrombosis in the
microcirculation. Such distal embolization explains in part the “no- reflow”
phenomenon that can complicate both spontaneous and iatrogenic plaque
disruption and prevent effective reperfusion of the distal microcirculation.
Coronary heart disease may leads to angina. Angina causes the
following feeling across the chest.
Clinical Features: Squeezing, pressure, heaviness, tightening, burning,
aching. Angina might also cause the following symptoms: Indigestion, heart
burn, weakness, sweating, nausea, cramping.
Diagnosis
ECG may show evidence of previous myocardial infarction. The most
convincing ECG evidence of myocardial ischemia is obtained by
demonstrating reversible ST segment depression or elevation with or without
T wave inversion at the time the patient is experiencing symptoms. Coronary
artery calcium scanning with CT is a screening tool that has no role in
patients with established CAD in whom the presence of coronary artery
calcification is a given. Furthermore, the specificity of the coronary calcium
score for obstructive coronary lesions is low. Although CT coronary
angiography is showing promise for noninvasive detection of obstructive
CAD in major epicardial arteries, it is still limited by a high number of false-
positive results (up to 50% with severe calcification and coronarystents),
specific patient selection (heart rate must be regular and <70 beats/min;
patient must hold breath for 15 seconds), and high dose radiation exposure.
Magnetic resonance imaging may be used for stress perfusion or stress wall
motion imaging as well as noninvasive coronary angiography. Most heart
valve prostheses and vascular stents are compatible with MRI; however,
MRI cannot be used in the presence of certain implanted metal objects or
medical devices, such as pacemakers or implantable cardioverter
defibrillators.
However, electronic rhythm management devices and other
cardiovascular devices are being developed that could be compatible with
MRI. Exercise tolerance test is usually performed using a standard treadmill
or bicycle ergometer protocol to ensure a progressive and reproducible

Page | 3
increase in workload while monitoring the patients ECG, blood pressure and
general condition.
Raynaud’s Diseases
It is caused by intense vasospasm of peripheral arteries. Raynaud's is a
rare disorder that affects the arteries. Arteries are blood vessels that carry
blood from your heart to different parts of yourbody.
Causes: Many causes of Reynaud’s disease.
Example includes:
 Diseases and conditions that directly damage the arteries or damage
the nerves that control the arteries in the hands andfeet
 Repetitive actions that damage the nerves that control the arteriesin
the hands andfeet
 Injuries to the hands andfeet
 Exposure to certain chemicals. E.g. beta adrenoceptor,ergotamine
and derivatives
 Medicines that narrow the arteries or affect bloodpressure
 Occupational exposure to vibrating tools andcold
 Cryoglobulinemia
 CRESTsyndrome

Fig 2: Raynaud’s disease

Clinical Features
 Turn pale or white and thenblue
 Feel numb, cold, orpainful
 Turn red, throb, tingle, burn, or feel numb as blood flow returnsto
the affected areas

Page | 4
Diagnosis
Your doctor will look at your fingers and toes to check the health of
your skin and nails and to check blood flow to these areas. Cold stimulation
test can be used to trigger Raynaud's symptoms. For this test, a small device
that measures temperature is taped to your fingers. Your hands are then
exposed to cold-they're usually briefly put into ice water. Your hands are
then removed from the cold, and the device measures how quickly your
fingers return to their normal temperature. If you have Raynaud's, it may
take more than 20 minutes for your fingers to return to their normal
temperature. Because results of this type of test are not always consistent,
your doctor may do other tests to check for Raynaud’s.
Pericardial effusion
Collection of fluid in pericardial cavity.
Causes:viral infection, tubercular and non-infective like uraemia,
myxedema, neoplastic, myocardial infection.
Clinical Features
Clinical features of pericardial effusion are dry cough, dyspnoea, fever
on and off, palpitation, weakness, precordial pain, pain in upper abdomen,
giddiness, difficulty in swallowing. Sign of the pericardial effusion are rapid
pulse, hypotension, JVP raise, bilateral and pitting type of pedal oedema,
peripheral cyanosis presented dyspnoeic.
Diagnosis
Low voltage of QRS complexes in ECG, pear shaped cardiac shadow,
transverse cardiac diameter increased, oligaemic lung fields.
Management
Rest and easily digestible, nutritive diet.
Aortic Aneurysm
An aortic aneurysm is an enlargement (dilatation) of the aorta to greater
than 1.5 times normal size. They usually cause no symptoms except when
ruptured. Occasionally, there may be abdominal, back, or leg pain.
Causes
Atheromatous disease-affects ascending or descending aorta, aortitis and
collagen vascular diseases-affect thoracic aorta: cystic medial necrosis,
marfan’s syndrome, ehlers-danlos syndrome.

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 Fig 3: Aortic aneurysm

Clinical Features
Most intact aortic aneurysms do not produce symptoms. As they
enlarge, symptoms such as abdominal pain and back pain may develop.
Compression of nerve roots may cause leg pain or numbness. Untreated,
aneurysms tend to become progressively larger, although the rate of
enlargement is unpredictable for any individual.
Rarely, clotted blood which lines most aortic aneurysms can break off
and result in an embolus. Aneurysms can be found on physical examination.
Medical imaging is necessary to confirm the diagnosis and to determine the
anatomic extent of the aneurysm. Signs are aneurysm may be palpable in
abdominal aorta, evidence of widespread vascular disease, stigmata of distal
embolisation, haemodynamic collapse (hypotension, tachycardia, shock),
with rupture of aneurysm.
Management
Emergency surgery.
Rheumatic Heart Disease
Rheumatic heart disease (RHD) is characterised by permanent damage
to the valves of the heart that develops as a serious consequence of repeated
episodes of acute rheumatic fever (ARF), an autoimmune reaction to a
Group A streptococcus (GAS) bacterial infection. Rheumatic heart disease is
a chronic cardiac condition with an infectious aetiology, causing high
disease burden in low-income settings. Affected individuals are young and

Page | 6
associated morbidity is high. However, RHD is relatively neglected due to
the populations involved and its lower incidence relative to other heart
diseases.

Fig 4: Rheumatic Heart disease

The resulting immune response targets both the bacteria and some of the
body’s own tissues that contain similar molecules to those in the bacteria,
including the heart, skin, joints and nervous system.
Rheumatic heart disease results from persisting inflammation of the
heart after acute or recurrent episodes of rheumatic fever. It typically affects
the valves of the heart, especially the mitral and aortic valves. Chronic
inflammation may cause narrowing of the valves resulting in decreased
blood flow through the heart or leakage of the valves causing blood to flow
in the wrong direction. This may eventually lead to arrhythmias, such as
atrial fibrillation, or heart failure, where the heart is unable to pump enough
blood to meet the body’s needs. Rheumatic fever typically affects children
between five and 15 years old for the first time but the effects of rheumatic
heart disease often first present in adulthood. Environmental factors such as
poor sanitation and crowded living conditions increase the transmission of
the bacteria that cause rheumatic heartdisease.
Clinical Features
Rheumatic fever is a systemic illness typically presenting with fever,
anorexia, lethargy and joint pains. Arthritis includes skin rashes (erythema
marginatum), carditis (breathlessness, palpitations, chest pain), chorea,
subcutaneous nodules and neurological features. Pulses are supporting
evidence of preceding streptococcal infection: recent scarlet fever, raised

Page | 7
antistreptolysin O or other streptococcal antibody titers, positive throat
culture.
Investigations
Blood tests may be performed in order to detect components of the
inflammatory and immune responses that cause rheumatic heart disease.
Diagnosis of damage to the heart is primarily achieved by echocardiography,
which is an ultrasound imaging of the heart. This can detect abnormally
narrow, thickened or leaky valves as well abnormal function of the heart’s
chambers. Rheumatic fever patients have raised ESR or c reactive protein,
leukocytosis, first degree or second degree AV block.
Management
Prevention of rheumatic heart disease centers on early detection and
treatment of streptococcal throat infections that cause rheumatic fever. This
involves appropriate antibiotic therapy. If moderate or severe heart disease is
established, an operation may be necessary to repair or replace the damaged
heart valves. This may involve the insertion of a tube and balloon into the
heart to dilate a narrowed heart valve through ‘balloon valvotomy’.
Alternatively, surgical repair or replacement of a damaged heart valve may
be performed. The selection of the appropriate procedure is dependent on a
number of factors, including the extent of disease of the patient and the level
of expertise of the treating doctor. These procedures aim to improve
symptoms and quality of life, restore heart function and prevent deterioration
of the heart that may lead to complications such as arrhythmias and heart
failure.
Buerger’s Disease
It is characterized by acute inflammation with thrombosis involving
both arteries and absent of pulses in lower limbs.
Causes: causes are unknown. May be causes are smoking, diabetes
mellitus, senile atherosclerosis.
Clinical Features
Clinical features of buerger’s diseases are pain in lower limbs, worse at
night, better by hanging leg down. Signs are poor peripheral arterial
pulsation of affected limb, low temperature in affected limb, skin is scaling,
dry, colour changes are there.
Complication
Gangrene and ulceration of toes.

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Diagnosis
Calcified vascular lesion in radiograph of limb, degree of obstruction in
colorDoppler.
Management
Avoid exposure to cold, reduce smoking, prevent, control infection in
toes, reflex heating oflimb.
Valve Heart Disease
Valvular heart disease (VHD) encompasses a number of common
cardiovascular conditions that account for 10% to 20% of all cardiac surgical
procedures in the United States. A better understanding of the natural history
coupled with the major advances in diagnostic imaging, interventional
cardiology, and surgical approaches have resulted in accurate diagnosis and
appropriate selection of patients for therapeutic interventions. A thorough
understanding of the various valvular disorders is important to aid in the
management of patients with VHD. Appropriate work-up for patients with
VHD includes a thorough history for evaluation of causes and symptoms,
accurate assessment of the severity of the valvular abnormality by
examination, appropriate diagnostic testing, and accurate quantification of
the severity of valve dysfunction and therapeutic interventions, if necessary.
It is also important to understand the role of the therapeutic interventions vs
the natural history of the disease in the assessment of outcomes. Prophylaxis
for infective endocarditis is no longer recommended unless the patient has a
history of endocarditis or a prostheticvalve.
AR = aortic regurgitation; AS = aortic stenosis; AVR = aortic valve
replacement; CAD = coronary artery disease; CMR = cardiac magnetic
resonance imaging; CT = computed tomography; ECG =
electrocardiography; LV = left ventricular; MR = mitral regurgitation; MS =
mitral stenosis; MV = mitral valve; RV = right ventricular.
Etiology and Pathophysiology
Isolated AR is significantly less common than pure AS. Degenerative
and bicuspid aortic valve disease shows a different degree of both
regurgitation and left ventricular obstruction; however, stenosis is usually
pre-eminent. More frequently, AR is a consequence of aortic dilation and the
deformation of the annulus valve. Overall prevalence of significant native
AR has been reported in between 2.0% and 2.5% of patients 70 years to 83
years of age, without genderdifferences.

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 Fig 5: Valves diseases
Although smaller studies reported a higher incidence of up to 13%. Age,
aortic valve fibrocalcification, and female sex were considered independent
factors related to AR, while several studies failed to find a relationship with
arterial hypertension.
Aortic Regurgitation
The incidence of clinically significant aortic regurgitation (AR)
increases with age, typically peaking in the fourth to sixth decade of life. It is
more common in men than women. The prevalence of AR in the
Framingham study was reported to be 4.9%, with regurgitation of moderate
or greater severity occurring in 0.5%. AR may be caused by malfunction of
the valve leaflets themselves, by dilatation of the aortic root and annulus, or
may be due to acombination.
Rheumatic disease is still the most common aetiology of AR in
developing countries; however, in Western Europe and North America the
leading cause of AR is either congenital (particularly due to bicuspid
leaflets) or degenerative disease, including annuloaortic ectasia.
Understanding the mechanism leading to AR is essential for proper patient
management, including the surgical approach. Thus, knowledge of the
morphology of the valve leaflets, the annulus and the ascending aorta are
essential.

Page | 10
 Fig 6: Aortic Regurgitation

Clinical Features
Aortic regurgitation clinical features are mild to moderate of aortic
regurgitation, awareness of heart beat, palpitations, sever aortic
regurgitation, heart failure, angina. Signs are large volume or ‘collapsing
pulse’, bounding peripheral pulses, capillary pulsation in nail beds-quincke’s
sign, femoral bruit (pistol shot)-duroziez’s sign, head nodding with pulse-de
musset’s sign, early diastolic murmur, systolic murmur of increased stroke
volume, Austin flint murmur (soft mid diastolic), thrusting apex, fourth heart
sound, enlarge LV, heartfailure.
Diagnosis
The ECG may be normal in mild AR. With greater degrees of
regurgitationLVhypertrophywithorwithoutstrainpatterncanbeseen.
Chest x ray shows evidence of LV enlargement. Dilatation of the
ascending aorta and aortic knob may be seen. Aneurysmal dilatation of the
aorta can be present, particularly in patients in whom the AR is related to
primary disease of the aortic wall. Echocardiography presently is the
principal tool for diagnosis and grading of AR severity as well as for serial
follow up. Colour Doppler is a highly sensitive and specific technique for
detecting AR and provides visualisation of the regurgitant jet. Continuous
and pulsed wave Doppler offer additional haemodynamic information and
aid quantitation. Importantly, two dimensional echocardiography permits
evaluation of LV size and function as well as visualisation of valve

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structures and of the aorta. Three dimensional echocardiography may play an
increasing role in obtaining more precise measurements of ventricular
volumes and may offer enhanced images of valve morphology. Aortic root
angiography and cardiac magnetic resonance imaging (MRI) are alternative
imaging techniques, particularly in rare instances when echocardiography is
technically impossible or technically limited. Radionuclide ventriculography
can be used to serially assess LV ejection fraction at rest and during exercise.
Management
Treatment may be required for underlying conditions such as
endocarditis or syphilis. Aortic valve replacement is indicated if aortic
regurgitation causes symptoms.
Aortic Stenosis
Although valvular heart disease (VHD) is less frequent than coronary
artery disease (CAD), heart failure or hypertension, it is of interest for
several reasons. Aortic stenosis (AS) is a common valvular heart disease in
the Western populations, with an estimated overall prevalence of 3% in
adults over 75 years. To understand its patho-biological processes represents
a priority. In elderly patients, AS usually involves trileaflet valves and is
referred to as degenerative calcific processes. Rheumatic fever as a cause of
AS already had begun to wane in developed countries and was replaced
pathogenetically by degenerative calcificdisease.
The ambiguous term “degenerative” suggested that AS stemmed from
wear and tear on the valve over time, perhaps explaining its greater incidence
in older patients. Although calcification of the aortic valve is a disease of the
elderly population, there is evidence that it is not simply a consequence of
aging.

Fig 7: Aortic stenosis

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 Causes: In infants, children, adolescents are congenital aortic stenosis,
congenital subvalvular aortic stenosis, congenital supravalvular aortic
stenosis. In young adults to middle aged are calcification and fibrosis of
congenitally bicuspid aortic valve, rheumatic aortic stenosis. In middle aged
to elderly causes are calcification of bicuspid valve, senile degenerative
aortic stenosis, rheumatic aortic stenosis.
Clinical Features
Aortic stenosis is exertional dyspnoea, pulmonary oedema, angina,
exertional syncope, sudden death. Signs of aortic stenosis are ejection
systolic murmur, slow rising carotid pulse, reduced pulse pressure, LVH,
thrusting left ventricle, signs of left ventricular failure (Crepitations,
pulmonary oedema).
Diagnosis
Electrocardiogram (ECG)-triggered CT scan of the heart and the whole
aorta, including femoral and subclavian arteries, is performed. Not only can
aortic annulus size be studied using MSCT but also leaflet and annulus
calcification. The latter can be removed during surgery but, if present, might
stand in the way of TAVI. Other important characteristics to be taken into
account are distances between the annulus and the coronary ostia that could
differ from standard and could result in ostial occlusion after implantation.
On the other hand, left ventricular outflow tract (LVOT) and proportions of
the ascending aorta are mandatory to achieve a precise and safe implantation.
Moreover, the peripheral access site and the descending aorta can be
evaluated for anomalies such as major calcification, stenosis, and other
factors that could hinder the procedure. MSCT is now an essential tool in
terms of access site evaluation, prosthesis sizing, and reducing the
paravalvular leakage and risk of complications.
Management
Patients with symptomatic aortic stenosis and a valve gradient indicative
of moderate or severe stenosis should have aortic valvereplacement.
Mitral Stenosis
Mitral stenosis (MS) is a form of valvular heart disease. Mitral stenosis
is characterized by narrowing of the mitral valve orifice. Today, the most
common cause of mitral stenosis is rheumatic fever, but the stenosis usually
appears clinically relevant only after several decades.

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Causes
The most common cause of mitral stenosis is rheumatic fever.
Uncommon causes of mitral stenosis are calcification of the mitral valve
leaflets and congenital heart disease.
Other causes of mitral stenosis include infective endocarditis, mitral
annular calcification, endocardial fibroelastosis, malignant carcinoid
syndrome, systemic lupus erythematosus, Whipple disease, Fabry disease,
and rheumatoid arthritis. His prevalence of rheumatic disease in developed
countries is declining with an estimated incidence of 1 in 100,000. The
prevalence is higher in developing nations than in the United States. In
Africa, for example, the prevalence is 35 cases per 100,000. Rheumatic
mitral stenosis is more common in females. The onset is usually between the
third and fourth decade of life.

Fig 8: Mitral stenosis

Clinical Features
Mitral stenosis is exertional dyspnoea, nocturnal dyspnoea, cough,
ankle/leg oedema, abdominal swelling (right heart failure), acute pulmonary
oedema symptoms, secondary to arterial/venous emboli symptoms (stoke,
haemoptysis, chest pain).
Signs of mitral stenosis are atrial fibrillation, mitral facies, loud 1st heart
sound, opening snap mid diastolic murmur, raised pulmonary capillary
pressure crepitations, pulmonary oedema, effusions, pulmonary hypertension
signs, RV heave, loud P2.

Page | 14
Diagnosis
Mitral stenosis is evaluated using noninvasive and invasive measures.
Noninvasive tests are the electrocardiogram (ECG), chest x-ray,
echocardiogram, and exercise echocardiogram. An invasive test for mitral
stenosis would include a cardiac catheterization. On the ECG, the P wave
changes suggest left atrial enlargement. A presence of right axis deviation
and right ventricular hypertrophy suggest severe pulmonary hypertension.
ECG frequently detects atrial arrhythmias such as atrial fibrillation. On the
chest x-ray, the early stages of mitral stenosis findings are normal heart size,
straightening of the left border of the cardiac silhouette, prominent main
pulmonary arteries, dilatation of the upper pulmonary veins, and
displacement of the esophagus by an enlarged left atrium. During the severe
chronic stage of mitral stenosis, the chest x-ray will have enlargement of all
the chambers, pulmonary arteries, and pulmonary veins.
Management
Mitral stenosis is by mitral valvotomy, balloon valvuloplasty or mitral
valve replacement.
Tricuspid Stenosis
Tricuspid valve stenosis (TS) is rare, affecting less than 1% of patients
in developed nations and approximately 3% of patients worldwide. Detection
requires careful evaluation, as it is almost always associated with left- sided
valve lesions that may obscure its significance.
Primary TS is most frequently caused by rheumatic valvulitis. Tricuspid
valve stenosis is usually progressive when due to rheumatic disease or
carcinoid, versus a fixed stenosis in the setting of congenital abnormalities.
Moreover, most stenotic tricuspid valves have some element of tricuspid
regurgitation. This is in contrast to purely regurgitant tricuspid valves, which
have no element of TS. Stenotic tricuspid valves always demonstrate
structural abnormalities, such as fibrous thickening of the leaflets or
subvalvular mural plaque as seen in carcinoid. Each etiology of TS has its
own distinct pattern of leaflet and chordal pathology.

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 Fig 9: Tricuspid stenosis
Tricuspid stenosis is an uncommon valvular abnormality commonly
associated with other valvular lesions. Ebstein’s anomaly is a rare congenital
heart malformation characterized primarily by abnormalities of the tricuspid
valve and right ventricle. Endomyocardial fibrosis is a restrictive
cardiomyopathy observed in tropical and subtropical regions. It may cause
right ventricular distortion with apparent apical displacement of the tricuspid
valve, mimicking Ebstein’s anomaly. Eosinophilia, rheumatic in origin are
the most commonly cited aetiological link in endomyocardial fibrosis.

Fig 10: Tricuspid stenosis echocardiogram

Clinical Features
Tricuspid valve clinical features are mitral or aortic disease symptoms,
abdominal swelling, hepatic discomfort, peripheral oedema, fatigue. Signs
are raised JVP, mid diastolic murmur is increased by inspiration, right heart
failure-ascites, peripheral oedema.
Management
Tricuspid stenosis is requires surgery. Either replaced or subjected to
valvotomy at the time of surgery. Balloon valvuloplasty can be used to treat
rare cases of isolated tricuspid stenosis.

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Tricuspid Regurgitation
Tricuspid valve regurgitation (TR) presents challenges to modern day
clinical practice. Its natural history is not well understood. Previously,
uncertainty existed as to whether TR is an independent factor of outcome or
rather a surrogate marker of right ventricular disease and other co- morbid
conditions including pulmonary hypertension. However, more recently
studies has shown increasing TR severity is associated with worse survival
regardless of left ventricular (LV) function and pulmonary hypertension.

Fig 11: Tricuspid regurgitation

Primary valvular disease accounts for 10% of cases of TR in adults.
Patients with congenital disease may have primary TV disease such as in
Ebstein’s anomaly, atrioventricular defects and myxomatous prolapse.
Acquired primary conditions include endocarditis, rheumatic disease,
carcinoid or flail leaflet caused by trauma. There is an increasing population
of patients with isolated primary TR caused by endomyocardial biopsy or
intracardiac leads. Secondary TR results from annular dilation and leaflet
tethering leading tomalcoaptation.
Clinical Features
TR are rheumatic heart disease, endocarditis, particularly in intravenous
drug abusers, ebstein’s congenital anomaly(primary) and RV dilation due to
chronic LHF, right ventricular infarction, pulmonary hypertension
(secondary). Signs of tricuspid regurgitation are raised JVP, large systolic
wave in JVP, pansystolic murmur (left sterna edge), systolic hepatic
pulsation.

Page | 17
 Fig 12: Tricuspid regurgitation echocardiography

Management
Tricuspid regurgitation, which is due to RV dilation, gets better when
the cause of right ventricular over load is corrected.
Pulmonary Stenosis
Pulmonary stenosis is a condition characterized by obstruction to blood
flow from the right ventricle to the pulmonary artery.
This obstruction is caused by narrowing (stenosis) at one or more points
from the right ventricle to the pulmonary artery. Areas of potential
narrowing include thickened muscle below the pulmonary valve, stenosis of
the valve itself, or stenosis of the pulmonary artery above the valve. The
most common form of pulmonary stenosis is obstruction at the valve itself,
referred to as pulmonary valvarstenosis.

Fig 13: Pulmonary stenosis & ECG changes

Causes
Pulmonary stenosis occurs when the pulmonary valve doesn’t grow as it
should or the area below or above the valve doesn't grow fully in a baby

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during the first 8 weeks of pregnancy. Why this happens isn't known. Some
congenital heart defects are passed down through families (genetic defects).
Clinical Features
Symptoms are right heart failure, carcinoid syndrome and signs are giant
a wave in the JVP, RV hypertrophy as well as dilation, systolic murmur,
systolic thrill over pulmonary outflow, P2 soft and delayed, valvular PS may
have an ejection click.

Fig 14: Pulmonary stenosis echocardiogram

Diagnosis
Echocardiogram is typically normal in the presence of mild pulmonary
stenosis. With moderate-to-severe pulmonary stenosis the electrocardiogram
may show enlargement of the right ventricle and thickening of its muscle.
An echo uses sound waves (ultrasound) to make a moving picture of the
heart and heart valves. This test is most helpful in diagnosing
pulmonarystenosis.
Chest X-Ray: A chest X-ray may show changes of the heart or
pulmonary artery.
ECG: An ECG records the electrical activity of the heart. It shows
abnormal rhythms (arrhythmias), and finds heart muscle stress. Although the
ECG is often normal, it may show abnormalities that are found with
pulmonary stenosis.
Management
Mild pulmonary stenosis often does not need treatment. Moderate or
severe stenosis needs repair.

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 Valvotomy: This is surgery to remove scar tissue from the pulmonary
valve leaflets. This lets the valve open as it should.
Balloon Dilation or Valvuloplasty: A cardiac cath is done as in a
diagnostic test. The catheter has a balloon on the tip. When the catheter
reaches the narrowed valve or area, the provider inflates the balloon for a
short time to stretch it open. Children who have had balloon dilation may
need to take antibiotics to prevent heart infection after being discharged from
thehospital.
Valvotomy: This is surgery to remove scar tissue from the pulmonary
valve leaflets. This lets the valve open as it should.
Pulmonary Regurgitation
Isolated pulmonary regurgitation, in an otherwise normal heart, is well
tolerated for decades. However, in a meta-analysis reported in the literature,
29% of patients had developed symptoms within 40 years. Many patients
with a right ventricle to pulmonary artery conduit develop a mixture of
obstruction and regurgitation across the conduit. However, some of these
patients have regurgitation as the dominant lesion, and feature in pulmonary
valve replacement series. In pulmonary regurgitation secondary to
pulmonary hypertension, the clinical picture is dominated by the primary
lung disease or the high pulmonary vascular resistance rather than the
volume load. Severe acute pulmonary regurgitation driven by a large duct
can occur in neonatal Ebstein's anomaly or following balloon dilation of
critical pulmonary stenosis or perforation of valvar pulmonary atresia.

Fig 15: Pulmonary regurgitation & echocardiogram

Causes
Infection endocarditis, complication after surgery to repair tetralogy of
fallot, carcinoid syndrome, rheumatic fever and complications after
catheterization are rare causes in the India.

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 Clinical Features: murmurs, chest pain, discomfort, fatigue,
lightheadedness or fainting.
Management
Pulmonary regurgitation is usually focused on the underlying cause that
created the valve problem (e.g. pulmonary hypertension). The need to
replace the pulmonary valve is very rare.
Infective Endocarditis (IE)
It is due to rare, life-threatening disease that has long lasting effects
even among patients who survive and are cured. IE disproportionately
affects those with underlying structural heart disease and is increasingly
associated with healthcare contact, particularly in patients who have
intravascular prosthetic material. In the setting of bacteraemia with a
pathogenic organism, infected vegetation may form as the end result of
complex interactions between invading microorganisms and the host
immune system. Once established, IE can involve almost any organ system
in the body. The diagnosis of IE may be difficult to establish and a strategy
that combines clinical, microbiological and echocardiography results has
been codified in the modified Duke criteria. In cases of blood culture-
negative IE, the diagnosis may be especially challenging and novel
microbiological and imaging techniques have been developed to establish its
presence. Once diagnosed, IE is best managed by a multidisciplinary team
with expertise in infectious diseases, cardiology and cardiac surgery.
Antibiotic prophylaxis for the prevention of IE remains controversial. Efforts
to develop a vaccine targeting common bacterial causes of IE are ongoing,
but have not yet yielded a commercially available product.
IE is a relatively rare but life-threatening disease.In a systematic review
of the global burden of IE, crude incidence ranged from 1.5 to 11.6 cases per
100,000 person-years, with high quality data availablefrom only 10-mostly
high-income-countries.

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 Fig 16: Endocarditis

Causes
It is cause are bacteria like streptococci (viridians 30 -40%), enterococci
(10-15%), other streptococci (20-25%).
Pathophysiology
Experimentally, the normal valvular endothelium is resistant to bacterial
colonization upon intravascular challenge. Thus, the development of IE
requires the simultaneous occurrence of several independent factors:
alteration of the cardiac valve surface to produce a suitable site for bacterial
attachment and colonization; bacteraemia with an organism capable of
attaching to and colonizing valve tissue; and creation of the infected mass or
‘vegetation’ by ‘burying’ of the proliferating organism within a protective
matrix of serum molecules (for example, fibrin) and platelets.
Clinical Features
Clinical features of endocarditis are cerebral emboli, subconjunctival
haemorrhages, varying murmurs, conduction disorders, cardiac failure,
haematuria, osler’s nodes, systemic emboli, petechial rash, loss of pulses,
roth’s SPOS in fundi, petechial haemorrhages on mucous membranes and
fundi, splenomegaly, digital clubbing, splinter haemorrhages, weight loss,
night sweats, fever, tiredness, develops new signs of valve dysfunction or
heart failure.
Investigations
The diagnosis of IE typically requires a combination of clinical,
microbiological and echocardiography results. Historically, and as is

Page | 22
probably still the case in resource-limited settings, IE was diagnosed
clinically based on classic findings of active valvulitis (such as cardiac
murmur), embolic manifestations and immunological vascular phenomena in
conjunction with positive blood cultures. These manifestations were the
hallmarks of subacute or chronic infections, most often in young patients
with rheumatic heart disease. In the modern era in developed countries,
however, IE is usually an acute disease with few of these hallmarks because
the epidemiology has shifted towards healthcare-associated IE, often with
early presentations due to S. aureus. Blood culture is the most important
initial laboratory test in the workup of IE. Bacteraemia is usually continuous
and the majority of patients with IE have positive blood cultures.
Echocardiography is the second cornerstone of diagnostic efforts and should
be performed in all patients in whom IE is suspected. Transthoracic
echocardiography (TTE) may enable visualization of vegetations in many
patients. These include 3D TEE, cardiac CT, cardiac MRI and F-
fluorodeoxyglucose PET-CT.
Blood Culture Positivity for Either of the following
 Typical microorganism (viridans group streptococci, S. gallolyticus,
HACEK organisms, S. aureus, community acquired enterococci in
the absence of a primary focus) from 2 separate bloodcultures.
 Persistent bacteremia (two positive cultures >12 hours apart or three
positive cultures or a majority of ≥4 culture positive results >1 hour
apart).
Serology
Single positive blood culture for C. Burnetii or antiphase 1 IgG antibody
titre of more than 1:800.
Thus, IE diagnosis cannot be made on the basis of a single symptom,
sign or diagnostic test. Rather, the diagnosis requires clinical suspicion, most
commonly triggered by systemic illness in a patient with risk factors,
Followed by evaluation according to the diagnostic schema outlined in
the modified Duke criteria. It is worth keeping in mind that the Duke criteria
were originally developed to facilitate epidemiological and clinical research
efforts and the application of the criteriatotheclinicalpractice setting is more
difficult.
Management
In the modern era, management of IE typically requires a
multidisciplinary team including, at a minimum, an infectious disease

Page | 23
specialist, a cardiologist and a cardiac surgeon. All patients should receive
antimicrobial therapy and a subset may benefit from cardiovascular surgical
intervention.
Cardiomyopathy
It is a genetic disorder of cardiac myocytes that is characterized by
cardiac hypertrophy, unexplained by the loading conditions, a non-dilated
left ventricle and a normal or increased ejection fraction. Cardiac
hypertrophy is usually asymmetric with greatest involvement most
commonly of the basal interventricular septum subjacent to the aortic valve.
It is occasionally restricted to other myocardial regions, such as the
apex, the mid-portion as well as the posterior wall of the left ventricle. At the
cellular level, cardiac myocytes are hypertrophied, disorganized, and
separated by areas of interstitial fibrosis. A diverse array of mechanisms,
mirroring the diversity of the causal genes and mutations, are implicated in
the pathogenesis of HCM. The mechanistic events in HCM might be
categorized into four sets of interlockingmechanisms.

Fig 17: Cardiomyopathy & ECG

The primary defect is the mutation. Initial or proximal phenotypes are
defined as those resulting from the direct effects of the mutations on the
structure and function of the sarcomere proteins. The intermediary (or

Page | 24
secondary) phenotypes include the molecular changes that occur in response
to the changes in the sarcomere protein structure and function. Examples of
the latter include altered gene expression and activation of the signaling
pathways, such as the MAPK and TGFB1pathways.
The tertiary effects are the ensuing histological and pathological
phenotypes, which are the consequence of perturbation of a myriad of
secondary molecular events in the myocardium, such as activation of the
hypertrophic signaling pathways. These molecular and histological changes
lead to the clinical phenotypes of HCM (quaternary). It is important to note
that there is a mechanistic distinction between cases of HCM caused by
sarcomere protein mutation and the phenocopy conditions, since ventricular
hypertrophy in the latter may, at least in part, result from storage of material,
such as glycogen and in part because of functional defects in myocytes, such
as impairedcontraction.

Fig 18: Cardiomyopathyechocardiogram

Clinical Features
Angina on effort, dyspnoea on effort, syncope, sudden death. Signs of
Cardiomyopathy is jerky pulse, palpable left ventricular hypertrophy, double
impulse at the apex, mid systolic murmur at the base, pansystolic murmur,
signs of left ventricular out flow tract obstruction which may be augmented
by standing up, inotropes and vasodilators.
Diagnosis
ECG in patients with idiopathic DCM has no specific diagnostic role,
and abnormalities ranging from isolated T wave and ST segment changes to
septal pathological Q waves, wide QRS complex in patients with LV fibrosis
might be present.
Prolongation of atrioventricular (AV) conduction, and bundle branch
block can be observed. Echocardiography in DCM has characteristic
patterns, although it is not possible to make differential diagnosis by

Page | 25
echocardiography between idiopathic and other secondary LV dilation with
dysfunction. M-mode echocardiography shows LV dilation with diffuse
hypokinetic walls. Although cardiomyopathy is diffuse pathology, there may
be segmental differences of the degree of hypokinesis revealed by two
dimensional echocardiography, which causes difficulties for differentiation
from ischemic cardiomyopathy. Ventricular dilation usually is not
accompanied by sufficient hypertrophy, which causes increase of volume-to-
massratio.
Management
Beta adrenoceptor antagonists help to relieve angina and sometimes
prevent syncopal attacks but no pharmacological treatment is definitely
known to improve prognosis.
Pericarditis
Pericarditis is a common disorder caused by inflammation of the
pericardium and can occur as an isolated entity or as a manifestation of an
underlying systemic disease. It is diagnosed in approximately 0.1% of
hospitalized patients and in 5% of patients admitted to the emergency
department with noncardiac chest pain. In most patients, the cause of acute
pericarditis is thought to be idiopathic because the yield of diagnostic tests to
confirm etiology has been relativelylow.

Fig 19: Pericarditis

Etiology
Acute myocardial infraction, viral, uraemia, malignant disease, trauma
(blunt chest injury), connective tissue disease (SLE), bacterial infection,
rheumatic fever, tuberculosis.

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Clinical Features
Pericarditis symptoms are retro eternal pain and radiates to the shoulders
and neck. Pain worst by deep breathing, movement, a change of position,
exercise and swallowing, low grade fever.

Fig 20: Pericarditis ECG & echocardiogram

Diagnosis
Typical ECG changes in acute pericarditis include wide-spread upward
concave ST-segment elevation and PR-segment depression.
Transthoracic echocardiography is recommended in patients with
suspected acute pericarditis who have evidence of hemodynamic
compromise. The finding of a significant pericardial effusion supports the
diagnosis and guides further management, especially if there is evidence of
cardiac tamponade and a need for emergentpericardiocentesis.
Management
The pain can usually be relieved by NSAID’s, anti-inflammatory agents
may be required. Purulent pericarditis requires treatment with antimicrobial
therapy, if necessary, surgical drainage.

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 Chapter - 2
Diseases of the Endocrinology

Thyroid Gland
The thyroid gland secrets predominantly thyroxine (T4), and only a
small amount of triiodothyronine (T3); approximately 85% of T3is produced
by monodeiodination of T4in other tissues such as liver, muscle and kidney.
T4 is probably not metabolically active until converted to T3 and may be
regarded as a prohormone. Thyrotropin releasing hormone (TRH) come from
hypothalamus and converted to Thyroid stimulation hormone (TSH) at
glands/targets levels, T3, T4 at target hormones. There is a negative feedback
of thyroid hormones on the thyrotrophs such that in hyperthyroidism, when
plasma concentrations of T3 and T4 are raised. TSH secretion is suppressed
and in hypothyroidism due to disease of the thyroid gland low T3 and T4 are
associated with high circulating TSH levels. The anterior pituitary is very
sensitive to minor changes in thyroid hormone levels within the normal
range. Although the reference range for total T4 is 60-150 nmol/l, a rise or
fall of 20 nmol/l in an individual in whom the levels is usually 100 nmol/l
would on the one hand be associated with undetectable TSH and o the other
hand with a raised TSH. The combination of normal T3 and T4 and
suppressed or raised TSH is known as “sub clinical hyperthyroidism and sub
clinical hypothyroidism respectively”. Excessive circulating levels of free
thyroid hormones called ‘hyperthyroidism’ and decreased circulating levels
of free thyroid hormones called ‘hypothyroidism’.
Hyperthyroidism
Hyperthyroidism is the clinical syndrome which results from exposure
of the body tissues to excess circulating levels of free thyroid hormones. It is
a common disorder with a prevalence of about 20/1000 females; male are
affected five times less frequently. In over 90% of patients hyper thyroidism
is due to Graves’ disease, multinodular goiter or an autonomously function
solitary thyroid nodule (toxic adenoma). It may be caused by any one of the
following:
a) Graves' disease
b) Toxic multinodular goiter

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 c) Toxic solitary nodule ("hot" nodule)
d) Ingestion of thyroid hormones (thyrotoxicosis factitia)
e) Subacute thyroiditis
f) Chronic thyroiditis
g) TSH-producing pituitary adenoma
h) Trophoblastic tumors (choriocarcinoma or hydatidiform mole)
i) Thyroid carcinoma
j) Struma ovarii

Fig 1: Background of thyroid gland

Graves’s Disease
The most common cause of hyperthyroidism in iodine sufficient areas is
Graves’ disease. In Sweden, the annual incidence of Graves’ disease is
increasing, with 15-30 new cases per 100 000 inhabitants in the 2000. The
cause of Graves’ disease is thought to be multifactorial, arising from the loss
of immunotolerance and the development of autoantibodies that stimulate
thyroid follicular cells by binding to the TSH receptor. Several studies have
provided some evidence for a genetic predisposition to Graves’ disease. The
genes involved in Graves’ disease are immune- regulatory genes and thyroid
autoantigens such as the thyroglobulin and TSH-receptor genes. Given the
higher prevalence of Graves’ disease in women, sex hormones and
chromosomal factors, such as the skewed inactivation of the X chromosome,
are suspected to be triggers. Other factors such as infection, vitamin D and
selenium deficiency, thyroid damage, and immunomodulating drugs are also
suspected.

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 Causes Frequency (%)
Graves disease 76
Multinodular goiter 14
Autonomously functioning solitary thyroid nodule 5
Thyroiditis 3
Iodide induced e.g.drugs etc., 1
Extra thyroidal source of thyroid hormone excess 0.2
TSH induced 0.2
Follicular carcinoma + metastases 0.1

Pathogenesis
Graves’ disease is an autoimmune disorder caused by antibodies that
bind to and stimulate the TSH receptor (TSHR), often called thyrotropin
receptor antibodies (TRAb) or thyroid stimulating immunoglobulin (TSI).
These oligoclonal IgG antibodies act as TSH agonists. They are specific for
the disorder and are found in 80% to 100% of untreated patients. TSH
receptor antibodies can have different grades of functional activity
determined by the differences in conformational molecular binding that
induces structural changes in the TSH receptor. Those that bind to the
ectodomain, or extracellular portion of the TSHR, with high affinity are
stimulating in nature, whereas antibodies that recognize various other
epitopes are less stimulatory, neutral, or even blocking. Multiple antibodies
may be present in an individual patient and the degree of thyroid stimulation
is determined by the bioactivity and relative concentration of the different
antibodies. More recently, it has been suggested that the extracellular A-
subunit of the TSH receptor is the predominant immunogen in Graves’
disease. Timers of the subunit, either shed from a trimeric holoreceptor or
components that have undergone multimerization to form trimers, are
responsible for pathologic antibody formation. Evidence comes from studies
showing that immunization with purified TSHR-A subunit produced only
nonfunctioning antibodies. Mouse models of Graves’ disease have been
successfully established by immunization with recombinant adenovirus
vectors expressing the A- subunits of the TSHR.
TSHR-stimulating antibodies activate the TSHR, resulting in binding of
Gs/Gq proteins that trigger cyclic AMP (cAMP) and inositol trisphosphate
(IP3)-mediated pathways.
This promotes thyroid growth, increased vascularity, iodide uptake, and
increased thyroid hormone production and release. Different mechanisms
have been proposed to explain the development of autoimmunity in Graves’
disease and include the following:

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 Failure of activated T cells to undergo anergy, deletion, and apoptosis:
The development of self-tolerance occurs by a process of elimination of self-
reacting T cells during the process of maturation in the thymus and
peripheral immune system. There is a combination of both positive and
negative selection and T-cells reactive to endogenous peptides are triggered
to undergo apoptosis. When self-reactive T-cells escape deletion, such as
those recognizing thyroid antigens [TSH receptor, thyroid peroxidase (TPO),
thyroglobulin], an autoimmune process is initiated.
Bystander Activation of Thyroidal T-Cells
This refers to activation of thyroid specific T cells in susceptible
individuals indirectly as a result of inflammation [via cytokines, such as
interferon (IFN)-γ] produced by non-thyroid specific bystander immune cells
which could have arisen from an infection and infiltrated the thyroid gland.
This phenomenon of T-cell activation has been demonstrated in animal
models of thyroiditis. Expression of major histocompatibility complex
(MHC) Class II molecules by the thyroid cells: Thyroid cells in general do
not express MHC molecules, which are essential for the presentation of
antigens to immune cells. Epithelial cells from patients with autoimmune
thyroid disease over express MHC/human leucocyte antigen (HLA) class II
molecule which leads to an augmentedpresentation of thyroid antigens and
activation of thyroid specific T-cells. MHC molecule expression can be
induced by cytokines and interferon’s produced in the thyroid gland from an
infection ortrauma.

Fig 2: Pathogenesis of gravesdisease

Clinical Features
Hyperthyroidism usually develops insidiously and most patients have
had symptoms for at least six months before presentation. Almost every

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system is affected and the clinical feature are goiter (diffuse + bruit,
nodular), weight loss despite normal or increased appetite, hyperdefecation,
diarrhoea, steatorrhoea, anorexia, vomiting, sinus tachycardia, atrial
fibrillation, increase pulse pressure, angina, cardiomyopathy, cardiac failure,
dyspnoea, asthma, tremor, muscle weakness, proximal myopathy,periodic
paralysis, increased sweating, alopecia, pigmentation, vitiligo, pretibial
myxoedema, amenorrhoea, infertility, spontaneous abortion, loss of libido,
impotence, diplopia, loss of visual acuity, heat intolerance, fatigue,
gynaecomastia, thirst, osteoporosis.
Graves’ Ophthalmopathy
The cardinal feature is accumulation of hydrophilic glycosaminoglycans
in the orbital muscles and the connective tissue, which causes swelling and
edema. Glycosaminoglycans are produced by the stimulation of orbital
fibroblasts and adipocytes by cytokines from activated T-cells that infiltrate
the orbit. TSHR and insulin-like growth factor 1 (IGF-1) receptors (IGF-1R)
are expressed by orbital fibroblasts in higher quantities in individuals with
thyroid-associated ophthalmopathy than in healthy individuals. In vitro,
stimulation of orbital fibroblasts with TSH and IGF-1 cause a synergistic
increase in glycosaminoglycans production. Stimulation of the receptor by
TRAbs activates an inflammatory response and cytokine production; though
it is still not known if the TSHR in the orbital tissues acts as the primary
antigen that initiates the autoimmune response. A role of stimulatory IGF-1R
autoantibodies has also been proposed but is still questionable. A recent
study by Krieger et al. showed no evidence of IGF-1R stimulating antibodies
in patients with Graves’ ophthalmopathy, but demonstrated
immunoglobulins that bind to TSHR and then result in a cross talk with the
IGF-1R leading to its activation. The presentation of Graves’
ophthalmopathy can range from being a very mild disease to potentially
eyesight threatening severe disease that could be irreversible. Symptoms
include eyelid retraction, edema, proptosis, a pressure-like sensation at the
back of the eyes, dry eyes, foreign body or gritty sensation in the eyes,
tearing, photophobia, optic neuropathy, and cornealulceration.

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 Fig 3: Different between normal graves opthalmopathy and CT image

Diagnosis
Serum TSH should be measured first, because it has the highest
sensitivity and specificity in the diagnosis of thyroid disorders. If low, serum
freeT4 or free T4 index, and free or total T3concentrations should be
measured to distinguish between subclinical hyperthyroidism. It also
identifies disorders with increased thyroid hormone concentrations and
normal or only slightly raised TSH concentrations, as in patients with TSH-
secreting pituitary adenomas or peripheral resistance to thyroid hormone. A
thyroid radioactive iodine uptake test in patients with Graves’ disease would
show diffusely increased uptake. However, radioactive iodine uptake would
be normal or high with an asymmetrical and irregular pattern in toxic
multinodular goitre, and a localised and focal pattern in toxic adenoma, with
suppressed uptake in the remaining thyroid tissue. Radioactive iodine uptake
in patients with thyrotoxicosis from extrathyroidal sources of thyroid
hormone or from release of preformed thyroid hormones, as in silent or
painful thyroiditis, will be very low. Thyroid ultrasound and thyroid
radioactive iodine uptake have similar sensitivity for the diagnosis of
Graves’ disease (95·2% and 97·4%, respectively). Advantages of ultrasound
are absence of exposure to ionising radiation, and higher accuracy in the
detection of thyroid nodules and lower cost than with radioactive
iodineuptake.
Management
It can be manage with anti-thyroid drugs and constitute homoeopathic
medications.

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Parathyroid Gland
The parathyroid glands are unique organs responsible for maintaining
the critical function of calcium homeostasis. There are commonly four
parathyroid glands that weigh approximately 40 grams each and are
generally located posterior and inferior to the thyroid in the neck. These
organs secrete parathyroid hormone (PTH), which controls calcium
regulation. Secretion of PTH is modulated not only by serum calcium but
also phosphorus and vitamin D through negative and positive feedback
loops. In the bone, PTH binds to PTH type 1 receptors (PTH1R) to assist
with calcium resorption. In the kidney, PTH acts to increase renalcalcium,
decrease phosphate reabsorption, and activate metabolism of vitamin D. In
the intestine, PTH transcriptionally upregulates 1 alpha hydroxylase, leading
to increased production of 1,25-dihydroxyvitamin D, which in turn enhances
calcium and phosphorus reabsorption. These actions of PTH on the bones,
kidneys, and intestines are a careful orchestration of interrelated processes
driven by feedback loops. Subsequently, excessive or insufficient secretion
of PTH can lead to disruption of these loops and, in turn, alterations in
calcium homeostasis. Both the direct action of PTH on the heart and
alterations of calcium homeostasis (e.g., hypercalcemia or hypocalcemia)
comprise the two primary mechanisms by which diseases of the parathyroid
affect the cardiovascular system. In recent years, clinical and molecular
research has bolstered awareness of several cardiovascular complications
that are associated with parathyroid disorders-namely, hypertension,
arrhythmias, heart failure, and calcific disease of vessels andvalves.
Primary Hyperparathyroidism
One of the more common disorders of the parathyroid glands is primary
hyperparathyroidism (PHPT), an overproduction of PTH thatsubsequently
leads to hypercalcemia. This is most commonly due to a solitary parathyroid
adenoma, but about 15% of cases can be caused by diffuse hyperplasia of the
glands.5While the typical complications and symptoms of PHPT are well
known (e.g., nephrolithiasis, osteoporosis, constipation, and weakness),
cardiovascular complications are increasingly gainingrecognition.
Indeed, patients with symptomatic PHPT have increased mortality due
to myocardial infarction, stroke, and other cardiovascular causes, and they
also have increased all-cause mortality.
Secondary Hyperparathyroidism
Secondary hyperparathyroidism (SHPT) is seen early in chronic kidney
disease (CKD) and is almost always present in ESRD. While the exact

Page | 34
sequence of events leading to SHPT is not definitively established, it is
generally thought to be driven early on by disturbances in renal phosphate
handling and by the more recently discovered bone-derived fibroblast
growth factor 23. In fact, even small decreases in calcium levels caused by
these processes are enough to stimulate the parathyroid to secrete PTH.
Secondary hyperparathyroidism is an important contributor to cardiovascular
mortality in ESRD and CKD, especially in more advanced stages. Indeed, in
ESRD patients, the 5-year mortality is as high as 50%, with CVD as the
leading cause of death, and is not explained solely by traditional risk factors
such as age, diabetes, and smoking.

Fig 4: Parathyroid gland

Excess PTH (as seen in primary and secondary hyperparathyroidism) is
associated with a higher incidence of hypertension, left ventricular
hypertrophy, heart failure, cardiac arrhythmias, and valvular calcific disease,
which may contribute to higher cardiac morbidity andmortality.
Hypoparathyroidism
Hypoparathyroidism is an uncommon condition characterized by absent
or low PTH levels, hypocalcemia, and hyperphosphatemia. The etiology of
hypoparathyroidism is broad and can be congenital or acquired.
For example, DiGeorge syndrome, which is due to a chromosomal
deletion at 22q11.2, is characterized by parathyroid hypoplasia in addition to
cardiac defects, thymic hypoplasia, neurocognitive problems, and renal and
skeletal abnormalities, among others. The cardiac effects from
hypoparathyroidism stem from the resulting hypocalcemia.

Page | 35
 For example, hypocalcemia causes QT prolongation, which can
predispose patients to potentially life threatening arrhythmias. Additionally,
dilated cardiomyopathy from chronic hypocalcemia is a well-known but
uncommon complication. Decreased PTH states (as seen in congenital and
acquired disorders of the parathyroid glands) are associated with cardiac
arrhythmias and dilated cardiomyopathy.
Management
The most common treatment is to remove the enlarged gland (or
glands). This surgery cures the problem 95 percent of the time. Instead of
surgery, some people with mild or no symptoms of primary
hyperparathyroidism may decide to try hormone replacement therapy or
medicationoptions.
Adrenal Gland
Adrenal gland is divided in to 3 zones. Those are zona glomerulosa,
zonae fasciculate and reticulans in cortex region. Zona glomerulosa will
release aldosterone (angiotensin II), zonae fasciculate release cortisol
(ACTH) and zona reticulans release adrenal androgens (ACTH principal
stimuli). Do to sympathetic nervous system will release adrenaline, nor
adrenaline in medulla region.

Fig 5: Adrenal Hormones

Principal function of adrenal hormones glucocorticoids: carbohydrate
metabolism regulation, increase protein catabolism, immunomodulation,
cardiovascular regulation. In mineralocorticoids are sodium retention,
potassium excretion. In catecholamines are increase heart rate, modulate
vascular tone (vasoconstriction by noradrenaline and vasodilation by
adrenaline), antagonize insulin action.

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 Fig 6: Regulation of adrenal gland secretion

Hyperfunction of the Adrenal Gland

Excess glucocorticoid caused formed Cushing’s syndrome.
Cushing’s syndrome
Cause of cushing syndrome are classified as a ACTH dependent:
Pituitary dependent bilateral adrenal hyperplasia (i.e. cushing disease),
ectopic ACTH syndrome (bronchial carcinoid, small cell lung carcinoma,
pancreatic carcinoma), iatrogenic (ACTH therapy) (or) Cushing's syndrome,
a potentially lethal disorder characterized by endogenous hypercortisolism,
may be difficult to recognize, especially when it is mild and the presenting
features are common in the general population. However, there is a need to
identify the condition at an early stage, as it tends to progress, accruing
additional morbidity and increasing mortality rates. Once a clinical suspicion

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is raised, screening tests involve timed measurement of urine, serum or
salivary cortisol at baseline or after administration of dexamethasone, 1 mg.
Each test has caveats, so that the choice of tests must be individualized for
each patient. Once the diagnosis is established, and the cause is determined,
surgical resection of abnormal tumor/tissue is the optimaltreatment.
When this cannot be achieved, medical treatment (or bilateral
adrenalectomy) must be used to normalize cortisol production.
Non ACTH depend are iatrogenic (chronic glucocorticoid therapy e.g.
for asthma), adrenal adenoma, adrenal carcinoma. Pseudo Cushing
syndrome, i.e. cortisol excess as part of another illness are alcohol excess,
major depressive illness, primary obesity (mild biochemical features, some
clinicaloverlap).
Clinical Features
Weight loss, menstrual irregularity, hirsutism, psychiatric, backache,
muscle weakness, central obesity, plethora, moon face, hypertension,
bruising, striae, muscle weakness presented.

Fig 7: Cushing syndrome

Investigations
A clinical practice guideline from the Endocrine Society recommends
use of at least two of three different screening tests: 24-hour urine free

Page | 38
cortisol (UFC) excretion, late night/bedtime salivary cortisol levels and the 1
mg overnight dexamethasone suppression test (DST; or alternatively the 2
mg 2-day DST). The screening tests all reflect different physiologic
abnormalities in Cushing's syndrome: high integrated daily cortisol
production (UFC), loss of bedtime salivary or serum cortisol nadir, and
impaired response to glucocorticoid negative feedback. Thus, they are
complimentary, and the use of more than one test is extremely helpful, as the
results generally should corroborate eachother.
Other tests have not been widely validated for this use (e.g., 0.5 mg
DST, fractional overnight UFC), or are not widely available (24-hour 17-
hydroxycorticosteroid excretion), and are not recommended. The result of
each cortisol screening test (saliva, serum, urine) is considered normal if it
falls within the normal reference range; cortisol values 8 hours after
administration of 1 mg dexamethasone at 2,300 to 2,400 hours should
normally be <1.8 µg/dL (50 nmol/L). Because of this, prescribers of a
screening test must know about certain characteristics of the cortisol assay
used to measure the result, to avoid misinterpretation.
Management
This is essential, as untreated Cushing’s syndrome has a 50% – 60%
five year mortality. Most patients are prepared for surgery with medical
therapy for a few weeks.
Hypofunction of the Adrenal Gland
Addison’s disease
This is a rare condition with an estimated incidence in the developed
world of eight cases per million populations. However, adrenal insufficiency
is a well-recognized complication in patients with AIDS and may result from
a variety of causes including tuberculosis, fungal and cytomegalovirus
infections. Classically, hyperpigmentation is associated with the disease, and
intraoral pigmentation is perceived as the initial sign and develops earlier
than the dermatological pigmentation. The symptoms of the disease usually
progress slowly and an event of illness or accident can make the condition
worse and may lead to a life threatening crisis. In this case, several oral as
well as systemic manifestation of the Addison's disease was encountered.
Aetiology: Whereas primary adrenal insufficiency last century was most
commonly due to tuberculosis, autoimmune disease currently accounts for
most of the cases presenting outside of the newborn period. The various
etiologies of Addison’s disease can be grouped into three categories:

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 1) Adrenal dysgenesis
2) Adrenal destruction
3) Impaired steroidogenesis
Congenital adrenal hypoplasia (AHC), mutations of steroidogenic
factor-1 (SF-1), and ACTH unresponsiveness can all lead to adrenal
dysgenesis/hypoplasia, albeit the latter usually results in isolated deficiency
of glucocorticoids. Autoimmune polyglandular syndrome (APS),
adrenoleukodystrophy (ALD), adrenal hemorrhage, adrenal metastases,
infections, and amyloidosis can all lead to destruction of adrenal gland.
Congenital adrenal hyperplasia (CAH), mitochondrial disorders, the
Smith-Lemli-Opitz syndrome (SMOS), an enzyme deficiency in cholesterol
metabolism, can all lead to impaired steroidogenesis. At birth, adrenal
hemorrhage from anoxia/sepsis is most common, adrenal insufficiency from
CAH usually presents in neonates, and in older children it often occurs as
part of an autoimmune poly glandular syndrome or APS. In boys,
adrenoleukodystrophy, DAX-1-related disorders are increasingly recognized,
whereas adults have increasing incidences of infectious and metastatic
adrenal failures.

Fig 8: Addison’s disease

Clinical features
Glucocorticoid insufficiencies are weight loss, malaise, anorexia,
nausea, vomiting, gastrointestinal like diarrhoea or constipation, postural
hypotension, hypoglycemia. Mineralocorticoid insufficiency is hypotension.
Increased ACTH secretion are pigmentation occurs over sun exposed areas,
pressure areas e.g. elbows, knees, palmar creases, knuckles, mucous
membranes, conjunctivae, recent scars. Losses of adrenal androgen are

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decrease in body hair, especially in female. In chronic presentation
symptoms are chronic fatigue syndrome or depression and it is the
pigmentation that commonly raises suspicion. The blood pressure may be
normal with the patient lying down. Postural hypotension (i.e. a fall in
systolic pressure of at least 20 mm Hg) is almost invariably present. Vitiligo
is present in 10-20%.
Investigation
A morning serum cortisol level higher than 500 nmol/L (18 g/dL)
usually excludes Addison disease, while a level below 165 nmol/L (6 g/dL)
is suggestive of adrenal insufficiency. However, most patients will need a
short synacthen test for confirmation or exclusion of Addison disease. This
involves injecting 250 g of synacthen (tetracosactrin; synthetic analogue of
adrenocorticotrophic hormone (ACTH]) intramuscularly or intravenously.
Blood samples for serum cortisol are taken at 0, 30, and 60 minutes. An
increase in serum cortisol level 30 or 60 minutes after the synacthen
injection to above 500 nmol/L (18 g/dL) is considered a normal response,
although the threshold cortisol level may vary according to local laboratory
reference ranges. If the cortisol response to synacthen is inadequate, plasma
ACTH level should be measured. A raised plasma ACTH level confirms the
diagnosis of Addison disease, whereas patients with secondary adrenal
insufficiency due to pituitary or hypothalamic disorders have a low or
inappropriately normal plasma ACTH level. Plasma renin activity is elevated
in Addison disease and is sometimes a useful investigation to distinguish
between Addison disease and secondary adrenalinsufficiency.
Management
Patients with Addison’s disease always need glucocorticoid replacement
therapy and usually, but no always, mineralocorticoid. If the Addison’s
disease results from tuberculosis then this will need to be treated
appropriately.

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 Chapter - 3
Diseases of the Gastroenterology

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a very common digestive
disorder worldwide with an estimated prevalence of 18.1-27.8% in North
America. Approximately half of all adults will report reflux symptoms at
some time. It’s defined as “Gastroesophageal reflux disease is a condition of
troublesome symptoms and complications that result from the reflux of
stomach contents into the esophagus”. Diagnosis of Gastroesophageal reflux
disease is typically based on classic symptoms and response to acid
suppression after an empiric trial. Gastroesophageal reflux disease is an
important health concern as it is associated with decreased quality of life and
significant morbidity. Successful treatment of Gastroesophageal reflux
disease symptoms has been associated with significant improvement in
quality of life, including decreased physical pain, increased vitality, physical
and social function, and emotional well-being. While Gastroesophageal
reflux disease medications are not particularly expensive, the cost of treating
Gastroesophageal reflux disease patients has been deemed 2-fold more
costly than comparable individuals without Gastroesophageal refluxdisease.

Fig 1: Gastroesophageal reflux disease

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Etiology and Pathophysiology
Risk factors for Gastroesophageal reflux disease include older age,
excessive body mass index (BMI), smoking, anxiety/depression, and less
physical activity at work.Eating habits may also contribute to
Gastroesophageal reflux disease, including the acidity of food, as well as
size and timing of meals, particularly with respect to sleep. Recreational
physical activity appears to be protective, except when performed post
prandially. Gastroesophageal reflux is primarily a disorder of the lower
esophageal sphincter (LES) but there are several factors that may contribute
to its development. The factors influencing Gastroesophageal reflux disease
are both physiologic and pathologic. The most common cause is transient
lower esophageal sphincter relaxations (TLESRs). TLESRs are brief
moments of lower esophageal sphincter tone inhibition that are independent
of a swallow. While these are physiologic in nature, there is an increase in
frequency in the postprandial phase and they contribute greatly to acid reflux
in patients with Gastroesophageal reflux disease. Other factors include
reduced lower esophageal sphincter (LES) pressure, hiatal hernias, impaired
esophageal clearance, and delayed gastricemptying.
Clinical Features
Gastroesophageal reflux disease (GERD) is defined as symptoms or
mucosal damage produced by the abnormal reflux of gastric contents into the
esophagus or beyond, into the oral cavity (including larynx) or lung.
Gastroesophageal reflux disease can be classified as non-erosive reflux
disease (NERD) or erosive reflux disease (ERD) based on the presence or
absence of esophageal mucosal damage seen on endoscopy. The following
document will provide a brief overview of the epidemiology, clinical
symptoms and complications of Gastroesophageal reflux disease as well as a
more comprehensive review of the current approach to diagnosis and
management.Typical symptoms are Acid regurgitation, heartburn,Epigastric
fullness, epigastria pressure, epigastric pain, dyspepsia, nausea,bloating,
belching (atypical symptoms). Extra oesophageal symptoms arechronic
cough, bronchospasm, wheezing, hoarseness, sore throat, asthma, laryngitis,
dentalerosions.

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Fig 2: Barium esophagram and Upper endoscopy of Gastroesophageal reflux disease

 Complications
 Oesophagitis
 Barrett’soesophagus
 Anaemia
 Benign oesophageal stricture
Diagnosis
The diagnosis of Gastroesophageal reflux disease is typically made by a
combination of clinical symptoms, response to acid suppression, as wellas
objective testing with upper endoscopy and esophageal pH monitoring. For
example, the combination of moderate to severe typical symptoms and
endoscopic changes (erosive esophagitis or Barrett’s esophagus) are highly
specific (97%) for Gastroesophageal reflux disease (confirmed with pH
testing). However, a well ken history alone can prove very valuable in the
diagnosis, especially in the setting of heartburn and acid regurgitation which
have a very high specificity (89% and 95%, respectively), albeit low
sensitivity (38% and 6%) for Gastroesophagealreflux disease. This can allow
one to make a presumptive diagnosis and begin empiric therapy, thereby
avoiding a comprehensive and costly evaluation in every patient presenting
with uncomplicated symptoms.
Ambulatory PH Monitoring
Ambulatory reflux monitoring is the only modality allowing direct
measurement of esophageal acid exposure, reflux episode frequency and
association between symptoms and reflux episodes. It is typically used to
evaluate patients with persistent symptoms despite medical therapy,

Page | 44
particularly those without endoscopic evidence of Gastroesophageal reflux
disease, in order to confirm the diagnosis. It can also be employed to monitor
the control of reflux in those on therapy with persistent symptoms
Upper Endoscopy
Upper endoscopy is the primary modality used in the evaluation of the
esophageal mucosa in patients with Gastroesophageal reflux disease and also
allows for biopsies of concerning lesions (e.g., Barrett’s metaplasia,
strictures or masses). It is important though to understand that there are
limitations with the use of upper endoscopy in the diagnosis of
Gastroesophageal reflux disease. For instance, while an endoscopy showing
esophagitis or Barrett’s esophagus essentially confirms the diagnosis of
Gastroesophageal reflux disease (high specificity), a normal endoscopy does
not refute the diagnosis. In fact, most patients with typical symptoms of
Gastroesophageal reflux disease will have no endoscopic evidence of
Gastroesophageal reflux disease on esophagogastroduodenoscopy.
Barium Esophagram
Barium esophagram was once recommended as a screening test for
Gastroesophageal reflux disease, but is no longer part of the diagnostic
evaluation. A 1996 study of 125 patients compared barium esophagram to
esophageal pH monitoring to assess the accuracy of barium screening as a
predictor of abnormal esophageal acid exposure. A significantly greater
degree of abnormal esophageal acid exposure occurred in patients who had a
hiatal hernia or spontaneous reflux on bariumradiography.
However, the sensitivity and specificity of barium radiography for
abnormal degrees of acid reflux were insufficient and therefore this test is no
longer recommended in the diagnosis of Gastroesophageal reflux disease.
Esophageal Manometry
Esophageal manometry is most useful for the evaluation of dysmotility
and has only limited utility in the evaluation of Gastroesophageal reflux
disease [13]. Gastroesophageal reflux disease is a chronic disease that
typically requires long term management in the form of lifestyle
modification, medical therapy and, for a subset of patients, surgical therapy
and constitutional homeopathic treatment.
Achalasia Cardia
Neuromuscular motility disorder of oeophagus due to degeneration of
Auerbach’s plexus causing muscular hypertrophy and impaired oesophageal
emptying and characterized by dysphagia and regurgitation offood.

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 Causes: Exact cause is unknown. But more in female when compared to
males.
Clinical Features: Dysphagia, food is retained for hours, food is foul
smelling, sensation of food sticking, can pinpoint site of obstruction, initially
difficulty in swallowing liquids, less marked with solids, substernal
discomfort and worse by after fast eating or drinking,better by coldwater.
Diagnosis
Barium meal examination: Dilation and elongation of esophagus, upper
part of barium is horizontal and lower part shows smooth, pointed end.
Endoscopy can show the dilation of oesophagus.
Management
To prevent regurgitation-avoid lying down one to two hours after meals,
avoid straining and coughing, avoid wearing tight corsets.
Gastritis
Gastritis is a histological diagnosis, although it can sometimes be
recognized at endoscopy.
Acute Gastritis
It is often erosive and hemorrhagic. Neutrophils are the predominant
inflammatory cell in the superficial epithelium. Many cases result from
aspirin or NSAID ingestion.
Acute gastritis often produces no symptoms but may cause dyspepsia,
anorexia, nausea or vomiting, haematemesis or melaena. Treatment should
be directed to the underlying cause. Short term symptomatic therapy with
antacids, acid suppression or antiemetic, homoeopathic medicines may be
necessary.

Fig 3: Histopathology of Chronic gastritis

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Chronic Gastritis
The most common cause of chronic gastritis is H. Pylori. The
predominant inflammatory cells are lymphocytes and plasma cells.
Correlation between symptoms and endoscopic or pathological findings I
spoor. Most patients are asymptomatic and do ot require any treatment.
Socioeconomics and environmental hygiene are inevitably the most
important background factors in transmission of H. pylori infection
worldwide, these socioeconomic factors being, thereby, the background
factors also in epidemiology of chronic gastritis and its sequelae. The
infection rate in childhood and the age-specific prevalence of H. pylori
gastritis are high in the “old” birth cohorts born decades earlier than the
prevalence in the “young” birth cohorts born more recently and in whom the
infection rate of H. pylori at childhood is low. Thus, the mean prevalence of
gastritis at the population level reflects the average of the prevalence of
chronic gastritis in different birth cohorts, and the mean rate of H. pylori
infection at pediatricage.
Peptic Ulcer Disease
The term peptic ulcer refers to an ulcer in the lower oesophagus,
stomach or duodenum in the jejunum after surgical anastomosis to the
stomach, or, rarely in the ileum adjacent to a meckel’s diverticulum.
Ulcer in the stomach or duodenum may be acute or chronic: both
penetrate the muscularis mucosae but the acute ulcer shows no evidence
offibrosis.
Etiology
Peptic ulcer disease includes both gastric and duodenal ulcerswhich
posed a major threat to the world's population over the past two centuries
with a high morbidity and mortality. The evolution of knowledge regarding
etiopathogenesis of peptic acid disease from acid-driven disease to an
infectious disease has opened up this topic for various studies to find the best
possible options for management of this disease. The discoveryof
Helicobacter pylori has evinced great interest in the role played by this
microbe. The eradication of this organism has been found to be of paramount
importance to minimize the complications of peptic ulcers. The management
of peptic ulcer disease and its complications remain a challenge. In addition,
non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin,
smoking, excessive alcohol use, emotional stress and psychosocial factors
are increasingly important causes of ulcers and their complications even in
H. pylori negative patients. Other rare causes of peptic ulcer disease in the

Page | 47
absence of H. pylori, NSAIDs, and aspirin also exist. Epidemiological
studies reveal a very strong association between H. pylori infection and
peptic ulcer disease. More than half the world's population has a chronic H.
pylori infection of thegastroduodenal mucosa, yet only 5-10% develops
ulcers. Factors that determine whether the infection will produce the disease
depends on the pattern of histological changes, gastritis induced changes in
homeostasis of gastric hormones and acid secretion, gastric metaplasia in the
duodenum, interaction of H. pylori with the mucosal barrier,
immunopathogenesis, ulcerogenic strains, and genetic factors. Management
of peptic acid disease varies from using H2 receptor antagonist, proton pump
inhibitors (PPI) to triple chemotherapy and sequential regimen for H. pylori.
Similarly treating perforation varies from a conservative non operative
approach to a surgicalapproach.

Fig 4: Histopathology of peptic ulcer

Pathology
Chronic gastric ulcer is usually single, 90% are situated on the lesser
curve within the antrum or at the junction between body and antral mucosa.
Chronic duodenal ulcer usually occurs in the first part of the duodenum just
distal to the junction of pyloric and duodenal mucosa, 50% are on the
anterior wall. Gastric and duodenal ulcers coexist in 10% of patients and
more than one peptic ulcer is found in 10-15% ofpatients.

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 Fig 5: Pathophysiology of Peptic ulcer
A chronic ulcer extends to below the muscularis mucosa and the
histology shows four layers: surface debris, an infiltrate of neutrophils,
granulation tissue and collagen.

Fig 6: Endoscopy of peptic ulcer

Clinical Features
Peptic ulcer disease is a chronic condition with a natural history of
spontaneous relapse and remission lasting for decades.
Pain is referred to the epigastrium and is often so sharply localized that
the patient can indicate its site with two or three fingers (the pointing sign).
Hunger pain occurs intermittently during the day, often when the stomach is
empty. Pain wakes the patients from sleep and may be relieved by food, a
drink of milk or antacids; this symptoms is very characteristic of duodenal
ulcer. Pain is ameliorated by food, milk and by belching and vomiting.
Relief by vomiting is more typical of gastric ulcer than of duodenal ulcer.
Periodicity pain present and last for several weeks at a time. Between

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episodes the patient feels perfectly well. Other symptoms that occur,
especially during episodes of pain, include water brush, heartburn, loss of
appetite and vomiting. Persistent vomiting occurring daily suggests gastric
outletobstruction.
Investigation
The diagnosis can be made by double contrast barium meal examination
or by endoscopy. Endoscopy is the preferred investigation because it is more
accurate and has the enormous advantage that suspicious lesions and HP
status can be evaluated bybiopsy.
Complication
 Perforation
 Gastric outletobstruction
 Bleeding
Management
Cigarette smoking, aspirin and NSAIDs should be avoided. Alcohol in
moderation is not harmful and no special dietary advice is required, but to
avoid very spicy food. All patients with proven acute or chronic duodenal
ulcer disease and those with gastric ulcer who are helicobacter pylori
positive should be offered eradication therapy as primary therapy. Treatment
is based upon a proton pump inhibitor taken simultaneously with 2
antibiotics for one week and along with homoeopathic treatment.
Tropical Sprue
Intestinal malabsorption syndrome characterized by steatorrhea,
glossitis, stomatitis, abdominal distention and weight loss.
Etiology
Prolong residence in hills, chronic dysentery, fatigue, excessive fatty
diet.
Clinical Features
Diarrhoea is persistent frequently worse by morning, stools are pale,
frothy, bulky, extremely offensive, steatorrhoea, float on water, anorexia,
sore mouth, weakness, irritability, loss of weight. Signs are pulse is fast,
weak, anaemia moderate to severe, cheilosis, angular stomatitis, abdomen
distention, doughy feel.

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Diagnosis
Barium meal x ray of small intestine can find out altered mucosal
pattern, intestinal dilation, clumped, scattered barium.
Management
Adequate physical and mental rest, control diarrhoea with anti-diarrhea
drugs, low roughage diet.
Inflammatory Bowel Disease
Ulcerative colitis and crohn’s disease are chronic inflammatory bowel
disease which pursues a protracted relapsing and remitting course, usually
extending over years. The incidence of inflammatory bowel disease (IBD)
varies widely between populations: Crohns disease appears to be very rare in
the underdeveloped world yet ulcerative colitis, although still unusual, is
becoming morecommon.
Ulcerative Colitis
Ulcerative colitis (UC) is a chronic disease with recurrent uncontrolled
inflammation of the colon. The rectum is always affected with inflammation
spreading from the distal to the proximal colonic segments. The terminal
ileum is typically not involved but some patients with extensive disease may
show endoscopic signs of “backwash ileitis”. As the course of disease and
extent vary considerably among patients, an individualized diagnostic and
therapeutic approach isnecessary.

Fig 7: Ulcerative colitis

Only a minority of patients have chronic, unremitting symptoms.
Emotional stress, intercurrent infection, gastroenteritis, antibiotics or NSAID
therapy may provoke a relapse. Rectal bleeding and mucus discharge.
Sometime accompanied by tenesmus.

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 Fig 8: Endoscopy of ulcerative colitis
The disease remains confined to the rectum in approximately 25% of
cases, and in the remainder of cases, ulcerative colitis spreads proximally
and contiguously. Pancolitis occurs in 10% of patients. The distal terminal
ileum may become inflamed in a superficial manner, referred to as backwash
ileitis. Even with less than total colonic involvement, the disease is strikingly
and uniformly continuous. As ulcerative colitis becomes chronic, the colon
becomes a rigid foreshortened tube that lacks its usual haustral markings,
leading to the lead pipe appearance observed on bariumenema.
Clinical Features
Some patients pass frequent, small volume fluid stools, while other are
constipated and pass pellet stools. Weight loss, malaise, anorexia and
abdominal pain occur and the patient is toxic with fever.
Complications
 Severe, life threatening inflammatory of thecolon
 Perforation of the small intestine orcolon
 Life threatening acute haemorrhage
 Fistula and perianaldisease
 Cancer
 Seronegativearthritis
 Erythema nodosum, pyoderma gangrenosum, oral aphthous ulcers,
conjunctivitis, iritis, primary sclerosing cholangitis, gall stones,
fatty liver, portal pyaemia, liver abscess, amyloidosis, oxalate
calculi, deep vein thrombosis, portal or mesenteric veinthrombosis.

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Investigations
Blood tests are like complete blood test, vit B12, ESR, serum albumin
etc., Bacteriology like stool cultures are performed to exclude superimposed
enteric infection in patients who present with exacerbations of inflammatory
bowel disease. Sigmoidoscopy, barium studies, plain radiographs and
radionuclidescans.
Management
Drug treatment, nutritional therapy, surgical treatment and
homoeopathic medicines.
Crohns Disease
The sites most commonly involved in order of frequency are terminal
ileum and right side of colon, colon alone, terminal ileum alone, ileum and
jejunum. Characterized, the entire wall of the bowel is oedematous and
thickened. There are deep ulcers which often appear as linear fissures, thus
the mucosa between them is described as cobblestone. Deep ulcer may
penetrate through the bowel wall to imitate abscesses orfistulae.
Its prevalence has continually increased over the past 50 years with the
highest incidence being reported in northern Europe, the United Kingdom
and North America.

Fig 9: Crohns disease

Fistula may develop between adjacent loops of bowel or between
affected segmens of bowel and the bladder, uterus or vagina and may appear
in the perineum. Characteristically, the changes are patchy. Even when a
relatively short segment of bowel is affected, the inflammatory process is
interrupted by islands of normal mucosa and the change from the affected
part is abrupt. A small lesion separated in this way from a major area of
involvement is referred to as a “skip” lesion. The mesenteric lymph nodes
are enlarged and the mesentery thickened. Histologically, chronic

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inflammation is seen through all the layer of the bowel wall, which is
thickened as a result. There are focal aggregates of epithelioid histiocytes,
which may be surrounded by lymphocytes and contain giant cells. Lymphoid
aggregates or microgranulomas are also seen, and when these are near to the
surface of the mucosa they often ulcerate to form tiny aphthous like ulcers.
Clinical Features
Chronic diarrhoea, defined as a decrease in faecal consistency for more
than 4 weeks, is the most common presenting symptom. Abdominal pain
(70%), weight loss (60%) and blood, mucus or both in stools (40-50%) are
also common findings in Crohns disease. Extraintestinal manifestations
affect approximately a third of patients with inflammatory bowel disease.
The most commonly observed extraintestinal manifestation is primary
peripheral arthritis (33%); aphthous stomatitis, uveitis, erythema nodosum
and ankylosing spondylitis can be seen whilst pyoderma gangrenosum,
psoriasis and primary sclerosing cholangitis are relatively uncommon.
Fistulae, a complication of Crohns disease, occurs in up to 35% of patients
with Crohns disease, with perianal fistula occurring in 20%.

Fig 10: Endoscopy of Crohns disease

Risk Factors
Crohns disease has a peak age prevalence of 30-39 years old and gender
influence differs in various demographics. In a Canadian and New Zealand
population, females are 10-30% more likely to acquire the disease than
males. Other inflammatory diseases have been implicated with Crohns
disease including asthma, psoriasis, pericarditis, ankylosing spondylitis,
atopic dermatitis and primary sclerosing cholangitis. Their impact tends to
be most influential duringchildhood.

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Different Diagnosis
Other cases of right iliac fossa mass: caecal carcinoma, appendix
abscess, infection (tuberculosis, yersinia, actinomycosis), mesenteric
adenitis, pelvic inflammatory disease, lymphoma.
Management
Intravenous fluids, antibiotics for proven infection, nutritional support,
avoidance of opiates, antidiarrheal agents and homoeopathic management.
Coeliac Disease
Gluten sensitive intestinal malabsorption syndrome characterized by
steatorrhea, rapid weight loss and growth retardation.
Causes: etiology is unknown, evidence pints towards gluten sensitivity.
Clinical Features
Diarrhoea is persistent, frequent passage of stools by morning. Stools
are pale, frothy, bulky, extremely offensive, steatorrhoea. Signs are fever
slightly raised, hypotension, pallor, weak and emaciated.
Diagnosis
In barium meal x ray can find loss of mucosal patter of small intestine,
intestinal dilation, clumped, scattered barium.
Management
Control of diarrhoea with anti diarrhoea drugs and gluten free diet, low
roughagediet.
Diverticulitis
Inflammation of diverticulum called diverticulitis. It is commonly
occurring in sigmoid and descending colon and characterized by lower
abdominal colicky pain, with increasing constipation.
Causes: Due to atrophy of muscular coat of colon, obesity, faecolith
(obstruction of diverticulum).
Clinical Features
Pain in abdomen especially left iliac fossa, discomfort, gradually
increasing in severity and frequency, worse by pressure, tight clothing, better
by after defecation, passing flatus, nausea, vomiting, stools are small, hard,
frequent, flatulence, abdominal distension, low grade fever. Signs are
localized tenderness in left iliac fossa, muscle guarding.

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Diagnosis
Barium enema examination, diverticula clearly visualized after barium
evacuation.
Management
High fiber diet, avoid constipation, physical as well as mental rest.

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 Chapter - 4
Diseases of the Nephrology

Glomerulonephritis
Glomerulonephritis (GN) means “inflammation of glomeruli”. It
excludes glomerular diseases without cell proliferation or nephritic
presentations, such as minimal change disease, membranous nephropathy,
and focal segmental glomerulosclerosis that can, none the less, chronically
compromise renal function. In primary glomerulonephritis, disease is almost
entirely restricted to the kidneys (as in IgA nephropathy or post streptococcal
glomerulonephritis) while in secondary glomerulonephritisit occurs in
association with more diffuse inflammation (as in systemic lupus
erythematosus or systemic vasculitis). Prompt diagnosis of
glomerulonephritis is vital as patients with even mildly impaired renal
function, hypertension, and urinary abnormalities may rapidly lose kidney
function if not treatedurgently.
Nearly 200 years ago, Richard Bright first described glomerular disease,
diagnosing proteinuria in his patients by using a candle to heat urine on a
spoon to determine whether it precipitated with heat.Bright also first
recognized the relationship of scarlatina (due to streptococcal infection) to
subsequent glomerulonephritis in the 1800s. With the advent of
immunopathology, studies of serum sickness models in rabbits by Germuth
and Dixon provided seminal insights into the immune mechanisms that
underlie most forms ofglomerulonephritis.
Causes
Causes of glomerulonephritis are systemic vasculitis, SLE, good
pasture’s (anti GBM) disease, aggressive phase of other inflammatory
nephritis, viral infection, bacterial endocarditis, Lupus.
Types of Glomerulonephritis
Post Infectious Endocapillary Glomerulonephritis
Post streptococcal glomerulonephritis is the best known example of
endocapillary glomerulonephritis, the most common form of acute

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glomerulonephritis seen after some bacterial, viral, fungal, and parasitic
infections. Although this pattern of glomerular injury after a streptococcal
infection remains an important cause of acute renal failure in the developing
world.

Fig 1: Glomerulonephritis ultrasound

Mesangioproliferative Glomerulonephritis/IgA Nephropathy

IgA nephropathy is the commonest of all glomerulonephritisworldwide.
Thus although only 4%-13% of patients present with acute nephritis. 9 Peak
presentation is during the second and third decades showing a 2:1 male
preponderance with attacks sometimes after infection. IgA nephropathy is
the classic mesangioproliferative glomerulonephritis where cellular
proliferation may be either diffuse or focal but affects predominantly the
mesangium. Immunofluorescence shows para mesangial deposition of IgA
(with some IgG and IgM) together with alternative pathway complement
components, while electron microscopy shows mesangial dense deposits.
Polymeric IgA1 is deposited in the kidney after overproduction of systemic
IgA1 polymers (possibly in response to infection) together with impaired
clearance through both the hepatic and the myeloidroutes.
In addition abnormal glycosylation of IgA may make it more prone to
self-aggregate and form immune complexes with affinity for the mesangium.
The disease is associated with a raised serum concentrations of IgA in
50% of patients, but serum complement levels are normal as complement
activation is restricted to the kidneysalone.
Henoch Schonlein Purpura
However, as a small vessel vasculitis, HSP also has the systemic
features of a purpuric rash largely affecting the lower limbs, arthritis or
arthralgia, and abdominal pain sometimes in association with rectal
bleeding.The disease is most commonly seen in those less than 20 years of
age.

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Rapidly Progressive Glomerulonephritis
The rapidly progressive glomerulonephritis are the most serious of all
glomerulonephritis with the potential to destroy renal function within days.
Although causes are heterogeneous, they are united by the histological
finding of extensive crescents (a proliferation of parietal epithelial cells and
mononuclear phagocytes with possible fibroblasts in Bowman’s capsule)
affecting more than 50% of glomeruli. Causes fall into three broad categories
with different presentations, treatments, and prognoses. Biopsy shows a focal
or diffuse proliferative glomerulonephritis with extensive crescents. The
pathogenesis of vasculitis remains the focus of much research but direct
immunoglobulin deposition in the glomerulus is not thought to play a
significant part (hence the term pauci-immune). Serologically, however,
these diseases are linked in about 90% of cases by the finding of
antineutrophil cytoplasmic antibodies (ANCA).
Antibody staining is usually directed against the neutrophil cytoplasm in
Wegener’s with an antigen specificity for proteinase 3 on ELISA, whereas in
microscopic polyangiitis it is generally perinuclear in pattern and is directed
against myeloperoxidase. A direct causative role for ANCA in small vessel
vasculitis remains controversial with experimental evidence pointing
towards roles for neutrophils, macrophages, and T-cells in itspathogenesis.
Membranoproliferative Glomerulonephritis
This rare form of glomerulonephritis has enjoyed renewed interest after
the discovery that a subtype of MCGN type I is associated with chronic
hepatitis C infection. MCGN commonly presents as a nephrotic syndrome
but in 16%-30% of patients the initial presentation is with acute nephritis.
The disease can be subdivided into types I and II, with its idiopathic forms
mostly seen in children and young adults with cases presenting at a younger
age in type II than in type I disease, with a slight female preponderance.
Type I MCGN shares some features with lupus nephritis, and a similar
histological picture can also be seen with endocarditis and infected
arteriovenous shunts. In type II MCGN, patients may have an associated
partial lipodystrophy giving them a very gaunt facial appearance.

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 A. Normal B. Abnormal
Fig 2: Glomerulonephritis

Lupus Nephritis
Renal involvement in systemic lupus erythematosus can present with
proteinuria, haematuria, nephrotic syndrome, or with an acute nephritis. It is
rarely the first manifestation of systemic lupus but usually occurs within five
years and may be the first presentation leading to a definitive diagnosis.24
Patients (most commonly women in their 20s and 30s with a black
preponderance) will frequently have suffered lethargy, arthralgia or arthritis,
skin rashes, and the symptoms of pleurisy and pericarditis in the months
before presentation.
25 More than any other glomerulonephritis, lupus nephritis can change
and evolve over time so that in a patient with an initially benign glomerular
lesion, a new presentation with acute glomerulonephritis should prompt
repeat biopsy and if needed more aggressive treatment. High titres of
antinuclear antibodies and anti-double stranded DNA antibodies together
with low complement levels are helpful in a nephritic flare, although changes
in such markers often precede the actual glomerular inflammation,
sometimes bymonths.
Clinical Features
Clinical features of glomerulonephritis are pink or cola coloured urine
from red blood cells in urine, foamy urine due to excess protein
(proteinuria), swelling evident in face, hand, feet and abdomen and
hypertension.

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Renal Calculi
Formation of stone in any part of urinary tract.
Causes: decrease fluid intake, chronic diarrhoea, urinary tract
obstruction, recurrent urinary tract infection, polycystic kidney disease,
vitamin D toxicity, excessive intake of calcium, hyperoxaluria, crohn’s
disease, gout, myeloproliferative disorders, excessive intake of oxalate.
Clinical Features
Pain in renal region, nausea and vomiting, sudden onset of pain, pain
starts from loin and radiates to down wards forwards towards to knee and
rolls, strangury, haematuria, pain worse by movement, changing position,
walking up stairs. Sign is tenderness of renalangle.
Complications
Impaction and obstruction, stricture of ureter, anuria.
Diagnosis
Macroscopic for blood, pus, sediments in urine. Microscopic also can
find RBC’s and pus cells. In radio opaque calculi in x ray KUB, Ultra sound
abdomen can found calculi more than 1 cm cast a specific shadow.
Management
Plenty of fluids, control and treatment of infection.To remove stone and
prevent complications.
Renal Failure
Renal failure is failure of the excretory function of the kidneys, leading
to retention of nitrogenous waste products of metabolism. Sudden and
usually reversible loss of renal function, which develops over a period of
days or weeks. An increase in plasma Creatinine concentration to more than
200 micro mol/l is often used as the biochemicaldefinition.
Causes
Causes of renal failure are pre renal, intrinsic renal, post renal and
systemicdiseases.
Pre renal are systemic (heart failure, shock), local (renal artery
occlusion/stenosis, diseases affecting arterioles), intrinsic renal are acute
tubular necrosis/toxic/septic renal failure, glomerular disease-primary
component of systemic disease, interstitial disease, in post renal are stones,
inflammation, tumor, in systemic diseases are acting via one or more of these
three categories.

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 Fig 3: Pathogenesis of renal failure

Clinical Features
Decreased urinary sodium concentration especially in septic patients.
Decreased urine output, although occasionally urine output remains normal,
fluid retention, causing swelling in your legs, ankles or feet, Shortness of
breath, fatigue, confusion, nausea, weakness, irregular heartbeat.
Chronic Renal Failure
Chronic kidney disease (CKD) is recognized as a major health problem
affecting approximately 13% of the United States population. Numbers of
prevalent CKD patients will continue to rise, reflecting the growing elderly
population and increasing numbers of patients with diabetes and
hypertension. As numbers of CKD patients increase, primary care
practitioners will be confronted with management of the complex medical

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problems unique to patients with chronic renal impairment. As well
documented in the literature, the nephrologist rarely manages the medical
needs of CKD patients until renal replacement therapy is required. In this
chapter we will define CKD staging and discuss five complications
associated with CKD: anemia, hyperlipidemia, nutrition, osteodystrophy,
and cardiovascularrisk.
Classification ofCKD
 Stage 1: normal eGFR ≥ 90 mL/min per 1.73 m2 and persistent
albuminuria
 Stage 2: eGFR between 60 to 89 mL/min per 1.73m2
 Stage 3: eGFR between 30 to 59 mL/min per 1.73m2
 Stage 4: eGFR between 15 to 29 mL/min per 1.73m2
 Stage 5:eGFR of < 15 mL/min per 1.73 m2 or end stage renal
disease
While anemia in CKD can result from multiple mechanisms (iron,
folate, or vitamin B12 deficiency; gastrointestinal bleeding; severe
hyperparathyroidism, systemic inflammation, and shortened red blood cell
survival).
Decreased erythropoietin synthesis is the most important and specific
etiology causing CKD associated anemia. Erythropoietin is a glycoprotein
secreted by the kidney interstitial fibroblast and is essential for the growth
and differentiation of red blood cells in the bone marrow. In CKD, tubular
atrophy generates tubulointerstitial fibrosis, which compromises renal
erythropoietin synthetic capacity and results in anemia. The anemia of CKD
increases morbidity and mortality from cardiovascularcomplications (angina,
left ventricular hypertrophy (LVH) and worsening heart failure). The term
“CKD-associated mineral and bone disorders” comprises abnormalities in
bone and mineral metabolism and/or extra- skeletal calcification secondary
to CKD pathophysiology. Renal osteodystrophy is the spectrum of
histological changes, which occur in bone architecture of patients with CKD.
The kidney is the primary site for phosphate excretion and 1-α-hydroxylation
of vitamin D. CKD patients develop hyperphosphatemia as a result of
inadequate 1, 25 dihydroxy-vitamin D levels that reflect reduced synthesis
from parenchymalscarring.

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 Fig 4: Chronic Renal Failure
Hypertension is a traditional cardiovascular risk factor which contributes
to the cardiovascular risk associated with CKD. Szcech and colleagues
demonstrated that patients with hypertension are at increased risk for new or
recurrent cardiovascular events in individuals with stage 2-3 CKD. CKD
patients are more likely to develop congestive heart failure (CHF). Bibbins et
al. evaluated the association between CKD and new-onset CHF in African
and Caucasians Americans.
Dyslipidemia is a major risk factor for cardiovascular morbidity and
mortality and is common among patients with CKD. As patients progress
through the stages of CKD, nutritional requirements are altered and
metabolism of protein, water, salt, potassium, and phosphorous are affected.
Urethritis
Inflammation of urethra characterized by dysuria, thick, purulent
discharge per urethra.
Causes: gonococcal urethritis-neisseriagonorrhea, Chlamydia
trachomatis, STD.
Clinical Features
Severe scalding pain on urination, frequent urination, urgency to pass
urine, burning during micturition, fever, headache, malaise, thick and
greenish yellow purulent discharge. Signs are fast pulse, temperature more
than 100 degree C, lymph nodes enlarged, external urethral meatus red,
swollen.

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Complications
Chronic cervicitis, infertility, bartholinitis.
Diagnosis
Gram stained urethral discharge.
Management
Improvement of general health, antibiotics, simultaneous treatment of
sexualpartner.
Nephrotic Syndrome
When substantial amount of protein are lost in the urine, a series of
secondary phenomena occur. Evidence of fluid retention or oedema and
more than 3.5 g of proteinuria per day. The disease that cause nephritic
syndrome always affect the glomerulus and tend to be non-inflammatory or
subacute examples of inflammatoryglomerulonephritis.
It is caused by increased permeability through the damaged basement
membrane in the renal glomerulus especially infectious or thromboembolic.
It is the result of an abnormality of glomerular permeability that may be
primary with a disease specific to the kidneys or secondary to congenital
infections, diabetes, systemic lupus erythematosus, neoplasia, or certain drug
use. Nephrotic syndrome is an important chronic disease in children. The
estimated annual incidence of nephrotic syndrome in healthy children is two
to seven new cases per 100,000 children younger than 18 years of age. More
common in boys than girls in younger age groups, but once adolescence is
reached there is no significant difference between genders. Increased
incidence and more severe disease seen in African American and
Hispanicpopulations.
Causes
Primary Cause: Minimal change nephropathy, focal
glomerulosclerosis, membranous nephropathy, hereditary nephropathies.
Non inflammatory glomerulonephritis-minimal change nephropathy, focal
and segmental glomerulosclerosis (FSGS), membranous nephropathy,
proliferative/inflammatory glomerulonephritis-mesangiocapillary
glomerulonephritis (MCGN), subacute proliferative nephritis, systemic lupus
erythematosus (SLE), diabetic nephropathy andamyloidosis.
Infection: HIV, hepatitis B virus, human immunodeficiency virus,
hepatitis C, cytomegalovirus, toxoplasmosis, parvovirus B1, amyloidosis and
paraproteinemias, preeclampsia.

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 Fig 5: Nephrotic syndrome

Pathophysiology
The glomerular capillaries are lined by a fenestrated endothelium that
sits on the glomerular basement membrane, which in turn is covered by
glomerular epithelium, or podocytes, which envelops the capillaries with
cellular extensions called foot processes, these processes interdigitate with
special cell junctions called the slit diaphragm which together forms the
glomerular filter. Normally, larger proteins (greater than 69 kD) are excluded
from filtration. Destruction of podocytes above a critical mass also leads to
irreversible glomerular damage. Proteinuria that is more than 85% albumin
is selective proteinuria. Albumin has a net negative charge, and it is
proposed that loss of glomerular membrane negative charges could be
important in causing albuminuria. Nonselective proteinuria, being a
glomerular leakage of all plasma proteins, would not involve changes in
glomerular net charge but rather a generalized defect in permeability.
Mutations in several podocyte proteins have been identified in families
with inherited nephrotic syndrome; a plasma factor may alter glomerular
permeability, especially in patients with the steroid-resistant nephrotic
syndrome and lastly altered T-lymphocyte polarized immune responses, in
that the T-cells could result in the production of a permeability factor.
Increased plasma levels of IgE, IgG4, and association with atopy suggest
type II cytokine bias in patients with MCNS. In vitro studies suggest that
podocytes express receptors for IL-4 and IL-13, the activation of these
receptors might disrupt glomerular permeability resulting in proteinuria. No
particular cytokine triggers the nephrotic syndrome. Many of the
complications of nephrotic syndrome can be linked to dysregulated lipid
metabolism and dyslipidemia. These abnormalities include elevated plasma
levels of cholesterol, triglycerides, and the apolipoprotein B; decreased

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lipoprotein lipase activity in the endothelium, muscle and adipose tissues;
decreased hepatic lipaseactivity, and increased levels of the enzyme PCSK9.
Also, there is an increase in the plasma levels of immature HDL particles
and reduced cholesterolefflux.
Clinical Features
Clinical features of nephrotic syndromes are oedema accumulates
predominantly in the lower limb in adults, extending to the genitalia and
lower abdomen as it gets more severe. In morning, the upper limbs and face
may be more affected. In children, ascites occurs early and oedema is often
seen only in the face. Blood volume may be normal, reduced or increased.
Investigation
Urine Test: Urine samples over 24 hours (for an accurate measure),
proteinuria (3 g protein) is diagnostic. Lipiduria, the presence of free lipid or
lipid within tubular cells, within casts, or as free globules, suggests a
glomerular disorder.
Blood Tests: The serum albumin level is classically low in nephrotic
syndrome, serum albumin often is < 2.5 g/dL.
Creatinine concentrations vary by degree of renal impairment. Total
cholesterol and triglyceride levels are typically increased. Serologic studies:
The role of testing for secondary causes of nephrotic syndrome.

Fig 6: Nephrotic syndrome ultrasonography

Ultrasonographic: Individuals with a single kidney may be prone to
developing focal glomerulosclerosis, having only one kidney is also a
relative contraindication to kidney biopsy.
Ultrasonography also demonstrates renal echogenicity. Increased renal
echogenicity is consistent with intrarenal fibrosis

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Renal Biopsy
Indicated for the following: congenital nephrotic syndrome, children
older than 8 years at onset, steroid resistance, frequent relapses or steroid
dependency, significant nephritic manifestations.
Different Diagnosis
The differential diagnosis includes:
 Hepatic: Insufficiency, hepatocellular cirrhosis, Budd-Chiari
syndrome
 Digestive: Exudative enteropathy, lymphangiectasia, malnutrition
 Cardiac: Hereditary angioneuroticedema
 Immune: Anaphylaxis
 Complications
 Generalized edema
 Respiratorydistress
 Sepsis
 Peritonitis
 Thromboembolism
 Failure to thrive
Patient Education
Advise to take low salt diet intake.
Interstitial Nephritis
It is divided in to acute and chronic interstitial nephritis.
Acute Interstitial Nephritis: It is refers to acute inflammation within
the tubule interstitium. Acute interstitial nephritis (AIN) is an under
recognized and under diagnosed cause of acute kidney injury (AKI). It is
estimated to account for 15-20% of cases of AKI; it is the reported diagnosis
in 2.8% of all kidney biopsies, and 13.5% of biopsies done specifically for
acute renal failure. Considerable evidence implicates antigen initiated cell-
mediated injury in the pathogenesis of AIN. Drugs account for 70% of all
cases, with over 150 different agents incriminated. The remaining cases are
due to infections, autoimmune diseases, and rarely idiopathic. Early
tribulations and classifications notwithstanding, most diseases of the kidney
continued to be considered as tubulopathies rather than glomerulopathies
through the first decades of the 20th century. It is within this context that the

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pathologic diagnosis of “acute interstitial nephritis” (AIN) was described in
1898 by William Thomas Councilman (1854-1933), then pathologist in chief
at the BrighamHospital.

Fig 7: Interstitial Nephritis

Causes
Drugs: Penicillins, NSAIDs, allopurinol, furosemide.
Infections: Leptospirosis, tuberculosis, pyelonephritis,
cytomegalovirus, Hantavirus.
Systemic disease: Sarcoidosis, Sjogren’s syndrome, myeloma. Renal
biopsies show intense inflammation with polymorphonuclear leucocytes and
lymphocytes surrounding tubules and blood vessels and occasional
eosinophils (figure 7).
Investigations
Laboratory markers of tubular dysfunction are evident before
decrements in filtration rate and consequent increments in blood urea
nitrogen (BUN) and serum creatinine levels. The principal hallmarks of
glomerular disease (salt retention, oedema, hypertension) are
characteristically absent. The early diagnosis of acute interstitial nephritis by
detecting tubular dysfunction is central to its diagnosis at a potentially
reversible stage.
Chronic Interstitial Nephritis
It is defined as a “chronic inflammation within the tubule interstitium”.
Causes: chronic glomerular disease, immune/inflammatory disease,
tumors (myeloma), drugs (NSAIDs, analgesic nephropathy).

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 Metabolic/congenital (Wilson’s disease, hypokalemia, medullary sponge
kidney hypercalciuria, sickle cell nephropathy), toxins (lead, Chinese herbs,
Balkan nephropathy).
Clinical Features
Hypotension, polyuria, sodium and water depletion. Patients present in
adult life with chronic renal failure, hypertension and small kidneys.
Polycystic Kidney Disease
Polycystic kidney disease (PKD) is an inherited disorder characterized
by cystic expansion of the kidneys producing progressive kidney
enlargement and renal insufficiency, in addition to various extrarenal
manifestations. The disease can be inherited in autosomal dominant and
recessive forms. Autosomal dominant polycystic kidney disease (ADPKD) is
characterized by slow but progressive enlargement of the kidneys with renal
failure occurring by the fifth to sixth decade of life. Polycystic kidney
disease (PKD) is the most common genetic cause of kidney failure in adults
and children. PKD is characterized by progressive cystic dilation of the renal
tubules, which results in nephromegaly and often culminates in end stage
renal disease. The disease occurs in approximately 1:800 to 1:1,000 people
and accounts for 2.5% of all cases of end stage renal disease. In patients with
polycystic kidney diseases (PKDs), the kidneys contain multiple fluid filled
cysts, although other organs may also beaffected.
Pathology
Small cysts of proximal tubular epithelium are present in infancy and
enlarge at a variable rate. In full developed adult polycystic kidney disease
the kidneys are asymmetrically enlarged and contain numerous cysts. These
differ in size and are surrounded by a variable amount of parenchyma which
often shows extensive fibrosis and arteriolosclerosis.
Clinical Features
Hypertension, which may or may not be associated with deterioration of
renal function. Vague discomfort in loin or abdomen due to increasing mass
of renal tissue, acute loin pain or renal colic due to haemorrhage in to a cyst,
haematuria, urinary tract infection, renalfailure.

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 Fig 8: Polycystic kidney disease ultrasonography

Investigations
The diagnosis is made on the basis of clinical features, family history
and ultrasound (figure 8).

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 Chapter - 5
Diseases of the Neurology

Alzheimer’s disease
Alzheimer’s disease exists along a spectrum, from early memory
changes to functional dependence and death. Using a case illustration, we
review the evaluation and diagnosis of mild cognitive impairment and the
diagnosis and management of Alzheimer’s disease at each stage, including
the management of both cognitive and behavioral/psychiatric aspects of the
disease and end-stage and end-of-life care. Dementia is a clinical syndrome
characterized by progressive decline in two or more cognitive domains,
including memory, language, executive and visuospatial function,
personality, and behavior, which causes loss of abilities to perform
instrumental and/or basic activities of daily living. Alzheimer’s disease (AD)
is by far the most common cause of dementia and accounts for up to 80% of
all dementia diagnoses. Although the overall death ratein the United States
from stroke and cardiovascular disease is decreasing, the proportion of
deaths related to AD is going up, increasing by 89% between 2000 and 2014.
Current treatments available include cholinesterase inhibitors for patients
with any stage of AD dementia and memantine for people with moderate-to-
severe AD dementia. These medications have been shown to enhance the
quality of life for both patient and caregiver when prescribed at the
appropriate time during the course of illness; however, they do not change
the course of illness or the rate ofdecline.
Clinical Features
Both short term and long term memory are affected, apraxia, visuo
spatial impairment, anosognosia, depression, cannot identify person and the
clinical features are made acutely worse by coexistent intercurrent illness2.
Management
There is no specific treatment for this condition.
Parkinson’s disease
Parkinson’s disease (PD) was first described by Dr. James Parkinson in
1817 as a “shaking palsy.” It is a chronic, progressive neurodegenerative

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disease characterized by both motor and non-motor features. The disease has
a significant clinical impact on patients, families, and caregivers through its
progressive degenerative effects on mobility and muscle control. The motor
symptoms of Parkinson’s disease are attributed to the loss of striatal
dopaminergic neurons, although the presence of non-motor symptoms
supports neuronal loss in non-dopaminergic areas as well. The term
Parkinsonismis a symptom complex used to describe the motor features of
Parkinson’s disease, which include resting tremor, bradykinesia, and
muscular rigidity. Parkinson’s disease is the most common cause of
Parkinsonism, although a number of secondary causes also exist, including
diseases that mimic Parkinson’s disease and drug- induced causes.
Parkinson’s disease is one of the most common neurodegenerative disorders.
The Parkinson’s disease Foundation reports that approximately 1 million
Americans currently have the disease. Although it is primarily a disease of
the elderly, individuals have developed Parkinson’s disease in their 30s and
40s. Gender differences pertaining to the incidence of Parkinson’s disease
are reflected in a 3:2 ratio of males to females, with a delayed onset in
females attributed to the neuroprotective effects of estrogen on the
nigrostriatal dopaminergic system. Parkinson’s disease variable but
pronounced progression has a significant impact on patients, families, and
society. Advanced and end- stage disease may lead to serious complications,
including pneumonia, which are often associated with death.
Parkinson’s disease is a disorder of the extrapyramidal system, which
includes motor structures of the basal ganglia, and is characterized by the
loss of dopaminergic function and consequent diminished motor function,
leading to clinical features of the disease. Progressive degeneration of
dopaminergic neurons in the substantia nigra pars compacta (SNpc), which
project to the striatum (the nigrostriatal pathway), results in the loss of
dopaminergic function in individuals with PD.
Typically, patients experience the motor features of Parkinson’s disease
only after 50% to 80% of dopaminergic neurons have been lost, suggesting
the involvement of a compensatory mechanism in the early stages of
thedisease.
Two types of dopamine receptors, D1 (excitatory type) and D2
(inhibitory type), influence motor activity in the extrapyramidal system.
Components of this system include the basal ganglia, which involves the
internal globus pallidal segment (GPi) of the ventral striatum, and the pars
reticulata portion of the substantia nigra (SNpr). These components are part
of larger circuits located in the thalamus and the cortex. The loss of

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dopamine in the striatum of Parkinson’s disease patients results in increased
activity in the GPi/SNpr circuits and subsequent gamma aminobutyric acid
(GABA) dysfunction, leading to inhibition of the thalamus. The end result is
the decreased ability of the thalamus to activate the frontal cortex, resulting
in the decreased motor activity characteristic of Parkinson’s disease.
Accordingly, restoring dopamine activity in the striatum through D2 and D1
receptor activation with dopaminergic therapies mediates clinical
improvement in the motor symptoms of Parkinson’s disease4. In addition,
dopaminergic loss results not only in reduced activation of the thalamus but
also in increased cholinergic activity due to the loss of dopamine’s normal
inhibitory influence.
Clinical Features
Clinical features of Parkinson’s disease are tremor, rigidity,
bradykinesia, may be absent initially, when nonspecific symptoms of
tiredness, aching limbs, mental slowness, small handwriting may be noticed.
Most patients have difficulty with rapid fine movements, tremor also affects
the legs, mouth as well as tongue, slowness of gait difficulty with tasks such
as fastening buttons, shaving or writing, postural righting reflexes are
impaired early on in the disease, speech become softer, indistinct.

Fig 1: Parkinson’s MRI brain & SPECT

Investigations
The differential diagnosis of PD should include a comprehensive history
and physical examination. Difficult or questionable cases should be referred
to a movement-disorder specialist for further evaluation. There are no
definitive tests to confirm the diagnosis of PD; therefore, a clinical diagnosis
requires the clinician to review the patient’s history, to assess symptoms, and
to rule out alternative diagnoses, such as multiple-system atrophy, DLB
disease, and essential tremor. The cardinal motor features of PD-described as
the “classical triad”-include a 4-Hz to 6-Hz resting tremor, “cogwheel”
rigidity, and bradykinesia.

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Management
The primary goal in the management of PD is to treat the symptomatic
motor and non-motor features of the disorder, with the objective of
improving the patient’s overall quality of life. Appropriate management
requires an initial evaluation and diagnosis by a multidisciplinary team
consisting of neurologists, primary care practitioners, nurses, physical
therapists, social workers, and pharmacists. Effective management should
include a combination of non-pharmacological and pharmacological
strategies to maximize clinical outcomes. To date, therapies that slow the
progression of PD or provide a neuroprotective effect have not been
identified.
Guillain Barre’s Syndrome
It is acute inflammatory demyelinating polyneuropathy. Guillain Barré
syndrome (GBS) was first described in 1916 (Guillain G, 1916) and is
approaching its 100th anniversary. Our knowledge of the syndrome has
hugely expanded since that time.
Once originally considered to be only demyelinating in pathology us
now recognizes both axonal and demyelinating subtypes. Numerous
triggering or antecedent events including infections are recognized and GBS
is considered an immunological response to these. GBS is now considered to
be a clinical syndrome of an acute inflammatory neuropathy encompassing a
number of subtypes with evidence of different immunological mechanisms.
Some of these are clearly understood while others remain to be fully
elucidated. Complement fixing antibodiesagainst peripheral nerve
gangliosides alone and in combination are increasingly recognised as an
important mechanism of nerve damage. New antibodies against other nerve
antigens such as neurofascin have been recently described. Research
databases have been set up to look at factors associated with prognosis and
the influence of intravenous immunoglobulin (IvIg) pharmacokinetics in
therapy. Exciting new studies are in progress to examine a possible role for
complement inhibition in the treatment of thesyndrome.
Early studies reported oedema of the peripheral nerves with sparse
inflammatory infiltrate. Classic studies by Asbury and colleagues
emphasised the importance of perivascular lymphocytes which resembled
the findings in the animal model experimental allergic neuritis.
Clinical Features
Clinical features of Guillain barre’s syndromes are muscle weakness,
paresthesia especially distal and limb pains often precede the weakness,
facial or bulbar weakness, respiratory failure can develop within hours.

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Diagnosis
A lumbar puncture should be done before treatment. A cerebrospinal
fluid (CSF) white cell count of over 10/μl raises the possibility of
leptomeningeal malignancy, HIV or an alternative infectious diagnosis (eg
Lyme disease or poliomyelitis), but in clinical trials CSF cell counts up to
50/μl are permitted. IvIg can very occasionally cause aseptic meningitis.
Typically, the CSF protein is raised after the first week, often to more than 1
g/l. Routine blood tests should include creatine kinase, biochemistry and Ig
levels. These are done to exclude other causes of weakness and to reduce the
risks of ivIg. In renal failure ivIg is relatively contraindicated and it is more
likely to cause anaphylaxis in patients with IgA deficiency.
Management
Treatment should be started as soon as possible, but there is no evidence
that starting it 12 hours earlier (e.g. overnight) makes any difference. First-
line treatment is now usually ivIg because of its ease of administration.
Adequate pain relief and a multidisciplinary approach to rehabilitation are
essential, as is patient education during the slow but steady recovery, with
improvements to be expected for up to two years.
Myasthenia Gravis
It is characterized by progressive inability to sustain a maintained or
repeated contraction of striated muscle (fatigability). Acquired myasthenia
gravis is a relatively uncommon disorder, with prevalence rates that have
increased to about 20 per 100,000 in the US population. This autoimmune
disease is characterized by muscle weakness that fluctuates, worsening with
exertion, and improving with rest. In about two-thirds of the patients, the

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involvement of extrinsic ocular muscle presents as the initialsymptom,
usually progressing to involve other bulbar muscles and limb musculature,
resulting in generalized myasthenia gravis. Although the cause of the
disorder is unknown, the role of circulating antibodies directed against the
nicotinic acetylcholine receptor in its pathogenesis is wellestablished.

Fig 3: Myasthenia gravis

The nerve terminals innervating the neuromuscular junctions (NMJ) of
skeletal muscles arise from the terminal arborization of α-motor neurons of
the ventral horns of the spinal cord and brain stem. The NMJ itself consists
of synaptic cleft and 20nm thick space that contains acetylcholinesterase
(AChE) along with other supporting proteins/proteoglycans [12]. The NMJ
postsynaptic membrane has deep folds with acetylcholine receptors (AChR)
tightly packed on the top of these folds. When the nerve action potential
reaches the synaptic bouton, depolarization opens voltage gated Calcium
channels on the presynaptic membrane, triggering release of ACh into the
synaptic cleft. The ACh diffuses into the synaptic cleft to reach postsynaptic
membrane receptors where it triggers off the end-plate potential (EPP) and
gets hydrolyzed by AChE within the synaptic cleft. MuSK (muscle specific
tyrosine kinase), a postsynaptic transmembrane protein, forms part of the
receptor for agrin, a protein present on synaptic basal lamina. Agrin/MuSK
interaction triggers and maintains rapsyn-dependent clustering of AChR and
other postsynaptic protein. Rapsyn, a peripheral membrane protein on the
postsynaptic membrane, is necessary for the clustering of AChR. Mice
lacking agrin or MuSK fail to form NMJs and die at birth due to profound
muscle weakness.
Clinical Features
The disease usually presents between the age of 15 and 50 years with
women affected more often than men. Symptoms are abnormal fatigable
weakness of the muscles, movement is initially strong, it rapidly weakness,

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ptosis, diplopia, limb muscle may be affected, mostly commonly those of the
shoulder girdle, respiratory muscles may be involved, aspiration may occur
if the cough is ineffectual. Sudden weakness from a cholinergic or
myasthenic crisis may require ventilator support.

Fig 4: Myasthenia gravis electromyography

Diagnosis
For a patient with ptosis, a small cube of ice is placed over the eyelid for
about 2 minutes. Improvement of the ptosis after this procedure suggests a
disorder of neuromuscular transmission. All patients with MG should have a
computed tomography (CT) scan of the chest done with contrast. Routine
chest radiography may be done but should not be done in place of the CT
scan of thechest.
Management
Thymectomy should be performed as soon as feasible in any patient
with myasthenia not confined to extra ocular muscles, unless the disease has
been established for more than 7 years. Plasma exchange are removing
antibody from the blood may produce marked improvement.

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 Chapter - 6
Diseases of the Respiratory System

Chronic Obstruction Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is the name for a group
of lung conditions that cause breathing difficulties. It includes:
 Emphysema-damage to the air sacs in thelungs
 Chronic bronchitis-long term inflammation of theairways
Chronic obstructive pulmonary disease is a common condition that
mainly affects middle aged or older adults who smoke. Many people do not
realise they have it. The breathing problems tend to get gradually worse over
time and can limit your normal activities, although treatment canhelp keep
the condition undercontrol.
Definition
Chronic obstructive pulmonary disease is the respiratory disorder
characterized by airflow obstruction mainly resulting from chronic
bronchitis, emphysema. This does not change markedly over several months.
The impairment of lung function is largely fixed but may be partially
reversible by bronchodilator therapy. Historically, the term chronic
bronchitis was used to define any patient who coughed up sputum on most
days of at least three consecutive months or more for more than two
successive years. Emphysema referred to the pathological process of a
permanent destructive enlargement of the airspaces distal to the terminal
bronchioles. According to WHO the death rate from Chronic obstructive
pulmonary disease currently exceeds 5000 per year in north, west, east, south
India and this condition accounts for over 10% of all hospital medical
admission in the India.
Causes
Chronic obstructive pulmonary disease is cigarette smoking and a direct
correlation exists between the number of cigarettes smoked in pack year (one
pack year =20 cigarettes smoked daily for one year) and the likelihood of
developing the disease. Smoking is thought to have its effect by inducing

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persisting airway inflammation and causing a direct imbalance in antioxidant
capacity and antiproteinase/proteinase load in the lungs.
Individual susceptibility (homoeopathy) to smoking is, however, very
wide, with only 15 to 20% of smokers likely to develop clinically significant
Chronic obstructive pulmonary disease. A small additional contribution to
the severity of chronic obstructive pulmonary disease has been reported in
patients exposed to dusty or air polluted environments. Also causes of low
birth weight, bronchial hyper responsiveness and the formation of chronic
obstructive pulmonary disease. Alpha antitrypsin deficiency can cause
emphysema in non-smokers but this risk is increased strongly in enzyme
deficient patient who smoke. Stopping smoking slows the average rate of
decline in forced expiration volume from 50-70 ml/year to 30 ml/year (equal
to non-smokers).
Pathology
Chronic obstructive pulmonary disease patients develop airway wall
inflammation hyper trophy of the mucus secreting glands and increase in the
number of goblet cells in the bronchi and bronchioles with a consequent
decrease in ciliated cells. Its leads to less efficient transport of the increased
mucus in the airways and loss of alveolar attachments around such airway
makes them more liable to collapse during expiration. Emphysema is usually
centriacinar, involving respiratory bronchioles, alveolar ducts and centrally
located alveoli. Paraseptal emphysema develops with the latter responsible
for blebs on the lung surface and giant bullae. Pulmonary vascular
remodelling caused by persistent hypoxaemia results in pulmonary
hypertension and right ventricular hypertrophy and dilation.

Fig 1: Difference between normal and COPD bronchus, alveoli

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Clinical Features
Patient have a shortness of breath (SOB) and coughing as a normal part
of aging, but these could be signs of chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease can progress for years without
noticeable shortness of breath. Symptoms of chronic obstructive pulmonary
disease can be different for each person, but common symptoms are:
 Increased shortness of breath
 Frequent coughing (with and without mucus)
 Increased breathlessness
 Wheezing
 Tightness in the chest
Patients will suffer recurrent respiratory infections, exertional
breathlessness, regular morning cough, severe wheeze. Sputum may be
scanty, mucoid, tenacious and occasionally streaked with blood during
infective exacerbations. Frankly purulent sputum is indicative of bacterial
infection. Shortness of breath is aggravated by infection, excessive cigarette
smoking and adverse atmospheric condition. In auscultation method can find
crepitations (crackles) which usually, but not always, disappear after
coughing may be clear audible over lower zones.
Classification of Chronic obstructive pulmonary disease: It is divided in
to mild, moderate and severe. In mild Chronic obstructive pulmonary disease
is spirometry Forced expiration volume is 60-70% predicted and symptoms
are smokers cough or exertional breathlessness.
In moderate Chronic obstructive pulmonary disease is Forced expiration
volume is 40-50% predicted and exertional breathlessness, cough, sputum
and wheeze presented. In severe Forced expiration volume is 60-70%
predicted is Forced expiration volume is less than 40% predictedand
exertional breathlessness, cough, sputum, wheeze and swollen legs
presented.
Investigation
Investigation of chronic obstructive pulmonary disease is spirometry,
pulse x ray of chest (anterior posterior view and lateral view), pulse oximetry
to know the oxygen percentage and haematology (polycythemia may
develop but should not be assumed to be secondary without measurement of
PaO2).
CT scan can be used to quantify the extent and distribution of
emphysema.

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 Fig 2: Chest radiograph of chronic obstructive pulmonary disease

Management
Chronic obstructive pulmonary disease can be managed by antibiotics,
stop smoking completely/permanently, bronchodilator therapy, surgical
intervention, homoeopathic medication.
Bronchiectasis
It is defined as a ‘abnormal dilation and chronic enlargement of the
bronchi/bronchus’. The passageways from the trachea to the alveoli that are
the air exchanging parts of the lungs. It may be acquired or less commonly,
congenital. Bronchiectasis may occur in a single portion of the lung
(localized) or throughout the lungs (diffuse) and is the major lung
abnormality of cystic fibrosis. It may have several different contributing
factors, such as abnormal cilia, and its course may vary greatly from causing
no symptoms to causing death.
Etiology of Bronchiectasis
 Congenital cause of bronchiectasis is ciliary dysfunction syndromes
like primary ciliary dyskinesia (immotile cilia syndrome),
kartagener's syndrome, young syndrome, cystic fibrosis and
primary hypogammaglobulinemia
 Acquired in children causes are pneumonia (complication,
whooping cough or measles), primary tuberculosis, foreignbody
 Acquired in adults causes are suppurative pneumonia, pulmonary
tuberculosis, allergic bronchopulmonaryaspergillosis and bronchial
tumors

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 Fig 3: Chest Radiograph and CT images of Bronchiectasis

Pathology
Bronchiectasis cavities may be lined by granulation tissue, squamous
epithelium or normal ciliated epithelium. There may also be inflammatory
changes in the deeper layers of the bronchial wall and hypertrophy of the
bronchial arteries. Chronic inflammatory and fibrotic changes are usually
found in the surrounding lung tissue.
Clinical Features
Bronchiectasis may occur any part of the lungs, but the more efficient
drainage by gravity of the upper lobes usually produces less serious
symptoms and complication than the lower lobes. Chronic productive of
cough usually aggravated by morning and often brought on by changes of
posture. Sputum often copious and persistently purulent in advanced disease
(due to accumulation of pus in dilated bronchi/bronchus). Fever, malaise and
increased cough, sputum volume when spread of infection causes
pneumonia, which is frequently associated with pleurisy. Recurrent pleurisy
in the same site often occurs in this condition (due to inflammatory changes
in lung and pleura surrounding dilated bronchi). Purulent sputum,
haemoptysis. It is called dry bronchiectasis.
Associated symptoms are weight loss, anorexia, lassitude, excessive
sweating at night time and digital clubbing.
Investigation
In advanced disease the cystic bronchiectasis spaces may be visible.
Abnormalities produced by associated pulmonary infection and collapse are
evident. A diagnosis of bronchiectasis can only be made with certainty by
CT scan. Ciliary function test when patients suspected of having a ciliary
dysfunction syndrome.

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Management
Bronchiectasis can be managed with postural drainage, antibiotic
therapy, surgical treatment and homoeopathic treatment.
Cystic Fibrosis
Cystic fibrosis (CF) is the most common, life shortening genetic disease
in Caucasians. It affects the transport of salt and water across cells and
affects different organs, but lung disease is responsible for the majority of
symptoms, burden of care, and lost years of life. The gene that causes the
disease has now been identified andsequenced.
Epidemiology
Cystic fibrosis affects at least 30,000 people in the United States;
between 900 and 1,000 new cases are diagnosed every year (1). One in 29
people of Caucasian ancestry is an unaffected carrier of the CF gene
mutation. In the United States, cystic fibrosis occurs at a rate of 1 in 3,400
births. While it occurs in persons of all racial and ethnic backgrounds, it is
most common in Caucasians of Northern European ancestry. Historically,
half of affected individuals were diagnosed by five months of age, though
the average age at diagnosis was five years, and some individuals were not
diagnosed until adulthood. In 2010, however, all states began requiring that
newborns undergo screening for cystic fibrosis. This should be helpful
because early diagnosis and treatment reduce symptoms, improve health, and
reduce costs associated with diseasecomplications.
Cystic fibrosis is caused by mutations in the cystic fibrosis
transmembrane regulator (CFTR) gene.
A recessive genetic disorder, it is inherited when two carrier parents
(who have one normal gene and one gene with a mutation) each contributes
the abnormal CFTR gene to their child. Thus, the likelihood that two carrier
parents will have an affected child is 1:4 for each pregnancy.
The abnormality in the CFTR gene causes a defective CFTR protein to
be produced, resulting in abnormal transport of salt (sodium and chloride)
and water across cells that line the respiratory, digestive, and genital tracts.
This results in a reduction of water in the fluid lining the airways.
Diminished water causes the respiratory secretions to become thicker and
clog small airways. The stagnant sputum becomes infected as bacteria that
are inhaled or brought into the lungs through the mouth become lodged
there. Persistent stagnation allows persistent infection and chronic
inflammation to develop. Inflammatory cells trapped in the sputum add to
itstenacity.

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Clinical Features
The bronchi dilate and their walls weaken, setting up a condition called
bronchiectasis that results in further airflow obstruction. The vicious cycle of
airway obstruction, inflammation, and persistent infection leads to a
progressive decline in lung function and eventually causes respiratory failure
and death.
Clogged mucus secretions in the digestive tract can lead to malnutrition
and vitamin deficiencies. The genital tract abnormality can lead to infertility
in men and women.
Environmental exposures worsen cystic fibrosis lung disease. Children
who are exposed to tobacco smoke have lower lung function and more
pulmonary exacerbations than those who live in smoke free environments.
High levels of air pollution are associated with an increased rate of adverse
pulmonaryevents.

Fig 4: Chest radiograph of cystic fibrosis

Management
All the patients with cystic fibrosis who produce sputum should have
regular chest physiotherapy, which should be performed more frequently
during exacerbations. Cystic fibrosis can be managed by potential for
somatic gene therapy and homoeopathic constitutional remedies.
Pneumonia
Pneumonia is a “lung infection characterized by severe cough and fever
mainly resulting from bacteria, virus or fungi”. It involving the lung alveoli
(air sacs) and can be caused by microbes, including bacteria, viruses, or
fungi. It is the leading infectious cause of hospitalization and death in the
India and exacts an enormous cost in economic and human terms. Healthy
individuals can develop pneumonia, but susceptibility is greatly increased by
a variety of personal characteristics. Community acquired pneumonia occurs

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outside of the hospital (Streptococcus pneumonia), hospital acquired
pneumonia occurs contracted by a patient in a hospital at least 48-72 hours
after being admitted. It is bacterial infection rather than viral infection. It
includes post-operative pneumonia and most common pathogens are gram
negative bacilli(staphylococcus).
Pneumonia was described 2,500 years ago by Hippocrates, the father of
medicine. Pneumonia occurs commonly in individuals living in theirhome
communities (community acquired pneumonia) as well as in individuals who
are hospitalized for other reasons (hospital acquired pneumonia). The lobular
Pneumonia is a radiological and pathological term refereeing to
homogeneous consolidation (red hepatisation) of one or more lung lobes,
often with associated pleural inflammation. Bronchopneumonia referees to
more patchy alveolar consolidation associated with bronchial and
bronchiolar inflammation often affecting both lowerlobes.
Stages of Pneumonia
Four stages of lobar pneumonia have been described. In the first stage,
which occurs within 24 hours of infection, the lung is characterized
microscopically by vascular congestion and alveolar edema. Many bacteria
and few neutrophils are present. The stage of red hepatization(2-3 d), so
called because of its similarity to the consistency of liver, is characterized by
the presence of many erythrocytes, neutrophils, desquamated epithelial cells,
and fibrin within thealveoli.
In the stage of gray hepatization (2-3 d), the lung is gray brown to
yellow because of fibrinopurulent exudate, disintegration of RBCs, and
hemosiderin. The final stage of resolution is characterized by resorption and
restoration of the pulmonary architecture. Fibrinous inflammation may lead
to resolution or to organization and pleuraladhesions.

Fig 5: Radiograph of Pneumonia

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Clinical Features
Patients present with complains of severe cough, high grade fever,
malaise, often associated with pleuritic chest pain, which is occasionally
referred to the shoulder or anterior abdominal wall. The cough is
characterized by short, painful and at first dry, but later becomes productive
and may become rust coloured or even frankly blood stained. The sudden
onset of rigors due to high grade fever, in children vomitingor a febrile
convulsion. Appetite is usually lost and headache is a frequent
accompanying symptoms. In advance pneumonia confusion can be an early
and dominantproblem.
Physical signs tachycardia, hypoxaemia, hypotension, confusion and
tachypnoea. Pleurisy often results in diminution of respiratory movements
and a pleural rub on the affected side. At a variable time after onset,
generally within two days, signs of consolidation appear. The percussion
note and high pitched bronchial breath sounds.
If a pleural effusion develops, physical signs of fluid in the pleural space
are usually found, but bronchial breath sounds can persist and thepresence of
an empyema may be suspected only from the recurrence or persistence
ofpyrexia.

Fig 6: Gram positive diplococci characteristic of strep. Pneumonia

Investigations
In lobar pneumonia, the chest radiograph shows a homogeneous opacity
localized to the affected lobe or segment; this usually appears within 12 - 18
hours of the onset of the illness. Radiological examination is also particularly
helpful if a complication such as pleural effusion, intrapulmonary abscess
formation or empyema is suspected.

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Differential Diagnosis
 Pulmonary infraction like bacterialpneumonia
 Pulmonary/pleural tuberculosislike
 Pulmonary oedema, especially if unilateral andlocalized
 Inflammatory conditions below the diaphragm condition such as
cholecystitis, peptic ulcer, acute pancreatitis, hepaticamoebiasis
 Pulmonary eosinophilia, wegener'sgranulomatosis
Management
Pneumonia can be manage by oxygen should be administered to all
hypoxaemic patients, antibiotic treatment, mild analgesics for pleural pain,
physiotherapy, homoeopathic medicines.
Tuberculosis
Tuberculosis remains one of the major global health threats leading to
morbidity and mortality. One in three persons across the world representing
2-3 billion individuals are known to be infected with Mycobacterium
Tuberculosis (M. Tuberculosis) of which 5-15% are likely to develop active.
In 2014, an estimated 9.6 million people fell ill due to tuberculosis, around
1.5 million people died from the disease including 1.1 million HIV negative
persons and 400,000 HIV patients. While tuberculosis is present in every
country majority of tuberculosis sufferers live in low income and middle
income countries especially in regions such as Sub Saharan Africa and South
East Asia. Over the past decade, significant progress has been made towards
tuberculosis control with most of the tuberculosis targets set as part of the
Millennium Development Goals having beenachieved.
In all, effective diagnosis and treatment of tuberculosis has been
estimated to have saved over 40 million lives between 2015 and 2019. The
End tuberculosis strategy serves as the key guide for countries to reduce
tuberculosis deaths by 90% by 2030 as well as achieve an 80% reduction in
tuberculosis incidence rate compared with 2015. In this respiratory disorder
paper, I provide a general overview of tuberculosis by highlighting the
basics.
Pathology
The initial primary tuberculosis usually formed in the lung, but
occasionally in the tonsil or alimentary tract, especially the ileocaecal region.
Primary infection differs from subsequent infections in that the primary
focus in lung, tonsil or bowel is almost invariably accompanied by caseous

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lesions in the regional lymph nodes, such as the mediastinal, cervical or
mesenteric groups respectively. Primary infection and the associated lymph
node lesions heal and calcify.

Fig 7:Primary pulmonary tuberculosis

1) Spread from primary focus to hilar and mediastinal lymph glands to
form the primary complex
2) Direct extension of the primary focus-Progressive pulmonary
tuberculosis
3) Spread to the pleura pleural effusion
4) Blood borne spread: Pulmonary, skeletal, renal, genitourinary;
massive spread-military tuberculosis and meningitis
In a few, healing, particularly in lymph nodes, is incomplete and viable
tubercle bacilli may enter the blood stream. Lesions more common in the
lungs, bones, joints and kidneys and lesions may develop months or even
years after primary infection. Sometimes primary infections do not heal.
Infection may also be carried by lymphatics from tuberculosis
mediastinal lymph nodes to the pleura or pericardium, with the production of
tuberculosis pleurisy or pericarditis. Rarely a caseous tuberculosis focus
ruptures in to a vein and produces acute dissemination throughout the body,
a condition known as acute military tuberculosis. Meningitis often
complicates this condition. Post primary pulmonary tuberculosis
characteristic pathological feature of which is the tuberculous cavity, formed
when the caseated and liquefied centre of a tuberculous pulmonary lesion is
discharged in to a bronchus. Blood bonrne dissemination to other organs is
uncommon in post primary pulmonary tuberculosis.

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 Fig 8: Radiograph & C T of Pulmonary tuberculosis

Clinical Features
Persistent cough, haemoptysis, pleural pain not associated with an acute
illness, spontaneous pneumothorax, lethargy, weight loss.
Investigation
Microscopy
Sputum smear microscopy still remains the basis for diagnosis of
tuberculosis in developing countries. Sputum smears can be screened using
fluorochrome stains such as an auramine stain where mycobacteria appear as
fluorescent rods against a dark background using an ultraviolet light
microscope. Other specimens should be stained using the Ziehl-Neelsen
method-mycobacteria are seen as pink rods against a blue or
greenbackground.
Culture
Culture still remains the gold standard for diagnosis of tuberculosis, and
it also permits the diagnosis of drug resistance, including the emerging
mutations. Traditional egg based (Lowenstein Jensen) and agar based
(Middlebrook 7H10/11) methods are widely used. Patients with pulmonary
disease should have three sputum samples sent for microscopy and culture. If
sputum is not expectorated, an induced sputum, bronchoalveolar lavage or
gastric aspirate can be examined. Gastric aspirates are particularly useful in
diagnosing children. Other specimens taken depend on the sites affected, but
may include cerebrospinal fluid (CSF), blood, peritoneal and pericardial
fluid, early morning urine, lymph node aspirates or tissue samples. CSF
should be tested for cell count, protein and glucose because tuberculous
meningitis is associated with an elevated lymphocyte count, high protein and
lowglucose.

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 Fig 9: Examination of sputum

Tuberculin Skin Testing

Popularly known as Mantoux test involves injecting the purified protein
derivative (PPD) of mycobacterial tuberculosis intradermally in the forearm
and the resulting reaction is read after 48-72 hours. A positive skin test is
indicated by a skin reaction at the point of the injection. A blood test has
recently been developed which measures interferon g released from T cells
in response to stimulation with mycobacterial antigens. Studies using ESAT-
6 and CFP-10, two antigens absent from the BCG vaccine strain, have shown
promising results for the diagnosis of active and latent infection.
Management
BCG is a strain of bovine tuberculin of low virulence which is used for
intradermal vaccination (0.1 ml of reconstituted freeze dried vaccine),
conferring protection for up to 7 years. Vaccination reduces the incidence of
pulmonary tuberculosis in young adults by 80% and minimizes the risk of
serious disseminated disease-military tuberculosis and tuberculous
meningitis.
Chemoprophylaxis: Healed tuberculous scars may still contain viable
bacteria and if cellular immunity is suppressed for any reason there may be
recrudescence ofdisease.
Chemotherapy:Is the mainstay of modern treatment of tuberculosis,
although the occasional patient still requires surgery for drainage of an
empyema, caseating tuberculous lymph nodes or more rarely, resection of
bronchiectasis areas of the lung, or emergency surgery to prevent spinal
paraplegia, antituberculosis drugs (ATD) and homoeopathy medicines used
in tuberculosis.

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Bronchial Asthma
Bronchial asthma is heterogeneous pulmonary disorder characterized by
recurrent episodes of cough, breathlessness and wheezing, which may
resolve spontaneously or after the use of bronchodilator medication. The
global prevalence of asthma is anticipated to be approximately 4.5
percentages. There are about 334 million patients with asthma affecting all
age groups, across the world. The prevalence of asthma has increased over
time and an additional 100 million people worldwide are expected to
develop asthma by the year 2025.
The prevalence of asthma has increased over time and an additional 100
million people worldwide are expected to develop asthma by the year 2025.
Although asthma is a major health problem in the world, there are some
important issues, particularly its management. Asthma is seen in all ages of
life, from earliest infancy up to old age. It has observed that males were
more prone to asthma than the female.
Etiology
Heredity: It is estimated that about 30 percent of patients will give us a
family history of allergy and asthma or either of these.
Allergies: Allergies can be allotted in large number of patients for
causing or precipitating asthmatic assaults. Usually, a massive exposure to
allergens is followed by an acute asthmatic attack. In immediate onset of
asthma, the symptoms of asthma (acute occur within a few minutes of
exposure.
Environmental Cause: Winds, rains, sudden changes in the climate
aggravate allergic manifestations. Physical agents like colds, hearts etc., do
start an allergic phenomenon and hence could be called as pseudo allergens.
Emotional: Emotional disturbances do play a vital role in the llife of an
asthmatic.
Infections: Repeated upper respiratory infections are the main
precipitating factors in m any cases.
Type of Asthma
Extrinsic is hereditary disposition. It starts early in life and serum
levelsof IgE are elevated. It occurs due too pollens of trees, grass andweeds.
Intrinsic Asthma: it is also known as idiopathic asthma. Serum IgE
levels are normal. It usually starts late in life and perennial symptoms are
common.

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 Catarrhal asthma/millers asthma is seen in association with acute or
chronic catarrhal disorders, the mucous membrane of the throat and
bronchial tubes being in a n altered state, in severe cases badly inflamed.
Hay asthma is a type of asthmatic breathing that occurs in association
with acute bronchial irritation and catarrh. It is summer catarrhal affection
that passes under the name of rose cold or hay fever.
Miller’s asthma is frequently applied to spasmodic group or laryngismus
stridulus and by some authors is still mentioned as a type of asthma
occurring children.
Atopic asthma is definite antigenic etiology. There is a definite history
of allergy and through the hyper sensitivity tests one finds that the patient
shows a positive result.
Non atopic asthma is no allergic factor in this kind of asthma. Intrinsic
asthmatics when tested for IgE levels would not have a rise in IgE levels.
Pathophysiology
Current theoris include early exposure toaero allergens, early viral
infections, diet or paradoxically, fever childhood infections resulting from
improved public health standards.

Fig 10: Pathophysiology of asthma flow chart

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Clinical Features
In episodic asthma paroxysms of wheeze and dyspnoea occur at any
hour of the day or night are of sudden onset and may be preceded by a
feeling of tightness in the chest. Expiration is exhausting, while inspiration is
short and gasping. Patient adopts to an upright position, fixing the shoulder
girdle to assist the accessory muscles of expiration. In severe attacks there is
tachycardia, pulsus paradoxus and central cyanosis. The symptoms usually
sets in suddenly and generally at night, occurring, as a rule, without the least
premonition, although it may be attendee inchildren by a stage of cold,
cough and ordinary catarrhal symptom prior to the development of
asthmaticbreathing.
The eyes are prominent and starring and the patient is compelled to lie
or sit with his mouth partly open in order to get sufficient breath for his
needs. The temperature usually not elevated, and may even be subnormal.
The surface is usually cold and clammy and sometimes cyanosis is so
pronounced that a fatal issue is feared.
Investigation
Completed blood picture, x- ray, sputum examination, ECG, pulmonary
function test, arterial blood gases, measurement of serum IgE, detection of
IgE antibody etc.,
Management
In acute severe asthma has to give oxygen, high doses of inhaled beta 2
adrenoreceptor agonists, systemic corticosteroids. In chronic asthma can be
managed with homoeopathicmedicines.
Pleural Effusion
Pleural effusion is used when serous fluid accumulates in the pleural
space. The passive transudation of fluid in to the pleural cavity occurs in
cardiac failure and in conditions causing hypoproteinemia such as nephritic
syndrome, liver failure and severe malnutrition. Pleural effusion may be
unilateral or bilateral. Bilateral effusion often occurs in cardiac failure, but is
also seen in much less common disorders such as the connective tissue
diseases and hypoproteinemia.
Etiology
There are many causes of pleural effusions. The following is a list of
some of the major causes: pneumonia, tuberculosis, pulmonary infract,
malignant disease, subdiaphragmatic disorder (subphrenic abscess,

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pancreatitis etc.), cardiac failure, hypoproteinemia (nephritic syndrome, liver
failure, malnutrition), connective tissue disease, acute rheumatic fever, post
myocardial infarction syndrome, meigs syndrome (ovarian tumour plus
effusion), myxoedema, uraemia, asbestos related benign pleural effusion,
yello nail syndrome.
Symptoms
Chest pain, difficulty breathing, painful breathing (pleurisy), cough is
either dry or productive. Deep breathing increase pain, fever, chills, loss
ofappetite.

Fig 11: Pleural effusion

Investigations
Radiological examination shows a dense uniform opacity in the lower
and lateral parts of the hemithorax, shading off above and medially in to
translucent lung (see figure 12). Occasionally the fluid is localized below the
lower lobe (subpulmonary effusion), the appearances simulating an elevated
hemidiaphragm. A localized opacity may be seen when the effusion is
loculated-for example in an inter lobar fissure. Ultrasonography helps to
localize an effusion prior to aspiration and pleural biopsy. Pleural aspiration

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can absolute proof that an effusion is present can be obtained only by the
aspiration fluid. Pleural biopsy is always indicated whenever a diagnostic
aspiration of pleural fluid is performed because the chances of obtaining a
diagnosis from pleural biopsy material are much greater than by examination
of the pleural liquid alone.

Fig 11: Radiograph of Pleural effusion

Management
Aspiration of pleural fluid may be necessary to relieve breathlessness. It
is inadvisable to remove more than one liter on the first occasion because re
expansion pulmonary oedema occasionally follows the aspiration of larger
amounts.
Empyema
The term empyema defines “pus in the pleural space”, gram-positive, or
culture from the pleural fluid. Empyema is usually associated with
pneumonia but may also develop after thoracic surgery or thoracic trauma. In
the United States, there are approximately 32,000 cases per year. Empyema
is associated with elevated morbidity and mortality, around 20% to 30% of
patients affected will either die or required further surgery in the first year
after developing empyema. Early intervention is crucial in the management
ofempyema.
Etiology
Around 20% of patients with pneumonia will develop a parapneumonic
effusion that may lead to empyema. Seventy percent of patients with
empyema have parapneumonic effusion, the other 30% of cases are related
to trauma, post thoracic surgery, esophageal ruptures, or cervical infections,
and a small number are not related to previous pneumonia or intervention,
this is known as primary empyema. Also, comorbidities of the patients need
to be taken into consideration. For community-acquired empyema, gram
positive bacteria are more common, especially Streptococcus species. In this

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setting, the presence of gram-negative bacteria has been associated with
increased comorbidities of patients with alcohol abuse, gastroesophageal
reflux disease (GERD), and diabetes. In hospital acquired empyema,
Staphylococcus aureus arecommon.
Pathophysiology
Development of empyema can be described in a sequence of events.
During an inflammatory process such as pneumonia, there is an increase in
fluid production in the pleural cavity known as the exudates stage. As the
disease progresses microorganisms, usually bacteria, can colonize the fluid
and generated an empyema. This fluid is characterized by elevated lactate
dehydrogenase, proteins, neutrophils, and deadcells.
Macroscopically is a thick opaque fluid found in the fibrinopurulent
stage. After the resolution of the infection and as a consequence of the
inflammation, there is a process of fibrosis that can lead to restriction of the
lung parenchyma. Appropriate and early intervention is vital to decrease
complications and mortality.
Clinical Features
The presentation may be similar to pneumonia, and cough, sputum
production, fever, and pleuritic type chest pain may be present. Patients with
empyema may have symptoms for a more extended period. Research has
shown that patients presented after a median of 15 days after the onset of
symptoms. On physical exam there may be dullness to percussion on the
affected area, egophony, increase palpable fremitus, and finecrackles.

Fig 12: Radiological & CT of Empyema

Investigation
To evaluate for the presence of any pleural effusion, the first test that
should be ordered is a chest x-ray. It is a widely available and simple test,

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but it is not 100% sensitive. A certain amount of fluid needs to be present to
be detected, usually 75 ml in a lateral view, and approximately 175 ml in an
anterior view. On an x-ray, some of the characteristics of a pleural effusion
are blunted due to costodiaphragmatic angles and lungs filled with
radiolucent fluid. If an effusion is suspected with the chest x-ray, the next
step is anultrasound.
Ultrasound is increasingly common because of its benefits, namely
because it is widely available, it can be done at a patient's bedside, it is more
sensitive at identifying pleural effusions than an x-ray.
It allows differentiation between parenchyma and pleural fluid, and it
also has a therapeutic use. Ultrasound can be useful in guiding a chest tube
placement during thoracentesis. CT scan of the chest must be done in
patients with empyema. It may be an alternative option after a chest -ray or
ultrasound. CT scan ideally is done with intravenous (IV) contrast to
enhance the pleura. CT scan can also be diagnostic and therapeutic,
thoracentesis and tube thoracotomy can be performed under this modality.
Some of the characteristics on CT scan are thickening of the pleura (present
in approximately 80% to 100% patients), pleural enhancement, split pleural
sign, bubbles in the absence of tube drainage, and septation. With a CT scan
practitioners can better assess the lung parenchyma and the position of a
chesttube.
Management
Treatment of empyema usually involves medical and surgical treatment.
In community-acquired empyema, use antibiotics. Antibiotic should be given
for 2 to 6 weeks, depending on patient response, source control, and
organism. Tube thoracostomy is the most common type of drainage, bore
tube versus smaller tubes have not shown any difference regarding mortality
and prognosis, but bigger tubes are associated with more pain. For this
reason, small tubes are frequently placed. The position of the tube should be
confirming with an x-ray or CT scan. Lack of clinical improvement in the
first 24 hours is usually related to tube malposition or blockage. Blockage of
the chest tube can be prevented with frequent flushing, but the necessary
amount and frequency of this process is unclear. Any indication of a
persistent fluid or other locations should be addressed with more aggressive
therapy including a larger tube, more tubes, or surgery. The chest tube can
usually be removed when the daily production of pleural fluid is proximal
350 ml/day orless.

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 Chapter - 7
Diseases of the Hepatic System

Jaundice
Jaundice/Hyperbilirubinemia define as “the yellow discoloration
appearance of the sclera, skin and mucous membranes resulting from an
increased bilirubin concentration in the body fluids”. It is a multifactorial
disorder with many symptoms. Generally, the physiological jaundice is the
most prevalent type however in some regions pathological jaundice is also
common. This review article focuses on a brief introduction to jaundice, its
types and causes, measuring the bilirubin level, clinical approaches towards
hyperbilirubinemia, different precautionary measures for the parents of
babies suffering from hyperbilirubinemia. Acute jaundice is often an
indicator of significant underlying disease and occurs secondary to intra and
extra hepatic etiologies. A retrospective study of more than 700 individuals
found that most cases (55%) of acute jaundice in adults are caused by intra
hepatic disorders, including viral hepatitis, alcoholic liver disease, and drug
induced liverinjury.
The remaining 45% of acute jaundice cases are extra hepatic and include
gallstone disease, hemolysis, and malignancy. My article provides a
systematic approach to the diagnosis of jaundice in adults and reviews
common etiologies of hyperbilirubinemia. It is detectable clinically when the
plasma bilirubin exceeds 3 mg/dl. Internal tissues and body fluids are
coloured yellow but not the brain.
Unconjugated bilirubin is produced (250-300mg daily) from the
catabolism of haem after removal of its iron component. Unconjugated
bilirubin is conjugated by the endoplasmic reticulum enzyme. Glucuronyl
transfers, in to bilirubin mono and diglucuronide.

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 Fig 1: Pathophysiology of jaundice

Causes
Causes of cholestatic jaundice is Primary biliary cirrhosis, primary
sclerosing cholangitis, alcohol, drugs, viral hepatitis, autoimmune hepatitis,
severe bacterial infections, post-operative, hodgkin’s lymphoma, pregnancy,
idiopathic recurrent cholestasis and extrahepatic is carcinoma of ampullary
pancreatic, bile dut, cystic fibrosis, parasitic infection and traumatic biliary
structures.
Clinical features
In cholestasis early symptoms are dark urine, pale stools, pruritus.
Cholangitis are fever, rigors, pain and hepatic abscess. Late features are
xanthelasma and xanthomata, malabsorption are weight loss, steatorrhoea,
osteomalacia and bleeding tendency.
Investigations
In portal/hepatic venous obstruction can do angiography. Ultrasound in
cases of dilated bile duts and abnormal parenchyma/no dilated ducts. PTC,

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ERCP in case of dilated bile ducts and liver biopsy for abnormal
parenchyma. Focal liver lesions (tumor, cyst, abscess) are fine needle
aspiration/FNA.
Ascites
It is free fluid in the peritoneal cavity.
Causes
Common causes of ascites are malignant disease (hepatic, peritoneal),
cardiac failure, hepatic cirrhosis and other causes are hypoproteinemia-
nephritic syndrome, protein-losing enteropathy, malnutrition.
Hepatic venous occlusion like budd chiari syndrome, veno occlusive
disease, infection-tuberculosis, spontaneous bacterial, peritonitis,
pancreatitis, lymphatic obstruction, rare-meigs syndrome, vasculitis,
hypothyroidism, renal dialysis.
Pathogenesis
Liver failure and portal hypertension in cirrhosis cause sodium and
water retention in the body. Because of this cause localization of fluid
collection in the peritoneum due to the high venous pressure in the
mesenteric circulation. The means where by Na+ and water retention occurs
are unknown.

Fig 2: Pathophysiology of Ascites

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 The mechanisms for renal sodium retention remain poorly understood
but include activation of the rennin angiotensin system with secondary
aldosteronism, increased sympathetic nervous activity, alteration of atrial
natriuretic hormone secretion and altered activity of the kallikreinkinin
system.
Clinical Features
It causes abdominal distension with fullness in the flanks, shifting
dullness on percussion, divarication of the umbilicus, hernia, abdominal
striae, meralgia paresthetica, scrotal oedema. Pleural effusion can be found
in some cases, usually on the right side.
Investigation
Ultrasonography can confirm ascites. Abdominal radiographs can show
ascites, but they are insensitive and non-specific. Ascites protein
concentrations below 25 g/l or serum ascites albumin gradients above 1.5 are
usually found in ascites due to cirrhosis. Cytological examination can reveal
malignant cells and polymorphonuclear leucocyte counts above.
Diagnosis
In the great majority of patients ascites is caused by malignant disease,
cirrhosis or cardiac failure. However the presence of cirrhosis does not
necessarily mean that this is the cause of the ascites. Asciteswith a protein
concentration above 25 g/l raises the possibility of infection (especially
tuberculosis), malignancy, hepatic venous obstruction, pancreatic ascites or
rarely, hypothyroidism.
Management
Restriction of dietary sodium intake is essential to achieving negative
Na balance in patients with ascites. Ascitescan be mange with anti-diuretic
drugs.
Acute Hepatic Failure
Acute failure is rare syndrome in which hepatic encephalopathy,
characterized by mental changes progressing from confusion to stupor and
coma.
Causes
Acute liver failure (ALF) is the culmination of severe liver cell injury
from a variety of causes including viral hepatitis, toxins, metabolic disorders,
and vascular insults. In India, viral hepatitis A and E are the most common
cause for ALF. About 15-22% of ALF occur without any identifiablecause.

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 Wilson's disease accounts for 6-12% of cases of ALF. ALF due to
Wilson disease occurs mainly in young females. It should be suspected when
patient has very high serum bilirubin and low alkaline phosphatase at
presentation. Hemolysis, elevated liver enzymes, low plateletsyndrome, and
acute fatty liver of pregnancy are two overlapping syndromes occurring in
the second half of pregnancy.
Acute Budd Chiari syndrome can rarely present as ALF. Early
recognition and prompt treatment can result in good recovery. Ischemic liver
injury occurs in setting of cardiac arrest or intractable hypotension. Here, the
aminotransferases will be markedly elevated and responds dramatically to
stabilization of circulatory problem.
Acute liver failure occurs in <20% of autoimmune hepatitis. Presence of
autoantibodies and a compatible picture on biopsy helps to make a diagnosis.
Amanita Phalloides mushrooms, heat stroke, and malignant infiltration of the
liver are rare causes of liverinjury.
Pathology
Extensive parenchymal necrosis is the most common histological
appearance. Severe fatty degeneration is characteristic of fulminant hepatic
failure caused by drugs such as tetracycline, pregnancy and Reye’s
syndrome.
Clinical Features: Clinical features are reduced alertness and poor
concentration, progressing through behavioral abnormalities such as
restlessness, aggressive outbursts and mania, to drowsiness and coma.

Fig 3: Systemic manifestation of acute liver failure

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Investigation
Toxicology screen of blood and urine, IgM anti HBs, IgM anti HAV,
anti HEV, cytomegalovirus, herpes simplex, Epstein barr virus,
ceruloplasmin, serum copper, urinary copper, ultrasound of liver, Doppler of
hepatic veins, chest radiograph, Auto antibodies like ANF, AMA, ASMA,
LKM.
Complication
Complication of acute hepatic failure are encephalopathy, cerebral
oedema, respiratory failure, hypotension, hypothermia, infection, bleeding,
pancreatitis, renal failure, metabolic like hypoglycemia, hypokalemia,
hypocalcaemia, hypomagnesaemia, acid base disturbance.
Management
Acute hepatic failure patients should be observed in ICU with clear
observation like.
Neurological-conscious level, pupils-size, equality, reactivity, fundi-
papilloedema, plantar responses.
Cardiorespiratory-pulse, blood pressure, central venous pressure,
respiratory rate.
Fluid balance-input-oral, intravenous and output are hourly urine output,
24 hours sodium output vomiting, diarrhoea.
Blood analyses-peripheral blood count, Creatinine, blood urea, serum
electrolytes, calcium, magnesium, glucose, prothrombin time.
Infection surveillance like cultures-blood, urine, throat, sputum, chest
radiograph and temperature.
Hepatitis
It is inflammation of the liver which results in damage to hepatocytes
with subsequent cell death.
Hepatitis A, B, and C cause acute infection of the liver that may
manifest as an acute icteric illness or be detected incidentally as raised
transaminase levels.
Hepatitis A Virus
Hepatitis A virus (HAV) is transmitted faeco orally. There is evidence
for sexual transmission between homosexual men with several outbreaks
reported. The specific risk factors are not well defined but probably relate to

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Oro anal or digital rectal contact, particularly in settings such as public
saunas and dark rooms. Acute icteric hepatitis appears after an incubation
period of 15-45 days, symptoms last for about 6 weeks, and it is only rarely
fatal. Infectivity lasts from approximately 2 weeks before the onset of
jaundice to 1 week after.
Hepatitis B Virus
Hepatitis B virus (HBV) infection is transmitted vertically (mother to
child), parenterally, and sexually. There is a much lower risk to household
contacts of acute cases and high infectivity carriers of individuals seen in
STD clinics, those at greatest risk of infection are homosexual men and
injecting drug users. Acute hepatitis B has an incubation period of 40-160
days with symptoms lasting up to 12 weeks. Fulminant hepatitis occurs in
about 1% and may be fatal [6]. About 5% of infected adults are
asymptomatic. About 5-10% of immunocompetent patients and up to 40% of
immunocompromised patients develop chronic infection. Symptomatic acute
infection very rarely leads to chronicity. Infectivity lasts from approximately
2 weeks before the onset of jaundice until the loss of infection markers.
Cirrhosis or liver cancer may develop in up to 20% of chronic carriers over
10-50years.
Hepatitis C Virus
Hepatitis C virus (HCV) is transmitted parenterally although there is a
low rate of sexual and vertical transmission, which is more likely to occur
within the setting of HIV/HCV co‐infection. Them ajority (60-70%) develop
chronic infection. As with HBV infection, cirrhosis and liver cancer ensue in
20% or more over the next 10-50 years.

Fig 4: Flow chart of Hepatitis

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Clinical Features
Symptoms of hepatitis are fatigue, flu like symptoms, dark urine, pale
stool, abdominal pain, loss of appetite, yellow skin and eyes, weight loss,
anorexia and difficulty in concentration. Severe hepatitis may be associated
with encephalopathy, increasing jaundice and prolongation of the
prothrombin time.

Fig 5: Ultrasound finding of hepatitis

Cirrhosis of the Liver

Cirrhosis is defined as the histological development of regenerative
nodules surrounded by fibrous bands in response to chronic liver injury that
leads to portal hypertension and end stage liver disease.
Recent advances in the understanding of the natural history and
pathophysiology of cirrhosis, and in treatment of its complications, resulting
in improved management, quality of life and life expectancy of cirrhotic
patients.
Etiology
Cirrhosis of the liver causes are any cause of chronic hepatitis, alcohol,
primary biliary cirrhosis, primary sclerosing cholangitis, secondary biliary
cirrhosis (stone, strictures), haemochromatosis, wilson’s disease, alpha 1
antitrypsin deficiency.
Pathophysiology
Fibrosis describes encapsulation or replacement of injured tissue by a
collagenous scar. Liver fibrosis results from the perpetuation of the normal
wound healing response resulting in an abnormal continuation of
fibrogenesis (connective tissue production and deposition). Fibrosis

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progresses at variable rates depending on the cause of liver disease,
environmental and host factors. Cirrhosis is an advanced stage of liver
fibrosis that is accompanied by distortion of the hepaticvasculature.
It leads to shunting of the portal and arterial blood supply directly into
the hepatic outflow (central veins), compromising exchange between hepatic
sinusoids and the adjacent liver parenchyma, i.e., hepatocytes. The hepatic
sinusoids are lined by fenestrated endothelia which rest on a sheet of
permeable connective tissue (the space of Disse) which contains hepatic
stellate cells (HSC) and some mononuclear cells. The other side of the space
of Disse is lined by hepatocytes which execute most of the known liver
functions. In cirrhosis the space of Disse is filled with scar tissue and
endothelial fenestrations are lost, a process termed sinusoidal capillarization.
Histologically, cirrhosis is characterized by vascularized fibrotic septa that
link portal tracts with each other and with central veins, leading to
hepatocyte islands that are surrounded by fibrotic septa and which are devoid
of a central vein. The major clinical consequences of cirrhosis are impaired
hepatocyte (liver) function, an increased intrahepatic resistance (portal
hypertension) and the development of hepatocellular carcinoma (HCC). The
general circulatory abnormalities in cirrhosis (splanchnic vasodilation,
vasoconstriction and hypoperfusion of kidneys, water and salt retention,
increased cardiac output) are intimately linked to the hepatic vascular
alterations and the resulting portal hypertension.
Cirrhosis and its associated vascular distortion are traditionally
considered to be irreversible but recent data suggest that cirrhosis regression
or even reversal is possible.
Clinical Features
Cirrhosis of the liver symptoms are weakness, fatigue, muscle cramps,
weight loss, anorexia, nausea, vomiting, upper abdominal discomfort,
gaseous abdominal distension, hepatomegaly, jaundice, ascites, spider
telangiectasia, palmar erythema, cyanosis, loss of llibido, hair loss, bruises,
purpura, epistaxis, menorrhagia, splenomegaly, collateral vessels, variceal
bleeding, fetor hepaticus, pigmentation, digital clubbing, low grade fever. In
endocrine changes in men are gynaecomastia, testicular atrophy, impotence
and for females are breast atrophy, irregular menses, amenorrhea.
Investigation
Ultrasonography, computerized tomography (CT) and magnetic
resonance imaging (MRI) are not sensitive to detect cirrhosis, and final
diagnosis still relies onhistology.

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 However, their specificity is high when an obvious cause is present and
imaging reveals an inhomogeneous hepatic texture or surface, rarefied
hepatic central vein, an enlarged caudate lobe, splenomegaly or collateral
veins. Ultrasonography and Doppler ultrasonography of portal and central
vein diameters and velocities are useful screening tests for portal
hypertension and vessel patency. Contrast ultrasonography examines the
appearance of echogenic microbubbles in the hepatic vein. Elasticity
measurement (Fibroscan) is a promising technique based on the velocity of
an elastic wave via an intercostally placed transmitter. Liver biopsy is
considered the gold standard for diagnosis of cirrhosis, and sequential
histological grading of inflammation and staging of fibrosis can assess risk
of progression. A liver biopsy is obtained by either a (radiographically
guided) percutaneous, a transjugular or laparoscopic route. A greater risk of
bleeding following a biopsy has been observed with larger diameter needles.
Complications
Cirrhosis of liver complications is variceal bleeding, ascites and renal
failure.

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 Chapter - 8
Diseases of the Connective Tissues

Lumbar Spondylosis
It is defined as a “degenerative changes in the discs and lumbar spine
are almost universal in the elderly” (or) is a chronic, noninflammatory
disease caused by degeneration of lumbar disc and/or facet joints. Its affects
approximately 60-85% of adults during some point in their lives.
Fortunately, for the large majority of individuals, symptoms are mild and
transient, with 90% subsiding within 6 weeks. Pain, defined as pain
symptoms persisting beyond 3 months, affects an estimated 15-45% of the
population. Degenerative spine changes are remarkably common in
population studies. Symmons’ et al. Study of individuals aged 45-64 years
identified 85.5% of participants to demonstrate osteophytes within the
lumbar spine. O’Neill et al. explored osteophytosis within a UK adult
population over age 50 years, finding 84% of men and 74% of women to
demonstrate at least one vertebral osteophyte, with increased incidence
among individuals with more physical activity, self-reported back pain, or
higher BMI scores. Despite marked variability within the population, men
appear to have more significant degenerative changes than women, both with
regard to number and severity of osteophyteformation.
Causes
Age: An extensive autopsy study in 1926 reported evidence of
spondylitis deformans to increase in a linear fashion from 0% to 72%
between the ages of 39 and 70 years.
Hereditary
Genetic factors likely influence the formation of osteophytes and disk
degeneration. Spector and MacGregor proposed that 50% of thevariability
found in osteoarthritis can be attributed to heritable factors. Similarly, twin
studies evaluating the progression of degenerative changes in lumbar MRI
imaging suggest that approximately half (47-66%) of the variance could be
explained by genetic and environmental factors, attributing only 2-10% of
variance to physical loading and resistance training.

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 Occupation: Disk generation has long been associated with certain
activities.

Fig 1: Lumbar Spondylosis

Pathogenesis
The high incidence of simultaneous degenerative changes to the
intervertebral disk, vertebral body, and associated joints suggests a
progressive and dynamic mechanism, with interdependent changes occurring
secondary to disk space narrowing.
Phase I (Dysfunction Phase): It describes the initial effects of
repetitive microtrauma with the development of circumferential painful tears
of the outer, innervated anulus, and associated end-plate separation that may
compromise disk nutritional supply and waste removal. Such tears may
coalesce to become radial tears, more prone to protrusion, and impact the
disk’s capacity to maintain water, resulting in desiccation and reduced disk
height. Fissures may become ingrown by vascular tissue and nerve endings,
increasing innervation and the disk’s capacity for pain signal transmission.
Phase II (Instability Phase): It is characterized by the loss of
mechanical integrity, with progressive disk changes of resorption, internal
disruption, and additional annular tears, combined with further facet
degeneration that may induce subluxation and instability.
Phase III (Stabilization Phase): It continued disk space narrowing and
fibrosis occurs along with the formation of osteophytes and transdiscal
bridging.
Schneck presents a further mechanical progression, building upon this
degenerative cascade of the intervertebral disk, to explain other degenerative
changes of the axial spine. He proposes several implications of disk space

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narrowing. Adjacent pedicles approximate with a narrowing of the superior
inferior dimension of the intervertebral canal. Laxity due to modest
redundancy of the longitudinal ligaments enables bulging of the ligamentum
flavum and potential for spine instability. Increased spine movement permits
subluxation of the superior articular process (SAP), causing a narrowed
anteroposterior dimension of the intervertebral and upper nerve root canals.
Laxity may also translate into altered weight mechanisms and pressure
relationships on vertebral bone and joint spaces believed to influence
osteophyte formation and facet hypertrophy to both inferior and superior
articular processes with risks for projection into the intervertebral canal and
central canal, respectively. Oblique orientations of the articular processes
may further cause retrospondylolisthesis, with resulting anterior
encroachment of the spinal canal, nerve root canal, and intervertebral canal.
Clinical Features
Postural low back pain is often provoked by prolonged sitting, standing,
bending or lifting. Acute episodes with symptoms and signs of nerve root
compression are similar to those following acute disc prolapsed.
Investigations
Imaging tests can provide detailed information to guide diagnosis and
treatment.
 Neck X-Ray: An X-ray can show abnormalities, such as bone
spurs, that indicate cervical spondylosis. Neck X-ray can also rule
out rare and more serious causes for neck pain and stiffness, such as
tumors, infections or fractures.
 CT scan: A CT scan can provide more detailed imaging,
particularly of bones.
 MRI: MRI can help pinpoint areas where nerves might bepinched.
 Myelography: A tracer dye is injected into the spinal canal to
provide more detailed X-ray or CTimaging.
 Electromyography: This test measures the electrical activity in
your nerves as they transmit messages to your muscles when the
muscles are contracting and atrest.
 Nerve Conduction Study: Electrodes are attached to your skin
above the nerve to be studied. A small shock is passed through the
nerve to measure the strength and speed of nervesignals [3].

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Osteoarthritis
Osteoarthritis also called as degenerative joint disease. It involved more
than one disease. Osteoarthritis is the clinical and pathological outcome of a
range of disorders that results in structural and functional failure of synovial
joints. Traditionally, it has been considered a disease of articular cartilage.
The current concept holds that osteoarthritis involves the entire joint organ,
including the subchondral bone, menisci, ligaments, periarticular muscle,
capsule, and synovium. Osteoarthritis is the most prevalent form of arthritis,
with an associated risk of mobility disability (defined as needing help
walking or climbing stairs) for those with affected knees being greater than
that due to any other medical condition in peopleaged.

Fig 2: Normal knee and Osteoarthritis knee

Osteoarthritis is classified into Two Groups

Primary osteoarthritis can be localised or generalised, the latter more
commonly found in postmenopausal women, with development of
Heberden’s nodes. Secondary osteoarthritis has an underlying cause, such as
trauma, obesity, Paget’s disease, or inflammatory arthritis.
Causes: osteoarthritis etiology is unknown and degenerative joint
changes occur in response to a recognizable local or systemic factor. In
developmental causes are perthes diseases, slipped capital femoral epiphysis,
epiphysiolysis, hip dysplasia, epiphyseal dysplasias, intra articular acetabular
labrum. Traumatic causes are intra articular fracture, meniscectomy,
occupational e.g. elbows of pneumatic drill operators, hypermobility e.g.
Ehlers danlos syndrome, long leg arthropathy. Metabolic causes are
alkaptonuria (ochronosis), haemochromatosis, Wilson’s disease,

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chondrocalcinosis. Inflammatory causes are rheumatoid arthritis, gout, septic
arthritis, haemophilia. Aseptic necrosis are corticosteroids, sickle cell
disease, decompression sickness, SLE and other collagenesis. In neuropathic
causes are tabes dorsalis, syringomyelia, diabetes mellitus, peripheral nerve
lesions. In endocrine is acromegaly and Paget’s disease, gaucher’sdisease.
Pathogenesis
Cartilage is made of water (70%) and a type II collagen framework with
proteoglycans and glycosaminoglycans (consisting mainly of aggrecan and
also chondroitin), produced by chondrocytes. Proteoglycans in turn bind to
hyaluronate which stabilize the macromolecule. Chondrocytes receive
nutrition from the synovium by diffusion and the synovial fluid is circulated
by joint movement. It has been postulated that if the joint stops moving (as a
result of a fracture or immobility) and chondrocytes lose their source of
nutrition, they go into shock and cartilage repair ceases. Metalloproteinases
are produced, which catalyse collagen and proteoglycan degradation. The
synovium has been shown to be variably inflamed in osteoarthritis producing
increased levels of inter leuk in-1(IL-1) and tumour necrosis factor-alpha
(TNF-α), cytokines that induce nitric oxide and metalloproteinase
production. Interleukin-6 (IL-6) and mechanical loading of the joint also
induce catabolic cytokine receptors. These bind IL-1 and TNF-α within
cartilage causing more destruction. It is thought that the osteophytes and
subchondral sclerosis seen in osteoarthritis may be the body’s way of trying
to compensate for lack of cartilage, although some researchers have found
bony changes before cartilage changes in animal models. This sort of
abnormal bone is also thought to lead to further degradation of the cartilage
surrounding it. Poor synthesis of cartilage building blocks may be caused by
dysfunctional forms of insulin like growth factor-1 and transforming growth
factor beta, agents which normally promote new cartilageformation.

Fig 3: X-ray normal knee and osteoarthritis knee

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Clinical Features
Osteoarthritis most frequently involved are those of the spine, hips,
knees and hands. Common patterns of joint involvement include the nodal
and non-nodal types of primary generalized osteoarthritis with prominent
involvement of the knee and hands (distal interphalangeal joints, proximal
interphalangeal joints, carpometacarpal joints of thumbs), as well as
osteoarthritis confined to the knee or hips. All symptoms are gradual in
onset. Pain is at first intermittent and is provoked by the use of the joint and
relieved by rest. As the disease progresses, movement in the affected joint
becomes increasingly limited, initially as a result of pain and muscular
spasm, but later because of capsular fibrosis, osteophyte formation and
remodeling of bone.
Muscle wasting is an important factor in the progress of the disease, as
in the absence of normal muscular control the joint becomes more prone to
injury. Nodal osteoarthritis occur predominantly in middle aged women. It
affects the terminal interphalangeal joints of the fingers, with the
development of gelatinous cysts or bony out growths on the dorsal aspect of
these joints (Heberden’s nodes, see fig.4). The onset is sometimes acute,
with considerable pain, swelling and inflammation.

Fig 4: Nodal osteoarthritis

Heberden’s nodes seldom cause serious disability. Similar lesions may
affect the proximal interphalangeal joints (Bouchard’s Nodes) (figure 4), and
the disorder also frequently involves the carpometacarpal joints of the
thumbs, the spinal apophyseal joints, the hips and the knees.

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Investigation
The blood count and ESR are characteristically normal. Several
radiograph scoring systems have been employed to assist the measurement
of osteoarthritis progression. Other techniques include chondrometry, where
minimal inter bone distance is measured using a special compass magnifying
glass calibrated to 0.1 mm. Synovial fluid is viscous and has a low cellcount.
Plain Radiographs: The following changes may be seen on plain
radiographs: Joint space narrowing, Osteophytes, bony cysts and sub
chondral sclerosis.
M.R.I
This is already well established for use in assessing ligament and
meniscal tears in the knee. It has no place in routine clinical assessment of
osteoarthritis, but may be a specific and sensitive way of quantifying
cartilage loss. Currently, magnetic resonance imaging has not proved to be
sensitive enough in the detection of preclinical osteoarthritis. Changes in
surface morphology and full thickness cartilage defects can be seen, but
fibrillation cannot yet be evaluated.
Management
Weight loss-Encourage overweight patients with osteoarthritis of the hip
and knee to lose weight through a combination of diet and exercise.
Physical therapy consists of several strategies to facilitate resolution of
symptoms and improve functional deficits, including range of motion
exercise, muscle strengthening, muscle stretching, and soft tissue
mobilisation.
Knee braces and orthotics-For those with instability of the knee and
varus misalignment, valgus bracing and orthotics shift the load away from
the medial compartment and, in doing so, may provide relief of pain and
improvement in function.
GOUT
Gout is a picturesque presentation of uric acid disturbance. It is the most
well understood and described type of arthritis. Gout is a systemic disease
that results from the deposition of monosodium urate crystals (MSU) in
tissues. Increased serum uric acid (SUA) above a specific threshold is a
requirement for the formation of uric acid crystals. Despite the fact that
hyperuricemia is the main pathogenic defect in gout, many people with
hyperuricemia do not develop gout or even form UA crystals. In fact, only

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5% of people with hyperuricemia above 9 mg/dL develop gout. Accordingly,
it is thought that other factors such as genetic predisposition share in the
incidence of gout. The general prevalence of gout is 1–4% of the general
population. In western countries, it occurs in 3–6% in men and 1–2% in
women.
In some countries, prevalence may increase up to 10%. Prevalence rises
up to 10% in men and 6% in women more than 80 years old. Annual
incidence of gout is 2.68 per 1000persons.
Factors Predisposing to Hyperuricemia
Renal failure, drugs (diuretics, low does of aspirin), lead poisoning,
hyper parathyroidism, myxoedema, down’s syndrome, lactic acidosis
(alcohol, exercise, starvation, vomiting, toxaemia of pregnancy, type 1
glycogen storage disease), unidentified inherited defect, myeloproliferative
disorder, lymphoproliferative disorder, hypoxanthine, phosphoribosyl
pyrophosphate synthetaseoveractivity, glucose 6 phosphate deficiency,
idiopathic, Deficiency of enzymes involved in purine metabolism leads to
overproduction of UA.

Fig 5: Radiology of the Gout

Pathophysiology
Urate is the ionized form of uric acid present in the body. Uric acid is a
weak acid with pH of 5.8. Urate crystals deposition in tissues starts to occur
when serum uric acid level rises above the normal threshold. Pathological
threshold of hyperuricemia is defined as 6.8 mg/dl. Some factors may affect
the solubility of uric acid in the joint. These include synovial fluid pH, water
concentration, electrolytes level, and other synovial components such as
proteoglycans and collagen.

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 SUA level in the body is determined by the balance between its
production either from purine intake in diet or endogenous production by
cellular turnover and its excretion by the kidneys and GIT. Increased
production of UA is responsible for only 10% of cases of gout while the
remaining 90% are caused by its renal under excretion. Factors affecting
SUA levels include age and gender. SUA is low in children. After puberty,
SUA levels start to increase to reach their normal levels. In men, levels are
higher than in women. However, SUA levels in postmenopausal women
increase to reach men’s levels. This explains why gout is usually a disease of
middle aged and older men, and postmenopausal women. Rarely, it may
happen in children and young adults in some rare inborn errors of purine
metabolism. These enzymatic defects result in increased SUA with
consequent production of UA crystals in kidneys andjoints.
Clinical Features
The ankle, knee, small joints of the feet and hands, writs, elbow follow
in decreasing order of frequency. The onset may be insidious or explosively
sudden, often waking the patient from sleep. The effected joint in hot, red,
swollen with shiny overlying skin and dilated veins, painful and tender.
Investigation
The serum urate level is usually raised but it is important to appreciate
that this does not prove the diagnosis because asymptomatic hyper uricaemia
is very common. Among patients with SUA levels between 7 and 7.9 mg/dL
only 0.09% will develop gout every year. As for patients with SUA between
8 and 8.9 mg/dl, 0.4% out of them may develop gout. With hyperuricemia
above 9 mg/dl, only 0.5% of patients may get gout. The gold standard of
diagnosis is the identification of MSU crystals in synovial fluid aspirate
using polarized light microscopy. In chronic tophaceous gout, the main
radiographic features are:
 Tophi which are articular or periarticular soft tissue densenodules
 MSU deposits in the cartilaginouspart
 Joint space narrowing in advanceddisease
 Bone erosions are characteristic. They are well circumscribed intra-
articular or juxta articular lesions with overhanging margins. They
result from the growth of tophi into the bone, hence are usually seen
neartophi
 Periarticular osteopenia is usually absent and proliferating bone can
be seen mostly as irregularspicules

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 Doppler US can distinguish between active/hot tophi and inactive/cold
ones based on their Doppler signal. Conventional CT is not helpful in the
diagnosis of acute gout as it can’t detect inflammation, synovitis,
tenosynovitis and osteitis. This handicap is however, more than
counterbalanced by its role in chronic gout. It is able to detect erosions better
than Magnetic Resonance Imaging (MRI) or CR. Nuclear Scintigraphy is
rarely used for evaluation. Positive results are often found incidentally when
a study is performed for other indications.
Rheumatoid Arthritis
It is the most common form of chronic inflammatory joint disease.
Rheumatoid arthritis (RA) is an inflammatory rheumatic disease with
progressive course affecting articular and extra-articular structures resulting
in pain, disability and mortality. Persistent inflammation leads to erosive
joint damage and functional impairment in the vast majority of patients. The
course of disease may be also different according to the presence or absence
of several variables including genetic background, frequency of swollen
joints, autoantibody in the serum and the severity of inflammatory process.
The initial presenting features of early RA do not substantially differ from
other inflammatory arthritis. So prior to definite diagnosis patients with early
RA are usually classified as undifferentiated arthritis which difficultly can be
discriminated from other inflammatory arthritis. Up to now, early RA was
denoted to patients with disease duration of less than 2 years preferentially
less than 12 months but currently most rheumatologists are willing to see the
patients with symptom duration of less than 6 weeks. At present, "early"
rheumatoid arthritis is regarded as patients with symptom duration <3
months as early disease.
Rheumatoid arthritis can involve most synovial joints, but rarely the
DIPs or the thoracic, lumbar and sacral spine. The most commonly affected
joints include the MCP and PIP joints of the hands, wrists and MTP joints of
the feet. Joint destruction begins early in the disease with erosive changes
often seen after only six months. The clinical exam can disclose synovial
thickening and swelling, indicators of joint inflammation.
Causes
Some people appear to have genetic factors that make it more likely.
One theory is that bacteria or a virus triggers RA in people who have this
genetic feature. In RA, the immune system's antibodies attack the synovium,
which is the smooth lining of a joint. When this happens, pain and
inflammation result. Inflammation causes the synovium to thicken.

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Eventually, if left untreated, it can invade and destroy cartilage-the
connective tissue that cushions the ends of the bones. The tendons and
ligaments that hold the joint together can also weaken and stretch.
The joint eventually loses its shape and configuration. The damage can
be severe.
Pathophysiology
The earliest changes are swelling and congestion of the synovial
membrane and the underlying connective tissues, which become infiltrated
with lymphocytes (especially CD4 T cells), plasma cells and macrophages.
Effusion of synovial fluid in to the joint space takes place during active
phases of the disease. Hypertrophy of the synovial membrane occurs, with
the formation of lymphoid follicles resembling an immunologically active
lymph node. Inflammatory granulation tissue (pannus) spread over and under
the articular cartilage, which is progressively eroded and destroyed. Latterly,
fibrous or bony ankylosis may occur. Muscles adjacent to inflamed joints
atrophy and there may be focal infiltration with lymphocytes. Subcutaneous
nodules consist of a central area of fibrinoid material surrounded by a
palisade of proliferating mononuclear cells. Similar granulomatous lesions
may occur in the pleura, lung, pericardium and sclera. Lymph nodes are
often hyperplastic, showing many lymphoid follicles with large germinal
centres and numerous plasma cell in the sinuses and medullarycords.
Immunofluorescence show that the plasma cells in the synovium and
lymph nodes synthesis rheumatoid factors.

Fig 6: Pathology of rheumatoid arthritis

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Clinical Features
Early symptoms of rheumatoid arthritis may appear as vague pain with
gradual appearance without classic symptoms of joint swelling or tenderness.
These unusual symptoms are usually non-specific, and may persist for
prolong period. Early articular manifestations of rheumatoid arthritis may be
indistinguishable from other rheumatic diseases. Prolong duration of
morning stiffness with arthralgia, or arthritis in a limited number of joints
may be a clue for considering rheumatoid arthritis diagnosis. Involvement of
small joints of the hands or feet with swelling and tenderness particularly
symmetric pattern of involvement along with positive compression test is
highly suggestive of rheumatoid arthritis.

Fig 7: The hand in rheumatoid arthritis

Presence of some clinical features such as polyarthritis, symmetric
arthritis,hand arthritis, pain upon squeezing the metacarpophalangeal or
metatarsophalangeal joints, and morning stiffness greater than 30 minutes
can be helpful not only in estimating the future course of arthritis but also in
limiting the spectrum of differential diagnosis. Identification of all involved
joints by precise clinical examination is essential. Counting the tender and
swollen joints, and calculation of disease activity score are logical methods
for the determination of disease severity and response to treatment. In
rheumatoid arthritis will be there swan neck deformity of the hands, wasting
of the small muscles of the hands and synovial swelling at the writs, the
extensor tendon sheaths, the metacarpophalangeal and proximal
interphalangeal joints (figure 7).
Extra Articular Manifestation of Rheumatoid Arthritis
Extra articular manifestation of rheumatoid arthritis are fever, weight
loss, fatigue, susceptibility to infection. In musculo skeletal are
musclewasting, tenosynovitis, bursitis, osteoporosis. In haematological are
anaemia, thrombocytosis, eosinophilia. Vasculitis are digital arteritis, ulcers,

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pyoderma gangrenosum, mononeuritis multiplex, visceral arteritis. In cardiac
are pericarditis, myocarditis, endocarditis, conduction defects, coronary
vasculitis, granulomatous aortitis. In pulmonary system are nodules, pleural
effusion, fibrosing alveolitis, bronchiolitis, captain’s syndrome. In
neurological system are cervical cord compression, compression
neuropathies, peripheral neuropathy, mononeuritis multiplex and also
amyloidosis.

Fig 8: Radiological feature of rheumatoid arthritis

Subcutaneous nodules occur in about 20% of patients. They are usually
seen at sites of pressure of friction, such as the extensor surfaces of the
forearms below the elbow, bilateral posterior of the ankle joint (figure 9).

Fig 9: Rheumatoid nodules

Air Way Manifestation

The presence of airway disease in RA is estimated to affect 20-30% of
patients. Manifestations can include cricoarytenoid arthritis, pulmonary
fibrosis and small airway disease, typically seen as bronchiolitis obliterans
on histopathology, with obstructive abnormalities on lung function testing.
Lung disease is more frequent in RA patients who are male, seropositive,
smoke, and have longstanding disease. Some types of RA-associated lung
disease are steroid responsive, but some patients have a progressive course

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leading to end-stage fibrosis and death. In addition to lung disease secondary
to RA, patients are also at risk for pulmonary toxicities from RA-related
medications, including methotrexate, leflunomide and even anti-
TNFmedications.
Cardiac Vascular System Manifestation
Rheumatoid arthritis patients have a 40% increased risk of mortality as
compared to the general population after 20 years of disease. This increased
risk of mortality is primarily attributed to an increased incidence of
cardiovascular disease. The propensity for vascular changes is found even in
newly diagnosed patients, indicating that common mechanisms may exist
linking synovitis resulting in joint destruction with endothelial dysfunction
resulting in atherosclerosis.
Bone Manifestation
The bones of rheumatoid arthritis patients are affected in both a local
and systemic manner. At a local level, factors that stimulate osteoclasts
resulting in increased bone resorption are released from inflammatory and
fibroblastic pannus cells. Additionally, inflammatory cytokines prevent a
compensatory increase in the rate of periarticular bone formation, resulting
in net bone loss. This inhibition of osteoblastic activity is via a combination
of impaired mineralization and impaired osteoblast differentiation. Bony
changes in rheumatoid arthritis patients are not only seen in a periarticular
distribution. Rheumatoid arthritis is a known risk factor for osteoporosis,
with up to 30% of patients affected by some estimates. The risk of
osteoporosis in rheumatoid arthritis patients is greater at the femoral neck
than in the spine, but both areas can be involved.
Investigations
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
provide the best information about the acute phase response. The level of
CRP was shown to be significantly correlated with the severity of disease as
well as radiographic changes. Auto antibodies such as rheumatoid factor and
anti-CCP are very helpful for the diagnosis of rheumatoid arthritis. Anti-
CCP antibody demonstrated a comparable sensitivity but a greater specificity
than rheumatoid factor for the diagnosis of rheumatoid arthritis.
Radiographic signs of rheumatoid arthritis such as joint space
narrowing, erosions and subluxation develop at later stage of rheumatoid
arthritis process. Plain radiography is the standard method in investigating
the extent of anatomic changes in rheumatoid arthritis patients. However,

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there are few data regarding the value of conventional radiographic
examination in recent onset arthritis. Synovitis is the early findings of
rheumatoid arthritis and is strong predictor of bone erosion. Soft tissue
swelling and mild juxtaarticular osteoporosis may be the initial radiographic
features of hand joints in early-rheumatoid arthritis. Sonography is also a
reliable technique that detects more erosions than radiography especially in
early rheumatoid arthritis. In early rheumatoid arthritis, sonography can
detect greater number of erosions and in a greater number of patients than
canradiography.
Complications
Septic arthritis may complicate rheumatoid arthritis, particularly in
patient with long standing nodular seropositive disease.
Sjogren’s Disease
This is an autoimmune disorder, characterized by lymphocytic
infiltration of the salivary and lacrimal gland leading to xerostomia and
kerato conjunctivitis sicca. Primary Sjogren’s syndrome: age of onset in
between 40 to 60, male are more than females, HLA-B8/DR3.
Clinical Features
Common clinical features of primary Sjogren’s syndrome is
keratoconjunctivitis sicca, xerostomia, salivary gland enlargement and rare
clinical manifestations are anaemia, leucopenia, thrombocytopenia,
lymphadenopathy, lymphoreticular, malignancy.
Hepatomegaly, malignancy, hepatomegaly, hyperglobulinemic, purpura,
vasculitis, neuropathy, myositis, fibrosing alveolitis, glomerulonephritis,
renal tubular acidosis.
Secondary sjogren’s disease is age of onset 40 -60 age, male are more
than females. Common clinical features are mild kerato conjunctivitis sicca,
dry mouth, and other associated auto immune disorders are systemic lupus
erythematosus, progressive systemic, sclerosis, primary biliary cirrhosis,
chronic active hepatitis, polymyositis, thyroiditis.
Investigations
The salivary flow rate is reduced and reduction in lacrimal secretion can
be demonstrated by sue of the schirmer teartest.
Reiter’s Disease
It is the triad of non-specific urethritis, conjunctivitis and reactive
arthritis that follows bacterial dysentery or exposure to sexually transmitted

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infection. In 1916, Hans Reiter described the classic triad of arthritis,
nongonococcal urethritis, and conjunctivitis (Reiters syndrome, RS) in a
Prussian soldier with diarrhea, during the First World War.
Clinical Features
Symptoms generally appear within 1-3 weeks but can range from 4-35
days from onset of inciting episode of urethritis/ cervicitis or diarrhea. Signs
and symptoms usually remit within 6 months. However, a significant
percentage of patients have recurrent episodes of arthritis (15-50%), and
some patients develop chronic arthritis (15-30%). Cardiac signs such as
aortic regurgitation caused by inflammation of aortic wall and valve are rare.
Other rare manifestations are central or peripheral nervous system lesions
and pleuro pulmonary infiltrates.

Fig 10: Reiter’s disease

It is triggered by bacterial infection that enters via mucosal surfaces
usually, (but not always) associated with human leukocyte antigen (HLA)-
B27. The syndrome was the first rheumatologic disease noted in association
with Human Immunodeficiency Virus. It is most common in individuals
aged between 15-35 years; and it is rarely seen in children. The male-to-
female post venereal ratio is 5-10:1, while the post-enteric ratio is 1:1. The
incidence is estimated at 3.5 per 100,000, and is uncommon among Negroes.
Investigations
The ESR is often raised during the acute phase and may remain so long
after joint symptoms have settled. The synovial fluid has the characteristics
of a low viscosity inflammatory effusion with leucocyte counts as high as
50000/mm3 but it is sterile onculture.
Osteoporosis
Osteoporosis, defined as low bone mass leading to increased fracture
risk, is a major health problem that affects approximately 10 million world
people.

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 Osteoporosis is characterized by low bone mass, structural deterioration,
and porous bone, which are associated with higher fracture risk. Bone loss
related to declining estrogen levels increases fracture risk in postmenopausal
women, who make up the majority of osteoporosis cases. Screening and
diagnosis use a bone mineral density (BMD) measurement that estimates
bone strength. Osteoporosis is the most common bone disease in humans,
representing a major public health problem. It is more common in
Caucasians, women, and older people. Osteoporosis is a risk factor for
fracture just as hypertension is for stroke. Osteoporosis affects an enormous
number of people, of both sexes and all races, and its prevalence will
increase as the population ages. It is a silent disease until fractures occur,
which causes important secondary health problems and evendeath.
It was estimated that the number of patients worldwide with
osteoporotic hip fractures is more than 200 million. Osteoporosis is also an
important health issue in Turkey, because the number of older people is
increasing. The incidence rate for hip fracture increasesexponentially with
age in all countries as well as in Turkey, which is evident in the fracturk
study.
Bone tissue is continuously lost by resorption and rebuilt by formation;
bone loss occurs if the resorption rate is more than the formation rate. The
bone mass is modeled (grows and takes its final shape) from birth to
adulthood: bone mass reaches its peak (referred to as peak bone mass (PBM)
at puberty; subsequently, the loss of bone mass starts. PBM is largely
determined by genetic factors, health during growth, nutrition, endocrine
status, gender, and physical activity. Bone remodeling, which involves the
removal of older bone to replace with new bone, is used to repair
microfractures and prevent them from becoming microfractures, thereby
assisting in maintaining a healthy skeleton. Menopause and advancing age
cause an imbalance between resorption and formation rates (resorption
becomes higher than absorption), thereby increasing the risk of fracture.
Causes
Osteoporosis causes are genetic (low body weight, family history),
endocrine (hypogonadism, early menopause, thyrotoxicosis,
hyperparathyroidism), gastro intestinal disease (inflammatory bowel disease,
malabsorption, chronic liver disease), inflammatory disease (ankylosing
spondylitis, rheumatoid arthritis), inherited (homocystinuria, gaucher’s
disease, osteogenesis imperfecta), life style (diet/calcium intake, exercise/
immobility, high trained athletes), other are anorexia nervosa, myeloma,
neoplasia, mastocytosis, pregnancy associated, juvenile.

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Classification
Osteoporosis can be classified into two main groups by considering the
factors affecting bone metabolism:
 Primaryosteoporosis
 Secondaryosteoporosis

Fig 11: Osteoporosis and health bone

Primary Osteoporosis
It is also known as postmenopausal osteoporosis, caused by the
deficiency of estrogen, mainly affecting the trabecular bone; therefore,
women are more susceptible to osteoporosis than men, as evident by a
men/women ratio of 4/5.7.
Secondary Osteoporosis
It is also called senile osteoporosis, and it is related to bone mass lost
due to the aging of cortical and trabecular bones.
Pathogenesis
Genetic factors are important in the pathogenesis of osteoporosis and
family studies suggest that genetic influences account for more than 70% of
individual variance in bone mass. The molecular genetic basis by which
bone mass is regulated is incompletely defined, but may involve subtle
variations in the structure or regulation of genes which are involved in
forming bone matrix and regulating bone turnover. Calcium intake is also
important in determining the rate of post-menopausal bone loss. It may also
occur as a complication of endocrine, inflammatory and neoplastic
conditions and drug treatment side effect, substance abuse.

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Clinical Features
Osteoporosis is a silent disease until the patient experiences a fracture. A
recent fracture at any major skeletal site, such as vertebrae (spine), proximal
femur (hip), distal forearm (wrist), or shoulder in an adult older than 50
years with or without trauma, should suggest that the diagnosis of
osteoporosis needs further urgent assessment involving diagnosis and
treatment [21].
Diagnosis
Osteoporosis screening is based on BMD measurement, usually by
DXA, which is then used to predict fracture risk. Hip BMD measurement by
DXA is the best predictor of future hip fracture risk. In 2011, Nayak et al.
demonstrated through modeling analysis that screening for postmenopausal
osteoporosis leads to more quality-adjusted life years compared with no
screening. In addition, DXA scans were cost effective, especially when
treatment was started for women with a T-score of -2.5 or more negative,
with screening repeated every 5years.

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 Chapter - 9
Diseases of the Oncology

Breast Cancer
It is a malignant proliferation of epithelial cells lining the duct or lobules
of the breast. Breast cancer is one of the most common cancers in women
worldwide, accounting for approximately 570,000 deaths in 2015. Over1.5
million women (25% of all women with cancer) are diagnosed with breast
cancer every year throughout the world. Breast cancer is a metastatic cancer
and can commonly transfer to distant organs such as the bone, liver, lung and
brain, which mainly accounts for its incurability. Early diagnosis of the
disease can lead to a good prognosis and a high survival rate. In North
American, the 5-year relative survival rate of breast cancer patients is above
80% due to the timely detection of this disease. There're numerous risk
factors such as sex, aging, estrogen, familyhistory, gene mutations and
unhealthy lifestyle, which can increase the possibility of developing breast
cancer. Most breast cancer occurs in women and the number of cases is 100
times higher in women than that in men.

Fig 1: Breast ductal endoscopy

The following are Risk Factors for Breast Cancer

Age: The chances of breast cancer increase as one gets older.
Family History: The risk of breast cancer is higher among women who
have relatives with the disease.

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 Having a close relative with the disease (sister, mother, daughter)
doubles w woman’s risk.
Personal History: Having a breast cancer diagnosis in one breast
increases the risk of cancer in the other breast or the chance of an additional
cancer in the originalbreast.
Women diagnosed with certain benign (non-cancerous) breast
conditions have an increased risk of breast cancer. These include atypical
hyperplasia, a condition in which there is abnormal proliferation of breast
cells but no cancer has developed.
Menstruation: Women who started their menstrual cycle at a younger
age (before 12) or went through menopause later (after 55) have a slightly
increased risk.
Breast Tissue: Women with dense breast tissue (as documented by
mammogram) have a higher risk of breast cancer.
Exposure to previous chest radiation or use of diethylstilbestrol increase
the risk of breast cancer. Having no children or the first child after age 30
increases the risk of breast cancer. Breast feeding for one and a half to two
years might slightly lower the risk of breast cancer. Being overweight or
obese increases the risk of breast cancer. Both in pre and postmenopausal
women but at different rates. Use of oral contraceptives in the last 10 years
increases the risk of breast cancer slightly. Using combined hormone therapy
after menopause increases the risk of breast cancer. Alcohol consumption
increases the risk of breast cancer and this seems to be proportional to the
amount of alcohol used. A recent meta-analysis reviewing the research on
alcohol use and breast cancer concluded that all levels of alcohol use are
associated with an increased risk for breast cancer. This includes even light
drinking. Exercise seems to lower the risk of breast cancer. Breast tumors
usually start from the ductal hyperproliferation, and then develop into benign
tumors oreven metastatic carcinomas after constantly stimulation by various
carcinogenic factors.Tumor microenvironments such as the stromal
influences or macrophages play vital roles in breast cancer initiation and
progression. The mammary gland of rats could be induced to neoplasms
when only the stroma was exposed to carcinogens, not the extracellular
matrix or the epithelium. Macrophages can generate a mutagenic
inflammatory microenvironment, which can promote angiogenesis and
enable cancer cells to escape immunerejection.
Different DNA methylation patterns have been observed between the
normal and tumor-associated microenvironments, indicating that epigenetic

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modifications in the tumor microenvironment can promote the
carcinogenesis.
Recently, a new subclass of malignant cells within tumors called the
cancer stem cells (CSCs) are observed and associated with tumor initiation,
escape and recurrence. This small population of cells, which may develop
from stem cells or progenitor cells in normal tissues, have self-renewal
abilities and are resistant to conventional therapies such as chemotherapy
and radiotherapy. Signaling pathways including Wnt, Notch, Hedgehog, p53,
PI3K and HIF are involved in the self-renewal, proliferation and invasion of
bCSCs.
Clinical Features
 A lump in the breast orarmpit
 Bloody nippledischarge.
 Inverted nipple
 Orange peel texture or dimpling of the breast skin (PeauD’orange)
 Breast pain or sorenipple
 Swollen lymph nodes in the neck orarmpit
 A change in the size or shape of the breast ornipple

Fig 2: Breast cancer ductal ductography& mammography

Screening
Brest cancer is virtually unique among the epithelial tumors in adults in
that screening (in the form of annual mammography) improves survival.
Meta-analysis examining out comes from every randomized trial of
mammography conclusively shows a more than 25% reduction in the chance
of dying from breast cancer with annual screening after age 50 years.

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 The data for women between ages 40 to 50 are almost as positive.
Ductography should be performed precisely, and interpreted meticulously, so
as not to miss important signs of breast cancer, and to avoid delayed
diagnosis. Previous articles have extensively reviewed ductography
techniques, and reported on the nonspecific findings of benign and malignant
diseases which can be responsible for nipple discharge. Complete ductal
obstruction is not pathognomonic of breast cancer, and can be observed in
both benign and malignant tumors. This finding was noted in 5-47% of
benign diseases, and in 67-83% of cancers, by ductographyIn approximately
70% of obstructing papillomas, contrast material was observed to partially
outline the leading edge of a lesion, resulting in a meniscus-like appearance.
By way of contrast, the shape of the cut-off site in the carcinoma on
ductography often assumes an irregular, moth eaten appearance (Figure 2).
Multiple irregular filling defects in non-dilated peripheral ducts are highly
suggestive of malignancy. Shen et al. reported on their results with
ductoscopy in 415 patients with nipple discharge. They found an intraductal
lesion in 166 patients (40%). They found the majority of benign lesions to be
present in the main segmental ducts and the first branch while DCIS lesions
were situated more peripherally in the first and second branches. The
average distance for a DCIS lesion was 3.3 cm, and the most distant lesion
was situated 5cm from the nipple. In contrast benign papillomas were
situated at an average distance of 2.7 cm and the nearest at 0.5 cm. DCIS
lesions were associated with bleeding, circumferential ductal obstruction,
and gross fungating projections. The positive predictive value with
ductoscopy in detecting DCIS was 80% which increased to 100% when
combined with ductal lavage cytology. Dooley evaluated the role of
ductoscopy in patients undergoing definite surgery for atypical ductal
hyperplasia (ADH), ductal carcinoma in situ (DCIS), and breast cancer to
assess intra ductal extent of disease and in achieving disease free
surgicalmargins.
Management
Breast conserving treatments, consisting of the removal of the primary
tumor by some form of lumpectomy with or without irradiating the breast,
result in a survival that is as good as for slightly superior to that after
extensive surgical procedures, such as mastectomy or modified radical
mastectomy with or without further irradiation. The use of systemic therapy
after local management of breast cancer substantially improves survival.
More than one third of the women who would otherwise die of
metastatic breast cancer remain disease free when treated with the

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appropriate systemic regimen. One approach so called neo adjuvant
chemotherapy-involves the administration of adjuvant therapy before
definitive surgery and radiation therapy. Because the objective response rates
of patients with breast cancer to systemic therapy in this setting exceed 75%
many patients will be down staged and may become candidates for beast
conservingtherapy.
Lung Cancer
The term lung cancer is used for tumors arising from the respiratory
epithelium (bronchi, bronchioles and alveoli). Mesotheliomas, lymphomas
and stromal tumors are distinct from epithelial lung cancer. Lung cancer is
the third most frequently diagnosed cancer in Germany in both men and
women. The annual incidence in Germany is 65 per 100 000 for men and 21
per 100 000 for women. The peak incidence is between the ages of 75 and 80
years. At the same time, both in Germany and worldwide, lung cancer is the
most frequent cause of death from cancer among men, and in Germany it is
the third most frequent cause of death from cancer among women. In men
the figures are steady or slightly reducing, but in women the rate is going up.
Both incidence and mortality rates reflect cigarette consumption in a given
population about 20 years ago. Lung cancer is by far the most common
malignant tumor originating in the lung. The four major histological types of
lung cancer are:
 Squamous cell carcinoma (30% to 40% of lungcancers)
 Adenocarcinoma (25% to30%)
 Non-small cell lung carcinoma (less than 10%)
 Small cell lung carcinoma (15% to20%)
These four types are subdivided into numerous subtypes. A notable
subtype is broncho alveolar carcinoma (synonym: alveolar cell carcinoma), a
rare subtype of adenocarcinoma, that lines the alveoli as it grows. Lung
cancers can be classified according to a variety of criteria. Histological a
distinction is made between small cell lung carcinoma (15% to 20%) and
non-small cell lung carcinoma, because of differences in their biological
behavior and the implications of these differences for treatment
andprognosis.

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 Fig 3: CT scan of Breast cancer of lung & PET

Clinical Features
Cough (8% to 75%), hemoptysis (6% to 35%), pain, wheezing (0% to
2%), poststenotic pneumonia, dyspnea (3% to 60%), stridor (0% to 2%),
Chest pain (20% to 49%), hoarseness, upper airway inflow obstruction,
Horner’s triad, pleural effusion, pericardial effusion, dysphagia, raised
diaphragm, Weight loss (0% to 68%), night sweats, fatigue, fever (0% to
20%), Bone pain (6% to 25%), headache, neurological or psychiatric
abnormalities, paraplegia, hepatomegaly, pathological fractures, Cushing
syndrome, syndrome of inappropriate ADH secretion, Lambert Eaton
syndrome, Pierre-Marie-Bamberger syndrome, etc.
Diagnosis
PET/PET-CT imaging is of central importance in tumor staging. Ruling
out distant metastases by a negative finding saves further diagnostic
procedures, while the detection of structures suggestive of metastasis can
guide the next step and move the diagnostic process rapidly forward. In
patients in clinical stages IB to IIIB, in whom curative therapy should be
attempted, PET/PET-CT scanning (if available) should be carried out for
mediastinal N-staging and for M-staging; in stage IA this examination
should be considered. In addition to history, clinical exam, and routine
laboratory tests, the diagnostic workup of small cell lung cancer should
include CT of the chest and abdomen (at least liver and adrenals), bone
scintigraphy, and contrast-enhanced cranial CT or cranial MRI. PET is not
recommended for regular staging.
Management
Local therapy modalities are surgery and radiotherapy. For systemic
therapy, conventional chemotherapy and increasingly also targeted therapies
(i.e. interventions that affect tumor-specific structures at the molecular level)

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are employed. Chemotherapy is polychemotherapy-so long as the patient’s
condition permits. Treatment for lung cancer is often multimodal.
Radiotherapy and chemotherapy can be administered simultaneously as
radiochemotherapy. Chemotherapy, radiotherapy, and radiochemotherapy
may precede surgery (neoadjuvant therapy) or may follow it (adjuvant
therapy). If a lung tumor with mixed histology contains a combination of
small cell lung cancer and non-small cell lung cancer, it should be treated as
small cell lung cancer.
Gastrointestinal Tract Cancer
About 85% of stomach cancers are adenocarcinomas with 15% due to
lymphomas and gastrointestinal stromal tumors (GIST) and
leiomyosarcomas. Gastric adeno carcinomas may be sub divided in to two
categories; a diffuse type in which cell cohesion is absent, so that individual
cells infiltrate and thicken the stomach, wall without forming a discrete mass
and an intestinal type is characterized by cohesive neoplastic cells that form
gland like tubular structures. Cancer is the leading cause of mortality in both
developed and developing countries.
Annually, it causes around seven million deaths (about 13% of all
causes of death) in the world and is the second most common cause of death
in developed countries and among the top three causes of adult death in
developing countries. Malignancies of the upper gastrointestinal (UGI) tract
form a heterogeneous group of cancers characterized by uniqueepidemiology
and biology. Also, esophageal cancer (EC) is among the 10 most common
tumors and is the 6th leading cause of malignancy deaths worldwide.
Smoking, alcohol consumption, Helicobacter pylori infection, dietary habits
and obesity may be risk factors of gastric cancer. Most epidemiologic studies
reported a risk of gastric cancer between 1.5 and 3.5 for subjects with
relatives with gastriccancer.
Clinical Features
Gastric cancers, when superficial and surgically curable, usually
produce no symptoms.
As the tumor become more extensive, patients may complain of an
insidious upper abdominal discomfort varying in intensity from a vague, post
prandial fullness to a severe, steady pain, anorexia often with slight nausea is
very common but is not the usual presenting complaint. Weight loss,
vomiting with nausea, dysphasia and early satiety may be the major
symptoms caused by diffuse lesions originating in thecardia.

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 Fig 4: Contrast radiographic of GIT
Gastric carcinomas spread by direct extension through the gastric wall to
the perigastric tissues, occasionally adhering to adjacent organs such as the
pancreas, colon or liver. The disease also spreads via lymphatics or by
seeding of peritoneal surfaces. Metastases to intra-abdominal and supra
clavicular lymph nodes occur frequently as do metastatic nodules to the
ovary (krukenbergs tumor), Perio umbilical region or peritoneal Cul de sac
(blumers shelf palpable on rectal or vaginal examination). Malignant ascites
may also develop. The liver is the most common site for hematogenous
spread of tumor.
The presence of iron deficiency anaemia in men and of occult blood in
the stool in both sexes mandates a search for an occult gastro intestinal tract
lesion.
Diagnosis
Double contrast radiographic examination is the simplest diagnostic
procedure for the evaluation of a patient with epigastric complaints. Gastric
ulcer that appear benign by radiography present special problems. If
complete healing can be visualized by x ray within 6 weeks and if a follow
up contrast radiograph obtained several months later shows a normal
appearance.

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Management
Completes surgical removal of the tumor with resection of adjacent
lymph nodes offers the only chance for cure. A subtotal gastrectomy is
treatment of choice for patient with distal carcinomas, while total or near
total gastrectomies are required for more proximaltumours.
Prostate Cancer
Benign and malignant changes in the prostate increase with age.
Autopsies of men in eighth decade of life show hyperplastic changes in more
than 90% and malignant changes in more than70% of individuals.
Aetiology
The relative risk of developing prostate cancer is higher (RR = 2.48;
95% CI 2.25-2.74) in men who have a first-degree relative with prostate
cancer.
This risk is higher in men under 65 (RR = 2.87; 95% CI 2.21-3.74)
compared to older men, and if the affected relative was a brother rather
Thana father (RR = 3.14; 95% CI 2.37-4.15). Family history is clearly
important, but only 35% of the familial risk is currently explained by known
genes. Although rare (about 1 per 300), a BRCA2 mutation confers up to an
8.6-fold increased risk in men below 65 years of age, and such mutations
have also been related with aggressive cancer. Some studies, but not all,
havesuggested that the risk for prostate cancer is increased in men with a
history of urinary tract infections. Infectionsmight influence the risk for
prostate cancer by causing chronic intra-prostatic inflammation, and
pathological studies have also suggested that inflammation may be involved
in the development of prostate cancer. Smoking is associated with a
moderate increase in the risk of prostate cancer. This association is much
stronger and the increase more pronounced for aggressive or fatal cancers,
particularly in current or heavy smokers who appear to be at a 2-fold or
higher risk. For sex hormones, a pooled analysis of individual participant
data from 18 studies found no significant associations but more data are
needed to explore the relationship where both, decreased overall risk and an
increased risk of high- grade cancer have been reported. Or insulin-like
growth factors (IGFs), a pooled analysis of individual participant data from
12 studies showed a significant positive association between circulating IGF-
I and prostate cancer risk more data are required on IGF-II and IGF
bindingproteins.

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 Fig 5: MRI of the Prostate cancer
Clinical Features
Most prostate cancer diagnoses are made in symptomatic men. Prostate
cancer should be suspected in men over 50 years old presenting with lower
urinary tract symptoms (LUTS), visible haematuria or erectile dysfunction.
LUTS are also a common presenting symptom of benign conditions affecting
the prostate, such as benign prostatic hyperplasia (BPH) and prostatitis,
creating a diagnostic challenge. The widespread use of PSA as a screening
test for prostate cancer in some countries has led to increasing diagnoses
being made in asymptomatic men. Men may present to their doctor
complaining of LUTS or other genitourinary symptoms, and are thus
investigated for prostate cancer. It also is suspected that there are a
significant number of men who go through life and die with undiagnosed
prostate cancer; this suspicion is based on the findings of autopsy studies
showing that up to three quarters of men over the age of 85 had neoplastic
changes in the prostate, not all of whom had been diagnosed prior to their
death.
LUTS are very common as men get older, with studies estimating a
prevalence of greater than 50% in men aged 50 years and above, increasing
further with increasing age. Other genitor urinary symptoms may also
suggest that an undiagnosed prostate cancer is present. Visible haematuria is
well established as a high-risk symptom for possible urological cancer,
including prostatecancer.
Diagnosis
Debate continues around the role of PSA in the early detection and
diagnosis of prostate cancer. PSA levels can be raised by a number of benign
conditions, including BPH, prostatitis, ejaculation, and exercise (false
positive). PSA can be within the normal range for up to 25% of men with
prostate cancer (false negative). Urine dipstick testing, with or without

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microscopy, culture and sensitivities (MC&S) should be performed prior to
PSA testing to rule out lower urinary tract infection. The current gold
standard diagnostic test for prostate cancer is a prostate biopsy, usually via a
transrectal (TRUS) or transperineal approach guided by ultrasound. Primary
care clinicians suspecting prostate cancer after assessing a patient or finding
an elevated PSA result should refer on a cancer pathway to their local
urological service for diagnostic testing.
Management
Localized prostate cancers are those that appear to be non-metastatic
after staging studies are performed. Patients with localized disease are
managed by radical surgery, radiation therapy or active surveillance. Choice
of therapy requires the consideration of several factors: the presence of
symptoms, the probability that the untreated tumor will adversely affect the
patient during his life time and thus require treatment and the probability that
the tumor can be cured by single modality therapy directed at the prostate or
requires both local and systemic therapy to achieve cure. As most of the
tumors detected are deemed clinical significant most men undergo treatment.
Radical prostatectomy is to excise the cancer completely with a clear margin
to maintain continence by preserving the external sphincter and to preserve
potency by preserving the autonomic nerve in the neurovascular bundle.
Radiation therapy is given by external beam by radioactive sources implant
in to the gland or by acombination.

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 Chapter - 10
Diabetes Mellitus

Diabetes mellitus refers to a group of common metabolic disorders that share

the phenotype of hyperglycemia. Several distinct types of diabetes mellitus
are caused by a complex interaction of genetics and environmental factors
depending on the etiology of diabetes mellitus.
Factors contributing to the hyperglycemia include reduced insulin
secretion, decreased glucose utilization and increased glucose production.
The metabolic dysregulation associated with diabetes mellitus causes
secondary pathophysiologic changes in multiple organ systems that impose a
tremendous burden on the individual with diabetes and on the health care
system. In the United States, diabetes mellitus is the leading cause of end
stage renal disease, non-traumatic lower extremity amputations and adult
blindness. It also predisposes to cardiovascular diseases. With an increasing
incidence worldwide diabetes mellitus willbe the leading cause of morbidity
and mortality for the seeablefuture.
Classification of Diabetes Mellitus
Diabetes mellitus classified on the basis of the pathogenic process that
leads to hyperglycemia, as opposed to earlier criteria such as onset or type of
therapy. The two broad categories of diabetes mellitus are designated type 1
and type 2. Both types of diabetes are preceded by a phase of abnormal
glucose homeostasis as the pathogenic processes progress. Type 1 diabetes
mellitus is the result of complete or near total insulin deficiency. Type 2
diabetes mellitus is a heterogeneous group of disorders characterized by
variable degrees of insulin resistance, impaired insulin secretion and
increased glucose production.Distinct genetic and metabolic defects in
insulin action and secretion give rise to the common phenotype of
hyperglycemia in type 2 diabetes mellitus and have important potential
therapeutic implications now that pharmacologic agents are available to
target specific metabolic derangements. Type 2 diabetes mellitus is preceded
by a period of abnormal glucose homoeostasis classified as impaired fasting
glucose or impaired glucose tolerance.

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 Two features of the current classification of diabetes mellitus diverge
from previous classifications. First, the terms insulin dependent diabetes
mellitus [IDDM] and non-insulin dependent diabetes mellitus [NIDDM] are
obsolete. Since many individuals with type 2 diabetes mellitus eventually
require insulin treatment for control of glycaemia. The use of the term
NIDDM generally considerable confusion. A second difference is that age is
not a criterion in the classification system. Although type 2 diabetes mellitus
most commonly develops before the 30, an auto immune beta cell
destructive process can develop at any age. It is estimated that between 5 and
10 % individuals who develop diabetes mellitus after age of 30 years have
type 1 diabetes mellitus. Although type 2 diabetes mellitus more typically
develops with increasing age, it is now being diagnosed more frequently in
children and young adults, particularly in obese adolescents.
Other Types of Diabetes Mellitus
Other etiologies for diabetes mellitus include specific genetic defects in
insulin secretion or action, metabolic abnormalities that impair insulin
secretion, mitochondrial abnormalities and a host of conditions that impair
glucose tolerance. Maturity onset diabetes of the young [MODY] is a
subtype of diabetes mellitus characterized by autosomal dominant
inheritance, early onset hyperglycemia [usually < 25 years] and impairment
in insulin secretion. Mutations in the insulin receptor cause a group of rare
disorders characterized by severe insulinresistance.
Diabetes mellitus can result from pancreatic exocrine disease when the
majority of pancreatic islets are destroyed. Cystic fibrosis related diabetes
mellitus is an important consideration in the patient population
.Hormones that antagonize insulin action can also lead to diabetes
mellitus. Thus diabetes mellitus is often a feature of endocrinopathies such
as acromegaly and Cushing’s disease. Viral infections have been implicated
in pancreatic islet destruction but are an extremely rare cause of diabetes
mellitus. A form of cute onset of type 1 diabetes mellitus, termed fulminant
diabetes, has been noted in Japan and may be related to viral infection
ofislets.
Pathophysiology
Type 2 diabetes mellitus is characterized by impaired insulin secretion,
insulin resistance, excessive hepatic glucose production and abnormal fat
metabolism.

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 Obesity, particularly visceral or central [as evidenced by the hip- waist
ratio], is very common in type 2 diabetes mellitus [80% or more are obese].
In the early stages of the disorder, glucose tolerance remains near
normal, despite insulin resistance, because the pancreatic beta cell
compensate by increasing insulin output. As insulin resistance and
compensatory hyperinsulinemia progress, the pancreatic islets in certain
individuals are unable to sustain the hyperinsulinemic state. IGT,
characterized by elevations in postprandial glucose, then develops. A further
decline in insulin secretion and an increase in hepatic glucose production
lead to overt diabetes with fasting hyperglycemia. Ultimately beta cell
failure census.
Clinical Features
Type 2 diabetes mellitus present with polyuria and polydipsia, but
unlike type1 diabetes, patients are often older [over 40 years] and frequently
obese. However, with the increase in obesity and sedentary life style in our
society, type 2 diabetes is now seen in children and adolescent with
increasing frequency. In some medical attention is sought because of
unexplained weakness or weight loss. Most frequently, however, the
diagnosis s made after routine blood or urine testing in asymptomatic
persons. The infrequency of ketoacidosis and milder presentation in type 2
diabetes is presumably because of higher portal vein insulin levels in these
patients than in type 1 diabetics, which prevents unrestricted hepatic fatty
acid oxidation and keeps the formation of ketone bodies in check. In the
decompensated state, these patients may develop hyperosmolar nonketotic
coma due to severe dehydration resulting from sustained osmotic diuresis
[particularly in patients who do not drink enough water to compensate for
urinary losses from chronic hyperglycemia].
Typically, the patient is an elderly diabetic who is disabled by stroke or
an infection and is unable to maintain adequate water intake. Furthermore,
the absence of ketoacidosis and its symptoms [nausea, vomiting, respiratory
difficulties] delays the seeking of medical attention until severe dehydration
and coma occur.
Diagnosis
Urine Testing
Testing the urine for glucose is the usual procedure for detecting
diabetes, using sensitive glucose specific dipstick methods. If possible, the
test for urinary glucose should be performed on urine passed 1-2 hours after

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a meal since this will detect more cases of diabetes than a fasting urine
specimen. Glycosuria always warrants full assessment.
The greatest disadvantage of using urinary glucose as a diagnostic or
screening procedure is the individual variation in renal threshold. Thus some
undoubtedly diabetes individuals will have a negative urine test while other
non-diabetic individuals with a low renal threshold for glucose
concentration, using an accurate laboratory method rather than a side room
technique, is therefore essential in making the diagnosis. Ketone bodies can
be identified by the nitroprusside reaction, which is primarily specific for
acetoacetate and is conveniently carried out using tablets or test papers.
Ketonuria may be found in normal people who have fasting or exercising
strenuously for long periods, who have been vomiting repeatedly, or who
have been eating a diet high in fat and low in carbohydrate. Ketonuria is
therefore not pathognomonic of diabetes but, if associated with glycosuria,
the diagnosis of diabetes is practically certain.
Oral Glucose Tolerance Test (OGTT)
When random blood glucose values are elevated but are not diagnostic
of diabetes, glucose tolerance is usually assessed by the glycemic response to
oral ingestion of a glucose load. The diagnostic criteria for diabetes mellitus
and normality recommended by the World Health Organization (WHO) in
1980 are shown in table 2. The values are based on the threshold for risk of
developing vascular disease. Intermediate readings are classified as
‘impaired glucose tolerance ‘(IGT) and indicate the need for further
evaluation. Many patients and indicate the need for further evaluation. Many
patients with IGT progress to frank diabetes with time, and it may be
necessary, therefore, to keep such patients under review and to repeat the
OGTT at a later date.
Management
Various drugs are effective in reducing hyperglycemia in patients with
type 2 diabetes mellitus. Although their mechanisms of action are different
most depend up on a supply of endogenous insulin and they therefore have
no hypoglycemia effect in patients with type 1 diabetes.
Low calorie and sugar free drinks are useful for patients with diabetes.
As diabetes is a risk factor for macro vascular disease intake of fat should be
restricted to less than 40% if energy with less than 10% as saturated fat.

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 Chapter - 11
Infectious Diseases

Yellow Fever
Yellow fever caused by a flavivirus. It is normally a zoonosis of
monkeys that inhabit tropical rainforests in west and central Africa and south
and Central America. It can be transmitted to humans through the bites of
certain Aedesor Haemagogus species of mosquitoes and has distinct
transmission cycles in the jungle (sylvatic cycle), in the African savannah
(intermediate cycle), and in cities (urban cycle).
Pathology
In the liver acute mid zonal necrosis leads to deposits of hyaline called
councilman bodies and intra nuclear eosinophilic inclusion called torres
bodies, another characteristic features is the absence of inflammatory
infiltrate. The kidneys show tubular degeneration, which may partly be due
to reduced blood flow. Haemorrhage is due to liver damage and
disseminated intravascular coagulation.

Fig 1: Flavivirus life cycle

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Clinical Features
Clinically, many people infected with YFV are asymptomatic. Others
develop symptoms including sudden fever, chills, headache, low back pain,
myalgia, nausea, vomiting, and/orfatigue.
After an incubation period of approximately 3 to 6 days. Most with YFV
disease improve within 3 to 4 days. However, roughly 15% go on to develop
a more severe form of YFV disease with high fever, bleeding diatheses,
abdominal pain, renal failure, cardiovascular instability, and/or liver failure
and jaundice (hence the name “yellow fever”), and 20% to 50% of these
patients may die. Additionally, neurologic complications may occur in those
with YFV disease including headache, photophobia, agitation, seizures,
encephalopathy, or rarely cerebral edema andcoma.
Diagnosis
Virus isolation from blood in first 4 days. Post mortem liver biopsy.
Management
Patients should be nursed under a mosquito net until the viraemic stage
has passed. A single vaccination with the 17 D nonpathogenic strain of virus
given full protection for at least 10years.
Dengue
This disease is the most common Flavivirus infection of humans and is a
risk in May tropical and subtropical countries. The dengue virus, a member
of the genus Flavivirus of the family Flaviviridae, is an arthropoda-borne
virus that includes four different serotypes (DEN-1, DEN-2, DEN-3, and
DEN-4). Two and a half billion people reside in dengue-endemic regions and
roughly 400 million infections occurring per year, with a mortality rate
surpassing 5-20% in some areas. The first reported case of dengue like
illness in India was in Madras in 1780, the first virologically proved
epidemic of DF in India occurred in Calcutta and Eastern Coast of India in
1963-1964. Dengue virus infection presents with a diverse clinical picture
that ranges from asymptomatic illness to DF to the severe illness of dengue
hemorrhagic fever/dengue shock syndrome (DHF/DSS).
Etiopathogenesis
DF is a severe flu-like infection that involves individuals of all age
groups (infants, children, adolescents, and adults). Transmission among
human beings occurs by the mosquito Aedes aegypti and chiefly occurs
during the rainy season.

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 The proposed etiologies for dengue virus infection are:
 Viral replication, primarily inmacrophages
 Direct skin infection by thevirus
 Immunological and chemical-mediated mechanism induced by
host–viralinteraction

Fig 2: Dengue virus

Classification
Grade I: Only mild bruising or a positive tourniquet test.
Grade II: Spontaneous bleeding into the skin and elsewhere.
Grade III: Clinical sign of shock.
Grade IV: Severe shock-feeble pulse, and blood pressure cannot be
recorded.
Here, grades III and IV comprise DSS.
Clinical Features
Prodrome are 2 days malaise and headache. Sudden onset of fever,
backache, arthrlgias, headache, generalized pains (break bone fever), pain on
eye movement, lacrimation, anorexia, nausea, vomiting, relative bradycardia,
prostration, depression, lymphadenopathy, backache, arthrlgias, headache,
generalized pains (break bone fever), pain on eye movement, lacrimation,

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anorexia, nausea, vomiting, relative bradycardia, prostration, depression,
lymphadenopathy, sclera injection. Fever continuous or saddle back with
break on fourth or fifth day, usually lasts 7 to days. Rash are occurred
transient macular in first 1-2 days. Maculopapular, scarlet morbilliform from
days 3-5 on trunk, spreading centrifugally sparing palms and sole. May
desquamate on resolution. DHF (Dengue hemorrhagic fever) is frequently
seen during a secondary dengue infection. However, in infants it may also
occur durring a primary infection due to maternally attained dengue
antibodies. Clinical parameters: Acute-onset febrile phase-high-grade fever
lasting from 2 days to 1 week. Hemorrhagic episodes (at least one of the
following forms): Petechiae, purpura, ecchymosis, epistaxis, gingival and
mucosal bleeding, GIT or injection site, hematemesis and/or malena.
Laboratory parameters: Thrombocytopenia (platelet count <100,000/cu mm).
The hemorrhagic episodes in DHF are associated with multifactorial
pathogenesis. Vasculopathy, deficiency and dysfunction of platelets and
defects in the blood coagulation pathways are the attributed factors.
Decreased production of platelets and increased destruction of platelets may
result in thrombocytopenia in DHF. The impaired platelet function causes
the blood vessels to become fragile and this results in hemorrhage. High
plasma escape cases are marked by frank shock with low pulse pressure,
cyanosis, hepatomegaly, pleural and pericardial effusions, and ascites.
Severe ecchymosis and gastrointestinal bleeding followed by epistaxis may
also be noted in a few cases. Bradycardia, confluent petechial rashes,
erythema, and pallor are seen during this phase.
Investigations
Cautious attention should be directed at DF if a patient suffers from high
fever within 2 weeks of being in the tropics or subtropics.
A decreased number of white blood cells (leukopenia), accompanied by
a decreased number of platelet count (thrombocytopenia) and metabolic
acidosis are the initial changes on laboratory examinations. Microbiological
laboratory testing confirms the diagnosis of DF. Virus segregation in cell
cultures, nucleic acid demonstration by polymerase chain reaction (PCR),
and serological detection of viral antigens (such as NS1) or particular
antibodies are the preferred microbiological assays. Viral segregation and
nucleic acid demonstration provide precise diagnosis, although the high cost
limits the availability of thesetests.
Management
There is no specific treatment. Fluid replacement and antipyretic
therapywith paracetamol is the preferred therapy following the febrile phase.

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Care should be taken not to use other non-steroidalanti-inflammatory drugs.
Oral lesions are infrequently seen and are often misguided as platelet defects.
Significant hemorrhagic manifestations need platelet transfusions.
Mumps
Mumps is spread by droplet infection and affects mainly children of
school age and young adults. The infectivity rate is not high and there is
serological evidence that 30-40% of infections are clinically unapparent.
Clinical Features
Malaise, fever, trismus, pain near the angle of the jaw, swelling of one
or both parotid gland. The sub Mandibular salivary glands may also be
involved.
Investigation
Different diagnosis is from salivary calculus, which is unilateral, and
sarcoidosis which cause bilateral chronic parotitis.
Management
Mumps vaccine is given in two dose with measles and rubella vaccines
shortly after the first birthday and prior to school entry for prevention.
Enteric Fever
Typhoid and paratyphoid fever in many countries where sanitation o
primitive.Salmonella entericasubspecies enterica serovar Typhi (Salmonella
Typhi) is the cause of typhoid fever and a human host-restricted organism.
Our understanding of the global burden of typhoid fever has improved in
recent decades, with both an increase in the number and geographic
representation of high-quality typhoid fever incidence studies, and greater
sophistication of modeling approaches.
The 2017 World Health Organization Strategic Advisory Group of
Experts on Immunization recommendation for the introduction of typhoid
conjugate vaccines for infants and children aged >6 months in typhoid-
endemic countries is likely to require further improvements in our
understanding of typhoid burden at the global and nationallevels.
Causes
The enteric fever are caused by infection with salmonella typhi and
salmonella paratyphi A and B. Humans are the reservoir (defined as the
habitat in which the agent normally lives, grows, and multiplies) of
Salmonella Typhi. Salmonella Typhi has limited capacity to multiply outside

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of the human host, but it may survive for extended periods in the
environment.
Pathology
The mode of Salmonella Typhi transmission is considered to be largely
indirect and predominantly vehicle-borne through contaminated water or
food. Water and food usually serve as passive vehicles for Salmonella Typhi.
While Salmonella Typhi may survive for extended periods on vehicles,
multiplication of Salmonella Typhi in water and food is uncommon. Some
group Salmonella Typhi transmission into 2 broad patterns. In short-cycle
transmission, food and water are contaminated by fecal shedding in the
immediate environment, and transmission is mediated through inadequate
hygiene and sanitation measures. In long-cycle transmission there is
contamination of the broader environment, such as pollution of untreated
water supplies by human feces and use of raw human feces or untreated
sewage as a crop fertilizer.

Fig 3: Typhoid fever

Clinical Features
First week symptoms are fever, headache, myalgia, bradycardia,
constipation (diarrhoea and vomiting). End of the first week is rose spots on
trunk, splenomegaly, cough, abdominal distension and diarrhoea. End of the
second week is delirium, complications, then coma and death.
Investigations
Although there is a decline in the incidence of S. Typhi, the true
isolation of S. Typhi from blood cultures is still challenging. Diagnosis of
typhoid fever by conventional blood culture is challenging and time
consuming as it takes about 24-48 h, after which the culture bottle flags
positive. Although it is the gold standard method for detection of S. Typhi in

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the blood, turnaround time plays a significant role in the management.
WIDAL slide agglutination test is the second most commonly prescribed
test. Yet, poor sensitivity and specificity is a limitation. Due to this,
commercial rapid diagnostic tests (RDTs) are of great interest. However,
owing to the poor sensitivity and specificity rates, definite detection is still
limited. Typhidot-M, TUBEX-TM and Test-it are the three serological-based
tests that have been evaluated. Performance of these tests have been shown
to be poor and variable due to the high rates of disease burden in Asia, which
is endemic for typhoid. In contrast, evaluation done in the Philippines has
shown high sensitivity and specificityrates.
Complication
Complication of the enteric fever is perforation and haemorrhage of
bowel, bone and joint infection, meningitis, cholecystitis, myocarditis,
nephritis.
Management
Several antibiotics are effective in enteric fever.
Prevention
Those who propose to travel to or live in countries where enteric
infections are endemic should be inoculated with one of the three available
typhoid vaccines two inactivated inject able and one oral live attenuated).
Malaria
Human malaria is caused by plasmodium falciparum, plasmodium
vivax, plasmodium ovale and plasmodium malariae. Malaria is a parasitic
infection transmitted by mosquitoes that has afflicted humans over the
millennia. Once endemic in the United States and Canada, it is now confined
to more tropical and subtropical climates, particularly Africa. Despite
advances in knowledge, malaria continues to cause significant morbidity and
mortality worldwide. Malaria is one of the most prevalent human infections
worldwide. Over 40% of the world's population live in malaria-endemic
areas.
Exact numbers are unknown, but an estimated 300 to 500 million cases
and 1.5 to 2.7 million deaths occur each year [3]. Ninety percent of deaths
occur in sub-Saharan Africa, the majority involving children less than 5
years of age. Malaria disproportionately affects the poor, in whom higher
morbidity and mortality can be largely attributed to lack of access to
effective treatment; 60% of malaria deaths worldwide occur in the poorest
20% of the population.

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 Fig 4: Malaria
Plasmodia species are the parasites responsible for malaria. Only 4 of
the over 100 species of plasmodia are infectious to humans. The parasite is
transmitted by night biting Anopheles mosquitoes. High parasite burdens
combined with the unique ability of infected erythrocytes to adhere to host
endothelium contribute to microvascular occlusion, metabolic derangement
and acidosis, which lead to the manifestations of severe malaria (acute
respiratory distress syndrome, renal insufficiency and cerebralmalaria).
In addition, a vigorous cytokine response to parasite proteins released
during schizont rupture can contribute to adverse clinical outcomes.
Clinical Features
Fever, headache, a feeling of cold and arthralgias are common
presenting symptoms in children. Anemia, splenomegaly and hepatomegaly
are commonly associated with malaria.
Complications
 Organ damage due to anoxia are brain is confusion,coma
 Kidney: oliguria, uraemia (acute tubular necrosis)
 Lung: Cough pulmonaryoedema
 Intestine: Diarrhoea, congestion, possibly leaky tobacteria

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  Liver: Jaundice, encephalopathy (rare)
 Hypoglycemia, shock secondary to septicaemia, hypotension shock,
metabolic acidosis, splenic rupture
Investigations
Hematologic abnormalities are common: thrombocytopenia (platelet
count < 150 х 109/L) occurs in up to 70% of patients and anemia in 25%.
The leukocyte count is normal or low; leukocytosis is seen in less than 5% of
cases and is a poor prognostic factor. A high degree of suspicion and rapid
diagnosis are essential to optimize outcome. Thick and thin peripheral blood
smears, stained with Giemsa stain (or, alternatively, Wright's or Field's
stains), remain the “gold standard” for routine clinical diagnosis. Rapid
antigen detection tests (RDT) RDTs currently available can identify only P.
falciparum and P. vivax, however. Malaria rapid test, manufactured by
Makro Medical (Pty) Ltd., is the only test currently licensed for use in
Canada. Important shortcomings of RDTs include their inability to quantitate
parasitemia and suboptimal test performance with low-level parasitemia.
Further more, because antigenemia may persist for prolonged periods even
after treatment.
Management
The treatment of malaria depends on the infecting plasmodia species,
the geographic area of acquisition (which affects the likelihood of drug
resistance) and the severity of infection. Falciparum malaria in the
nonimmune person is a medical emergency and requires rapid initiation of
antimalarial therapy. If the species cannot be immediately identified, the
patient should be assumed to have drug-resistant falciparum malaria until
proven otherwise. Hospital admission is advised for those with falciparum
malaria or in whom the infecting species cannot be identified, and for those
who are severely ill.

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 Chapter - 12
Diseases of the Blood

Anemia
Diminished oxygen carrying capacity of the blood.
Causes: Decreased or ineffective marrow production like lack of iron,
B12 or folate, hypoplasia, invasion by malignant cells and peripheral causes
are blood loss, haemolysis, hypersplenism.
Clinical Features
Symptoms of anaemia are lassitude, breathlessness on exertion, fatigue,
palpitations, throbbing in head and ears, dizziness, tinnitus, headache,
diminish of vision, insomnia, paraesthesia in fingers and toes, angina. Signs
are pallor of skin, mucous membranes, palms of hands, conjunctive,
tachycardia, cardiac dilation, systolic flow murmurs, oedema.
Diagnosis
Complete blood picture (Hb%) can be find out anaemia.
Iron Deficiency Anaemia
Iron deficiency usually results from loss of iron because of bleeding and
inadequate diet or malabsorption. Occasionally, iron may be lost in the urine
in the form of hemosiderin.
Causes: Iron deficiency is gastrointestinal bleeding-example, from
gastric erosions associated with anti-inflammatory drugs, neoplastic disease
and peptic ulcers. Hook worm and schistosoma is also very common in iron
deficiency anaemia, diet containing inadequate iron can cause or contribute
to iron deficiency anemia.
Clinical Features
Nausea, vomiting, weakness, dyspnoea, numbness, pallor, cardiomegaly
splenomegaly.
Diagnosis
The haematological findings are a reduced haemoglobin with normal or
slightly reduced red cell count and a low mean cell volume of less than 76 fl.

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Raised platelet count may suggested that bleeding is the cause of the
deficiency.
Management
Most patient can be treated orally and ferrous sulphate given as a tablet
containing 200 mg of the salt 8th hourly.
Megaloblastic Anaemia
This condition is caused by deficiency of vitamin B12 and folic acid.
Deficiency of either or both cause a failure of DNA synthesis and disordered
cell proliferation.
Causes
Nutritional deficiency, chronic alcoholism, pernicious anaemia,
carcinoma of stomach malabsorption syndrome, crohn’s disease, congenital
deficiency without gastric atrophy (rare), gastrectomy, pregnancy and
lactation.
Clinical Features
Progressive weakness, occasional angina pain, palpitation, numbness,
tingling in extremities, vomiting, diarrhoea. Signs are pallor, smooth tongue,
optic atrophy, soft systolic murmur at apex, splenomegaly cardiomegaly,
DTR’s diminished.
Diagnosis
Haemoglobin, platelet count and RBC count level is low, peripheral
smear is anisocytosis, poikilocytosis megalocytosis, polychromasia, punctate
basophilia, leucopenia and elevated ESR.
Management
Vitamin B12 therapy (inj. Vitamin AB12 1000 mcg IM one injection on
alternated days for total five injection, then once a week for 5 weeks, than
once in 3 to 6 months will be adequate for most patients.
Pernicious Anaemia
It is due to a failure of secretion of intrinsic factor by the stomach other
than from total gastrectomy. It is an autoimmune disease andin about 50% of
patient’s antibodies to intrinsic factor can be demonstrated. This disease is
rare before the age of 30, occur mostly between 45 to 65 years, and more
females compared to males. Hypovitaminosis B12 is common in adults and
in elderly patients with a prevalence ranging from 15%-40% according to the
various studies and definition used. It is often under diagnosed because of

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subtle or polymorphous clinical manifestations. Its main etiology is
represented by classic pernicious anemia (PA), also known as Biermer’s
disease. PA is an autoimmune atrophic gastritis that causes a deficiency in
vitamin B12 due to its malabsorption. It accounts for 20%-50% of the
documented causes of vitamin B12 (cobalamin) deficiency in adults
according to a recentseries.

Fig 1: Pernicious anemia

Pathology
Increased blood destruction, including unconjugated hyperbilirubinemia
and increased deposition of iron (hemosiderin) in the liver, spleen, kidneys
and bone morrow. The gastric mucosa is thin and atrophic.
Clinical Features
Anemia is the most frequently encountered clinical sign during PA,
together with accompanying functional manifestations, depending on their
severity. It can often include a hemolytic component with subicterus.
Hematological manifestations have also been commonly reported:
neutropenia, thrombocytopenia, pancytopenia, intramedullary hemolytic
component due to ineffective erythropoiesis, and pseudo thrombotic
microangiopathy.
He most frequent signs are the presence of macroovalocytes and
hypersegmented neutrophils on peripheral blood smears.
Diagnosis
Very low serum vitamin B12, often less than 50 ng/l, anti-intrinsic
factor antibodies in serum (present in 50%), macrocytic dysplastic blood
picture, megaloblastic marrow, abnormal vitamin B12 absorption test
corrected by addition of intrinsic factor.

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Management
It should be seriously considered when the haemoglobin level is so low
as to endanger life-for example, under 49 g./. Hydroxocobalamin is given
parenterally in a dosage of 1000 µg. After an initial dose injections are given
every 2 to 3 days for a future five dose. Maintenance therapy consists of
1000 µg parenterally every three months.
Haemolytic Anaemia
Various abnormalities may shorten the normal red cell life span of 120
days. Anaemia develops when marrow output no longer compensates. The
increased output of new erythrocytes is reflected in a raised reticulocyte
count, which given an indication of the severity of the process. Haemolytic
anaemia is the clinical condition in which antibodies of immunoglobulin G
(IgG) and/or immunoglobulin M (IgM) bind to red cell surface antigens and
initiate red cell destruction via the complement system and the reticulo
endothelial system. IHA is classified as either autoimmune, allow immune or
drug induced based on the antigenic stimulus responsible for the
immuneresponse.
Autoimmune Hemolytic Anemia (AIHA) is characterized by the
production of auto antibodies directed against red blood cells (RBC).
Usually these autoantibodies are directed against high incidence antigens.
But, often they exhibit reactivity against allogenic red cells.
First described by Coombs et al. in 1945, the anti-human globulin test
uses antibody to human globulin and in vivo coating of red cells with
antibody or complement.

Fig 2: Haemolytic anaemia

Causes: Congenital are hereditary spherocytosis, hereditary
elliptocytosis and lack of haemoglobin chain synthesis, thalassemias, amino

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acid substitution on the haemoglobin chain haemoglobin S,C,D glucose-6-
phosphate dehydrogenase deficiency, isoimmune (cold antibody, warm
antibody), alloimmune, mechanical artificial cardiac valves, burns,
infections. Warm autoantibodies react more strongly near 37 °C and exhibit
decreased affinity at a lower temperature. Cold auto antibodies on the other
hand, bind to red cells more strongly near 0-4 °C and generally show little
affinity at physiologic temperature. Occasionally patients have a
combination of warm and cold auto antibodies. It was observed by Petz and
Garratty in 1980 and Sokol et al. in 1981 that warm auto antibodies are
responsible for 48-70% of Haemolytic anaemia cases. Lymphoproliferative
disorders such as chronic lymphocytic leukemia, Hodgkin's disease, non-
Hodgkin's lymphoma and Waldenstrom's macroglobulinemia are the leading
causes of secondary cases. Cold-reactive auto antibodies cause two distinct
clinical entities: CAS, (cold hemagglutinin disease) and paroxysmal cold
hemoglobinuria (PCH). CAS represents approximately 16-32% of
Haemolytic anaemiacases.
Clinical Features
Signs and symptoms may include fatigue, dizziness, heart palpitations,
pale skin, headache, fever, confusion, lightheadedness, weakness or inability
to do physical activity, dark urine, yellowing of the skin and the whites of
the eyes (jaundice), heart murmur, increased heart rate and a spleen or liver
that is larger thannormal.
Diagnosis
Bilirubin test measures the level of red blood cell haemoglobin that liver
has broken down and processed. Haemoglobin test indirectly reflects the
amount of red blood cells you have circulating in your blood (by measuring
the oxygen carrying protein within your red blood cells). Liver function test
is measures the levels of proteins, liver enzymes, and bilirubin in your blood.
Reticulocyte count is measures how many immature red blood cells, which
over time mature into red blood cells, that your body is producing. Bone
marrow aspiration or biopsy test can provide information about how many
red blood cells are being made and theirshape.
Management
Transfusion of red cells with a normal enzyme complement may be
required. Thereafter, the patient should be advised to avoid drugs which may
precipitate the disorder. Splenectomy is without value.

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Sickle Cell Anaemia
A hereditary disorder characterized by abnormal haemoglobin in the
RBC which makes them to assume a sickle shape at low oxygen tension.

Fig 3: Sickle cell anaemia

Sickle cell disease (SCD) is the name for a group of genetic blood
disorders caused by sickle hemoglobin (Hb S). The 2 key features of SCD
are chronic hemolytic anemia and vaso occlusion. Although it is
fundamentally a blood disease, SCD affects the entire body, and the
pathophysiology begins in very early infancy. Pediatricians and family
practitioners are crucial partners in the multidisciplinary team that is required
to manage children with SCD. This book provides a broad overview of SCD
in childhood, focusing on common complications and current treatments.
Causes
Inheritance: Autosomal dominant and effect both male, female.
Pathology
Hb is the oxygen-carrying protein in blood. It is a tetramer of 4 proteins,
2 α-globins and 2 β-globins. Each globin has an associated oxygen-binding
heme group. The α-globins and β-globins are encoded by genes on different
chromosomes. The Hb S mutation (βS) is a single nucleotide substitution in
the sixth codon of the β-globin gene (HBB). This yields a protein with a
hydrophobic valine residue, instead of the normal hydrophilic glutamic acid
at the sixth position that is prone to polymerization on deoxygenation. He
polymerization of Hb S within red blood cells (RBCs) (“sickling”) on
deoxygenation underlies all the pathophysiology of SCD. As Hb S-
containing RBCs traverse the circulation undergoing cycles of oxygenation
and deoxygenation, rigid polymers of Hb S repeatedly form and damage the
RBC membrane, drastically shortening the RBC life span. RBCs also
become dehydrated, relatively inflexible, and abnormally adhesive.
Consequently, they are prone to adhere to the endothelium of blood vessels,

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in concert with leukocytes and platelets, impeding the flow of blood. This
microvascular obstruction, called vaso occlusion, leads to ischemia,
infarction, and ischemia reperfusion injury of multiple organs and tissues.
This pathophysiology produces an ongoing inflammatory response and
endothelial dysfunction. Some complications of SCD can be considered to
be primarily a consequence of either hemolysis or vaso occlusion.
For example, chronic hemolysis predisposes to bilirubinate
cholelithiasis, whereas vaso occlusive ischemia and infarction of bone
marrow is thought to cause the acute painful event (“crisis”), the hallmark of
SCD. The pathophysiology of SCD is more complex than a simple “log jam”
model of vaso occlusion by irreversibly sickled RBCs.
Clinical Features
Thrombosis follows and an area of tissue infarction results causing
severe pain, swelling and tenderness (infarction crisis), weakness, leg
ulceration, pallor, splenomegaly (moderate), biliary colic.
Diagnosis
Low haemoglobin, raised (20,000-50,000/cu mm), less than 1000, blast
cells are 30%-90%, diminished platelet count, increased reticulocytes,
normoblasts present, bone marrow preponderance of appropriate primitive
cells.
Management
Preliminary experience with allogeneic transplantation has introduced
the prospect of cure for the first time in the management of sickle cell
patients, plenty of fluids, bed rest, maintain oral hygiene, well balanced,
nutritious, easily digestiblediet.
Leukaemia
Abnormal proliferation of leukopoiesis tissues characterized by
remarkable rise in blood leukocytes count, unexplained by reactive
leukocytosis. It is considered to be multi factorial, including exogenous or
endogenous exposures, genetic susceptibility, and chance. The survival rate
of pediatrics leukaemia has improved to approximately 90% in recent trials
with risk stratification by biologic features of leukaemic cells and response
to therapy, therapy modification based on patient pharmacodynamics and
pharmacogenomics, and improved supportive care. However, innovative
approaches are needed to further improve survival while reducing adverse
effects. An estimated 6000 new cases (3400 male and 2600 female) of acute
lymphoblastic leukaemia (ALL) are diagnosed annually in the US. Patients
are predominantly children.

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 Approximately 60% of cases occur at age <20 years. LL, like cancer in
general, is likely to arise from interactions between exogenous or
endogenous exposures, genetic (inherited) susceptibility.

Fig 4: Leukaemia
Type: Acute leukaemia and chronic leukaemia.
Causes: Exact causes is not known. Neoplastic theory–resemble
malignant neoplasm, infiltrate and destroy normal tissues and interfere with
their normal activity.
Clinical Features
Fever, chill weight loss, weakness, fatigue, nausea, vomiting, anorexia,
apin and aches all over, petechiae, bruises, bleeding from nose, gums,
haematemesis, haematuria, sore throat, stomatitis. Signs are pallor severe,
generalized lymphadenopathy, cutaneous haemorrhage, bleeding gums,
stomatitis, rapid pulse, hepatosplenomegaly, soft systolic murmur at apex.
Diagnosis
Morphological identification of lymphoblasts by microscopy and
immunophenotypic determination of lineage commitment and developmental
stage by flow cytometry are essential for correct diagnosis of ALL.
Chromosomal analysis still plays an important role in the initial cytogenetic
work-up. RT-PCR, FISH/multiplex ligation dependent probe amplification,
and flow cytometry are used to identify leukaemia specific translocations,
submicroscopic chromosomal abnormalities, and cellular DNA content,
respectively. After genome wide analysis becomes time and cost effective, it
may replace many current diagnostic techniques.
Management
Treat with fresh blood transfusion, plenty of oral fluids, correct anemia,
well balanced nutritional diet, adequate rest, maintain oral hygiene.

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Aplastic Anaemia
Most acquired aplastic anemia (AA) is the result of immune-mediated
destruction of hematopoietic stem cells causing pancytopenia and an empty
bone marrow, which can be successfully treated with either
immunosuppressive therapy (IST) or hematopoietic stem-cell transplantation
(HSCT). For these patients, comparable long term survival is attainable with
immunosuppressive treatment (IST) with anti-thymocyte globulin (ATG)
and cyclosporine (CsA). Although several etiopathogenic triggers have been
proposed in AA, the majority of cases are idiopathic, with a small percentage
of cases occurring after an episodeof seronegativehepatitis.
Acquired AA is a rare disease; almost half of cases occur during the first
three decades of life. The incidence in Western countries is two cases per
million per year and about 2-3-fold higher in Asia. During the lastcentury,
AA was attributed to an idiosyncratic reaction to drug or chemical exposure.
The association of medical drug use to AA is of great importance, as it is
devastating to patients and physicians and presents serious legal
consequences and problems in pharmaceutical drug development.
Causes: Drugs are like cytotoxic drugs, idiosyncratic, antibiotics, anti-
rheumatic agents, immunosuppressives, benzene toluene solvent abuse,
radiations, viral hepatitis, pregnancy, paroxysmal nocturnal
haemoglobinuria.

Fig 5: Aplastic Anemia

Pathology
In most cases, AA behaves as an immune-mediated disease. An immune
response dominated by oligoclonal expanded cytotoxic T-cells targets
hematopoietic stem and progenitor cells, inducing their death via apoptosis
and hematopoietic failure. Recovery of autologous hematopoiesis in patients
who failed to engraft after stem cell transplant and responsiveness to
immunosuppressive therapies are the major clinical evidences supporting an

Page | 160
immune pathophysiology underlying acquired AA. Although a nonimmune
pathophysiology has been inferred from a failure to respond to
immunosuppression, refractoriness to therapy is also consistent with very
severe stem cell depletion, a “spent” immune response, or immunological
mechanisms resistant to currenttherapies.
Removal of lymphocytes from aplastic bone marrows improves colony
numbers in tissue culture, and their addition to normal marrow inhibited
hematopoiesis in vitro. The effector cells within the lymphocyte subset are
activated cytotoxic T cells bearing a Th1 profile, expressing and secreting
interferon-γ. T-bet, a transcription factor that binds to the interferon-γ
promoter region and is critical for Th1 polarization, is up- regulated in T-
cells of patients with AA. Specific CD8+CD28- cell clones are expanded in
AA peripheral blood, as manifest by skewed usage of the Vβ repertoire; and
oligoclonal recognize and induce apoptosis of autologous myeloid cells.
Regulatory T cells, which control and suppress auto reactive T cells, are
decreased at presentation in almost all patients with AA. In a mouse model
of immune mediated marrow failure, addition of T regulatory cells abrogated
pancytopenia induced by the infusion of lymph node cells. Why T-cells are
activated in AA is unclear. HLA-DR2 is over represented among patients,
suggesting a role for antigen recognition, and its presence is predictive of a
better response to cyclosporine. Polymorphisms in cytokine genes,
associated with an increased immune response, also are more prevalent, such
as for tumor necrosis factor-α (TNF2) promoter at -308, interferon-γ, and
interleukin 6 genes. These alterations in nucleotide sequence and in gene
regulation suggest a genetic basis for aberrant T cell activation in bone
marrow failure.
Clinical Features
Weakness, nausea, vomiting, weight loss, fatigue.
Diagnosis
A fatty bone marrow remains basic to diagnosis, but sophisticated
testing now can be directed at distinguishing among diverse
pathophysiologies and discriminating among similar, sometimes overlapping
diseases why in the differential diagnosis.
Management
Replacement of a failed bone marrow is curative of the underlying
disease. Transplant has been limited by its complications, graft rejection and
graft-versus-host disease (GVHD), and the availability of suitable donors.

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For immune aplastic anemia, transplant is always preferred in the young
patient, and when undertaken expeditiously after diagnosis using his to
compatible sibling donor, results are excellent, with more than 90% long
term survival in young children.
More than 80% in adolescents, and a low rate of complications short and
long term. Umbilical cord transplantation also has been successful in aplastic
anemia, mainly in children due to the relationship between donor inoculum
cell numbers and recipient weight, with survival approximating 90%. A
potential donor half matched to the patient should be present in virtually
every family. As even single antigen disparities markedly affect outcomes of
transplants, overcoming major histocompatibility differences had seemed an
insuperable barrier. T cell depleting strategies, pre transplant by cytotoxic
drugs and biologics, and post-transplant with cyclophosphamide have been
utilized to prevent GVHD.
Hodgkin’s disease
Hodgkin lymphoma (HL) is a rare cancer that arises from immune cells
known as B lymphocytes (B cells) and typically affects the lymph nodes and
sometimes other organs or abnormal painless, progressive lymphoid
proliferation with irregular fever, weight loss, excessive sweating having a
chronic course marked by episodes of exacerbation and remissions. Hodgkin
lymphoma (HL) is a rare cancer of the immune system that typically affects
lymph nodes and sometimes other organs.
Although the majority of patients can be potentially cured with the use
of multi-agent chemotherapy and radiotherapy, a proportion of them will
relapse or develop resistant disease for which treatment options are limited.
In recent years, new agents have been developed and tested in HL with
encouraging results. The first descriptions of what came to be known as
Hodgkin disease date back to 1832 when the eminent British pathologist
Thomas Hodgkin described an autopsy case series of patients with
lymphadenopathy and splenic enlargement. It was not till the late 1990s that
our understanding of the entity as a malignancy arising from germinal center
or post germinal center B cells led to the term ‘Hodgkin lymphoma’ (HL)
gaining favor. Characteristically, the cancer cells form a minority of the
tumor and are surrounded by a reactive inflammatory milieu comprising
lymphocytes, eosinophils, neutrophils, histiocytes and plasma cells. These
malignant cells can be pathognomonic multinucleate giant cells or large
mononuclear cells and are together referred to as Hodgkin and Reed
Sternberg (HRS) cells.

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 Causes: Exact causes unknown, history of infections mononucleosis.

Fig 6: Hodgkin’s disease

Clinical Features
Cervical lymph nodes enlargement with painless, unilateral, chest pain,
cough, dyspnoea, dysphagia, hoarseness, fever irregular with sweat,
alternating pyrexia and apyrexia, associated with enlarged mediastinal and
abdominal lymph nodes, pruritus, anorexia, weight loss, sweating. Signs are
mid anaemia, pallor, slight temperature; lymph nodes are moderately
enlarged, discrete, rubbery, non-tender, splenomegaly, hepatomegaly.
Stages:
Stage 1: Single abnormal lymph node.
Stage 2: Involvement of lymph nodes (above diaphragm).
Stage 3: Involvement of lymph nodes (above and below diaphragm).
Stage 4: Extra lymphatic involvement.
Diagnosis
Low HB%, raised TLC, eosinophils raised in 15%, raised ESR.
Management
Well balanced diet. In determining the optimal treatment for patients
with Hodgkin lymphoma, the factors that play a major role include the
histologic features of the disease (classical Hodgkin lymphoma compared
with nodular lymphocyte predominant Hodgkin lymphoma). The stage of the
disease (particularly whether the patient has early or advanced stage disease),
the presence of clinical factors that suggest a poor prognosis, the presence of
systemic symptoms, and the presence or absence of a bulky mass, defined as
a single site of disease greater than 10 cm in diameter. Fludeoxyglucose
(FDG) ePET also plays a key role in defining the initial treatment.

Page | 163
 References

1. Mulle JG, Vaccarino V. Cardiovascular disease, psychosocial factors,

and genetics: The case of depression. Progress in cardiovascular
diseases. 2013;55:557–562.
2. Vaccarino V, Johnson BD, Sheps DS, Reis SE, Kelsey SF, Bittner V, et
al. Depression, inflammation, and incident cardiovascular disease in
women with suspected coronary ischemia: The national heart, lung, and
blood institute-sponsored wise study. Journal of the American College
of Cardiology. 2007;50:2044–2050.
3. Daugherty SL, Masoudi FA, Ellis JL, Ho PM, Schmittdiel JA, Tavel
HM, et al. Age-dependent gender differences in hypertension
management. Journal of hypertension. 2011;29:1005–1011.
4. Ling SM, Wigley FM. Raynaud’s phenomenon in older adults:
diagnostic considerations and management. Drugs Aging. 1999;15:183.
5. LeRoy EC, Medsger TA, et al. Raynaud’s phenomenon: A proposal for
classification. Clin Exp Rheumatol. 1992;10:485.
6. Wigley FM. Clinical practice Raynaud’s phenomenon. New Engl J
Med. 2002 Sep 26;347:1001–1008.
7. Ouriel K, Green RM, Donayre C, et al. An evaluation of new methods
of expressing aortic aneurysm size: Relationship to rupture. J Vasc
Surg. 1992;15:12–8.
8. Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA
Cancer J Clin. 1990;40:9–26.
9. Lederle FA, Johnson GR, Wilson SE, Chute EP, Littooy FN, Bandyk D.
et al. Prevalence and associations of abdominal aortic aneurysm detected
through screening. Aneurysm Detection and Management (ADAM)
Veterans Affairs Cooperative Study Group. Ann Intern
Med. 1997;126:441–9.
10. Omran AR. The epidemiologic transition. A theory of the epidemiology
of population change. Milbank Mem Fund Q. 1971;49(4):509–538.
11. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et
al. Disability-adjusted life years (DALYs) for 291 diseases and injuries
in 21 regions, 1990-2010: a systematic analysis for the global burden of
disease study 2010. Lancet. 2012;380:2197–2223.

Page | 164
12. Epping-Jordan JE, Pruitt SD, Bengoa R, Wagner EH. Improving the
quality of health care for chronic conditions. Quality & safety in health
care. 2004;13(4):299–305.
13. Otto CM, Bonow RO. Valvular heart disease. In: Libby P, Bonow RO,
Mann DL, Zipes DP, editors. Eds.Braunwald's Heart Disease: A
Textbook of Cardiovascular Medicine 8th ed.Philadelphia, PA: WB
Saunders; 2007:1625-1712.
14. Bouma BJ, van den Brink RBA, van der Meulen JH, et al. To operate or
not in elderly patients with aortic stenosis: the decision and its
consequences. Heart 1999; 82:143-148.
15. Wilson PWF, D'Agostino RB, Levy D, Belanger AM, Silbershatz H,
Kannel WB. Prediction of coronary heart disease using risk factor
categories. Circulation 1998;97:1837-1847.
16. Lieberman EB, Bashore TM, Hermiller JB, et al. Balloon aortic
valvuloplasty in adults: failure of procedure to improve long term
survival. J Am Coll Cardiol. 1995; 26:1522-1528.
17. Del Rio JM, Grecu L, Nicoara A. Right Ventricular Function in Left
Heart Disease. Semin Cardiothorac Vasc Anesth. 2019 Mar;23(1):88-
107.
18. Perlowski A, St Goar F, Glower DG, Feldman T. Percutanenous
therapies for mitral regurgitation, Curr Probl Cardiol. 2012; 37(2):42-68.
19. Ailawadi G. Tricuspid Valve. Mastery of Cardiothoracic Surgery. 3rd
Edition. Wolters Kluwer 2013:779-86.
20. Odenwald T, Taylor AM. Pulmonary valve interventions. Expert Rev
Cardiovasc Ther. Nov. 2011; 9(11):1445–57.
21. Contrepois A. Towards a history of infective endocarditis. Medical
history. 1996;40:25–54.
22. Osler W. The Gulstonian Lectures, on Malignant Endocarditis. British
medical journal. 1885; 1:577–579.
23. Bin Abdulhak AA, et al. Global and regional burden of infective
endocarditis, 1990–2010: a systematic review of the literature. Glob
Heart. 2014;9:131–143.
24. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D,
Moss AJ, Seidman CE, Young JB. Contemporary definitions and
classification of the cardiomyopathies: an American Heart Association

Page | 165
 Scientific Statement from the Council on Clinical Cardiology, Heart
Failure and Transplantation Committee; Quality of Care and Outcomes
Research and Functional Genomics and Translational Biology
Interdisciplinary Working Groups; and Council on Epidemiology and
Prevention. Circulation. 2006;113:1807–1816.
25. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B,
O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, et al. Report of
the 1995 World Health Organization/International Society and
Federation of Cardiology Task Force on the Definition and
Classification of cardiomyopathies. Circulation. 1996;93:841–842.
26. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P,
Dubourg O, Kühl U, Maisch B, McKenna WJ, et al. Classification of the
cardiomyopathies: a position statement from the European Society Of
Cardiology Working Group on Myocardial and Pericardial
Diseases. Eur Heart J. 2008;29:270–276.
27. Maisch B, Seferovic PM, Ristic AD, et al. Guidelines on the diagnosis
and management of pericardial diseases executive summary: The task
force on the diagnosis and management of pericardial diseases of the
European Society of Cardiology. Eur Heart J. 2004;25(7):587-610.
28. Zayas R, Anguita M, Torres F, et al. Incidence of specific etiology and
role of methods for specific etiologic diagnosis of primary acute
pericarditis. Am J Cardiol. 1995; 75(5):378-382.
29. Spodick DH. Diagnostic electrocardiographic sequences in acute
pericarditis: significance of PR segment and PR vector
changes. Circulation 1973;48(3):575-580.
30. Bruce MA, Spodick DH. Atypical electrocardiogram in acute
pericarditis: characteristics and prevalence. J ElectroCardiol. 1980;
13(1):61-66.
31. Adams AC, Astapova I, Fisher FM, Badman MK, Kurgansky KE, Flier
JS, Hollenberg AN, Maratos-Flier E. Thyroid hormone regulates hepatic
expression of fibroblast growth factor 21 in a PPARalpha-dependent
manner. J Biol Chem 285: 14078–14082, 2010.
32. Araki O, Ying H, Zhu XG, Willingham MC, Cheng SY. Distinct
dysregulation of lipid metabolism by unliganded thyroid hormone
receptor isoforms. Mol Endocrinol 23: 308–315, 2009.
33. Arrojo EDR, Bianco AC. Type 2 deiodinase at the crossroads of thyroid
hormone action. Int J Biochem Cell Biol 43: 1432–1441, 2011.

Page | 166
34. Astapova I, Hollenberg AN. The in vivo role of nuclear receptor
corepressors in thyroid hormone action. Biochim Biophys Acta 1830:
3876–3881, 2013.
35. Baxter JD, Webb P. Thyroid hormone mimetics: potential applications
in atherosclerosis, obesity and type 2 diabetes. Nature Rev Drug
Discov 8: 308–320, 2009.
36. Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis
PJ. Integrin alphaVbeta3 contains a cell surface receptor site for thyroid
hormone that is linked to activation of mitogen activated protein kinase
and induction of angiogenesis. Endocrinology 146: 2864–2871, 2005.
37. Hedberg CW, Fishbein DB, Janssen RS, et al. An outbreak of
thyrotoxicosis caused by the consumption of bovine thyroid gland in
ground beef. N Engl J Med. 1987;316:993–98.
38. Cooper DS, Biondi B. Subclinical thyroid
disease. Lancet. 2012;379:1142–54..
39. Nyström HF, Jansson S, Berg G. Incidence rate and clinical features of
hyperthyroidism in a long-term iodine sufficient area of Sweden
(Gothenburg) 2003-2005. Clin Endocrinol (Oxf) 2013;78:768–76..
40. Abraham P., Avenell A., Park C.M., Watson W.A., Bevan J.S. (2005) A
systematic review of drug therapy for Graves' hyperthyroidism. Eur J
Endocrinol 153: 489–498.
41. Abraham-Nordling M. (2005) Graves' disease: A long-term quality-of-
life follow up of patients randomized to treatment with antithyroid
drugs, radioiodine, or surgery. Thyroid 15: 1279–1286.
42. Allannic H., Fauchet R., Orgiazzi B., Madec A.M., Genetet B., Lorcy
Y., et al. (1990) Antithyroid drugs and Graves' disease: A prospective
randomized evaluation of the efficacy of treatment duration. J Clin
Endocrinol Metab 70: 675–679.
43. Amodio F., Di Martino S., Esposito S., Iorio S., Hierholzer J., Rea G., et
al. (2001) Role of flowmetric analysis and of color-Doppler
ultrasonography with contrast media in the different phases and follow-
up of Graves' disease. Radiol Med 102: 233–237.
44. Bartalena L., Marcocci C., Bogazzi F., Manetti L., Tanda M.L.,
Dell'Unto E., et al. (1998) Relation between therapy for hyperthyroidism
and the course of Graves' ophthalmopathy. N Engl J Med 338: 73–78.
45. Brent G.A. (2008) Graves' disease. N Engl J Med 358: 2544–2554.

Page | 167
46. Jacobsen R., Lundsgaard C., Lorenzen J., Toubro S., Perrild H., Krog-
Mikkelsen I., et al. (2006) Subnormal energy expenditure: A putative
casual factor in the weight gain induced by treatment of
hyperthyroidism. Diabetes Obes Metab 8: 220–227.
47. Kubota S., Amino N., Matsumoto Y., Ikeda N., Morita S., Kudo T., et
al. (2008) Serial changes in liver function tests in patients with
thyrotoxicosis induced by Graves' disease and painless
thyroiditis. Thyroid 18: 283–28.
48. Shoback D, Sellmeyer D, Bikle DD. Metabolic bone disease. : Gardner
DG, Shoback D, Greenspan's basic & clinical endocrinology. 9th ed.
New York, NY: The McGraw-Hill Companies; 2011. p 227– 284.
49. Pyram R, Mahajan G, Gliwa A. Primary hyperparathyroidism: Skeletal
and non-skeletal effects, diagnosis and management. Maturitas. 2011.
November; 70 3: 246– 55.
50. Schlüter KD. PTH and PTHrP: Similar Structures but Different
Functions. News Physiol Sci. 1999. December; 14: 243– 9. .
51. Brown J, de Boer IH, Robinson-Cohen C, et al. Aldosterone,
parathyroid hormone, and the use of renin-angiotensin-aldosterone
system inhibitors: the multi-ethnic study of atherosclerosis. J Clin
Endocrinol Metab. 2015. February; 100 2: 490– 9.
52. Kiernan TJ, O'Flynn AM, McDermott JH, Kearney P. Primary
hyperparathyroidism and the cardiovascular system. Int J Cardiol. 2006.
November 18; 113 3: E89– 92.
53. Silver J, Naveh-Many T. FGF-23 and secondary hyperparathyroidism in
chronic kidney disease. Nat Rev Nephrol. 2013. November; 9 11: 641–
9.
54. Iacobellis G., Petramala L., Cotesta D., et al. Adipokines and
cardiometabolic profile in primary hyperaldosteronism. Journal of
Clinical Endocrinology and Metabolism. 2010; 95(5):2391–2398. doi:
10.1210/jc.2009-2204.
55. Rossi G. P., Sticchi D., Giuliani L., et al. Adiponectin receptor
expression in the human adrenal cortex and aldosterone-producing
adenomas. International Journal of Molecular Medicine. 2006;
17(6):975–980.
56. Maniero C., Fassina A., Seccia T. M., et al. Mild hyperparathyroidism: a
novel surgically correctable feature of primary aldosteronism. Journal of
Hypertension. 2012; 30(2):390–395. .

Page | 168
57. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO,
Stewart PM, et al. The diagnosis of Cushing's syndrome: an Endocrine
Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;
93:1526–1540.
58. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J,
Savage MO, et al. Treatment of Cushing's syndrome: an Endocrine
Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;
100:2807–2831.
59. eltzer K, Pengpid S, James C. The globalization of whitening:
prevalence of skin lighteners (or bleachers) use and its social correlates
among university students in 26 countries. Int J Dermatol. 2016;
55:165–172.
60. Baid SK, Rubino D, Sinaii N, Ramsey S, Frank A, Nieman LK.
Specificity of screening tests for Cushing's syndrome in an overweight
and obese population. J Clin Endocrinol Metab. 2009; 94:3857–3864..
61. Grossman AB. Thomas Addison and his disease. Grand Rounds. 2004;
4:L8–9.
62. Hiatt JR, Hiatt N. The conquest of Addison's disease. Am J Surg. 1997;
174:280–3.
63. Stewart PM, Krone NP. The adrenal cortex. In: Kronenburg HM,
Melmed S, Polonsky KS, Reed Larson P, editors. Williams Textbook of
Endocrinology. 12th ed. Philadelphia PA: Saunders Elsevier; 2011. pp.
515–20.
64. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the
epidemiology of gastro-oesophageal reflux disease: a systematic
review. Gut. 2014;63:871–880.
65. Locke GR, 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ., 3rd
Prevalence and clinical spectrum of gastroesophageal reflux: a
population-based study in Olmsted County, Minnesota.
Gastroenterology.1997;112:1448–1456.
66. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R Global Consensus
Group. The Montreal definition and classification of gastroesophageal
reflux disease: a global evidence-based consensus. Am J Gastroenterol.
2006;101:1900–1920.
67. Bloom BS, Jayadevappa R, Wahl P, Cacciamanni J. Time trends in cost
of caring for people with gastroesophageal reflux disease. Am J
Gastroenterol. 2001; 96:S64–69.

Page | 169
68. Zheng Z, Nordenstedt H, Pedersen NL, Lagergren J, Ye W. Lifestyle
factors and risk for symptomatic gastroesophageal reflux in
monozygotic twins. Gastroenterology. 2007;132:87–95.
69. Tefera L, Fein M, Ritter MP, Bremner CG, Crookes PF, Peters JH,
Hagen JA, DeMeester TR. Can the combination of symptoms and
endoscopy confirm the presence of gastroesophageal reflux disease? Am
Surg. 1997;63:933–936.
70. Giannini EG, Zentilin P, Dulbecco P, Vigneri S, Scarlata P, Savarino V.
Management strategy for patients with gastroesophageal reflux disease:
a comparison between empirical treatment with esomeprazole and
endoscopy-oriented treatment. Am J Gastroenterol. 2008;103:267–275.
71. Katzka DA, Paoletti V, Leite L, Castell DO. Prolonged ambulatory pH
monitoring in patients with persistent gastroesophageal reflux disease
symptoms: testing while on therapy identifies the need for more
aggressive anti-reflux therapy. Am J Gastroenterol. 1996;91:2110–2113.
72. Kwiatek MA, Pandolfino JE. The Bravo pH capsule system. Dig Liver
Dis. 2008;40:156–160.
73. Aksglaede K, Funch-Jensen P, Thommesen P. Intra-esophageal pH
probe movement during eating and talking. A videoradiographic
study. Acta Radiol. 2003;44:131–135.
74. Ravi K, Francis DL. New technologies to evaluate esophageal
function. Expert Rev Med Devices. 2007;4:829–837.
75. Weusten BL, Roelofs JM, Akkermans LM, Van Berge-Henegouwen
GP, Smout AJ. The symptom-association probability: an improved
method for symptom analysis of 24-hour esophageal pH
data. Gastroenterology. 1994;107:1741–1745.
76. DeVault K, McMahon BP, Celebi A, Costamagna G, Marchese M,
Clarke JO, Hejazi RA, McCallum RW, Savarino V, Zentilin P, et al.
Defining esophageal landmarks, gastroesophageal reflux disease, and
Barrett’s esophagus. Ann N Y Acad Sci. 2013;1300:278–295.
77. Schindler R. Chronic gastritis. Klin Wochenschr. 1966; 44:601–12.
78. Siurala M. The story of gastritis. Scand J Gastroenterol Suppl. 1991;
186:1–3.
79. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading
of gastritis. The updated Sydney System. International Workshop on the
Histopathology of Gastritis, Houston 1994. Am J Surg

Page | 170
 Pathol. 1996;20:1161–81.
80. Lau WY, Leow CK. History of perforated duodenal and gastric
ulcers. World J Surg. 1997; 21:890–6.
81. Bertleff MJ, Lange JF. Perforated peptic ulcer disease: A review of
history and treatment. Dig Surg. 2010; 27:161–9.
82. Lagoo S, McMahon RL, Kakihara M, Pappas TN, Eubanks S. The sixth
decision regarding perforated duodenal ulcer. JSLS. 2002; 6:359–68.
83. Van Doorn LJ. Detection of Helicobacter pylori virulence-associated
genes. Expert Rev Mol Diagn. 2001; 1:290–8.
84. Van Doorn LJ, Figueiredo C, Sanna R, Plaisier A, Schneeberger P, de
Boer W, et al. Clinical relevance of the cagA, vacA, and iceA status
of Helicobacter pylori. Gastroenterology. 1998; 115:58–66.
85. Ballinger A, Smith G. COX-2 inhibitors vs. NSAIDs in gastrointestinal
damage and prevention. Expert Opin Pharmacother. 2001; 2:31–40.
86. Beaugerie L., Seksik P., Nion-Larmurier I., Gendre J., Cosnes J.
(2006) Predictors of Crohn’s disease. Gastroenterology 130: 650–656.
87. Bernstein C., Blanchard J., Rawsthorne P., Yu N. (2001) the prevalence
of extraintestinal diseases in inflammatory bowel disease: a population-
based study. Am J Gastroenterol 96: 1116–1122.
88. Buisson A., Chevaux J., Allen P., Bommelaer G., Peyrin-Biroulet L.
(2012) Review article: the natural history of postoperative Crohn’s
disease recurrence. Aliment Pharmacol Ther 35: 625–633.
89. Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F.
(2013). Neonatal hyperbilirubinemia and Rhesus disease of the
newborn: incidence and impairment estimates for 2010 at regional and
global levels. Pediatr Res, 1: 86–100.
90. American Academy of Pediatrics Practice Parameter
(1994). Management of hyperbilirubinemia in the healthy term
newborn. Pediatrics, 94: 558–65.
91. Young Infants Clinical Signs Study Group (2008). Clinical signs that
predict severe illness in children under age 2 months: a multicentre
study. Lancet, 371(9607): 135–42.
92. Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A,
Caballería J, Rodés J, Rozman C. Compensated cirrhosis: natural history
and prognostic factors. Hepatology. 1987; 7:122–128.

Page | 171
93. Guevara M, Cárdenas A, Uriz J, Ginès P. Prognosis in patients with
cirrhosis and ascites. In: Ginès P, Arroyo V, Rodés J, Schrier RW,
editors. Ascites and renal dysfunction in liver disease: pathogenesis,
diagnosis and treatment. Malden: Blackwell; 2005. p. 260–270.
94. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas
R, Escorsell A, Garcia-Pagan JC, Makuch R, Patch D, et al. Hepatic
venous pressure gradient predicts clinical decompensation in patients
with compensated cirrhosis. Gastroenterology. 2007; 133:481–488. .
95. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA,
McHutchison JG. The serum-ascites albumin gradient is superior to the
exudate-transudate concept in the differential diagnosis of ascites. Ann
Intern Med. 1992; 117:215–220.
96. Devictor D, Tissieres P, Afanetti M, Debray D. Acute liver failure in
children. Clin Res Hepatol Gastroenterol. 2011; 35:430–437.
97. Trey C, Davidson CS. Te management of fulminant hepatic failure. Prog
Liver Dis. 1970; 3:282–298.
98. Ostapowicz G, Fontana RJ, Schiodt F V, et al. Results of a prospective
study of acute liver failure at 17 tertiary care centers in the United
States. Ann Intern Med. 2002; 137:947–954.
99. O’Grady JG, Williams R. Classifcation of acute liver
failure. Lancet. 1993; 342:743.
100. Struve J, Giesecke J, Lindh G. et al Heterosexual contact as a major
route for transmission of acute hepatitis B amongst adults. J
Infect 199020111–121.
101. Gilson R J, de Ruiter A, Waite J. et al Hepatitis B virus infection in
patients attending a genitourinary medicine clinic: risk factors and
vaccination coverage. Sex Transm Infect 199874110–115.
102. Hoofnagle J H. Chronic hepatitis B. N Engl J Med 1990323 337–339.
103. Hoofnagle J. Hepatitis C: the clinical spectrum of disease. Hepatology
199726(suppl 1)15S–20S.
104. Bircher J, Benhamou JP, McIntyre N, Rizzetto M, Rodes J,
editors. Oxford Textbook of Clinical Hepatology. 2nd Edition Oxford
University Press; 1999.77.
105. Schaffner H, Popper H. Capillarization of the
sinusoids. Gastroenterology. 1963; 44:339–42.

Page | 172
106. Bellentani S, Pozzato G, Saccoccio G, et al. Clinical course and risk
factors of hepatitis C virus related liver disease in the general
population: report from the Dionysos study. Gut. 1999; 44:874–80.
107. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild
cognitive impairment. Arch Neurol. 2001;58:1985–1992.
108. Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment–
beyond controversies, towards consensus: report of the International
Working Group on Mild Cognitive Impairment. J Intern Med. 2004;
256:240–246.
109. Parkinson J. An Essay on the Shaking Palsy. London: Sherwood,
Neely, and Jones; 1817. pp. 1–16.
110. Twelves D, Perkins KS, Counsell C. Systematic review of incidence
studies of Parkinson’s disease. Mov Disord. 2003;18:19–31.
111. Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of
Parkinson’s disease in primary care: a case-control study. Lancet
Neurol. 2015;1:57–64.
112. Driver JA, Logroscino G, Gaziano JM, et al. Incidence and remaining
lifetime risk of Parkinson disease in advanced
age. Neurology. 2009;72:32–38.
113. Guillain G, Barré J, Strohl A. Sur UN syndrome de radiculo-nevrite
avec hyperalbuminose du liquide cephalorachidien sans reaction
cellulaire. Remarques sur les characteres clinique ET graphique des
reflexes tendinaux. Bulletins ET Memories de la Societe Medicale des
Hopitaux de Paris. 1916; 40:1462–1470.
114. Winer JB, Hughes RAC, Osmond C. A prospective study of acute
idiopathic neuropathy. I. Clinical features and their prognostic
value. Journal of Neurology Neurosurgery & Psychiatry. 1988;
51(5):605–612.
115. Reid AC, Draper IT. Pathogenesis of papilloedema and raised
intracranial pressure in Guillain-Barré syndrome. British Medical
Journal. 1980;281(6252):1393–1394.
116. Goddard EA, Lastovica AJ, Argent AC. Campylobacter 0:41 isolation in
Guillain-Barré syndrome. Archives of Disease in Childhood. 1997;
76(6):526–528.
117. Robertson N. Enumerating neurology. Brain. 2000;123(4):663–664.

Page | 173
118. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past,
present, and future. Journal of Clinical
Investigation. 2006;116(11):2843–2854.
119. Marsteller HB. The first American case of myasthenia gravis. Archives
of Neurology. 1988; 45(2):185–187.
120. Simpson JA. Myasthenia gravis, a new hypothesis. Scott Medical. 1960;
5:419–436.
121. Gilhus NE, Verschuuren JJ: Myasthenia gravis: subgroup classification
and therapeutic strategies. Lancet Neurol. 2015; 14(10):1023–36.
10.1016/S1474-4422(15)00145-3.
122. Morgan BP, Chamberlain-Banoub J, Neal JW, et al. The membrane
attack pathway of complement drives pathology in passively induced
experimental autoimmune myasthenia gravis in mice. Clin Exp
Immunol. 2006;146(2):294–302.
123. Aaron S., Vandemheen K., Hebert P., Dales R., Stiell I., Ahuja J.
Outpatient oral prednisone after emergency treatment of chronic
obstructive pulmonary disease. N Eng J Med .2003; 348: 2618–2625.
124. Barr R, Rowe R, Camargo C. Methylxanthines for exacerbations of
chronic obstructive pulmonary disease: meta-analysis of randomized
trials. BMJ.2003; 327: 643.
125. Bilton D. Update on non-cystic fibrosis bronchiectasis. Curr Opin Pulm
Med. 2008; 14:595–599.
126. Twiss J, Metcalfe R, Edwards E, et al. New Zealand national incidence
of bronchiectasis too high“for a developed country. Arch Dis
Child. 2005; 90:737–740.
127. Dodge JA, Lewis PA, Stanton M, Wilsher J. Cystic fibrosis mortality
and survival in the UK: 1947-2003. Eur Respir J 2007; 29:522-6.
128. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak
Z, et al. Identification of the cystic fibrosis gene: cloning and
characterization of complementary DNA. Science 1989; 245:1066-73.
129. Leung AK, Hon KL, Leong KF, Sergi CM. Measles: a disease often
forgotten but not gone. Hong Kong Med J. 2018; 24(5):512-520.
130. Grief SN, Loza JK. Guidelines for the Evaluation and Treatment of
Pneumonia. Prim. Care. 2018; 45(3):485-503.
131. Hirsh AE, Tsolaki AG, DeRiemer K, Feldman MW, Small PM. Stable

Page | 174
 association between strains of Mycobacterium tuberculosis and their
human host populations. Proc Natl Acad Sci USA. 2004; 101:4871–6.
132. Rothschild BM, Martin LD, Lev G, Bercovier H, Bar-Gal GK,
Greenblatt CL, et al. Mycobacterium tuberculosis Complex DNA from
an Extinct Bison Dated 17,000 Years before the Present. Clin Infec
Dis. 2001; 33:305–11.
133. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma
management and prevention: GINA executive summary. Eur Respir
J. 2008; 31:143–178.
134. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding
P, et al. Asthma exacerbations and sputum eosinophil counts: a
randomised controlled trial. Lancet. 2002; 360:1715–1721.
135. Collins TR, Sahn SA. Thoracocentesis: clinical value, complications,
technical problems and patient experience. Chest. 1987; 91:817–822.
136. Porcel JM, Light RW. Diagnostic approach to pleural effusion in
adults. Am Fam Physician. 2006; 73:1211–1220.
137. Davies CW, Kearney SE, Gleeson FV, Davies RJ. Predictors of
outcome and longterm survival in patients with pleural infection. Am J
Respir Crit Care Med. 1999; 160:1682–7.
138. Ashbaugh DG. Empyema thoracis. Factors influencing morbidity and
mortality. Chest. 1991; 99:1162–5.
139. Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F.
(2013). Neonatal hyperbilirubinemia and Rhesus disease of the
newborn: incidence and impairment estimates for 2010 at regional and
global levels. Pediatr Res, 1: 86–100.
140. American Academy of Pediatrics Practice Parameter (1994).
Management of hyperbilirubinemia in the healthy term newborn.
Pediatrics, 94: 558–65.
141. Young Infants Clinical Signs Study Group (2008). Clinical signs that
predict severe illness in children under age 2 months: a multicentre
study. Lancet, 371(9607): 135–42.
142. Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A,
Caballería J, Rodés J, Rozman C. Compensated cirrhosis: natural history
and prognostic factors. Hepatology. 1987; 7:122–128.
143. Guevara M, Cárdenas A, Uriz J, Ginès P. Prognosis in patients with
cirrhosis and ascites. In: Ginès P, Arroyo V, Rodés J, Schrier RW,

Page | 175
 editors. Ascites and renal dysfunction in liver disease: pathogenesis,
diagnosis and treatment. Malden: Blackwell; 2005. p. 260–270.
144. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas
R, Escorsell A, Garcia-Pagan JC, Makuch R, Patch D, et al. Hepatic
venous pressure gradient predicts clinical decompensation in patients
with compensated cirrhosis. Gastroenterology. 2007;133:481–488. .
145. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA,
McHutchison JG. The serum-ascites albumin gradient is superior to the
exudate-transudate concept in the differential diagnosis of ascites. Ann
Intern Med. 1992; 117:215–220.
146. Devictor D, Tissieres P, Afanetti M, Debray D. Acute liver failure in
children. Clin Res Hepatol Gastroenterol. 2011;35:430–437.
147. Trey C, Davidson CS. Te management of fulminant hepatic failure. Prog
Liver Dis. 1970; 3:282–298.
148. Ostapowicz G, Fontana RJ, Schiodt F V, et al. Results of a prospective
study of acute liver failure at 17 tertiary care centers in the United
States. Ann Intern Med. 2002; 137:947–954.
149. O’Grady JG, Williams R. Classifcation of acute liver
failure.Lancet.1993; 342:743.
150. Struve J, Giesecke J, Lindh G. et al Heterosexual contact as a major
route for transmission of acute hepatitis B amongst adults. J
Infect 199020111–121.
151. Gilson R J, de Ruiter A, Waite J. et al Hepatitis B virus infection in
patients attending a genitourinary medicine clinic: risk factors and
vaccination coverage. Sex Transm Infect 199874110–115.
152. Hoofnagle J H. Chronic hepatitis B. N Engl J Med 1990323 337–339.
153. Hoofnagle J. Hepatitis C: the clinical spectrum of disease.
Hepatology 199726(suppl 1)15S–20S.
154. Bircher J, Benhamou JP, McIntyre N, Rizzetto M, Rodes J,
editors. Oxford Textbook of Clinical Hepatology. 2nd Edition Oxford
University Press; 1999.77.
155. Schaffner H, Popper H. Capillarization of the sinusoids.
Gastroenterology.1963; 44:339–42.
156. Bellentani S, Pozzato G, Saccoccio G, et al. Clinical course and risk
factors of hepatitis C virus related liver disease in the general
population: report from the Dionysos study. Gut. 1999; 44:874–80.

Page | 176
157. Frymoyer JW. Back pain and sciatica. N Engl J Med. 1988; 318:291–
300.
158. Geen J, Edelaar M, Janssen M, et al. The long-term effect of
multidisciplinary back training: a systematic
review. Spine. 2007;32(2):249–55.
159. Andersson GB. Epidemiological features of chronic low
pain. Lancet. 1999; 354:581–5.
160. Martin JA, Buckwalter JA. Roles of articular cartilage aging and
chondrocyte senescence in the pathogenesis of osteoarthritis. Iowa
Orthop J 2001;21: 1-7.
161. Peach CA, Carr AJ, Loughlin J. Recent advances in the genetic
investigation of osteoarthritis. Trends Mol Med 2005; 11: 186-91.
162. Dieppe PA, Lohmander LS. Pathogenesis and management of pain in
osteoarthritis. Lancet 2005;365: 965-73.
163. Dalbeth N., Merriman T.R., Stamp L.K. Gout Lancet. 2016;
388(10055):2039–2052.
164. Pascual E., Sivera F. Time required for disappearance of urate crystals
from synovial fluid after successful hypouricaemic treatment relates to
the duration of gout. Ann Rheum Dis. 2007; 66(8):1056–1058.
165. Singh J.A. Challenges faced by patients in gout treatment: a qualitative
study. J Clin Rheumatol: Practical Rep Rheum Musculoskelet
Dis. 2014;20(3):172–174.
166. Birch JT Jr, Bhattacharya S. Emerging trends in diagnosis and treatment
of rheumatoid arthritis. Prim Care. 2010; 37:779–92.
167. El Miedany Y, Youssef S, Mehanna AN, El Gaafary M. Development of
a scoring system for assessment of outcome of early undifferentiated
inflammatory synovitis. Joint Bone Spine. 2008; 75:155–62.
168. Gossec L, Combescure C, Rincheval N, et al. Relative Clinical influence
of Clinical, Laboratory, and Radiological Investigations in Early
Arthritis on the Diagnosis of Rheumatoid Arthritis. Data from the
French Early Arthritis Cohort ESPOIR. J Rheumatol. 2010; 37:2486–92.
169. Tomiak C, Dorner T. Sjogren’s syndrome. Current aspects from a
rheumatological point of view. Z Rheumatol. 2006; 65:505–517.
170. Qin B, Wang J, Yang Z, et al. Epidemiology of primary Sjögren’s
syndrome: a systematic review and meta-analysis. Ann Rheum
Dis. 2015; 74:1983–1989.

Page | 177
171. Fox PC, Bowman SJ, Segal B, et al. Oral involvement in primary
Sjögren syndrome. J Am Dent Assoc. 2008; 139:1592–1601.
172. Tauros JD, Lipsky PE. Ankylosing Spondylitis, Reactive arthritis and
Undifferentiated Spondiloarthropathy. In: Braunwald E, Isselbacher KJ,
Petersdorf RG, Wilson JD, Martin JB, Fauci AS, editors. Harrison's
Principles of Internal Medicine. 14th Edition. Publishers - McGraw -
Hill Book Company; 1998. pp. 1906–1909.
173. Amor B. Reiter's syndrome. Diagnosis and clinical features. Rheum Dis
Clin North Am. 1998 Nov; 24(4):677–695.
174. Hughes RA, Keat AC. Reiter's syndrome and reactive arthritis: a current
view. Semin Arthritis Rheum. 1994; 24(3):190–210.
175. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S,
et al. Clinician’s guide to prevention and treatment of
osteoporosis. Osteoporos Int. 2014; 25:2359–81.
176. Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et
al. The recent prevalence of osteoporosis and low bone mass in the
United States based on bone mineral density at the femoral neck or
lumbar spine. J Bone Miner Res. 2014; 29:2520–6.
177. Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST,
Hodgson SF, et al. American Association of Clinical Endocrinologists
Medical Guidelines for Clinical Practice for the diagnosis and treatment
of postmenopausal osteoporosis. Endocr Pract. 2010; 16:1–37.
178. Stewart BW, Wild CP. World Cancer Report 2014. Geneva,
Switzerland: WHO Press; 2014.
179. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J
Clin. 2017; 67:7–30.
180. Sonnenschein C, Soto AM. Carcinogenesis explained within the context
of a theory of organisms. Progress in biophysics and molecular
biology. 2016; 122:70–76.
181. Dumars C, Ngyuen JM, Gaultier A. et al. Dysregulation of macrophage
polarization is associated with the metastatic process in
osteosarcoma. Oncotarget. 2016; 7:78343–78354.
182. Smalley M, Piggott L, Clarkson R. Breast cancer stem cells: obstacles to
therapy. Cancer Lett. 2013; 338:57–62.
183. Valenti G, Quinn HM, Heynen G. et al. Cancer Stem Cells Regulate

Page | 178
 Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in
Mammary Gland Tumors. Cancer Res. 2017; 77:2134–2147.
184. Kasper M, Jaks V, Fiaschi M. et al. Hedgehog signalling in breast
cancer. Carcinogenesis. 2009; 30:903–911.
185. Hegan DC, Lu Y, Stachelek GC. et al. Inhibition of poly(ADP-ribose)
polymerase down-regulates BRCA1 and RAD51 in a pathway mediated
by E2F4 and p130. Proc Natl Acad Sci U S A. 2010; 107:2201–2206.
186. Martinez JS, von Nicolai C, Kim T. et al. BRCA2 regulates DMC1-
mediated recombination through the BRC repeats. Proc Natl Acad Sci U
S A. 2016; 113:3515–3520.
187. Shih C, Padhy LC, Murray M. et al. Transforming genes of carcinomas
and neuroblastomas introduced into mouse
fibroblasts. Nature. 1981;290:261–264.
188. Jung M, Russell AJ, Liu B. et al. A Myc Activity Signature Predicts
Poor Clinical Outcomes in Myc-Associated Cancers. Cancer Res. 2017;
77:971–981.
189. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA.
Invasive mediastinal staging of lung cancer: ACCP evidence-based
clinical practice guidelines. Chest. ((2nd edition)) 2007; 132:202–220.
190. Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of
non-small cell lung cancer: ACCP evidenced-based clinical practice
guidelines. Chest. ((2nd edition)) 2007; 132:178–201.
191. Jett JR, Schild SE, Keith RL, Kesler KA. Treatment of non-small cell
lung cancer, stage IIIB: ACCP evidence-based clinical prac-tice
guidelines. Chest. ((2nd edition)) 2007; 132:266–276.
192. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial
irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;
357:664–672.
193. Silvestri GA, Littenberg B, Colice GL. The clinical evaluation for
detecting metastatic lung cancer. A meta-analysis. Am J Respir Crit
Care Med. 1995; 152:225–230.
194. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial
of pemetrexed versus docetaxel in patients with non-small cell lung
cancer previously treated with chemotherapy. J Clin
Oncol. 2004;22:1589–1597.

Page | 179
195. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing
supportive care alone with supportive care with oral topotecan in
patients with relapsed small cell lung cancer. J Clin
Oncol. 2006;24:5441–5447.
196. Kaneko S, Yoshimura T. Time trend analysis of gastric cancer incidence
in Japan by histological types, 1975–1989. Br J
Cancer. 2001;84(3):400–405.
197. Munoz N, Franceschi S. Epidemiology of gastric cancer and
perspectives for prevention. Salud Publica Mex. 1997;39(4):318–330.
198. Camargo MC, Burk RF, Bravo LE, et al. Plasma selenium
measurements in subjects from areas with contrasting gastric cancer
risks in Colombia. Arch Med Res. 2008;39(4):443–451.
199. Jedrychowski W, Wahrendorf J, Popiela T, Rachtan J. A case-control
study of dietary factors and stomach cancer risk in Poland. Int J
Cancer. 1986;37(6):837–842.
200. Lagergren J, Bergström R, Lindgren A, Nyrén O. The role of tobacco,
snuff and alcohol use in the aetiology of cancer of the oesophagus and
gastric cardia. Int J Cancer. 2000; 85(3):340–346.
201. Simpson J, Roman E, Law G, Pannett B. Women’s occupation and
cancer: preliminary analysis of cancer registrations in England and
Wales, 1971–1990. Am J Ind Med. 1999;36(1):172–185.
202. Forman D, Newell DG, Fullerton F, et al. Association between infection
with Helicobacter pylori and risk of gastric cancer: evidence from a
prospective investigation. BMJ. 1991;302(6788):1302–1305.
203. González CA, Megraud F, Buissonniere A, et al. Helicobacter
pylori infection assessed by ELISA and by immunoblot and noncardia
gastric cancer risk in a prospective study: the Eurgast-EPIC project. Ann
Oncol. 2012; 23(5):1320–1324.
204. Imai S, Koizumi S, Sugiura M, et al. Gastric carcinoma: monoclonal
epithelial malignant cells expressing Epstein-Barr virus latent infection
protein. Proc Natl Acad Sci U S A. 1994;91(19):9131–9135.
205. Wang WH, Huang JQ, Zheng GF, Lam SK, Karlberg J, Wong BC. Non-
steroidal anti-inflammatory drug use and the risk of gastric cancer: a
systematic review and meta-analysis. J Natl Cancer
Inst. 2003;95(23):1784–1791.
206. Bombardier C, Laine L, Reicin A, et al. VIGOR Study Group
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen

Page | 180
 in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J
Med. 2000; 343(21):1520–1528.
207. Hsing AW, Hansson LE, McLaughlin JK, et al. Pernicious anemia and
subsequent cancer. A population based cohort
study. Cancer. 1993;71(3):745–750.
208. Offerhaus GJ, Tersmette AC, Huibregtse K, et al. Mortality caused by
stomach cancer after remote partial gastrectomy for benign conditions:
40 years of follow up of an Amsterdam cohort of 2633 postgastrectomy
patients. Gut. 1988;29(11):1588–1590.
209. Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM.
Gastric adenocarcinoma: review and considerations for future
directions. Ann Surg. 2005; 241(1):27–39.
210. Hirota WK, Zuckerman MJ, Adler DG, et al. Standards of Practice
Committee, American Society for Gastrointestinal Endoscopy ASGE
guideline: the role of endoscopy in the surveillance of pre-malignant
conditions of the upper GI tract. Gastrointest Endosc. 2006;63(4):570–
580.
211. Rhodes, C.J. (2004). Processing of the insulin molecule. In Diabetes
Mellitus, D. LeRoith, S.I. Taylor, and J.M. Olefsky, eds. (Philadelphia,
PA: Lippincott Williams & Wilkins), pp. 27–50.
212. Harding, H.P., Novoa, I., Zhang, Y., Zeng, H.,Wek, R., Schapira,M.,
and Ron, D. (2000a). Regulated translation initiation controls stress-
induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108.
213. Harding, H.P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken,
H., Sabatini, D.D., and Ron, D. (2001). Diabetes mellitus and exocrine
pancreatic dysfunction in perk2/2 mice reveals a role for translational
control in secretory cell survival. Mol. Cell 7, 1153–1163.
214. Shaffer, A.L., Shapiro-Shelef, M., Iwakoshi, N.N., Lee, A.H., Qian,
S.B., Zhao, H., Yu, X., Yang, L., Tan, B.K., Rosenwald, A., et al.
(2004). XBP1, downstream of Blimp-1, expands the secretory apparatus
and other organelles, and increases protein synthesis in plasma cell
differentiation. Immunity 21, 81–93.
215. Nishitoh, H.,Matsuzawa, A., Tobiume, K., Saegusa, K., Takeda, K.,
Inoue, K., Hori, S., Kakizuka, A., and Ichijo, H. (2002). ASK1 is
essential for endoplasmic reticulum stress-induced neuronal cell death
triggered by expanded polyglutamine repeats. Genes Dev. 16, 1345–
1355.

Page | 181
216. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Diabetic retinopathy.
Diabetes Care 2004; 27:2540-53.
217. Rema M, Premkumar S, Anitha B, Deepa R, Pradeepa R, Mohan V.
Prevalence of diabetic retinopathy in urban India: The Chennai Urban
Rural Epidemiology Study (CURES) eye study, I. Invest Ophthalmol
Vis Sci 2005;46:2328-33.
218. Raman R, Rani PK, Reddi Rachepalle S, Gnanamoorthy P, Uthra S,
Kumaramanickavel G, et al. Prevalence of diabetic retinopathy in India:
Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular
Genetics Study report 2. Ophthalmology 2009;116:311-8
219. Raman R, Ganesan S, Pal SS, Kulothungan V, Sharma T. Prevalence
and risk factors for diabetic retinopathy in rural India. Sankara
Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic
Study III (SN-DREAMS III), report no 2. BMJ Open Diabetes Res Care
2014; 2:e000005.
220. Nirmalan PK, Tielsch JM, Katz J, Thulasiraj RD, Krishnadas R,
Ramakrishnan R, et al. Relationship between vision impairment and eye
disease to vision-specific quality of life and function in rural India: The
Aravind Comprehensive Eye Survey. Invest Ophthalmol Vis Sci 2005;
46:2308-12.
221. Nirmalan PK, Tielsch JM, Katz J, Thulasiraj RD, Krishnadas R,
Ramakrishnan R, et al. Relationship between vision impairment and eye
disease to vision specific quality of life and function in rural India: The
Aravind Comprehensive Eye Survey. Invest Ophthalmol Vis Sci 2005;
46:2308-12.
222. Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, et
al. Retinal microvascular abnormalities and incident stroke: The
atherosclerosis risk in communities study. Lancet 2001; 358:1134-40.
223. Fuller J H, Stevens LK, Wang SL. Risk factors for cardiovascular
mortality and morbidity: The WHO mutinational study of vascular
disease in diabetes. Diabetologia 2001; 44 Suppl 2:S54-64.
224. Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J.
Type II diabetes mellitus and cardiovascular risk factors: Current
therapeutic approaches. Exp Clin Cardiol 2007; 12:17-28.
225. Adler AI, Stevens RJ, Manley SE, Bilous WR, Cull AC, Holman RR
(2003) Development and progression of nephropathy in type 2 diabetes:
The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney
int. 225-232.

Page | 182
226. Vrhovac B, Jakšić B, Reiner Ž, Vucelić B (2008) Interna medicina.
Zagreb: Naklada Ljevak. pp 1258-1259.
227. Kimmelstiel P, Wilson C (1936) Benign and malignant hypertension
and nephrosclerosis. A clinical and pathological study. Am. j.
pathol.12:45-8
228. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H
(1982) Microalbuminuria as a predictor of clinical nephropathy in
insulin dependent diabetes mellitus. Lancet. 1:1430-1432.
229. Mogensen CE (1984) Microalbuminuria predicts clinical proteinuria and
early mortality in maturity onset diabetes. New eng. j. med. 310:356-
360.
230. Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D
(1990) Prevalence of complications in IDDM by sex and duration.
Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes.
39:1116-1124.
231. Chaturvedi N, Bandinelli S, Mangili R, Penno G, Rottiers RE, Fuller JH
(2001) Microalbuminuria in type 1 diabetes: rates, risk factors and
glycemic threshold. Kidney int. 60:219-227.
232. Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, Binder C,
Parving HH (2004) Predictors of the development of microalbuminuria
and macroalbuminuria in patients with type 1 diabetes: inception cohort
study. Brit. med. j. 328:1105-1108.
233. Tripathi BK, Srivastava AK. (2006) Diabetes mellitus: complications
and therapeutics. Med Sci Monit. Jul; 12(7):RA130-47.
234. Kamijo M, Cheian P V, Sima AA F. (1993) the preventive effect of
aldose reductase inhibition on diabetic optic neuropathy in the BB/W
rat. Diabetologia. Oct; 36(10):893-8.
235. Mooradian A D. (1997)Central nervous system complications of
diabetes mellitusaPerspective from blood brain barrier.Brain ResRev.;
23:210-18.
236. Northam EA, Rankins D, Lin A, Wellard RM, Pell GS, Finch
SJ,Werther GA, Cameron FJ (2009)Central nervous system function in
youth with type 1 diabetes 12 years after disease onset. Diabetes Care;
32:445–450.
237. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM.
(1999)Diabetes mellitus and the risk of dementia: The Rotterdam Study.
Neurology. Dec 10; 53(9):1937- 42.

Page | 183
238. Jason D. Huber, Reyna L. VanGilder, and Kimberly A. Houser.
Streptozotocin induced diabetes progressively increases blood brain
barrierpermeability in specific brain regions in rats. Am J Physiol Heart
Circ Physiol, 2006;291: 2660–68.
239. Huang TJ, Price SA, Chilton L, Calcutt NA, Tomlinson DR,
Verkhratsky A, et al. (2003)Insulin prevents depolarization of the
mitochondrial inner membrane in sensory neuronsof type 1 diabetic rats
in the presence of sustained hyperglycemia. Diabetes. Aug; 52(8):2129-
36.
240. Tsai EC, Hirsch IB, Brunzell JD and Chait A: Reduced plasma peroxyl
radical trapping capacity and increased susceptibility of LDL to
oxidation in poorly controlled IDDM. 1994: 43; 1010 –1014.
241. Enkins AJ, Klein RL, Chassereau CN, Hermayer KL and LopesVirella
MF: LDL from patients with well controlled IDDM is not more
susceptible to in vitro oxidation. 1996: 45; 762–767.
242. Diwadkar VA, Anderson JW, Bridges SR, Gowri MS and Oelgten PR:
Postprandial low density lipoproteins in type 2 diabetes are oxidized
more extensively than fasting diabetes and control samples, Proc Soc
Exp Biol Med 1999: 222;178 –184.
243. Chisholm DJ, Campbell LV, Kraegen EW: Pathogenesis of the insulin
resistance syndrome (syndrome X). Clin Exp Pharmacol Physiol. 1997:
24; 782–784.
244. BD chaurasion. Human anatomy, volume II, CBS publisher and
distribution, New Delhi. 1996. 246-250.
245. Thornalley PJ: Cell activation by glycated proteins; AGE receptors;
receptor recognition factors and functional classification of AGEs. Cell
Mol. Biol 1998: 44; 1013–1023.
246. Robert. American Diabetes Association. Diabetes Care. 2008; 31(1):
S12–S54.
247. V Aristidis. Aldose Reductase Inhibitors for the Treatment of Diabetic
Neuropathy. Contemporary Diabetes: Diabetic Neuropathy: Clinical
Management, Second Edition, Edited by: A. Veves and R. Malik.
Humana Press Inc., Totowa, NJ: 309-320.
248. Robert. Evidence Based Nutrition Principles and Recommendations for
the Treatment and Prevention of Diabetes and Related Complications.
Clinical Diabetes. 2002; 20(2): S50–S60.

Page | 184
249. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes:
estimates for the year 2000 and projections for 2030. Diabetes Care
2004; 27:1047-53.
250. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients
with diabetes. JAMA 2005; 293:217-28.
251. Prompers L, Huijberts M, Apelqvist J, et al. Optimal organization of
health care in diabetic foot disease: introduction to the Eurodiale study.
Int J Low Extrem Wounds 2007; 6:11-7.
252. Levin ME. Foot lesions in patients with diabetes mellitus. Endocrinol
Metab Clin North Am 1996; 25:447-62.
253. Boulton AJ, Meneses P, Ennis WJ. Diabetic foot ulcers: A framework
for prevention and care. Wound Repair Regen 1999; 7:7-16.
254. Apelqvist J, Ragnarson Tennvall G, Larsson J, et al. Long term costs for
foot ulcers in diabetic patients in a multidisciplinary setting. Foot Ankle
Int 1995; 16:388-94.
255. Gordon PA. Effects of diabetes on the vascular system: current research
evidence and best practice recommendations. J Vasc Nurs 2004; 22:2-
11.
256. Jeffcoate WJ, Price P, Harding KG. Wound healing and treatments for
people with diabetic foot ulcers. Diabetes Metab Res Rev 2004; 20
Suppl 1:S78-89.
257. Widatalla AH, Mahadi SE, Shawer MA, et al. Implementation of
diabetic foot ulcer classification system for research purposes to predict
lower extremity amputation. Int J Diabetes Dev Ctries 2009; 29:1-5.
258. Davidsons. Principal and practice of medicine, 18th edition. Churchill
Living stone, UK. 1999. pp. 480-482.
259. Armstrong DG, Lavery LA, Vela SA, et al. choosing a practical
screening instrument to identify patients at risk for diabetic foot
ulceration. Arch Intern Med 1998; 158:289-92.
260. Lipsky BA, Polis AB, Lantz KC, et al. The value of a wound score for
diabetic foot infections in predicting treatment outcome: a prospective
analysis from the SIDESTEP trial. Wound Repair Regen 2009; 17:671-
7.
261. Cruciani M, Lipsky BA, Mengoli C. Are granulocyte colony stimulating
factors beneficial in treating diabetic foot infections: A meta-analysis?
Diabetes Care 2005; 28:454-60.

Page | 185
262. Monath TP, Gershman M, Staples JE, Barrett A. Yellow fever vaccine
In: Plotkin SA, Orenstein WA, Offit PA, editors. , eds. Vaccines.
Philadelphia, PA: Saunders; 2012:870–968.
263. Staples JE, Gershman MD, Fischer M. Yellow fever vaccine:
recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-7):1–27.
264. Lindsey NP, Rabe IB, Miller ER, Fischer M, Staples JE. Adverse event
reports following yellow fever vaccination, 2007-13. J Travel Med.
2016;23(5).
265. Phanichyakarn P, Pongpanich B, Israngkura PB, Dhanamitta S,
Valyasevi A. Studies on dengue hemorrhagic fever. III. Serum
complement (C3) and platelet studies. J Med Assoc Thai. 1977;60:301–
6.
266. Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, Wongtapradit L,
Nithipanya N, Kalayanarooj S, et al. Natural history of plasma leakage
in dengue hemorrhagic fever: A serial ultrasonographic study. Pediatr
Infect Dis J. 2007; 26:283–90.
267. Byatnal A, Mahajan N, Koppal S, Ravikiran A, Thriveni R, Parvathi
Devi MK. Unusual yet isolated oral manifestations of persistent
thrombocytopenia – A rare case report. Braz J Oral Sci. 2013; 12:233–6.
268. Noble CG, Chen YL, Dong H, Gu F, Lim SP, Schul W, et al. Strategies
for development of dengue virus inhibitors. Antiviral Res. 2010;
85:450–62.
269. Itoda I, Masuda G, Suganuma A, Imamura A, Ajisawa A, Yamada K, et
al. Clinical features of 62 imported cases of dengue fever in Japan. Am J
Trop Med Hyg. 2006; 75:470–4.
270. Ahmed FU, Mahmood CB, Sharma JD, Hoque SM, Zaman R, Hasan
MH. Dengue fever and dengue haemorrhagic fever in chidren the 2000
outbreak in Chittatong, Bangladesh. Dengue Bulletin. 2001; 25:33–9.
271. Chadwick D, Arch B, Wilder-Smith A, Paton N. Distinguishing dengue
fever from other infections on the basis of simple clinical and laboratory
features: Application of logistic regression analysis. J Clin Virol. 2006;
35:147–53.
272. Shivpuri A,Shivpuri A. Dengue-An overview. Dent Med Probl. 2011;
48:153–6.
273. Bhattacharya SS, Das U, Choudhury BK. Occurrence & antibiogram of

Page | 186
 Salmonella typhi & S. paratyphi aisolated from Rourkela, Orissa. Indian
J. Med. Res. 2011; 133(4):431.
274. Akinyemi KO, Iwalokun BA, Oyefolu AO, et al. Occurrence of
extended-spectrum and AmpC β-lactamases in multiple drug resistant
Salmonella isolates from clinical samples in Lagos, Nigeria. Infect.
Drug Resist. 2017; 10:19.
275. Kalra SP, Naithani N, Mehta SR, et al. current trends in the
management of typhoid fever. Med. J. ArMed. Forces India. 2003;
59(2):130–135.
276. Divyashree S, Nabarro LE, Veeraraghavan B, et al. Enteric fever in
India: current scenario and future directions. Trop. Med. Int.
Health. 2016;21(10):1255–1262.
277. Rahman BA, Wasfy MO, Maksoud MA, et al. Multi-drug resistance and
reduced susceptibility to ciprofloxacin among Salmonella
entericaserovarTyphi isolates from the Middle East and Central
Asia. New Microbes New Infect. 2014; 2(4):88–92.
278. Wain J, Hosoglu S. The laboratory diagnosis of enteric fever. J. Infect.
Dev. Ctries. 2008;2(6):421–425.
279. Flayhart D, Borek AP, Wakefield T, et al. Comparison of BACTEC
PLUS blood culture media to BacT/Alert FA blood culture media for
detection of bacterial pathogens in samples containing therapeutic levels
of antibiotics. J. Clin. Microbiol. 2007; 45(3):816–821.
280. Keddy KH, Sooka A, Letsoalo ME, et al. Sensitivity and specificity of
typhoid fever rapid antibody tests for laboratory diagnosis at two sub-
Saharan African sites. Bull. World Health Organ. 2011;89(9):640–647.
281. Committee to Advise on Tropical Medicine and Travel (CATMAT).
Canadian recommendations for the prevention and treatment of malaria
among international travelers 2000. Can Commun Dis
Rep 2000;26(S2):1-42.
282. Zucker JR. Changing patterns of autochthonous malaria transmission in
the United States: a review of recent outbreaks. Emerg Infect
Dis 1996;2:37-43.
283. Svenson JE, MacLean JD, Gyorkos TW, Keystone J. Imported malaria.
Clinical presentation and examination of symptomatic travelers. Arch
Intern Med 1995; 155:861-8.
284. Owusu-Agyei S, Koram KA, Baird JK, Utz GC, Binka FN, Nkrumah

Page | 187
 FK, et al. Incidence of symptomatic and asymptomatic Plasmodium
falciparum infection following curative therapy in adult residents of
northern Ghana. Am J Trop Med Hyg 2001;65:197-203.
285. Humar A, Ohrt C, Harrington MA, Pillai D, Kain KC. ParaSight-F® test
compared with the polymerase chain reaction and microscopy for the
diagnosis of Plasmodium falciparum malaria in travelers. Am J Trop
Med Hyg 1997; 56: 44-8.
286. Pieroni P, Mills CD, Ohrt C, Harrington MA, Kain KC. Comparison of
the ParaSight-F® test and the ICT Malaria PF® test with the
polymerase-chain-reaction for the diagnosis of Plasmodium
falciparum malaria in travelers. Trans R Soc Trop Med Hyg 1998;
92:166-9.
287. Snounou G, Viriyakosol S, Jarra W, Thaithong S, Brown KN.
Identification of the four human malarial species in field samples by the
polymerase chain reaction and detection of a high prevalence of mixed
infections. Mol Biochem Parasitol 1993;58:283-92.
288. Geerligs PDP, Brabin BJ, Eggelte TA. Analysis of the effects of malaria
chemoprophylaxis in children on haematological responses, morbidity
and mortality. Bull World Health Organ 2003;81:205-16.
289. Cot M, Le Hesran JY, Miailhes P, Esveld M, Etya'ale D, Breart G.
Increase of birth weight following chloroquine chemoprophylaxis
during the first pregnancy: results of a randomized trial in
Cameroon. Am J Trop Med Hyg 1995; 53: 581-5.
290. Mutambu S, Shiff C. Implementing and sustaining community-based
mosquito net interventions in Africa. Parasitol Today 1997; 13:204-6.
291. Marchant T, Schellenberg JA, Edgar T, Nathan R, Abdulla S, Mukasa
O, et al. Socially marketed insecticide-treated nets improve malaria and
anaemia in pregnancy in southern Tanzania. Trop Med Int Health 2002;
7:149-58.
292. Fletcher C. The Plasmodium falciparum genome project. Parasitol
Today 1998; 14:342-4.
293. Anderson G.J., Frazer D.M., McLaren G.D. (2009) Iron absorption and
metabolism. Curr Opin Gastroenterol 25: 129–135.
294. Clouse R.E., Costigan D.J., Mills B.A., Zuckerman G.R.
(1985) Angiodysplasia as a cause of upper gastrointestinal
bleeding. Arch Intern Med 145: 458–461.

Page | 188
295. Lysionek A.E., Zubillaga M.B., Salgueiro M.J., Caro R.A., Leonardi
N.M., Ettlin E., et al. (2003) Stabilized ferrous gluconate as iron source
for food fortification: Bioavailability and toxicity studies in rats. Biol
Trace Elem Res 94: 73–78.
296. Navas-Carretero S., Sarria B., Perez-Granados A.M., Schoppen S.,
Izquierdo-Pulido M., Vaquero M.P. (2007) A comparative study of iron
bioavailability from cocoa supplemented with ferric pyrophosphate or
ferrous fumarate in rats. Ann Nutr Metab 51: 204–207.
297. Rockey D.C. (1999) occult gastrointestinal bleeding. N Engl J Med 341:
38–46.
298. Rockey D.C., Cello J.P. (1993) Evaluation of the gastrointestinal tract in
patients with iron-deficiency anemia. N Engl J Med 329: 1691–1695.
299. Till S.H., Grundman M.J. (1997) Prevalence of concomitant disease in
patients with iron deficiency anaemia. BMJ 314: 206–208.
300. Wish J.B. (2006) Assessing iron status: Beyond serum ferritin and
transferrin saturation. Clin J Am Soc Nephrol 1(Suppl 1): S4–S8.
301. Zhang A.S., Enns C.A. (2009) Molecular mechanisms of normal iron
homeostasis. Hematology Am Soc Hematol Educ Program 1: 207–214.
302. Ahlquist DA, McGill DB, Schwartz S, Taylor WF, Owen RA
1985. Fecal blood levels in health and disease. A study using
HemoQuant. N Engl J Med 312: 1422–1428.
303. Ahmed F, Khan MR, Akhtaruzzaman M, Karim R, Williams G,
Torlesse H, Darnton-Hill I, Dalmiya N, Banu CP, Nahar B 2010. Long-
term intermittent multiple micronutrient supplementation enhances
hemoglobin and micronutrient status more than iron + folic acid
supplementation in Bangladeshi rural adolescent girls with nutritional
anemia. J Nutr 140: 1879–1886.
304. Best C, Neufingerl N, Del Rosso JM, Transler C, van den Briel T,
Osendarp S 2011. Can multi-micronutrient food fortification improve
the micronutrient status, growth, health, and cognition of
schoolchildren? A systematic review. Nutr Rev 69: 186–204.
305. Burgmann H, Looareesuwan S, Kapiotis S, Viravan C, Vanijanonta S,
Hollenstein U, Wiesinger E, Presterl E, Winkler S, Graninger W
1996. Serum levels of erythropoietin in acute Plasmodium
falciparum malaria. Am J Trop Med Hyg 54: 280–283.
306. Crowell R, Ferris AM, Wood RJ, Joyce P, Slivka H 2006. Comparative
effectiveness of zinc protoporphyrin and hemoglobin concentrations in

Page | 189
 identifying iron deficiency in a group of low-income, preschool-aged
children: Practical implications of recent illness. Pediatrics 118: 224–
232.
307. Erdem A, Erdem M, Arslan M, Yazici G, Eskandari R, Himmetoglu O
2002. The effect of maternal anemia and iron deficiency on fetal
erythropoiesis: Comparison between serum erythropoietin, hemoglobin
and ferritin levels in mothers and newborns. J Matern Fetal Neonatal
Med 11: 329–332.
308. Finch CA, Huebers H 1982. Perspectives in iron metabolism. N Engl J
Med 306: 1520–1528.
309. Gore FM, Bloem PJ, Patton GC, Ferguson J, Joseph V, Coffey C,
Sawyer SM, Mathers CD 2011. Global burden of disease in young
people aged 10–24 years: A systematic analysis. Lancet 377: 2093–
2102.
310. Hurrell RF, Lynch S, Bothwell T, Cori H, Glahn R, Hertrampf E,
Kratky Z, Miller D, Rodenstein M, Streekstra H, et al. 2004. Enhancing
the absorption of fortification iron. A SUSTAIN Task Force report. Int J
Vitam Nutr Res 74: 387–401.
311. Kemna EH, Tjalsma H, Podust VN, Swinkels DW 2007. Mass
spectrometry-based hepcidin measurements in serum and urine:
Analytical aspects and clinical implications. Clin Chem 53: 620–628.
312. Kovac S, Anderson GJ, Alexander WS, Shulkes A, Baldwin GS
2011. Gastrin-deficient mice have disturbed hematopoiesis in response
to iron deficiency. Endocrinology 152: 3062–3073.
313. Kroot JJ, Kemna EH, Bansal SS, Busbridge M, Campostrini N, Girelli
D, Hider RC, Koliaraki V, Mamalaki A, Olbina G, et al. 2009. Results
of the first international round robin for the quantification of urinary and
plasma hepcidin assays: Need for standardization. Haematologica 94:
1748–1752.
314. Lanas A, García-Rodríguez LA, Polo-Tomás M, Ponce M, Alonso-
Abreu I, Perez-Aisa MA, Perez-Gisbert J, Bujanda L, Castro M, Muñoz
M, et al. 2009. Time trends and impact of upper and lower
gastrointestinal bleeding and perforation in clinical practice. Am J
Gastroenterol 104: 1633–1641.
315. Lee AI, Okam MM 2011. Anemia in pregnancy. Hematol Oncol Clin
North Am 25: 241–259.

Page | 190
316. Lozoff B, Jimenez E, Wolf AW 1991. Long-term developmental
outcome of infants with iron deficiency. N Engl J Med 325: 687–694.
317. McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B
2009. Worldwide prevalence of anaemia, WHO Vitamin and Mineral
Nutrition Information System, 1993–2005. Public Health Nutr 12: 444–
454.

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 Text Book of Medicine

Authors

Dr. Siva Rami Reddy E is a well known name in the literary circles of
Medical. He has done M.D. (Medicine) and Ph.D. He is working as a
professor and head, post graduate guide, department of practice of medicine
in SGN Homoeopathic medical college & hospital, research center, India. He
has reviewed 200 international research papers. He is examiner for many
universities in India. He is also engaged in private practice for the last 15
years. He is a member of many scientific societies, published 77 Original
research papers and review papers in journal of national and international
repute, presented many papers at various national and international
conferences/seminars, published 5 book chapters and 3 books. He is actively
engaged in research as well as teaching of under graduate and post graduate
courses and has delivered many lectures on various topics of current medical
sciences. He has awarded Dr. Sarvepalli Radhakrishnan life time
achievement award, international young scientist, international research
scholar award and best teacher national award.
Mail id: dr.sivaramireddy@gmail.com

Dr. Tanuja B is MDS (Periodnotology) from G. Pulla Reddy Dental

College & Hospital, Kurnool. She is presently working as a Senior Lecturer,
Department of Periodnotology and Implantology in G. Pulla Reddy Dental
College & Hospital, Kurnool, A.P, India. She has written various
publications for students and practitioners of dental.

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