Compilation Liver Cirrhosis (4) - 1

Compilation on liver cirrhosis by Nagabharana H.M guided by Dr .
Roopa halder (dept of kaya chikitsa)

CONTENTS
Compilation on liver cirrhosis by Nagabharana H.M guided by Dr . Roopa halder (dept of kaya chikitsa)
BAPUJI AYURVEDIC MEDICAL COLLEGE
Dept of Kayachikitsa.
Compilation work on liver cirrhosis by- Nagabharana HM guided by – DR. Roopa Halder
Liver Cirrhosis
Manuscript
BAMC-KC liver cirrhosis
1. INTRODUCTION
 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.
 At present, liver transplantation remains the only curative option for a
selected group of patients, but pharmacological therapies that can halt
progression to decompensated cirrhosis or even reverse cirrhosis are

currently being developed.
 This concise overview focuses on diagnosis, complications and
management of cirrhosis, and novel clinical and scientific developments .
2.EPIDEMIOLOGY
Cirrhosis deaths per million persons in 2012
9-44 45-68 69–88 89–104 105–122 123–152

153–169 170–204 205–282 283–867
 The exact prevalence of cirrhosis worldwide is unknown. Cirrhosis

prevalence was estimated at 0.15% or 400,000 in the USA ,
 where it accounted for more than 25,000 deaths and 373,000 hospital
discharges in 1998 .
 This may be an underestimation as we recognize the high prevalence of
undiagnosed cirrhosis in both NASH (nonalcoholic steato hepatitis) and
hepatitis C.
 Similar numbers have been reported from Europe, and numbers are even
higher in most Asian and African countries where chronic viral
hepatitis B or C are frequent.
 Since compensated cirrhosis often goes undetected for prolonged periods
of time, a reasonable estimate is that up to 1% of populations may have
histological cirrhosis.
3.ETIOLOGY OF CIRRHOSIS
 The etiology of cirrhosis can usually be identified by the patient’s history

combined with serologic and histologic evaluation .
 Alcoholic liver disease and hepatitis C are the most common causes in
the Western world, while hepatitis B prevails in most parts of Asia and
sub-Saharan Africa.
 After the identification of the hepatitis C virus in 1989 and of
nonalcoholic steatohepatitis (NASH) in obese and diabetic subjects, the
diagnosis of cirrhosis without an apparent cause (cryptogenic cirrhosis) is
rarely made.
 It is important to know the etiology of cirrhosis, since it can predict
complications and direct treatment decisions. It also allows the
discussion of preventive measures, e.g., with family members of patients

with alcoholic cirrhosis or chronic viral hepatitis, and consideration of
(genetic) testing and preventive advice for relatives of patients with
genetic diseases, such as hemochromatosis or Wilson’s disease.
 Frequently multiple etiological factors contribute to the development of
cirrhosis, as exemplified in epidemiological studies that identified regular
(moderate) alcohol consumption, age above 50 years.
 male gender as risk factors in chronic hepatitis C , or older age obesity ,
insulin resistance /type 2 diabetes, hypertension, and hyperlipidemia (all
features of the metabolic syndrome ) in NASH
4.PATHOGENESIS AND PATHOPHYSIOLOGY OF CIRRHOSIS
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 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 hepatic vasculature. 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 (Figure 1)
BAMC-KC BAMC-KC
 The major clinical consequences of cirrhosis are impaired hepatocyte

(liver) function, an increased intrahepatic resistance (portal
hypertension) and the development of hepatocellular carcinoma (HCC).
liver cirrhosis
 The general circulatory abnormalities in cirrhosis (splanchnic

vasodilation, vasoconstriction and hypoperfusion of kidneys, water and
liver cirrhosis
salt retention, increased cardiac output) are intimately linked to the

hepatic vascular alterations and the resulting portal hypertension.
SCHEMATIC PRESENTATION OF CIRRHOSIS
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Figure 1(Vascular and architectural alterations in cirrhosis)

Mesenteric blood flows via the portal vein and the hepatic artery
BAMC-KC
that extend branches into terminal portal tracts.

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BAMC-KC
 NORMAL LIVER:
 Terminal portal tract blood runs through the hepatic sinusoids where
liverliver
fenestrated sinusoidal endothelium which rest on loose connective tissue

(space of Disse’) allow for extensive metabolic exchange with the lobular
cirrhosis
cirrhosis
hepatocytes;
 sinusoidal blood is collected by terminal hepatic venules which disembogue
into one of the 3 hepatic veins and finally the caval vein.
 CIRRHOSISED LIVER:
 Activated myofibroblasts that derived from perisinusoidal hepatic stellate
cells and portal or central vein fibroblasts proliferate and produce excess
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BAMC-KC
extracellular matrix (ECM).

BAMC-KCliver
 This leads to fibrous portal tract expansion, central vein fibrosis and
capillarization of the sinusoids, characterized by loss of endothelial
fenestrations, congestion of the space of Disse’ with ECM, and
livercirrhosis
separation/encasement of perisinusoidal hepatocyte islands from sinusoidal

cirrhosis
blood flow by collagenous septa.

 Blood is directly shunted from terminal portal veins and arteries to central
veins, with consequent (intrahepatic) portal hypertension and compromised
liver synthetic function
MOLECULAR PATHOLOGY OF HEPATIC FIBROSIS AND

CIRRHOSIS
 The scar tissue in cirrhosis is composed of a complex assembly of
different extracellular matrix (ECM) molecules, comprising the
fibril forming interstitial collagens type I and III, basement
membrane collagen type IV, noncollagenous glycoproteins like
fibronectin and laminin, elastic fibers and glycosaminoglycans
and proteoglycans among others .
 Toxins, viruses, cholestasis, or hypoxia can trigger a wound
healing reaction termed fibrogenesis, i.e., the excess synthesis
and deposition of ECM.
 Initially, fibrogenesis is counterbalanced by removal of excess
ECM by proteolytic enzymes, such as certain matrix

metalloproteinases (MMPs) .
 Chronic damage usually favours fibrogenesis over fibrolysis,
with an upregulation of tissue inhibitors of MMPs (TIMPs) .
 The major hepatic ECM producing cells are myofibroblasts that
either derive from activated hepatic stellate cells (HSC) or
perivascular fibroblasts.
 Myofibroblast activation is mainly driven via fibrogenic
cytokines and growth factors that are released by activated
macrophages (Kupffer cells), other inflammatory cells and bile
duct epithelia .
 The most prominent profibrogenic cytokine is transforming
growth factor β which suppresses inflammation, but drives

fibrogenic gene expression in these Myofibroblasts .
5.SIGNS & SYMPTOMS
CLINICAL PRESENTATION :
 Cirrhosis is frequently indolent, asymptomatic and
unsuspected until complications of liver disease present. A
sizable proportion of these patients never come to clinical
attention, and previously undiagnosed cirrhosis is still
frequently found at autopsy .
 The diagnosis of asymptomatic cirrhosis is usually made
when incidental screening tests such as liver transaminases or
radiologic findings suggest liver disease and patients undergo
further evaluation and liver biopsy.
 The recognition that 20% of HCV patients and perhaps as
many as 10% of patients with NASH may progress to

cirrhosis has led to the frequent use of biopsy in these high
risk groups prior to development of clinical signs of
cirrhosis.
 However, initial clinical presentation of patients with
decompensated cirrhosis is still common and is characterized
by the presence of dramatic and life-threatening
complications, such as variceal hemorrhage, ascites,
spontaneous bacterial peritonitis, or hepatic encephalopathy.
General physical and laboratory signs that are frequently found in cirrhosis
are summarized in tables As follows from next page,
GENERAL
FINDINGS DESCRIPTION ETIOLOGY
Jaundice Yellow Compromised hepatocyte
discoloration of excretory function, occurs when
skin, cornea and serum bilirubin >2mg/ dl
mucous membranes
Spider angiomata Central arteriole Elevated estradiol, decreased
with tiny radiating estradiol degradation in liver
vessels, mainly on
trunk and face
Nodular liver Irregular, hard Fibrosis, irregular regeneration
surface on palpation
Splenomegaly Enlarged on Portal hypertension, splenic
palpation or in congestion
ultrasound
Ascites Proteinaceous fluid Portal hypertension
in abdominal cavity,
clinically detected
when ≥1.5 L
Caput medusae Prominent veins Portal hypertension, reopening
radiating from of the umbilical vein that
umbilicus shunts blood from the portal
vein
Cruveilhier Epigastric vascular Shunts from portal vein to
Baumgarten murmur umbilical vein branches, can
syndrome be present without Caput
medusae
Palmar erythema Erythema sparing Elevated estradiol, decreased
the central portion of estradiol degradation in liver
the palm
White nails Horizontal white Hypoalbuminemia
bands and/or
proximal white
nail plate
Hypertrophic Painful proliferative Hypoxemia due to right-to-
osteoarthropathy/ osteoarthropathy of left shunting, porto-
Finger clubbing long bones pulmonary hypertension
Dupuytren’s Fibrosis and Enhanced oxidative stress,
contracture contraction of the elevated hypoxanthine (alcohol
palmar fascia exposure or diabetes)
Gynecomastia, Benign proliferation Enhanced conversion of
loss of male hair of glandular male androstenedione to estrone and
pattern breast tissue estradiol, decreased estradiol
degradation in liver
Hypogonadism Mainly in Direct toxic effect of alcohol or
alcoholic cirrhosis iron
and
hemochromatosis
Flapping tremor Asynchronous Hepatic encephalopathy,
(asterixis) flapping motions disinhibition of motor neurons
of dorsiflexed
hands
Foetor hepaticus Sweet, pungent Volatile dimethylsulfide,
smell especially in portosystemic
shunting and liver failure
Anorexia, fatigue, Occurs in >50% of Catabolic metabolism by
weight loss, muscle cirrhotics diseased liver, secondary to
wasting anorexia
6.LAB INVESTIGATION & IMAGINORY TECHNIQUE IN
DIAGNOSING LIVER CIRRHOSIS
 INTRODUCTION
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 Ultrasonography, computerized tomography (CT) and magnetic resonance

imaging (MRI) are not sensitive to detect cirrhosis, and final diagnosis still
relies on histology.
 However, their specificity is high when an obvious cause is present and
imaging reveals an inhomogeous hepatic texture or surface, rarefied hepatic
central vein, an enlarged caudate lobe, splenomegaly or collateral veins.
 However, other etiologies such as portal vein thrombosis, parasitic diseases
or hematological malignancies need to be excluded, and normal radiographic
findings do not exclude compensated cirrhosis. The major role of radiography
is for the detection and quantitation of complications of cirrhosis, i.e., ascites,
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HCC, and hepatic or portal vein thrombosis.

 ULTRASONOGRAPHY
 Ultrasonography provides important information on hepatic architecture, is
cheap and widely available. Nodularity and increased echogenicity of the
liver are often found in cirrhosis but are also present in steatosis.
 There is typically atrophy of the right lobe and hypertrophy of the left and
especially caudate lobes. However, the width of the caudate relative to the
right lobe is a poor predictor of cirrhosis .
 Ultrasonography and Doppler ultrasonography of portal and central vein
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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. Their appearance after antecubital injection
is correlated inversely with fibrosis .
 Ultrasonography is the first imaging modality for suspected HCC, but its
sensitivity and specificity to detect HCC is below that of CT or MRI , and
nodular lesions should be confirmed by helical CT and/or MRI.
 A high degree of suspicion, e.g., in patients with an alfa-fetoprotein above
200 μg/L, or pretransplant evaluation requires these more rigorous techniques
even in the absence of ultrasonographic lesions.
 Contrast ultrasonography, harmonic imaging and power Doppler improve
detection of HCC via sensitive visualization of abnormal vessels but are not
yet generally available .
CT & MRI
 Conventional CT and MRI are not useful to define the severity of cirrhosis ,
while helical CT and MRI with contrast are the modalities of choice when
HCC or vascular lesions are suspected . In a comparison MRI was superior to
helical CT for detection of small HCC of 1-2cm size . MRI has also been
shown to be effective in determining hepatic iron and fat content in
hemochromatosis and liver steatosis,respectively .
 Elasticity measurement (Fibroscan) is a promising technique based on the
velocity of an elastic wave via an intercostally placed transmitter.
 Shear wave velocity is determined by pulse ultrasound and correlates with
liver stiffness, i.e., fibrosis. The examination is limited by morbid obesity,
ascites and small intercostal spaces.
 In a study of 327 patients with hepatitis C, histological cirrhosis was
differentiated from milder stages of fibrosis with a receiver- operating
characteristics (ROC) curve of 0.97 which is considered an almost ideal test .
 Elasticity scans have the ability to sample 1/500 of the liver and represent a
useful, non-invasive test for diagnosing or excluding cirrhosis.
CT SCAN
MRI
LABORATORY DESCRIPTION ETIOLOGY
TEST
AST and ALT Often normal or Leakage from damaged
moderately elevated hepatocytes; AST to ALT
ratio often above 1,
especially in alcoholic
cirrhosis (relative vitamin B6
deficiency)
ALP Elevated <3-fold, except Cholestasis

for PBC and PSC
GGT More specific for liver Cholestasis
than ALP, high in active
alcoholics
Bilirubin Elevated later than Cholestasis, decreased
GGT and ALP, hepatocyte and renal
important predictor of excretory function
mortality (exacerbated by systemic
inflammation)
Albumin Decreased in advanced Decreased hepatic
cirrhosis production, sequestration into
ascites and interstitium
(exacerbated in systemic
inflammation),
DD: malnutrition, protein
losing enteropathy
Prothrombin Decreased in advanced Decreased hepatic
time cirrhosis production of factor V/VII
(While thrombin production
is maintained), DD: vitamin
K deficiency (e.g., due to
mechanical biliary
obstruction)
Immune Increased (mainly IgG) Shunting of portal venous

globulins blood carrying (intestinal)
antigens to lymph tissues
with resultant stimulation of
plasma cells (26)
Sodium Hyponatremia Unability to excrete free
imbalance water via the kidneys due to
increased activity of
antidiuretic hormone
(vasopressin 2 receptor effect)
(27)
Anemia Macro-, normo- or Folate deficiency,
microcytic anemia hypersplenism, direct toxicity
(alcohol), gastrointestinal
blood loss (e.g., via
esophageal varices)
Thrombocytes Thrombocytopenia Hypersplenism,
and leukocytes (Leukopenia) dysfibronogenemia,
reduced hepatic A
thrombopoietin production b
b
(28) r
eviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase;
DD, differential diagnosis; GGT, gamma glutamyl transpeptidase; PBC, primary biliary cirrhosis; PSC,
primary sclerosing cholangitis
LIVER BIOPSY
 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. However, biopsy is prone to considerable
sampling variability in all liver diseases .
 Thus when staging fibrosis in hepatitis C patients using the METAVIR
system which is simple and uses only 4 stages (stage 4 being cirrhosis), one
third of scores differed by at least one stage when a biopsy from the left liver
lobe was compared to that from the right lobe, and with similar results for
grading of inflammation .
 In hepatitis C, correct staging was only achieved for 65% and 75% of cases
when biopsies were 15 mm and 25 mm in length, respectively , while in
clinical practice only 16% of biopsies reach 25mm in length. Despite these
shortcomings, biopsy is still required to confirm cirrhosis in patients with
compensated liver function and to suggest its cause.
 Biopsy confirmation of cirrhosis is not necessary when clear signs of
cirrhosis, such as ascites, coagulopathy, and a shrunken nodular appearing
liver are present.
 either a (radiographically-guided) percutaneous, a transjugular or
laparoscopical route. A greater risk of bleeding following a biopsy has been
observed with larger-diameter needles.
 In suspected cirrhosis a cutting is preferred over a suction needle, in order to
prevent tissue fragmentation .
 2 to 3 percent of patients require hospital admission for management of
complications; pain or hypotension are the predominant causes.
 60% of complications occur within two, and 96% within 24 hours after
biopsy.
 Mortality, mainly due to severe bleeding is 1 in 10,000 to 12,000, and likely
higher in cirrhosis .
 Blood products should be replaced when platelets are below 70,000/μL or
prothrombin time is prolonged by more than four seconds, and/or a
transjugular or laparoscopic approach chosen. Aspirin and other anti-platelet
agents should be stopped at least a week before biopsy.
ETIOLOGY SPECIFIC DIAGNOSTIC VALUE
PHYSICAL (LABORATORY) OF
ASSOCIATIONS PARAMETERS LIVER
BIOPSY
HBV Arthritis HBsAg, (HBeAg), +
anti-HBc, HBV-DNA
HCV Cryoglobulinemia, anti-HCV, HBV-RNA +
HDV (HBsAg), anti-HDV, ++ (HDAg)
HDV-RNA
Alcoholic AST/ALT ≥2, CDT↑, ++
γGT↑ (Mallory
bodies,
steatosis,
granulocyt
es
>hepatocyte
ballooning)
NASH Overweight/obesity Uric acid, fasting ++ (Mallory
, metabolic glucose/insulin/triglyce bodies,
syndrome, type 2 rides, steatosis,
diabetes hepatocyte
ballooning>
granulocyte
s)
Autoimmune Autoantibodies +++
(ANA, anti-LKM, (bridging
anti-SLA), γ- necrosis)
globulins↑↑
PBC Sicca-syndrome, AMA, ALP/γGT↑, ++
xanthelasma cholesterol↑ (cholangitis
, paucity of
bile ducts,
granuloma,
ductopenia)
PSC Ulcerative colitis Anti-pANCA (70%), +++
(90%) ALP/γGT↑ (concentric
imaging: beaded intra- peri-bile
(and extra-) hepatic ductular
bile ducts fibrosis,
ductopenia)
Hemochrom Arthritis, Fasting transferrin ++
atosis myocarditis, saturation >60% (♂), (periportal
diabetes >50% (♀), ferritin↑↑, Fe- loaded
HFE mutation hepatocytes,
quant. liver
Fe
Wilson’s Neurological Coeruloplasmin↓, +++ (quant.
urinary Cu (24h) ↑, liver Cu)
slit-lamp: corneal
Cu deposits
α1- Pulmonary fibrosis α1-AT ↓, +++ (α1-
Antitrypsin α1-AT subtyping AT-
loaded
hepatocytes
)
Congenital +++ (bile
ductular
plate
malformati
ons etc.)
A1-AT, α1 antitrypsin; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibodies; CDT,
carbohydrate deficient transferrin; Cu, copper; Fe, iron; HBV/ HCV/HDV, hepatitis B/C/D virus;
HBc/HBe/HBs Ag, hepatitis B core/envelope/surface antigen; LKM, liver kidney membrane; SLA, soluble
liver antigen; pANCA, perinuclear neutrophil cytoplasmic antigen.
NONINVASIVE MARKERS OF FIBROGENESIS AND FIBROLYSIS
 Non-invasive serological markers to cross-sectionally stage liver fibrosis

have been extensively reviewed . Although showing potential,
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particularly for the diagnosis of cirrhosis, none meet the criteria for an
ideal surrogate fibrosis marker.
 A problem is the heterogeneity of liver diseases, with different stages
being present in different areas of the liver, particularly between stages 1
to 3. These markers either reflect hepatic function or turnover of the
ECM.
 Combinations have been developed since no single biomarker has
adequate sensitivity and specificity.
 Unfortunately, current ECM-derived serum markers correlate mainly
with fibrosis stage, and to a lesser degree with fibrogenesis.
 We consider the performance of the majority of these biomarkers to be
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similar with a diagnostic accuracy approaching 80% for the

differentiation between mild fibrosis and moderate to severe fibrosis .
 However, the performance is consistently better at both spectrums of
disease from no fibrosis to cirrhosis, and importantly, for predicting
cirrhosis.
 Hepatic elasticity measurement (Fibroscan) in combination with these
serum indices may yield a better prediction of histological fibrosis than
either test alone , and a recent study showed that Fibroscan was superior
to Fibrotest in hepatitis C patients with persistently normal or low
transaminases .
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 Several of these tests are now available for use in clinical practice and
there is a clinical role for surrogate fibrosis markers. A simple algorithm
for using biomarkers is given in .
 The major focus for research is to identify new biomarkers that allow
assessment of the dynamic processes of fibrogenesis and fibrolysis, in
order to monitor the effect of antifibrotic therapies in patients.
 This may be achievable with serum proteomics or glycomics , or novel
imaging techniques for sensitive assessment of fibrogenesis representing
the whole liver.
 Such techniques could be based on CT or MRI imaging with the use of
contrast media that target activated HSC.
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 Their validation likely requires parallel analysis of the liver

transcriptome of patients with slow or rapid fibrosis progression , an
approach that requires invasive sampling of liver tissue.
 Numerous agents with proven direct and indirect antifibrotic effects in
experimental animals would merit clinical testing , and efficient reversal
therapies likely require antifibrotic drug combinations .
 Of note, many potential antifibrotics possess a reasonable safety profile,
while their long-term safety in cirrhotic patients has to be proven.
However, optimization of such treatment heavily relies on the
availability of sensitive non-invasive markers or techniques that allow
their rapid testing in low numbers of patients.
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 In order to achieve quick restitution of the functional parenchymal mass in

concert with reversal of cirrhosis, the combination of antifibrotic therapy
and hepatocyte renewal is attractive.
 Thus hepatocyte transplantation improved liver function and ameliorated
or even reversed advanced fibrosis .
 Hepatocyte engraftment was increased by oxidative preconditioning and
HSC activation , and infusion of HGF, a potent hepatocyte mitogen,
improved liver function .
 The isolation and in vitro expansion of hepatocyte stem or progenitor
cells for cell transplantation may hold promise for an unlimited donor
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pool .
 Reports that infusion of bone marrow stem cells replenished hepatocytes,
either by hepatocytic transdifferentiation , fusion with hepatocytes , or
indirectly by hepatotrophic growth factors released from stem cells
engrafted in the hepatic vasculature sparked much enthusiasm.
 However, efficiency of stem or progenitor cell engraftment is generally
low and the manipulations that are currently needed to allow for
sufficient engraftment in humans would incur great risks for patients
with cirrhosis and liver failure, necessitating considerable refinement
before this techniques can be applied to patients.
 Similarly, the observation that genetic restitution of telomerase, an
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enzyme that abrogates cellular ageing by preventing chromosomal

telomer shortening, can accelerate hepatic regeneration and ameliorate
experimental liver fibrosis has evoked much interest .
 However, increased telomerase activity also favours
hepatocarcinogenesis which dampens the enthusiasm for this approach .
UTILIZATION OF BIOMARKERS FOR STAGING LIVER

FIBROSIS AND DIAGNOSIS OF CIRRHOSIS
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7.TREATMENT AND REVERSIBILITY OF CIRRHOSIS
 Elimination of the triggerthat lead to cirrhosis is likely to retard

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progression to a higher CPT class and to reduce the incidence of

HCC. There is evidence that causal treatment may even reverse
cirrhosis, although in some of the reports sampling variability
cannot be excluded.
 Patients with alcoholic cirrhosis must abstain, since continued
alcohol consumption drives hepatitis which favours hepatic
fibrogenesis and decompensation . Liver function often worsens
in the first 2-3 weeks of withdrawal, since alcohol has an
immunosuppressive effect .
 Patients with compensated replicating HCV-cirrhosis benefit
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from interferon-based antiviral treatment.

 Viral eradication and a consequently lowered risk of hepatic
decompensation and hepatocellular carcinoma can be achieved
in up to 40 and 70% of patients with genotypes 1 and 2 or 3,
respectively .
 In a recent meta-analysis 75 out of 153 biopsy-proven cirrhotics
showed reversal of cirrhosis on biopsy after successful treatment
, but results need conformation in view of biopsy sampling
variability.
 How far maintenance interferon for 3-4 years can prevent
hepatic decompensation or hepatocellular carcinoma in subjects
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with stage 3 or 4 fibrosis who did not respond to interferon-

ribavirin therapy is currently evaluated in large prospective
trials (HALT-C, EPIC-3 and COPILOT) .
 Longterm treatment with oral nucleoside and nucleotide
inhibitors of HBV polymerase may not only retard or reverse
cirrhosis but were also shown to prevent complications of end
stage liver disease.
 In a 3 year study of lamivudine for HBV, follow up liver
biopsies suggested reversal of cirrhosis in 8/11 patients (73%)
and in 436/651 patients with HBV-cirrhosis treated with
lamivudine for a mean of 32 months a >50% reduction of hard
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clinical endpoints, as defined by hepatic decompensation,

hepatocellular carcinoma, spontaneous bacterial peritonitis,
bleeding gastroesophageal varices, or death related to liver
disease was attained .
 In replicating HBV-cirrhosis (>105 copies/mL) lamivudine
treatment frequently resulted in clinical improvement, even after
decompensation .
 The high rate of lamivudine resistance which reaches 56% and
70% after 3 and 4 years of treatment, respectively, is now of
lesser concern, since equally well tolerable alternatives like
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adefovir , entecavir or telbivudine , or their combinations are

available which display lower rates of viral resistance and a
different mutational profile.
 In one large study, adefovir treatment was successfully used in
patients with lamivudine resistance pre-transplant, leading to
suppression of HBV viral replication to undetectable levels in
76% of patients with either a stabilization or improvement in
CTP score and a 90% survival .
PHARMACOLOGICAL AND CELLULAR REVERSAL OF HEPATIC
FIBROSIS AND CIRRHOSIS
 Many advances have occurred in the clinical care of patients with

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cirrhosis and the complications of end stage liver disease.

 The majority of these have focused on treatment of the underlying cause
of cirrhosis and management of complications of portal hypertension.
 The next 10 years may see us focus on the primary prevention and
treatment of cirrhosis.
 Examples are the use of non-invasive tests to screen for earlier stages of
fibrosis and to monitor antifibrotic drug effects, and pharmacological
targeting of fibrogenesis pathways.
 Stem cell or hepatocyte transplantation aiming at reconstitution of liver
function may become a clinical reality.
 Continued basic and clinical research is critical to be able to finally
remove cirrhosis as an irreversible condition and a major contributor to
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morbidity and mortality in our patients.
FEASIBILITY OF PHARMACOLOGICAL REVERSAL OF

CIRRHOSIS
 The observations that even cirrhosis can regress once the
fibrogenic trigger is eliminated can be explained by the dynamic
processes of fibrogenesis and fibrolysis
 even in cirrhosis . While the central role of activated HSC
(myofibroblasts) in fibrogenesis is unchallenged, other cells
contribute.
 Thus macrophages/Kupffer cells retarded progression in early
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but promoted progression in advanced fibrosis .

 Furthermore, regression from macro- to micronodular cirrhosis
and possible cirrhosis reversal depends on the degree of ECM
crosslinking, which is catalyzed by enzymes such as tissue
transglutaminase .
 The rapid progress in understanding the molecular mechanisms
that lead to cirrhosis or its reversal have spawned the
development of antifibrotic drugs.
 We can classify the therapeutic approaches to reversal of
fibrosis as primary and secondary.
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 Primary approaches focus on treatment of the underlying

disease such as HBV and HCV that have convincingly been
shown to result in regression of (compensated) cirrhosis .
 The secondary approach is to develop pharmacotherapy that is
directly focused on the mechanism of fibrogenesis, intrinsic
antifibrotic drugs, irrespective of the etiology of the liver
disease.
 The major obstacle to antifibrotic drug development has been
the difficulty in defining validated endpoints for clinical trials.
The combination of a slowly evolving disease (years to decades)
and an established endpoint (liver biopsy) which has limited
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sensitivity and significant sampling variability represents a

stumbling block for study design. In particular, without short
term surrogate markers for liver fibrosis, exploratory studies are
hampered by the need for significant sample size and high risk
of failure.
 MECHANISM OF ANTIFIBROTIC DRUGS
IN PATHOLOGICAL CONDITION
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Initiation and maintenance of fibrogenesis

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 With continuous injury, primarily to hepatocytes or bile duct epithelia,

and / or mechanical stress the normally quiescent hepatic stellate cells and
portal/perivenular fibroblasts undergo activation and transdifferentiation
to myofibroblasts. These myofibroblasts produce excessive amounts of
collagens, downregulate certain matrix metalloproteinases (MMPs) and
show an enhanced expression of the physiological inhibitors of the MMPs
(TIMP-1 and -2). TIMP-1 can also promote myofibroblast proliferation
and inhibit their apoptosis.
ACTION OF ANTI FIBROTIC DRUG AGAINST PATHOLOGY
. Antifibrotic approaches and candidates for combination therapy
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Page 20
A
B
BAMC-KC liver cirrhosi
 An important principle is inhibition of TGFβ, either by blocking

molecules that induce its proteolytic activation from latent
TGFβ, or by its direct inhibition.
cirrhosis
 However, this has to be a targeted approach, since complete

abrogation of TGFβ leads to cellular dedifferentiation and
severe (intestinal) inflammation.
 AT, angiotensin; AT1R, angiotensin 1 receptor; CTGF,
connective tissue growth factor; ET-1, endothelin-1; ETAR,
endothelin A receptor; FASL, FAS ligand; MMF,
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mycophenolate mofetil; MMP, matrix metalloproteinase; NGF,

nerve growth factor; PDGF, platelet derived growth factor;
TGF, transforming growth factor; tPA tissue plasminogen
activator; PPAR, peroxisome proliferator activated receptor.
LIVER TRANSPLANTATION
 The ultimate therapy for cirrhosis and end stage liver disease is liver
transplantation.
 Indications and contraindications for liver transplant are given in.
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The most recent survival data from the United Network of Organ
Sharing (UNOS) indicates a 1 year survival of 83%, a 5 year
survival of 70% and an 8 year survival of 61% .
 Survival is best in patients who are at home at the time of
transplant compared to those who are in the hospital or in the ICU.
 A great advance in liver transplantation has been the improvement
in immunosuppressive regimens so that allograft loss from
rejection is now relatively rare .
 The major issues that remain in the care of the patient post liver
transplantation are recurrent disease in the transplant, particularly
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HCV, and longterm consequences of immunosuppressive agents

such as hypertension, hyperlipidemia and renal disease.
INDICATIONS AND CONTRAINDICATIONS FOR ORTHOTOPIC
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LIVER TRANSPLANTION
INDICATIONS
 Advanced Chronic Liver Failure

 - CPT score > 7
 - Qualifying MELD Score for Organ Allocation
 Acute Liver Failure
 Unresectable Hepatic Malignancy Inherited Metabolic
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Disorders General
 No alternative form of therapy No absolute contraindications
 Willingness to comply with follow up care Ability to provide
for costs of OLT
CONTRAINDICATIONS
 HIV seropositivity Methadone dependence Stage 3 HCC *
 Absolute Extrahepatic malignancy
 AIDS
 Cholangiocarcinoma
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 Severe, uncontrolled systemic infection Multiorgan failure

 Advanced cardiopulmonary disease Active substance abuse
8. COMPLICATIONS OF CIRRHOSIS
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 Turcotte (CPT) classification is widely used .One-year survival

treat the common complicationsof cirrhosis such as variceal
bleeding, ascites, spontaneous bacterial peritonitis and
encephalopathy .
 It is important to note that bacterial infections are frequent,
especially in decompensated cirrhotics, exacerbating hepatic
dysfunction, encephalopathy and portal hypertension and
underlining the need for vigilance and rigorous antibiotic
treatment in cirrhosis.
 Enhanced bacterial translocation from the intestine, a
compromised immune function and an excessive
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proinflammatory cytokine release have been implicated in the

pathogenesis of the cirrhosis-associated systemic inflammatory
syndrome .
 An example is the failure to control esophageal variceal bleeding
with associated bacterial infection .
 An important realization for the clinician is that once
complications have developed, suitable patients should be
referred to a Liver Center that specializes in both the care of
patients with end stage liver disease and liver transplantation.
Special attention has also to be paid to the circulatory and
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cardiac abnormalities in cirrhosis that can preclude transplant

eligibility.
 The hepatopulmonary syndrome which occurs in 15-20% of
cirrhotics is due to overproduction of NO and overexpression of
the endothelin B receptor with consequent pulmonary arteriolar
vasodilation and hypoxemia .
 It is largely reversible after transplantation. Portopulmonary
hypertension is rare, but its prevalence rises to 16-20% of
patients with refractory ascites.
 It is likely caused by an excess of pulmonary arteriolar
vasoconstrictors andbyprofibrogenic
Compilation on liver cirrhosis Nagabharana H.M
factors like TGFβ1 .
guided by Dr . Roopa halder (dept of kaya chikitsa)
 The condition is considered irreversible and a pulmonary artery
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pressure >40 mmHg precludes liver transplantation .

 Cirrhotic cardiomyopathy is characterized by a blunted stress
response of the heart, combined with hypertrophy .
 Severe forms increase postoperative mortality and preclude
transplantation.
HEPATOCELLULAR CARCINOMA
 HCC is one of the commonest solid organ tumors worldwide
and cirrhosis is the major risk factor for progression to HCC .
Other risk factors are listed in Table.
 The pathogenic appears to be the development of regenerative
nodules with small cell dysplasia and then invasive HCC.
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 The mortality rate of HCC associated with cirrhosis is rising in

most developed countries, whereas mortality from non-HCC
complications of cirrhosis is decreasing .
 Cirrhosis due to HCV is associated with the highest HCC
incidence in Japan compared to the West, followed by hereditary
hemochromatosis (5-year cumulative incidence 17-30%).
 In cirrhosis due to HBV, the major cause for HCC-related
deaths in the world, the 5-year cumulative incidence of HCC is
15% in high endemic areas and 10% in the West.
 5-year HCC incidence is lower in alcoholic cirrhotics, or in
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patients with biliary cirrhosis (8% and 4%, respectively).

 HCC is increasing in the USA, where its incidence had
increased from 1.8 per 100,000 to 2.5 per 100,000 over one
decade, mainly attributable to HCV infection .
 Screening for HCC is one of the most important tasks in
following patients with cirrhosis.
 Current AASLD and EASL guidelines recommend at least one
annual screening for HCC in patients with cirrhosis using
imaging with ultrasound, triphasic CT scan or gadolinium
enhanced MRI .
 Serum alfa-fetoprotein,which was an integral component of
prior screening algorithms, is no longer recommended due to its
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poor sensitivity and specificity.

 Once HCC is detected, multiple treatment modalities are
available that depend on tumor size, tumor number and local
expertise.
 In the non-cirrhotic patient, surgical resection is an option and
can be curative. However, most patients with cirrhosis will not
tolerate liver resection or have microscopic satellite lesions, and
the best option for cure is with liver transplantation.
 The Milan criteria have suggested that the mortality and
recurrence rate of HCC is acceptable if liver transplant is
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performed for either a solitary tumor <5cm in diameter or no

more than 3 tumors with the largest being <3cm in diameter.
 Alternative treatments for HCC patients who do not meet the
criteria for surgical resection or transplant are radiofrequency
ablation, chemoembolization, alcohol ablation and cyberknife
radiotherapy .
 Selection of these modalities depends on local expertise, and
randomized trials suggesting that they improve long term
survival are scarce.
RISK FACTORS FOR HEPATOCELLULAR CARCINOMA
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 Cirrhosis Decompensated cirrhosis

 Viral Hepatitis B and C
 NASH
 Type 2 diabetes
 Aflatoxin exposureCo-infection with multiple viruses;
 HBV, HCV and HIV (risk 2-6 fold)
 Increasing Age
 Male Sex
 Positive family history of HCC
 Associated secondary alcohol abuse (risk 2-4 fold) or NASH as a co-factor
COMPLICATIONS OF CIRRHOSIS, THEIR PREVENTION AND
TREATMENT
TIPSS: Transjugular intrahepatic porto-systemic shunt; vasoconstrictors:
vasopressin, octreotide/somatostatin, terlipressin; non-selective beta blockers:
nadolol, propranolol
COMPLICATION PREVENTION TREATMENT
Variceal bleeding Non selective Acute: Resuscitaton

beta blockers Vasocontrictors Sclerotherapy
Band Ligation
Variceal TIPSS
band ligation Surgical Shunts
Chronic: Variceal obliteration

TIPS
Surgical Shunts
Ascites Low sodium

diet Low sodium diet
Diuretics
Large volume paracentesis
TIPSS(Leveen / Denver shunts)
Renal failure Avoid

hypovolemia Discontinue diuretics
Rehydration
Albumin infusion
Hepato renal syndrome :

Add Terlipressin or Mido drine
(noradrenaline) & Somatostatin
(Octreotide)
Encephalopathy Avoid precipitants Treat precipitating factors ,like Infection , bleeding,
Electrolyte imbalance.
Rx.
Sedatives, Neomycin, Metronidazole
High protein intake & Lactulose
Spontaneous bacterial Treat Ascites

peritonitis
Early diagnostic paracentesis
Antibiotics
Secondary prophlaxis with antibiotics such as
Levofloxacin
HEPATO PROTECTIVE DRUGS

• Sharapunkha (Tephrosa purpurea) • Bhoomyamalaki (Phyllanthus neruri)
• Rohitaka(Tecoma undulata) • Katukarohini (Picrorhiza kurroa)
• Pippali - Long pepper (Piper longum) • Kumari (Aloe vera)
• Draksha - raisins (Vitis vinifera) • Aragwadha(Cassia fistula)
• Guduchi - Giloy (Tinospora cardifolia) • Bhringaraja (Eclipta alba)
•
• Punarnava (Boerrhavia diffusa) • Amalaki (Emblica officinalis)
•
• Nimba - Neem Patola - pointed gourd • Neeli (Indigofera
• Parpataka(Pumaria parviflora) tinctoria)
• Kiratatikta (Swertia chirata)
• Bhoonimba (Andrographis paniculata)
• Daruharidra (Berberis aristata)
SOME IMPORTANT FORMULATIONS

• Arogyavardhini Vati • Vidaradi asava
• Kumaryasava. • Mahatiktakam Kashayam
• amalaki choorna • Vasaguluchyadi Kashayam
• Pathya katphaladi Kashaya • Lohasavam
• Rohitakarishtha • Mridwikasavam
• Pippalyasava • Ayaskriti
•
• Guduchi satwa • Loha bhasma
• Punarnavasava • Mandura Bhasma
• Bhoonimbadi khada • Punarnava Mandura
• Patola katu rohinyadi kashaya • Loha Mandura
• Avipattikara choorna • Rasasindhoora
• Danti haritaki leham • Mandura Vataka
• Drakshadi leham etc . • Chinchadi leham
9. NATURAL HISTORY AND PROGNOSIS
The natural history of cirrhosis is dependent on both the etiology and

treatment of the underlying cause. Annual rates of decompensation are
4% for HCV, 10% for HBV and the incidence of HCC is between 2 - 7%
per year.
 Decompensation in alcoholic cirrhosis with continued alcohol
use is even more rapid and often associated with alcoholic
hepatitis on a background of cirrhosis.
** Compilation on liver cirrhosis by Nagabharana H.M guided by Dr . Roopa halder (dept of kaya chikitsa)
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 Once decompensation has occurred, mortality without

transplant is as high as 85% over 5 years.
 Numerous studies have attempted to develop a classification
system that can both characterize the degree of liver injury and
predict the prognosis of patients with cirrhosis based on clinical
and laboratory parameters.
 Due to its low level of complexity and its fairly good predictive
value, the Child-Pugh-rates for patients with CPT A, B, and C
cirrhosis are 100, 80, and 45 percent, respectively
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 CPT class predicts the development of complications, such as

variceal hemorrhage and the response of patients to surgical
interventions .
 More recently with the pressure in the allocation of scarce liver
donors for transplantation, the Model for End Stage Liver
Disease (MELD) has been developed to more precisely evaluate
short term mortality .
 MELD best predicts 3 month survival of cirrhotics, irrespective
of etiology.
 It is based on creatinine, bilirubin and INR, but lacks features
of portal hypertension, such as ascites.
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 It gives priority to patients who are most likely to die without a

liver transplant, such as those with hepatorenal failure.
 In the USA the replacement of the former individualized
system of organ allocation, which was heavily based on waiting
time, by MELD reduced mortality on the waiting list without
change in post-transplant outcome.
 The system is currently considered for further refinement, such
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as giving extra points to patients with HCC and hyponatremia
<130mEq/mL . CPT and MELD scores can vary greatly when
single parameters are modified by medical treatment, such as
substitution of albumin, removal of ascites or diuretic treatment.
Here, an increasing MELD score over time is a better predictor
of cirrhosis severity and progression
RECENT ADVANCES AND FUTURE DIRECTIONS

Genetic predisposition for cirrhosis
 The variable rates of development of cirrhosis amongst
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individuals with similar risk factors such as HCV or alcohol

abuse had long been unexplained. Recently, a growing number
of functional genetic polymorphisms that likely
 increase the risk of fibrosis progression has been described.
Implicated genes encode cytokines/chemokines and their
receptors , molecules involved in fibrogenesis or fibrolysis ,
blood coagulation , antigen presentation , iron uptake , oxidative
and antioxidative metabolism , detoxification and polygenetic
traits linked to the metabolic syndrome and NASH.
 In a recent gene association study 1,609 out of 24,882 single
nucleotide polymorphisms (SNPs) were found to be associated
with fibrosis progression in chronic hepatitis C, with the DDX5
gene having a high positive predictive value .
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 Together with established extrinsic risk factors like excess

alcohol consumption, obesity or advanced age these SNPs will
allow the establishment of risk profiles for the individual patient
LIVER BIOPSY
COMPLICATIONS OF LIVER CIRRHOSIS
PARACENTESIS FOR ASCTIS
my Final verdict about cirrhosis
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 liver cirrhosis is a kind of disease which happens due to different

kind of causes which is discussed as earlier in this Compilation.
 Whatever may be the cause , the main thing which happens here is
the normal physiology of healing is altered and more more fibrotic
changes happens in liver cells.
 This disease alters the normal anatomical as well as physiological
character of hepatic cells thus compromising liver function.
 So in order to avoid cirrhosis and cirrhosis induced ESLD ( end
stage liver disease like HCC ) one should take care of their liver's
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health over the years.

 People should get educated by health professionals about.
 alcohol intake & social support- helping individual to get rid of
any kind of addiction which leads to liver cirrhosis.
 educating about food & life style which plays an important role in
the condition such as fatty liver disease.
 ayurveda graduates should look in to help population with the
motto - ‘’ swasthasya swasthya rakshanam’’ (keeping healthy
individuals as healthy) instead of working only under motto ‘’
aturasya vikara prashamanam’ (treating the disordered).
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 The role of ayurveda Vaidyas is significant in the upcoming

decades to educate people in forms of simple food charts /
nutrition plans in accordance with dosha , rasa , prakriti, kala
which will save the patients from suffering in ICU & getting
expensive treatments like Albumin infusion/ Terlipressin abuse,
excessive abdominal tapping in the later phase of live this.
 These statement may look silly but it will be heart of next trend in
health system.
 educating people about vaccine preventable hepatitis mainly
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hepatitis B as it is the most dangerous type with high incidence of

HCC / other ESLD ( end stage liver disease).
 Finally, I would like to conclude by saying that everyone should
take care of their liver and give it as much as importance as they
give for their heart .
“A good hearted person can die with bad liver inside him.”
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- Nagu Hollatti
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Compilation on liver cirrhosis by Nagabharana H.M guided by Dr .

Roopa halder (dept of kaya chikitsa)

progression to decompensated cirrhosis or even reverse cirrhosis are

9-44 45-68 69–88 89–104 105–122 123–152

 The exact prevalence of cirrhosis worldwide is unknown. Cirrhosis

 The etiology of cirrhosis can usually be identified by the patient’s history

discussion of preventive measures, e.g., with family members of patients

response resulting in an abnormal continuation of fibrogenesis

sheet of permeable connective tissue (the space of Disse) which contains

 The major clinical consequences of cirrhosis are impaired hepatocyte

 The general circulatory abnormalities in cirrhosis (splanchnic

salt retention, increased cardiac output) are intimately linked to the

Figure 1(Vascular and architectural alterations in cirrhosis)

that extend branches into terminal portal tracts.

fenestrated sinusoidal endothelium which rest on loose connective tissue

extracellular matrix (ECM).

separation/encasement of perisinusoidal hepatocyte islands from sinusoidal

blood flow by collagenous septa.

MOLECULAR PATHOLOGY OF HEPATIC FIBROSIS AND

ECM by proteolytic enzymes, such as certain matrix

growth factor β which suppresses inflammation, but drives

many as 10% of patients with NASH may progress to

are summarized in tables As follows from next page,

 Ultrasonography, computerized tomography (CT) and magnetic resonance

HCC, and hepatic or portal vein thrombosis.

ALP Elevated <3-fold, except Cholestasis

Immune Increased (mainly IgG) Shunting of portal venous

 Biopsy is considered the gold standard for diagnosis of cirrhosis, and

 Non-invasive serological markers to cross-sectionally stage liver fibrosis

similar with a diagnostic accuracy approaching 80% for the

 Their validation likely requires parallel analysis of the liver

 In order to achieve quick restitution of the functional parenchymal mass in

enzyme that abrogates cellular ageing by preventing chromosomal

UTILIZATION OF BIOMARKERS FOR STAGING LIVER

 Elimination of the triggerthat lead to cirrhosis is likely to retard

progression to a higher CPT class and to reduce the incidence of

from interferon-based antiviral treatment.

with stage 3 or 4 fibrosis who did not respond to interferon-

clinical endpoints, as defined by hepatic decompensation,

adefovir , entecavir or telbivudine , or their combinations are

 Many advances have occurred in the clinical care of patients with

cirrhosis and the complications of end stage liver disease.

morbidity and mortality in our patients.

FEASIBILITY OF PHARMACOLOGICAL REVERSAL OF

but promoted progression in advanced fibrosis .

 Primary approaches focus on treatment of the underlying

sensitivity and significant sampling variability represents a

Initiation and maintenance of fibrogenesis

 With continuous injury, primarily to hepatocytes or bile duct epithelia,

BAMC-KC liver cirrhosis

 An important principle is inhibition of TGFβ, either by blocking

 However, this has to be a targeted approach, since complete

mycophenolate mofetil; MMP, matrix metalloproteinase; NGF,

HCV, and longterm consequences of immunosuppressive agents

 Advanced Chronic Liver Failure

 Severe, uncontrolled systemic infection Multiorgan failure

 Turcotte (CPT) classification is widely used .One-year survival

proinflammatory cytokine release have been implicated in the