Vitebsk state medical university

Pathological physiology department.

Liver cirrhosis

Student; pathkunaraja ramraj

Group:40
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Content

Topic page

Definition 3

Signs and symptoms 4-5

Complicatio 6-7

Causes 7-9

Pathopysiology 10

Diagnosis 11

Lab findings 11-13

Pathology 13-14
Preventing complications 16-17

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Defintion

Cirrhosis  is a consequence of chronic liver disease characterized by replacement of

liver tissue by fibrosis, scar tissue and regenerative nodules (lumps that occur as a
result of a process in which damaged tissue is regenerated), leading to loss of liver
function. Cirrhosis is most commonly caused by alcoholism, hepatitis B and C, and fatty
liver disease, but has many other possible causes. Some cases are idiopathic, of
unknown cause.

Ascites (fluid retention in the abdominal cavity) is the most common complication of

cirrhosis, and is associated with a poor quality of life, increased risk of infection, and a
poor long-term outcome. Other potentially life-threatening complications are hepatic
encephalopathy (confusion and coma) and bleeding from esophageal varices. Cirrhosis
is generally irreversible, and treatment usually focuses on preventing progression and
complications. In advanced stages of cirrhosis the only option is a liver transplant.

The word "cirrhosis" derives from Greek meaning yellowish, tawny (the orange-yellow

colour of the diseased liver) + Eng. med. suff. -osis. While the clinical entity was known
before, it was René Laennec who gave it the name "cirrhosis" in his 1819 work in which
he also describes the stethoscope.

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Signs and symptoms

Some of the following signs and symptoms may occur in the presence of cirrhosis or as

a result of the complications of cirrhosis. Many are nonspecific and may occur in other
diseases and do not necessarily point to cirrhosis. Likewise, the absence of any does
not rule out the possibility of cirrhosis.

 Spider angiomata or spider nevi. Vascular

lesions consisting of a central arteriole surrounded by many smaller vessels
because of an increase in estradiol. These occur in about 1/3 of cases
 Palmar erythema. Exaggerations of normal
speckled mottling of the palm, because of altered sex hormone metabolism.
 Nail changes.
 Muehrcke's lines - paired horizontal bands separated by normal color
resulting from hypoalbuminemia (inadequate production of albumin).
 Terry's nails - proximal two-thirds of the nail plate appears white with distal
one-third red, also due to hypoalbuminemia
 Clubbing - angle between the nail plate and proximal nail fold > 180
degrees
 Hypertrophic osteoarthropathy. Chronic
proliferative periostitis of the long bones that can cause considerable pain.
 Dupuytren's contracture. Thickening and
shortening of palmar fascia that leads to flexion deformities of the fingers. Thought to
be caused by fibroblastic proliferation and disorderly collagen deposition. It is
relatively common (33% of patients).
 Gynecomastia. Benign proliferation of
glandular tissue of male breasts presenting with a rubbery or firm mass extending
concentrically from the nipples. This is caused by increased estradiol and can occur
in up to 66% of patients.

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 Hypogonadism. Manifested as impotence,
infertility, loss of sexual drive, and testicular atrophy because of primary gonadal
injury or suppression of hypothalamic or pituitary function.
 Liver size. Can be enlarged, normal, or
shrunken.
 Splenomegaly (increase in size of the
spleen). Caused by congestion of the red pulp as a result of portal hypertension.
 Ascites. Accumulation of fluid in the
peritoneal cavity giving rise to flank dullness (needs about 1500 mL to detect flank
dullness).
 Caput medusa. In portal hypertension, the
umbilical vein may open. Blood from the portal venous system may be shunted
through the periumbilical veins into the umbilical vein and ultimately to the abdominal
wall veins, manifesting as caput medusa.
 Cruveilhier-Baumgarten murmur. Venous
hum heard in epigastric region (on examination by stethoscope) because of
collateral connections between portal system and the remnant of the umbilical vein
in portal hypertension.
 Fetor hepaticus. Musty odor in breath as a
result of increased dimethyl sulfide.
 Jaundice. Yellow discoloring of the skin,
eye, and mucus membranes because of increased bilirubin (at least 2–3 mg/dL or
30 mmol/L). Urine may also appear dark.
 Asterixis. Bilateral asynchronous flapping
of outstretched, dorsiflexed hands seen in patients with hepatic encephalopathy.
 Other. Weakness, fatigue, anorexia, weight
loss.

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Complication

As the disease progresses, complications may develop. In some people, these may be
the first signs of the disease.

 Bruising and bleeding resulting from decreased production of coagulation factors.

 Jaundice as a result of decreased processing of bilirubin.
 Itching (pruritus) because of bile salt products deposited in the skin.
 Hepatic encephalopathy - the liver does not clear ammonia and related
nitrogenous substances from the blood, which are carried to the brain, affecting
cerebral functioning: neglect of personal appearance, unresponsiveness,
forgetfulness, trouble concentrating, or changes in sleep habits.
 Sensitivity to medication caused by decreased metabolism of the active
compounds.
 Hepatocellular carcinoma is primary liver cancer, a frequent complication of
cirrhosis. It has a high mortality rate.
 Portal hypertension - blood normally carried from the intestines and spleen
through the hepatic portal vein flows more slowly and the pressure increases; this
leads to the following complications:
 Ascites - fluid leaks through the vasculature into the abdominal
cavity.
 Esophageal varices - collateral portal blood flow through vessels
in the stomach and esophagus. These blood vessels may become enlarged and
are more likely to burst.

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 Problems in other organs.
 Cirrhosis can cause immune system dysfunction, leading
to infection. Signs and symptoms of infection may be aspecific are more difficult
to recognize (e.g., worsening encephalopathy but no fever).
 Fluid in the abdomen (ascites) may become infected with
bacteria normally present in the intestines (spontaneous bacterial peritonitis).
 Hepatorenal syndrome - insufficient blood supply to the kidneys,
causing acute renal failure. This complication has a very high mortality (over
50%).
 Hepatopulmonary syndrome - blood bypassing the normal lung
circulation (shunting), leading to cyanosis and dyspnea (shortness of breath),
characteristically worse on sitting up
 Portopulmonary hypertension - increased blood pressure over
the lungs as a consequence of portal hypertension
 Portal hypertensive gastropathy which refers to changes in
the mucosa of the stomach in patients with portal hypertension, and is associated
with cirrhosis severity.

Causes

Cirrhosis has many possible causes; sometimes more than one cause is present in the
same patient. In the Western World, chronic alcoholism and hepatitis C are the most
common causes.

 Alcoholic liver disease (ALD). Alcoholic cirrhosis develops for between 10% and
20% of individuals who drink heavily for a decade or more. [8] Alcohol seems to injure
the liver by blocking the normal metabolism of protein, fats, and carbohydrates.
Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly,
jaundice, and anorexia. AST and ALT are both elevated but less than 300 IU/L with

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 a AST:ALT ratio > 2.0, a value rarely seen in other liver diseases. Liver biopsy may
show hepatocyte necrosis, Mallory bodies, neutrophilic infiltration with perivenular
inflammation.
 Non-alcoholic steatohepatitis (NASH). In NASH, fat builds up in the liver and
eventually causes scar tissue. This type of hepatitis appears to be associated with
diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with
corticosteroid medications. This disorder is similar to that of alcoholic liver disease
but patient does not have an alcohol history. Biopsy is needed for diagnosis.
 Chronic hepatitis C. Infection with the hepatitis C virus causes inflammation of
the liver and a variable grade of damage to the organ that over several decades can
lead to cirrhosis. Cirrhosis caused by hepatitis C is the most common reason for liver
transplant. Can be diagnosed with serologic assays that detect hepatitis C antibody
or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used
screening test in the US.
 Chronic hepatitis B. The hepatitis B virus causes liver inflammation and injury
that over several decades can lead to cirrhosis. Hepatitis D is dependent on the
presence of hepatitis B and accelerates cirrhosis in co-infection. Chronic hepatitis B
can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG
and HBV DNA are determined to assess whether patient will need antiviral therapy.
 Primary biliary cirrhosis. May be asymptomatic or complain of fatigue, pruritus,
and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent
alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin.
Gold standard diagnosis is antimitochondrial antibodies with liver biopsy as
confirmation if showing florid bile duct lesions. It is more common in women.
 Primary sclerosing cholangitis. PSC is a progressive cholestatic disorder
presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic
bone disease. There is a strong association with inflammatory bowel disease (IBD),
especially ulcerative colitis. Diagnosis is best with contrast cholangiography showing
diffuse, multifocal strictures and focal dilation of bile ducts, leading to a beaded
appearance. Non-specific serum immunoglobulins may also be elevated.
 Autoimmune hepatitis. This disease is caused by the immunologic damage to the
liver causing inflammation and eventually scarring and cirrhosis. Findings include
elevations in serum globulins, especially gamma globulins. Therapy with prednisone
and/or azathioprine is beneficial. Cirrhosis due to autoimmune hepatitis still has 10-

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 year survival of 90%+. There is no specific tool to diagnose autoimmune but it can
be beneficial to initiate a trial of corticosteroids.
 Hereditary hemochromatosis. Usually presents with family history of cirrhosis,
skin hyperpigmentation, diabetes mellitus, pseudogout, and/or cardiomyopathy, all
due to signs of iron overload. Labs will show fasting transferrin saturation of > 60%
and ferritin > 300 ng/mL. Genetic testing may be used to identify HFE mutations. If
these are present, biopsy may not need to be performed. Treatment is
with phlebotomy to lower total body iron levels.
 Wilson's disease. Autosomal recessive disorder characterized by low
serum ceruloplasmin and increased hepatic copper content on liver biopsy. May also
have Kayser-Fleischer rings in the cornea and altered mental status.
 Alpha 1-antitrypsin deficiency (AAT). Autosomal recessive disorder. Patients may
also have COPD, especially if they have a history of tobacco smoking. Serum AAT
levels are low. Recombinant AAT is used to prevent lung disease due to AAT
deficiency.
 Cardiac cirrhosis. Due to chronic right sided heart failure which leads to liver
congestion.
 Galactosemia
 Glycogen storage disease type IV
 Cystic fibrosis
 Hepatotoxic drugs or toxins
 Certain parasitic infections (such as schistosomiasis)
 Lysosomal acid lipase deficiency (LAL Deficiency) is a rare autosomal recessive
genetic condition and is characterized by hepatomegaly, persistently abnormal LFTs
and type II hyperlipidemia. Splenomegaly and evidence of mild hypersplenism may
affect some patients. Untreated, LAL Deficiency may lead to fibrosis, cirrhosis, liver
failure and death.

Pathopysiology

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The liver plays a vital role in synthesis of proteins (e.g., albumin, clotting
factors and complement), detoxification and storage (e.g., vitamin A). In addition, it
participates in the metabolism of lipids and carbohydrates.

Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the
cause. If the cause is removed at this stage, the changes are still fully reversible.

The pathological hallmark of cirrhosis is the development of scar tissue that replaces
normal parenchyma, blocking the portal flow of blood through the organ and disturbing
normal function. Recent research shows the pivotal role of the stellate cell, a cell type
that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic
parenchyma leads to activation of the stellate cell, which becomes contractile
(called myofibroblast) and obstructs blood flow in the circulation. In addition, it
secretes TGF-β1, which leads to a fibrotic response and proliferation of connective tissue.
Furthermore, it secretes TIMP 1 and 2, naturally occurring inhibitors of matrix
metalloproteinases, which prevents them from breaking down fibrotic material in the
extracellular matrix.

The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace
the entire liver architecture, leading to decreased blood flow throughout.
The spleen becomes congested, which leads to hypersplenism and increased
sequestration of platelets. Portal hypertension is responsible for most severe
complications of cirrhosis.

Diagnosis

The gold standard for diagnosis of cirrhosis is a liver biopsy, through

a percutaneous, transjugular, laparoscopic, or fine-needle approach. A biopsy is not
necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore,

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there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for
complications due to liver biopsy.

Lab findings
The following findings are typical in cirrhosis:

 Aminotransferases - AST and ALT are moderately elevated, with AST > ALT.
However, normal aminotransferases do not preclude cirrhosis.
 Alkaline phosphatase - usually slightly elevated.
 Gamma-glutamyl transferase – correlates with AP levels. Typically much higher
in chronic liver disease from alcohol.
 Bilirubin - may elevate as cirrhosis progresses.
 Albumin - levels fall as the synthetic function of the liver declines with worsening
cirrhosis since albumin is exclusively synthesized in the liver
 Prothrombin time - increases since the liver synthesizes clotting factors.
 Globulins - increased due to shunting of bacterial antigens away from the liver to
lymphoid tissue.
 Serum sodium - hyponatremia due to inability to excrete free water resulting from
high levels of ADH and aldosterone.
 Thrombocytopenia - due to both congestive splenomegaly as well as
decreased thrombopoietin from the liver. However, this rarely results in platelet
count < 50,000/mL.
 Leukopenia and neutropenia - due to splenomegaly with splenic margination.
 Coagulation defects - the liver produces most of the coagulation factors and thus
coagulopathy correlates with worsening liver disease.
There is now a validated and patented combination of 6 of these markers as non-
invasive biomarker of fibrosis (and so of cirrhosis) : FibroTest

Other laboratory studies performed in newly diagnosed cirrhosis may include:

 Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-

mitochondria, anti-LKM)
 Ferritin and transferrin saturation (markers of iron
overload), copper and ceruloplasmin (markers of copper overload)
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 Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in
distinguishing various causes
 Cholesterol and glucose
 Alpha 1-antitrypsin

Imaging

Ultrasound is routinely used in the evaluation of cirrhosis, where it may show a small
and nodular liver in advanced cirrhosis along with increased echogenicity with irregular
appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal
hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein).

A new type of device, the FibroScan (transient elastography), uses elastic waves to
determine liver stiffness which theoretically can be converted into a liver score based on
the METAVIR scale. The FibroScan produces an ultrasound image of the liver (from
20–80 mm) along with a pressure reading (in kPa.) The test is much faster than a
biopsy (usually last 2.5–5 minutes) and is completely painless. It shows reasonable
correlation with the severity of cirrhosis.

Other tests performed in particular circumstances include abdominal CT and liver/bile

duct MRI (MRCP).

Endoscopy

Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is

performed in patients with established cirrhosis to exclude the possibility of esophageal
varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or
banding) and beta blocker treatment may be commenced.

Rarely diseases of the bile ducts, such as primary sclerosing cholangitis, can be causes
of cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of biliary tract and
pancreas) can show abnormalities in these patients, and may aid in the diagnosis.

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Pathology

Macroscopically, the liver is initially enlarged, but with progression of the disease, it
becomes smaller. Its surface is irregular, the consistency is firm and the color is often
yellow (if associates steatosis). Depending on the size of the nodules there are three
macroscopic types: micronodular, macronodular and mixed cirrhosis. In micronodular
form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm. In
macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. The
mixed cirrhosis consists in a variety of nodules with different sizes.

However, cirrhosis is defined by its pathological features on microscopy: (1) the

presence of regenerating nodules of hepatocytes and (2) the presence offibrosis, or the
deposition of connective tissue between these nodules. The pattern of fibrosis seen can
depend upon the underlying insult that led to cirrhosis; fibrosis can also proliferate even
if the underlying process that caused it has resolved or ceased. The fibrosis in cirrhosis
can lead to destruction of other normal tissues in the liver: including the sinusoids,
the space of Disse, and other vascular structures, which leads to altered resistance to
blood flow in the liver and portal hypertension.

As cirrhosis can be caused by many different entities which injure the liver in different
ways, different cause-specific patterns of cirrhosis, and other cause-specific
abnormalities can be seen in cirrhosis. For example, in chronic hepatitis B, there is
infiltration of the liver parenchyma with lymphocytes; incardiac cirrhosis there
are erythrocytes and a greater amount of fibrosis in the tissue surrounding the hepatic
veins in primary biliary cirrhosis, there is fibrosis around the bile duct, the presence
ofgranulomas and pooling of bile; and in alcoholic cirrhosis, there is infiltration of the
liver with neutrophils.

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Grading

The severity of cirrhosis is commonly classified with the Child-Pugh score. This score
uses bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to
classify patients in class A, B or C; class A has a favourable prognosis, while class C is
at high risk of death. It was devised in 1964 by Child and Turcotte and modified in 1973
by Pugh et al

More modern scores, used in the allocation of liver transplants but also in other
contexts, are the Model for End-Stage Liver Disease (MELD) score and its pediatric
counterpart, the Pediatric End-Stage Liver Disease (PELD) score.

The hepatic venous pressure gradient, i.e., the difference in venous pressure between
afferent and efferent blood to the liver, also determines severity of cirrhosis, although
hard to measure. A value of 16 mm or more means a greatly increased risk of dying

Management

Generally, liver damage from cirrhosis cannot be reversed, but treatment could stop or
delay further progression and reduce complications. A healthy diet is encouraged, as
cirrhosis may be an energy-consuming process. Close follow-up is often necessary.
Antibiotics will be prescribed for infections, and various medications can help with
itching. Laxatives, such as lactulose, decrease risk of constipation; their role in
preventing encephalopathy is limited.

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Treating underlying causes

Alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol.

Treatment for hepatitis-related cirrhosis involves medications used to treat the different
types of hepatitis, such as interferon for viral hepatitis and corticosteroids for
autoimmune hepatitis. Cirrhosis caused by Wilson's disease, in which copper builds up
in organs, is treated with chelation therapy (e.g., penicillamine) to remove the copper.

Preventing further liver damage

Regardless of underlying cause of cirrhosis, alcohol and paracetamol, as well as other

potentially damaging substances, are discouraged. Vaccination of susceptible patients
should be considered forHepatitis A and Hepatitis B.

Preventing complications

Ascites
Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium
retention). Diuretics may be necessary to suppress ascites.

Esophageal variceal bleeding

For portal hypertension, propranolol is a commonly used agent to lower blood pressure
over the portal system. In severe complications from portal hypertension, transjugular
intrahepatic portosystemic shunting is occasionally indicated to relieve pressure on the

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portal vein. As this can worsen encephalopathy, it is reserved for those at low risk of
encephalopathy, and is generally regarded only as a bridge to liver transplantation or as
a palliative measure.

Hepatic encephalopathy
High-protein food increases the nitrogen balance, and would theoretically
increase encephalopathy; in the past, this was therefore eliminated as much as possible
from the diet. Recent studies show that this assumption was incorrect, and high-protein
foods are even encouraged to maintain adequate nutrition.

Hepatorenal syndrome
The hepatorenal syndrome is defined as a urine sodium less than 10 mmol/L and
a serum creatinine > 1.5 mg/dl (or 24 hour creatinine clearance less than 40 ml/min)
after a trial of volume expansion without diuretics.

Spontaneous bacterial peritonitis

Cirrhotic patients with ascites are at risk of spontaneous bacterial peritonitis.

Transplantation
If complications cannot be controlled or when the liver ceases functioning, liver
transplantation is necessary. Survival from liver transplantation has been improving over
the 1990s, and the five-year survival rate is now around 80%, depending largely on the
severity of disease and other medical problems in the recipient. In the United States,
the MELD score is used to prioritize patients for transplantation. Transplantation
necessitates the use of immune suppressants (cyclosporine or tacrolimus).

Decompensated cirrhosis
In patients with previously stable cirrhosis, decompensation may occur due to various
causes, such as constipation, infection (of any source), increased alcohol
intake, medication, bleeding from esophageal varices or dehydration. It may take the
form of any of the complications of cirrhosis listed above.

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Patients with decompensated cirrhosis generally require admission to hospital, with
close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition
and medical treatment - often
with diuretics, antibiotics, laxatives and/or enemas, thiamine and
occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is
generally avoided as it would add to the already high total body sodium content that
typically occurs in cirrhosis.

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Literature
Robins pathological physiology
Internet.

Thank you

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