Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic

architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense fibrotic tissue.

Symptoms may not develop for years and are often nonspecific (eg, anorexia, fatigue, weight loss).
Late manifestations include portal hypertension, ascites, and, when decompensation occurs, liver
failure. Diagnosis often requires liver biopsy. Cirrhosis is usually considered irreversible. Treatment is
supportive.
Cirrhosis is a leading cause of death worldwide. The causes of cirrhosis are the same as those of
fibrosis (see Table 1: Disorders and Drugs That Can Cause Hepatic Fibrosis). In developed countries,
most cases result from chronic alcohol abuse or chronic hepatitis C. In parts of Asia and Africa,
cirrhosis often results from chronic hepatitis B. Cirrhosis of unknown etiology (cryptogenic cirrhosis)
is becoming less common as many specific causes (eg, chronic hepatitis C, steatohepatitis) are
identified. Injury to the bile ducts also can result in cirrhosis, as occurs in mechanical bile duct
obstruction, primary biliary cirrhosis (see Primary Biliary Cirrhosis (PBC)), and primary sclerosing
cholangitis (see Sclerosing Cholangitis).

Pathophysiology
There are 2 primary ingredients:

Hepatic fibrosis

Regenerating liver cells

In response to injury and loss, growth regulators induce hepatocellular hyperplasia (producing
regenerating nodules) and arterial growth (angiogenesis). Among the growth regulators are cytokines
and hepatic growth factors (eg, epithelial growth factor, hepatocyte growth factor, transforming growth
factor-, tumor necrosis factor). Insulin, glucagon
, and patterns of intrahepatic blood flow determine how and where nodules develop.
Angiogenesis produces new vessels within the fibrous sheath that surrounds nodules. These vessels
connect the hepatic artery and portal vein to hepatic venules, restoring the intrahepatic circulatory
pathways. Such interconnecting vessels provide relatively low-volume, high-pressure venous drainage
that cannot accommodate as much blood volume as normal. As a result, portal vein pressure increases.
Such distortions in blood flow contribute to portal hypertension, which increases because the
regenerating nodules compress hepatic venules.
The progression rate from fibrosis to cirrhosis and the morphology of cirrhosis vary from person to
person. Presumably, the reason for such variation is the extent of exposure to the injurious stimulus and
the individual's response.
Complications:
Portal hypertension (see Portal Hypertension) is the most common serious complication of cirrhosis,
and it, in turn, causes complications, including GI bleeding from esophageal, gastric, or rectal varices
and portal hypertensive gastropathy. In patients with cirrhosis, portal hypertension can also lead to
ascites, acute kidney injury (hepatorenal syndromesee Renal and Electrolyte Abnormalities), and
pulmonary hypertension (portopulmonary hypertension). Ascites is a risk factor for spontaneous

bacterial peritonitis. Portopulmonary hypertension can manifest with symptoms of heart failure.
Complications of portal hypertension tend to cause significant morbidity and mortality.

Cirrhosis can cause other cardiovascular complications. Vasodilation, intrapulmonary right-to-left

shunting, and ventilation/perfusion mismatch can result in hypoxia (hepatopulmonary syndrome).

Progressive loss of hepatic architecture impairs function, leading to hepatic insufficiency; it manifests
as coagulopathy, acute kidney injury (hepatorenal syndrome), and hepatic encephalopathy. Hepatocytes
secrete less bile, contributing to cholestasis and jaundice. Less bile in the intestine causes
malabsorption of dietary fat (triglycerides) and fat-soluble vitamins. Malabsorption of vitamin D may
contribute to osteoporosis. Undernutrition is common. It may result from anorexia with reduced food
intake or, in patients with alcoholic liver disease, from malabsorption due to pancreatic insufficiency.

Blood disorders are common. Anemia usually results from hypersplenism, chronic GI bleeding, folate
deficiency (particularly in patients with alcoholism), and hemolysis.

Cirrhosis results in decreased production of prothrombotic and antithrombotic factors. Hypersplenism

and altered expression of thrombopoietin contribute to thrombocytopenia. Thrombocytopenia and
decreased production of clotting factors can make clotting unpredictable, increasing risk of both
bleeding and thromboembolic disease (even though INR is usually increased). Leukopenia is also
common; it is mediated by hypersplenism and altered expression of erythropoietin and granulocytestimulating factors.

Pearls & Pitfalls

Consider thromboembolic
complications in patients with
cirrhosis, even if INR is elevated.

Hepatocellular carcinoma frequently complicates cirrhosis, particularly cirrhosis resulting from chronic
hepatitis B or C, hemochromatosis, alcohol-related liver disease, 1-antitrypsin deficiency, or glycogen
storage disease.

Histopathology:
Cirrhosis is characterized by regenerating nodules and fibrosis. Incompletely formed liver nodules,
nodules without fibrosis (nodular regenerative hyperplasia), and congenital hepatic fibrosis (ie,
widespread fibrosis without regenerating nodules) are not true cirrhosis.

Cirrhosis can be micronodular or macronodular. Micronodular cirrhosis is characterized by uniformly

small nodules (< 3 mm in diameter) and thick regular bands of connective tissue. Typically, nodules
lack lobular organization; terminal (central) hepatic venules and portal triads are distorted. With time,
macronodular cirrhosis often develops. The nodules vary in size (3 mm to 5 cm in diameter) and have
some relatively normal lobular organization of portal triads and terminal hepatic venules. Broad fibrous
bands of varying thickness surround the large nodules. Collapse of the normal hepatic architecture is
suggested by the concentration of portal triads within the fibrous scars. Mixed cirrhosis (incomplete
septal cirrhosis) combines elements of micronodular and macronodular cirrhosis. Differentiation
between these morphologic types of cirrhosis has limited clinical value.

Symptoms and Signs

Cirrhosis may be asymptomatic for years. One third of patients never develop symptoms. Often, the
first symptoms are nonspecific; they include generalized fatigue (due to cytokine release), anorexia,
malaise, and weight loss (see Table 2: Common Symptoms and Signs Due to Complications of
Cirrhosis). The liver is typically palpable and firm, with a blunt edge, but is sometimes small and
difficult to palpate. Nodules usually are not palpable.
Clinical signs that suggest a chronic liver disorder or chronic alcohol use but are not specific for
cirrhosis include muscle wasting, palmar erythema, parotid gland enlargement, white nails, clubbing,
Dupuytren contracture, spider angiomas (< 10 may be normal), gynecomastia, axillary hair loss, t