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by Jesse M. Civan, MD

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 ( 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).


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-α, 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.


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 syndrome—see 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 granulocyte-stimulating 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, α 1 -antitrypsin deficiency, or glycogen storage disease.


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 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, testicular atrophy, and peripheral neuropathy.

Once complications of cirrhosis develop, decompensation inexorably ensues.

Common Symptoms and Signs Due to Complications of Cirrhosis

Symptom or Sign

Possible Cause

Abdominal distention


Abdominal discomfort with fever or hepatic encephalopathy (infrequently with peritoneal signs)

Spontaneous bacterial peritonitis

Calf pain or swelling, symptoms of pulmonary embolism



Hepatopulmonary syndrome

Confusion, lethargy

Hepatic encephalopathy

Dyspnea, hypoxia

Hepatopulmonary syndrome

Portopulmonary hypertension

Fatigue, pallor

Anemia due to bleeding, hypersplenism, undernutrition with deficiency of folate (or iron or vitamin B 12 ), chronic disease, or effects of alcohol (eg, bone marrow suppression)

Fluid overload, oliguria, symptoms of renal failure

Hepatorenal syndrome

Fragility fracture (due to a fall from standing height or less)


Symptoms of infection




Petechiae, purpura, bleeding

Thrombocytopenia caused by splenomegaly due to portal hypertension or the direct effects of alcohol on bone marrow

Coagulopathy due to impaired liver synthetic function, vitamin K deficiency, or both

Pruritus, xanthelasmas


Rectal bleeding

Rectal varices


Portal hypertension


Fat malabsorption

Upper GI bleeding

Esophageal varices

Portal hypertensive gastropathy


  • Liver function tests, coagulation tests, CBC, and serologic tests for viral causes

  • Sometimes biopsy (eg, when clinical and noninvasive tests are inconclusive or when biopsy results may change management)

  • Identification of cause based on clinical evaluation, routine testing for common causes, and selective testing for less common causes

General approach

Cirrhosis is suspected in patients with manifestations of any of its complications (see Common Symptoms and Signs Due to Complications of Cirrhosis), particularly portal hypertension or ascites. Early cirrhosis should be considered in patients with nonspecific symptoms or characteristic laboratory abnormalities detected incidentally during laboratory testing, particularly in patients who have a disorder or take a drug that might cause fibrosis.

Testing seeks to detect cirrhosis and any complications and to determine its cause.

Laboratory tests

Diagnostic testing begins with liver function tests, coagulation tests, CBC, and serologic tests for viral causes (eg, hepatitis B and C). Laboratory tests alone may increase suspicion for cirrhosis but cannot confirm or exclude it. Liver biopsy becomes necessary if a clear diagnosis would lead to better management and outcome.

Test results may be normal or may indicate nonspecific abnormalities due to complications of cirrhosis or alcoholism. ALT and AST levels are often modestly elevated. Alkaline phosphatase and γ-glutamyl transpeptidase (GGT) are often normal; elevated levels indicate cholestasis or biliary obstruction. Bilirubin is usually normal but increases when cirrhosis progresses, particularly in primary biliary cirrhosis (see Primary Biliary Cirrhosis (PBC) : Diagnosis). Decreased serum albumin and a prolonged PT directly reflect impaired hepatic synthesis—usually an end-stage event. Albumin can also be low when nutrition is poor. Serum globulin increases in cirrhosis and in most liver disorders with an inflammatory component. Anemia is common and usually normocytic with a high RBC distribution width. Anemia is often multifactorial; contributing factors may include chronic GI bleeding (usually causing microcytic anemia), folate nutritional deficiency (causing macrocytic anemia, especially in alcohol abuse), hemolysis, and hypersplenism. CBC may also detect leukopenia, thrombocytopenia, or pancytopenia.

Diagnostic imaging

Imaging tests are not highly sensitive or specific for the diagnosis of cirrhosis by themselves, but they can often detect its complications. In advanced cirrhosis, ultrasonography shows a small, nodular liver. Ultrasonography also detects portal hypertension and ascites.

CT can detect a nodular texture, but it has no advantage over ultrasonography. Radionuclide liver scans using technetium-99m sulfur colloid may show irregular liver uptake and increased spleen and bone marrow uptake. MRI is more expensive than other imaging tests and has little advantage.

Identification of the cause

Determining the specific cause of cirrhosis requires key clinical information from the history and examination, as well as selective testing. Alcohol is the likely cause in patients with a documented history of alcoholism and clinical findings such as gynecomastia, spider angiomas (telangiectasia), and testicular atrophy plus laboratory confirmation of liver damage (AST elevated more than ALT) and liver enzyme induction (a greatly increased GGT). Fever, tender hepatomegaly, and jaundice suggest the presence of alcoholic hepatitis.

Detecting hepatitis B surface antigen (HBsAg) and IgG antibodies to hepatitis B (IgG anti-HBc) confirms chronic hepatitis B. Identifying serum antibody to hepatitis C (anti-HCV) and HCV-RNA points to hepatitis C. Most clinicians also routinely test for the following:

  • Autoimmune hepatitis: Suggested by a high antinuclear antibody titer (a low titer is nonspecific and does not always mandate further evaluation) and confirmed by hypergammaglobulinemia and the presence of other autoantibodies (eg, anti–smooth muscle or anti-liver/kidney microsomal type 1 antibodies)

  • Hemochromatosis: Confirmed by increased serum Fe and transferrin saturation and possibly results of genetic testing

  • α 1 -Antitrypsin deficiency: Confirmed by a low serum α 1 -antitrypsin level and genotyping

If these causes are not confirmed, other causes are sought:

  • Presence of antimitochondrial antibodies (in 95%) suggests primary biliary cirrhosis.

  • Strictures and dilations of the intrahepatic and extrahepatic bile ducts, seen on magnetic resonance cholangiopancreatography (MRCP), suggest primary sclerosing cholangitis.

  • Decreased serum ceruloplasmin and characteristic copper test results suggest Wilson disease.

  • The presence of obesity and a history of diabetes suggest nonalcoholic steatohepatitis.

Liver biopsy

If clinical criteria and noninvasive testing are inconclusive, liver biopsy is usually done. For example, if well-compensated cirrhosis is suspected clinically and imaging findings are inconclusive, biopsy should be done to confirm the diagnosis. Sensitivity of liver biopsy approaches 100%. Nonalcoholic fatty liver disease (NAFLD) may be evident on ultrasound scans. However, nonalcoholic steatohepatitis (NASH), often associated with obesity, diabetes, or the metabolic syndrome, requires liver biopsy for confirmation. In obvious cases of cirrhosis with marked coagulopathy, portal hypertension, ascites, and liver failure, biopsy is not required unless results would change management. In patients with coagulopathy and thrombocytopenia, the transjugular approach to biopsy is safest. When this approach is used, pressures can be measured and thus the transsinusoidal pressure gradient can be calculated.


All patients with cirrhosis, regardless of cause, should be screened regularly for hepatocellular carcinoma. Currently, abdominal ultrasonography is recommended every 6 mo, and if abnormalities compatible with hepatocellular carcinoma are detected, contrast-enhanced MRI or triple-phase CT of the abdomen (contrast-enhanced CT with separate arterial and venous phase images) should be done. Contrast-enhanced ultrasonography appears promising as an alternative to CT or MRI but is still under study in the US.

Upper endoscopy to check for gastroesophageal varices should be done when the diagnosis is made and then every 2 to 3 yr. Positive findings may mandate treatment or more frequent endoscopic monitoring.


Prognosis is often unpredictable. It depends on factors such as etiology, severity, presence of complications, comorbid conditions, host factors, and effectiveness of therapy. Patients who continue to drink alcohol, even small amounts, have a very poor prognosis. The Child-Turcotte-Pugh scoring system uses clinical and laboratory information to stratify disease severity, surgical risk, and overall prognosis ( Child-Turcotte-Pugh Scoring System and Interpretation of the Child-Turcotte-Pugh Scoring System).

Child-Turcotte-Pugh Scoring System

Clinical or Laboratory Factor

Degree of Abnormality

Points Assigned*

Encephalopathy (grade )










Mild (or controlled by diuretics)


At least moderate despite diuretic treatment


PT (seconds prolonged)

< 4




> 6




< 1.7




> 2.3


Albumin (g/dL)

> 3.5




< 2.8


Bilirubin (mg/dL)

< 2




> 3


*Risk (grade) is based on the total number of points:

  • Low (A): 5–6

  • Moderate (B): 7–9

  • High (C): 10–15

Encephalopathy is graded based on symptoms:

  • 1: Sleep disturbances; impaired concentration; depression, anxiety, or irritability

  • 2: Drowsiness, disorientation, poor short-term memory, uninhibited behavior

  • 3: Somnolence; confusion; amnesia; anger, paranoia, or other bizarre behavior

  • 4: Coma

Interpretation of the Child-Turcotte-Pugh Scoring System


Risk (Grade)

Survival Rate (%)




Low (A)




Moderate (B)




High (C)



However, the Child-Turcotte-Pugh scoring system has limitations; for example, assessments of the severity of ascites and encephalopathy are subjective; interrater reliability of results is thus decreased. In contrast, the Model for End-Stage Liver Disease (MELD) score estimates the severity of end-stage liver disease, regardless of cause, based solely on objective results of laboratory tests: serum creatinine, serum total bilirubin, and INR. The MELD score is used to determine allocation of available organs to liver transplant candidates. Variations of the MELD score are sometimes used for other purposes (eg, to estimate risk of 90-day mortality in patients with alcoholic hepatitis, to predict risk of postoperative mortality in patients with cirrhosis). A variation that incorporates serum Na has been extensively studied but is not yet widely used clinically in the US.

For patients ≥ 12 yr, the MELD score is calculated using the following formula:


Ln equals natural logarithm. If a patient has had ≥ 2 hemodialysis treatments or 24 h of continuous venovenous hemodialysis in the week before MELD scoring, creatinine is calculated using 4 mg/dL, the maximum creatinine level allowed in the model. The MELD score should be calculated differently for patients who have hepatocellular carcinoma. For patients who are 12 to 17 yr old and who have a urea cycle disorder, organic acidemia or hepatoblastoma, the MELD score is set at 30. Higher MELD scores predict higher risk.

A MELD score calculator is available at the website of the Organ Procurement and Transplantation Network (OPTN) of the Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services ( MELD score calculator ).

For patients < 12 yr, the corresponding Pediatric End-Stage Liver Disease (PELD) score is calculated using the following formula:


Ln equals natural logarithm; listing age factor is 0.436 if patients are < 1 yr of age or if they were < 1 yr when added to the transplant list until they are age 2 yr. Growth equals 0.667 if height or weight is > 2 standard deviations below mean values for age. If patients have certain disorders, including urea cycle disorders, organic acidemia, or hepatoblastoma, the PELD score is 30.

Higher PELD scores predict higher risk.

A PELD score calculator is available at the website of the Organ Procurement and Transplantation Network (OPTN) of the Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services ( PELD calculator ).


  • Supportive care

In general, treatment is supportive and includes stopping injurious drugs, providing nutrition (including supplemental vitamins), and treating the underlying disorders and complications. Doses of drugs metabolized in the liver should be reduced. All alcohol and hepatotoxic substances must be avoided. Withdrawal symptoms during hospitalization should be anticipated in patients who have cirrhosis and have continued to abuse alcohol. Patients should be vaccinated against viral hepatitis A and B unless they are already immune.

Patients with varices need therapy to prevent bleeding (see Dubin-Johnson Syndrome and Rotor Syndrome : Prognosis). No evidence supports treating small esophageal varices. Medium and large esophageal varices should be treated prophylactically with nonselective β-blockers or endoscopic banding (ligation). If gastric varices are not amenable to endoscopic banding and do not respond to nonselective β-blockers, balloon-occluded retrograde transvenous obliteration or endoscopic cyanoacrylate injection may be used.

Transjugular intrahepatic portosystemic shunting (TIPS—see Treatment) should be considered if patients have complications of portal hypertension that are refractory to standard treatments, including ascites and recurrent variceal bleeding.

Liver transplantation is indicated for patients with end-stage liver disease or hepatocellular carcinoma (see Liver Transplantation). Risk of death without liver transplantation begins to exceed risks of transplantation (eg, perioperative complications, chronic immunosuppression) when the MELD score is more than about 15. Thus, if the score is ≥ 15 or if cirrhosis has decompensated clinically, patients should be referred to a transplantation center.

Key Points

  • Morbidity and mortality in cirrhosis usually result from its complications (eg, complications of portal hypertension, liver failure, hematologic problems).

  • Do liver biopsy if a clear diagnosis would lead to better management and outcome.

  • Evaluate all patients with cirrhosis for autoimmune hepatitis, hereditary hemochromatosis, and α 1 -antitrypsin deficiency, as well as for the more common causes, alcoholic and viral hepatitis.

  • Evaluate all patients periodically for gastroesophageal varices and hepatocellular carcinoma.

  • Predict prognosis using the Child-Turcotte-Pugh and MELD scoring systems, and refer patients with a MELD score ≥ 15 to be evaluated for a liver transplant.

  • Treat cirrhosis supportively, including using therapies to prevent bleeding.

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