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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: Fibrosis and Cirrhosis: 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, such as mechanical bile duct obstruction, primary biliary cirrhosis (see Fibrosis and Cirrhosis: Primary Biliary Cirrhosis (PBC)), and primary sclerosing cholangitis (see Gallbladder and Bile Duct Disorders: Sclerosing Cholangitis).
Pathophysiology
Two primary ingredients exist: hepatic fibrosis and 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 “bridges” 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 Approach to the Patient With Liver Disease: Portal Hypertension) is the most common serious complication in the form of GI bleeding from esophageal, gastric, or rectal varices or portal hypertensive gastropathy. Portal hypertension can be massive. Cirrhosis can cause other cardiovascular complications. Vasodilation and intrapulmonary right-to-left shunting and ventilation/perfusion mismatch can result in hypoxia (hepatopulmonary syndrome). A cardiac myopathy can also accompany cirrhosis.
Ascites can develop, with a risk of spontaneous bacterial peritonitis. Splenic congestion with hypersplenism may occur, resulting in splenomegaly and consequent cytopenia. This includes platelet sequestration.
Progressive loss of hepatic architecture impairs function, leading to hepatic insufficiency, manifest by coagulopathy, renal failure (hepatorenal syndrome—see Approach to the Patient With Liver Disease: Renal and Electrolyte Abnormalities), 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 results from hypersplenism, chronic GI bleeding, folate deficiency (particularly in patients with alcoholism), and hemolysis. Clotting may be impaired because of either a coagulopathy or thrombocytopenia. Coagulopathy results from impaired hepatic synthesis of the factors necessary for clotting, malabsorption of vitamin K due to impaired bile secretion into the duodenum, or both. Thrombocytopenia may be caused by hypersplenism (platelet sequestration), and/or alcohol excess (directly inhibiting the bone marrow). Pancytopenia also occurs with alcoholism.
Hepatocellular carcinoma frequently complicates cirrhosis, particularly cirrhosis resulting from chronic hepatitis B and C viruses, hemochromatosis, alcohol-related liver disease, α1antitrypsin deficiency, and 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 rather 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 eg, generalized fatigue (due to cytokine release), anorexia, malaise, and weight loss (see Table 2: Fibrosis and Cirrhosis: 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's contracture, spider angiomas (< 10 may be normal), gynecomastia, axillary hair loss, testicular atrophy, and peripheral neuropathy.
Once complications of cirrhosis develop, decompensation inexorably ensues.
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Table 2
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Common Symptoms and Signs
Due to Complications of Cirrhosis
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Symptom or Sign
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Possible Cause
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Abdominal distention
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Ascites
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Abdominal discomfort with fever or hepatic encephalopathy (infrequently with peritoneal signs)
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Spontaneous bacterial peritonitis
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Clubbing
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Hepatopulmonary syndrome
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Confusion, lethargy
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Hepatic encephalopathy
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Dyspnea, hypoxia
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Hepatopulmonary syndrome
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Fatigue, pallor
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Anemia due to bleeding, hypersplenism, undernutrition with deficiency of folate (or iron or vitamin B12), chronic disease, or effects of alcohol (eg, bone marrow suppression)
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Fluid overload, oliguria, symptoms of renal failure
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Hepatorenal syndrome
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Fragility fracture (due to a fall from standing height or less)
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Osteoporosis
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Jaundice
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Cholestasis
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Petechiae, purpura, bleeding
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Thrombocytopenia from: splenomegaly due to portal hypertension direct effects of alcohol on the bone marrow
Coagulopathy due to impaired liver synthetic function and/or vitamin K deficiency
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Pruritus, xanthelasmas
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Cholestasis
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Rectal bleeding
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Rectal varices
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Splenomegaly
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Portal hypertension
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Steatorrhea
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Fat malabsorption
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Upper GI bleeding
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Esophageal varices
Portal hypertensive gastropathy
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Diagnosis
General approach:
Cirrhosis is suspected in patients with manifestations of any of its complications (see Table 2: Fibrosis and Cirrhosis: 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 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 detect 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 below). 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: microcytic from chronic GI bleeding; macrocytic from folate nutritional deficiency or hemolysis (especially in alcohol abuse) and hypersplenism. CBC may also detect leucopenia, 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 also 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 findings and selective testing. Alcohol is the likely cause in patients with a documented history of alcoholism and clinical findings such as gynecomastia, spider angiomas (telangiectasia), 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.
If common causes such as alcohol or viral hepatitis are not confirmed, other less common causes are sought:
Liver biopsy:
If clinical criteria and noninvasive testing are inconclusive, liver biopsy is usually done. Its sensitivity approaches 100%. Nonalcoholic steatohepatitis (NASH), often associated with obesity, diabetes, or the metabolic syndrome, may be evident on ultrasound scans but requires liver biopsy for confirmation. In obvious cases of cirrhosis with a marked coagulopathy, portal hypertension, ascites, and liver failure, biopsy is not required when management would not change.
Monitoring:
Patients with cirrhosis, particularly if due to chronic viral hepatitis B or C or hemochromatosis, should be screened for hepatocellular carcinoma (eg, measuring α-fetoprotein levels and ultrasonography every 6 to 12 mo—see Liver Masses and Granulomas: Screening).
Prognosis
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 (see Table 3: Fibrosis and Cirrhosis: Child-Turcotte-Pugh Scoring System).
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Table 3
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Child-Turcotte-Pugh
Scoring System
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Clinical or Laboratory Factor
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Degree of Abnormality
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Points Assigned*
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Encephalopathy (grade†)
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None
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1
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1-2
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2
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3-4
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3
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Ascites
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None
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1
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Mild (or controlled by diuretics)
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2
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At least moderate despite diuretic treatment
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3
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PT (seconds prolonged)
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< 4
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1
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4-6
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2
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> 6
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3
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Or INR
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< 1.7
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1
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1.7-2.3
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2
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> 2.3
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3
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Albumin (g/dL)
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> 3.5
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1
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2.8-3.5
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2
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< 2.8
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3
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Bilirubin (mg/dL)
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< 2
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1
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2-3
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2
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> 3
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3
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*Risk (grade) is based on the total number of points:
Low (A): 5-6
Moderate (B): 7-9
High (C): 10-15
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†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
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Table 4
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Interpretation of the Child-Turcotte-Pugh
Scoring System
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Points
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Risk (Grade)
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Survival Rate (%)
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1-yr
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2-yr
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5-6
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Low (A)
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100
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85
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7-9
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Moderate (B)
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80
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60
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10-15
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High (C)
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45
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35
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Treatment
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 with varices need therapy to prevent bleeding (see Approach to the Patient With Liver Disease: Prognosis and Treatment). Liver transplantation is indicated for end-stage liver failure in suitable candidates.
Primary
Biliary Cirrhosis (PBC)
Primary biliary cirrhosis is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, cirrhosis, and liver failure. Patients usually are asymptomatic at presentation but may experience fatigue or have symptoms of cholestasis (eg, pruritus, steatorrhea) or cirrhosis (eg, portal hypertension, ascites). Laboratory tests reveal cholestasis, increased IgM, and, characteristically, antimitochondrial antibodies in the serum. Liver biopsy may be necessary for diagnosis and staging. Treatment includes ursodeoxycholic acid, cholestyramine (for pruritus), supplementary fat-soluble vitamins, and, ultimately for advanced disease, liver transplantation.
Etiology
and Pathophysiology
Primary biliary cirrhosis (PBC) is the most common liver disease in adults associated with chronic cholestasis. Most (95%) cases occur in women aged 35 to 70. PBC also clusters in families. A genetic predisposition, perhaps involving the X chromosome, probably contributes. There may be an inherited abnormality of immune regulation. An autoimmune mechanism has been implicated; antibodies to antigens located on the inner mitochondrial membranes occur in > 95% of cases. These antimitochondrial antibodies (AMA), the serologic hallmarks of PBC, are not cytotoxic and are not involved in bile duct damage. PBC is associated with other autoimmune disorders, such as RA, systemic sclerosis, Sjögren's syndrome, CREST syndrome, autoimmune thyroiditis, and renal tubular acidosis.
T cells attack the small bile ducts. CD4 and CD8 T lymphocytes directly target biliary epithelial cells. The trigger for the immunologic attack on bile ducts is unknown. Exposure to foreign antigens, such as an infectious (bacterial or viral) or toxic agent, might be the instigating event. These foreign antigens might be structurally similar to endogenous proteins (molecular mimicry); then the subsequent immunologic reaction would be autoimmune and self-perpetuating. Destruction and loss of bile ducts lead to impaired bile formation and secretion (cholestasis). Retained toxic materials such as bile acids then cause further damage, particularly to hepatocytes. Chronic cholestasis thus leads to liver cell inflammation and scarring in the periportal areas. Eventually, hepatic inflammation decreases, while hepatic fibrosis progresses to cirrhosis.
Autoimmune cholangitis is sometimes considered to be a separate disorder. It is characterized by autoantibodies, such as antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies, and has a clinical course and response to treatment that are similar to PBC. However, in autoimmune cholangitis, AMA are absent.
Symptoms and Signs
About half of patients present without symptoms. Symptoms or signs may develop during any stage of the disease and may include fatigue or reflect cholestasis (and the resulting fat malabsorption, which may lead to vitamin deficiencies and osteoporosis), hepatocellular dysfunction, or cirrhosis.
Symptoms usually develop insidiously. Pruritus, fatigue, and dry mouth and eyes are the initial symptoms in > 50% of patients and can precede other symptoms by months or years. Other initial manifestations include right upper quadrant discomfort (10%), an enlarged, firm, nontender liver (25%), splenomegaly (15%), hyperpigmentation (25%), xanthelasmas (10%), and jaundice (10%). Eventually, all the features and complications of cirrhosis occur. Peripheral neuropathy and other autoimmune disorders associated with PBC may also develop.
Diagnosis
In asymptomatic patients, PBC is detected incidentally when liver function tests detect abnormalities, typically elevated levels of alkaline phosphatase and γ-glutamyl transpeptidase (GGT). PBC is suspected in middle-aged women with classic symptoms (eg, unexplained pruritus, fatigue, right upper quadrant discomfort, jaundice) or laboratory results suggesting cholestatic liver disease: elevated alkaline phosphatase and GGT but minimally abnormal aminotransferases (ALT and AST). Serum bilirubin is usually normal in the early stages; elevation indicates disease progression and a worsening prognosis.
If PBC is suspected, liver function tests and tests to measure serum IgM (increased in PBC) and AMA should be done. ELISA tests are 95% sensitive and 98% specific for PBC; false-positive results can occur in autoimmune hepatitis (type 1). Other autoantibodies (eg, ANA, anti-smooth muscle antibodies, rheumatoid factor) may be present. Extrahepatic biliary obstruction should be ruled out. Ultrasonography is often done first, but ultimately MRCP and sometimes ERCP are necessary. Unless life expectancy is short or there is a contraindication, liver biopsy is usually done. Liver biopsy confirms the diagnosis; it may detect pathognomonic bile duct lesions, even in early stages. As PBC progresses, it becomes morphologically indistinguishable from other forms of cirrhosis. Liver biopsy also helps stage PBC, which has 4 histologic stages:
Autoimmune cholangitis is diagnosed when AMA are absent in a patient who otherwise would be diagnosed with PBC.
Prognosis
Usually, PBC progresses to terminal stages over 15 to 20 yr, although the rate of progression varies. It may not diminish quality of life for many years. Patients who present without symptoms tend to develop symptoms over 2 to 7 yr but may not do so for 10 to 15 yr. Once symptoms develop, median life expectancy is 10 yr. Predictors of rapid progression include the following:
The prognosis is ominous when pruritus disappears, xanthomas shrink, jaundice develops, and serum cholesterol decreases.
Treatment
All alcohol use and hepatotoxic drugs should be stopped. Ursodeoxycholic acid (15 mg/kg po once/day) decreases liver damage, prolongs survival, and delays the need for liver transplantation. About 20% of patients do not have biochemical improvement after ≥ 4 mo; they may have advanced disease and require liver transplantation in a few years. Other drugs proposed to decrease liver damage have not improved overall clinical outcomes or are controversial.
Pruritus may be controlled with cholestyramine 6 to 8 g po bid. This anionic-binding drug binds bile salts and thus may aggravate fat malabsorption. If cholestyramine is taken long-term, supplements of fat-soluble vitamins should be considered. Cholestyramine can decrease absorption of ursodeoxycholic acid, so these drugs should not be given simultaneously.
Some patients with pruritus respond to ursodeoxycholic acid and ultraviolet light; others may warrant a trial of rifampin or an opioid antagonist, such as naltrexone . Patients with fat malabsorption due to bile salt deficiency should be treated with vitamins A, D, E and K. For osteoporosis, weight-bearing exercises, bisphosphonates, or raloxifene may be needed in addition to Ca and vitamin D supplements. In later stages, portal hypertension (see Approach to the Patient With Liver Disease: Portal Hypertension) or complications of cirrhosis (see Fibrosis and Cirrhosis: Complications) require treatment.
Liver transplantation has excellent results. The general indication is decompensated liver disease: uncontrolled variceal bleeding, refractory ascites, intractable pruritus, and hepatic encephalopathy. Survival rates after liver transplantation are > 90% at 1 yr, > 80% at 5 yr, and > 65% at 10 yr. The AMA tends to persist after transplantation. PBC recurs in 15% of patients in the first few years, rising to over 30% by 10 years. So far recurrent PBC after liver transplantation follows a benign course. Cirrhosis rarely occurs.
Last full review/revision August 2007 by Eldon A. Shaffer, MD
Content last modified August 2007
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