Cirrhosis

Portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more is the most common serious complication of cirrhosis, and it, in turn, causes complications, including

Ascites fluid can become infected (spontaneous bacterial peritonitis Spontaneous Bacterial Peritonitis (SBP) Spontaneous bacterial peritonitis (SBP) is infection of ascitic fluid without an apparent source. Manifestations may include fever, malaise, and symptoms of ascites and worsening hepatic failure... read more ). 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 Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more (hepatorenal syndrome), and hepatic encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more . Hepatic encephalopathy is characterized by asterixis, confusion, or hepatic coma and is the result of the liver's inability to metabolize the toxins from the gastrointestinal (GI) tract. Elevated serum ammonia level may help the diagnosis of hepatic encephalopathy, but the level does not correlate well with the severity of hepatic encephalopathy.

Hepatocytes secrete less bile, contributing to cholestasis and jaundice Jaundice Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L)... read more . Less bile in the intestine causes malabsorption of dietary fat (triglycerides) and fat-soluble vitamins. Malabsorption of vitamin D may contribute to osteoporosis. Undernutrition and sarcopenia are common. They may result from anorexia with reduced food intake or, in patients with alcoholic liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more , from malabsorption due to pancreatic insufficiency.

Blood disorders are common. Anemia usually results from hypersplenism, chronic GI bleeding, folate deficiency Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more (particularly in patients with alcoholism), and hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more .

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 international normalized ratio [INR] is usually increased). Leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to < 4000/mcL (⁹/L). It is usually the consequence of a reduced number of circulating neutrophils, although... read more is also common; it is mediated by hypersplenism Hypersplenism Hypersplenism is cytopenia caused by splenomegaly. (See also Overview of the Spleen.) Hypersplenism is a secondary process that can arise from splenomegaly of almost any cause (see table Common... read more and altered expression of erythropoietin and granulocyte-stimulating factors.

Hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more frequently complicates cirrhosis from any cause (justifying clinical surveillance). The incidence of hepatocellular carcinoma in cirrhosis from specific etiologies are listed below (1 Pathophysiology reference 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... read more ):

Cirrhosis is characterized by regenerating nodules and bridging 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.

Cirrhosis is suspected in patients with manifestations of any of its complications (see table Common Symptoms and Signs Due to Complications of Cirrhosis Common Symptoms and Signs Due to Complications of Cirrhosis ), particularly portal hypertension or ascites. Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more 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.

Diagnostic testing begins with liver blood tests Laboratory Tests of the Liver and Gallbladder Laboratory tests are generally effective for the following: Detecting hepatic dysfunction Assessing the severity of liver injury Monitoring the course of liver diseases and the response to treatment... read more , coagulation tests, CBC, and serologic tests for chronic viral hepatitis (see tables Hepatitis B Serology Hepatitis B Serology* and Hepatitis C Serology Hepatitis C Serology ). Laboratory tests alone may increase suspicion for cirrhosis but cannot confirm or exclude it.

Test results may be normal or may indicate nonspecific abnormalities. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are often modestly elevated, but they can be normal. Alkaline phosphatase and gamma-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 cholangitis Primary Biliary Cholangitis (PBC) Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more . Decreased serum albumin and a prolonged prothrombin time (PT) directly reflect impaired hepatic synthesis—usually an end-stage event. Albumin can also be low when nutrition is poor.

Anemia is common and usually normocytic with a high red blood cell distribution width (RDW). Anemia is often multifactorial; contributing factors may include chronic gastrointestinal bleeding Overview of Gastrointestinal Bleeding Gastrointestinal (GI) bleeding can originate anywhere from the mouth to the anus and can be overt or occult. The manifestations depend on the location and rate of bleeding. (See also Varices... read more (usually causing microcytic anemia), folate deficiency Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more (causing macrocytic anemia, especially in alcohol abuse), hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more , and hypersplenism Hypersplenism Hypersplenism is cytopenia caused by splenomegaly. (See also Overview of the Spleen.) Hypersplenism is a secondary process that can arise from splenomegaly of almost any cause (see table Common... read more . CBC may also detect leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to < 4000/mcL (⁹/L). It is usually the consequence of a reduced number of circulating neutrophils, although... read more , thrombocytopenia Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more , or pancytopenia.

Conventional imaging tests are not highly sensitive or specific for the diagnosis of cirrhosis by themselves, but they can often detect its complications. Noninvasive imaging studies (eg, transient elastography, acoustic radiation force impulse imaging, two-dimensional shear wave elastography, and magnetic resonance elastography) are useful in detection of early cirrhosis when conventional imaging findings are equivocal and portal hypertension is not evident.

In advanced cirrhosis, ultrasonography shows a small, nodular liver. Ultrasonography also detects portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more and ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more .

CT and MRI with and without contrast can detect a nodular texture, varices, portal/splenic vein thrombosis, and delineate a liver lesion suspect for hepatocellular carcinoma. Radionuclide liver scans using technetium-99m sulfur colloid may show irregular liver uptake and increased spleen and bone marrow uptake, but it has limited use in contemporary practice.

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 laboratory findings of AST higher than ALT (especially AST/ALT ratio > 2), elevated gamma-glutamyl transpeptidase (GGT), and macrocytic anemia from B12 and folic acid deficiency Megaloblastic Macrocytic Anemias Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based... read more . Fever, tender hepatomegaly, and jaundice suggest the presence of acute alcoholic hepatitis Pathology .

Detecting serum antibody to hepatitis C (anti-HCV) and HCV-RNA indicates hepatitis C. Detecting hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBcAb) confirms chronic hepatitis B Hepatitis B, Chronic Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more . Chronic hepatitis B with very low HBV viral load can occur in HBV/HDV co-infection. Most clinicians also routinely test for the following:

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

Liver biopsy is invasive and is subject to sampling error, but it remains the gold standard for the diagnosis of cirrhosis. Liver biopsy is required in the following situations:

In obvious cases of cirrhosis with marked coagulopathy, portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more , ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , and liver failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more , biopsy is not required unless results would change management. In patients with ascites, coagulopathy, and thrombocytopenia, the transjugular approach to biopsy is safest. When this approach is used, pressures can be measured and thus the trans-sinusoidal pressure gradient can be calculated.

All patients with cirrhosis, regardless of cause, should be screened regularly for hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more . Currently, abdominal ultrasonography with or without serum alpha-fetoprotein (AFP) is recommended every 6 months, and if abnormalities suspect for HCC are detected, contrast-enhanced MRI or triple-phase CT of the abdomen (pre-contrast, arterial phase, and venous phase) should be done. Certain features in contrast imaging (Liver Imaging Reporting and Data System 5 criteria, including early arterial enhancement, washout in portal phase, enhancing capsule) can confirm HCC, sparing the patient a biopsy. Contrast-enhanced ultrasonography appears promising as an alternative to CT or MRI but is still under study.

Upper endoscopy to check for gastroesophageal varices Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may bleed massively but cause no... read more should be done if patients with cirrhosis have symptoms or signs of clinically significant portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more (ascites, platelet count < 150,000, or liver stiffness on transient elastography ≥ 20 kPa), and then every 2 to 3 years. Positive findings may mandate treatment (nonselective beta blockade with carvedilol, nadolol, or propranolol, or endoscopic banding) or more frequent endoscopic monitoring.

The Child-Turcotte-Pugh scoring system uses clinical and laboratory information to stratify disease severity, surgical risk, and overall prognosis (see tables Child-Turcotte-Pugh Scoring System Child-Turcotte-Pugh Scoring System and Interpretation of the Child-Turcotte-Pugh Scoring System Interpretation of the Child-Turcotte-Pugh Scoring System ). The Child-Turcotte-Pugh scoring system does, however, have limitations; for example, assessments of the severity of ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more and encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more are subjective; inter-rater reliability of results is thus decreased.