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Cirrhosis

By

Jesse M. Civan

, MD, Thomas Jefferson University Hospital

Last full review/revision Dec 2019
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Cirrhosis is a leading cause of death worldwide.

Etiology of Cirrhosis

The causes of cirrhosis are the same as those of fibrosis (see table Disorders and Drugs That Can Cause Hepatic Fibrosis Disorders and Drugs That Can Cause Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more ). In developed countries, most cases result from chronic alcohol abuse Alcohol Toxicity and Withdrawal Alcohol (ethanol) is a central nervous system depressant. Large amounts consumed rapidly can cause respiratory depression, coma, and death. Large amounts chronically consumed damage the liver... read more or chronic hepatitis C Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more . In parts of Asia and Africa, cirrhosis often results from 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 (see table Characteristics of Hepatitis Viruses Characteristics of Hepatitis Viruses Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more for additional information on hepatitis B and C). 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 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 , and primary sclerosing cholangitis Primary Sclerosing Cholangitis (PSC) Primary sclerosing cholangitis (PSC) is patchy inflammation, fibrosis, and strictures of the bile ducts that has no known cause. However, 80% of patients also have inflammatory bowel disease... read more .

Pathophysiology of Cirrhosis

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-alpha, 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

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 . 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 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 Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to have... read more Alcohol-Related Liver Disease , from malabsorption due to pancreatic insufficiency.

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 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.

Pearls & Pitfalls

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

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 of Cirrhosis

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 Common Symptoms and Signs Due to Complications of Cirrhosis Common Symptoms and Signs Due to Complications of Cirrhosis 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 ). 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 any complication of cirrhosis develops, additional decompensation is much more likely.

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Diagnosis of Cirrhosis

  • Liver tests, coagulation tests, complete blood count (CBC), and serologic tests for viral causes

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

  • Sometimes ultrasound elastography or magnetic resonance elastography

  • 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 table Common Symptoms and Signs Due to Complications of Cirrhosis Common Symptoms and Signs Due to Complications of Cirrhosis 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 ), 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.

Laboratory tests

Test results may be normal or may indicate nonspecific abnormalities due to complications of cirrhosis or alcohol use disorder Alcohol Use Disorders and Rehabilitation Alcohol use disorder involves a pattern of alcohol use that typically includes craving and manifestations of tolerance and/or withdrawal along with adverse psychosocial consequences. Alcoholism... read more . Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are often modestly elevated. 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. Serum globulin increases in cirrhosis and in most liver disorders with an inflammatory component.

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 Overview of Hemolytic Anemia , 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 read more , thrombocytopenia Overview of Platelet Disorders Platelets are 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 Overview of Platelet Disorders , or pancytopenia.

Diagnostic imaging

Conventional imaging tests are not highly sensitive or specific for the diagnosis of cirrhosis by themselves, but they can often detect its complications. Ultrasound elastography, magnetic resonance elastography, and acoustic radiation force impulse imaging are useful in detection of early cirrhosis when conventional imaging findings are equivocal and portal hypertension is not evident.

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 Pathology Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to have... read more Pathology .

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

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

Liver biopsy

If clinical criteria and noninvasive testing are inconclusive, liver biopsy Liver Biopsy Liver biopsy provides histologic information about liver structure and evidence of liver injury (type and degree, any fibrosis); this information can be essential not only to diagnosis but also... read more 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) Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more may be evident on ultrasound scans. However, NASH, often associated with obesity, diabetes, or the metabolic syndrome, requires liver biopsy for confirmation.

Monitoring

All patients with cirrhosis, regardless of cause, should be screened regularly for hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma 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 is recommended every 6 months, 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 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 Varices should be done when the diagnosis is made and then every 2 to 3 years. Positive findings may mandate treatment or more frequent endoscopic monitoring.

Prognosis for Cirrhosis

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.

Child-Turcotte-Pugh classification for severity of liver disease

Model for end-stage liver disease (MELD)

In contrast to the Child-Turcotte-Pugh classification, 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 international normalized ratio (INR). The MELD score is used to determine allocation of available organs to liver transplant Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more candidates because it can sort candidates by mortality risk (see table MELD Score and Mortality MELD Score and Mortality 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 ). 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 of the MELD score that incorporates serum sodium measurement (MELD-Na) more accurately predicts mortality in cirrhotic patients than the conventional MELD score, and is now used by the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) to prioritize patients on the liver transplant waiting list.

Table
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For selected patients with hepatocellular carcinoma (HCC), specific imaging criteria may be used to increase the MELD score, and this score changes over time according to a set schedule (the hepatocellular carcinoma MELD exception). In 2019, UNOS implemented a major policy update on how the HCC MELD exception is handled. Previously, HCC patients meeting criteria would receive adjusted MELD scores which increased every 3 months. However, under the new policy, patients are awarded a set adjusted MELD-Na score that varies regionally across the United States but is now constant over time. For patients who are 12 to 17 years 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.

Pediatric end-stage liver disease (PELD) score

For patients < 12 years, the corresponding pediatric end-stage liver disease (PELD) score is calculated. Higher PELD scores predict higher risk.

Treatment of Cirrhosis

  • 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 Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more unless they are already immune.

Patients with varices need therapy to prevent bleeding (see Treatment Treatment Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in developed countries), schistosomiasis (in endemic areas), or hepatic vascular abnormalities... read more ). No evidence supports treating small esophageal varices. Medium and large esophageal varices should be treated prophylactically with nonselective beta-blockers or endoscopic banding (ligation). If gastric varices are not amenable to endoscopic banding and do not respond to nonselective beta-blockers, balloon-occluded retrograde transvenous obliteration or endoscopic cyanoacrylate injection may be used.

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

Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more is indicated for patients with end-stage liver disease or hepatocellular carcinoma. 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 alpha-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.

More Information

  • Londoño MC, Cárdenas A, Guevara M: MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut 56(9):1283-1290, 2007.

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