Topic Resources
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.
Etiology
The causes of cirrhosis are the same as those of fibrosis (see table 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 (see table Characteristics of Hepatitis Viruses
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, and primary sclerosing cholangitis.
Pathophysiology
There are 2 primary ingredients:
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Hepatic fibrosis
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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.
Overview of Cirrhosis
VIDEO
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 is the most common serious complication of cirrhosis, and it, in turn, causes complications, including
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Gastrointestinal (GI) bleeding from esophageal, gastric, or rectal varices and portal hypertensive gastropathy
Ascites fluid can become infected (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.
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 international normalized ratio [INR] is usually
increased). Leukopenia is also common; it is mediated by hypersplenism and altered expression of erythropoietin and granulocyte-stimulating factors.
Hepatocellular carcinoma frequently complicates cirrhosis, particularly cirrhosis resulting from
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.
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 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 any complication of cirrhosis develops, additional decompensation is much more likely.
Diagnosis
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Liver tests, coagulation tests, complete blood count (CBC), and serologic tests for viral causes
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Sometimes biopsy (eg, when clinical and noninvasive tests are inconclusive, or when biopsy results may change management)
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Sometimes ultrasound elastography or magnetic resonance elastography
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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), 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 tests, coagulation tests, CBC, and serologic tests for chronic viral hepatitis (see tables Hepatitis B Serology and Hepatitis C Serology). 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 alcohol use disorder.
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.
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 (usually causing microcytic anemia), folate deficiency (causing macrocytic anemia, especially in alcohol abuse), hemolysis, and hypersplenism. CBC may also detect leukopenia, thrombocytopenia, 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.
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:
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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)
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Hemochromatosis: Confirmed by increased serum iron and transferrin saturation and possibly results of genetic testing
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Alpha-1 antitrypsin deficiency: Confirmed by a low serum alpha-1 antitrypsin level and genotyping
If these causes are not confirmed, other causes are sought:
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Strictures and dilations of the intrahepatic and extrahepatic bile ducts, seen on magnetic resonance cholangiopancreatography (MRCP), suggest primary sclerosing cholangitis.
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, 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.
Monitoring
All patients with cirrhosis, regardless of cause, should be screened regularly for hepatocellular carcinoma.
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
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
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
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 and 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 and encephalopathy are subjective; inter-rater reliability of results is thus decreased.
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 candidates because it can sort candidates by mortality risk (see table MELD Score and Mortality).
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.
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
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
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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 Portal Hypertension : Treatment).
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
(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
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
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Morbidity and mortality in cirrhosis usually result from its complications (eg, complications of portal hypertension, liver failure, hematologic problems).
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Do liver biopsy if a clear diagnosis would lead to better management and outcome.
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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.
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Evaluate all patients periodically for gastroesophageal varices and hepatocellular carcinoma.
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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.
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Treat cirrhosis supportively, including using therapies to prevent bleeding.
More Information
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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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