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Hepatic Granulomas

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Last full review/revision Aug 2021| Content last modified Aug 2021
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Hepatic granulomas have numerous causes and are usually asymptomatic. However, the underlying disorder may cause extrahepatic manifestations, hepatic inflammation, fibrosis, portal hypertension, or a combination. Diagnosis is based on liver biopsy, but biopsy is necessary only if a treatable underlying disorder (eg, infection) is suspected or if other liver disorders need to be ruled out. Treatment depends on the underlying disorder.

Hepatic granulomas, although sometimes insignificant, more often reflect clinically relevant disease. The term granulomatous hepatitis is often used to describe the condition, but the disorder is not true hepatitis, and the presence of granulomas does not imply hepatocellular inflammation.

Etiology of Hepatic Granulomas

Hepatic granulomas have many causes (see table Causes of Hepatic Granulomas Causes of Hepatic Granulomas Hepatic granulomas have numerous causes and are usually asymptomatic. However, the underlying disorder may cause extrahepatic manifestations, hepatic inflammation, fibrosis, portal hypertension... read more ); drugs and systemic disorders (often infections) are more common causes than primary liver disorders. Infections must be identified because they require specific treatments. Tuberculosis and schistosomiasis Schistosomiasis Schistosomiasis is infection with blood flukes of the genus Schistosoma, which are acquired transcutaneously by swimming or wading in contaminated freshwater. The organisms infect the vasculature... read more are the most common infectious causes worldwide; fungal and viral causes are less common. Sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis is the most common noninfectious cause; the liver is involved in about two thirds of patients, and occasionally, clinical manifestations of sarcoidosis are predominantly hepatic.

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Granulomas are much less common in primary liver disorders; 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 (PBC, previously primary biliary cirrhosis) is the only important cause. Small granulomas occasionally occur in other liver disorders but are not clinically significant.

Idiopathic granulomatous hepatitis is a rare syndrome of hepatic granulomas with recurrent fever, myalgias, fatigue, and other systemic symptoms, which often occur intermittently for years. Some experts believe it is a variant of sarcoidosis.

Pathophysiology of Hepatic Granulomas

A granuloma is a localized collection of chronic inflammatory cells with epithelioid cells and giant multinucleated cells. Caseation necrosis or foreign body tissue (eg, schistosome eggs) may be present. Most granulomas occur in the parenchyma, but 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 , granulomas may occur in the hepatic triads.

Granuloma formation is incompletely understood. Granulomas may develop in response to poorly soluble exogenous or endogenous irritants. Immunologic mechanisms are involved.

Hepatic granulomas rarely affect hepatocellular function. However, when granulomas are part of a broader inflammatory reaction involving the liver (eg, drug reactions Liver Injury Caused by Drugs Many drugs (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically... read more , infectious mononucleosis Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more Infectious Mononucleosis ), hepatocellular dysfunction is present. Sometimes inflammation causes progressive hepatic fibrosis 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 and portal hypertension Portal Hypertension 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 , typically with schistosomiasis Schistosomiasis Schistosomiasis is infection with blood flukes of the genus Schistosoma, which are acquired transcutaneously by swimming or wading in contaminated freshwater. The organisms infect the vasculature... read more and occasionally with extensive sarcoidal infiltration.

Symptoms and Signs of Hepatic Granulomas

Granulomas themselves are typically asymptomatic; even extensive infiltration usually causes only minor hepatomegaly and little or no jaundice. Symptoms, if they occur, reflect the underlying condition (eg, constitutional symptoms in infections, hepatosplenomegaly in schistosomiasis).

Diagnosis of Hepatic Granulomas

  • Liver tests

  • Imaging

  • Biopsy

Hepatic granulomas are suspected in patients with

  • Conditions that commonly cause granulomas

  • Unexplained hepatic masses found during imaging tests

  • Abnormalities detected by an imaging test that is done to evaluate asymptomatic elevations in liver enzymes, particularly alkaline phosphatase

When granulomas are suspected, liver 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 are usually done, but results are nonspecific and are rarely helpful in diagnosis. Alkaline phosphatase (and gamma-glutamyltransferase) is often mildly elevated but occasionally may be markedly elevated. Other test results may be normal or abnormal, reflecting additional hepatic damage (eg, widespread hepatic inflammation due to a drug reaction). Usually, imaging tests Imaging Tests of the Liver and Gallbladder Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more Imaging Tests of the Liver and Gallbladder , such as ultrasonography, CT, or MRI, are not diagnostic; they may show calcification (if granulomas are long-standing) or filling defects, particularly with confluent lesions. In sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis , granulomas appear hypodense on cross-sectional imaging and so can be misdiagnosed as liver metastases.

Diagnosis is based on 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 . However, biopsy is usually indicated only to diagnose treatable causes (eg, infections) or to rule out nongranulomatous disorders (eg, chronic viral hepatitis Causes of Hepatitis Hepatitis is an inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more ). Biopsy sometimes detects evidence of the specific cause (eg, schistosome eggs, caseation of tuberculosis, fungal organisms). However, other tests (eg, cultures, skin tests, laboratory tests, imaging tests, other tissue specimens) are often needed.

In patients with constitutional or other symptoms suggesting infection (eg, fever of unknown origin Fever of Unknown Origin (FUO) Fever of unknown origin (FUO) is body temperature ≥ 38.3° C (101° F) rectally that does not result from transient and self-limited illness, rapidly fatal illness, or disorders with clear-cut... read more [FUO]), specific measures are taken to increase the diagnostic sensitivity of biopsy for infections; eg, a portion of the fresh biopsy specimen is sent for culture, or special stains for acid-fast bacilli, fungi, and other organisms are used. Often, cause cannot be established.

Prognosis of Hepatic Granulomas

Hepatic granulomas caused by drugs or infection regress completely after treatment. Sarcoid granulomas may disappear spontaneously or persist for years, usually without causing clinically important liver disease. Progressive fibrosis and portal hypertension (sarcoidal cirrhosis) rarely develop.

In schistosomiasis Schistosomiasis Schistosomiasis is infection with blood flukes of the genus Schistosoma, which are acquired transcutaneously by swimming or wading in contaminated freshwater. The organisms infect the vasculature... read more , progressive portal scarring (pipestem fibrosis) is typical; liver function is usually preserved, but marked splenomegaly and variceal hemorrhage can occur.

Treatment of Hepatic Granulomas

  • Treatment of cause

Treatment is directed at the underlying disorder. When the cause is unknown, treatment is usually withheld, and follow-up with periodic liver tests is instituted. However, if symptoms of tuberculosis (eg, prolonged fever) and deteriorating health occur, empiric antituberculous therapy may be justified.

Corticosteroids may resolve liver biochemistry abnormalities and systemic manifestations of sarcoidosis, such as weight loss and extrahepatic involvement; however, they do not prevent hepatic fibrosis 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 . Thus, corticosteroids are typically recommended only in patients with systemic manifestations of sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis and only if tuberculosis and other infections can be excluded confidently.

Key Points

  • Hepatic granulomas can result from many drugs and systemic disorders; primary liver disorders are uncommon causes.

  • Tuberculosis and schistosomiasis are the most common infectious causes worldwide; sarcoidosis is the most common noninfectious cause.

  • Symptoms and complications are due mainly to the underlying condition rather than the granulomas themselves.

  • Treatment is directed at the cause.

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