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Hepatic Granulomas

by Steven K. Herrine, MD

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

Hepatic granulomas have many causes (see Table: Causes of Hepatic Granulomas); drugs and systemic disorders (often infections) are more common causes than primary liver disorders. Infections must be identified because they require specific treatments. TB and schistosomiasis are the most common infectious causes worldwide; fungal and viral causes are less common. 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.

Causes of Hepatic Granulomas

Cause

Examples

Drugs

Allopurinol, phenylbutazone, quinidine, sulfonamides

Infections, bacterial

Actinomycosis, brucellosis, cat-scratch fever, syphilis, TB*, other mycobacterial infections, tularemia, Q fever

Infections, fungal

Blastomycosis, cryptococcosis, histoplasmosis

Infections, parasitic

Schistosomiasis*, toxoplasmosis, visceral larva migrans

Infections, viral

Hepatitis C, cytomegalovirus infection

Liver disorders

Primary biliary cirrhosis

Systemic disorders

Hodgkin lymphoma, polymyalgia rheumatica, other connective tissue disorders, sarcoidosis*

*Most common causes.

Granulomas are much less common in primary liver disorders; 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

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 cirrhosis, 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, infectious mononucleosis), hepatocellular dysfunction is present. Sometimes inflammation causes progressive hepatic fibrosis and portal hypertension, typically with schistosomiasis and occasionally with extensive sarcoidal infiltration.

Symptoms and Signs

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

  • Liver function 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 function tests are usually done, but results are nonspecific and are rarely helpful in diagnosis. Alkaline phosphatase (and γ-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, 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.

Diagnosis is based on liver biopsy. However, biopsy is usually indicated only to diagnose treatable causes (eg, infections) or to rule out nongranulomatous disorders (eg, chronic viral hepatitis). Biopsy sometimes detects evidence of the specific cause (eg, schistosome eggs, caseation of TB, 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, 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

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, progressive portal scarring (pipestem fibrosis) is typical; liver function is usually preserved, but marked splenomegaly and variceal hemorrhage can occur.

Treatment

  • 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 function tests is instituted. However, if symptoms of TB (eg, prolonged fever) and deteriorating health occur, empiric antituberculous therapy may be justified.

Corticosteroids may benefit patients with progressive hepatic sarcoidosis, although whether these drugs prevent hepatic fibrosis is unclear. However, corticosteroids are not indicated for most patients with sarcoidosis and are warranted only if TB 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.

  • TB 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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