Hepatic Granulomas

A multifactorial infiltrative liver disorder with or without additional hepatic inflammation and fibrosis. The term “granulomatous hepatitis” is often used, but the condition is not a true hepatitis. Hepatic granulomas are found in about 3 to 10% of liver biopsies. They may be insignificant incidental findings, but more often they reflect clinically relevant disease –usually a systemic disorder rather than primary liver disease.

Etiology

The causes of liver granulomas are legion. Infectious disorders are the most important: bacterial (eg, TB and other mycobacterial infections, brucellosis, tularemia, actinomycosis); fungal (eg, histoplasmosis, cryptococcosis, blastomycosis); parasitic (eg, schistosomiasis –the most important worldwide, toxoplasmosis, visceral larva migrans); viral infections, which are less common (eg, infectious mononucleosis, cytomegalovirus); and numerous others (eg, Q fever, syphilis, cat-scratch fever).

Sarcoidosis is the most important noninfectious cause; liver involvement occurs in about 2/3 of patients and occasionally is the dominant clinical manifestation. A variety of drugs can be responsible (eg, quinidine, sulfonamides, allopurinol, phenylbutazone). Hepatic granulomas can also occur in polymyalgia rheumatica and other collagen-vascular diseases; in Hodgkin’s disease, sometimes without other morphologic evidence of the lymphoma; and in a host of other systemic conditions.

Granulomas are less common in primary liver disease. Of these, primary biliary cirrhosis is the only important cause; periportal granulomas are typical in this disorder, especially in the early stages, usually coupled with other characteristic histologic features. Small granulomas are occasionally seen in various other liver diseases, most often associated with fat droplets (lipogranulomas), but are of no clinical significance.

In many cases no etiology can be established. A few such patients have a syndrome of recurrent fevers, myalgias, fatigue, and other systemic symptoms, often occurring intermittently for years. Whether this “idiopathic granulomatous hepatitis” is a specific syndrome or a variant of sarcoidosis is debated.

Pathophysiology

Granuloma formation is incompletely understood. The lesions are regarded as a host attempt to protect against poorly soluble exogenous or endogenous irritants. Immunologic mechanisms convert cells of the mononuclear phagocytic system into the typical collection of epithelioid cells that constitute a granuloma; multinucleated giant cells are believed to derive from fusion of macrophages.

In the liver, granulomas often incite little or no hepatocellular reaction and merely serve as the morphologic clue to some underlying systemic process; hepatic disease is not apparent clinically and liver function is well preserved. However, when granulomas are part of a broader inflammatory reaction involving the liver (eg, drug reactions, infectious mononucleosis), clinical and biochemical evidence of hepatocellular dysfunction is usually present. Sometimes an aggressive inflammatory response ensues around the granulomas, resulting in progressive hepatic fibrosis and portal hypertension. This is typical of schistosomiasis and occasionally occurs in extensive sarcoidal infiltration.

Symptoms, Signs, and Laboratory Findings

Clinical features reflect the underlying etiology. Granulomas themselves are typically subclinical; even extensive infiltration usually produces only minor hepatomegaly and little or no jaundice. Fever, malaise, and other systemic symptoms are the usual presenting manifestations of an infective etiology; prolonged FUO is especially common in TB and fungal infections. The history is critical in establishing a drug etiology. Various systemic features may provide the clue to sarcoidosis, collagen-vascular disease, lymphoma, and other causes. Signs of primary liver disease are usually lacking, and hepatosplenomegaly is typically absent or mild except in schistosomiasis.

In most situations, liver function test results are only mildly deranged, usually with a disproportionate elevation of alkaline phosphatase. Bilirubin levels are typically normal or only mildly elevated, unless concomitant hepatocellular injury coexists. Enzyme values may simulate viral hepatitis if extensive hepatocellular necrosis is present (eg, in infectious mononucleosis or a drug reaction). A predominant cholestatic reaction suggests primary biliary cirrhosis, especially if long-standing. Other laboratory abnormalities depend on the specific cause.

Diagnosis

Liver biopsy is essential for diagnosis and should be considered whenever a systemic granulomatous disorder is suspected, even in the absence of apparent hepatic involvement. Biopsy demonstrates granulomas and may provide histologic evidence of the specific etiology (eg, schistosomal ova, caseation of TB, fungal organisms, primary biliary cirrhosis). However, the morphologic pattern is often nonspecific and the diagnosis must be pursued with appropriate studies (eg, cultures, skin tests, laboratory and x-ray studies, and other tissue specimens). Infective etiologies are especially important to establish in patients with FUO; this task often proves challenging. A portion of the fresh biopsy specimen should be sent for culture; special stains for acid-fast bacilli, fungi, and other organisms can sometimes prove the cause, though negative results do not exclude an infective etiology.

Prognosis and Treatment

Hepatic granulomas of infective or drug etiology regress completely after appropriate therapy. Sarcoid granulomas may disappear spontaneously or persist for years, usually without clinically important hepatic disease, but progressive fibrosis and portal hypertension occasionally develop (sarcoidal cirrhosis). In schistosomiasis, progressive portal scarring is the rule (“pipestem fibrosis”); hepatic function usually remains well preserved, but increasing portal hypertension leads to marked splenomegaly and risk of variceal hemorrhage.

Treatment depends on the underlying etiology. Without an etiologic diagnosis, it is generally best to follow the patient rather than blindly treat with antibiotics or other therapies. Antituberculous therapy may be justified in a patient with prolonged fever, a compatible clinical picture, and a downhill systemic course. Patients with progressive hepatic sarcoidosis may benefit from corticosteroid therapy, though it remains unclear whether this prevents hepatic fibrosis; corticosteroids are not indicated for most patients with sarcoidosis and should be given only if TB and other infective disorders can confidently be excluded. Corticosteroids usually suppress the recurrent fevers in patients with the syndrome of idiopathic granulomatous hepatitis.