GRANULOMATOUS HEPATITIS

Formation of granulomas in the liver is observed in a wide variety of diseases, both infectious and non-infectious. The essential event in granuloma formation is the transformation of the monocyte/macrophage into an epithelioid cell. This event is stimulated by the presence of antigen, either soluble or particulate (e.g. micro-organisms and/or their products) in a sensitized cell.

The most common infectious disease associated with granuloma formation in the liver is tuberculosis. Outside the liver, tuberculous granulomas usually exhibit caseation necrosis, but hepatic granulomas due to tuberculosis are characteristically noncaseating . Hepatic granulomas are present in more than 90% of patients with miliary tuberculosis, but are also extremely prevalent in pulmonary and in other extrapulmonary forms of the disease (70-80%). Tubercle bacilli can be demonstrated either by staining techniques or culture in approximately half of patients with miliary tuberculosis , but are detected much less frequently in the granulomas associated with other forms of tuberculosis.

Infections due to Mycobacterium tuberculosis and M. avium-intracellulare are very common in patients with AIDS. Most AIDS patients with tuberculosis have disseminated or other extrapulmonary forms of the disease, and lesions are commonly found in the liver. Sometimes typical granulomas are found, but often the granulomas are poorly formed or the lesions are abscesses rather than granulomas. Infection with M. avium-intracellulare usually occurs late in the course of AIDS, in patients who are profoundly immunocompromised. In such patients granulomas are poorly formed or absent .

Disseminated fungal infections are also commonly associated with granulomas in the liver. In the United States, disseminated histoplasmosis is the most common fungal infection associated with hepatic granulomas , and liver biopsy is a valuable technique in the diagnosis of this infection and in the diagnosis of disseminated African histoplasmosis . Hepatic candidiasis appears to be increasing in frequency among patients with cancer; in these patients the lesions often resemble abscesses rather than granulomas. Hepatic involvement is occasionally seen during systemic infection with a wide variety of other fungal organisms including Cryptococcus neoformans .

The adult trematode worms Schistosoma mansoni and S. japonicum reside in the portal and mesenteric veins ( and granulomas surrounding the eggs of these organisms may occur in the liver . If infection is extensive, portal hypertension, hepatosplenomegaly and oesophageal varices may result . Extensive liver involvement may also occur in visceral leishmaniasis (kala-azar) . In this disease there is marked proliferation of Kupffer cells, many of which are filled with the amastigote forms of Leishmania donovani . Other infectious diseases in which liver granulomas are sometimes observed include toxoplasmosis, visceral larva migrans, Q fever (see ), cat scratch disease, CMV infection, hepatitis B, and infectious mononucleosis.

Among non-infectious diseases, sarcoidosis is the disease most commonly associated with hepatic granulomas. In sarcoidosis and in other non-infectious causes of hepatic granuloma formation, the granulomas are noncaseating . Hepatic granulomas are also seen in Hodgkin's disease and in various hypersensitivity states such as erythema nodosum. In approximately 50% of patients with granulomas in the liver, the lesions appear to be limited to the liver and no cause can be found. Presence of extensive granuloma formation in the liver is often associated with fever, and this condition is a common cause of `fever of undetermined origin'.