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. There may be insignificant incidental findings, but more often they reflect clinically relevant disease --usually a systemic disorder rather than primary liver disease.
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.
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.
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.
Source: The Merck Manual
Some of our most commonly asked questions and our answers to them.
Learn about the Hepatitis C Virus (HCV).
Information about the transmission of Hepatitis C.
You'll find links to a comprehensive symptoms list, as well as various studies and discussions about Hepatitis C symptoms.
Learn about the conventional medical treatments used to fight Hepatitis C.
Numerous links to studies, info sheets, FAQs, and analysis of Ribavirin/Rebetron medicines.
Alternative methods of treatment due to side effects and dissatisfication with current medical treatments.
A number of herbal products useful in the management of liver disease.
Stories from those having direct experience with hepatitis c.
Receive the latest news on hepatitis treatments, clinical trials, social issues and important breakthroughs.
Learn about Hepatitis C Genotypes and their variants.
A state-by-state and worldwide reference listing physicians who treat HCV, including an email link to submit your physician for inclusion.
Convenient links to other sites external to Hepatitis-Central.
A Bulletin Board for discussions on hepatitis, treatments, etc.
An easy way to get involved in urging our government to do more for Hepatitis C awareness and treatment research.
Numerous links to various Hepatitis B related information, including transmission, symptoms and treatment.
A comprehensive resource of information relating to the liver biopsy.
Many discussions and analyses of cirrhosis, including causes, complications, pathology, symptoms, and much more.
Commonly used medical terms and definitions.
What they are and what they mean. Helps you interpret & understand all the various hepatitis lab tests likely to be encountered.
Liver Cancer/Hepatocellular Carcinoma studies, info sheets, FAQs, and analysis.
An exhaustive list of links to studies, info sheets, FAQs, and analysis of the various drugs used to treat liver disease.
Provides information regarding the best known liver supporting supplements.
Provides information regarding the best known milk thistle supplements.
Provides detailed information on how to analyze and interpret viral load numbers as well as a link to a convenient Viral Load Chart.
Learn more about various Hepatitis C related topics, including HCV, Ascites, Biopsies, and much more.
Recommended reading for those interested in hepatitis information.