Granuloma of the liver

Liver granulomas can be caused by a variety of reasons and are usually asymptomatic.

However, diseases that cause granuloma formation may be associated with extrahepatic symptoms and/or lead to liver inflammation, fibrosis, and portal hypertension. Diagnosis is based on liver biopsy, but biopsy is only necessary if a treatable disorder (such as infection) is suspected or other liver diseases have been excluded. Treatment of liver granulomas is determined by the underlying disorder.

Liver granulomas themselves may be of minor significance, but are often a manifestation of clinically significant 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.

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Causes of liver granuloma

A granuloma is a localized collection of chronic inflammatory cells together with epithelioid and multinucleated giant cells. Caseous necrosis or foreign body tissue (eg, eggs in schistosomiasis) may be present. Most granulomas are in the parenchyma, but granulomas may be seen in liver triads in primary biliary cirrhosis.

The mechanisms of granuloma formation are not fully understood. Granulomas can form in response to exogenous or endogenous stimuli, with immune mechanisms being involved.

Liver granulomas have many causes, most often drugs and systemic diseases (often infections) rather than primary liver lesions. Infections are very important to diagnose, as they require specific treatment. Worldwide, the main infectious causes of granuloma formation are tuberculosis and schistosomiasis; more rarely, granuloma is formed by a viral infection. Sarcoidosis is the main

Clinicians identify the following causes of liver granuloma formation:

• Medicines (eg, allopurinol, phenylbutazone, quinidine, sulfonamides)
• Infections
  • Bacterial (actinomycosis, brucellosis, cat scratch disease, syphilis, tuberculosis and other mycobacteria, tularemia)
  • Fungal (blastomycosis, cryptococcosis, histoplasmosis)
  • Parasitic (schistosomiasis, toxoplasmosis, visceral nematode larva)
  • Viral (cytomegalovirus, infectious mononucleosis, Q fever)
• Liver disease (primary biliary cirrhosis)
• Systemic diseases (Hodgkin's lymphoma, polymyalgia rheumatica and other connective tissue diseases, sarcoidosis)

The most common reasons are:

• The cause is non-infectious; liver damage is observed in approximately two thirds of patients and is sometimes dominant in the clinical picture.
• Granulomas are less common in primary liver diseases, of which primary biliary cirrhosis is the only important cause. Small granulomas occasionally develop in other liver diseases, but they are of little clinical significance.
• Idiopathic granulomatous hepatitis is a rare syndrome that includes liver granulomas, recurrent fever, myalgias, fatigue, and other systemic symptoms that recur periodically over many years. Some authors believe that it is a variant of sarcoidosis.
• Granulomas of the liver rarely impair hepatocellular function. However, if granulomas are part of a more general inflammatory response involving the liver (eg, drug reaction, infectious mononucleosis), hepatocellular dysfunction occurs. Sometimes the inflammation causes progressive liver fibrosis and portal hypertension, as is commonly seen in schistosomiasis and occasionally with extensive infiltration in sarcoidosis.

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Symptoms of liver granulomas

The granulomas themselves are usually asymptomatic; even significant infiltration usually causes only minor hepatomegaly and little or no jaundice. Symptoms, when present, reflect the underlying cause (eg, systemic signs of infection, hepatosplenomegaly in schistosomiasis).

Diagnosis of liver granulomas

If liver granulomas are suspected, liver function tests are done, but their results are nonspecific and rarely helpful in diagnosis. Alkaline phosphatase (and gamma-glutamyl transferase) levels are often mildly elevated but may be high in some cases. Other tests may be normal or abnormal, reflecting additional liver injury (eg, extensive inflammation due to a drug reaction). Imaging studies such as ultrasound, CT, or MRI are generally not diagnostic, but they may show calcifications (if the process is chronic) or filling defects, especially in confluent lesions.

Diagnosis is based on liver biopsy. However, biopsy is usually performed only to diagnose a treatable disorder (e.g., infection) or to differentiate from nongranulomatous lesions (e.g., chronic viral hepatitis). Biopsy sometimes reveals the presence of a specific cause (e.g., eggs in schistosomiasis, caseous decay in tuberculosis, fungal infection). However, other investigations are often necessary (e.g., culture, skin tests, laboratory and radiographic studies, other tissue samples).

In patients with systemic or other symptoms suggestive of infection (eg, fever of unknown etiology), specific tests should be used to enhance the diagnostic value of the biopsy to verify infection (eg, a portion of the fresh biopsy material is sent for culture and special staining for acid-fast bacilli, fungi, and other organisms). Quite often, the cause is not established.

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Treatment of liver granulomas

Granulomas of the liver caused by drugs or infections regress completely with treatment. Granulomas in sarcoidosis may resolve spontaneously or persist for many years, usually without the development of clinically significant liver disease. Progressive fibrosis and portal hypertension develop rarely (sarcoidosis cirrhosis). Schistosomiasis is characterized by progressive portal sclerosis (pipestem fibrosis, Simmers' fibrosis); liver function is usually preserved, but splenomegaly is noted and variceal bleeding may develop.

Treatment is directed at the underlying cause. If the cause is unknown, treatment is usually withheld and liver function tests are continued periodically. However, if signs of tuberculosis (eg, prolonged fever) and deterioration occur, empiric antituberculosis therapy may be warranted. In advanced liver sarcoidosis, glucocorticoids may be effective, although it is not known whether they can prevent the development of liver fibrosis. However, glucocorticoids are not indicated in most patients with sarcoidosis and should be used only if tuberculosis and other infections have been completely excluded.