Continuing Education Activity

Granulomatous hepatitis refers to the presence of granulomas in the liver. Etiologies of this condition cover a broad range that may be infectious, non-infectious, autoimmune, drug-induced, or idiopathic. Hepatic granulomas may be incidental findings but are more likely to be associated with an underlying systemic disorder. This activity provides a review of granulomatous hepatitis, including its etiologies, pathology, evaluation, management and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the pathophysiology of granulomatous hepatitis.
• Describe the appropriate evaluation process for granulomatous hepatitis.
• Outline the management options for granulomatous hepatitis.
• Summarize the importance of collaboration amongst the interprofessional team to enhance the care of patients with granulomatous hepatitis.

Introduction

Granulomatous hepatitis refers to the presence of granulomas in the liver. It has been attributed to multiple etiologies, with sarcoidosis and primary biliary cholangitis being the most common causes in the US, and tuberculosis worldwide. Granulomas may also be incidental findings, especially with the increased use of computed tomography (CT) and magnetic resonance imaging (MRI), but are most commonly found to be associated with an underlying systemic process. Manifestations may include right upper quadrant abdominal pain and tenderness, elevated alkaline phosphatase and transaminases, hyperbilirubinemia, jaundice, or fevers. Management is directed towards the treatment of the underlying cause.

Etiology

Hepatic granulomas have a wide range of etiologies that may be infectious or non-infectious in nature. The most common causes of granulomatous hepatitis include sarcoidosis, primary biliary cholangitis (PBC), tuberculosis, and drug-induced liver injury.[1] Sarcoidosis and primary biliary cholangitis are the most common causes in the US, while tuberculosis is the most common worldwide. Numerous drugs, including oral hypoglycemic agents such as sulfonylureas, antiepileptics such as phenytoin, antibiotics such as penicillin, sulfonamides, allopurinol, diltiazem, amiodarone, hydralazine, and exposure to toxic substances such as beryllium and silica have been described to be associated with granulomatous hepatitis likely due to hypersensitivity reactions.[2][3][4] 

Talc, barium, and silicone from therapeutic and diagnostic procedures have also been found to be associated with this condition. Other causes include chronic hepatitis B and C infection, Bacille Calmette-Guerin (BCG) therapy, brucellosis, leprosy, histoplasmosis, coccidioidomycosis, schistosomiasis, amebic liver abscess, lymphoma, and malignant granuloma. It may also be idiopathic.[5] The term “idiopathic granulomatous hepatitis” generally refers to a syndrome of prolonged fevers, myalgias, arthralgias, and hepatosplenomegaly with the presence of hepatic granulomas of unclear etiology.[6][7]

Epidemiology

Hepatic granulomas are common as the liver is very rich in reticuloendothelial cells which are found in about 2% to 10% of liver biopsies. Unfortunately, they may be the result of a nonspecific reaction to numerous noxious stimuli and pose difficulty in providing a diagnostic yield. Around 10% to 36% of hepatic granulomas may be found to be idiopathic after an extensive evaluation. Systemic sarcoidosis is associated with hepatosplenic involvement in about 50% to 70% of cases. Granulomas in PBC are present in 25% to 50% of patients.

Mycobacterium tuberculosis (TB) can also cause hepatic granulomas with 25% in pulmonary TB and up to 90% in miliary tuberculosis. Tuberculosis and sarcoidosis are the most common causes and account for about 50% to 65% of cases of granulomatous hepatitis. Histoplasmosis associated granulomatous hepatitis is commonly found in endemic areas of the midwestern and central parts of the country, such as the Ohio River Valley, accounting for about 12% of cases in Ohio. Coccidioidomycosis is common in the southwestern parts of the US.[8][9][10]

Pathophysiology

Due to the rich blood supply and numerous Kupffer cells (stellate sinusoidal macrophages), the liver is a very common site for granuloma formation. Kupffer cells help clear foreign particles by phagocytosis and pinocytosis. When the macrophages are unable to clear the stimulus of inflammation, a further inflammatory process is initiated, resulting in an aggregation of macrophages around the source of the inflammatory stimulus. This aggregation, along with a peripheral cuff of lymphocytes, form an inflammatory focus called a granuloma.[11][12]

Histopathology

Hepatic granulomas may be classified into four main variants, namely, caseating, non-caseating, fibrin-ring, and lipogranulomas. Tuberculous granulomas and other infectious granulomas usually have necrotic centers that appear “cheese-like” and are hence called caseating. Sarcoidosis is classically characterized by noncaseating granulomas. Fibrin-ring variants are epithelioid cells in an encircling fibrin ring with a central vacuole. These fibrin-ring granulomas are seen in infections, may be drug-induced, or in Hodgkin lymphoma. Lipogranulomas are characterized by a central lipid vacuole and are seen in mineral oil ingestion or hepatic steatosis. In PBC, granulomas are present surrounding the damaged bile ducts. Granulomas in Q fever are typically characterized by an eosinophilic fibrinoid ring with a central clear space enclosing a fat vacuole. The presence of abundant eosinophils may suggest a drug-induced reaction. However, they are also seen in parasitic infections as well as Hodgkin’s disease.[8][9][12]

History and Physical

Hepatic granulomas, on their own, are typically asymptomatic and may not even present with laboratory abnormalities or features of hepatic dysfunction. Clinical manifestations are the result of the underlying systemic disease. A thorough history and physical examination are essential in the proper diagnosis of granulomatous hepatitis. Manifestations may be nonspecific; however, granulomatous hepatitis should be considered in any patient with abdominal pain and tenderness, especially in the right upper quadrant, fever of unknown origin, hepatomegaly, or mild transaminitis. Constitutional symptoms such as prolonged fevers, night sweats, chills, weight loss, anorexia, myalgias, and arthralgias are common, especially in tuberculosis and sarcoidosis. 

Patients may have ascites, spider angiomata, hepatic fibrosis with portal hypertension, and cirrhosis, as seen in PBC, sarcoidosis, or schistosomiasis. Details in their history such as ethnicity, current or recent medications, toxin exposures, family history, occupational exposures, recent travel, risk factors for opportunistic infections such as the use of immunosuppressive drugs or in patients with human immunodeficiency virus (HIV) may assist in establishing the etiology. Recent travel to endemic areas may provide a clue to infectious sources. Histoplasmosis is usually self-limited; however, it may present as progressive disseminated histoplasmosis in infants or in immunocompromised patients. These patients may present with hepatomegaly (62%) or abnormal liver function tests (84%). Schistosomiasis is characterized by progressive portal scarring called “pipestem fibrosis” with marked splenomegaly and variceal hemorrhage.[1][8][11][13]

Evaluation

Baseline investigational tools may include erythrocyte sedimentation rate, C-reactive protein, complete blood count with differential especially for the eosinophil count, comprehensive metabolic panel, prothrombin time/international normalized ratio, blood cultures, urine or sputum analysis/culture, stool studies for ova and parasites, TB skin test or interferon-gamma release assay, serology for antimitochondrial antibodies, angiotensin-converting enzyme levels, immunoglobulins, viral serology, or histoplasmosis antibodies or coccidioidomycosis antibodies. Transaminases are usually not greater than two times the upper limit of normal.

Imaging such as CT, MRI, or ultrasonography is sensitive in the visualization of liver lesions. A chest radiograph may aid in finding causation such as bilateral perihilar lymphadenopathy in sarcoidosis or nodular ground-glass opacities in miliary tuberculosis, or well-defined nodules as in histoplasmosis. Recently, the use of positron emission tomography (PET) imaging has been growing but requires further development.

Fine-needle liver biopsy is a paramount diagnostic tool in the diagnosis of granulomatous hepatitis, although it may be difficult to distinguish between different etiologies. The probability of finding a granuloma is proportional to the density of the granulomas in the liver and might be missed on biopsy. Evaluation for fungi, spirochete, acid-fast bacilli, ova, foreign bodies, fibrin, and lipid vacuoles is important.

Sarcoidosis is an inflammatory, multisystem granulomatous disease that is commonly seen in younger patients (20-40 years of age) with a second peak around age 60. Granulomas are common in the lung (95% of patients), liver, skin, lymph nodes, and eyes. It is one of the most common causes of granulomatous hepatitis in the US. It is common in those of Scandanavian descent and African-Americans. Women have been found to have a higher prevalence than men. Systemic sarcoidosis is associated with hepatosplenic involvement in about 50% to 70% of cases. Elevated alkaline phosphatase is the most common abnormality, consistent with a cholestatic pattern. Elevated transaminases may also be present. However, hyperbilirubinemia indicates more advanced disease. On imaging, the most common finding is hepatomegaly (5%-15%) and hepatic nodules in about 5%.

A classic feature of sarcoidosis is non-caseating epithelioid granulomas. Of note, the frequency of hepatic granulomas is not affected by the clinical activity of sarcoidosis or the degree of pulmonary involvement. Sarcoidosis is also associated with elevated angiotensin-converting enzyme levels (especially >2 times upper limit of normal) and hypercalcemia (due to production of 1,25-dihydroxy vitamin D by the granuloma), resulting in increased absorption of intestinal calcium with a low parathyroid hormone (PTH) level. Interestingly, there have been some studies that suggest an association between sarcoidosis and a mycobacterium. The majority of patients with hepatic involvement tend to be asymptomatic; however, they may develop ascites or esophageal varices due to extensive intrahepatic cholestasis leading to portal hypertension.[14]

Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is another common cause of granulomatous hepatitis in the US. It is an autoimmune chronic liver disease, commonly seen in middle-aged women, characterized by the destruction of the intrahepatic biliary ducts. Granulomas in PBC are present in 25% to 50% of patients and are found surrounding the damaged bile ducts. Anti-mitochondrial antibodies (AMA) are highly specific in the diagnosis of PBC and are present in about 95% of patients. On biopsy, it has a similar appearance to vanishing bile duct syndrome. Interestingly, sarcoidosis has been found to be associated with vanishing bile duct syndrome.[9]

Granulomas in pulmonary TB are called a Ghon focus. Mycobacterium tuberculosis can also cause hepatic granulomas with 25% in pulmonary TB and up to 90% in miliary tuberculosis. These hepatic granulomas may or may not have caseation. In hepatic granulomas associated with miliary tuberculosis, hypoalbuminemia and hyponatremia have been found in 88% and 65% of patients, respectively. The presence of acid-fast bacilli or fungus in Ziehl-Neelsen stain has historically been used in the diagnosis of Mycobacterium tuberculosis and Histoplasma, respectively. Polymerase chain reaction (PCR) has a sensitivity of 88% and a specificity of 100% in detecting M. tuberculosis. It is important to note that Histoplasmosis may be confused with Leishmania on histology. Fungal culture, methenamine silver staining of the tissue, or complement fixation tests help in differentiating and aid in diagnosis. 

Intravesical Bacille Calmette-Guerin (BCG), a strain of Mycobacterium bovis, has also been associated with granulomatous hepatitis. Administration of the live-attenuated BCG vaccine, especially in immunocompromised patients, may result in multiple hepatic granulomas. It causes nonspecific stimulation of the reticuloendothelial cells and so has been used historically in the treatment of certain malignancies, most commonly in the treatment of superficial bladder cancer. BCG therapy is also used in the therapy for melanoma, papillary carcinomas, and carcinomas in situ. Granulomatous hepatitis can be a rare but fatal complication of BCG therapy due to the widespread dissemination of BCG. The mycobacterium is only recovered on Ziehl-Neelsen stain in about 10% of all cases involving the liver. PCR is often negative as well.[15][16][17]

Mycobacterium avium complex (MAC) is a common opportunistic infection found on liver biopsy in those with HIV. The biopsy usually shows granulomatous inflammation consisting of foamy macrophages, especially in the portal tracts and parenchyma. Hepatomegaly, fevers, and a cholestatic liver profile are common.

Drug-induced granulomatous hepatitis is a diagnosis of exclusion. Some histological clues that may point to drug-induced pathology may include the presence of tissue eosinophilia, vasculitis, or unicellular hepatocytic degeneration and necrosis.[5][18]

Treatment / Management

Management of granulomatous hepatitis should be initiated, keeping the underlying cause in mind. Asymptomatic, incidental, or idiopathic granulomas may be monitored with regular follow up assessments and/or liver function tests. Most patients with symptomatic idiopathic granulomatous hepatitis respond well to corticosteroids. However, prior to initiating immunosuppression with corticosteroids, tuberculosis must be ruled out. Glucocorticoid therapy consists of prednisone 20 to 40 mg daily and is gradually tapered off over 4 to 8 weeks. A second course may be given if required. Methotrexate and infliximab may be alternatives for patients in which corticosteroids are not preferred or are contraindicated. In those who do not respond to corticosteroids, further evaluation for atypical infections, lymphoma, or other malignancies should be considered. Discontinuing the use of the drug or exposure to the toxin implicated may result in the resolution of the hepatic granulomas. 

Hepatic sarcoidosis management is tailored individually, as some patients may not require specific treatment, while others may require lifelong therapy. Corticosteroids are the mainstay of therapy and are first-line for idiopathic granulomatous hepatitis as well. Methotrexate, chloroquine, azathioprine, and ursodeoxycholic acid are second-line agents in the treatment of sarcoidosis or idiopathic granulomatous hepatitis. Only 5% of sarcoidosis involving the liver requires therapy, although symptoms due to portal hypertension will require a liver transplant. However, the requirement for liver transplant is rare as the majority respond well to systemic therapy. It is important to keep in mind that the use of interferon therapy in patients with both sarcoidosis and hepatitis C may result in either development or worsening of granulomatous disease. Some studies suggest steroid use in the first 6 months of presentation for any manifestation of sarcoidosis may have a >50% chance of developing chronic disease while <10% with no systemic therapy will require chronic therapy.

Ursodeoxycholic acid may help in symptom resolution of pruritus in sarcoidosis and PBC caused by cholestatic jaundice. Ursodeoxycholic acid therapy has been shown to reduce the progression of PBC and results in histologic improvement. It improves overall and transplantation-free survival. For those patients that do undergo liver transplantation in PBC, outcomes are excellent, with a 1-year survival rate of greater than 90%.

Infectious causes rely on appropriate antibiotic therapy. Granulomas associated with tuberculosis should be treated with rifampin, isoniazid (INH), pyrazinamide, and ethambutol. Histoplasmosis and coccidioidomycosis associated granulomas are treated with amphotericin or flucytosine. It is important to keep in mind that INH is associated with hepatic injury and so liver function tests and renal function should be monitored on a regular basis. INH should be used in combination with pyridoxine therapy to prevent the development of peripheral neuropathy. Treatment of BCG-associated infection comprises a similar drug regimen to active pulmonary TB (rifampin, isoniazid, and ethambutol) as it is susceptible to most anti-TB drugs except pyrazinamide.[11][15]

Differential Diagnosis

The differential diagnosis of granulomatous hepatitis is broad due to the numerous etiologies associated with it. Some differentials to consider are atypical infections, lymphomas, and solid-organ malignancies such as renal cell carcinoma.

Prognosis

Granulomas may regress with appropriate treatment, especially if drug-induced or infectious in etiology. Granulomas in sarcoidosis may resolve spontaneously or may persist for years. They may be asymptomatic or progress to fibrosis, portal hypertension, or cirrhosis. Ursodeoxycholic acid therapy has been shown to reduce the progression of PBC and results in histologic improvement. It improves overall and transplantation-free survival. For those patients that do undergo liver transplantation in PBC, outcomes are excellent, with a 1-year survival rate of greater than 90%.[8]

Complications

Granulomatous hepatitis may progress to fibrosis, portal hypertension, or cirrhosis, depending on the severity and underlying etiology. Prompt and appropriate therapy is required to prevent progression to significant hepatic dysfunction or fatal infection and, in some cases, may require lifelong therapy.

Deterrence and Patient Education

Granulomatous hepatitis refers to the presence of granulomas in the liver. Liver granulomas are common and are the result of an inflammatory reaction to numerous noxious stimuli. Patients should be educated that they may be asymptomatic incidental findings or found to be associated with an underlying systemic process. Granulomas may regress with appropriate treatment or persist for years and may still be asymptomatic, so patients should follow up regularly.

Enhancing Healthcare Team Outcomes

Granulomatous hepatitis refers to the presence of granulomas in the liver. Liver granulomas are common and are the result of an inflammatory reaction to numerous noxious stimuli. They may be asymptomatic incidental findings or found to be associated with an underlying systemic process. Granulomas may regress with appropriate treatment or persist for years and may still be asymptomatic. Hepatic granulomas have a wide range of etiologies that may be infectious or non-infectious in nature. The most common causes of granulomatous hepatitis include sarcoidosis, primary biliary cholangitis (PBC), tuberculosis, and drug-induced liver injury. However, around 10% to 36% of hepatic granulomas may be found to be idiopathic even after an extensive evaluation.

In patients with symptomatic granulomatous hepatitis with uncertain etiology, a consultation with a hepatology specialist is indicated. In those with concerns of tuberculosis but not confirmed, infectious disease consultation is paramount for proper antituberculous therapy and antibiotic stewardship. Some patients may be diagnosed with idiopathic granulomatous hepatitis initially and may subsequently be diagnosed with an underlying systemic disorder or infection, resulting in delayed therapy or fatal infection. The earlier the signs and symptoms of a complication are identified, the better is the prognosis and outcome. Collaboration in shared decision making and communication are key elements for a good outcome. The interprofessional care provided to the patient must use an integrated care pathway combined with an evidence-based approach to planning and evaluation of granulomatous hepatitis.