Hepatic granulomas are reported in 2-15% of all liver biopsies that are attributable to various causes. Owing to the diverse prognostic and therapeutic implications, a detailed workup of all liver biopsies with granulomatous lesions is mandatory. The cause of the disease may remain obscure in up to 50% cases of “idiopathic granulomatous hepatitis” (IGH). This disease runs a chronic relapsing course. Hepatocellular dysfunction may be an early predominant manifestation unlike that in the available literature. Timely recognition and diagnosis of IGH is imperative as the disease responds well to immunosuppressants that can prevent permanent liver damage. We report a case of a young boy with IGH who was successfully treated with immunosuppressive therapy.
Keywords: Febrile neutropenia, hepatic failure, idiopathic granulomatous hepatitis (IGH)
A wide range of infectious and noninfectious conditions can cause hepatic granulomas with different prognostic and therapeutic implications. Despite developments in serological, immunological, microbiological, and radiological investigations, often a specific etiology cannot be identified. Idiopathic granulomatous hepatitis (IGH) is a chronic relapsing disorder of unknown cause, characterized by fever and hepatic granulomas. The diagnosis of this disease is challenging, possible only by histopathological examination of liver. A clinician should be sensitized to suspect IGH that responds well to immunosuppressive drugs. We report a case of a young boy with IGH who was successfully treated.
An 11-year-old boy presented with fever for 1-month and jaundice, petechiae, melena, and anasarca for 10 days. He had severe pallor, icterus, firm hepatosplenomegaly with ascites, and signs of hepatic failure without encephalopathy. Blood tests of the patient revealed pancytopenia with direct hyperbilirubinemia, raised transaminases, raised prothrombin time, and low serum albumin. A workup of the etiology of fever and hepatitis includes the following tests: malarial antigen and typhoid serology, Mantoux test, blood culture, urine culture, antinuclear antibody test, hemoglobin electrophoresis, direct Coomb’s test, viral serology and serum ceruloplasmin test. These tests were inconclusive. Ultrasound revealed hepatomegaly (span 15 cm) with homogenous echotexture and splenomegaly (span 9 cm). The result of the upper gastrointestinal endoscopy was normal.
The patient was treated symptomatically with antibiotics and blood transfusion. However, febrile neutropenia persisted and jaundice worsened. Bone marrow aspiration showed normal erythroid and myeloid reaction. Liver biopsy [Figure 1]a revealed chronic inflammatory infiltrate with granulomatous hepatitis (GH) and microsteatosis, without fibrosis; stain for acid-fast bacillus (AFB) was negative. Sarcoidosis was excluded (serum calcium and angiotensin-converting enzyme levels were normal). Tuberculosis was considered the most probable cause as per clinico-epidemiological data and antitubercular therapy (ATT) was started but there was poor response. In view of obscure etiology and unfavorable response to ATT, a possibility of IGH was kept. ATT was continued and oral prednisolone (2 mg/kg/day) was started. The patient became afebrile and anicteric after 2 weeks of steroid therapy. A 3-month follow-up revealed that he had developed steroid toxicity and was shifted to methotrexate (7.5 mg/week) with low dose alternate day steroids. Subsequent visits showed the regression of hepatosplenomegaly with normalization of liver functions. ATT was stopped after 6 months. Methotrexate with alternate day prednisolone was continued, as repeat biopsy at 1 year showed persistent granulomas. After the 2 years of therapy the liver function test (LFT) of the patient revealed that liver span (8 cm) and architecture were normal with occasional granulomas on histology [Figure 1]b. So the therapy was stopped. He is asymptomatic since then.
GH is characterized by inflammatory granulomas featuring epithelioid follicles and giant cells with/without necrosis infiltrating the liver.  It is found in 2-15% of all liver biopsy specimens and most are periportal in location. , Granulomas may result from response to drugs, toxins, infections, systemic inflammatory diseases, or neoplasms [Table 1].  The composition of granuloma can suggest a particular etiology but the primary cause of this condition may not be found in up to 50% of the patients with IGH even after extensive workup.  A case of IGH was first reported in 1973.  Though the age of patients reported with GH usually varies from 16 years to 60 years (mean age 54.2 years), IGH rarely occurs during childhood. 
The presentations are varied from asymptomatic to having anorexia, weight loss, myalgia, abdominal pain, or tender hepatomegaly. Hepatosplenomegaly, pyrexia of unknown origin (PUO), and chronic infirmity are the most frequent clinical associations. , Hepatocellular dysfunction is rarely reported, though cholestasis may be the earliest biochemical change in most of the cases, unlike our case where jaundice and hepatic dysfunction were predominant manifestations.
Investigations should be targeted to detect common etiologies like infections and immunological disorders. Importance of a meticulous history of drug intake and toxin exposure must be emphasized. A careful examination of liver biopsy, including special stains and culture, may be helpful in the diagnosis of fungal, mycobacterial, and other infectious entities. Tuberculosis seems to be the most frequent cause of GH  with noncaseous granulomas and AFB demonstrable in only 10% of the cases.  Imaging studies have no value in reaching a definite etiological diagnosis.
There are no established guidelines on the management of this disease in adults or children.  Limited data are available from case reports and small studies. Empirical trial of ATT should be given , and the patient should be observed for 4-8 weeks for signs of response. If there is no clinical or laboratory improvement, then IGH should be suspected and steroid therapy started with fortnightly monitoring. , Steroids should be tapered to a minimal maintenance dose and continued till a symptom-free period of 1-2 years. Repeat biopsy may be done after 1 year. Steroid sparing immunosuppressants are effective alternatives if the patient shows steroid resistance or toxicity.  Low dose methotrexate (15 mg/week or 0.2 mg/kg/week) may be used, duration of therapy varying from months to years. Cyclosporine, azathioprine, and cyclophosphamide are other potential agents but are associated with toxic side effects. 
IGH should be considered in patients presenting as PUO and liver failure. The present case suggests that IGH can occur at a much younger age than commonly reported. Immunosuppressive drugs should be considered early, as the response to therapy makes prognosis favorable.
We would like to thank the entire team of the admitting unit, especially Dr. Malobika Bhattacharya, Dr. Ashish Gupta, and Dr. Neha Joshi.
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