Idiopathic Granulomatous Hepatitis (IGH) is a rare
cause of pyrexia of uncertain origin (PUO). Generally reported to affect
middle aged adults, IGH is uncommon in children. We report a child with
IGH who became symptomatic at the age of 5 years and was diagnosed and
treated successfully with immunosuppressive drugs at 12 years of age.
Case report
This male child first presented at the age of 5 years
with high grade fever and hepatosplenomegaly. Investigations for PUO
were inconclusive. The child responded to an empirical course of
antimalarials. During the subsequent seven years, the child was
repeatedly hospitalized with recurrent episodes of high grade fever
almost every year. Each febrile episode lasted for 2 to 12 weeks and was
associated with massive hepatosplenomegaly. Defervescence, either
spontaneous or induced by empirical therapy was associated each time
with regression of liver and spleen sizes. Additional clinical features
and investigations done over the period of illness are outlined in
Table I. Bone marrow and liver showed presence of non-caseating
granulomas with epitheloid cells. These were diffusely scattered in the
bone marrow, while in the liver, they were mainly located in the
periportal regions. Initially, the granulomas were attributed to
tuberculosis and the child was given three courses of antitubercular
therapy (including the multi-drug resistant regime) over the course of
the illness. He underwent splenectomy during his fifth hospitalization
due to features of hypersplenism. Splenic histology was normal.
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Table I
During his last hospitalization, the child weighed 38
kg on admission. He had massive hepatomegaly and obstructive jaundice.
There was no lymphadenopathy or bony tenderness. He remained febrile for
a period of 90 days during which he suffered a weight loss of 12 kg,
developed anemia and neutropenia. The liver and bone marrow continued to
show granulomas without any evidence of patho-gens or malignancy on
special staining studies. Investigations to look for other causes of
hepatic granulomas were negative. There was no improvement in the fever
despite empirical therapy. The child was diagnosed as a case of
idiopathic granulomatous hepatitis and put on prednisolone (2 mg/kg/day)
and methotrexate (7.5 mg per week).
Thereafter, the child improved with regression of
jaundice and hepatomegaly, waning of biochemical and hematological
abnormalities and weight gain. Prednisolone was gradually tapered to a
dose of 10 mg on alternate days over the next four months and
methotrexate was continued. Follow up liver and bone marrow biopsies
showed regression in granulomas. Steroids were discontinued successfully
and low dose methotrexate was continued.
Discussion
Idiopathic granulomatous hepatitis is a condition
characterized by recurrent fever and granulomas in the liver and other
organs when other causes of hepatic granulomas have been excluded(1,2).
Hepatic granulomas are not uncommon, seen in up to
30% of routine liver biopsy specimens and can result from a number of
infective and non-infective conditions. Of these, tuberculosis and
sarcoidosis together account for 50 -65% of cases. 26-50% of cases
remain undiagnosed despite extensive investigations(3,4). A thorough
search for the common etiologies must be carried out before the
diagnosis of idiopathic granulomatous hepatitis is made. However, the
very existence of this condition has been disputed as extra abdominal
investigation may prove sar-coidosis as the cause of febrile hepatic
granulomatosis(5). Our patient was exten-sively evaluated and
empirically treated for mycobacterial and fungal disease. Classic
sarcoidosis was unlikely in the absence of significant lymphadenopathy,
iritis, rash, arthropathy, pulmonary infiltrates, eosino-philia,
hypercalcemia or elevated angiotensin converting enzyme levels. Other
causes of hepatic granuloma were ruled out by extensive investigations.
The age of patients reported with this condition
usually varies from 16 to 60 years. In their series of 88 patients,
Sartin and Walker(4) found the mean age to be 54.2 years. The prominent
symptom is fever, which is often relapsing in character although
continuous and remittent fever patterns have also been described(1).
Forty four per cent of patients first presented as PUO in one series(4).
Other symptoms, all of which were present in our patient, include
malaise, chills, weight loss, abdominal pain, anorexia, night sweats,
nausea, jaundice, diarrhea and abdominal distension.
There are no typical biochemical, hematologic or
immunologic abnormalities. Most investigations help to rule out other
conditions. Common laboratory abnormalities include a raised ESR,
positive C-reactive protein, hypergammaglobulinemia, hypo-albuminemia,
normocytic anemia and neutrophilic leucocytosis(6). Liver function tests
show raised bilirubin, alkaline phos-phatase and a variable, often mild
rise of aminotransferases. Hepatic histology reveals granulomas in all
cases. The commonest finding is of multiple lesions consisting of
typical focal nodular aggregations of lymphocytes, mononuclear cells and
epitheloid cells. Caseation is absent as a rule. Most granulomas are
distributed randomly through-out the hepatic parenchyma although
periportal granulomas are also seen(1). Our patient had predominantly
periportal granulomas. Other organs such as the kidney, lymph node,
spleen, bone marrow, skin, muscle and lung may also show the presence
ofgranulomas(1,6-8). Our search for extrahepatic granulomas yielded
positive results in the bone marrow.
The natural history of the disease is long, with
multiple remissions and exacerbations. Occasional episodes, particularly
with renal involvement can be serious and often life threatening.
Response to corticosteroids is usually dramatic(1,9,10). Our patient did
not respond to prednisolone alone and required addition of methotrexate.
Response to immunosuppressants such as methotrexate or cyclophosphamide
in patients resistant or intolerant to steroids has been earlier
reported(1,11).
In a case of prolonged PUO with organo-megaly and
histological evidence of granulo-matous lesions, the possibility of IGH
must be borne in mind, when thorough search fails to reveal an etiology.
The case also suggests that IGH can rarely occur at a much younger age
than commonly reported in the literature. The disease is amenable to
immunosuppressive therapy and has a good prognosis.
Contributors: RGH drafted the manuscript and
contributed to patient management. He will act as guarantor. AG managed
the case and reviewed the literature. AKD assisted in drafting and
critically reviewed the manuscript.
Funding: None.
Competing interests: None stated.
