Sarcoidosis in Preschool Children With Hepatic Involvement Mimicking Juvenile Rheumatoid Arthritis

Abstract

Sarcoidosis is a chronic, multisystem, granulomatous disorder of unknown cause that occurs most commonly in people between 20 and 40 years of age. It most often affects the lung, lymph nodes, skin, eye, and liver. It rarely occurs in children, and when it does, 75% of cases occur in those between the ages of 9 and 15 years, with only a small number of cases occurring in children less than 6 years of age (1,2). The early manifestations of sarcoidosis in children may mimic those of juvenile rheumatoid arthritis (JRA). Sarcoidosis in preschool children manifests by the triad of skin, joint, and eye involvement without pulmonary disease. Unless analysis of biopsy specimens of skin, conjunctiva, or synovial tissue shows noncaseating granulomas, a diagnosis of sarcoidosis may be missed (3). Early differentiation of sarcoidosis from JRA is important in planning treatment strategies and in counseling patients and families. We present a case of sarcoidosis in a 4-year-old child whose initial diagnosis was JRA based on results of analysis of two previous skin specimens. A correct diagnosis of sarcoidosis was established after analysis of a liver specimen that showed noncaseating granulomas. Hepatic granulomas are present in 60% to 90% of the liver biopsy specimens of patients with sarcoidosis, and liver biopsy should be considered in children in whom skin or other tissue biopsies have not been helpful in establishing a diagnosis. CASE REPORT A 4-year-old girl was referred to our institution for evaluation of suspected JRA. Her initial symptoms began at age 2 and consisted of macular eruptions on both legs and swelling of the left knee with decreased range of motion. Laboratory evaluation at that time revealed hemoglobin of 7.9 g/dl, normal erythrocyte sedimentation rate (ESR), and normal leukocyte count. Analysis of a skin biopsy specimen revealed panniculitis. This initial episode was followed by recurrent attacks of fever, generalized maculopapular rash, hepatosplenomegaly, enlarged lymph nodes, and bilateral knee effusions with decreased range of motion. Results of chest radiograph and rheumatoid factor and antinuclear antibody tests were normal as were second ESR and leukocyte determinations, except for persistent microcytic anemia. An eye examination showed uveitis. Juvenile rheumatoid arthritis was diagnosed, and therapy with 75 mg oral naproxen three times a day and prednisone eye drops was begun. Eight months later, the patient was referred to our institution for symptoms persisting despite treatment. Her physical examination revealed epitrochlear, axillary, and cervical lymphadenopathy; hepatosplenomegaly; a generalized macular rash; and swollen ankles and knees. An eye examination showed diffuse uveitis with posterior synechia. Laboratory findings revealed microcytic anemia; an ESR of 76 mm/h (normal, <20 mm/h), total bilirubin 0.3 mg/dl (normal, 0.0-1.5 mg/dl), aspartate transaminase 28 U/l (normal 10-55 U/l), alanine transaminase 35 U/l (normal 0-45 U/l), γ-glutamyl transpeptidase 66 U/l (normal, 0-35 U/l), and ceruloplasmin 76 mg/dl (normal, 30-65 mg/dl). Test results for α-feto protein, rheumatoid factor, antinuclear antibody, and hepatitis antibodies (HBsAg, HBsAb, HBcAb, anti-HCV) were negative. Serology was negative for Epstein-Barr virus, cytomegalovirus, and Toxoplasma. An immunodeficiency profile (mature T cell, T-helper/inducer, T-suppressor/cytotoxic, and B cell percentages and absolute numbers) produced normal findings, and angiotensin-converting enzyme level was normal. Liver and spleen scans showed moderate diffuse hepatomegaly with hepatocellular dysfunction. A computed tomogram showed diffuse hepatosplenomegaly. Examination of a percutaneous liver biopsy specimen revealed numerous nonnecrotizing granulomas consisting of epithelioid histiocytes in the liver parenchyma (Fig. 1). Trichrome and reticulum stains were unremarkable except for slight fibrosis associated with the granulomas (Fig. 2). Acid-fast stain was negative. Gomori's methenamine silver stain was negative for fungi. On the basis of the histologic changes, sarcoidosis was diagnosed. Therapy with 0.5 mg/kg oral prednisone was begun and the patient was progressing well with decreased joint swelling and a normal ESR 6 months later.FIG. 1: Liver biopsy specimen: An epithelioid cell granuloma characterized by lymphocytes and epithelioid cells (hematoxylineosin; high-magnification view).FIG. 2: Trichrome stain shows granulomas with surrounding fibrosis.DISCUSSION Sarcoidosis is uncommon in children and is rare in infants and young children. In children more than 10 years of age, it resembles the adult disease with prominent pulmonary and mediastinal involvement. Sarcoidosis in preschool-aged children is characterized by skin, joint, and eye disease. The reason for these differences in features between the age groups is unknown (4). In our patient, a rash and swollen joints were the initial symptoms. A presumptive diagnosis of JRA was made because of the clinical manifestation and characteristic skin biopsy findings. A definite diagnosis was established after results of analysis of a liver specimen were obtained. Skin involvement occurs in 64% of all cases of childhood sarcoidosis, and a rash is often the initial symptom (1). Sarcoid arthritis in young children is a persistent, nondestructive synovial thickening that predominantly affects the large joints (5). In children in whom arthropathy precedes the other features, JRA may be the initial diagnosis. Ophthalmologic manifestations occur frequently in sarcoidosis and JRA and include anterior uveitis, iris nodules, and posterior synechia (1). In sarcoidosis in preschool children, the other organs involved include liver and spleen (52%), lymph nodes (42%), parotid gland (13%), bone (13%), and lung (13%) (1). Tissue diagnosis is usually obtained by skin, synovium, or lymph node biopsy. Histologically, sarcoidosis is characterized by the presence of noncaseating epithelioid cell granulomas in affected organs. Granulomas may resolve or convert into hyaline connective tissue. Demonstration of granulomas may be difficult. Approximately 20% to 30% of cases have hepatomegaly, with or without biochemical evidence of liver dysfunction. Usually, these changes reflect a cholestatic pattern with an elevated alkaline phosphatase level, whereas bilirubin and aminotransferase levels are only mildly elevated. Hepatic granulomas are found in 60% to 90% of the liver biopsy specimens of patients with sarcoidosis. The granulomas tend to occur diffusely throughout the liver, generally in large numbers. They occur in portal tracts and hepatic parenchyma, although they are generally more frequent in portal and periportal areas (6,7). Sarcoid granulomas are numerous enough on liver specimens to make sampling error unlikely. In one study, the average density of granuloma was 1/0.51 mm2 of liver tissue (the average needle biopsy specimen is 7-15 mm2 in area). Because of this, false-negative results in analysis of liver biopsy specimens are rare (8). Histologically, in addition to the presence of granulomas, the most common abnormalities are cholestatic changes in 58% of patients, inflammatory changes in 41%, vascular changes in 20%, and fibrosis in 21% (9). Portal hypertension and intrahepatic cholestasis with cirrhosis are rare complications of hepatic sarcoidosis, and use of corticosteroids does not prevent the development of portal hypertension (6,10). Hepatic involvement can also occur as one of the systemic manifestations of JRA. Moderate to severe enlargement of the liver is often associated with only mild derangement noted in results of functional studies and with relatively nonspecific histopathologic changes. Hepatic histology shows nonspecific periportal collections of inflammatory cells and hyperplasia of Kupffer cells in contrast to the presence of granulomas in sarcoidosis (11). Chronic liver disease is unusual. Most children recover with or without corticosteroid therapy, but a few progress to irreversible pulmonary fibrosis and blindness. The long-term benefit from corticosteroid therapy in hepatic sarcoidosis is difficult to assess because of great variations in both the natural history of the disease and the stage of the disease at the time of instituting the therapy. In conclusion, the diagnosis of sarcoidosis and JRA may be confusing, because both disorders typically affect the joints, eyes, and skin in young children. Distinguishing between the two conditions may be difficult clinically, and tissue biopsy may be necessary to establish a definitive diagnosis. Because liver involvement occurs in approximately half of preschool children with sarcoidosis, liver biopsy is an important diagnostic tool in cases in which other tissue biopsies are not helpful or affected organs are not easily accessible. Early recognition of sarcoidosis in children may prevent some complications, such as blindness, pulmonary insufficiency, and renal impairment.