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• W2006207856 abstract "Autoimmune hepatitis (AIH) is characterized by female predominance, hypergammaglobulinemia, autoantibodies, and a good response to immunosuppression. Its etiology is unknown. A model for its pathogenesis is that environmental triggers, associated with failure of immunological tolerance mechanisms and genetic predisposition, may contribute to the induction of a T-cell–mediated immune response against hepatic antigens, triggering a necroinflammatory and fibrotic process (1). Among these triggering agents are some drugs, toxins, and viral infections (hepatitis A-B-C, Epstein-Barr, Coxsackie, Hantavirus, herpes simplex, and measles). Molecular sequences that are shared among viruses and autoproteins may trigger autoimmune processes (2,3). Infectious agents such as Escherichia coli, mycobacteria, chlamydia, Helicobacter species, lactobacilli, Novosphingobium aromaticivorans, and betaretroviruses may elicit loss of immunological tolerance and induce primary biliary cirrhosis (4), and bacteria such as Coxiella burnetii(2) and Brucella abortus may induce overlap syndrome (AIH and primary biliary cirrhosis) (5). We report a unique case of coexistent leprosy and AIH in a child. A 9-year-old girl originally from São Luiz (northern region of Brazil) and now living in Ribeirão Preto (state of São Paulo) had been presenting with hypochromic lesions on arms and legs for 1 year. Two months before referral to our service, she had received a histopathological diagnosis of leprosy. Investigation of the patient revealed altered hepatic enzymes. Mother and father had a history of treatment of paucibacillary and multibacillary leprosy, respectively. Physical examination revealed no jaundice, annular plaques with erythema-infiltrated borders on arms and legs associated with paresthesia, and mild hepatomegaly, but no splenomegaly or lymphadenopathy. Laboratory tests: aspartate aminotransferase 363 U/L (RV < 32 U/L); alanine aminotransferase 419 U/L (RV < 31 U/L); γ-glutamyl transpeptidase 36 U/L (RV 11–50 U/L); alkaline phosphatase 1129 U/L (RV < 645 U/L); albumin 4.1 g/dL; γ-globulin 1.64 g/dL; serum immunoglobulins (immunoglobulin [Ig] G 1150.0 mg/dL [mean for the age 892 mg/dL], IgA 131.0 mg/dL [mean for the age 153 mg/dL], IgM 187.0 mg/dL [mean for the age 90 mg/dL]); normal bilirubin levels; negative anti-nuclear antigen, anti-mitochondrial, anti-liver-kidney-microsome, anti-human T-lymphotropic virus I/II, and hepatitis A/B/C antibodies; antismooth muscle 1:80; α1-antitrypsin 1.66 g/L; serum copper 96.2 μg% (RV 70–140 μg%); urinary copper 2.05 μg/24 hours (RV < 60 μg/24 hours); ceruloplasmin 0.286 g/L; anti-PGL-1 0.8 mg/dL (RV < 0.9 mg/dL). Normal abdominal ultrasound. Before- and after-treatment immunological assessments by enzyme-linked immunosorbent assay (serum interferon-γ [IFN-γ] and tumor necrosis factor-α) are shown in Table 1. A liver biopsy (Fig. 1) revealed a cellular inflammatory infiltrate, with predominance of CD8+ T cells (Fig. 2A). A skin biopsy (Fig. 2B) revealed tuberculoid pole leprosy, and electroneuromyography showed sensory neuropathy of the left ulnar nerve.TABLE 1: Serum levels of IFN-γ and TNF-α assessed by ELISA of the patient before and after treatment of autoimmune hepatitisFIGURE 1: A, Representative photomicrographs of chronic active hepatitis before treatment. We observed a moderate portal fibrosis with an abundant mixed portal inflammation, including plasmocytes. The black arrows point to frequent eosinophils. (I and III—Masson trichrome stain, original magnification ×20 and ×40, respectively; II and IV—H&E stain, original magnification ×20 and ×40, respectively). B, Representative photomicrographs of chronic active hepatitis after treatment. We detected a reduction of portal fibrosis with a scantly portal inflammation. (I and III—Masson trichrome stain, original magnification ×20 and ×40, respectively; II and IV—H&E stain, original magnification ×20 and ×40, respectively). The Fite-Faraco staining to Mycobacterium leprae was negative in both biopsies.FIGURE 2: A, Representative photomicrographs of chronic active hepatitis—I and II, before treatment, and III and IV, after treatment. We observed a diminishing of inflammatory cells, both labeled by CD4 and CD8. There is a predominance of CD8-positive cells before and after treatment. (I and III—CD4 immunostaining; II and IV—CD8 immunostaining, respectively, original magnification ×40). B, Skin representative photomicrographs showing dermis with lymphohistiocytic infiltrate arranged in tuberculoid granulomas and Langhans giant cells. The black arrow points to few acid fast bacilli. (I and II, H&E and Faraco stain, original magnification ×20 and ×100, respectively).Meticorten 1 mg · kg−1 · day−1 and azathioprine 1.5 mg · kg−1 · day−1 was initiated, with transaminase normalization after 1 month. Treatment for leprosy was started with clofazimine 50 mg/day and rifampicin 300 mg/month (multibacillary multidrug therapy scheme of 12 doses, without dapsone). The corticoid dose was reduced to a maintenance dose of 2.5 mg/day. After 2 years of treatment, a follow-up liver biopsy was obtained (Fig. 1B and 2A-III and IV), and the maintenance dose of the corticoid was continued. The skin lesions improved, with recovery of nerve sensitivity. During a 3-year follow-up in our service, both diseases improved. DISCUSSION Leprosy is a multisystemic disease in which Mycobacterium leprae and/or inflammatory cells infiltrate the skin, nerves, and internal organs (6). Despite minimal genetic variations among the M leprae strains isolated worldwide, 2 fully distinct forms of the disease may manifest in susceptible human hosts: a localized tuberculoid (T) or paucibacillary form that may spontaneously resolve, and a disseminated virchowian (V) form, lepromatous or multibacillary, which progresses if untreated. Different patterns of immunological responses account for these various forms of leprosy. In the V form, intense antibody production indicates that humoral immunity does not contribute to host defense. CD4+ T cells that produce a type 1 (TH1) response predominate in T forms, whereas CD8+ T cells that induce a type 2 (TH2) response predominate in V forms (7). Our patient presented elevated serum levels of IFN-γ and tumor necrosis factor-α before treatment, supporting the notion that leprosy can be linked in part to abnormalities in inflammatory pathway activation and that probably the leprosy antigen provoked a skewed TH1 type response. Visceral involvement is more common in multibacillary patients and is mild or absent in paucibacillary (T) patients (6). In the V form, the incidence of hepatic manifestations is 48% to 100%, compared with approximately 20% in the T form. The most common finding is the presence of granulomas in the parenchyma, a direct result of the hematogenic propagation of M leprae possibly related to disease duration and/or to the number of organisms circulating in blood. “Lepromatous hepatitis” has been used to describe self-limited infiltrating granulomas in the portal and centrolobular regions, consisting of Virchow cells, with or without lymphocytes, minimal fibrosis, and frequent alcohol-acid–resistant bacilli. It is more common in multibacillary leprosy but may occasionally occur in the paucibacillary form (6). Hepatic involvement usually is asymptomatic, with normal hepatic function. When changes are present, they may not correlate with the number of hepatic granulomas, load of acid-resistant bacilli, or disease duration. If liver function is abnormal, other etiologies should be excluded. Hepatitis B virus antigenemia has been reported in 6% to 40% of patients with leprosy, especially in V forms. Infection with hepatitis C virus ranges from 2% to 7% among patients with leprosy. Hepatitis B or C virus infection is not associated with a specific type of leprosy, but rather with disease duration, exposure to needles and scalpels, confinement in communities, and hospitalization or treatment in poorly equipped health services (6). This unique case is the first documentation of coexistence of AIH and leprosy. A possible explanation is the stimulation of specific B lymphocytes for normal hepatic antigens by T lymphocytes activated against M leprae–infected hepatic cells. This leads to autoantibody production and consequent onset of AIH, although experimental models suggest that AIH can also be secondary to the dysregulated T-cell response. Moreover, the increased level of IFN-γ observed may corroborate a T-cell abnormality. Whether this is due to the observed CD8+ T cell predominance, as shown by the liver biopsy, remains for future studies. The patient responded well to immunosuppression for AIH. Only later was treatment for leprosy provided with clofazimine and rifampicin administered. Dapsone was avoided due to several adverse effects including liver and dermatologic reactions (8)." @default.
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• W2006207856 title "Autoimmune Hepatitis Associated With Leprosy in a Child" @default.
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