A 66-year-old Caucasian woman, with a past history of diabetes mellitus type 2, osteoporosis and no history of liver disease, developed liver dysfunction. She presented with fatigue, progressive jaundice, weight loss of 10 kg and mild epigastric and right upper quadrant abdominal pain over a period of two months. She denied any alcohol or drug abuse or exposure to blood products. She had no antecedents of other autoimmune disorders, and no family history of autoimmune or liver disease. For the previous two years she had received treatment with enalapril but this was stopped as she complained of discomfort. She had also taken metformine for diabetes mellitus, risendronate for osteoporosis, and herbal medicines (Centaurea Aspera L and Coutarea latiflora DC) for hypoglycaemia (self-medicated). Physical examination showed moderate mucocutaneous jaundice without stigmata of chronic liver disease. Blood tests revealed elevated aspartate aminotransferase (AST) 784 U/L (reference interval 0–36), alanine aminotransferase (ALT) 794 U/L (reference interval 0–41), serum bilirubin 6.10 mg/dl (reference interval < 1.40), and _-globulin fraction 26.90% with selective Immunoglobulin G (IgG) elevation (2290 mg/dl). Full blood count, creatinine, urea, electrolytes and pancreatic enzymes were within normal limits. Serological tests for viral hepatitis (HAV, HBV, HCV, CMV, EBV) were negative. alpha-1-antitrypsin phenotype, serum ceruloplasmin, iron and ferritin levels were normal. X-ray tests (abdominal echography and computerized tomography, echoendoscopy) did not show any abnormality. Indirect immunofluorescence (IFI) on HEp-2 cell lines showed ANA with a speckled and cytoplasmic pattern at 1/320 titer. Anti-SMA positivity was evidenced by IFI on rodent liver, kidney and stomach sections ("in house" technique) and corresponded to Factin specificity in an enzyme linked immunoassay (ELISA) from INOVA Diagnostics (San Diego, US). Anti-SLA detection by Dot-blot (D-tek. Mons-BELGIUM) was confirmed by two different techniques; an ELISA with prokaryotically expressed SLA protein (Euroimmun UK. Ltd. Cardiff, UK) and an immunoprecipitation assay (IPA) as described by Costa et al. [7]. HLA (Histocompatibility Leukocyte Antigen) genotyping by PCR-SSP (Dynal Biotech, Oslo, Norway) showed HLA-DRB1* 04; DR B1* 07 genotype.
Tumoral markers (CEA, CA 12.5) were negative except for CA 19.9: 443.2 U/ml (reference interval < 37.0). Liver histology disclosed severe piecemeal necrosis (interface hepatitis), lobular damage manifested by anisonucleosis, ballooning degeneration, hepatocellular swelling and acidophil bodies. Furthermore a severe infiltration of lymphocytes and neutrophils with scarce plasmatic cells and eosinophils, and periportal and pericellular fibrosis, were detected (figure 1A). The inflammatory infiltrates affected most of the portal tracks with fibrosis.
Withdrawal of the medication resulted in normalization of liver function within 3 weeks and according to the AASLD practice guidelines published in 2002, we did not initiate any treatment. Six months later, there was no biochemical or serological alteration, IgG levels were normal and SMA and anti-F-actin were negative. ANA showed only a speckled pattern and anti-SLA remained positive. The second liver biopsy showed chronic hepatitis with mild activity and septal fibrosis, despite clinical and biochemical resolution. Lobular liver cell damage ameliorated, no bridging necrosis or multiacinar necrosis was found and small regenerative hepatocytes were seen (figure 1B).