Treatment with interferon (IFN) for non-A, non-B hepatitis (NANBH) has proven useful in adults. Before discovery of hepatitis C virus (HCV) as the major agent of blood-borne NANBH and availability of antibody to HCV (anti-HCV) assay, diagnosis of NANBH was made by the exclusion of other known viral, autoinmune or metabolic liver diseases. Up to now, interferon therapy in children with chronic NANBH has not been performed but we are conducting a trial in children. In one child a surprising observation of the liver disease was made under iFN therapy. The case was a female caucasian child aged 11 years at the time of the first discovery of abnormal transaminase levels. They remained increased (120 to 310 IU/L, normal<45) for 5 years. Clinical and laboratory data discarded hepatitis A (HAV), hepatitis B (HBV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), alpha1-anti-trysin deficiency, Wilson's disease or other known causes of liver disease. A liver biopsy was taken and analyzed by two independent expertise pathologists. The histology was consistent with chronic active hepatitis but not suggestive of autoinmunity. In May 1989 she entered interferon therapy after routine auto-antibody tests were negative (anti-nuclear, anti-mitochondrial, anti-smooth muscle, anti-reticulin, anti-RNP, anti-SSA/Ro, anti-SSB/LA) with levels of 277, 137 and 1680 mg/dl for total IgA (normal 100-300), IgM (normal 80-250) and IgG (normal 800-1600), respectively.
For interferon therapy, 3 million units of recombinant IFN-alpha 2b (Schering-Plough) were given thrice a week by subcutaneous injection. During the second month since transaminases increased markedly resembling acute hepatitis with clinical symptoms, therapy was stopped. No viral agents or other causes of liver disease were found. Two months later transaminases reached pre-treatment values and IFN was re-administered with the same dosage and schedule. Three months later transaminases increases markedly again and interferon was discontinued permanently. At the moment anti-HCV was determined but results negative. Since transaminases remained increases for 1 month following discontinuation of IFN, steroids (40 mg/day) were then administered and transaminases fell 2 weeks later. At that time, azathioprine (50 mg/day) was administered together with steroids. Transaminases remained near normal and the dose of steroids was lowered (from 40 to 10 mg/day and to 10 mg every other day) until completion at 4 months.
Restrospectively, liver-kidney microsomal antibodies (LKM-1) were assayed by radioimmunoassay and by Western blot against a 50 kDa protein from human liver microsomes (WB-Mik) and against human recombinant cytochrome P-450 dbl as the major target antigen of liver-kidney microsomal antibodies (WB-rLKM). Before IFN treatment, LKM-1 auto-antibodies (RIA and WB-Mik) were present at low titers. With IFN therapy, LKM-1 antibody titers rose dramatically and fell only when steroids were given. Interferon is known to increase auto-antibody production in man and should not be administered in autoinmune hepatitis. Routine auto-antibody tests did not allow diagnosis of autoimmune disease but assays for LKM-1 antibodies did so. We conclude that testing for LKM-1 should be mandatory before IFN administration in NANBH without anti-HCV to prevent IFN-associated autoimmune reactivation of liver cell injury.