Delayed Liver Function Impairment Secondary to Interferon β-1a Use in Multiple Sclerosis
A 56-year-old Taiwanese woman was diagnosed as having multiple sclerosis in May 2000. Her first attack presented as left optic neuritis in December 1998. Her second attack, with brain stem encephalitis, developed in May 2000. Cranial MRI studies showed T2-weighted hyperintense lesions in the inferior medulla and upper cervical spinal cord at C1 level at that time. Her IgG index was 0.77 (reference <0.5), but oligoclonal bands were not found in the cerebrospinal fluid. Autoimmune factors such as anti-SSA/SSB antibody, antinuclear antibody, and rheumatoid factor were within the normal ranges. She was diagnosed as having multiple sclerosis and received interferon β-1a (Rebif 44 μg subcutaneous injection 3 times a week) starting in October 2002. She had sensations of chill after interferon use at first, but could tolerate it. The results of liver function tests in March 2005 were still within the normal range: alanine transaminase (ALT) 13 U/l [upper limit of normal (ULM) <36 U/l]. Recurrent thoracic myelopathy developed in March 2006. The thoracic MRI studies showed T2-weighted hyperintense lesions in the central gray matter around the T5–T6 level (two segments). However, her anti-aquaporin 4 (AQP4) antibody test result was negative (the manufacturer's recommended level for seropositivity was ≥5 U/ml; assessed by Elisa RSR AQP4 Ab kits; provided by Kronus, Ltd.). She was still diagnosed as having multiple sclerosis rather than neuromyelitis optica (NMO) according to Wingerchuk et al.'s [] criteria for NMO in 2006 and McDonald's diagnostic criteria for multiple sclerosis in 2010 [], and she continued to receive interferon therapy. After the thoracic myelitis, mycophenolate prednisolone and cyclophosphamide were also used to control her disease. However, she could not tolerate the side effects of these medications. Her medications were changed to azathioprine 50 mg daily in December 2006. During this period, she also received carbamazepine 100 mg twice a day. Follow-up liver function tests in October 2007 then showed impaired liver function: aspartate transaminase (AST) 93 U/l [2.7 × ULM (<34 U/l)] and ALT 100 U/l (2.8 × ULM). She only had mild general malaise without other symptoms such as jaundice. She did not consume any alcohol and denied taking any over-the-counter medication. However, she took some Chinese herbs with unknown content sometimes. Initially, azathioprine was suspected to induce liver function impairment, and the dose was reduced to 25 mg daily in December 2007 and further reduced to 25 mg every other day in January 2008. However, her liver function gradually worsened in the next few months. In May 2008, the results of her liver function tests were as follows: AST 213 U/l (6.3 × ULM); ALT 282 U/l (7.8 × ULM); alkaline phosphatase (ALK-P) 145 U/l [1.5 × ULM (<94 U/l)]; total bilirubin 0.7 mg/dl (ULM <1.3 mg/dl). Detailed hepatological evaluation was started. Results of hepatitis markers (HBsAg and anti-HCV antibody) and autoimmune titers (antinuclear antibody, anti-smooth muscle antibody, and anti-mitochondrial antibody) were all within the normal ranges. In addition, she did not have any other drug reactions such as renal insufficiency, hemolytic anemia, leucopenia, and thrombocytopenia besides liver function impairment. Drug-induced hepatitis was highly suspected. Interferon β-1a was reduced to 44 μg twice a week; carbamazepine and azathioprine were discontinued in May 2008. She also stopped taking Chinese herbs after that time. Her liver function improved after reducing the interferon dose and discontinuing other concomitant medications [July 2008: AST 51 U/l (1.5 × ULM); ALT 80 U/l (2.2 × ULM); r-glutamyl transpeptidase (r-GT) 110 U/l (ULM <71 U/l)]. Then, her liver function returned into normal ranges after interferon was discontinued in August 2008 [January 2009: AST 23 U/l; ALT 27 U/l; r-GT 75 U/l (1.06 × ULM)]. After a period of follow-up, interferon β-1a (22 μg twice a week) and carbamazepine (100 mg twice a day) were added again in March 2009. However, her liver enzymes were elevated again [April 2009: AST 43 U/l (1.3 × ULM); ALT 69 U/l (1.9 × ULM); r-GT 436 U/l (6.1 × ULM)] a month later. So, interferon was discontinued, while carbamazepine treatment was continued (100 mg twice daily). Her liver enzymes returned to normal ranges [AST 24 U/l; ALT 31 U/l; r-GT 150 U/l (2.1 × ULM)] again in May 2009. The results of her liver function test remained in the normal ranges at follow-up (November 2010: AST 18 U/l; ALT 19 U/l). The Roussel Uclaf Causality Assessment Method (RUCAM) scale for this patient after receiving interferon treatment is 8 [].