Serum Concentration-Dependent Hepatotoxicity in Individuals Receiving Oral Salsalate

Abstract

To the Editor, Salsalate, an older, ‘‘safer’’ oral nonsteroidal anti-inflammatory agent is a nonacetylated dimer of salicylic acid with an established safety profile in treatment of inflammatory conditions. It has been under consideration by the Food and Drug Administration (FDA) for over-the-counter (OTC) sale as an oral analgesic, antipyretic, and antirheumatic drug product since 1972. There is however, renewed interest in this drug as recent studies have shown that salsalate not only improves glycemic and inflammatory parameters in young obese adults but also improves body composition and metabolic alteration in human immunodeficiency virus (HIV) lipodystrophy by inhibiting nuclear factor kappa-B (NF-jB), a central integrator of proinflammatory signals [1, 2]. Since the product is inexpensive and generic, several National Institutes of Health (NIH)-funded clinical trials with salsalate are ongoing to test its effect on subacute inflammation and coronary plaque (TINSAL-T2D; NCT00624923), insulin resistance (NCT00330733), and bed-rest-induced vascular dysfunction (NCT00553995). The usual dosage for salsalate is 3,000 mg daily, given in divided doses. Some of the reversible adverse reactions reported in clinical trials such as tinnitus, nausea, hearing impairment, rash, and vertigo appear to occur more commonly with serum concentration above 30 mg/dl. Although a range of liver test abnormalities from asymptomatic elevation in transaminases to fatal fulminant hepatic failure have been reported with nonsteroidal anti-inflammatory drug (NSAID) use, data regarding salsalate specifically are sparse [4, 5]. These reactions were generally felt to be idiosyncratic in nature and independent of dose. We recently conducted a clinical trial using salsalate and wish to report our experience with salsalate-induced liver injury that exhibited a relationship with serum salsalate concentrations. In order to test the hypothesis that salsalate may improve the endothelial dysfunction that is frequently seen in patients with underlying HIV infection, we conducted a prospective study, approved by our institutional review board [3]. Eleven adults with documented HIV infection (CD4 count C 350/ll) not receiving any antiretroviral therapy and no known underlying liver disease were enrolled into this study. Each participant received 1,500 mg salsalate (Disalcid , 3M Pharmaceuticals, CA, USA) orally twice daily (the maximum daily dose approved by the FDA) with intended duration of treatment of 8 weeks. Serum liver chemistries, serum salicylate levels, and flow-mediated dilation of brachial artery (to measure endothelial function) were measured at baseline, and at 4 and 8 weeks after the initiation of salsalate treatment. The baseline characteristics were: mean age 37 ± 10 years, eight males, mean body mass index (BMI) 26.4 ± 7.8 kg/m, aspartate aminotransferase (AST) 25 ± 5 IU/l, alanine aminotransferase (ALT) 22 ± 9 IU/l, alkaline phosphatase 71 ± 18 IU/l, and total bilirubin 0.8 ± 0.3 mg/dl. During the study period, four patients developed elevated aminotransferases by 4 weeks following the initiation of salsalate whereas another seven participants exhibited no increase in liver biochemistries (Table 1). Two of the subjects with elevated aminotransferases had associated symptoms consisting of nausea, vomiting, fever, fatigue, and abdominal discomfort between weeks 2 and 3 after the initiation of therapy. Serum salicylate concentration measured 24–48 h after stopping the salsalate was R. Juluri S. Gupta R. Vuppalanchi (&) Division of Gastroenterology, Indiana University School of Medicine, 1050 Wishard Blvd., RG 4100, Indianapolis, IN 46202, USA e-mail: rvuppala@iupui.edu