Diclofenac‐induced adverse drug reactions and hyperbilirubinemia caused by a variant gene

A 76 years old man with a history of hyperbilirubinemia associated with diclofenac use was referred to our laboratory for genetic study. He began to use diclofenac (100 mg per day) 1 year prior for joint pain relief, and 1 month later, he developed fatigue, dizziness, and tarry stool. An endoscopic survey confirmed upper gastrointestinal (GI) bleeding and laboratory results revealed anemia (Hb = 11.7 g/dl) and hyperbilirubinemia (direct and total bilirubin, 20.5 and 61.6 μmol/L, respectively). However, the patient's aspartate transaminase (AST) and alanine transaminase (ALT) were normal (29 and 22 IU/L, respectively). He was diagnosed with NSAID-induced gastropathy and instructed to stop using diclofenac. The patient recovered 2 days later.

To study the chemical pathology of the hyperbilirubinemia, we re-valuated the patient's Hb, total bilirubin, direct bilirubin, AST, and ALT levels and analyzed the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 gene1 and eight single nucleotide polymorphisms (SNPs) related to diclofenac metabolism,2, 3 namely linked polymorphisms 416 G>A and 1196 A>G in the cytochrome P 450 (CYP) 2C8 gene (CYP2C8*3), 430 C>T (CYP2C9*2), and 1075 A>C (CYP2C9*3) in the CYP2C9 gene, 352 A>G (CYP3A4*4), 653 C>G (CYP3A4*5), and 20070 T>C (CYP3A4*18A) in the CYP3A4 gene, 802 C>T in the UGT2B7 gene (UGT2B7*2a), and −118 T9>T10 in the UGT1A9 gene (UGT1A9*1u). Written informed consent was obtained from the patient, and the study protocol was approved by the research committee of Cathay General Hospital (IRB No. CGH-P110001). The results indicated normal levels of Hb, AST, ALT, and bilirubin. The eight SNPs related to diclofenac metabolism were absent. However, a homozygous variant at nucleotide 1091 (1091TT) was observed in the UGT1A1 gene (Figure 1). The presence of the 1091 C>T variant (p.Pro364Leu) in exon 4 of the UGT1A1 gene was a cause for concern. Four exons (exons 2–5) are common to the alternatively spliced products transcribed from the UGT1A gene locus, namely UGT1A1 and UGT1A3–UGT1A10. Therefore, the amino acid variant, p.Pro364Leu, should be present in other functional UGT1A products, including UGT1A9. Because the p.Pro364Leu variant UGT1A9 protein exhibited lower glucuronosyltransferase activity on acetaminophen and propofol than its wild-type counterpart (5.0% and 29.0% of wild-type UGT1A9 activity, respectively4), patients with 1091 TT in UGT1A1 likely metabolize diclofenac at a lower rate than those with the wild type gene, and the diclofenac is thus retained at a higher blood concentration or for an extended duration, leading to liver injury (from elevated bilirubin levels, although liver enzymes may be normal) in susceptible patients. However, bilirubin glucuronidation in people carrying 1091TT UGT1A occurs at 35.6% of normal efficiency5 and in itself may not be sufficient to manifest as complete Gilbert's syndrome as it did in our patient (total bilirubin/direct bilirubin = 13.7/3.4 μmol/L at baseline), although hyperbilirubinemia occurs in the situation of drugs-induced (including diclofenac) liver injury. In addition, GI bleeding exacerbates bilirubin metabolism by supplying excess unconjugated bilirubin to the liver. As we know, this is the first reported case involving diclofenac-induced hyperbilirubinemia and GI bleeding in a patient with the 1091TT homozygous variant of the UGT1A1 gene.

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Variation status at nucleotide 1091 in the UGT1A1 gene: (A) the patient, (B) the wild type

All authors declare no conflict of interest.

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