Late‐onset celecoxib‐induced combined hepato‐nephrotoxicity

Celecoxib is a commonly used selective cyclooxygenase (COX)-2 inhibitor. Sporadic cases of hepatic or renal toxicity have been described with its use. All but three of these cases were reported with short-term use, typically a couple of days or weeks [1–3]. We report the first known case of late-onset celecoxib-induced hepato-nephrotoxicity, of which we obtained histological evidence. We present the case of a 56-year-old hypertensive man on ramipril 10 mg day−1 for >3 years who was prescribed celecoxib 200 mg one to two tablets per day for osteoarthritic pain. Baseline laboratory at the time of celecoxib prescription showed blood urea nitrogen (BUN) 16 mg dl−1 (normal 8–20 mg dl−1), creatinine (Cr) 1.0 mg dl−1 (normal <1.2 mg dl−1), alanine aminotransferase (ALT) 23 U l−1 (normal 5–50 U l−1), aspartate aminotransferase (AST) 20 U l−1 (normal 5–40 U l−1), alkaline phosphatase (ALK) 60 U l−1 (normal 35–110 U l−1) and total bilirubin (TBil) 0.5 mg dl−1 (normal 0.3–1.2 mg dl−1). He was a nondrinker and nonsmoker with no known risk factors for liver or renal disease. Ten months after prescription of celecoxib, the patient described intermittent right upper quadrant pain, fatigue, and decreased appetite. Over the course of two more months, his symptoms progressed to lethargy and jaundice, requiring hospitalization. He described having had progressively dark urine and pale stools for 2 weeks. His examination showed temperature 36.2°C, blood pressure 140/68 mmHg, pulse 80 per minute and respiration 20 per minute. There was scleral icterus, but no palmar erythema or spider angiomata. The neck was supple without lymphadenopathy. The heart was regular and lungs were clear. The abdomen was benign, without hepatosplenomegaly or ascites. There was no peripheral oedema. Laboratory tests on admission were haemoglobin 12.4 g dl−1, white blood cells 16 000 µl−1, platelets 283 000 µl−1, prothrombin time 12.4 s, BUN 109 mg dl−1, Cr 5.2 mg dl−1, ALT 3 U l−1, AST 17 U l−1, ALK 77 U l−1, TBil 32.4 mg dl−1, direct bilirubin 28.7 mg dl−1 and albumin 4.1 g dl−1. The antinuclear and hepatitis A IgM antibodies, hepatitis B surface antigen, hepatitis B core IgM antibodies, and hepatitis C antibodies were negative. Abdominal ultrasound and computed tomography were normal. Liver and renal biopsy specimens were obtained within 24 h of admission (Figure 1) and were suggestive of drug-induced toxicity. Celecoxib was stopped, with ensuing rapid symptomatic and biochemical improvement. At 7 days, laboratory tests showed BUN 19 mg dl−1, Cr 1.9 mg dl−1 and TBil 8.7 mg dl−1, and the patient was discharged. At 6 weeks' follow-up, laboratory tests were BUN 7 mg dl−1, Cr 1.1 mg dl−1 and TBil 0.9 mg dl−1. Histopathology. (a) Liver biopsy, medium-power light microscopy, reticulin stain, with evidence of focal hepatocyte dropout. (b) Liver biopsy, high-power light microscopy, H&E stain, with evidence of grade 2/4 lymphocytic inflammation. (c) Kidney biopsy specimen, high-power light microscopy, H&E stain, with evidence of small foci of injured tubular epithelium (black arrows) and scattered bile casts (white arrows) Celecoxib-induced nephrotoxicity has been described primarily with short-term use, as soon as within 2 weeks, although there have been two cases after 10 months of continuous use [1, 3]. Celecoxib-induced hepatotoxicity is also seen primarily with short-term use, as soon as within 2 days, with only one case reported after 10 months of use [2]. Celecoxib-induced nephrotoxicity has been reported in the form of acute interstitial (tubulo)nephritis [3–9], nephrotic syndrome [3], membranous glomerulopathy [7], papillary necrosis [8] and unbiopsied acute renal failure [1]. Celecoxib-induced hepatotoxicity has been reported as a hepatocellular [2], cholestatic [10–13], or combined pattern [14]. Recovery from renal or hepatic toxicity has been rapid in most cases, although some showed recovery delayed beyond 3 months. It is unclear if there exist pathophysiological differences between celecoxib-induced nephrotoxicity and hepatotoxicity or between the toxicity associated with short-term and prolonged use. In our case, because of the late onset of symptoms and the combined hepato–renal manifestations, drug toxicity was not initially considered highly likely. Therefore, biopsy specimens were obtained to rule out other aetiologies. The lack of other susceptibility factors, including excess celecoxib use, the histology showing hepatic cholestasis and tubulonephritis, and the prompt symptomatic and biochemical improvement collectively supported idiosyncratic celecoxib toxicity. For safety reasons, given the evidence was convincing with Roussel UCLAF causality assessment method score 7 [15], we did not re-challenge the patient. This case is reported to heighten awareness of late-onset renal, hepatic, or even combined toxicity with the use of celecoxib.