Here's a good read guys:
NSAID-Induced Acute Hepatic and Renal Disease
Ronald S. Siegel, M.D.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used throughout the world. It is estimated that between fifteen and twenty-five million Americans use them on a daily basis to treat pain and inflammation.1 This class of drugs has many well-known side effects including ulcer disease, gastrointestinal bleeding, acute colitis, central nervous system dysfunction, renal insufficiency, and mild hepatic injury. Adverse effects of drugs have been reported to account for up to 7% of hospital admissions, and of those, the gastrointestinal, renal, nervous system, and allergic effects of NSAIDs account for almost 30%.2 The following case illustrates unusually severe multisystem effects of a commonly-used NSAID.
Case Report
A 46-year-old Caucasian female was in her usual state of good health until 10 days prior to admission, when she began experiencing "flu-like" symptoms of fatigue, nausea, intermittent non-bloody emesis, and diarrhea. She denied fever, chills, abdominal pain, bloody stool, skin rash or arthralgias. Two days prior to admission, she noted persistent emesis and decreased urine output. One day prior to admission, she noted she was yellow. She denied intravenous drug use, transfusions, alcohol use, or known exposure to hepatitis. Her only medications prior to admission were over-the-counter naproxyn sodium 220 mg, 6 to 12 tablets daily, and acetaminophen 500 mg, 2 to 4 tablets intermittently, for 6 weeks prior to onset of illness, for treatment of back pains. She had no allergies and denied any significant past medical history.
On admission, she was a thin, acutely ill, deeply icteric female. Temperature was 98ºF, blood pressure 128/67 mm Hg, pulse 100 beats/minute, and respiration 22 breaths/minute. Pertinent physical findings included deep scleral icterus, jaundice without spider angiomata, purpura, or petechiae, and normal heart and lungs. The abdomen was soft with slight mid-epigastric tenderness and no hepato-splenomegaly, rebound or guarding. Extremities revealed no cyanosis, clubbing or edema. Neurologic examination was normal. Laboratory data included a white blood cell count of 10,600 with normal differential, platelet count 103,000, hemoglobin 11.5, hematocrit 31.8%, sodium 115 meq/l, potassium 6.1 meq/l, chlorides 76 meq/l, carbon dioxide 17 mm/l, urea nitrogen 112 mg%, creatinine 10.4 mg%. Liver tests included bilirubin 13.5mg/dL, aspartate aminotransferase (AST) 173 U/L, alanine aminotransferase (ALT) 750 U/L, alkaline phosphatase 668 U/L, albumen 2.8 g/dL and international normalized ratio 1.0. Hepatitis A, B, and C antibodies, Epstein- Barr virus antibodies and cytomegalovirus antibodies were negative. Acetaminophen level was undetectable, anti-nuclear antibody less than 1:40, and compliment C3 and C4 normal. Blood and stool cultures were negative. Abdominal ultrasound revealed mild hepatosplenomegaly, normal gall bladder, no biliary dilatation, normal kidneys, and no hydronephrosis.
Following rehydration and correction of electrolyte abnormalities, her nausea and abdominal pain resolved but the creatinine remained elevated at 10.4 mg%. Hemodialysis was started on hospital day 3 with gradual improvement in creatinine, although she remained anuric throughout the hospital stay. By hospital day 4, bilirubin was 3.1 mg/dL, AST 115 U/L, ALT 127 U/L, alkaline phosphatase 406 U/L. By hospital day 10, bilirubin was 1.5 mg/dL ALT 31 U/L, AST 13 U/L. On hospital day 10, a renal biopsy was performed, revealing acute tubulo-interstitial nephritis, with a diffuse lymphocytic infiltrate, and no evidence of chronic disease, vasculitis, viral inclusions, or immune complex deposition. Hemodialysis was continued and she was started on prednisone, but there was no improvement in creatinine levels. One week after discharge, her liver tests were completely normal, but she remains oliguric on hemodialysis 4 months after discharge.
Discussion
In the case presented, no other specific disease entities were identified that could have accounted for this patient's illness, and it is presumed that both the renal and hepatic dysfunction were due to the effects of naproxyn. Severe liver disease due to NSAIDs is rare, although mild elevations of aminotransferases are quite common.3 In a large retrospective study of patients using a .variety of NSAIDs, the incidence of acute liver injury was 3.7 per 100,000 NSAID users, or 1.1 per 100,000 NSAID prescriptions, and sulindac was the only NSAID found to have a substantially greater risk of producing liver disease of all the NSAIDs studied.4
Most NSAIDs are metabolized by hepatic biotransformation and excreted through the urine. While the exact mechanism of naproxyn-induced liver injury is unknown, it is likely an idiosyncratic metabolic reaction due to aberrant metabolism of the drug where accumulation of toxic metabolites in hepatocytes bind to cell proteins and lead to necrosis.5 The markedly elevated bilirubin observed in this case dropped quite rapidly once dialysis was started, suggesting that acute renal failure was responsible for most of the bilirubin elevation. Typical of this type of injury is the inability to predict whether or not liver damage will occur, and the lack of relationship between the dose and the severity of the reaction.
Two forms of acute renal failure have been reported with NSAID use. Hemodynamically-mediated acute renal failure occurs in the setting of preexisting severe effective volume depletion seen with such disorders as congestive heart failure, cirrhosis, or severe gastrointestinal or renal salt and water losses. In these settings, NSAID inhibition of prostaglandin synthesis leads to renal vasoconstriction and decreased renal perfusion which can progress to acute renal failure.6 Acute interstitial nephritis is the other form of NSAID-induced acute renal failure. The exact mechanism is unknown, but it is postulated that NSAID-induced inhibition of cyclooxygenase may allow arachidonic acid to be preferentially converted to leukotrienes which can activate helper T-cells leading to an acute interstitial infiltrate of T-lymphocytes.7
Conclusion
Although severe liver injury and renal failure are rare with NSAID use, on occasion they can produce very severe illnesses due to the effect of toxic metabolites, or the potent effects of inhibition of prostaglandin synthesis on various organs. Patients frequently take much larger amounts than are recommended on the label, and because most people who use NSAIDs do not consider them "medicine," they may not tell their physicians about their use. In addition, as the baby boomer generation ages, there will be a large increase in the elderly population with a concomitant increase of chronic NSAID use to treat arthritis and pain. This in turn may well lead to a greater incidence of NSAID-induced disease. Physicians should periodically question their patients about the dosage and frequency of NSAID use and monitor both liver and renal function.
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