Sensitivity to a metabolite of diclofenac as a cause of acute immune hemolytic anemia.

A 75-year-old woman taking the nonsteroidal anti-inflammatory drug diclofenac (DCF) presented with acute Coombs-positive hemolytic anemia and subsequently developed renal failure. A drug-dependent antibody specific for red blood cells (RBCs) could not be demonstrated by in vitro testing with DCF. However, her serum was found to contain an IgM antibody that reacted strongly with RBCs in the presence of urine from any of four subjects who had ingested DCF. The active substance in urine was isolated, subjected to high-performance liquid chromatographic (HPLC) analysis, and found to be a glucuronide conjugate of a known DCF metabolite, 4'-hydroxydiclofenac (4'-OH DCF). Negative results were obtained with four other DCF metabolites. Two 4'-OH DCF glucuronides were synthesized in vitro using a liver microsomal system. One promoted agglutination of normal RBCs by the patient's serum and was identified as the glucuronide ester of 4'-OH DCF by proton nuclear magnetic resonance (NMR) analysis. Studies with a panel of RBCs showed that the patient's antibody reacted preferentially with the e antigen of the Rh system. Acute immune hemolytic anemia in this patient appears to have been caused by sensitization to DCF modified by 4' hydroxylation and glucuronidation. This is the first reported example of immune cytopenia caused by sensitivity to a glucuronide conjugate of a drug metabolite. Since glucuronidation is a common pathway of drug metabolism, studies of the frequency with which glucuronide derivatives of primary medications cause immune cytopenia seem warranted.

Quinine-induced immune thrombocytopenia with hemolytic uremic syndrome: clinical and serological findings in nine patients and review of literature.

Quinine-induced immune thrombocytopenia with hemolytic uremic syndrome (HUS) is a recently defined clinical entity. In this paper we have attempted to characterize the natural history and laboratory abnormalities typical of quinine-induced immune thrombocytopenia associated with hemolytic uremic syndrome in nine patients experiencing ten episodes of the disease. In addition, review of other reported cases of probable quinine-induced HUS is presented. The disease was characterized by the onset of chills, diapheresis, nausea and vomiting, abdominal pain, decreased urine output, and petechiae following quinine exposure. All patients experience significant anemia, severe thrombocytopenia, increased lactate dehydrogenase, elevated serum creatinine, and oliguria. Quinine-dependent platelet-reactive antibodies were identified in eight of nine using flow cytometry. Unexpectedly, drug-dependent antibodies reactive with red cells and granulocytes were identified in four and eight patients, respectively. All patients were treated with plasma exchange (range 1-12 procedures), and seven required hemodialysis. All survive without residual abnormality. Our experience with nine patients with quinine-induced HUS and the nine additional cases reported by others and reviewed in this paper establishes this condition as a distinct clinical entity. Adult patients presenting with HUS should routinely be asked about exposure to quinine in the form of medication or beverages. The mechanism by which quinine-dependent antibodies produce renal failure is uncertain, but preliminary studies (described elsewhere) suggest that drug-induced antibodies reactive with endothelial cells and possibly margination of granulocytes in renal glomeruli may be responsible for this complication. The prognosis in quinine-induced HUS is better than in other forms of adult HUS.

Biliary lithotripsy. Determination of stone fragmentation success and potential tissue injury in swine.

Application of extracorporeal shock wave lithotripsy to gallbladder stones was studied in 37 adult female swine. Twenty-two sows underwent cholecystostomy with implantation of human gallstones. In 20 animals, after a 10-day recovery period, extracorporeal shock wave lithotripsy, 2000 shocks (an amount determined in preliminary water bath studies to be effective), was performed. In 10 of these implanted swine, frequent focal point refocusing and biplanar ultrasonography were employed. Two animals served as operative controls. Fifteen other animals without gallstone implantation were studied for adverse effects of extracorporeal shock wave lithotripsy on tissue. These animals (unimplanted) received 5000 shocks; 7 animals were killed 1 to 4 days after treatment and the others were killed after 4 weeks. Biochemical tests (total bilirubin, alkaline phosphatase, lipase, amylase, alanine aminotransferase, and lactate dehydrogenase determinations) were performed on all animals at entry and every second or third day until they were killed. Successful fragmentation, defined as all residual gallstone fragments being less than or equal to 4 mm in greatest dimension, was achieved in 14 of 20 animals overall, but in 10 of 10 animals in which focal point refocusing had been used. Slight perivascular hemorrhage and minimal coagulation necrosis were seen histologically only in the liver parenchyma adjacent to the gallbladder bed. The remainder of the liver was grossly and histologically normal. No injuries to the colon, duodenum, common bile duct, or pancreas were observed. No alterations suggesting injury or altered function occurred in any of the biochemical tests.