here t h e case o f a patient with jaundice associated with flurazepam hydrochloride.

Cholestatic Jaundice Associated with Flurazepam Hydrochloride MARY H. FANG, M.D.; ALLEN L GINSBERG, M.D.; and WILLIAM O.DOBBINS III, M.D. George Washington University School of Medicine and Health Sciences; Washington, D.C. FLURAZEPAM

HYDROCHLORIDE

(Dalmane®),

a

com-

m o n l y used h y p n o t i c available since 1970, h a s n o t previously been linked w i t h hepatic toxicity (1). W e report

A 70-year-old white man was admitted on 5 September 1977 with a Zy^-month history of anorexia, weakness, and fatigue. Two and one-half weeks before admission, he had noticed brown urine and clay-colored stools. Pruritis and jaundice had occurred 1 week later. He denied abdominal pain and significant weight loss. A cholecystectomy and an appendectomy had been done in 1969 and coronary artery bypass in 1972. He now has class III angina. He had been treated with tolbutamide for 12 years and phenformin for 3 years for diabetes mellitus. Phenformin was withdrawn 3 months before admission. The patient had been taking chlorthalidone, isosorbide dinitrate (Isordil®), digoxin, and topical glyceryl trinitrate (Nitrol® ointment) for many years. He had used flurazepam hydrochloride, 30 mg nightly, for 5 months only. The patient had no history of liver disease, exposure to hepatotoxins, or use of alcohol. Physical examination showed the patient to be jaundiced. Vital signs were normal, there was no evidence of heart failure, and the lungs were clear. There was a grade 2 / 6 systolic ejection murmur at the lower sternal border. The liver span was 10 cm, and the liver was palpable 2 fingerbreadths below the right costal margin. Hematocrit was 42%; leukocyte count 8 1 0 0 / mm3 (no eosinophils); bilirubin 6.6 mg/dl; alkaline phosphatase 232 IU/litre; serum glutamic oxalacetic transaminase (SGOT) 111 IU/litre; serum glutamic pyruvic transaminase 179 I U / litre; lactic dehydrogenase 158 IU/litre; prothrombin time, normal; serum albumin 4.3 g/dl; total protein 6.6 g/dl; hepatitis B surface antigen (HBsAg), negative; blood urea nitrogen 36 mg/dl; creatinine 1.4 mg/dl; and blood sugar 439 mg/dl. There was no acetonuria. Liver enzyme concentrations 4 months before admission were normal. Chest roentgenogram revealed no evidence of acute disease. The patient was asymptomatic throughout hospitalization except for the presence of pruritis. Liver-spleen scan showed a normal-sized liver with homogeneous uptake. Abdominal sonogram revealed no significant abnormalities. The duodenal sweep was normal on upper gastrointestinal series. Percutaneous cholangiogram revealed a normal biliary system. Diabetes was controlled on Lente®insulin, 25 U/day. The patient remained jaundiced with no significant change in alkaline phosphatase or serum transaminase. A percutaneous liver biopsy showed the presence of intrahepatic cholestasis, with acute and chronic portal inflammation that included moderate numbers of eosinophils, some ballooning of hepatic cells, and moderate steatosis. The morphologic abnormalities seen on light microscopy were considered suggestive of drug-induced cholestasis. Flurazepam was withdrawn on 15 September at our recommendation. Within 3 weeks, SGOT and bilirubin levels were normal. Alkaline phosphatase concentration was 104 IU/litre 1 month after discharge (Table 1). Pruritis resolved 4 months after discharge. There is substantial, although indirect, evidence supporting our c o n t e n t i o n that flurazepam h y d r o c h l o r i d e therapy resulted in intrahepatic cholestasis. T h e patient had been taking chlorthalidone a n d isosorbide dinitrate for 10 years, digoxin for 2 0 years, a n d topical glyceryl

Table 1. Representative Serum Chemistries* and Their Relation to Treatment with Flurazepam Hydrochloride

11 Apr (Dalmane® Started) Bilirubin, mg/dl Alkaline phosphatase, IU/litre SGOT, IU/litre SGPT, IU/litre

0.5 90 18 40

1 Sept

5 Sept (Admission)

9 Sept

12 Sept (Dalmane Stopped)

29 Sept

6 Oct

20 Oct

7.0 207 82 225

6.6 232 111 159

5.0 230 115 174

4.5 225 133 181

1.7 183 52 79

1.0 142 32 59

0.6 104 28 47

* Normal values: alkaline phosphatase, < 90 IU/litre; SGOT (serum glutamic oxalacetic transaminase), < 40 IU/litre; SGPT (serum glutamic pyruvic transaminase), < 30 IU/litre. Brief Reports

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trinitrate for V/2 years without adverse effects. Lente insulin does not cause intrahepatic cholestasis. The patient's serum was negative for HBsAg, and he did not have typical clinical, laboratory, or histologic evidence for viral hepatitis. Cholestatic viral hepatitis cannot be ruled out but would be most unusual. Thus flurazepam hydrocholoride would be the most reasonable cause of the intrahepatic cholestasis. The liver enzymes rapidly returned to normal after stopping flurazepam therapy while other medications were continued. We could not justify a challenge with flurazepam because it would not be essential to the future care of the patient. Flurazepam is a 1,4-benzodiazepine derivative closely related to chlordiazepam and diazepam. Diazepam (Valium®) has been reported to cause intrahepatic cholestasis associated with chills, fever, jaundice, and pruritis (2); the jaundice and pruritis persisted for 6 months. Chlordiazepoxide hydrochloride (Librium ) has induced cholestatic jaundice, pruritis, nausea, vomiting, and epigastric pain in one patient after 5 weeks of therapy (3). Another patient developed painless jaundice after receiving chlordiazepoxide hydrochloride for 5 days (4). Franks and Jacobs (5) have also reported a case in which intrahepatic cholestasis developed while the patient was receiving benzodiazepine drugs (5). The authors thank Dr. Joseph Ney for allowing us to see this patient in consultation. REFERENCES 1. G R E E N B L A T T DJ, SHADER RI, K O C H - W E S E R J: Flurazepam hydrochlo-

ride, a benzodiazepine hypnotic. Ann Intern Med 83:237-241, 1975 2. KLATSKIN G: Toxic and drug-induced hepatitis, in Diseases of the Liver, 4th ed., edited by SCHIFF L. Philadelphia, J. B. Lippincott Company, 1975, p. 680 3. ABBRUZZESE A, SWANSON J: Jaundice after therapy with chlordiazepoxide hydrochloride. NEnglJMed 273:321-322, 1965 4. CACIOPPO J, MERLIS S: Chlordiazepoxide hydrochloride (Librium) and jaundice: report of a case. Am J Psychiatry 117:1040-1041, 1961 5. FRANKS E, JACOBS WH: Cholestatic jaundice possibly due to benzodiazepine-type drugs. Mo Med 72:605-606, 1975 © 1978 American College of Physicians

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September 1978 • Annals of Internal Medicine • Volume 89 • Number 3

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Cholestatic jaundice associated with flurazepam hydrochloride.

here t h e case o f a patient with jaundice associated with flurazepam hydrochloride. Cholestatic Jaundice Associated with Flurazepam Hydrochloride M...
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