Could diclofenac (Voltaren) or ranitidine (Zantac) cause lethal fulminant liver failure? Are the re

Fråga: Could diclofenac (Voltaren) or ranitidine (Zantac) cause lethal fulminant liver failure? Are the relatives of the patient likely to face an increased risk of reacting in the same way if treated with diclofenac or other NSAIDs?

A 41-year-old man had knee surgery in June/August 1998. Diclofenac was instituted at a dose of 50 mg three times daily on September 16th, 1998 because of knee pain. After six days treatment he discontinued diclofenac due to strong epigastric pain and loose stools. He visited a general practitioner on October 4 because of the gastric pain, tiredness and that he did not feel well. The doctor prescribed ranitidine, 150 mg x 2. Four days later the patient went to the emergency ward at a hospital, still with pain in his stomach. He was sent home after investigation and prescribed a double dose of ranitidine. On October 10th he came back again and was admitted to the ward with suspicion of gastritis or ulcers. Liver enzymes that day were ALAT 0.90, ALP 5.4, bilirubin 28, AST 0.52, and CRP 127. A gastroscopy showed varices. Biopsy showed no morphological diagnostic discovery. The patients´ status deteriorated and ascites was found on a computer scan three days later. On October 12th bilirubin was increased to 84, ALT 0.95 and PK was normal, 92. The 14:th of October bilirubin was 177, ALT 2.26 and AST 1.35. The PK was still normal 107. The patient died two days later of fulminant liver failure. Blood test the same day showed bilirubin 219, ALT 2.11, AST 1.35, CRP 77, ALP 9.7 and the PK decreasing to 46. Autopsy showed a severe necrosis of the liver.

The case has been reported to SADRAC (The Swedish Adverse Drug Reactions Advisory Committee).

Sammanfattning: Both diclofenac and ranitidine have been associated with fatal fulminant liver failure due to immunoallergic or metabolic idiosyncrasy at a low rate of incidence. The liver failure probably developed before ranitidine treatment was started which makes this drug a less likely cause of the fatal outcome. Even if this case is difficult to assess as laboratory signs do not follow the clinical course in time too well, diclofenac is probably the cause of the liver failure. It cannot be excluded that genetic mechanisms may predispose to rare adverse drug reactions like the present one. However, the actual case cannot be used to make any predictions whatsoever about any increased risk to develop similar reactions among relatives.

Svar: It is well known that diclofenac, a nonsteroidal anti-inflammatory drug, may cause rare cases of liver dysfunction (1-3). In contrast to the most frequently reported side effects caused by NSAID treatment, such as gastrointestinal disturbances (15-25 per cent) (7), liver disease caused by NSAID therapy is rare (5). In one reference the incidence is stated to be 1-5 per 100000 exposed patients (13). In the diclofenac Phase III short-term (1227 patients) and long-term (1173 patients) trials in the United States, hepatitis was found in 0 per cent respectively 0.26 per cent (7). According to another reference one probable case and ten possible cases of NSAID-induced liver disease were identified in more than 100000 patients treated with diclofenac, naproxen or piroxicam (5). In a study of all cases of hepatic dysfunction caused by diclofenac or other NSAIDs and reported to the Australian Adverse Drug Reactions Advisory Committee between 1981 to 1989, only 26 cases were thought to have diclofenac as the sole cause of liver injury. One of the patients died from massive hepatic necrosis. A correlation was noted between the cumulative dose received by the patient and the severity of liver damage assessed by the peak transaminase concentration. According to the same reference the manufacturer reported 15 deaths over a 14-year period (5). In a retrospective study 180 cases of diclofenac-associated hepatotoxicity were reported to the FDA. Ninety of the patients had jaundice and seven of these died (14).

Mild ASAT/ALAT elevations occurred in 2-25 per cent of the patients treated with diclofenac (4) and according to another reference in 15 per cent (5). In most of the cases recovery was rapid but some had a fatal course (7). Mixed/hepatocellular injury, acute or chronic active hepatitis, cholestasis, focal or multilobar necrosis, massive necrosis and fulminant hepatic failure have been reported after diclofenac treatment (4-7). The period from first dose intake until the first symptoms from liver affection appeared varied from 5-8 days to 4-11 months, but in most cases was between two weeks and 2.5 months. According to this reference several of the cases were fatal (4).

A search in SWEDIS (8) on diclofenac reveals 98 cases of side effects related to the liver and biliary system. Two fatal cases from diclofenac occurred between 1982 and 1998. In some of the cases other drugs also could be responsible for the drug reaction. The WHO database contains 92 unvalidated reports of fatal cases between 1979 to 1998 after diclofenac treatment (9).

The mechanism behind the liver injury seems to be immunoallergic or can be characterized as metabolic idiosyncrasy. Diclofenac and other NSAIDs are metabolised to arenoxides and epoxides, which in turn are reactive. Impaired clearance of these metabolites (5) could explain the liver damage (1). Autoimmune injury has also been reported. Interestingly experiments with rat hepatocytes show that inhibition of the cytochrome P-450 enzyme CYP2C reduces cell injury (13). If this has any clinical value in humans remains to be investigated.

Ranitidine is likely to be an infrequent cause of drug-induced cholestatic hepatitis. Like for diclofenac this may be due to an immunoallergic reaction (6). The Drug Information Centres has answered questions about ranitidine and liver affections before (11-12). There are a few clinical reports indicating that it may cause cholestatic hepatitis (10). The incidence of elevated liver enzymes during trials varied from 1-4 per cent and in healthy volunteers 24 per cent when given intravenously. The elevations were mild and transient (4). The Netherlands Centre for Monitoring of Adverse reactions reports six cases of liver injury and one fatal case has been reported from France (7). Eighteen symptomatic hepatic injuries with a causal relationship to ranitidine were reported to FDA in a two-year period. In another study with FDA-reports the incidence was estimated to 1:75000 - 150000 prescriptions. Other trials have estimated the frequency of hepatic injury to 0.08-0.09 per cent (4).

A search in SWEDIS reveals 47 cases of liver side effects, one of which was fatal. Ranitidine was evaluated as the probable cause of the fulminant liver failure, but piperacillin could not be excluded in this case. In the WHO database there are 40 unvalidated reports of hepatic adverse reactions with fatal outcome between 1983 to 1994 (9). 1 Drugline no 12960 (year 1996)

2 Drugline no 12114 (year 1995)
3 Drugline no 06951 (year 1989)
4 Stricker BHCh. Drug-induced hepatic injury. 2nd ed. Amsterdam: Elsevier; 1992

5 Manoukian AV, Carson JL. Nonsteroidal anti-inflammatory drug-induced hepatic disorders. Incidence and prevention. Drug Safety 1996; 15: 64-71

6 Farrell GC. Drug-induced liver disease. Edinburgh: Churchill Livingstone; 1994
7 Dukes MNG, editor. Meyler´s Side effects of drugs. 13th ed. Amsterdam: Elsevier; 1006
8 Swedis (The Swedish catalogue of approved medical products)
9 Intdis (International Drug Information System): WHO:s adverse drug reactions database
10 Davies DM, editor. Textbook of adverse drug reactions. 4th ed. Oxford: Oxford University Press; 1991
11 Drugline no 13659 (year 1996)
12 Drugline no 05431 (year 1987)
13 Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med 1998; 105: 13S-19S

14 Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the food and drug administration as adverse reactions. Hepatology 1995; 22: 820-827