Dextropropoxyphene Induced Hepatotoxicity Mimicking Biliary Tract Disease

Gut: first published as 10.1136/gut.27.4.444 on 1 April 1986. Downloaded from Gut, 1986, 27, 444-449

Case reports Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease

M F BASSENDINE, K W WOODHOUSE, M BENNETT, AND 0 F W JAMES From the Departments of Medicine and Pathology, Freeman Hospital and the Department of Medicine (Geriatrics), Royal Victoria Infirmary, Newcastle upon Tyne.

SUMMARY Three patients are described with recurrent jaundice, upper abdominal pain -and rigors attributable to dextropropoxyphene hepatotoxicity. The diagnosis was established in each patient by rechallenge; post challenge hepatic histology is reported in two. Twelve previous patients with probable dextropropoxyphene hepatic toxicity have been described and are reviewed. In 10 of the 15 patients, a clinical diagnosis of gall stone disease was made. Liver function tests are usually hepatitic shortly after challenge, but more cholestatic after a few days. No fatalities have been described, but as dextropropoxyphene is widely available in many different analgesic preparations possible toxicity should be considered in patients with relapsing jaundice mimicking biliary disease, in whom gall stones have been excluded.

as an accompanied by dark urine, pale stools, malaise, and Dextropropoxyphene is widely used analgesic http://gut.bmj.com/ both alone and in combination with other drugs. pruritus. Investigations: bilirubin 76 imol/l, alkaline Although several reports have suggested that it may phosphatase 121 IU/l (normal<92), aspartate amino- rarely cause liver damage,-9 a causal relationship transferase 169 IU/l (normal<37). Autoantibody has only been firmly established by rechallenge in a screen negative. HBsAg negative, anti HBs negative, total of six patients and in only two was hepatic anti HBc negative, HAV IgM negative. Abdominal histology available after the rechallenge. We report ultrasound - no abnormality of intrahepatic or extra- three patients in whom dextropropoxyphene was hepatic biliary tree but poor sonar subject. ERCP: responsible for hepatotoxicity. normal biliary tree, normal gall bladder. Liver on September 29, 2021 by guest. Protected copyright. biopsy showed focal lobular mononuclear cell in- Case histories flammatory infiltrate accompanied by centrilobular cholestasis. An occasional acidophil body and PATIENT 1 double nucleated hepatocytes were also seen. Portal A 52 year old woman had two episodes of un- tracts showed a focal mononuclear cell inflammatory explained jaundice in 1981 and 1982. On each infiltrate. Liver function tests settled to normal after occasion jaundice lasted about two weeks and was a further four weeks (total abnormality of liver accompanied by pruritus, nausea, and intolerance of function tests seven weeks). On further inquiry from fatty foods. No investigations were carried out. The the patient's general practitioner it transpired that patient had osteoarthritis of the right knee for which she had been given a prescription for Distalgesic she took various analgesics, usually Benorylate (an (paracetamol plus dextropropoxyphene) in the aspirin-paracetamol ester). She had a known allergy month before the latest episode of jaundice to penicillin. The patient was admitted to hospital although the patient had only remembered taking with a history of sudden onset of jaundice for a third Benorylate. Accordingly, the patient was readmit- time three weeks previously, the jaundice had been ted to hospital and given a 'challenge' of 32-5 mg preceded by epigastric pain for a few hours and was dextropropoxyphene by mouth. After 10 hours she experienced cramplike abdominal pain in the right Address for correspondence: Dr 0 F W James, Medical Unit No 1, Freeman upper quadrant accompanied by nausea and fever. Hospital, Newcastle upon Tync, NE7 7DN. Liver function tests are shown in Figure 1. Liver Received for publication 2 August 1985. biopsy was carried out six days after challenge. This 444 Gut: first published as 10.1136/gut.27.4.444 on 1 April 1986. Downloaded from

Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease 445

r biopsy-, jaundice starting about 12 hours after taking Distal- Casel I gesic tablets (she normally took paracetamol alone). .E 600 T:Cas;el"o""o On each occasion jaundice lasted a few days and was E Co ;e2 .--. accompanied by dark urine and pale stools. The , 500 o CasK~~~~~~~~~~o;ej3A following investigations had been carried out: bilirubin 40 IU/l, AST 270, alkaline phosphatase 22 D 400- KAU (N<13). Abdominal ultrasound showed 300- normal intra- and extrahepatic biliary tree. Oral cholecystogram normal, intravenous cholangiogram 200 normal. In addition autoantibody screen, HBV markers and HAV IgM were all negative. She was admitted to hospital and given an oral challenge 16 24 34 dose of 32-5 mg dextropropoxyphene. After 10 140- hours she developed cramping upper abdominal 120- pain, fever, and nausea. Liver function tests are shown in Figure 1. Liver biopsy was carried out 48 100 / \ hours after the challenge. This showed normal *.280 hepatic architecture, but hypertrophied Kupffer 2z cells were seen throughout the lobules. An in- 60o flammatory infiltrate of eosinophils and lympho- 40- K> cytes was present in most portal tracts (Fig. 4). No 204 , polymorphs, significant oedema or bile ductule proliferation were seen. Liver function tests had 0@D1COz aim//////// 1 2 3 4 5 6 7 16 24 34 returned to normal after 16 days except for a raised %300] alkaline phosphatase of 138. She remained quite well with normal liver function tests after seven 2001 ~ weeks. http://gut.bmj.com/ PATIENT 3 1F 2 3 4 5 6 7 16 24 34 51 A 22 year old nurse was admitted to hospital with Days sciatica. She was treated with pelvic traction and Fig. 1 (Case 1) Liverfunction tests after oral Xchallenge analgesics (paracetamol, pentazocine, codeine with 32-5 mg dextropropoxyphene at time 0 in ceases phosphate). She was subsequently given aspirin and 1, 2and3. Distalgesic. She then developed severe epigastric

pain, nausea, and vomiting followed by rigors and on September 29, 2021 by guest. Protected copyright. again showed centrilobular cholestasis. C)edematous sweating. A few days later she became mildly icteric portal tracts contained numerous eosinc)phils and a with pruritus and pale stools. Her sciatica had eased few mononuclear cells. The eosinophilIs were not so all analgesics were stopped. Investigations were infrequently situated around bile ducts ((Fig. 2) and as follows: bilirubin 46, AST 149, alkaline phos- occasionally were seen passing throug}h the base- phatase 290, amylase 125 IU/I (normal<300). HBV ment membrane. Ultrastructurally diilatation of markers, HAV IgM, autoantibodies, all negative. canaliculi with loss of microvilli was seen, most Ultrasound showed no abnormality in the biliary marked in the centrilobular areas. rhe biliary tree and gall bladder. Liver function tests returned concretions had a granular appearance and within to normal after 10 days except for a raised alkaline the cytosol, mitochondria showed elonigation and phosphatase of 138. Three months later liver func- curling of the cristae (Fig. 3). After tihe onset of tion tests were normal, and she was readmitted and jaundice she had pruritus and malaise, liPver function given a 'challenge' with dextropropoxyphene tests were still abnormal after 24 days (E,ilirubin 35, 32-5 mg by mouth. Twenty four hours later she alkaline phosphatase 96, AST 102) but had returned became nauseated and vomited several times and to normal after five weeks. developed upper abdominal pain which lasted 12 hours. Liver function tests are shown in Figure 1. PATIENT 2 Liver biopsy was refused. A 65 year old woman with a long history of facial pain reported three episodes of jaundice in the three Discussion months before hospital referral. On ea(ch occasion she developed upper abdominal pain, fever, and Dextropropoxyphene has been widely used as an Gut: first published as 10.1136/gut.27.4.444 on 1 April 1986. Downloaded from

446 Bassendine, Woodhouse, Bennett, and James

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Fig. 2 (Case 1) Near the central veins, cholestasis was indicated by bile thrombi (arrow) (original magnification X1280). Oedematous portal tracts contain both eosinophils and lymphocytes (original magnification x512).

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j,a. tf Fig. 3 (Case 2) Electromicrograph shows dilated bile canaliculae, containing granular material. Adjacent hepatocyte mitochondria show curling of the cristae (original magnification x6000). Gut: first published as 10.1136/gut.27.4.444 on 1 April 1986. Downloaded from

Dextropropoxyphene induiced hepatotoxicity mimicking biliary tract disease 447

Fig. 4 Portal tract shows an increase in lymphocytes with an occasional eosinophil. Kupffer cells are hypertrophied within the adjacent sinusoids (original magnification X320). http://gut.bmj.com/ Table Details ofpatients

Reference Age Sex Cliniical features Challenge Histology 1. Klein and Magida 39 M Fever, anorexia, malaise Mixed/hepatitic Intrahepatic cholestasis periportal 1971 LFFs infiltrate, round cells, polymorphs and cosinophils 2. Daikos and Kosmidis 47 M Upper abdominal pain then dark Mixed LFTs on September 29, 2021 by guest. Protected copyright. 1975 urine, pale stools 3. Lee and Rees 1977 56 M Relapsing jaundice, upper Mixed LFTs Mild portal fibrosis (before abdominal pain followed by jaundice challenge) 66 F Malaise and tiredness found to Pyrexia, mildly have abnormal LFTs abnormal LFTs 4. Ford et al. 1977 54 F Rigors, jaundice, pruritus Intrahepatic cholestasis, portal A gall stones-laparotomy tracts infiltrated with plasma cells, lymphocytes, eosinophils 32 F Recurrent epigastric pain, nausea, dairk urine, pale stools 45 F Pruritus, pale stools and dark Intrahepatic cholestasis urine then jaundice. A gall stones-laparotomy 5. Pramming aind 62 F Abdominal pain '? gall stones Mixed LFTs Cholestasis, intrahepatic oedema Peterson 1978 6. Van Brcnkilen and 72 F Fever, abdominal pain, Hepatitic LFTs Schrijver 1978 jaundice-'3 gall stoncs 7. Adverse Drug 56 F Nausea and rclapsing jaundice Committee Australia mixed LFTs 1979 8. Lindholm 1979 77 F Fever and jaundice Cholcstattic LFTs 9. Kerst and Strik 46 F Recurrent cholestasis Intrahepatic cholestasis 1979 LFTs= livcr function tests. Gut: first published as 10.1136/gut.27.4.444 on 1 April 1986. Downloaded from 448 Bassendine, Woodhouse, Bennett, and James

analgesic both alone and, more commonly, in LIVER HISTOLOGY combination with other drugs. Indeed Distalgesic is In both of the present patients where postchallenge the second most commonly prescribed analgesic in biopsies are available the portal tract infiltrate of the United Kingdom.'( Dextropropoxyphene is eosinophils and lymphocytes is suggestive of a drug present in many preparations (currently at least hypersensitivity reaction. Although not very fully eight are listed in the British National Formulary) documented only one previous histological report and has been in use for more than 15 years. Hepatic has shown a portal infiltrate of plasma cells, toxicity reliably attributable to dextropropoxyphene lymphocytes and eosinophils. Other previous liver is rare - only 12 cases have hitherto been reported in biopsies have only described cholestasis. In patient 1 the literature.1-9 The first report was in 1971. Liver where liver biopsy was carried out six days post- biopsies have been carried out in only six patients challenge during the more cholestatic phase of the and rechallenge with dextropropoxyphene alone has 'illness', centrilobular cholestasis was a feature. The been carried out in only five patients (in two of ultrastructural changes with biliary concretions are whom a liver biopsy was also available). The similar to those found in chlorpromazine jaundice. previously reported cases are summarised in the Table. The present three patients are important for POSSIBLE MECHANISM OF HEPATOTOXICITY a number of reasons. The rarity of hepatic toxicity from dextropropoxyphene, the clinical features of fever and rigors shortly after exposure, the marked hepatic toxicity CLINICAL HISTORY after a small challenge dose and the histological In each case the history was of epigastric pain, features all point to the probability of a hyper- nausea and vomiting and the symptoms were sensitivity or immune mechanism. In this connection accompanied by fever and/or rigors followed by it is of interest that 1 patient had a history of jaundice, pale stools and dark urine. In all three hypersensitivity to other drugs (penicillins). The patients a clinical diagnosis of biliary tract disease hypersensitivity could be to dextropropoxyphene was made. The symptoms described have been a itself or to a normal or abnormal metabolite. The feature of over half of the previously documented same dose of dextropropoxyphene in different

cases and this was sufficiently convincing to lead to individuals gives rise to a wide variation in plasma http://gut.bmj.com/ laparotomy for cholecystectomy in two. In all three concentrations that result from differences in of our patients different analgesics had been taken absorption and biotransformation.11 All three of our over a variable period thus the incrimination of patients were women, as were nine of 12 of the dextropropoxyphene was difficult and only proven previous cases. Men and women have been shown to by rechallenge. have different propoxyphene kinetic profiles after a single dose, women exhibiting more extensive first pass biotransformation to 12

nor-propoxyphene. on September 29, 2021 by guest. Protected copyright. RECHALLENGE Elimination of nor-propoxyphene may be influenced In each instance symptoms of severe malaise and by the rate of conjugation so plasma concentrations abdominal pain began within 24 hours after re- of dextropropoxyphene and nor-propoxyphene challenge with a low dose of dextropropoxyphene depend on rates of absorption, metabolism - hydrochloride (32.5 mg) - equivalent to the predominantly N-demethylation - and conjugation. contents of only 1 tablet of the majority of com- However the 'normal' half-life of propoxyphene pound preparations or half a tablet of the non after a single dose is three hours and nor- compound preparation. In patients 1 and 2 liver propoxyphene is 16-8 hours so that peak concentra- function tests became abnormal within 24 hours and tions of dextropropoxyphene metabolite(s) could were predominantly hepatitic initially. This was account for the time scale of the drug's hepato- followed by a more prolonged cholestatic phase; toxicity. The mechanism of this rare hepatotoxic three weeks postchallenge patient 1 still had a raised reaction requires further investigation. serum bilirubin and patient 2 a raised alkaline phosphatase. The marked abnormality of liver We thank Dr R Lendrum for permission to publish function tests after challenge ultimately returned details of case 3 and also Mrs A Asch who prepared completely to normal. Each patient felt unwell for the manuscript. about two weeks. In patient 3 where rechallenge followed only one dose liver function tests were References slower to become abnormal, were less deranged and returned to normal more quickly. This patient's 1 Klein NC, Magida MG. Propoxyphene (Darvon) period of ill health was short. hepatotoxicity. Am J Dig Dis 1971; 16: 467-9. Gut: first published as 10.1136/gut.27.4.444 on 1 April 1986. Downloaded from

Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease 449

2 Daikos GK, Kosmidis JC. Propoxyphene jaundice. 8 Lindholm L. Fever, skin and liver reactions in a patient JAMA 1975; 232: 835. treated with Paraflex comp. Lakartidningen 1979; 76: 3 Lee TH, Rees PJ. Hepatotoxicity of dextropropoxy- 2795-6. phene. Br Med J 1977; II: 296-7. 9 Kerst AJFA, Strik HPM. Bijwerkingen van Genees- 4 Ford MJ, Kellett RJ, Busuttil A, Finlayson NDC. middelen. Ned Tidschr Geneeskd 1979; 123: 1570-2. Dextropropoxyphene and jaundice. Br Med J 1977; II: 10 A new look at Distalgesic. [Editorial]. Drug Ther Bull 674. 1978; 16: 71-2. 5 Pramming S, Petersen HO. Dextropropoxifene and 11 Verebely K, Inturrisi CE. Disposition of propoxyphene liver involvement. Ugeskr Laeg 1978; 140: 2249. and norpropoxyphene in man after a single dose. Clin Pharmacol Ther 1974; 15: 302-9. 6 Breukelen FJM van, Shrijver H. Icterus during treat- 12 Inturnsi CE, Colburn WA, Verebey K, Dayton HE, ment with D-propoxyphene (Depronal). Ned T Geneesk Woody GE, O'Brien CP. Propoxyphene and nor- 1978; 122: 870-2. propoxyphene kinetics after single and repeated doses 7 Adverse Drug Reactions Advisory Committee. of propoxyphene. Clin Pharmacol Ther 1982; 31: Dextropropoxyphene. Med J Aust 1979; 2: 494. 157-67. http://gut.bmj.com/ on September 29, 2021 by guest. Protected copyright.