Postgraduate Medical Journal (1989), 65, 45 -48

Ulceration of the entire small intestine accompanied by rash,hepatitis and pancytopenia

R.H.R. Park', P.R. Mills', B.J.Z. Daneshl, R.I.Russell', D.H. Kennedy3,C. McArdle2 and F.D. Lee4

'Gastroenterology Unit, 2University Department ofSurgery and 4Department ofPathology, Royal Infirmary,Glasgow and Clinical Department ofInfectious Diseases, Ruchill Hospital, Glasgow, UK.

Summary: A case of acute mucosal ulceration of the entire small intestine accompanied by skin rash,hepatitis and marrow suppression is reported. Recovery was complicated by a severe protein losingenteropathy and small intestinal strictures and the patient died post-operatively of a pulmonary embolism.The aetiology remains unknown.

Introduction

Ulceration of the small intestine distal to theduodenum may be associated with Crohn's disease,idiopathic chronic ulcerative enteritis, polyarteritis,ischaemia, drugs or neoplasms.'2 The ulceration isusually localized although multiple areas throughoutthe small intestine can be involved.34 Small bowelhistology frequently shows transmural changes andmany cases present with acute perforation.5 We reporta case of fatal acute mucosal ulceration of the entiresmall intestine, which may have been drug related.

Case report

A 46 year old woman was admitted in May 1984 to aninfectious diseases unit with a 5-day history of aninfluenza-like illness, widespread maculo-papularrash, nausea, vomiting and jaundice. On the day ofadmission she had developed generalized abdominalpain with watery, blood-stained diarrhoea. She hadpreviously been well apart from low back pain of twomonths duration for which she had taken diclofenacsodium (Voltarol retard) for 3 weeks, followed by a 3week course of suprofen (Suprol) and 2 weeks beforeadmission had taken a combination of paracetamoland chlormezanone (Lobak).On admission she was jaundiced, apyrexial and had

a widespread maculo-papular rash. Apart from atachycardia of 100/min, cardiorespiratory examina-tion was normal. She had slight abdominal tenderness.Initial results showed normal haemoglobin, white cellcount, erythrocyte sedimentation rate, urea and elect-

rolytes, serum bilirubin 49 ILmol/l (2.9 mg/dl), aspar-tate aminotransferase activity 930 IU/l, alanineaminotransferase activity 1545 IU/l, alkaline phos-phatase activity 455 IU/I (laboratory reference rangeup to 92 IU/1), total protein 69 g/l, albumin 46 g/l,gamma glutamyl transpeptidase activity 799 IU/1.Forty-eight hours later she became pancytopenic witha total white blood count of 1.6 x 109/l, 31% neut-rophils, haemoglobin 10.9 g/dl, platelets 110,000 x -

109/l. Coagulation screen was normal. Bone marrowaspirate showed a hypocellular marrow with matura-tion arrest of all cell lines. Within a few days ofadmission the pancytopenia, rash and abnormal liverfunction tests had all resolved. A liver biopsy was notperformed in view of the clinical improvement. How-ever, her diarrhoea persisted and she rapidly lost 5 kgin weight. On two occasions she passed string-likeslough per rectum (Figure 1).

Initially an infective aetiology was suspected butstool investigations for the presence of salmonellae,shigellae, campylobacter, parasites, enteroviruses,Clostridium difficile and toxin, and serological tests foryersiniosis, amoebiasis, typhoid, hepatitis A, hepatitisB, Epstein-Barr virus,cytomegalovirus and parvoviruswere all negative. Small bowel radiology demon-strated continuous mucosal oedema and ulcerationwith reduction in the bowel lumen from the third partof duodenum to the terminal ileum. The proximalcolon appeared normal (Figure 2). A jejunal biopsyshowed complete mucosal ulceration to the level ofthemuscularis mucosa with oedema of the submucosaand the mucosa replaced by granulation tissueintensely infiltrated by lymphocytes, plasma cells andeosinophils (Figure 3). Sigmoidoscopy rectal biopsyand upper gastrointestinal endoscopy with biopsyfrom the second part of duodenum were normal.

The Fellowship of Postgraduate Medicine, 1989

Correspondence: R.H.R. Park, M.B., Ch.B., M.R.C.P.,Gastroenterology Unit, The Royal Infirnary, Glasgow G3 12ER, UK.Accepted: 26 July 1988

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Figure 1 String like slough passed per rectum.

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Figure 2 Barium meal and follow through.

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Figure 3 Jejunal biopsy (haematoxylin and eosin x 50).

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CLINICAL REPORTS 47

By the fourth week, at the time of transfer, herserum albumin had dropped to 14 g/l due to a severeprotein losing enteropathy measured at 710 ml/day(normal <25 ml/day by the 5"CrC13 method). A6-week course of intravenous nutrition with bowelrest, high dose steroids and albumin infusions failed toproduce any clinical response. She subsequentlydeveloped bilious vomiting due to proximal smallbowel strictures. In view of the obstructive symptomsand deteriorating clinical condition a laparotomy wasperformed at which the entire small intestine lookedabnormal with slight serosal hyperaemia, absence ofperistaltic activity and a thickened mesentery withenlarged lymph nodes. Approximately 60% of thesmall intestine from proximal jejunum to distal ileumwas removed. The resected specimen showed con-tinous ulceration throughout its length (Figure 4). Onthe luminal surface there was a confluent fibrinopuru-lent pseudo-membrane which was partially detachedin places. No doubt this was the source of thestring-like slough passed per rectum early on in thecourse of the disease. The histology was similar to thejejunal biopsy. In particular there was only minimaltransmural inflammation, no granulomas in the bowelwall and no evidence ofvascular or neoplastic disease.At the distal resection edge the villous architecture wasalmost normal and the inflammatory changes wererelatively mild. In this distal area eosinophils wereparticularly numerous and there was also apoptoticcell damage.Her clinical condition improved slightly but 7 weeks

post-resection she died of a pulmonary embolus.Post-mortem examination failed to provide any addi-tional information. Histology of the small intestinewas unchanged. There were no significant abnor-malities in the renal or hepatic histology.

DiscussionThis case appears unique in several of its features. Theacute onset of almost complete mucosal ulceration ofthe whole of the small bowel in combination with askin rash, hepatitis and marrow suppression all sug-gest a toxic insult. Extensive investigations failed toreveal any infective agent and there was no clinical norhistological evidence of pre-existing enteropathy,inflammatory bowel disease or vascular insufficiency.The small bowel ulceration persisted and led to severeincapacity and multiple strictures while the otherfeatures settled rapidly. This clinical picture has notbeen described before and raises the possibility of anidiosyncratic drug reaction.

There is no doubt that exposure to non-steroidalanti-inflammatory agents took place. There is alsopathological evidence to support the possibility ofdrug involvement including the apoptotic cell damageand the presence of numerous eosinophils in the distalileum which had not undergone frank ulceration.6'7Unfortunately as the patient had taken three differentdrugs shortly before her presentation it is difficult toimplicate one drug. However, the Committee onSafety ofMedicines has received one report ofenteritis(although not extensive small bowel ulceration), withdiclofenac sodium, and many reports of various othergastrointestinal side effects with diclofenac sodium,suprofen, chlormezanone and paracetamol (Commit-tee on Safety of Medicines - personal communica-tions). The exact aetiology of this fatal case remainsunknown. Although drug-related disease remains aconceivable cause, the low back pain may haveindicated the onset of the disease process before theintroduction of the drugs.

This case has been reported to the Committee onSafety of Medicines.

Figure 4 Resected small bowel.

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References

1. Jewell, D.P. Ulcerative enteritis. Br Med J 1983 287:1740-1741.

2. Mills, P.R. Small intestine ulceration. Curr Opin Gast-roenterol 1985, 1: 254-256.

3. Glynn, M.J., Pendower, J., Shousha, S. & Parkins, R.A.Recurrent bleeding from idiopathic ulceration of smallbowel. Br Med J 1983, 288: 975-976.

4. Thomas, W.E.G. & Willamson, R. Idiopathic ulcerationof the small bowel. Br Med J 1984, 288: 1835.

5. Davies, D.R. & Brightmore, T. Idiopathic and druginduced ulceration of the small intestine. Br J Surg 1970,57: 134-139.

6. Rampton, D.S. Non-steroidal anti-inflammatory drugsand the lower gastrointestinal tract. ScandJ Gastroenterol1987, 22: 1-4.

7. Sommerville, K.W. & Hawkey, C.J. Non-steroidal anti-inflammatory agents and the gastrointestinal tract. Post-grad Med J 1986, 62: 23-28.

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