SMALL-INTESTINAL INJURY IN WOMEN WHO HAVE HAD PELVIC RADIOTHERAPY

1471

careful follow-up of the coagulation defects is essential in order to clarify the role of D.I.C. in severely ill infants. The resulting coagulation profile seems to be of prognostic value and may also be used as a baseline to evaluate therapeutic procedures such as systemic heparinisation, exchange transfusion, and the infusion of fresh frozen plasma or coagulation factor concentrates. We thank Prof. A. L. Clark and Dr D. R. L. Davies for their assistance in the early part of the study; the consultant pxdiatricians of the Birmingham Maternity Hospital who allowed us to investigate their patients; the nurses of the special-care baby unit for preparing infants’ heels before blood collection; and the United Birmingham Hospitals Endowment Research Fund for a research grant to J. S.

Requests for reprints should be addressed

to

J. S.

REFERENCES 1.

Chessells, J. M., Wigglesworth, J. S. Archs

Dis. Childh.

1971, 46,

253. 2. 3. 4. 5. 6.

Chadd, M. A., Elwood, P. C., Gray, O. P., Muxworthy, S. M. Br. med. J. 1971, iv, 516. Hathaway, W. E., Mull, M. M., Pechet, G. S. Pediatrics, Springfield, 1969, 43, 233. Whaun, J. M., Oski, F. A. Can. med. Ass. J. 1972, 107, 963. Abildgaard, C. F. J. Pediat. 1969, 74, 163. Chessells, J. M., Wigglesworth, J. S. Archs Dis. Childh. 1970, 45, 539.

Oski, F. A., Naiman, J. L. Hematologic Problems in the Newborn. Philadelphia, 1972. 8. Gray, O. P., Ackerman, A., Fraser, A. J. Lancet, 1968, i, 545. 9. Hambleton, G., Appleyard, W. J. Archs Dis. Childh. 1973, 48, 31. 10. Cade, J. F., Hirsh, J., Martin, M. Br. med. J. 1969, ii, 281. 11. Hardisty, R. M., Ingram, G. I. C. Bleeding Disorders. Oxford, 7.

1965. 12. Dormandy, K. M., Hardisty, R. M. J. clin. Path. 1961, 14, 543. 13. Dacie, J. V., Lewis, S. M. Practical Hœmatology. London, 1968. 14. Stuart, J., Barrett, B. A., Prangnell, D. R. Unpublished. 15. Stefanini, M. Am. J. clin. Path. 1950, 20, 233. 16. Wolf, P. J. clin. Path. 1953, 6, 34. 17. Sharp, A. A., Eggleton, M. J. ibid. 1963, 16, 551. 18. Owren, P. A., Aas, K. Scand. J. clin. Lab. Invest. 1951, 3, 201. 19. Merskey, C. in Human Blood Coagulation, Hæmostasis and Thrombosis (edited by R. Biggs); p. 444. Oxford 1972. 20. Bleyer, W. A., Hakami, N., Shepard, T. H. J. Pediat. 1971, 79, 838.

SMALL-INTESTINAL INJURY IN WOMEN WHO HAVE HAD PELVIC RADIOTHERAPY A. NEWMAN J. KATSARIS L. M. BLENDIS M. CHARLESWORTH L. H. WALTER Medical Research Council Gastroenterology Unit, and Departments of Gastroenterology and Radiology, Central Middlesex Hospital, and Department of Radiotherapy, Hammersmith Hospital, London

17 women who had had radiotherapy for pelvic malignancy were studied. 12 of them had noted a permanent change in their bowel habit, ranging from abandonment of the use of laxatives to frequent bouts of diarrhœa necessitating a change in life-style. 16 of 17 patients had abnormal cholyl-glycine-1-[14C] breath tests, including all 12 with symptoms. 8 of the 11 small-bowel X-rays were abnormal, but only 1 of 13 rectal biopsies showed changes of inflammation and another showed vascular thickening, which is regarded as characteristic of radiation damage to the gut. No subject had noted blood in her stools. It is concluded that the alteration in stool habit and the interruption of enterohepatic circulation are caused by radiation

Summary

to the small bowel and that such injury is an almost invariable accompaniment to all forms of

injury

pelvic radiotherapy. Introduction THE small intestine is extremely radiosensitive and may be injured by radiotherapy directed at the pelvic organs. In published reports, estimates of the frequency of small-bowel injury range from 0.5 to 23% of irradiated patients in hospital for treatment of the serious manifestations of radiation enteropathy 2-S Although a spectrum of pathological change has been associated with radiation injury,6 in many cases the symptoms are due either to the creation of a blind-loop syndrome from strictures or fistulae, or to damage to active transport processes in the ileum, which lies in the pelvis and is invariably heavily irradiated. In both situations the enterohepatic circulation (E.H.C.) of bile-salts is interrupted. This circulation may be involved in the pathogenesis of the clinical syndromes. A breath test has been described as a means of assessing the integrity of the E.H.C., and in view of its simple, non-invasive nature it is well suited to epidemiological studies.7,8 We have determined the frequency of small-bowel injury from pelvic irradiation by inquiring about changes in bowel habit and by performing breath tests on a randomly selected group of women who had been irradiated in the past, and we have acquired other information about the gastrointestinal tracts of these patients.

Patients and Methods Patients attending a gynaecology clinic who had received intracavitary radium, external X ray, telecobalt radiotherapy, alone or in combination, and who were judged to be free of recurrent malignancy, were invited to parNone had sought medical help for gastroticipate. Of 20 consecutive patients seen intestinal problems. between January and July, 1973, 17 agreed to participate in the study after it had been fully explained to them. Of the three who declined, one did so because of advanced age and the other two because of anxiety. The patients were given a formal questionary to assess any change in stool habit which may have occurred during or subsequent to radiotherapy. The scoring on this questionary was: O=no change; +=formerly constipated and now no longer so, but not suffering from diarrhoea; ++==2-3 loose, painless motions per day with occasional episodes of several days’ duration of troublesome diarrhoea; + + + =frequent troublesome bouts of diarrhoea necessitating an alteration in life-style. A complete physical examination was performed. The subjects then had a cholyl-glycine-l-[14C] breath test performed in a standard manner with breath monitored at intervals for three hours after the ingestion of 5 µCi of cholyl-glycine-l- [14C]] -ethanol (specific activity 19 mCi per mmol) given just before breakfast. Since only bacteria can deconjugate bile-acids, the appearance of

14C-labelled carbon dioxide in the breath indicates abnormal between bacteria and bile-salts. Normally the upper intestine is nearly sterile and the conjugated bile-acids are actively reabsorbed in the terminal ileum, so that only a small amount of the administered label appears in the exhaled breath. In blind-loop syndromes there is bacterial contamination of the small intestine, while in ileal dysfunction there is interference with active bileacid reabsorption. In either situation a large amount of contact

1472 the administered specific activity appears in breath as 14C-labelled carbon dioxide. In our experience a peak exhalation of more than 0-7 x 10-3% of the administered specific activity per mmole carbon dioxide during a threehour test is abnormal. The subjects were then invited to attend for smallintestinal X-rays, sigmoidoscopy and rectal biopsy, measurement of serum folate and vitamin-B12 levels and haemoglobin, and assessment of peripheral-blood-cell morphology. 13 of the 17 agreed to return for some or all of these studies. The X-rays and biopsies were interpreted without knowledge of the subject’s questionary or breathtest scores.

Results

The 17

subjects were in good general condition; patient was found to have nephrolithiasis of an undetermined type (tables i and II). During the course of radiotherapy 12 subjects had had diarrhoea, which was occasionally bloody; they passed from three to twenty stools per day. In all

one

this diarrhoea subsided within six weeks of stopping therapy. However, after an interval of from six weeks to five years, 12 of the subjects noted an increase in bowel frequency, which, though not sufficiently severe for them to seek medical help, was a definite, consistent alteration in their stool habits. During the interval between the initial bout of diarrhoea and the permanent increase in stool frequency, bowel habit was as it had been before

cases

The presence, onset, and severity of the permanent change in stool frequency did not depend on the nature of the lesion treated, the type of radiation received, the dose administered, or whether or not surgery was performed. There was no correlation between the severity of the early diarrhoea and the degree of permanent alteration of stool habit present at the time of our study. 16 of the 17 subjects had abnormal breath tests, including all 12 with symptoms of increased bowel frequency. Only subject 9 was normal. Of 13 subjects tested, all had normal haemoglobin

radiotherapy.

levels, peripheral-blood-cell morphology, and serum folate and vitamin-B12 levels. Of 11 small-bowel X-ray examinations, abnormalities were noted in 8. Subjects 3 and 12 had definite dilatation of the small intestine with loops wider than 3 cm. in diameter. Subject 4 had an irritable ileum, which, despite determined efforts, could not be made to retain barium. Subjects 2, 7, 13, 14, and 16 had coarse ileal mucosal folds measuring more than 2 mm. in diameter. The upper limit of normal for these folds is 1.5 mm.9 On sigmoidoscopy, in 8 cases the rectum had an oedematous mucosa with absent vascular pattern. In the remaining 5 cases the rectum was normal. Rectal biopsies were normal in 9 cases and showed

inflammatory changes the muscularis

TABLE I-DETAILS OF THERAPY

*

Prophylactic irradiation of ovaries

for carcinoma of breast.

TABLE II-INTESTINAL COMPLICATIONS

in

mucosse

subject 7, hypertrophy of subjects 3 and 6, and

in

1473

vascular thickening suggestive of radiation injury6 in

subject

2.

Discussion Radiation injury to the intestines may be classified by reference to time of onset of symptoms and to anatomical site of injury. Acute injury, occurring during or shortly after therapy, is characterised by diarrhoea, tenesmus, bloody diarrhoea, nausea, and vomiting. It may have its origin in the colon or in the small intestine and has been extensively studied In both clinically and in experimental animals." most cases in which sublethal doses of radiation have been administered the symptoms of acute enteritis subside and the histology of the involved gut returns towards normal." 12 of our subjects had an acute postradiation intestinal syndrome, which in all cases cleared within six weeks of stopping radio-

therapy. Chronic radiation injury has been less well studied and is believed to occur in a minority of irradiated patients.’ Our study shows that in subjects who have received pelvic radiotherapy late radiation damage often develops with permanent alteration of bowel habit and an interruption of the E.H.C. Our data support the idea that both of these phenomena originate in the small intestine. Convincing evidence of chronic large-bowel injury was lacking in this series, since only 1 of 13 patients had an inflamed rectal mucosa and none had blood in her stools. Inflammation of the colon or rectum causes neither alteration of the E.H.c. nor abnormal The breath test does not small-intestinal X-rays. between distinguish stagnant loops or ileal damage, but we believe one or both of these mechanisms must be invoked to explain our findings. Another possible but unlikely cause of abnormal breath tests in these subjects would be intestinal hurry.’ Although bile-acid wasting and steatorrhoea

stones,14 and up to two-thirds of them may be expected to have hyperoxaluria .15 All the subjects we studied were contacted in a gynxcology clinic, where they were attending routine follow-up visits after being successfully treated for pelvic malignancy. We excluded any women with evidence of recurrent malignancy, since it would have been difficult to separate symptoms of radiation from those of malignant recurrence. We are not aware of any factors that would make this a less than random grouping of irradiated women, and the presence in our series of women with no symptoms who had abnormal breath tests supports our suggestion that interruption of the E.H.C. is a common

injury

sequel

to

irradiation.

We thank the gynaecologists of the Central Middlesex Hospital for allowing us to study their patients. Requests for reprints should be addressed to A. N., Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada.

experimentally

may

occur

secondary

to

a

motility disturbance,

REFERENCES

Desjardins, A. U. Am. J. Roentg. 1931, 26, 151. Requarth, W., Roberts, S. Archs Surg., Chicago, 1956, 73, 682. Yuen, B. H., Boyes, D. A. Am. Surg. 1970, 36, 642. Calame, R. J., Wallach, R. C. Surgery Gynec. Obstet. 1967, 125,

1. 2. 3. 4.

39. 5. Aune, E. F., White, B. V. J. Am. med. Ass. 1951, 147, 831. 6. Rubin, P., Casarett, G. W. Clinical Radiation Pathology; vol. I, p. 193. Philadelphia, 1968. 7. Fromm, H., Hofmann, A. F. Lancet, 1971, ii, 621. 8. Sherr, H. P., Sasaki, Y., Newman, A., Banwell, J. G., Wagner, H. N., Hendrix, T. R. New Engl. J. Med. 1971, 283, 656. 9. Mason, G. R., Dietrich, P., Friedland, G. W., Hanks, G. E. Clin. Radiol. 1970, 21, 232. 10. Sullivan, M. F. Gastrointestinal Radiation Injury. Amsterdam, 1968. 11. Trier, J. S., Browning, T. H. J. clin. Invest. 1966, 45, 194. 12. Fromm, H., Thomas, P. J., Hofmann, A. F. Gastroenterology, 1973, 64, 1077. 13. Duncan, W., Leonard, J. C. Q. Jl Med. 1965, 34, 319. 14. Heaton, K. W., Read, A. E. Br. med. J. 1969, iii, 494. 15. Dowling, R. H. J. clin. Path. 1973, 5, 59.

RECURRENT ACUTE RENAL FAILURE INDUCED BY PHENAZONE HYPERSENSITIVITY

a

study 12 of tests of terminal ileal function did not show that such cases were accompanied by positive breath tests. The pathological lesions of chronic radiation injury6 in the small bowel are varied, consisting of fistulous communication between affected bowel and neighbouring viscera; small-vessel endarteritis with intestinal fibrosis, ischsemic strictures, or mucosal ulcers; partial villous atrophy; free perforations; and lymphatic obstruction with lymphangiectasia. Malabsorptive disorders in irradiated patients mirror this spectrum of pathological change and range in importance from moderate steatorrhoea in patients with stagnant loops or reduced absorbing surface to severe steatorrhcea and intestinal protein loss in patients with lymphangiectasia.13 It is important to recognise the cause of malabsorption, since rational forms of therapy are available for some forms of illness-e.g., fat restriction for lymphatic obstruction, cholestyramine for the damaged ileum, and broadspectrum antibiotics for blind-loop syndromes not amenable to surgical correction. The nutritional importance of subclinical E.H.C. interruption is not yet known. Patients with this abnormality have an increased frequency of gallrecent

JOAQUIN ORTUNO Service

JULIO BOTELLA

of Nephrology, Clinica Puerta Spain

de

Hierro, Madrid,

32-year-old male patient had three episodes of acute renal failure between January, 1968, and January, 1970. He recovered from the attacks, but their cause was not determined. Summary

A

The results of renal biopsies performed on two occasions were compatible with acute tubular necrosis. In

October, 1970, another episode similar to the preones began but did not progress to established renal failure. Each episode was precipitated by phenazone hypersensitivity. Since the discovery of this allergy the patient has been completely well. The possibility of drug allergies should always be investigated in cases of acute renal failure of unknown vious

origin. Introduction ACUTE

patient.1 only five

renal failure rarely recurs in the same A review of published reports uncovered cases with two and one case with three