1122

Questionable Routines

IS JEJUNAL BIOPSY REALLY NECESSARY IN COW’S MILK PROTEIN INTOLERANCE? ERIC SUMITHRAN

N. IYNGKARAN

Departments of Pathology and Pœdiatrics, Medical Faculty, University of Malaya, Kuala Lumpur, Malaysia

Thirty-nine infants suspected of having cow’s milk protein intolerance (C.M.P.I.) were investigated, and jejunal biopsies were performed before and after challenge with cow’s milk. Thirty patients had significant jejunal mucosal damage after milk challenge, but symptoms of diarrhœa and vomiting developed in only twenty-two. The patients with symptoms were subsequently managed on a diet free from cow’s milk until tolerance developed. However, the eight infants without symptoms (but with jejunal mucosal damage) made satisfactory clinical progress, with adequate weight-gain, on a diet of cow’s milk. Repeat jejunal biopsy specimens from two of these patients showed that there had been a definite improvement since the immediate post-challenge biopsy specimens were taken. Most patients with C.M.P.I. who need to be

Summary

treated with a diet from which cow’s milk has been eliminated may be detected by clinical means alone, and the remainder may continue on a cow’s milk diet unless or until symptoms develop. There seems to be no clinical justification for routine jejunal biopsy in infants in whom C.M.P.I. is suspected.

1. Kunin, C. M., Tupasi, T., Craig, W. A. Ann. intern. Med. 1973, 79, 255. 2. Achong, M. R., Hauser, B. A., Krusky, J. L. Can. med. Ass. J. 1977, 116,

256.

Wilfert, C. M., Cate, T. R., Osterhout, S. J. Am. med. Ass. 1977, 237,2819. 4. Jones, S. R., Pannell, J., Barks, J., Yanchiuk, V. A., Bratton, T., Trowne, R., McRee, E., Smith, J. W. Am. J. med. Sci. 1977, 273, 79. 5. Scheckler, W. E., Bennett, J. V., J. Am. med. Ass. 1970, 273, 79. 6. Roberts, A. W., Visconti, J. A. Am. J. hosp. Pharm. 1972, 29, 828. 7. Finland, M. Ann. intern, Med. 1972, 76, 1009. 8. Price, D. J. E., Sleigh, J. D. Lancet, 1970, ii, 1213. 9. Garrod, L. P. Br. med. J. 1975, iv, 561. 10. Veterans Administration Committee. J. Am. med. Ass. 1977, 237, 1134. 11. Chodak, G. W., Plaut, M. E. Archs Surg. 1977, 112, 326. 12. Veterans Administration Committee. J. Am. med. Ass. 1977, 237, 1003. 13. Study Group on Antimicrobial Drugs. Lancet, 1977, ii, 1351. 3. Castle, M.,

14. See ibid. 1976, i, 519. 15. Committee Report. Circulation, 1972,46,3. 16. Burke, J. F. Postgrad. Med. 1975, 58, 65. 17. McLean, L. D. Can. J. Surg. 1975, 18, 243. 18. Roy, A. D. J. Antimicrob. Chemother. 1976, 2, 233. 19. Michel, J., Sacks, T., Simchen, E. Israel J. med. Sci. 1977, 13, 549. 20. Ledger, W. J., Gee, C., Lewis, W. P. Am. J. Obstet, Gynec. 1975, 121, 1038. 21. Cruse, P. J. E., Foord, R. Archs Surg. 1973, 107, 206. 22. Burke, J. F. Surgery, 1961, 50, 161. 23. Alexander, J. W., Altemeier, W. A. Surg. Gynec. Obstet. 1965, 120, 243. 24. Stokes, E. J., Waterworth, P. M., Franks, V. Br. J. Surg. 1974, 61, 739. 25. Conte, J. E., Cohen, S. N., Robb. B. B. Ann. intern. Med. 1972, 76, 943. 26. Griffiths, D. A., Shorey, B. A., Simpson, R. A., Speller, D. C. E., Williams, N. B. Lancet,

27. 28.

1976, ii, 325.

Keighley, MR. B. Br. J. Surg. 1977, 64, 315. Downing, R., McLeish, A. R., Burdon, D. W., Alexander-Williams, J., Keighley, M. R. B. Dis. Colon Rectum. 1977, 20, 401. 29. Achong, M. R. Can. med. Ass. J. 1976, 115, 841. 30. McGowan, J. E. Jr., Finland, M. J. infect. Dis. 1974, 130, 165. 31. Ayliffe, G. A. J. J. Antimicrob. Chemother. 1975, 1, 255. 32. Veterans Administration Committee. J. Am. med. Ass. 1977, 237, 1001.

INTOLERANCE of cow’s milk protein in infants results in failure to thrive and diarrhoea with or without vomiting and is associated with mucosal damage in the small intestine. This syndrome appears within 3 months of birth and disappears by about the age of 1 year.’ The enteropathy is believed to be the result of an immunological reaction occurring in the small-intestinal mucosa after ingestion of cow’s milk, but nothing is known about the sequence or the nature of such a reaction. Cow’s milk protein intolerance (c.M.p.l.) also seems to be important in prolonging diarrhaea associated with enteric infections in infants.2

The diagnosis of C.M.P.I. is based on the clinical criteria described by Goldman et a1.3: (1) remission of symptoms after elimination of cow’s milk from the diet; (2) relapse within 48 hours of milk challenge; (3) reactions to three such challenges which are positive and have a similar onset, duration, and clinical features. However, some workers regard these criteria as being rigid, impractical, and leading to underdiagnosis of this disorder :’.5 Moreover frequent milk challenges are

required. Others have advocated the use of jejunal biopsy in the diagnosis of C.M.P.I.4.5 This is based on the histological demonstration of mucosal damage in the proximal jejunum after challenge with cow’s milk. At least two biopsies need to be done-one while the infant is recovering on a diet free of cow’s milk and another after challenge with cow’s milk. Many paediatricians question the need for intestinal biopsies in this transient condition. Although intestinal biopsy is a relatively safe procedure, the infant is subjected to some discomfort, as well as to the hazards of radiation. Moreover the skills of a doctor trained in obtaining intestinal-biopsy specimens and support of a pathology laboratory are needed. In the University of Malaya, we have been using a clinical and histological approach in the diagnosis of C.M.P.I.2 We have analysed our data to determine whether we can dispense with jejunal biopsies.

PATIENTS AND METHODS

1-9 weeks were studied. They all on a diet of cow’s milk and presented with failure to thrive and diarrhcea. All were investigated to exclude lactose intolerance, enteric infection, and immune deficiency. They subsequently made good progress when their diet was changed to soya-bean or breast milk. Symptoms disappeared and they gained weight. After 6-8 weeks the infants were admitted for challenge with cow’s milk. A "baseline" jejunal biopsy was taken with a paediatric Watson capsule, this was followed by an oral 5 ml dose of cow’s milk. In the absence of symptoms, the dose of milk was doubled hourly for the first 4 h, and subsequently 3-hourly until total daily fluid requirements were met. A second jejunal biopsy specimen was taken 24 h after the introduction of cow’s milk, irrespective of the presence or absence of symptoms. Infants with symptoms were changed to soya-bean or breast milk, while those without symptoms continued on a diet of cow’s milk unless or until symptoms developed. The weight-gain of all infants was carefully monitored. The biopsy specimens were examined under a dissecting microscope as well as histologically without the technician know-

Thirty-nine patients aged

were

1123

ing whether they were obtained pre-challenge or post-chailenge. A mucosal imprint was made to detect Giardia lamblia. RESULTS

Thirty patients had significant jejunal mucosal damage after milk challenge (table I). Pre-challenge biopsy specimens from seventeen of these infants were normal, and in thirteen there was evidence of mild parTABLE I-HISTOLOGICAL ABNORMALITIES PRE-CHALLENGE AND POST-CHALLENGE

P.v.A.=partial villous atrophy. s.v.A.=subtotal villous atrophy. tial villous atrophy. Post-challenge biopsy specimens from the thirty infants showed significant reduction in villous height and damage to the villous epithelium, as shown by stunting of the epithelial cells, and an increase in lymphocytic infiltration in the lamina propria. In two infants the mucosa was completely flat (subtotal villous atrophy). In some cases the mucosal damage was patchy, with severely damaged areas alternating with areas of slight damage. The damage, however, in all cases, was obvious, and there was no difficulty in distinguishing between pre-challenge and post-challenge specimens. In nine infants no change was observed in the mucosa after milk challenge. Only eleven infants (37%) had symptoms (vomiting and diarrhoea) within 48 h of milk challenge (table 11), TABLE 11-HISTOLOGICAL ABNORMALITY AND SYMPTOMS

the extent of mucosal damage seems to determine whether or not symptoms develop in the patient. In those who react strongly, there is pronounced partial villous atrophy or subtotal villous atrophy, and vomiting and diarrhoea develop within 48 h. Such cases fulfil Goldman’s criteria. Infants at the other end of the scale have histological evidence of partial villous atrophy (often patchy) but no symptoms. C.M.P.I. may be diagnosed clinically in almost 75% of cases. Half these cases present with acute symptoms (within 48 h) while in the other half symptoms develop in 1-2 weeks. In about a quarter of C.M.P.I. cases symptoms do not develop on reintroduction of cow’s milk, and these cases can only be diagnosed by pre-challenge and post-challenge jejunal biopsy. However, these infants without symptoms make satisfactory clinical progress with adequate weight-gain while on a cow’s milk diet. Although in theory continued antigen challenge would be expected to cause further damage to the smallintestinal mucosa, the mucosa seems to recover despite the continued intake of cow’s milk. About 75% of patients with C.M.P.I. who need to be treated with a cow’s milk-free diet until tolerance develops (between 31 and 58 weeks of age)6 can be diagnosed by clinical means alone, and the remainder may continue on cow’s milk unless or until symptoms develop. Thus there seems to be no clinical justification for routine jejunal biopsy in infants in whom c.M.p.l. is sus-

pected. Requests

Pathology,

tor

reprints should be addressed to E. S., Department of Faculty, University of Malaya, Kuala Lumpur,

Medical

Malaysia. REFERENCES 1.

Kuitunen, P., Rapola, J., Savilahti, E. Visakorpi, J. K. Acta pœdiat. scand. 1973, 62, 585. 2. Iyngkaran, N., Robinson, M. J., Sumithran, E., Lam, S. K., Puthucheary, S. D., Yadav, M. Archs Dis. Childh. (in the press). 3. Goldman, A. S., Anderson, D. W., Sellars, W. A., Saperstein, S. Kniker, W. T., Halpern, S. R. Pediatrics, 1963, 32, 425. 4. Walker-Smith, J. Archs Dis. Childh. 1975, 50, 347. 5. Shiner, M., Ballard, J., Brook, C. G. D., Herman, S. Lancet, 1975, ii, 1060. 6. Kuitunen, P., Visakorpi, J. K., Savilahti, E., Pelkonen, P. Archs Dis. Childh.

1975, 50, 351.

Round the World these included all eight infants with severe jejunal mucosal damage. Six more infants (20%) presented with diarrhoea before the end of the week, and over the next week symptoms developed in a further five patients. None of the remaining eight (27%) patients on cow’s milk followed up over the next 3 months had any symptoms, and all had adequate weight-gain. In two of these infants, a repeat jejunal biopsy was done while they were on cow’s milk, and the jejunal mucosa in both cases surprisingly showed evidence of only slight partial villous atrophy. This showed that there had been a definite improvement since the immediate post-challenge biopsy specimens were taken. CONCLUSIONS

Milk

challenge produces

the small-intestinal

mucosa

wide range of damage in of infants with C.M.P.L, and a

United States HEALTH INSURANCE

MEDICAL costs have risen to such a peak here that the prihealth insurance companies, despite the ever-increasing insurance premiums, have found their profits squeezed almost out of existence, and some firms are getting out of health insurance altogether, just as they got out of medical-malpractice insurance. Opinion in the private-business world seems to be that a national health insurance scheme might in fact be less costly and no more inefficient than private enterprise in the medical field. As this has long been the opinion ofthe unions, too, the outlook for opponents of a national health scheme-including those private companies in health-insurance and the Blue Cross and Blue Shield organisations-is rather grim. The proposals for cutting medical costs all seem rather trivial in relation to the size of the problem, especially when they are considered alongside the still formidable burden of medical malpractice and the great increases in funds needed to support vate

Is jejunal biopsy really necessary in cow's milk protein intolerance?

1122 Questionable Routines IS JEJUNAL BIOPSY REALLY NECESSARY IN COW’S MILK PROTEIN INTOLERANCE? ERIC SUMITHRAN N. IYNGKARAN Departments of Pathol...
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