BLOOD GROUPS AND THE INTESTINE

Editorial, Lancet (Dec.3, 1966)

COMMENTS

Intestinal alkaline phosphatase is an enzyme manufactured in the small intestine, which has the primary function of splitting cholesterol and long chain fatty acids. As the article states, numerous reports have associated a lack of secretion of this particular enzyme in individuals with type A blood. Later studies suggested that it was this inability to break down fat, which in part predisposed type A to both higher levels of cholesterol and increased incidence of heart attack, both of which have indeed been associated with type A over the other blood groups. Additional research showed that the amino acid phenylalanine was almost 100% effective in inhibiting alkaline phosphatase, and indeed our research has shown that many common sources of phenylalanine, including yams and sweet potatoes, cause a marked increase in the production of indican (a measurement of bowel putrefaction) in our type A patients.

Later studies showed that type A not only secreted almost no alkaline phosphatase in their intestines, but whatever little they did secrete was in and of itself inactivated by their own A antigen! Thus, we have here one of the strongest indications for the long term benefit of a low-fat diet in type A, both with regard to the susceptibility to cardiovascular disease, and (although not mentioned here) their additional susceptibility to cancer. Following the type A eating plan, with its emphasis on a low-fat diet and the avoidance of foods high in phenylalanine, is the best method to maximize digestive efficiency in type As, lower their level of intestinal dysfunction, and to influence their susceptibility to cardiovascular disease.

The descriptions by AIRD and his colleagues of the associations of blood group O with peptic ulcer (1) and of blood group A with gastric cancer (1) have been confirmed by others;(3,4) and the observations have been extended to cover associations of blood group A with pernicious anemia,(1) and with salivary tumors.(6,7) Moreover, inability to secrete ABH blood group substances in the gastrointestinal mucus (a genetically determined characteristic) has been shown to be associated with peptic ulcer (11,9) and possibly with gastric cancer and pernicious anemia.(9,10) The causes of these associations are not known. But a simple protective action of the ABO(H) blood group substances in the mucus seems an unlikely explanation, because the total titer of blood group substance is the same for ABH secretors as for non-secretors (in non-secretors Lewis substance is substituted for the A, B, and H mucopolysaccharides). Furthermore a blood group effect on peptic ulcer can be shown in non-secretors alone. But the large quantities of blood group mucopolysaccharides found in the gastrointestinal mucosa suggest that they have some function.(11-13)

Since the prevalence of both pernicious anemia and gastric cancer is higher in individuals of blood group A, and duodenal ulcer in those of blood group O, a hypothesis relating blood group effects to acid secretion naturally followed. Early work seemed to confirm that acid output tended to be greater in blood group O than in blood group A subjects,(14,15) but the observed differences, which were in elderly subjects, could well have been due to gastric atrophy (which would, by analogy with pernicious anemia, probably be more frequent and severe in blood group A than in blood group O individuals). Studies in younger healthy subjects have given conflicting results. In one series (16) gastric secretory potential, as measured by serum-pepsinogen levels, differed little between blood groups O and A; acid output was higher in blood group O subjects. In another study (17) however, gastric acid output was found to be higher in individuals of blood group O than in those of blood group A and slightly but not significantly greater in non-secretors than secretors.

Another approach has been to study possible associations between ulcer symptoms and prognosis and the ABO blood group and secretor characteristics. Although earlier work was inconclusive, LANGMAN and DOLL (8) found a higher frequency of blood group O among patients with bleeding gastric or duodenal ulcers than among those with non-bleeding ulcers. Non-secretors seemed more liable to need operation for ulcer, though blood group did not seem to have any striking effect on likelihood of operation, nor did secretor status seem to influence the likelihood of hemorrhage. The association of blood group O with hemorrhage has been confirmed by others,(19) and the strength of the association of blood group O with liability to ulcer rather than with bleeding clearly must be reassessed. All surveys of blood groups in ulcer patients so far reported have been largely retrospective, and since the individuals for whom blood group data are readily available are those with bleeding ulcer, a strong bias in favor of blood group O is introduced. The same kind of error may well be present in data collected on secretor status, and an unselected consecutive ulcer series will be required to solve these problems.

An intriguing blood group association with a serum isoenzyme of alkaline phosphatase has been described.(20) Serum alkaline phosphatase can be divided by starch-gel electrophoresis into two fractions, a faster moving component of liver or bone origin and a slower moving band probably derived from small intestine.(21) BECKMAN and his colleagues found that the frequency with which the slow-moving isoenzyme appeared in the serum was much affected by the subject's ABO blood group.(20) This observation has been confirmed (22-24) and it is now clear that the presence of the slow-moving band in the serum is affected by both ABO blood group and secretor status. It is rarely found in non-secretors, whatever their ABO blood group, but in secretors it can be distinguished progressively more often in those of blood groups A, AB, and O or B (the last two have equal effects).

A natural question is whether the blood group associations noted in disease could be more readily explained by relationships with the serum isoenzyme patterns of alkaline phosphatase. For instance, is absence of the slow-moving intestinal component in blood group A patients correlated with liability to gastric cancer? An association between peptic ulcer and the presence of the intestinal isoenzyme seems unlikely, because the disease is common in individuals of blood group O but not in those of blood group B. But simple comparisons of serum isoenzyme patterns in healthy individuals and patients with gastric cancer are impossible, for the presence or absence of the intestinal isoenzyme in the blood seems to depend greatly on diet. H. HARRIS and his colleagues (25) have shown that in normal individuals after an overnight fast the slow-moving component is present in considerably reduced amounts and can be clearly detected only in blood group O and B secretors. After normal meals the band of activity becomes much stronger in blood group O and B secretors; in blood group A secretors a weaker though distinct band appears; while in non-secretors little or none is detectable. Fat ingestion seems to stimulate the appearance of the intestinal isoenzyme in the serum. In blood group O or B secretors a synthetic breakfast of protein and carbohydrate did not seem to alter the serum alkaline phosphatase isoenzyme characteristics, but the substitution isocalorically of fat for part of protein and carbohydrate resulted in a notable increase in serum alkaline phosphatase activity. These findings agree well with independent observations showing that the administration of fat, but not protein or carbohydrate, increases the alkaline phosphatase content of human thoracic-duct lymph.(26,21) Further study of intestinal alkaline phosphatase should, however, increase our understanding of the relation between blood groups and alimentary function, and perhaps give us some idea of the physiological role of one form of alkaline phosphatase.

1. Aird, I., Bentall, H. H., Mehigan, J. A., Roberts, J. A. F. Br. Med. J. 1954, ii, 315.
2. Aird, I., Bentall, H. H., Roberts, J. A. F. ibid. 1953, i, 799.
3. Clarke, C. A., Cowan, W. K., Edwards, J. W., Howel Evans, A. W., McConnell, R. B., Woodrow, J. C., Sheppard, P. M. ibid. 1955, ii, 643.
4. Roberts, J. A. F. Br. Med. Bull. 1959, 15, 129.
5. Roberts, J. A. F. Br. J. Prev. Soc. Med. 1957, 11, 107.
6. Cameron, J. M. Lancet, 1958, i, 239.
7. Osborne, R. H., de George, F. V. Am. J. Hum. Genet. 1963, 15, 380.
8. Clarke, C. A., Edwards, J. V., Haddock, D. R. W., Howel Evans, A. W., McConnell, R. B., Sheppard, P. M. Br. Med. J. 1956, ii, 725.
9. Doll, R., Drane, H., Newell, A. C. Gut, 1961, 2, 352.
10. Callender, S. T., Denborough, M. A., Sneath, J. Br. Haematol. 1957, 3, 107.
11. Glynn, L. E., Holborow, E. J., Johnson, G. D. Lancet, 1957, ii, 1083.
12. Szulman, A. E. J. Exp. Med. 1960, 111, 785.
13. Szulman, A. E. ibid. 1962, 115, 977.
14. Koster, K. H., Sindrup, E., Seele, V. Lancet, 1955, ii, 52.
15. Sievers, M. L. Am. J. Med. 1959, 27, 246.
16. Niederman, J. C., Gilbert, E. C., Spiro, H. M. Ann. Intern. Med. 1962, 56, 564.
17. Hanley, W. B. Br. Med. J. 1964, i, 936.
18. Langman, M. J. S., Doll, R. Gut, 1965, 6, 270.
19. Merikas, G., Christakopoulos, P., Petropoulos, E. Am. J. Dig. Dis. 1966, 11, 790
20. Arfors, K. E., Beckman, L., Lundin, L. G. Acta Genet. Statist. Med. 1963, 13, 89.
21. Hodson, A. W., Larner, A. L., Raine, L. Clin. chim. Acta, 1962, 7, 255. 22. Arfors, K. E., Beckman, L., Lundin, L. G. ibid. p. 363.
22. Shreffl~r, D. C. Am. J. Hum. Genet. 1965, 17, 71.
23. Bamford, K. F., Harris, H., Luffman, J. E., Robson, E. B., Cleghorn, T. E. Lancet, 1965, i, 530.
24. Langman, M. J. S., Leuthold, E., Robson, E. B. Harris, J.. Luffman, J. E., Harris, H. Nature, Lond. 1966, 212, 4 1.
25. Keiding, N. R. Clin. Sci. 1964, 26, 29 1. 27. Blornstrand, R., Werner, W. Acta chir. Scand. 1965, 129, 177.