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85 LEADING ARTICLES The Blind-loop Syndrome THE LANCET LONDON 14 JANUARY 1967 STEATORRH(EA or macrocytic anemia often arise in c patients with abnormalities which may cause localised stasis of the gut contents-such as diverticula or surgically formed blind loops in the small intestine. Bacterial proliferation in the upper small intestine is a striking feature of this syndrome, for bacteria normally associated with the colonic flora cannot usually be found above the terminal ileum. A difficulty in the past has been how far mouth and throat organisms have con- taminated specimens of jejunal juice collected by intuba- tion, but Shiner’s capsule,l designed to collect samples without contamination, now seems to give a reliable assessment of the intestinal flora. Although a simple tube has given almost equally good results in a small comparative study, many workers will prefer the capsule, for it is easy to manipulate, and tube aspiration methods have sometimes yielded organisms which are certainly more typical of the mouth than the intestine. The steatorrhoea of the blind-loop syndrome is prob- ably due to malabsorption of dietary fat,3 although, in experimental animals with blind loops, lipids of endo- genous type may also appear in the faeces. 4 The malabsorption can be related to the effects of the metabolism of bile-salts by the bacteria. Normally a certain critical concentration of bile-salts seems necessary for micelle formation, and unconjugated bile-acids are likely to be much less efficient in promoting this action- for one thing, because of their lower solubility at the pH of the intestinal contents.5 A further mechanism causing steatorrhcea may be a direct toxic action of bile-acids on the mucosa, for they have been shown to inhibit the uptake and esterification of fats by in-vitro preparations of small intestine. s Free cholic and deoxycholic acids have been found in the intestinal fluid of rats with surgically formed stagnant loops of small intestine and in one patient with the blind-loop syndrome.3 Later work has confirmed this observation clinically, 7 a direct relation being noted between jejunal bacterial counts and steatorrhoea. Patients with bacterial counts of less than 100 X 10s per ml. had slight steatorrhcea, and no free bile-acids were found in the juice by thin-layer chromatography; but those with counts above 100 X 106 had pronounced 1. Shiner, M. Lancet, 1963, i, 532. 2. Kaiser, M. H., Cohen, R., Arteaga, I., Yawn, E., Mayoral, L., Hoffert, W. R., Frazier, D. New Engl. J. Med. 1966, 274, 500. 3. Donaldson, R. M. J. clin. Invest. 1965, 44, 1815. 4. Hoet, P. P., Eyssen, H. Gut, 1964, 5, 309. 5. Hoffman, A. F. Gastroenterology, 1965, 48, 484. 6. Dawson, A. M., Isselbacher, K. J. J. clin. Invest. 1960, 39, 730. 7. Tabaqchali, S., Booth, C. C. Lancet, 1966, ii, 12. steatorrhoea, and free bile-acids were easily demonstrated in the jejunal fluids. The organism most often cultured in this work was Escherichia coli, though Streptococcus facalis, proteus, and klebsiella were all found more than once in the 27 individuals studied. The ability of E. coli to deconjugate bile-salts is, however, doubtful, for SHINER and her co-workers,8 in their investigation of the jejunal flora, could not find a strain of E. coli which would split bile-salts. 15 of 25 strains of Bacteroides were capable of doing so; these were being obtained from jejunal fluid, although in previous investigations 9 SHINER et al. did not obtain this organism. This difference was probably due to the difficulties of culturing Bacteroides. Whether a lack of unsplit bile-salts in the lumen or a toxic action of free bile-acids on the mucosal cells is the main cause of the steatorrhoea is less certain. Deoxycholic acid seems in vitro to be toxic in concentrations of about 0-2 uzmoles per ml., while measurable effects can be found with cholic acid at about 1-0 ucmoles per my. 6 TABAQCHALI and BOOTH ’ found that such concentra- tions were reached in their patients with the blind-loop syndrome, but levels for toxicity found in vitro may not be applicable in vivo. Significantly perhaps, experiments in animals showed that the hydrolysis of fat was more or less unimpaired even when steatorrhrea was present; and the same was true in one patient with the blind-loop syndrome.3 Clinically the important fact is that sterilisa- tion of the intestine by antibiotics reduces bacterial counts and abolishes steatorrhrea. It is unfortunately . true, however, that relapse is inevitable if treatment l stops, so surgical removal of the blind loop is the only . reliable course. Macrocytic anaemia in the blind-loop syndrome seems almost always to be the result of vitamin-B12 deficiency, and high serum-folic-acid levels have even been found,10 probably because of synthesis by bacteria in the stagnant area.l1 Many bacterial strains seem able to take up vitamin B12 in vitro," 12 so that direct competition with the host for the available vitamin seems the likely cause of the deficiency. Vitamin B12 bound to intrinsic factor may also be removed by bacteria and, at least in rats, vitamin B12 taken up by bacteria cannot be removed by the host.12 A toxic effect of bacteria on the intestinal cells, reducing their capacity to absorb vitamin B12 and therefore making them less able to compete with bacteria, seems theoretically possible, though there is little experi- mental evidence for it. Experiments in rats have shown that absorption of the vitamin is unimpaired if bacterially contaminated intestinal pouches are not in continuity with the rest of the intestine.13 This and similar work 14 are much against a systemic toxic effect on absorption; furthermore, the structure of the jejunum does not seem to be altered by bacterial contamination, nor does the supernatant fluid obtained from bacterially con- 8. Drasar, B. S., Hill, M. J., Shiner, M. ibid. i, 1237. 9. Shiner, M., Waters, T. E., Gray, J. D. A. Gastroenterology, 1963, 45, 625. 10. Hoffbrand, A. V., Tabaqchali, S., Mollin, D. L. Lancet, 1966, i, 1339. 11. Doig, A., Girdwood, R. H. Q. Jl Med. 1960, 29, 333. 12. Donaldson, R. M., Corrigan, H., Natsios, G. Gastroenterology, 1962, 43, 282. 13. Donaldson, R. M. ibid. p. 271. 14. Hermann, G., Axtell, H. K., Starzl, T. E. ibid. 1964, 47, 61. B4

The Blind-loop Syndrome

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85LEADING ARTICLES

The Blind-loop Syndrome

THE LANCET

LONDON 14 JANUARY 1967

STEATORRH(EA or macrocytic anemia often arise in cpatients with abnormalities which may cause localised stasis of the gut contents-such as diverticula or

surgically formed blind loops in the small intestine. Bacterial proliferation in the upper small intestine isa striking feature of this syndrome, for bacteria normallyassociated with the colonic flora cannot usually be foundabove the terminal ileum. A difficulty in the past hasbeen how far mouth and throat organisms have con-taminated specimens of jejunal juice collected by intuba-tion, but Shiner’s capsule,l designed to collect sampleswithout contamination, now seems to give a reliableassessment of the intestinal flora. Although a simpletube has given almost equally good results in a smallcomparative study, many workers will prefer the capsule,for it is easy to manipulate, and tube aspiration methodshave sometimes yielded organisms which are certainlymore typical of the mouth than the intestine.The steatorrhoea of the blind-loop syndrome is prob-

ably due to malabsorption of dietary fat,3 although, inexperimental animals with blind loops, lipids of endo-genous type may also appear in the faeces. 4 The

malabsorption can be related to the effects of themetabolism of bile-salts by the bacteria. Normally acertain critical concentration of bile-salts seems necessaryfor micelle formation, and unconjugated bile-acids arelikely to be much less efficient in promoting this action-for one thing, because of their lower solubility at the pHof the intestinal contents.5 A further mechanism causingsteatorrhcea may be a direct toxic action of bile-acids onthe mucosa, for they have been shown to inhibit theuptake and esterification of fats by in-vitro preparationsof small intestine. s

Free cholic and deoxycholic acids have been found inthe intestinal fluid of rats with surgically formed stagnantloops of small intestine and in one patient with theblind-loop syndrome.3 Later work has confirmed thisobservation clinically, 7 a direct relation being notedbetween jejunal bacterial counts and steatorrhoea.Patients with bacterial counts of less than 100 X 10s perml. had slight steatorrhcea, and no free bile-acids werefound in the juice by thin-layer chromatography; butthose with counts above 100 X 106 had pronounced1. Shiner, M. Lancet, 1963, i, 532.2. Kaiser, M. H., Cohen, R., Arteaga, I., Yawn, E., Mayoral, L., Hoffert,

W. R., Frazier, D. New Engl. J. Med. 1966, 274, 500.3. Donaldson, R. M. J. clin. Invest. 1965, 44, 1815.4. Hoet, P. P., Eyssen, H. Gut, 1964, 5, 309.5. Hoffman, A. F. Gastroenterology, 1965, 48, 484.6. Dawson, A. M., Isselbacher, K. J. J. clin. Invest. 1960, 39, 730.7. Tabaqchali, S., Booth, C. C. Lancet, 1966, ii, 12.

steatorrhoea, and free bile-acids were easily demonstratedin the jejunal fluids. The organism most often culturedin this work was Escherichia coli, though Streptococcusfacalis, proteus, and klebsiella were all found more thanonce in the 27 individuals studied. The ability of E. colito deconjugate bile-salts is, however, doubtful, forSHINER and her co-workers,8 in their investigation of thejejunal flora, could not find a strain of E. coli whichwould split bile-salts. 15 of 25 strains of Bacteroideswere capable of doing so; these were being obtained fromjejunal fluid, although in previous investigations 9SHINER et al. did not obtain this organism. Thisdifference was probably due to the difficulties of culturingBacteroides.Whether a lack of unsplit bile-salts in the lumen or

a toxic action of free bile-acids on the mucosal cells is themain cause of the steatorrhoea is less certain. Deoxycholicacid seems in vitro to be toxic in concentrations of about0-2 uzmoles per ml., while measurable effects can befound with cholic acid at about 1-0 ucmoles per my. 6

TABAQCHALI and BOOTH ’ found that such concentra-tions were reached in their patients with the blind-loopsyndrome, but levels for toxicity found in vitro may notbe applicable in vivo. Significantly perhaps, experimentsin animals showed that the hydrolysis of fat was more orless unimpaired even when steatorrhrea was present; andthe same was true in one patient with the blind-loopsyndrome.3 Clinically the important fact is that sterilisa-tion of the intestine by antibiotics reduces bacterialcounts and abolishes steatorrhrea. It is unfortunately

. true, however, that relapse is inevitable if treatmentl stops, so surgical removal of the blind loop is the only. reliable course.

Macrocytic anaemia in the blind-loop syndrome seemsalmost always to be the result of vitamin-B12 deficiency,and high serum-folic-acid levels have even been found,10probably because of synthesis by bacteria in the stagnantarea.l1 Many bacterial strains seem able to take upvitamin B12 in vitro," 12 so that direct competition withthe host for the available vitamin seems the likely causeof the deficiency. Vitamin B12 bound to intrinsic factormay also be removed by bacteria and, at least in rats,vitamin B12 taken up by bacteria cannot be removed bythe host.12 A toxic effect of bacteria on the intestinal

cells, reducing their capacity to absorb vitamin B12 andtherefore making them less able to compete with bacteria,seems theoretically possible, though there is little experi-mental evidence for it. Experiments in rats have shownthat absorption of the vitamin is unimpaired if bacteriallycontaminated intestinal pouches are not in continuitywith the rest of the intestine.13 This and similar work 14are much against a systemic toxic effect on absorption;furthermore, the structure of the jejunum does notseem to be altered by bacterial contamination, nor doesthe supernatant fluid obtained from bacterially con-8. Drasar, B. S., Hill, M. J., Shiner, M. ibid. i, 1237.9. Shiner, M., Waters, T. E., Gray, J. D. A. Gastroenterology, 1963, 45, 625.

10. Hoffbrand, A. V., Tabaqchali, S., Mollin, D. L. Lancet, 1966, i, 1339.11. Doig, A., Girdwood, R. H. Q. Jl Med. 1960, 29, 333.12. Donaldson, R. M., Corrigan, H., Natsios, G. Gastroenterology, 1962,

43, 282.13. Donaldson, R. M. ibid. p. 271.14. Hermann, G., Axtell, H. K., Starzl, T. E. ibid. 1964, 47, 61.

B4

86

taminated diverticula seem to inhibit the mucosal

binding of vitamin B12. Successful competition be-tween bacteria and the host is therefore the most likelyexplanation of vitamin-B12 deficiency in the blind-loopsyndrome.

Hormones and Histones ?

THE gradual realisation that hormones can besecreted by tumours of tissues other than those normallymanufacturing them has aroused much interest. Wediscussed 1 the subject in 1964, and comprehensivereviews 2 3 have lately appeared. Such cases continueto be reported,4 and Fusco and ROSEN 6 have demon-strated gonadotrophin-like activity in four cases ofcarcinoma of the bronchus with gynsecomastia. These

syndromes may be much commoner than had beenrealised, and almost any tumour seems capable of

producing almost any endocrine disturbance. Until

recently evidence for hormone secretion by the tumourtissue was presumptive and depended on recognitionof the clinical and biochemical effects and their reversalwhen the neoplasm was removed. Intensive effortswere made to detect hormone-like activity in the bloodand in the tumour tissue and many of these efforts havenow been successful. All the hormones identified havebeen peptides, except for 5-hydroxytryptamine(5-H.T.) - - 11

and 5-hydroxytryptophane (5-H.T.P.) 9 from non-

carcinoid tumours of the bronchus.

What is the explanation of this synthesis of " foreignpeptides by tumours ? It has been suggested thatactive hormones might be elaborated by chance duringthe " chaotic protein synthesis characteristic of neo-

plastic growth". This would imply a mutation of thenuclear D.N.A. of malignant cells to code for aminoacidsequences in the biologically active part of hormonemolecules; probably only part of the molecule need becopied since, for example, only 20 out of the 84 amino-acids in parathyroid hormone are required for biologicalactivity, and since, even amongst these 20, some aremore important than others.1o Although a functionallycorrect sequence might arise randomly it is perhapsunlikely that it should do so very often. It is even less

probable that a tumour should thus produce morethan one hormone, as has been reported.11-13 A morelikely view is based on the realisation that all except thesex cells inherit identical genetic complements and canpotentially produce any peptide normally manufactured1. Lancet, 1964, i, 317.2. Bower, B. F., Gordan, G. S. Ann. Rev. Med. 1965, 16, 83.3. Hobbs, C. B., Miller, A. L. J. clin. Path. 1966, 19, 119.4. Jordan, G. W. Am. J. Med. 1966, 41, 381.5. Spittle, M. F. Post-Grad. med. J. 1966, 42, 523.6. Fusco, F. D., Rosen, S. W. New Engl. J. Med. 1966, 275, 507.7. Williams, E. D., Azzopardi, J. G. Thorax, 1960, 15, 30.8. Kinloch, J. D., Webb, J. N., Eccleston, D., Zeitlin, J. Br. med. J.

1965, i, 304.9. Gowenlock, A. H., Platt, D. S., Campbell, A. C. P., Wormsley, K. G.

Lancet, 1964, i, 304.10. Potts, J. T., Aurbach, G. D., Sherwood, L. M. Rec. Prog. Horm. Res.

1966, 22, 101.11. Rees, J. R., Rosalki, S. B., Maclean, A. D. W. Lancet, 1960, ii, 1005.12. Daly, J. J., Nelson, M. A., Rose, D. P. Post-Grad. med. J. 1963, 39, 158.13. Law, D. H., Liddle, G. W., Scott, H. W., Tauber, S. D. New Engl.

J. Med. 1965, 273, 292.

anywhere in the body.14 15 The D.N.A. of tumour cellsprobably differs quantitatively rather than qualitativelyfrom normal,16 and has the same potential. It isthus easier to understand why tissues can produceany peptide, than why they do not under normalconditions.

JACOB and MONOD 17 have shown in bacteria that

genes which code for the enzyme proteins concerned ina metabolic sequence are grouped together on thechromosome. The manufacture of messenger R.N.A.s

by such a group is stimulated by the adjacent operatorgene and the whole group is called the operon. A

regulator gene at a more distant locus on the chromo-some liberates a repressor which, it is suggested,slows the manufacture of the R.N.A.s by combiningwith the operator. Some metabolites (inducers) can

compete with the operator for the repressor, thus

stimulating activity of the genes; others activate the

repressors. JACOB and MONOD suggested that the

repressor is of low molecular weight, possibly an R.N.A.Extrapolation of this theory to multicellular organismsis hazardous, but some such system could cause

differentiation of totipotential tissues so that they pro-duce only specialised polypeptides. Histones are basic

proteins which can combine with acidic D.N.A., causingreversible repression of a large part of the molecule.18Much of the nuclear D.N.A. of the thymus is maskedand can be removed without loss of normal geneticfunction. 19 Whether histone rather than an R.N.A. isthe repressor, or whether they both represent steps inthe same process, is not clear. In summary, every cellretains the potentiality to produce any peptide, and thespecialised cell ceases to do so during differentiationbecause much of its D.N.A. is repressed, probably byhistones. The malignant cell, if this theory is correct,could revert to manufacture of polypeptides normallyforeign to it, either by deletion of the regulator gene orby inactivation of the repressor.

If de-repression initiates production of "foreign" "

hormone, the hormone should be identical with thatproduced physiologically. The final proof of this

depends on complete chemical analysis. Methods usedfor identification have included biological and immuno-assay, and investigation of the gross chemical propertiesof the substance. Corticotrophin ’20 21 antidiuretichormone,22 23 insulin ’24 25 and gastrin,26 have beendemonstrated by both types of assay, parathyroidhormone by immunoassay alone,27 and thyrotropin,2g14. Gellhorn, A. Cancer Res. 1963, 23, 961.15. Lipsett, M. B., Odell, W. D., Rosenberg, L. E., Waldmann, T. A.

Ann. intern. Med. 1964, 61, 733.16. Allfrey, V. G. Cancer Res. 1966, 26, 2026.17. Jacob, F., Monod, J. J. mol. Biol. 1961, 3, 318.18. Huang, R. C., Bonner, J. Proc. natn. Acad. Sci. U.S.A. 1962, 48, 1216.19. Allfrey, V. G., Mirsky, A. E. ibid. p. 1590.20. Liddle, G. W., Island, D. P., Ney, R. L., Nicholson, W. E., Shimizu, N.

Archs intern. Med. 1963, 111, 471.21. Jaret, L., Lacy, P. E., Kipnus, D. M. J. clin. Endocr. Metab. 1964, 24,

543.22. Lee, J., Jones, J. J., Barraclough, M. A. Lancet, 1964, ii, 792.23. Utiger, R. D. J. clin. Endocr. Metab. 1966, 26, 970.24. August, J. T., Hiatt, H. H. New Engl. J. Med. 1958, 258, 17.25. Oleesky, S., Bailey, I., Samols, E., Bikus, D. Lancet, 1962, ii, 378.26. Monaco, A. P., Lythgoe, J. P., Waddell, W. R. ibid. 1961, ii, 1016.27. Tashjian, A. H., Levine, L., Munson, P. L. J. exp. Med. 1964, 119, 467.28. Bates, R. W., Cornfield, J. Endocrinology, 1957, 60, 225.