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Paneth Cells and Cœliac Disease
318
ing evidence is now appearing to show that lithium salts have a useful prophylactic action in patients prone to quickly recurring attacks of mania or depression or both.18 The lithium ion has a unique influence on sodium transport across biological membranes 19 and the distribution of sodium in man; 20 and it may also exert its therapeutic effect through its action on sodium metabolism. If reversible biochemical abnormalities are responsible for depression, they may be initiated or sustained by hormonal changes. Endocrinological investigations into depression have been limited for the most part to the thyroid hormone and to hydrocortisone and its metabolites.21 As far as the thyroid gland is concerned, such estimations as protein-bound iodine,22 basal metabolic rate,23 or the uptake of radioactive iodine 24 have all given values within the normal range. Because of the familiar affective changes in Cushing’s syndrome or during the administration of corticotrophin or hydrocortisone, adrenocortical activity in depression has often been examined, using various indices, including plasma-hydrocortisone levels,25 urinary excretion of 17-hydroxycorticosteroids,26 and hydrocortisone-secretion rates.27Here, however, cause and effect are particularly hard to separate, and the hypothalamic-pituitaryadrenal system responds very readily to environmental changes even in normal subjects. 28 Indeed, it would be very unexpected if emotionally disturbed patients with depression did not show evidence of increased adrenocortical activity. Nearly all investigators have reported increased adrenocortical activity in at least a substantial proportion of patients, although some patients with a severe depressive illness do not, in fact, show any evidence of increased activity. How far this increase is secondary to the illness, or how likely it is to initiate the biochemical changes underlying depression, is uncertain. For example, could it be responsible for the changes in amine metabolism or electrolyte distribution? Hydrocortisone 29 can induce tryptophan pyrrolase and thus direct tryptophan metabolism away from the indoleamine pathway. The picture is complicated, however, because cortisone can also increase the hepatic decarboxylation of aromatic aminoacids.3O The effect of hydrocortisone on electrolyte distribution has not been studied, but it is unlikely to be responsible for the abnormalities found in affective disorders, since in mania, where the electrolyte shifts are even more striking than in depression, plasmahydrocortisone levels are normal. 31 The changes in monoamines and in electrolyte on
Schou, M., Baastrup, P. C. Wld Conf. Psychiat. 1966. Keynes, R. D., Swan, R. C. J. Physiol., Lond. 1959, 147, 626. Coppen, A., Malleson, A., Shaw, D. M. Lancet, 1965, i, 682. Michael, R. P., Gibbons, J. L. Int. Rev. Neurobiol. 1963, 5, 243. Bowman, K. M., Miller, E. R., Dailey, M. E., Simon, A., Mayer, B. F. J. nerv. ment. Dis. 1950, 112, 404. 23. Mezey, A. G., Coppen, A. Clin. Sci. 1961, 20, 171. 24. Dongier, M., Wittkower, E. D., Stephens-Newsham, L., Hoffman, M. M. Psychosom. Med. 1956, 18, 310. 25. Gibbons, J. L., McHugh, P. J. psychiat. Res. 1962, 1, 162. 26. Stenbäck, A., Jakobson, T., Rimon, R. J. psychosom. Res. 1966, 9, 355. 27. Gibbons, J. L. Archs gen. Psychiat. 1964, 10, 572. 28. Mason, J. W. Rec. Prog. Horm. Res. 1959, 15, 345. 29. Mandell, A. J., Ruben, R. T. Life Sciences, 1966, 5, 1153. 30. Davis, V. E. Endocrinology, 1963, 72, 33. 31. Coppen, A. Wld Conf. Psychiat. 1966. 18. 19. 20. 21. 22.
depression may be only part of a widespread metabolic abnormality, possibly induced by endocrinological changes as yet undefined. Nevertheless, the understanding already gained holds out the possibility distribution in
of a more rational treatment for this condition-and also a means of preventing it.
Paneth Cells and Cœliac Disease ONE of the few effective treatments at the command of the gastroenterologist is the gluten-free diet. Most patients with coeliac disease or idiopathic steatorrhrea lose their symptoms soon after this treatment beginsbut others continue to deteriorate in health. There has been no means of predicting which individuals among those with apparently identical degrees of mucosal damage would respond to the diet and which would The physician could perhaps therefore be forgiven for a natural inclination to blame the unresponsive patient for not adhering sufficiently strictly to the regimen prescribed. This attitude can often be well founded, but it is also true that those who do improve can be surprisingly lax in avoiding foods which contain gluten. Occasionally patients may be wrongly diagnosed as having coeliac disease or idiopathic steatorrhoea, for mucosal atrophy seems sometimes to arise in association with other diseases, such as ulcerative colitisor extraintestinal carcinoma .2 But the almost universal experience of the occasional failure to respond to the diet can hardly be the result of misdiagnosis every time. In their contributions to this issue Dr. CREAMER and Dr. PINK describe the natural history of the coeliac syndrome in 54 patients treated with a gluten-free diet. 38 responded rapidly and completely to the regimen, 8 partially, and 8 not at all. This last group contained 3 patients who had a pancreatic lesion, as judged at necropsy in 1 and by a diminished pancreatic exocrine response to stimulation with secretin in the other 2. The remaining 5 patients had severe damage to the small-intestinal mucosa, the surface epithelium being very abnormal and the crypts somewhat shortened. The striking histological abnormality in this group, however, seemed to be a diminution or complete absence of Paneth cells. Treatment with dietary supplements and corticosteroid drugs was moderately successful in 3 patients, but 2 continued to deteriorate in health and later died. In 2 of those treated more or less successfully with corticosteroid drugs, improvement was apparently accompanied by the reappearance of Paneth cells in biopsy specimens of the jejunal mucosa. CREAMER also describes 2 further patients with Panethcell deficiency, one with rapidly progressive Hodgkin’s disease, and the other with pustular psoriasis which was associated in exacerbations of the skin disease with steatorrhoea. Paneth cells were found in this patient in normal numbers during remission, but they were absent during an attack. not.
1. 2.
Salem, S. N., Truelove, S. C., Richards, W. C. D. Br. med. J. 1964, i, 394. Creamer, B. ibid. 1964, ii, 1435.
319
function in secreting a protein-carbohydrate complex which is necessary for the luminal nutrition of the crypt cells. The basis for this suggestion is that Paneth cells sprue, and a that severe malnutrition can on its own lead to pan- seem to release granules into the crypts,9 but no likely creatic atrophy.6 The reverse situation of mucosal enzymatic component of the intestinal fluid derived abnormality probably consequent upon pancreatic from this source seems to have been found.10 Paneth steatorrhoea has been noted,’ but here the degree of cells also seem to be more common in the ileum than mucosal abnormality seemed to be slight, and in fact in the jejunum, which could contradict the view that a formal picture has been found by others.8 they have a digestive function, but would perhaps The importance of Paneth-cell deficiency is hard to support the idea of a nutritional role in an area where define, for the physiological role of these cells is un- nitrogenous compounds are in low intraluminal conknown. Comparative anatomical studies suggest to centrations because of absorption higher in the intestine. CREAMER that Paneth cells are associated with a pattern Such a hypothesis presupposes that vascular delivery of short crypts which show concentrated activity, and of nutrients is, in some way, inadequate, or that the he goes on to speculate that the cells have a specialised Paneth cell produces a special substance or substances which the active crypt needs. Further investigation 3. Newsome, J. Gastroenterologia, 1948, 74, 257. 4. Dreiling, D. A. Gastroenterology, 1953, 24, 540. of this ill-understood cell could give interesting 5. Benson, G. D., Kowlessar, O. D., Sleisenger, M. H. Medicine, Baltimore, 1964, 43, 1. result.
Abnormalities of
pancreatic function have been patients with non-tropical possible explanation of the association is
recorded 3-5 in occasional
6. 7. 8.
Thompson, M. D., Trowell, H. C. Lancet, 1952, i, 1031. Madanagopalan, N., Shiner, M., Rowe, B. Am. J. Med. 1963, 38, 42. Choudhury, D. R., Cook, W. T., Tan, D. T., Banwell, J. G., Smits, B. J. Scand. J. Gastroent. 1966, 1, 57.
Annotations
9. 10.
Trier, J. S. Gastroenterology, 1966, 51, 560. Wright, R. D., Jennings, M. A., Florey, H. W., Lium, R. Q. Jl exp. Physiol. 1940, 30, 73.
stand these warnings. Another point which I.T.A.’s advisory committee might consider is that ’Alka-Seltzer ’ is recommended for the treatment of indigestion-yet it contains aspirin. DRUG COMMERCIALS Whether iron-containing preparations should be adverTHE aim of the Independent Television Authority and tised on television is also debatable. Under the Pharmacy its advertising advisory committee is to ensure that and Medicines Act, 1941, it is illegal to advertise to the advertising claims made in television commercials do not general public drugs for the treatment of Bright’s disease, cause harm. How far have they succeeded with drug epilepsy, tuberculosis, diabetes, and various other advertisements on what is probably the most persuasive conditions. The Act does not, however, forbid the and intrusive of all media ? Many of these commercials advertisement of remedies for anxmia, although selfare straightforward and harmless, but some seem to be of ansemia are patently and self-treatment diagnosis inviting trouble. and ’ Iron Jelloids ’ each unsatisfactory.’Phyllosan’ Several preparations advertised on television contain contain just enough iron to help in mild iron-deficiency phenacetin, whose association with nephropathy, some- anæmia—and to confuse hæmatological diagnosis. times fatal, has been recognised for some years. It is Again, for most of the people who buy them, vitamin one thing to permit unrestricted sale of this drug (and are a waste of money. Is it not time for that has been criticised): it is another to exhort people to supplements vitamin advertisements (on television and elsewhere) to buy it. Two preparations which contain phenacetin are state that extra vitamins are not needed by people eating ’ Yeast-Vite ’ and ’Cephos ’. (The phenacetin in a normal diet ? In the United States the Food and Drug ’Phensic’ is, we understand, being replaced by salicyla- Administration is introducing a regulation which will mide ; and both formulas were to be bought in London require such a statement to appear on the label of vitamin during the past week.) Yeast-vite, which has a rela- preparations. tively large dose of phenacetin (162 mg. in each tablet), is probably the most worrying, because it is advertised as " invaluable to those feeling tired and tense " and because the name suggests that it is a food supplement RESIDUAL BOVINE TUBERCULOSIS to be taken regularly for indefinite periods. None of the commercials warn the viewer against abuse of these BEFORE the 1939-45 war, bovine tuberculosis was still preparations. Any warning on the label or in the packet widespread in Britain. Griffithin 1937, reported that is in small print and probably escapes the notice of most 84-6% of primary abdominal tuberculosis and 50% of patients. This point applies equally to some oral decon- cervical adenitis was due to bovine infection. Up to 40% gestant preparations, such as ’Contac 400’, which of cows were infected,2 and in parts of North-eastern contain belladonna or a similar drug and a vasocon- Scotland over 10% of human pulmonary disease was strictor. The advertisement mentions rapid and lasting due to the bovine bacillus.3 While most infections were relief of nasal congestion, but warnings that the preparaconveyed by milk, direct droplet dissemination from tion should not be taken by persons with high bloodanimal to man, mainly in cowsheds, was also responsible. pressure or glaucoma appear only on the packet. No The attested-herds scheme initiated in 1935, together doubt some patients with glaucoma can read the small with pasteurisation, has drastically reduced the amount print, but probably many more do not even bother to 1. Griffith, A. S. Tubercle, 1937, 18, 529. try. Despite the Pharmaceutical Society’s advice, only 2. McDougall, J. B. Tuberculosis; p. 380. Edinburgh, 1949. a few pharmacists try to ensure that customers under3. Griffith, A. S., Smith, J. Lancet, 1940, ii, 291.
ing evidence is now appearing to show that lithium salts have a useful prophylactic action in patients prone to quickly recurring attacks of mania or depression or both.18 The lithium ion has a unique influence on sodium transport across biological membranes 19 and the distribution of sodium in man; 20 and it may also exert its therapeutic effect through its action on sodium metabolism. If reversible biochemical abnormalities are responsible for depression, they may be initiated or sustained by hormonal changes. Endocrinological investigations into depression have been limited for the most part to the thyroid hormone and to hydrocortisone and its metabolites.21 As far as the thyroid gland is concerned, such estimations as protein-bound iodine,22 basal metabolic rate,23 or the uptake of radioactive iodine 24 have all given values within the normal range. Because of the familiar affective changes in Cushing’s syndrome or during the administration of corticotrophin or hydrocortisone, adrenocortical activity in depression has often been examined, using various indices, including plasma-hydrocortisone levels,25 urinary excretion of 17-hydroxycorticosteroids,26 and hydrocortisone-secretion rates.27Here, however, cause and effect are particularly hard to separate, and the hypothalamic-pituitaryadrenal system responds very readily to environmental changes even in normal subjects. 28 Indeed, it would be very unexpected if emotionally disturbed patients with depression did not show evidence of increased adrenocortical activity. Nearly all investigators have reported increased adrenocortical activity in at least a substantial proportion of patients, although some patients with a severe depressive illness do not, in fact, show any evidence of increased activity. How far this increase is secondary to the illness, or how likely it is to initiate the biochemical changes underlying depression, is uncertain. For example, could it be responsible for the changes in amine metabolism or electrolyte distribution? Hydrocortisone 29 can induce tryptophan pyrrolase and thus direct tryptophan metabolism away from the indoleamine pathway. The picture is complicated, however, because cortisone can also increase the hepatic decarboxylation of aromatic aminoacids.3O The effect of hydrocortisone on electrolyte distribution has not been studied, but it is unlikely to be responsible for the abnormalities found in affective disorders, since in mania, where the electrolyte shifts are even more striking than in depression, plasmahydrocortisone levels are normal. 31 The changes in monoamines and in electrolyte on
Schou, M., Baastrup, P. C. Wld Conf. Psychiat. 1966. Keynes, R. D., Swan, R. C. J. Physiol., Lond. 1959, 147, 626. Coppen, A., Malleson, A., Shaw, D. M. Lancet, 1965, i, 682. Michael, R. P., Gibbons, J. L. Int. Rev. Neurobiol. 1963, 5, 243. Bowman, K. M., Miller, E. R., Dailey, M. E., Simon, A., Mayer, B. F. J. nerv. ment. Dis. 1950, 112, 404. 23. Mezey, A. G., Coppen, A. Clin. Sci. 1961, 20, 171. 24. Dongier, M., Wittkower, E. D., Stephens-Newsham, L., Hoffman, M. M. Psychosom. Med. 1956, 18, 310. 25. Gibbons, J. L., McHugh, P. J. psychiat. Res. 1962, 1, 162. 26. Stenbäck, A., Jakobson, T., Rimon, R. J. psychosom. Res. 1966, 9, 355. 27. Gibbons, J. L. Archs gen. Psychiat. 1964, 10, 572. 28. Mason, J. W. Rec. Prog. Horm. Res. 1959, 15, 345. 29. Mandell, A. J., Ruben, R. T. Life Sciences, 1966, 5, 1153. 30. Davis, V. E. Endocrinology, 1963, 72, 33. 31. Coppen, A. Wld Conf. Psychiat. 1966. 18. 19. 20. 21. 22.
depression may be only part of a widespread metabolic abnormality, possibly induced by endocrinological changes as yet undefined. Nevertheless, the understanding already gained holds out the possibility distribution in
of a more rational treatment for this condition-and also a means of preventing it.
Paneth Cells and Cœliac Disease ONE of the few effective treatments at the command of the gastroenterologist is the gluten-free diet. Most patients with coeliac disease or idiopathic steatorrhrea lose their symptoms soon after this treatment beginsbut others continue to deteriorate in health. There has been no means of predicting which individuals among those with apparently identical degrees of mucosal damage would respond to the diet and which would The physician could perhaps therefore be forgiven for a natural inclination to blame the unresponsive patient for not adhering sufficiently strictly to the regimen prescribed. This attitude can often be well founded, but it is also true that those who do improve can be surprisingly lax in avoiding foods which contain gluten. Occasionally patients may be wrongly diagnosed as having coeliac disease or idiopathic steatorrhoea, for mucosal atrophy seems sometimes to arise in association with other diseases, such as ulcerative colitisor extraintestinal carcinoma .2 But the almost universal experience of the occasional failure to respond to the diet can hardly be the result of misdiagnosis every time. In their contributions to this issue Dr. CREAMER and Dr. PINK describe the natural history of the coeliac syndrome in 54 patients treated with a gluten-free diet. 38 responded rapidly and completely to the regimen, 8 partially, and 8 not at all. This last group contained 3 patients who had a pancreatic lesion, as judged at necropsy in 1 and by a diminished pancreatic exocrine response to stimulation with secretin in the other 2. The remaining 5 patients had severe damage to the small-intestinal mucosa, the surface epithelium being very abnormal and the crypts somewhat shortened. The striking histological abnormality in this group, however, seemed to be a diminution or complete absence of Paneth cells. Treatment with dietary supplements and corticosteroid drugs was moderately successful in 3 patients, but 2 continued to deteriorate in health and later died. In 2 of those treated more or less successfully with corticosteroid drugs, improvement was apparently accompanied by the reappearance of Paneth cells in biopsy specimens of the jejunal mucosa. CREAMER also describes 2 further patients with Panethcell deficiency, one with rapidly progressive Hodgkin’s disease, and the other with pustular psoriasis which was associated in exacerbations of the skin disease with steatorrhoea. Paneth cells were found in this patient in normal numbers during remission, but they were absent during an attack. not.
1. 2.
Salem, S. N., Truelove, S. C., Richards, W. C. D. Br. med. J. 1964, i, 394. Creamer, B. ibid. 1964, ii, 1435.
319
function in secreting a protein-carbohydrate complex which is necessary for the luminal nutrition of the crypt cells. The basis for this suggestion is that Paneth cells sprue, and a that severe malnutrition can on its own lead to pan- seem to release granules into the crypts,9 but no likely creatic atrophy.6 The reverse situation of mucosal enzymatic component of the intestinal fluid derived abnormality probably consequent upon pancreatic from this source seems to have been found.10 Paneth steatorrhoea has been noted,’ but here the degree of cells also seem to be more common in the ileum than mucosal abnormality seemed to be slight, and in fact in the jejunum, which could contradict the view that a formal picture has been found by others.8 they have a digestive function, but would perhaps The importance of Paneth-cell deficiency is hard to support the idea of a nutritional role in an area where define, for the physiological role of these cells is un- nitrogenous compounds are in low intraluminal conknown. Comparative anatomical studies suggest to centrations because of absorption higher in the intestine. CREAMER that Paneth cells are associated with a pattern Such a hypothesis presupposes that vascular delivery of short crypts which show concentrated activity, and of nutrients is, in some way, inadequate, or that the he goes on to speculate that the cells have a specialised Paneth cell produces a special substance or substances which the active crypt needs. Further investigation 3. Newsome, J. Gastroenterologia, 1948, 74, 257. 4. Dreiling, D. A. Gastroenterology, 1953, 24, 540. of this ill-understood cell could give interesting 5. Benson, G. D., Kowlessar, O. D., Sleisenger, M. H. Medicine, Baltimore, 1964, 43, 1. result.
Abnormalities of
pancreatic function have been patients with non-tropical possible explanation of the association is
recorded 3-5 in occasional
6. 7. 8.
Thompson, M. D., Trowell, H. C. Lancet, 1952, i, 1031. Madanagopalan, N., Shiner, M., Rowe, B. Am. J. Med. 1963, 38, 42. Choudhury, D. R., Cook, W. T., Tan, D. T., Banwell, J. G., Smits, B. J. Scand. J. Gastroent. 1966, 1, 57.
Annotations
9. 10.
Trier, J. S. Gastroenterology, 1966, 51, 560. Wright, R. D., Jennings, M. A., Florey, H. W., Lium, R. Q. Jl exp. Physiol. 1940, 30, 73.
stand these warnings. Another point which I.T.A.’s advisory committee might consider is that ’Alka-Seltzer ’ is recommended for the treatment of indigestion-yet it contains aspirin. DRUG COMMERCIALS Whether iron-containing preparations should be adverTHE aim of the Independent Television Authority and tised on television is also debatable. Under the Pharmacy its advertising advisory committee is to ensure that and Medicines Act, 1941, it is illegal to advertise to the advertising claims made in television commercials do not general public drugs for the treatment of Bright’s disease, cause harm. How far have they succeeded with drug epilepsy, tuberculosis, diabetes, and various other advertisements on what is probably the most persuasive conditions. The Act does not, however, forbid the and intrusive of all media ? Many of these commercials advertisement of remedies for anxmia, although selfare straightforward and harmless, but some seem to be of ansemia are patently and self-treatment diagnosis inviting trouble. and ’ Iron Jelloids ’ each unsatisfactory.’Phyllosan’ Several preparations advertised on television contain contain just enough iron to help in mild iron-deficiency phenacetin, whose association with nephropathy, some- anæmia—and to confuse hæmatological diagnosis. times fatal, has been recognised for some years. It is Again, for most of the people who buy them, vitamin one thing to permit unrestricted sale of this drug (and are a waste of money. Is it not time for that has been criticised): it is another to exhort people to supplements vitamin advertisements (on television and elsewhere) to buy it. Two preparations which contain phenacetin are state that extra vitamins are not needed by people eating ’ Yeast-Vite ’ and ’Cephos ’. (The phenacetin in a normal diet ? In the United States the Food and Drug ’Phensic’ is, we understand, being replaced by salicyla- Administration is introducing a regulation which will mide ; and both formulas were to be bought in London require such a statement to appear on the label of vitamin during the past week.) Yeast-vite, which has a rela- preparations. tively large dose of phenacetin (162 mg. in each tablet), is probably the most worrying, because it is advertised as " invaluable to those feeling tired and tense " and because the name suggests that it is a food supplement RESIDUAL BOVINE TUBERCULOSIS to be taken regularly for indefinite periods. None of the commercials warn the viewer against abuse of these BEFORE the 1939-45 war, bovine tuberculosis was still preparations. Any warning on the label or in the packet widespread in Britain. Griffithin 1937, reported that is in small print and probably escapes the notice of most 84-6% of primary abdominal tuberculosis and 50% of patients. This point applies equally to some oral decon- cervical adenitis was due to bovine infection. Up to 40% gestant preparations, such as ’Contac 400’, which of cows were infected,2 and in parts of North-eastern contain belladonna or a similar drug and a vasocon- Scotland over 10% of human pulmonary disease was strictor. The advertisement mentions rapid and lasting due to the bovine bacillus.3 While most infections were relief of nasal congestion, but warnings that the preparaconveyed by milk, direct droplet dissemination from tion should not be taken by persons with high bloodanimal to man, mainly in cowsheds, was also responsible. pressure or glaucoma appear only on the packet. No The attested-herds scheme initiated in 1935, together doubt some patients with glaucoma can read the small with pasteurisation, has drastically reduced the amount print, but probably many more do not even bother to 1. Griffith, A. S. Tubercle, 1937, 18, 529. try. Despite the Pharmaceutical Society’s advice, only 2. McDougall, J. B. Tuberculosis; p. 380. Edinburgh, 1949. a few pharmacists try to ensure that customers under3. Griffith, A. S., Smith, J. Lancet, 1940, ii, 291.