The etiology of pellagra from the standpoint of a deficiency disease

TRANSACTIONS OF T H E

ROYAL SOCIETY OF TROPICAL MEDICINE AND

HYGIENE.

MAY 2,ST, ,920. VOLUME

XIV.

No.

,.

Proceedings of a Meeting of the Society held on Friday, May 2ist, I92O, at 8.30 p.m,, at **, Chandos Street, Cavendlsh Square, W. x., Professor W. J. R. SIMPSON, C.M.G., M.D., F.R.C.P.

THE

ETIOLOGY

(President),

OF PELLAGRA DEFICIENCY

FROM

in the Chair.

THE

STANDPOINT OF A

DISEASE.

BY EDWARD J. WOOD, S:B., M.D., D.T.M. (ENG.).

In spite of the tremendous amount of work done in the study of the etiology of pellagra, it must be reluctantly admitted that the solution of the problem is not yet accomplished. It is, however, encouraging to note the great interest which has been aroused, and the high type of scientific research which is being brought to bear on its solution. The Great War has stimulated the interest of a number of brilliant investigators, who were given ample opportunity for the study of the disease, especially in Egypt. It would seem highly improbable that the addition to the field of research workers in pellagra of the large number of British investigators whose interest was aroused in Egypt, could result in anything but an early solution of a problem which has vexed Europe since x735, and which during the past decade and a half has taken such terrific toll in the United States. My only justification for appearing before this Society to discuss the question of the cause of pellagra lies in the hope that it may help to form a link in the chain of evidence, ulttmately to result in a solution, for all my observations were made in the southern states of the United States, and chiefly in the State of North Carolina, where conditions of Jiving and general hygiene are far different from those encountered by the British observers in Egypt. It is reasonable to presume that light may be thrown on the subject by a consideration of its occurrence in areas so widely separated. I ask your indulgence in a rapid review of some of the more important work done in the United States and the more recent Egyptian reports. It is interesting to,note that there was no reference to the occurrence of pellagra in America until about t9o7,1 though an occasional case was reported of a sporadic nature.

- THE ETIOLOGY OF PELLAGRA

Careful consideration of the matter convinces me that it is a great error to assume that the disease has existed in that country unreeognised for many years. I saw my first cases in ~9o5, and took great care to consult the older physicians in the fields of its occurrence to learn if they had ever seenit, but~it Was as s t r a n g e ' t o t h e m as it was to me. It is, further, a notable fact that from I9o 5 to about x9o9, the disease assumed a very malignant and fulminating type. Since that time it has gradually assumed the character of the chronic process described in Italian literature This tact cannot but recall to one's mind the story of the visit to the Fiji Islands from Australia in x875 of H.M.S. Dido, with me'asles' a b o a r d . ' According to the account of Sir WILLIAM OSLER, 40,0o0 out of t5o, ooo population died in four months. It was presumed that this was virgin soil for measles, and that since that time the death-rate has gradually approached the usual normal. Certainly, a like state of things occurred with pellagra, as I saw it in North Carolina in those earlier years, while to-day it differs little from the Italian type of the disease. This single point has been a continual obstacle in the way of accepting any view which excluded an infectious element. In all the recent work done in the study of pellagra from a standpoint of a food deficiency, it must be admitted that there is still lacking an entirely satisfactory explanation of the seasonal incidence of the original outbreak as well as the recurrences. Dr. SAMBON~ has presented some very strong points in favour of a short period of incubation whmh cannot be overlooked or fail to receive the most serious consideration. His carefully recorded instances of such cases as that of the parents in a pellagrous district suffering from the disease, their removal to a non-pellagrous district where nonpellagrous Children were born, and the subsequent return after some years to the pellagrous district which was followed by the appearance o f ' t h e disease in the children, could only be ignored by the prejudiced. JOBLING and PETERSON~ studied pellagra in the city 'of Nashville, Tennessee, and concluded that there was a connection between the incidence of the disease and poor sewage disposal. Their conclusions suggest that a lack of screening and the ~part played by flies could not be ignored, though they emphasised the fact that the pellagrous class consumed relatively more carbohydrate and less protein than is required to make up a properly balanced ration. The THOMPSON-I~ICFADDEN4 Pellagra Commission made its observations in Spartanburg County, South Carolina. They concluded the disease was in some way related to a bacteriological infection, and they, too, regarded the disposal of human excreta as playing an important part. The work of JOSEPH GOLDBERGER,~ with which you are doubtless familiar, has for its basis ( I ) t h a t pellagra is essentially of dietetic origin; (2) that it depends on some undetermined error in a diet with a disproportionately high vegetable component and a disproportionately 10w protein component derived from animal or leguminous sources ; !3) that no pellagra developed in those who consumed a mixed, well-balanced diet which is suitably varied. In an orphanage, GOLDBERGER found 75 per cent. of the children pellagrins in i9~3, and the ones who escaped were the younger children whose diets were supplemented with cow's milk. His suggestions of a diet reform were adopted, an,d in i914, in the same institution, among 234 inmates there did not occur a single case. H e then selected what his experimental work indicated to be a faulty diet, and by an arrangement this diet was given to prisoners. Every effort was made to exclude all possible sources of error based on the various theories 0f etiology, A careful survey indicated that the only source of hygienic error rested in the diet. Resulting from this feeding experiment, a number of the men developed a disease condition regarded by GOLDBERGER and clinicians who had seen much of the disease as real pellagra. It is only fair to state at this point that there was criticism raised by some of the opponents of a food origin of the disease, because the skin lesions of the subjects of the experiment: were on the scrotum rather than the exposed portions of the skin surface. This led me to review my cases of pellagra, and I shall shew you photographs which readily sustain the point that the covered portions of the body surface may be the seat of the lesion. I n a number of cases I have found the skin lesions about the vulva, on the back, above and below the knees,

FROM THE STANDPOI.NT OF A DEFICIENCY DISEASE.

3

behind the knees, and, in fact, hardly a spot on the skin surface can be regarded as exempt from such a possibility. Too little attention has been paid to these atypical distributions, and it would be exceedingly unfair to discredit GOLDBEROER'S important work because of a lack of such knowledge. GOLDBERGER then fed by mouth the fmces of pellagrins to a number of volunteers. In no case did anything suggestive of the disease appear as a result. It is an important fact that in the United States the instances are neither single nor isolated where a dietetic reform in public institutions has resulted in a disappearance of pellagra, just as GOI,DBERC,FR demonstrated. W. H. WILSON,~ in Cairo, has contributed importantly to the subject. He regards pellagra as due to a defective protein supply in the diet. His work resulted from careful analyses of dints known to have produced pellagra, and with others regarded as preventive or curative. H e i t was who directed attention to the biologic value of protein in Such cases. The work of K. THOMAS* was depended on for the values of protein from various sources. T o maintain nitrogenous equilibrium it was found that various substances differed widely. The biological value of vegetable protein, and especially that derived from maize, was found to be tess .than that of milk or meat protein. THOMASestimated that the amount of tissue repair from 3 ° grams of meat or milk protein required ~oo grams of maize protein to be equal~s~d. It was thought that the inferiority of maize proteins could be explained by the large proportion of zein, which is devoid of both tryptophan and lysine, two amino-acids regarded as essential for animal nutrition. WILSON concluded that the danger from pellagra occurred when the biological value of the protein of the diet was below a certain point( F. B. BOVD8 and hit co,workers studied pellagra in Egypt among prisoners of war. They found that the level of biological protein could be so exactly determined that they were able to ~nticipate the disease. Their work pointed strongly to the fact that a rest diet was inadequate to protect against pellagra when the victim was put to work. In their series 3,ooo German prisoners , who supplemented the reasonably good priso n diet in various ways, according to the. well-known German appetite, escaped. But among 6,ooo Ottomans, not so fortunate as to be able to have this supplement, 3oo cases of pellagra developed in one year. It was found that if the disease was not far advanced it promptly responded to an increase in the biMogical protein value. These workers emphasised the importance of the part played by diarrhceal disease in disturbing the protein balance. A recent summary 0fthis 'Egyptian work shews that the absorption of protein from the intestines was less than 6 7 per cent., and that the metabolism of the Turkish prisoners of war is characterlsed by a low degree of assimilation of fat and nitrogen. At this point the justification of this communication seems apparent, for in my own work in America, on a carefully weighed Schmidt-Strassbu.rger test diet, a normal utilisation of both fat and nitrogen occurred in pellagra, even in the terminal stages of a fatal case. It has always, even since the days of CASAL, been a noteworthy fact that those living in the country districts were the victims of pellagra, while the urban population escaped. The Egyptian workers have proven, by careful analysis, that rural diets have lower values than urban diets, as there is a tendency for the agriculturist to send all his expensive animal foods to thebetter paid town dwellers and live chiefly on cereals. They suggested that the hill-man, depending more on his flocks for food, was more protected from pellagra than the valley-dweller , who largely depended on his cereal crop for his own sustenance. A. D. BIGLAND, 9 in an admirable review of the whole subject, refers to the biological protein value of WILSON, as indicating the greater readiness with which .meat protein is assimilated than the vegetable type. It is this assimilability which constitutes its biological value, and this point is placed by WmsoN at 4o grams per diem. BIGLAND concludes that pellagra occurs most often in the underfed, speaking exactly, but may occur in the well fed. He speaks of the food deficiency being from without or from within. A comparison is made with perilobular cirrhosis of the liver, which may occur in the alcoholic but also in the ngn-alcoholic~ This broader point of view may make possible an explanation of many of those baffling cases in which we have seen pellagra occur in the well-fed.

4

THE

ETIOLOGY OF PELLAGRA

J. I. E N W R I G H T 1o reports on the occurrence of pellagra among German prisoners of war, who were given the very "fat of the land" in the way of food, and whose dietary, which is published in detail,'will stand the closest scrutiny. In spite of such a diet definite pellagra occurred. CHITTENDEN and U N D E R H I L L , I i in the UIfited States, produced a condition in do.gs very suggestive of pellagra, on a diet which E. ~q. M c C o L L U ~ T M found defective only in Fat-soluble A, and the latter'sinvestigations on rats with the same type of diet resulted in failure to produce the pellagrous symptoms, but did bring about a retardation of nutrition and a condition approaching xerophthalmia. M c C o L L U m thinks there is good evidence that there occur sometimes cases of pellagra in individuals whose diets have included a certain amount of those things called by him protective foods, which include milk, eggs and leafy vegetables, and that the theory of infection is thereby supported. H e thinks this view is supported by the occurrence of the disease in badly sewered districts. Working under the suggestion of G O L D B E R G E R , after twelve years of a belief in an infectious nature of pellagra, 1 undertook to view it from the standpoint of beriberi. I was at once attracted by the report of P. A. NIGHTINGALE, I ~. who. had under his care the prisoners of a gaol in Rhodesia. These prisoners had always been fed on ropoko, a small cereal of the maize type, which 'was hand-ground by the prisoners, but owing to the failure of the crop they were forced to go outside, and buy commercial " mealie meal," which seems to conform to the commercial corn meal of the Southern States of America. The result of this food change was a disease the description of which is accompanied by diagrammatic sketches, making the diagnosis unmistakable. Appreciating that the trouble was due to the change of food, NIGHTINGALE immediately abandoned the "mealie meal" for ropoko again, and, in his own language, the result was "immediate and magical." It is to be hoped that my hearers will appreciate the difference between this observation and the old maize theory of the early Italian School. In NIGHTINGALE'S observations there was no thought of toxicity but rather of a deficiency. If pellagra is a deficiency disease, it may occur as often among those who eat wheat as among those who eat maize as the exclusive cereal diet. In either instance it is safe to say that milk, or other suitable animal protein, may readily offset the fault. So much impressed was I with NIGHTINGALE'S report, that I went to the maize-mill to learn how the grain suffered in the milling process. Briefly I14 found that in modern steam-milling the gr~in was "degerminated," that is, it was deprived of the germ, which latter was ground separately, and, with the bran, sold as cattle-food, having a great reputation.as a "milk maker. '~ It will be recalled that the Philippine workers, in the experiments with polished rice, rice-polish and beriberi shewed that phosphoric acid (P~O~) was a reliable indicator of antineuritic substance. In my maize work the same plan was adopted. We found that the commercial germ product contained i ' i 5 per cent. of P20~, while specially milled germ for experimental purposes often reached as high as z per cent. On the other hand, maize milled in the state of Ohio contained only o,29 per cent. When the grain was ground in lolo with no removal, according to the old plan, the P.zO5 content was o.78 per cent. The reason for the modern plan of milling is that the germ of maize contains so much fat that milling the grain without separating and removing this germ results in a product which early becomes rancid. The germ of maize is quite soft, and is poorly protected. If deterioration of an animal or vegetable source occurs, it is always the germ which suffers first arid foremost. Is it not worthy of consideration that, if LOMBROSO had regarded pellagra as a deficiency rather than a toxicity; resulting from the destruction by the various moulds of the essential portion of t h e grain, a solution might have been reached ? Substituting the word deficiency where he speaks of toxicity, makes his masterly work on the subject in close accord with many modern views. I then investigated the milling of wheat. It will be recalled that the antineuritc substance occurs in the cortical portion of the grain. Our afialyses shewed that the bran portions of wheat contained o'98 per cent. of P~O~, while average wheat contained only o-14 per cent. Experiments were undertaken on pigeons and chickens, having no point of originality except the substitution of deficient maize in place of polished rice in the production of

FROM T H E

S T A N D P O I N T OF A D E F I C I E N C Y DISEASE.

polyneuritis gallinarum. It was readily proven that the germ of maize contained the same property as the polish of rice. An alcoholic extract of the germ of maize was as effective in relieving the symptoms of polyneuritis as was the case with an alcoholic extract of hce polish. In the course of these experiments it developed that birds given grain, the phosphoric acid content of which was very gradually decreased, seemed to acquire a tolerance for the deficiency. But the young of.these birds hatched from :eggs laid during the experiment, while apparently free from polyneuritis at the hatching time, and -continuing so until after leaving the nest, promptly became polyneuritic on the diet of the parent birds, though these latter remained free from any definite indication of the disease. Pigeons, on a diet of maize with a phosphoric acid content considerably below normal and yet not low enough to produce polyneuritis gallinarum, manifested droopiness, loss of feathers, and a red-legged condition which seemed quite distiflctive. We have not yet dared to say that this condition i~ the analogue of pellagra as polyneuritis gallinarum is of beriberi. Pigeons fed on whole maize of the best quality were maintained in fair health, but withou t rapidity and extent of growth which Would occur on a more natural diet. The condition of red legs was readily relieved by a substitution of good maize. Repeating what has been done in the rice work in the Philippines by VEDDER and others, it was found that cooking the grain with sodium bicarbonate added materially to its deficiency. I have cured polyneuritis gallinarum in the fowl b y the administration of fresh cow's milk in almost .as striking a manner as with the alcoholic extract of the antineuritic portion of the cereals. Maize is frequently the bread cereal In pellagrous countries. The sam e experiments detailed above have been done with wheat. It is not then a question so much of the particular cereal as it is of the, portioh removed in the milling. It would appear that the deficient portion of the several cereals in' these experiments was the water-soluble B. The part played by milk, in my experiments in curing p01yneuritis gallinarum, may have .been due to the small fraction of water-soluble B, though it remains to be seen whether or not in pellagra the dietetic fault lies in the lack of one or both of these elements. The following experience illustrates the point, Applying the principle underlying NIGHTINGALE'Swork, together with the suggestions derived from animal experimentation, :I fed pellagrins with the germ of maize with notably prompt improvement.- In one particular case the patient was in exfremis, and was being fed by the tube. The food given in this way wa.s eight ounces of fresh cow's milk, three eggs and one or two ounces of sugar of milk. ~ There was no notable improvement until a gruel, made of whea~t bran, was added, when at once the general condition of the patient greatly improved, though she eventually died the sudden death which I have so frequently noticed in this disease. It is obvious that the pellagra class as a rule could never secure th e expensive protein which would protect, regardless of the type Of deficiency underlying the disease. Since this economic solution does not lie within our reach, it becomes the more important exactly to determine the type of dietetic fault, in order that it may be practically corrected with as little expense as possible. Our experiments led us to suspect that the water-soluble B was more at fault by its lack than the more expensive fat-soluble A. Applying this suspicion practically, we have advocated the consumption of the whole cereal without the removal of a part in the milling and the cooking of the cereal without bicarbonate of soda as a rising agent. We found that the balance between acid and alkali in many baking, powders was so crudely struck that for the present, at least, we are advocating that they be avoided. The results are already encouraging. Whenever possible, milk, fresh meat, vegetables and other sources of fat-soluble A are added. If the problem is one simply of a too low protein level, or a too low biologic protein, there are many classes of sufferers that cannot be reached. If, however, we can finally determine that water-soluble B is the deficient element, it can be readily supplied at small cost. There is still much more work to be done before this matter is settled. Many were impressed during the war with a belief that while beriberi may be a

6

T H E ETIOLOGY OI,' PELLAGRA

deficiency disease, there must have been added an infectious element. One strong p o i n t along this line mentioned t o - m e by a careful observer was the occurrence of jaundice. Surely, if this is a reasonable suspicion in the case of beriberi, the case of pellagra cannot be counted solved, at this time, especially in the light of such observations as those of ENRIGHT, JOBLING, the THOMPSON-MCFADDENPellagra Commission, McCoLLUM, and finally, but probably most important of all, the epidemiological observations of SAMBON in Italy, Roumama, the United States and the West Indies. That nutritional errors do play a large part I do not doubt, t'Jor do I believe that an individual on a well-balanced diet, especially when milk plays a part, will develop the disease, but I am unwilling at this time to exclude the possibility of an infectious element playing a part which may be secondary but no less essential. I n North Carolina, it was noticed that pellagra occurred chiefly in the foot-hills below the high mountains ; that, as a rule, along the Atlantic seaboard tile incidence of the disease was nmch less. O u r cotton mills are located in the foot-hills of the mountains, chiefly because of the water power so easily had there. In tim high mountains the disease did not occur except very rarely. At one time it looked as though this distribution would coincide with the distribution of some insegt pest, but such has not been demonstrated. There appeared to be a direct relationship between the lines of railroad travel and the occurrence of the disease. One might view this as an indication of an infection. On the other hand, I have observed that there seems to be a connection between the appearance of the disease and the introduction of such manufactured products as commercial maize meal and patent wheat flour, supplanting the old primitive plan o f taking to the local water mill a small portion of maize, which was ground in z'oto and consumed before rancidity could occur. So far as a careful investigation of the manner of life of the people far removed from railroad travel and those living on the llne of the railroad goes, the only real difference consisted in the manner of milling and cooking the cereal. The mountaineer in many instances violated every hygienic rule, and his diet was certainly not ideal, but he escaped the disease. On the other hand, the dweller in tile foot-hills, working with all his family in a cotton mill, took whatever tile local merchant provided and adopted all measures of shortening and making easy the cooking process. Consequently, the latter got wheat flour with no cortex, maize meal milled without bran or germ, and all manner of chemical rising agents. With this latter class, pellagra finds its greatest number of victims. It was interesting to trace the outbreak of pellagra in a village, timing its appearance with the abandonment of the old grist mill to which each farmer carried his small portion of cereal for primitive grinding. There seemed to be a striking coincidence in the appearance of tile disease with the adoption of modern errors in millit~g and cooking. The American pellagra problenq differs from the Egyptian, essentially in the fact that diarrhoeal diseases are relatively infrequent in the pellagra class. It is true that those infected with the ]Vecalor americanus fall an easier prey, and that we have much more amoebic dysentery than is usually thought, but, in spite of these exceptions, it must be granted that the element of chronic diarrhoea, so much stressed by the Egyptian workers, will not materially befog the atmosphere, and that the application of the Egyptian findings to our problem will be most helpful and instructlve. While the time has not arrived for a definite conclusion, we have found in North Carolina that, for all practical purposes, a careful analysis of each diet and a correction of its errors bring protection, and oftentimes relief. I acknowledge with appreciation my debt to Captain GroG. F. CA'rLnTT, of the United States Army, for great aid in the chemical portion of this work.

REFERENCES. I. WOOD,E.J. " The Occurrence of Pellagra in the United States." ,7our. Americmz Med. Assoc: 1909 2. SA~U~ON,L.W. Brit. 2kfed.Jour. July 5th, I9I 3. 3" JOBLINGAND PETICRSON. jrottr. Infectious Diseases. 1916. XVlII.

FROM THE STANDPOINT OF A DEFICIENCY DISEASE, 4. 5. 6. 78. 9. io. ix. I2. 13. 14.

Report of the THOMPSON-MCFADDEN Conunission, Archives of Int. ivied., Oct., 1914; /our. American 3led. Assoc., Sept. 261h, 1914. GOI.DBEI/G],:R,JOSEPH. U.S. Public Z-fealtk l-?eiOorts. 'Nov. I2th, I915 ; Nov. t7th, 1916. WILSON, W. J. (unpublished Work). Quoted by the Report on the Present State of Knowledge concerning Necessary Food Factors (Vitamines). Medical Research Committee. 1919 . TIIOMAS, K. A r c M v . f Phys. I9o 9. Report of a Committee of Inquiry regarding the Prevalence o f Pellagra among Turkish Prisoners of VVar. four. ]?oval Army Medical Corps. Nov., 1919, to March, 192o, inclusive. BIGLAND, A . D . " T h e Pellagra Outbreak in Egypt." The Lancet. May Ist, 192o. ENRIGHT, J . I . " T h e Pellagra Outbreak in Egypt." Tke Lancet. May 8th, 192o. CItlTTENDEN AND UNDERHILL. Am.dgour. PkvsioL I9I 7. McCoLLUM, E . V . The Newe~" Knowledge of Nutrition. The Macmillan Co. I9I 9. NIGHTINGALE, P . A . Transvaal ~Ied..four. 19I 2. WooD, E . J . " The Vitamin Solution of the Pellagra Problem." [our. American ]?led. Assoc. I916. " T h e Etiology of Pellagra : a Consideration of Vitamin Deficiency." Trans. Assoc. Amer. Phys., 1916 , and Amer. Jou~: Med. Sci., Dec., I916-

DiscussioN. , The PRESIDENT: Dr. Wool), with his great experience of pellagra, has given us a very valuable and suggestive paper. He has examined the different views held in regard to the causation of the disease, and he has done it m a modest and scientific spirit. H e has given credit to those who have worked seriously at the subject, while he has upheld his own views in a very convincing manner. This attitude is very different from that of a recent writer, who, I am afraid, does not quite comprehend the scope of the enquiry into pellagra instituted by the British Committee, and parodies the conclusions without apparently taking the trouble to study the reports connected with the investigation. Dr. WOOD, on the other hand, has made very important observations, and tie shews, as nlany other investigators have, that the incidence of pellagra falls particularly-upon those whose diet is at fault. H e has shewn clearly, on the map and in the paper, that the incidence of pellagra in the country ill which he has worked has fallen chiefly on the inhabitants who live on the foot-hills, and whose diet consists largely of wheat flour without the cortex, and maize that is milled and loses.its germ. He also attaches very great importance--and has good reasons for it--to the fact that in using various chemicals for baking purposes, for the raising of the bread, the last straw is put upon the vitamines which may have been left. H e differs fi'om many observers in thinking that the watersoluble B is more important than the fat-soluble A ; and certainly, if his views are correct, great economy will be practicable , whereas in the "no-protein" view there is likely to be a difficulty in practice owing to expense. With regard to these nutritional diseaSes, we find that they are increasing largely in immber. We now have, according to some, leprosy added, and tubercle as welt We were always under the impression that these people were fed badly, but'now we seem to be getting to the root of the matter as to the particular element which is wanting. But if leprosy and tubercle are deficiency diseases, they also have with them an infective element, and I am glad to see that Dr. WoOD does not lose sight of the fact of'the extraordinary virulence of pellagra in its first invasion of his country. The sudden spread of the disease over a large part of the country is a matter which must not be lost sight of, and supports the view that there is some other agent associated with the deficiency element. I take it this paper shews that the solution Of the problem has not yet come--that it is necessary for further resea-ch to be carried out. Dr. P. MANSON-BAHR: In the absence of Drs. BIGLAND and ENR1GHT, I have been asked to relate sonic of theil: extensive experiences of pellagra in Egypt, and to shew