Tropical sprue: a discussion of the aetiology, diagnosis and treatment with a description of nine personal cases treated with folic acid

The problems presented by sprue have been discussed and the conclusions arrived at are set down under the headings of the various sections of this thesis.1. THE PHYSIOLOGY OF NORMAL FAT ABSORPTION. (a) VERZAR and McDOUGALL'S partition theory of fat absorption is discussed in the light of FRAZER'S investigations, which show that the partition theory will not account for certain observations made by himself and his fellow workers, chief of which is the fact that fat can be demonstrated to be absorbed by the intestinal cell in particulate and non hydrolysed form. (b) FRAZER'S work has been extensively quoted and described in full. His findings point to the conclusion that the failure to absorb fat in sprue is dependant on a breakdown of the process in the intra cellular phase and that the fault probably is to be found in the process of phosphorylation. (c) FRAZER'S findings suggest that absorption of triglycerides and of fatty acids occurs by different routes, the triglyceride being absorbed by the lacteals into the systemic circulation whereas the fatty acids appear to be absorbed into the portal circulation and thence pass to the liver.2. THE BIOCHEMICAL CHANGES IN SPRUE. (a) Absorption defects occur in sprue which affect many dietary constituents and are not limited to fat alone. 150 (b) The fallacy of assessing fat excretion by determining the faecal fat in a single stool specimen is stated: the importance of putting the patient on a known fat intake for at least two days before doing a fat tolerance test and then estimating the amount of fat excreted in the collected stools of 2 to 5 days, in order to determine the percentage of ingested fat which is excreted, is described. Excretion of more than 10% of the ingested fat is regarded as evidence of deficient absorption. (c) The stools of cases of sprue are not always of the typical bulky and frothy character: they may be normal on cursory examination and, only when examined by laboratory methods will steatorrhoea be discovered. The watery diarrhoea which may occur in cases of sprue is described: it responds to sulphaguanidine and therefore may be mistaken for dysentery. (d) The carbohydrate metabolism is discussed and MAEGRAITH'S findings regarding the difference between the absorption of glucose by mouth and intravenously are given and also the difference between the absorption of glucose and of fructose. The typical "flat" glucose tolerance curve found in sprue is described. (e) The dehydration and changes in the blood sodium chloride described by BLACK are noted, and also the fact that sprue diets, which contain only a normal salt content, require augmentation.3. THE AETIOLOGY OF SPRUE. (a) The tendency to couple sprue with other diseases such as pellagra and pernicious anaemia is criticized and reasons for not regarding these diseases as being a series of overlapping clinical conditions due to the same basic aetiological factors are given. (b) The theory that tropical sprue, coeliac disease, idiopathic steatorrhoea and non tropical sprue are essentially the same is discussed and it is concluded that, in our present state of knowledge, there is insufficient evidence for regarding these conditions as having the same aetiology and, although it is admitted that they all show biochemical similarities, the term "sprue" in this thesis is used to refer to tropical sprue only. (c) Certain facts regarding geographical distribution, race, age and preceding infection are stated as they appear to have a bearing on the incidence of sprue. (d) The condition of "Hill Diarrhoea" is discussed. It is concluded that this condition is often one of the modes of onset of sprue: if it is not the precursor of recognisable sprue it is concluded that proper investigation of the cases will reveal the cause of the diarrhoea. "Hill Diarrhoea" is not admitted to be a disease entity. (e) The work done during the past fifteen years and the theories propounded are stated and criticized. STANNU.S'S theory that phosphorylation is dependent on catalysation by co- enzymes which catalyse the phosphorylation of fats and polysaccharides, and that these co- enzymes are identical for both, is discussed. It is concluded that, as cases of sprue often show defective fat absorption but a normal glucose tolerance curve, there is a difference between the factors which affect the phosphorylation of fats and sugars respectively. (f) It is concluded that no evidence has been established for regarding deficiency of the adrenal cortex as an aetiological factor in sprue. (g) The róle of vitamin deficiency in the causation of sprue is discussed. MANSON- BAHR'S theory that nicotinic acid and riboflavine deficiency is responsible for the incidence of sprue is criticized. LEISHMAN'S theory concerning interference with the biosynthesis of vitamins in the intestine is discussed. It is concluded that there is not sufficient evidence to support the theory that deficiency of the vitamin B2 complex is a fundamental factor in the aetiology of sprue, with the exception of folic acid, which, judged by the results of its administration, appears to replace a deficiency. (h) DAVIDSON and GIRDWOOD'S conception of a liberating factor in the liver, deficiency of which is responsible for the production of pernicious anaemia, is described. It is concluded that, in view of the inconstant blood picture in untreated sprue and its variable response to treatment, that deficiency of folic acid or "liberating factor" is not an aetiological factor in sprue, although it may play a part in the production of the blood picture in some cases. (i) The enormous increase in the incidence of sprue among our troops in India and the Far East during the last war is contrasted with its virtual non -occurrence among the prisoners -of -war in Japanese hands. These were living under identical or even greater hardship. It is emphasized that these prisoners did not develop signs of sprue when they were repatriated and were taking a diet which contained a normal fat content. The difference in the incidence of sprue between these two groups is attributed to the difference between the dietary fat intake of the two groups and it is concluded that a certain intake of fat is essential to the development of sprue and that this is an essential aetiological factor. (j) The type of fats in the diets of different races is considered and it is concluded that the type of fat ingested in the diet may be an aetiological factor of importance in sprue. It is suggested that diets in which fats occur mainly as vegetable oils may react differently to the circumstances which produce sprue from diets in which the fats are predominatingly of animal origin.4. THE DIAGNOSIS OF SPRUE. (a) An effort has been made to confine the condition of sprue within certain limits so that it may be possible to define it clinically. Therefore the clinical picture and differential diagnosis have been set down. The finding of steatorrhoea, which cannot be explained as being secondary to any other pathological process, is considered an essential which must be present at some phase in the course of the disease to warrant the diagnosis being made. (b) The X -ray findings in the intestine are described and it is noted that these findings are not confined to sprue but are seen in other deficiency syndromes. It is not considered justifiable to ascribe the dilatation of the colon to bulkiness of the stools because this finding occurs in cases which are in a state of clinical recovery and whose stools are not bulky: it is suggested that this dilatation of the colon must be due to atony of the large intestine. (c) The glucose tolerance curve, if flat in character, is of value in confirming the diagnosis of sprue but it is not exhibited in all cases. (d) Loss of weight is an important sign of active sprue: when the patient regains weight it is considered to be a sign of remission and reestablishment of absorption from the gut, although a degree of steatorrhoea and anaemia may persist after the body weight has returned to normal. 155 (e) The blood picture is described and it is noted that in some cases the blood changes are normal or slight in degree. (f) The differential diagnosis of sprue is discussed.5. THE TREATMENT OF SPRUE. (a) The treatment is described under sections dealing with the general management, dietary treatment, vitamin therapy, liver therapy and treatment with folic acid. (b) The general principles of treatment are stated and the importance of rest in bed and the treatment of dehydration is stated. (c) Graduated diets used in the Army are given in Appendix No. 3. (d) The use of vitamins other than Folic Acid is not considered to be so important in the treatment of sprue as many workers believe. The main indication for their use is to treat concomitant vitamin deficiencies, such as scorbutic symptoms, which may complicate sprue. Other than this it is not considered necessary to give vitamins, provided the diet is adequate in them. The fact that cases of sprue can be maintained on yeast as described by BLACK and FOUBMAN is noted but it is considered that this therapy has no advantage over a daily maintenance dose of 5 mgms. of folic acid by mouth. 156 (e) The results of liver therapy are discussed: crude extracts seem to be more beneficial in sprue than are more refined extracts: it is also noted that steatorrhoea may persist after general clinical improvement and that the response of the blood to liver therapy, even in cases which exhibit macrocytic anaemia, is usually not so complete as is the response in pernicious anaemia. (f) The early work on folic acid and the results of the first clinical trials by SPIES, DARBY et. al. are described. DAVIDSON and GIRDWOOD' S conception of a "liberating factor" (L.F.) in the liver which enables the liberation of free folic acid from conjugated folic acid is discussed. (g) Nine cases of sprue treated with folic acid are tabulated and summarised. It is noted that folic acid may produce clinical improvement in cases which have failed or ceased to respond to liver therapy. Folic acid causes rapid improvement in the general condition but in some cases the steatorrhoea does not revert to normal, though it may be improved, and often the blood picture cannot be restored to normal completely. (h) It is considered that larger doses of folic acid are necessary for the treatment of sprue than for the treatment of pernicious anaemia and 157 that maintenance therapy may be required for some time in order to retain the health recovered. (i) The action of folic acid in reducing the fluid in the stool is not understood. It is concluded that it must perform this by affecting the absorption of fluid from the large intestine. (j) It is considered that the use of folic acid represents an important advance in the treatment of sprue and that it should be used in all cases if available