Sprue. Its applied pathology, biochemistry and treatment

't81 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. XXIV. No. 2. August, 1930.

PAPER.

SPRUE. ITS APPLIED PATHOLOGY, BIOCHEMISTRY AND TREATMENT. BY

N. HAMILTON FAIRLEY, O.B.E., M.D., D.Sc., F.R.C.P. (Assistant Physician and Director of Pathology, London Hospital for Tropical Diseases ; Lecturer in Applied Pathology, London School of Hygiene and Tropical Medicine).

TABLE

OF CONTENTS.

I. Clinical Features and Etiology. II. Morbid Anatomy of Sprue. (1) (2) (3) (4)

Alimentary lesions. The viscera. The bone marrow. The causes underlying bone marrow changes. (a) Gastric derangement and megalocytic anaemia. (b) Malnutrition and aplasia of megaloblastic marrow.

III. The H~ematological Findings in Sprue. (1) (2) (3) (4)

The The The The

anmmia. colour index. average diameter of the corpuscle. blood picture and reticulocyte count.

182

SPRUE. IV. Gastric Secretion in Sprue. (1) Fractional test meal analysis. (2) Histamine injections. (3) Analysis of the present series. V. The Bilirubin Content of the Serum. VI. The Serum Calcium and Phosphorus in Sprue. (1) Total serum calcium. (2) Serum phosphorus. (3) Commentary. VII. The Blood Cholesterol in Sprue.

VIII. Analysis of F~ecal Fat in Sprue. IX. The Rational Therapeutics of Sprue. (1) General Treatment. (2) Diet. (a) Considerations underlying the selection of a suitable dietary. (b) Milk. (c) The fruit diet. (d) The red meat treatment. (e) High protein, low fat, low carbohydrate diet. ( f ) Intestinal features. (g) Weight. (h) Insulin and glucose treatment. (3) Liver Treatment in Sprue. (4) Reinforcement of Demonstrable Deficiencies. (a) HC1 administration. (b) Calcium deficiency. (c) Commentary. X. Symptomatic treatment. XI. Summary. XII. Conclusions.

N. HAMILTON FAIRLEY.

188

SPRUE. ITS

APPLIED

PATHOLOGY, BIOCHEMISTRY AND TREATMENT.*

Tropical sprue or psilosis was first accurately described by HILLARY in 1766, and though its identity as a separate clinical entity has from time to time been assailed, the pioneer tropical physicians such as HII~LARY in the Barbados, VAN DER BURG in Java, and MANSON in China, have never doubted that it was a disease sui generis. I. CLINICAL FEATURES AND ETIOLOGY. Once seen, the fully developed picture of sprue makes an indelible impression on the mind of the physician. Such a patient is not infrequently semistarved, mentally taciturn, intensely hungry, liable to indulge in dietetic orgies, and literally " wolfing " food with possibly fatal consequences. T h e skin is frequently parched, wrinkled, discoloured, and sometimes pigmented, the brownish yellow pigment being especially c o m m o n over the forehead, the malar eminences and at the bases of the finger nails. T h e anaemia is severe, and is generally associated with an extreme grade of emaciation. Apyrexia is invariable in uncomplicated sprue, and frequently the temperature is subnormal. T h e tongue is patchily inflamed, atrophic and sometimes ulcerated, while the thin abdominal parieties scantily protects the attenuated coils of gas-distended bowel visible beneath. Hypotension is marked, and the asthenia is profound. On questioning such a patient, one gets a history that the tongue is sore, that aphthous ulcers frequently involve the mouth, and that all condiments, spiced and hot foods cause intense pain. (Esophageal burning and flatulent dyspepsia are not infrequent. T h e patient complains bitterly of the passage per rectum,

* Acknowledgments.--The views expressed in these pages have been the outcome of several years' work on sprue both in India and London. I would take this opportunity of expressing my indebtedness first of all to my friend Colonel F. P. MACKtE, I.M.S., with whom I was originally associated at the Haffkine Institute, Bombay, and more recently to my colleagues at the London Hospital for Tropical Diseases, Dr. G. CA~MICHAELLOW, Dr. MANSON-BAHRand Sir LEONARDROGERS,who have all generously placed their clinical material at my disposal. Without their co-operation no complete investigation could have been made. In the new hospital laboratories, Mr. R. J. Bromfield in the biochemical section, and Mr. F. W. Foster and Mr. H. P. Lillies in the routine h~ematological examinations, have rendered invaluable assistance. The medical superintendent, Dr. W. E. COOKE, the resident medical officer, Dr. C. J. HACKETT, and Dr. K. LINDSAY, as well as the sisters and nursing staff, have had much additional work in connection with the investigation, and I wish to record my appreciation of the cordial manner in which they have always rendered assistance. Finally, the Hospital is indebted to Messrs. Eli Lilly & Co. for their generosity in placing at our disposal valuable supplies of liver extract for therapeutic purposes. /

184

SPRUE.

especially in the early morning, of several pale or greyish-white, bulky, gaseous stools. Abdominal distension and intestinal flatulence are also troublesome features; they tend to come on towards evening, and are most commonly related to the carbohydrate intake, abnormal fermentation of which leads to excessive acidity and gas production. (Edema of the feet, cramps, and tetany are occasionally observed. But sprue is not always so typically manifested as in the picture drawn above, nor do the stools by any means invariably conform to the classical type. Not infrequently enteritis is a primary lesion, and in endemic areas a recurrent apyrexial diarrhoea should always be suspect, as it may precede the onset of typical lingual and other manifestations by many months. Similarly, at the onset of acute relapses and as a terminal event frequent brown or yellowish fluid stools bereft of all distinctive sprue characteristics are commonly encountered. In yet another group the predominance of anaemia and gastric features may make early recognition difficult, and as the blood picture is megalocytic in type confusion with pernicious anaemia may readily occur. Here the absence of any evidence of subacute combined degeneration of the cord, the presence of marked loss of weight and certain laboratory tests to be detailed later in this paper may be the only means of making a diagnosis. The causation of sprue is unknown, but theories concerning its origin are almost as numerous as the mathematical possibilities will allow. Some would identify sprue with pellagra on the one hand, and pernicious anemia on the other, while certain observers have regarded amoebic or bacillary dysentery as a necessary antecedent. No one, however, has yet suggested why a dysenteric process essentially involving the colon should be followed by a disease which dominantly affects the small intestine. ELDERS (1919) holds on very insecure evidence that it is a deficiency disease due to lack of vitamins A and B and amino-acids, while SCOTT (1923) has developed the view that a decrease in ionic calcium due to parathyroid involvement is the essential cause. ASHFORD(1915) claims to have isolated a specific yeast, Monilia psilosis (ashfordi), which is the causative agent. The fungoid theory has, however, not been supported by recent work, and it is interesting to note that ASHFORD himself is placing increasing stress on the background of glandular deficiency on which moniliasis develops. Perhaps the most suggestive observation of recent years has been the isolation by MACKIE and GOR~. (19.298) of a pleomorphic organism allied to Bacillus mallei. Twice this was obtained in pure culture from the circulating blood of sprue cases, and in another instance from the duodenal contents, but the authors are rightly reticent about yet assessing its etiological significance. In the present communication it is not my object to dwell at further length on this vexed question of etiology except to point out that none of these theories have fundamentally changed the therapeutics of sprue, and that, in the absence

N. H A M I L T O N FAIRLEY.

135

of an accepted infective agent, so-called specific therapy, such as the administration of a monilia vaccine, has been attracting a decreasing number of adherents. This being the case, I believe the clinician must turn elsewhere for assistance, and in clinical, pathological and biochemical studies seek for the essential mechanism involved in the production of the sprue syndrome. This ascertained there is some prospect of establishing the treatment of this disease on a rational basis. II. MORBID ANATOMY OF SPRUE. From a pathological viewpoint the essential lesions of sprue consist of an atrophic enteritis, atrophy of the viscera consequent o n malnutrition, and a megaloblastic and aplastic condition of the red marrow. (1) Alimentary Lesions. In sprue inflammatory and atrophic lesions may extend from the tongue to the rectum, but one of the most characteristic features is their patchy distribution. In the early stages or during acute remissions the whole tongue may be inflamed and the papilla~ prominent. Localised areas of redness and injection of vessels are frequently encountered, while small ulcers also occur. More frequently all evidence of preceding inflammation has disappeared by the time the patient comes to autopsy. Fissuring is common, and thinning and atrophy of the mucous membrane with destruction or disappearance of the fungiform and filiform papilla~ are very characteristic. Sometimes the circumvallate papillm are destroyed as well. The oesophagus generally shows no characteristic changes. Not infrequently the stomach presents a normal appearance, though collapse, atony and thinning of its muscular coats,, focal congestion of vessels and petechial ha~morrhages in the mucosa may be found. Its microscopical pathology has been inadequately studied. Segments of the small intestine often present a ballooned and diaphanous appearance, atrophy in some cases being extreme and generalised. On section, ecchymoses, thinning of the mucous membrane, superficialerosion of epithelium, patchy congestion and injection of vessels may be met with. Submucous cysts occasionally occur, but actual macroscopical ulcers are infrequent. Somewhat similar changes may occur in the duodenum, but generally they are most marked in the ileum. Congestion of vessels and mucosal atrophy may also be observed in the colon, the walls of which may be normal, thickened or thinned. Occasionally pathological lesions terminate with striking abruptness at the pelvi-sigmoid flexure. Microscopic examination of the small intestine suggests that an atrophic enteritis constitutes the essential lesion in sprue, but, as in the tongue, the initial inflammatory lesions are patchy in distribution, transient in duration, and not always evident at autopsy. The earlier changes undoubtedly involve the villi which show an infiltration with small round cells and a degeneration

136

SPRUE.

and disappearance of their epithelial covering, finally culminating in an acellular shrunken condition described as " withering of the villus." The glands of Lieberktihn are not affected until later, but they, too, eventually degenerate, the cytoplasm showing a loss of staining reaction, and the nuclei swelling up and disintegrating. The submucous layer at certain stages shows congestion of vessels and leucocytic infiltration, while subsequently an increase in connective tissue cells may occur. The muscular tissue is certainly much reduced in bulk, but its fibres and nuclei appear healthy. The serous coat is normal. The entire absence of fat in the intestinal wall contributes to the appearance of tenuity which is so characteristic a naked eye as well as a microscopic feature in sprue, but we regard malnutrition as a secondary and not the primary factor responsible for intestinal atrophy. (2) The Viscera. Apart from loss of adipose tissue, muscular wasting, and atrophy of the internal organs, no changes of importance occur. That much-stressed physical sign--decrease in the size of the liver--does not imply specific atrophy of this organ, but is essentially related to chronic starvation in which depletion of the glycogen store resulting from deficient carbohydrate intake is an important factor. Similarly the pancreas, which has so often been incriminated, shows no constant pathological changes. Modern biochemical tests support these conclusions, for they fail to reveal any functional inefficiency of the liver and pancreas, or any significant alteration in the external secretion of the latter organ. The pathology of the parathyroids has been investigated by BARACH and MURRAY (1920) and BAUMGARTNERand THOMAS (1925) in cases of tetany, and by FAIRLEY and MACKIE (1929) in three cases of sprue showing decrease in ionic calcium. Microscopic examination in all five cases revealed no abnormality. In the starving animal 97 per cent. of the adipose tissue may disappear, and the weight of the liver be diminished by one-half, yet the brain and the heart may not have lost more than 3 per cent. of their original weight. In sprue great diminution in the size of the heart has been recorded, while microscopic section may show the presence of brown atrophy, but rarely of fatty change. MACKIE and FAIRLEY (1929) pointed out that as the heart is generally increased in weight in pernicious anaemia, this atrophy may prove an important differential finding at autopsy ; it possibly also underlies the low blood pressure and astheni~, which are such characteristic clinical features of this disease. (3) The Bone Marrow. Aplastic and megalocytic anaemia have for many years been recognised as occurring in sprue, but until recently the variable blood findings have never been explained in terms ot the underlying bone marrow changes.

N . H A M I L T O N FAIRLEY.

137

FAIRLEY and MACKIE (1926) described the occurrence of megaloblastic, hyperplastic and aplastie conditions of the bone marrow in sprue, and more recently (1929) reported a more extensive series of observations in eight fatal cases. They found in two a red megalobtastic marrow indistinguishable from that met with in pernicious anaemia ; in others a jellified, aplastic marrow in which the cellular elements were conspicuously absent, while the last group were of mixed intermediary type. The conclusion reached was that the primary response of the red marrow in sprue was essentially megaloblastic, and that aplasia was a later phenomenon. Areas of red marrow persisting in the latter condition were found to be megaloblastic, and these authors pointed out that it was the persistence of these loci which accounted for the high colour indices and the megaloeyfic type of the Price-Jones curves observed in the so-called aplastic anmmia of sprue. In fixed stained films aplastic anmmia is generally characterised by the preponderance of erythrocytes measuring less than 7.2 m. in diameter, while the colour index is low. Presumably this is because the aplasia primarily involves erythroblastic or normoblastic marrow. In sprue, on the other hand, it is a megaloblastic marrow which undergoes degenerative aplasia. KRJUKOFF(1928) investigated the red marrow of the ribs at biopsy. In all such cases even with counts of from 3 to 3½ million corpuscles per c.mm., a megaloblastic reaction was present. Generally, lymphoid erythroblasts of all sizes, including normoblasts and megaloblasts, were found, and even in the earliest stages when the red cells equalled 4½ millions per c.mm., and the colour index was 0.8, megaloblasts were demonstrated in the rib marrow at biopsy. (4) The Causes underlying Bone Marrow Changes. FAIRLEY, MACKIE and BILLIMORIA (1929) put forward the view that the basis of sprue anaemia lay in deficient blood production rather than excessive blood loss, and considered t h a t the trouble started in an ill-nourished bone m a r r o w which, poisoned b y s p r u e toxin of alimentary origin, undergoes a p r i m a r y megaloblastic h y p e r t r o p h y and secondary atrophy. I n the production of the latter state toxins p r o d u c e d b y a changed intestinal flora and secondary bacterial invaders were conceded to play some part. Since this paper was written m u c h f u n d a m e n t a l w o r k has b e e n done by A m e r i c a n investigators on the whole subject of blood f o r m a t i o n , and I believe the application of this knowledge t O sprue sheds n e w light on the m e c h a n i s m of the production of bone m a r r o w changes so peculiarly characteristic of this disease.

(a) Gastric derangement and megalocytic anaemia.--CASTLE (1929) has shown that normal gastric juice can elaborate f r o m beef muscle, material that promotes normal blood degeneration, b u t that this power is absent f r o m the gastric secretion of patients suffering f r o m pernicious anaemia. T h e absent factor is neither pepsin, hydrochloric acid, nor any other k n o w n constituent of gastric juice. CASTLE'S w o r k suggests that its absence underlies the megalocytic hyperplasia of the b o n e m a r r o w in pernicious anaemia, and he has shown that beef digested with n o r m a l gastric juice and re-fed to pernicious anaemia patients gives rise to a characteristic reticulocyte response comparable in all respects with that elicited b y feeding liver extract. I n sprue we know b o t h f r o m clinical observation a n d fractional test meal findings that the stomach is frequently involved, and it is not i m p r o b a b l e that a similar derangement of gastric secretion underlies the megalocytic anmmia so frequently observed.

188

SPRUE.

Certainly a repetition of CASTLE'S work substituting sprue for pernicious anmmia patients is indicated. Another alternative is that even if this substance be produced normally in the stomach it may not be adequately dealt with in the small intestine. VAUGHAN (1930) recently pointed out this possibility in an able review on the liver treatment of anaemia, suggesting that the intestinal wall in sprue may be unable to absorb the first stage of the breakdown product formed by the action of some enzyme present in the stomach on the protein of the food. The final product is obviously readily absorbed since the response to liver therapy as shown in the present series of cases is strictly comparable to that observed in pernicious anmmia.

(b) Malnutrition and aplasia of megaloblastic marrow.--Granted that some unknown derangement of gastric secretion or malabsorption underlies the megaloeytie anaemia of sprue, what is the explanation of the superadded aplasia of the bone marrow so characteristic of the former disease and so rarely if ever met with in true Addisonian anmmia ? MULLER (1927) has shown that the bone marrow of the healthy grain-fed pigeon is normally of the same type as that met with under the pathological conditions of a megaloblastic hyperplasia in man. DOAN, CUNNINGHAM and SABIN (1925) have minutely studied both the anmmia and the aplasia which such a marrow undergoes when pigeons are starved until they have lost approximately 125 grams in weight. This generally occurs in from ten to seventeen days, by which time the red marrow normally present in the tibia and fibula has become yellow and fatty, being transformed into a relatively acellular tissue. On re-feeding, this marrow undergoes a rapid regeneration, being first transformed into transparent greyish gelatinous marrow before restoration to its ordinary hyperplastic state. Atrophy of the intestinal mucosa with withering of the villi is a characteristic lesion of sprue. It results in deficient absorption of fat, calcium, and possibly other products of digestion. Profound nutritional disturbances follow, and I suggest on the analogy of MULLER'S findings in pigeons that malnutrition per se is the essential factor responsible for the aplastic transformation of the megaloblastic marrow observed so frequently at autopsy in sprue cases but not in Addisonian anmmia. Further, it is probable that the condition of the bone marrow is subject to considerable fluctuation from time to time, the quantity of frankly megaloblastic, aplastic and regenerative marrow present in the long bones being determined by the intensity of involvement of the gastrointestine at'ihe particular time at which the examination is made. i i i . THE H/EMATOLOGICAL FINDINGS IN SPRUE. When a sprue patient first seeks medical advice the anmmia is rarely so severe as that met with at a corresponding stage of pernicious antemia, but during

189

N. HAMILTON FAIRLEY.

its subsequent course grave anaemia may develop. Practically all patients dying from sprue present a megalocytic anaemia of severe type. (1) The Amemia. T h e grade of anaemia met with in the present series of cases admitted to the L o n d o n Hospital for Tropical Diseases during the past twelve months shows a remarkably close approximation to a recent tropical series,* and for purposes of comparison the average results are tabulated below. PROTOCOL No. I. THE H.ZEMOGLOBIN PERCENTAGE AND RED CELL COUNT IN SPRUE.

Series.

No. of Cases.

R.B.Cs. per c.mm.

Per cent. of H~emoglobin.

Colour Index.

Haffkine Institute, Bombay

63

3,242,000

65.5

1-0

London Hospital for Tropieal Diseases.

28

3,195,000

61.7

1.0

It will be seen that the series under review presents a slightly greater average grade of a n e m i a , but that in both the colour index averages unity. T h e following group distribution in the total red cell counts were noted : 1 case showed counts u n d e r 2 cases ,. . . . . 6 ,. . . . . . . 13 . . . . . . . , 6 . . . . . . . .

1,000,000 per c.mm. 2,000,000 ,, 3,000,000 ,, 4,000,000 ,, 5,000,000 ,,

Similarly, the haemoglobin values were subject to considerable variation, readings varying from 16 to 85 per cent. being recorded. T h e average value in the present series equalled 61.7 per cent. (2) Colour Index. Utilising the Haldane method of estimating h~emoglobin, the normal colour index may be taken as 0.9. In both the Bombay and L o n d o n series the mean was 1-0, showing that the average percentage reduction of h~emo* This series was reported by

FAIRLEY,

MACKIE and BILLIMORIA(1929).

140

SPRUE.

globin was, if anything, less than that of the corpuscles. were as follows : 1 case showed a colour index of 0.7 9 cases ,, ,, ,, 0.9 8 5 3

. . . . . . . . . . . . 1 case ,. 1 . . . .

. . . . . . . . . . . . . . . . . . . .

The actual results

1.0

1-1 1.2

1-35 1.5

Such uniform high colour indices indicate that in the anaemia of sprue the average load of h~emoglobin carried by each corpuscle is definitely in excess of that met with in health, and supports the megalocytic nature of the anaemia in this disease. Any doubt that may exist regarding this question is dispelled when actual measurements of the average diameter of the corpuscles are considered. (3) T h e A ¢ , e r a g e D i a m e t e r o f the C o r p u s c l e i n S p r u e . Several different methods of estimating the diameter of the red blood corpuscle, including direct microphotography, Price-Jones curves and halometer measurements, have been employed. Probably the most accurate is that of PONDER and MILLER (1924), in which corpuscles are photographed under suitable optical conditions, measurements being made from the negatives. Even with the greatest care an error of 0.2 microns is admitted. With this technique measurements for corpuscles suspended in plasma averaged 8"8 microns, for dried films 7"6 microns, and for dried and stained films 7.2 microns. PRICE-JoNES (1920) curves have also proved of great value in both clinical and experimental investigations for, besides giving the average diameter in the stained and fixed film (7.2 t~), the group distribution of different sized corpuscles is portrayed, and abnormal ranges accurately defined. HAMPSON and SHACKLE (1924) and PASSEY and BRAINE (1924) first investigated Price-Jones curves on a series of sprue cases under the care of Dr. CARMICHAELLOW. Later NEWHAM, MORRIS and MANSON-BAHR (1926), FAIRLEY, MACKIE and BILLIMORIA (1929) and ASHFORD (1930) have reported their findings. Forty-three out of fifty-one of the combined series showed megalocytic anaemia. All observers except NEWHAM, MORRIS and MANSON-BAHR tound an increase in the average diameter of the corpuscle with great frequency. A definite shift to the right undoubtedly occurs in the great majority of cases, and in most instances a well-defined widening of the base of the curve is also observed. In the present series of cases measurements made by means of Eve's halometer (1928) were substituted for the more informative Price-Jones curves. This instrument, based on the physical principle of diffraction grating,

N . H A M I L T O N FAIRLEY.

141

promises to be of considerable value in hmmatology provided the instrument is correctly calibrated and certain elementary precautions are adopted in its use. Clean, grease-free slides and uniform thin films are essential. In addition, where a series of observations are being made on the one case, it is an advantage if they can be made continuously b y the same worker, any slight individual variation in interpreting the exact point of peripheral contact of the halos at the red end of the spectrum thus being avoided. T h e initial readings in twenty-two cases of sprue were as follows : 1 case showed an average corpuscular diameter of 7.4 microns. 2 cases ,, ,. . . . . . . . . 7.6 ,, 2 ,, ,, ,, ,, ,, ,, ,, 7.8 ,, 4 . . . . . , ,, ,, .... 8.0 ,, 2 . . . . . . . . . . . . . . 8.2 ,, 8 ,, ,. . . . . . . . . ,, 8.4 ,, 3 ,, ,, ,, ,, ,. . . . . 8.6 ,, With this instrument a diameter of 7"6 microns in the dried unstained film is considered to be the u p p e r range of normality, and on this basis nineteen out of twenty-two anemias must be definitely regarded as megalocytic. T h e mean corpuscular diameter for the whole series equalled 8-16 microns, while in eleven cases the initial measurement either equalled or exceeded 8"4 microns. Another very interesting feature which also shows the value of the method is that clinical i m p r o v e m e n t was generally accompanied b y a progressive decrease in the average diameter of the red cell.

(4) The Blood Picture and Reticulocyte Counts in Sprue. T h e morphological and tinctorial changes observed in the blood picture in sprue are usually related to the degree of a n e m i a present, the milder grades generally showing less distinctive features. T h e outstanding characteristic of the blood film is u n d o u b t e d l y an anisocytosis with excess of megalocytes. Microcytes are m u c h less in evidence. Poikilocytosis and polychromasia may occur. Punctate basophilia, nucleated red cells and even megaloblasts may be encountered in severe cases with a red cell count under 2,000,000 corpuscles per c.mm., but they are observed with less frequency than in pernicious anaemia of similar intensity. Evidences of c o r p u s c u l a r regeneration, however, are often lacking in a frankly megalocytic blood picture, and the explanation of this fact as well as of certain other h~ematological anomalies is to be found in the hypoplastic or aplastic changes which the megaloblasfic marrow so frequently undergoes in this disease. In untreated cases reticulocytes occur within normal limits. T h e counts varied in ten consecutive cases of the present series between 0.1 to 2.0 per cent., the average equalling 1 per cent.

142

SPRUE.

IV. GASTRICSECRETION IN SPRUE. In pernicious anaemia a condition of achylia gastrica is present; consequently it becomes a matter of importance in every megalocytic anaemia to determine whether free HCI is present in the gastric juice. (1) Fractional Test Meal Analysis. Different observers have reported divergent results in fractional test meal examinations in sprue, and for purposes of comparison I have tabulated the results in a tropical series of twenty-six cases reported by FAIRLEY, MACKIE and MALANDKtlAR (1926) from Bombay with the series now under review. For this purpose the cases have been arranged in four groups, the achlorhydric comprising those showing no free acid, the hypochtorhydric those not exceeding N a maximum of 20 c.c. ~ HC1 and the hyperchlorhydric those exceeding N 60 c.c. 10 HC1. Those classified as normal show curves falling between 20 c.c. N and 60 c.c. iO HC1. PROTOCOL NO. 2. THE FRACTIONALTEST MEAL IN SPRUE. I

Series.

Total Cases.

Haffkine Institute, Bombay.

26

London Tropical Diseases Hospital.

18

Totals

..

44

Achlorhydric.

Hypochlorhydric.

Normal.

14

11

15

Hyperchlorhydric.

It will be seen from a perusal of this table that eleven out of the present series of eighteen cases, and thirty out of the combined series of forty-four cases showed free HC1 on fractional test meal analysis. Fourteen cases of achlorhydria remain in which this test affords information of no definite value in differentiating sprue from pernicious anaemia. (2) Histamine Injections. Achlorhydria as revealed by the fractional test meal is by no means synonymous with achylia gastrica. It may equally well result from psychical or other reflex causes leading to a temporary inhibition of the secretory activities of the oxyntic cells, or from a direct chemical neutralisation by regurgitated duodenal

N° HAMILTON FAIRLEY.

148.

juice, especially where free HC1 is present only in small quantity. The total~ chloride curve has been generally regarded as affording an index to the secretory function of the stomach, and until recently inorganic chloride has been accepted as originating for the most part from HC1 which has undergone neutralisation especially by regurgitated duodenal juice. In the Bombay series of achlorhydric cases the total and inorganic chloride curves often closely approximated. These findings were regarded by FAIRLEY, MACKIE and MALANDKItAR (1926) as indicating that the condition originated in some cases at least as a neutralisation achlorhydria. McLEAN, GRIFFITHS and WILLIAMS (1928) have shown that in an isolated Pavlov pouch produced experimentally in dogs, both sodium chloride and HC1 are secreted by the gastric mucosa, the chloride secretion being high at a time when acid secretion is low. This being the case, it is obvious that other measures must be adopted in the investigation of achlorhydria. Two tests are being used, both depending on the administration of substances which have a strongly stimulating effect on acid secretion. The first consists of the alcohol test meal, the second of the subcutaneous administration of histamine, and evidence is steadily accumulating that the latter procedure affords a satisfactory means of differentiating true achylia gastrica from neutralisation and other forms of achlorhydria. CARNOT, KOSKOWSKI and IABERT (1922) examined the gastric: secretion after histamine injection in cases of pernicious ansemia with achylia gastrica, and GOMPERTZ and VORHAUS (1925) used histamine hydrochloride injected subcutaneously (1 c.c. of 1/1,000 solution) to distinguish between pseudo-achylia and organic achylia gastrica in 17 cases showing a complete absence of free HC1 and markedly diminished total acidity after the Ewald test meal. Ten (59 per cent.) showed large amounts of free HCI as a result of histamine injections. FABER a n d HOLST (1928) failed to find free HC1 in patients with pernicious ansemia after histamine injections, but in one case the pepsin content increased. BLOOMFIELD and WYCKOFF (1927) did gastric analysis after histamine in two cases of sprue, and found that increased volume, and acidity resulted in both cases. (3) Analysis of the Present Series. In the present series of cases ~ to ½ mg. of this drug has been given during the progress of the fractional test meal two hours after the gruel has been administered. Thirteen out of eighteen cases showed a definite secretory response, while in five of the seven cases we may assume that a true achylia gastrica existed since no free HC1 resulted. Gastric involvement in sprue undoubtedly results in decreased acidity. I have observed a condition o f hyperacidity change into one of hypochlorhydria with the onset of this disease, the hyperchlorhydria reappearing with recovery some years later. Similarly a normal acid curve may give place to one of hypochlorhydria which in turlx may pass into achlorhydria or even achylia gastrica.

144

SERVE.

JOHANSEN (1929) investigated achylia in nineteen cases of pernicious anaemia treated with liver extract three to seventeen months previously. In all instances other symptoms had subsided or improved considerably, but in none did acid secretion follow histamine injection. In these sprue cases presenting achylia gastrica it was only possible to reinvestigate three. Of these two developed the power to respond to histamine within three months of treatment, and both were also secreting a small quantity of acid in the ordinary fractional test meal. The third case, re-examined at a month's interval, showed no secretory response whatever. Other cases of achlorhydria responding initially to histamine, were also observed to improve, one developing a hypoehlorhydric curve and another a normal curve after liver treatment and high protein dietary ~(Graph No. 1 and Protocol No. 3). GRAPH

%

Fasting

No.

I~

% 3.~ lhr I~|½

l.

FRACTIONAL

2hr2k2~

TEST-MEAL.

2 ~ 4 3 h r 3 ~ 3%

k

~

Starch 0

÷

+

+

+

+

+

+

+ +

150

140 tzo

0

+

+

2~3hr3~

3½

olo

o

o o I oo

o o!o

Bile

+l

+

+ trio

0

S~rch • 547

+

0

0 .0

I

q

~30

+

9.

3.~ lhr 1~41½ 1~ 2 h r 2 ~ 2 ~

oo'o

Bile

CASE NO.

510

cq ~

....

~474 438

(5

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The shaded area represents the limits of free HC1. (dimethyl indicator), of 80% of normal people. represents free HC1. • represents total acidity.

From'. these observations it appears evident that during and following ,clinical recovery the oxyntic cells tend to resume a more normal function, cases of achylia gastrica developing the power to respond to histamine and to produce small quantities of acid normally, while in achlorhydric and hypochlorhydric cases the original curve of acid secretion tends to be established. Observations along these lines are being continued. It is possible in some

N. HAMILTON FAIRLEY.

145

long standing cases that as in pernicious anaemia the achylia may prove to be permanent. The question affects after treatment, for absent or defective normal secretion is obviously an indication for continued acid medication. PROTOCOL NO. 3. THE EFFECTS OF TREATMENT ON ACID SECRETION AND THE

HISTAMINE RESPONSE IN SPRUE.

C ise o.

D a t e s of Observation.

Maximum Acid Secretion c.cm. NHC1.

Remarks.

Fractional

Test Meal.

Histamine.

3

19th Feb., 1930 6th May, 1930

0 5

0 8

Achylia. Hypochlorhydria.

11

9th Oct., 1929 29th Nov., 1929 3rd April, 1930

0 4 17.5

0 95 83

Achylia. Hypochlorhydria. Do.

27

23rd Sept., 1929 25th Sept., 1929 24th Oct., 1929

0 0 0

0 0 0

9

24th Feb., 1930 19th May, 1930

0 28

18 47

Achlorhydria. Low Normal.

15

21st Sept., 1929 4th March, 1930

0 20

30 50

Achlorhydria. Hypochlorhydria.

V.

Achylia. Do. Do.

T H E BILIRUBIN CONTENT OF TIIE SERUM.

The ha~molytic anmmias give high indirect Van den Bergh reactions, and on this account and also because pernicious anmmia during exacerbation is associated with hyperMlirubinmmia, I have since 1925 advocated performing this test on all cases of sprue immediately on admission to hospital. The technique adopted in the twenty cases under review is that advised by McNEE and KEEFER (1925), and it will be seen that the results approximate closely to the larger Bombay series recently reported by FAIRLEY,MACKIEand BILLIMORIA (1929). All cases gave negative direct reactions. In the accompanying protocol (No. 4) the indirect readings are expressed in terms of Van den Bergh units, and for purposes of comparison the Bombay series is included. Clinical biochemists are not yet agreed on what are to be regarded as the normal variations of the bilirubin content of sera derived from healthy people, the physiological maxima adopted by different observers varying from 0.6 to 2.0 units, i.e., 0.3 to 1.0 rag. per 100 c.c. The average for the present series.

146

SPRUE

of twenty cases was 0.74 units. MCNEE (1923) regards 0.6 units as the upper limit of normality, whereas SCHIFFS (1927) considers that only values above 1.2 units are of pathological significance. If the last criterion be adopted, only two Of the present series and three of the Bombay series can be regarded as pathological. Further, in the latter cases, malaria was a complicating

PROTOCOL NO. 4. BILIRUBIN CONTENT OF THE SERUM IN SPRUE. Indirect Van den Bergh Units.

1.2 or under. Over 1.2 units, e (0.6 mg. (0.6 rag. per cent.) per cent),

Under 0.6 (0.3 nag. per cent).

U n d e r 0.8

Series. Haffkine Institute (Bombay).

26

35

45

12

18

47

63

London Tropical Diseases Hospital. Totals ..

35

(0.4 rag. per cent.)

e Only these cases are likely to be confused with pernicious anaemia during exacerbations. factor. In pernicious anaemia, on the other hand, readings above 1.2 units are the rule during exacerbations, hence the data afforded by this reaction often prove most helpful in differentiating between the two diseases. The ha~mosiderin deposits sometimes noted in the viscera at autopsy as well as the mild grade of hyperbilirubin~emia referred to above, indicate that increased blood destruction does occur in sprue. H~emolysis, however, is an insignificant factor in the production of the anaemia which originates essentially in an ill-nourished megaloblastic bone marrow. The latter is subject to exacerbations and remissions similar to, and indeed probably governed by, those which involve the alimentary tract. VI.

THE SERUM CALCIUM AND PHOSPHORUS IN SPRUE.

For many years the clinician has associated tetany with chronic diarrhoea, and for mgch longer periods of time calcium in the form of lime has been administered empirically to sprue patients with variable degrees of benefit. This being the case, it is somewhat surprising that evidences of calcium deficiency in sprue were not recognised by the astute clinicians of the last century. The reason, however, probably lies not in any lack of observation on the part of past observers, but on the fact that tetany is really an uncommon complication

N. HAMILTON FAIRLEY.

of sprue. O n c e o b s e r v e d , i t p r o d u c e s so v i v i d a c l i n i c a l i m p r e s s i o n n o t l i k e l y e v e n i n its e a r l y m a n i f e s t a t i o n s t o b e o v e r l o o k e d .

147 t h a t it is

CANTLIE (1918) first drew attention to the fact that tetany m a y complicate sprue ; he cited six cases, and emphasised that it does not necessarily terminate fatally. BASSETTS~ITH (1919) recorded a fatal case which died of heart failure fourteen days after the tetany had subsided. E t h e r injections were given therapeutically. BARAeH and MURRAY (1920) investigated a similar case in great detail, and reported low calcium values unassociated with pathological changes in the parathyroids. T w o separate estimations of the total serum calcium gave values of 8-0 rag., and 6.5 rag. per 100 c.cm. T h e tetany was severe. T r e a t m e n t with intravenous calcium chloride and blood transfusion (800 c.c.) was unsuccessful, and at autopsy a perforated appendix and peritonitis was found to be the cause of death. T h e r e was an acute dilatation of the stomach, the bone m a r r o w was hypertrophic, and the parathyroids were normal. SCOTT (1923), in a series of i m p o r t a n t papers, focussed attention on the deranged calcium metabolism in this disease. H e p r o p o u n d e d a new theory as to the causation of sprue, suggesting that acid dyspepsia resulting from excessive proteid or fatty diet and bad cooking in endemic areas caused over production of secretin, excessive stimulation of pancreatic secretion with i n v o l v e m e n t of the parathyroids and resulting calcium deficiency. L a t e r in the same year successful results were reported in ten cases of sprue treated b y parathyroid extract and calcium lactate administered by the oral route, and since that date m a n y similar successes have appeared in the literature. SCOTT (1925) pointed out the value of estimating the ionic calcium of the s e r u m in sprue b o t h in diagnosis and as a gauge to ];he effects of treatment. T h e biochemical findings in 32 cases investigated shortly after admission to hospital were analysed. T h e total s e r u m calcium was found to be little if at all reduced (9.4 to 10.8 rag. per 100 c.cm.), whereas the ionic calcium, as estimated by VINES' m e t h o d (192l), was 20 to 30 per cent. below the normal (6.1 to 8.1 rag. per 100 c.cm.). As a consequence of these findings, SCOTT concluded that the calcium derangem e n t in sprue was not due to faulty absorption from the alimentary canal. FAIRLEY, MACKIE and SAeASA (1926) investigated the ionic, b u t not the total s e r u m calcium. U s i n g VINES' (1921) method, they confirmed SCOTT'S observations that the ionic calcium was lowered in sprue, readings of 7-4 to 9.0 rag. per 100 c.cm. being very constantly registered. T h e average in ten consecutive untreated cases was 7.7 rag. per 100 c.cm., and after SCOTT'S treatment the ionic calcium was observed to return to a normal value in several cases T h e clinical results with parathyroid and calcium were, however, n o t regarded as being superior to that attained by adequate dietetic treatment, nor was tetany encountered in any of their cases. ASHFORD and HERNANDEZ (1926) criticised the t e r m " ionized " and " ionic " calcium as used by VINES (1921), and estimated total and diffusible calcium in the blood sera of sprue cases, and of certain nutritional disturbances occurring in Porto Rico. T h e total s e r u m calcium was estimated by Tisdall's modification of K r a m e r and Tisdall's method, and readings varying from 7.2 to 10.8 rag. per 100 c.cm. were recorded, the average being 8-9 rag. per 100 c.cm. T h e diffusible calcium averaged 4.0 rag., w h i c h was regarded as significant, since the normal limits are 4.5 to 6.0 rag. per 100 c.cm. L o w calcium values were also found in other nutritional diseases, and in consequence hypocalc~emia was not considered to be p a t h o g n o m o n i c of sprue. T h o u g h ASHFORD and HERNANDEZ regard parathyroid deficiency as the basis of the low calcium findings, they report no benefit from parathyroid administered by the m o u t h . Collip's extract relieved m u s c u l a r cramps, and led to a temporary increase in s e r u m calcium, but the p e r m a n e n t i m p r o v e m e n t was found to be essentially d e p e n d e n t on i m p r o v e d alimentation. BAUMCARTNER (1927) found that the total calcium was decreased, readings of 3.1 mg. to 6.2 rag. per 100 c.cm. being recorded in cases of tetany. I n two cases the blood calcium was increased following dietetic treatment, calcium lactate and parathyroid administration. I n one fatal case a decrease in blood calcium was observed despite calcium lactate grs. x t.d.s, and dry parathyroid extract gr. 1/10 t.d.s.

148

SPRUE.

LINDER and HARRIS(1930) have recently studied the calcium and phosphorus metabolism in the chronic diarrhoea associated with tetany. The report is of great interest, as these observers investigated not only the blood chemistry, but the calcium and phosphorus balance over a period of 100 days in a case of sprue. They found that low calcium values (7.3 rag. to 7.5 mg. per 100 c.cm. were associated with a lowered serum phosphorus content (2.0 rag. per 100 c.cm. or less). Ergosterol and calcium salts were practically without therapeutic effects until a low fat diet was instituted ; then tetany disappeared, and the serum chemistry became normal. LINDERand HARRISpoint out that these facts cannot be explained on the supposition that fat restriction has promoted calcium and phosphorus retention since the established positive balances were considerably diminished. (1)

Serum Calcium.

I n the present series of cases, Mr. R. J. BROMFIELD and the writer have investigated the total serum calcium using KRAMER and TISDALL'S technique (1921) and the inorganic phosphorus b y BRIGG'S modification of BELL and DOtSEY'S m e t h o d (1922). I n twenty-one cases of sprue the following results were obtained : 2 cases gave values between 5.1 1 case ,, ,, ,, 6.1 2 cases . . . . . . 7.1 7 .... ,, ,, 8.1 5 . . . . . . . . 9.1 4 ,, ,, ,, ,, 10"1

to to to to to to

6 mg. per 7 mg. 8 mg. 9 mg. I0 mg. 11 mg.

cent. ,, ,, ,, ,, ,,

T h e twenty-one cases averaged 8.8 mg. per cent. T h e total serum calcium may normally be regarded as 9.1 to 11.0 mg. per cent., and the average of twenty-one eases of sprue considered in the present series equalled 8.8 rag. per 100 c.cm., which is almost identical with the findings of ASnFORD and H~RNANDEZ (1926) cited above. Nine of the series fell within normal limits, but twelve were definitely subnormal. T h r e e cases (Nos. 8, 17 and 33) were suffering f r o m tetany during the actual period of observation, the classical TROI~SSEAU and CltVOSTEK'S signs being elicited in" each case. T h e i r serum calcium was 5.8 and 6"4 and 5.2 mg. ~ per 100 c.cm. respectively. These three cases of tetany certainly resulted from a deficiency of calcium, and clinical i m p r o v e m e n t was closely related to the upward trend of the total serum calcium curve. It must not be thought, however, that deficient serum calcium necessarily indicates the severity of the disease. One of our cases died of anmmia and heart failure at a time when the s e r u m calcium was still 10.4 mg. per 100 c.cm. (2) Serum Phosphorus. Simultaneous observations on the calcium and phosphorus content of the This case I had an opportunity of investigating at University College Hospital through the courtesy of Dr. BATTY SHAW, F.R.C.P., and Dr. G. W. GOODtlART.

N . H A M I L T O N FAIRLEY.

14f4

serum were made in fourteen cases of sprue, using BRIGC'S method (1922)~ The results were as follows : 1 case showed 5 cases . . 4 . . . . 4 . . . .

phosphorus . . . . . . . . . . . . . . .

values between . . . . . . . . .

2.1 to 2-5 rag. per 100 c.crr,. 2"6 to 3"0 .... 3"1 to 3"5 .... 3.6 to 4"0 ....

The minimum value was 2.2 mg., and the maximum 4.0 mg., the average reading being 3.2 rag. per 100 c.cm. Normally the inorganic phosphorus varies from 2"0 mg. to 4.0 mg. per 100 c.cm., so that in the present series no rise was ever noted. (3) Commentary. In parathyroid tetany SALVESEN (1923) has shown that the serum phosphorus is high while the total calcium value is low. On the other hand, in conditions like osteomalacia and infantile tetany, which originate from, or are associated with, defective absorption of lime salts from the intestine, low serum calcium and decreased inorganic phosphorus are found. Our results favour the view that the low total calcium values of the serum observed in sprue Originate in defective intestinal absorption rather than from a condition of hypoparathyroidism, and the absence of demonstrable parathyroid lesions also bear this out. Nor must the effects of malabsorption of vitamins be overlooked. It is now known that vitamin D. is a derivative of ergosterol, or some closely related sterol, and that as such it can be synthetised in the skin under the influence of ultra-violet rays. HUNTER (1930), in his recent Goulstonian lectures, states that vitamin D. is the main factor governing the absorption of calcium, but whether or not it directly affects the calcium utilisation in the tissues remains for future metabolism experiments to decide. LINDER and HARRIS (1930) go further, and consider that in cases of diarrhoea associated with tetany the cause of calcium deficiency is lack of vitamin D., which enables the serum to hold larger amounts of serum and inorganic phosphorus without materially affecting the phosphorus and calcium balance. From this brief review it will be appreciated that the mode' of production of the hypocalcmmia in sprue is not one of mere theoretical interest. Important therapeutic issues are involved, for if it originates in defective parathyroid output, then Collip's parathormone should be administered. On the other hand, the evidence presented in this paper indicates that defective absorption is the basic factor concerned, and under these circumstances a low fat diet~. calcium salts and irradiated ergosterol per os are clearly indicated. VII. THE BLOOD CHOLESTEROLIN SPRUE. NEWttAM, MORRIS and MANSON-BAHR (1926), in a series of twelve cases of sprue investigated the cholesterol content of plasma and corpuscles, pointing

150

SPRUE.

out that in all cases of aneemia there was a definite hypocholesterolmmia which seemed to bear little or no relationship to the degree of a n e m i a present. T h e y also drew attention to the fact that as the cholesterol content of the blood was decreased in pernicious anaemia, its biochemical estimation would be of no value in differentiating the two diseases. Corpuscular cholesterol does not appear to vary much in health and disease, and in consequence it is in the plasma or serum content that variations are to be sought. In the present investigation undertaken in conjunction with Mr. R. J. ]~ROMFIELD, the total serum cholesterol has been estimated by the method of MYERS and WARDELL (1918) in ten cases of sprue suffering from variable grades of anaemia. T h e results are detailed in the accompanying protocol (No. 5). It will be n o t e d that the serum cholesterol averaged only 72.8 mg. per 100 c.cm., that the lowest reading was 40 mg., and the highest 102 mg. per 100 c.cm. All the cases showed a megalocytic anaemia, but its intensity was not necessarily correlated with the degree of hypocholesterola~mia. Normally serum cholesterol varies between 100-220 mg. per 100 c.cm. PROTOCOL NO. 5. CHOLESTEROL CONTENT OF SERUM.

Case No.

32 9 18 12 4 29 28 19 8

17

Serum Cholesterol (mg. per 100 e.cm.

Red Blood Corpuscles per c.mm.

40 46 54 60 72 79 82 95 98 102

2,200,000 900,000 2,200,000 3,300,000 3,000,000 2,90t),000 2,000,000 3,600,000 2,600,000 3,300,000

I I

Hmmoglobin (per cent.).

Colour Index.

Diameter of Corpuscle (Microns).

24 16 45 64 70

0.5 0"9 1.0 1.0 1.1 0.7 1.0 1-0 1.3 1.1

8.4 8.6 8.2 8.0 8.6 8.4 8.4 7.8 8-4 8.6

40

40 70 70 70

Average for series = 72.8 mg. per 100 c.cm. An interesting feature of serum cholesterol estimations was the rapid rise that occurred following liver extract t h e r a p y and a high protein diet. T h e first observation was always made shortly after admission to hospital before special treatment was commenced, the subsequent ones at periods stated on the accompanying graph (No. 2). Considering the low fat nature of the diet and the marked degree of hypocholesterokemia which existed in several of these cases, the results are very striking. Unfortunately, only total cholesterol was estimated in these cases, the proportion present as free cholesterol and cholesterol esters not being ascertained. Diet appears only to modify the ester

N. HAMILTON FAIRLEY.

151

cholesterol content of the serum, so the significance of these findings cannot adequately be assessed until information on the ratio of the two forms of cholesterol has been determined. This we hope to do in subsequent cases. GRAPH NO. 2. The rise in serum cholesterol following liver extract treatment and high protein dietary, zgo ].80

170 !60

0 0 i-4

z,0 "z30

~120

~ 110 * I00

9O o

7o 60 S0 4o zo

VIII.

20

30 paso

4o

-~o

60

ANALYSlS OF F ~ C A L FAT IN SPRUE.

CAMMIDGE (1914), THOMPSON (1925), FAIRLEY, MACKIE and MALANDKHAR (1926), and SOKHEY and MALANDKHAR(1928) have reported on the results of fmcal fat analysis in sprue. It has been generally customary to estimate total fat contents of the fa~ces, and also the proportion of neutral fat to fatty acids and soaps, high readings in the former indicating defective absorption from biliary,

152

SPRUE.

pancreatic or intestinal causes, and a low ratio in the latter defective fat splitting due to deficiency in pancreatic lipase. Results generally have shown a high total fat content varying from 25 to 60 per cent. of the dried faces, associated with effective splitting, the neutral fats not generally exceeding 33 per cent. o f the total. Most of these results, however, have been obtained on patients undergoing the milk cure, and SOKHEY and MALANDKHAR(1928) have recently shown that such results can have little or no significance, since the fat composition of the faces of bed-ridden patients on milk diets suffering from diseases other than sprue is almost exactly the same as that of sprue stools. Split fat forms more than 75 per cent. of the total fat just as in sprue. The authors do not state whether buffalo or cow's milk was fed to their patients, but their results certainly suggest that if faecal fat estimations are to be of value, the patient must not be on a high fat diet. The selection of a method is also a matter of difficulty, for all appear to. have been subjected to criticism on one ground or another, and there is no unanimity of opinion amongst chemists as to what really is the best technique for the routine fat analysis of the faeces. Probably the method of SAXON (1914} is preferable for moist fresh faeces, that of HOLT, COURTNE¥ and FALES (1919) GRAPH N o . Analysis 7o ~ : ~ , , l l i l ~ l l i ~ l l l l i l l l

•

•

I

LL

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60

Cue 1

(Si'X~ .....

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+

+°

ii .!lllllllii

il~!!iiiiii~iiiiiiill ~IIIIIIIII~I~IIIIIIII

3

of F~ecal Fats. '1

,*l+ll~+l,tl~lll~l'+'ll+ltllllllil~tlll

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,,VH-,~'UIIIIIIIIII!!!!~:~LIIIIIIH!!!!!!!ilIIIIIIIIII

~llilllllllfllllltl

:lllillll~:ll:ll:::illl~llililiIllIlli:LLT~I~::l:l::ll:~ :iilll;:,"f.~illlllllliillll~i]~'~,r~l'i::l:il:ll!lilillilill ...................................................... l l l l l l t l l l i ~ ,l l.l.iL~ 'illiill ll iIlIlt~l lllllilli l l t l l l l . . . . . . l l , 7 7 " W , ~ ] - J ~ i l i l i l t l l l l l fllI~llllllIIl~lllllillliFIIII .......... llil]N..~'liliilillli:iliH ' ' .' '.~. .' .~. H , l l f l i l l l l l l l IIIIIIIIII,,,,~ ........................... lll~4D+t41111111111111111111111111+llll . . . . . . . . . . . . . . . I . . . , .~ , , , , ...... Illll,II .......... , iIlili • . . . ~ . I I. i .i I . I U. J H.i~ ttl .t l il l l [l.1 4 1.t l l l l.l l l ~....... 4 J _~i l l f l~l l l .l l.l................. l.l .l l.H. .I.I.I.I .l .i l. . . . . ...... L i l , , , + ~ , , , , , , ~ [ , , l , l l l l , , [ , , , l ~ , ~ . - l l l l l l l l l l l l l l l i l l l

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...................... II Fr'I~7"T1G. . . . "~ h ....... ,,f#4~ ................... ilIHill;iitl~:llll:lllilll ::i::::i:i:::It::::::::::lll:lllll:iiiiii I :illllli:llll ill:ll, I[IIIIIIIIH-HIIill ....... ::llllllllllll

I llliiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii iiiiiiiiiiii!il !!iiiiiiiiillliiiiiiiiiiiiiiiiiiiiiiiiiiiii!!!iiiill

9

Weeks. Total fats

Neutral fat (unsplit)

iii iiiiill:

~iliLiiiiiil ,+t,!i!!!!!!,Li'

Fatty acids and soaps (split)

iiii

JN~!!!!!!! iii!~!!!!!! l l'rlll,,:Iti l , , l l t i l',I, l

iiii~iilH iii~iiiXli1o

N. HAMILTON FAIRLEY.

158

on dried samples. In the present series of cases the latter method was used, and the results of analysis of specimens collected both before and after a highprotein low-fat low-carbohydrate diet was given may be examined in graph (No. 3). Three cases of sprue, Nos. 18, 17 and 9, all showed a rapid decline in the total fat residue following this treatment, but it will be noted that in case No. 7 a rise in total fat residue occurred. Three years previously this patient had had a gastroenterostomy performed, and on admission the fractional test meal showed intense hyperchlorhydria. The clinical syndrome mimicked sprue with extraordinary exactitude, but faecal vomiting subsequently developed, and the patient was found to be suffering from a gastro-jejuno-colonic fistula, which short-circuited the small intestine, portion of the food passing directly through the fistulous communication into the colon. Mr. T. P. KILNER,F.R.C.S., rectified this defect at operation, and the patient is now making a most satisfactory recovery. The curves depicting the amount of split and unsplit fats are also shown, but call for no further comment as a more detailed report is being published later. IX. THE RATIONAL THERAPEUTICS OF SPRUE. Sprue is essentially an alimentary disease, and as such must be treated by measures best suited to rest the alimentary tract. It is also a disease of vicious circles, as, for example, when gastro-intestinal involvement leads to anaemia and anaemia by decreasing the effectiveness of the blood supply to the gut increases mucosal atrophy with further malabsorption and diarrhoea. Fortunately, laboratory methods now enable us to recognise such a state of affairs at a reasonably early stage in the evolution of the disease, while modern therapy has placed at our disposal means of effectually controlling them. The essentials of treatment may be epitomised as follows : - (1) The institution of alimentary rest by appropriate dietary. (2) The treatment of megalocytic anaemia, if present. (3) The reinforcement of demonstrable deficiencies by such means as HC1, calcium and vitamin D administration. It follows that treatment must be adapted to the individual requirements of the case, and where concomitant diseases, such as malaria and syphilis exist, specific therapy must be instituted. (1) General Treatment. The first essentials in treatment are rest and dietary, and it is interesting to note that these have been the common factors employed along with every new remedy advocated as a specific in the treatment of sprue. They must, in my opinion, remain the basis of all successful therapy. Both in the primary attack and during relapses these asthenic, poorly insulated patients must be put to bed under conditions that ensure mental as well as physical rest, while

154

SPRUE.

warmth and avoidance of chill are specially essential in Europe. These factors become obviously important when one considers the low calorie value of sprue diets during the first two or three weeks of the disease. (2) Diet. Though all agree that dietetic measures must play an important part in the cure of sprue, widely different opinions are held regarding its nature and composition. MANSON advocated the milk treatment, VAN DER BURG the fruit cure, while CANTLIEemployed a red meat dietary in his cases. ASHFORD(1924} in Porto Rico treats 95 per cent. of his cases on a liberal diet from which is eliminated sugar of commerce and the cereals. Vegetables, fruits and animal proteins are allowed. Some 5 per cent. of cases do not do well; these are fed o n CANTLIE'S meat diet, eupeptics like pancreafin, diastase and HC1 being added if required. At the Hospital for Tropical Diseases, L o w (1928) adheres to the classical milk treatment. MANSON-BAHR(1929) advocates commencing with the milk cure, but at an early date adopts a mixed dietary liberal in carbohydrate. Where this fails CANTLIE'S meat treatment is advised. Clinical observation has established the fact that patients with sprue recover under various dietetic r6gimes, but there is an astoundingly smag amount of information either in the literature or textbooks regarding the principles underlying the selection of a suitable dietary. This fact was first brought home to me personally in 1926, when I was suffering from sprue contracted while investigating this disease in Bombay. Carbohydrate as well as fat intolerance was marked in this particular instance, and I evolved the present diet largely as a result of observations in my own case. Insulin injections were also then employed along the lines advocated in this paper, blood sugar curves after the ingestion of both glucose and starch feeds being investigated at Hall Research Institute, Melbourne. Cure definitely followed the institution of this rdgime, both the " milk " and the " mixed diet " cures having proved unsuitable, though given adequate and prolonged trial. Results obtained in one case are of little or no significance, but recently through the courtesy of my colleagues~ Dr. CARMICHAEL Low, Dr. MANSON-BAHR and Sir LEONARD ROGERS, at the London Hospital for Tropical Diseases, a large series of cases has been placed at my disposal, and very successfully treated along the lines indicated. It is interesting to note that this dietary closely approximates in principle to that advocated by ASHFORD and his colleagues at the Porto Rico school. They also stress the importance of carbohydrate fermentation in the production of the sprue syndrome6, but attribute it to t h e activity of Monilia ashJbrdi engrafted; on a background of glandular deficiency.

(a) Considerations underlying the Selection of a Suitable Dietary.--We have already noted that atrophy of the villi and involvement of the secretory glands of the mucosa occur in the small intestine. This must impair the dual functions of the small gut, namely, absorption of the products of digestion which mainly

N. HAMILTON FAIRLEY.

]55

occurs in the ileum, and decreased secretion of the succus entericus, which is chiefly produced by the jejunum. Lesions of this nature, involving the lower portion of the small intestine, would naturally lead to mal-absorption, those involving the j e j u n u m to defective splitting of the disaccharides owing to a decrease or absence of invertase, maltase and lactase in the succus entericus. In the sprue stool we find evidence that these functions are in abeyance, for excessive fat and increased bulkiness are manifestations of mal-absorption, while its acidity and gaseous characteristics constitute evidence of abnormal carbohydrate fermentation. Salivary and pancreatic diastase are both present in adequate amounts in sprue, and evidence of undigested starch granules in the fmces are infrequent, though they may appear owing to rapidity of passage through the gut during the most acute phases of the diarrhoea. This being the case, it appears reasonable to postulate that disaccharide residues constitute a potent source of the excessive acid fermentation so characteristic a feature of many cases of this disease. Clinical evidence also strongly supports this conclusion for abdominal distension, intestinal flatulence and gaseous stools are essentially related to the carbohydrate and disaccharide moiety of the diet. This fact can be demonstrated clinically by increasing the proportion of starchy food and cane sugar in the food. Owing to its lactose content, excess of milk is liable to act in similar fashion. Glucose, on the other hand, is well tolerated, provided it is not given in excess. Recently THAYSEN and NORGAARD (1929) have shown by observations on the respiratory quotient before and after the ingestion of glucose, that in idiopathic steatorrhoea (including sprue and GeeHerter's disease) it is adequately absorbed and metabolised. Low blood sugar curves were demonstrated, but while admitting impaired absorption of fat, these observers could find no evidence of defective glucose absorption. Undoubtedly the advantage which the monosaccharides possess over other forms of carbohydrate in sprue is dependent on the fact that they are independent of the digestive juices, and are available for absorption immediately on reaching the small intestine. Before teaving this subject, it should, however, be pointed out that milder and less advanced cases of sprue are sometimes met with who deal adequately with starchy and disaccharide foodstuffs, and in whom fat intolerance is the chief complaint. Here it appears that the ileum rather than the jejunum is mainly implicated, and postmortem evidence also suggests that this is the portion of the small intestine to be dominantly involved. (b) M i l k . - - M i l k is a bland fluid which contains all the essential food elements, and by M:NSON (1907), L o w (1928) and many other tropical physicians it has been given priority over other less natural foodstuffs in the treatment of sprue. Its fat has a low melting point, is present in the state of'a fine emulsion, and should in consequence be readily absorbed. Undoubtedly it is successful in many cases, but it is equally certain that a proportion of cases do not improve, while in others it definitely disagrees.

156

SPRUE.

For several years at St. George's Hospital, Bombay, 'I studied in conjunction with Colonel F. P. MACKIE, I.M.S., the effects of milk treatment; in addition, many of the cases received calcium lactate and parathyroid. A number of advanced and acute cases died, others improved temporarily later to relapse, while another group attained clinical cure or at least got well enough to resume their ordinary occupation in the tropics. Any criticism, therefore, I have to offer is not due to inexperience of the method, but arises from clinical experience and a study of the deranged intestinal mechanism underlying the production of the sprue syndrome. Some very interesting experimental w o r k by ERLANGER and HEWLETT (1901) on the metabolism of dogs with shortened small intestines may be cited, for we have already seen that the jejuno-ileum is dominantly affected in sprue. They found that dogs from which 70 to 83 per cent. of the combined jejunum and ileum had been removed are peculiarly liable to be affected with diarrhoea which might be caused by a diet too rich in fat or one containing too much inert non-digestible material. On a diet poor in fat the dog with a shortened small intestine absorbed fat as well or almost as well as a normal dog, whereas with large amounts 25 per cent. of that ingested appeared in the f~eces as contrasted with 4.5 per cent. in normal dogs. In addition, the amount of nitrogen eliminated in the f~eces was doubled under these circumstances, although on a diet poor in fat there was no great difference between it and the normal dog. RYLE (1924) and many others strongly advocate fat restriction in the diet of patients with excess of fat in the stools, and LINDER and HARRIS (1930) urge it in cases of steatorrhcea associated with tetany on the basis that ergosterol is without effect on the calcium level until a fat poor diet is instituted. The Royal Society Committee during the War stated the desirable ratios of protein, fat and carbohydrate in a normal diet to be 1 . 0 : 1 " 0 : 5 " 0 . In cow's milk these ratios are 1 . 0 : 1 . 1 : 1 . 5 , while in buffalo's milk, which is largely used in t h e tropics, they are l ' 0 : 2 . 0 : 1.2. It therefore follows that in a condition frankly associated with an excess of f~ecal fat, both in the tropics and Europe the classical milk diet affords much larger proportions of fat than is contained in a normal diet. Actually the practical difficulties surrounding the milk cure in the tropics are not generally realised. In Bombay, JOSHI (1916) analysed fifty samples of buffaloes' milk, finding an average of 3"9 grammes of protein, 4-5 grammes of carbohydrate, and 8"6 grammes of fat, whereas Bos indicus gave values approximating to English standards. In India much buffalo milk is employed in the treatment of sprue, and the prevalent custom of regarding it as the equivalent of cow's mill~' and establishing the patient on the usual six pints per diem, containing approximately 292 grammes of fat, may and indeed frequently does result in disaster. JosHI (1916) also found that 90 per cent. of the milk samples examined bacteriologically were contaminated with microbes whose presence indicated dirt, while 80 per cent. showed evidence of dilution. The latter event may constitute no misfortune to the sprue patient especially if the milk has been

N . H A M I L T O N FAIR.bEY.

157

previously skimmed by the vendor as the fat content is thereby reduced to a less injurious level. PltAUSNITZ (1889) showed that milk given as an exclusive diet is not well absorbed, and that even in the healthy adult on 3 litres or 52 pints of milk daily not less than 9 per cent. was lost in the f~eces. HUTCHINSON (1923) states that the large amount of water which milk contains interferes with the action of the intestines when it is the sole article of diet, but that on a mixed diet it is better absorbed. Undoubtedly the bulkiness of milk is one of its disadvantages, and a more ideal food would be concentrated skimmed milk in which both its bulk and fat content would be decreased. In our Bombay series, except in a few acutely ill patients with a marked fat intolerance, milk up to 4 pints daily (1,500 calories) was reasonably well tolerated, but further increases were liable to be associated with large bulky, fatty stools, intestinal flatulence and distension. MANSON-BAHR (1929) records similar experiences in England. (c) The Fruit Diet.--The fruit treatment as advocated by VAN DER BURG in Java consisted of large quantities of pulpy fruit free from excessive acidity, coarse seeds and fibre. Special fruits, including strawberries, beel fruit, papaya and ripe bananas are reported on with enthusiasm by different observers. I would suggest that the main value of fruit apart from its vitamin C content, lies in the fact that it affords a very satisfactory source of carbohydrate in monosaccharide form which needs no further preparation by the intestinal enzymes before absorption. A pure fruit diet cannot, however, be continued indefinitely, as it is inadequate in calorie value, and too unbalanced in essential food constituents. It has, however, proved most useful in reinforcing the meat and milk diet in sprue. (d) The Red Meat Treatment.--It has long been recognised that patients with certain forms of defective digestion can deal more easily with underdone meat than with most other kinds of nourishment, and in the form of scraped beef or as the old Salisbury cure it has been advocated by CANTLIE (1906) and other physicians of tropical experience. Commencing with 2-ounce feeds from 1½ to 2 lbs. of lean minced underdone beef steak can ultimately be taken daily, the water intake being also increased to facilitate nitrogenous excretion. In sprue the results of this treatment are often very satisfactory, especially where abdominal distension, intestinal flatulence and copious gaseous stools have dominated the clinical picture. Why muscle fibre is so welt tolerated is not apparent for intestinal atrophy might with reason be expected to limit the production of erepsin in the succus entericus with resulting protein putrefaction and difficulty in adequately dealing with the protein moiety of the diet. That this is not the case is shown by the rapid amelioration of intestinal symptoms, the decrease in the size of the stool and its early return to normal characteristics. Microscopic examination also fails to show the presence of undigested muscle r,

158

SPRUE~

fibre in the excreta. The protein-fat-carbohydrate-ratio in lean rump steak is 1 : 0.3 : 0, and the energy value 750 calories per lb. It therefore constitutes for a limited time a satisfactory pabulum for sprue cases showing fat and carbohydrate intolerance. Its most dramatic cures have followed failures with the milk treatment in cases in which fatty and carbohydrate intolerance were most marked. The actual ratio of fat, protein and carbohydrate in meat, milk and high protein diets are epitomised in Protocol No. 6. As shown by WHIPPLE, ROBSCHEIT-ROBBINS and HOOPER (1920), meat protein is inferior only to liver itself as a blood former. In addition, it is well absorbed, leaving a small residue. Its disadvantage as an exclusive food lies in the fact that it cannot meet adequate calorie requirements over a prolonged period of time, it is deficient in calcium and vitamin content, and contains no carbohydrate. BAUMGARTNERand HUBBARD(1927) record that high protein diets (150 grams of protein daily) do not cause any signs of damage to the kidneys in sprue, and one case of the present series who made a complete clinical recovery had undergone nephrectomy several years previously. PROTOCOL NO. 6. T H E RATIO OF THE FUNDAMENTAL FOOD CONSTITUENTS IN M I L K , MEAT AND HIGH PROTEIN DIET.

Diet.

Protein•

Fat.

1.0

1.0

5-0

1.0

1.1

1-5

1.0

2.0

1.2

Lean Red Meat

1.0

0-3

0"0

ttigh Protein (No. 1)

1.0

0.3

1-2

*Normal mixed diet•. Milk (cow) . . . . Milk (buffalo)

..

Carbohydrate.

(e) High Protein, Low Fat, Low Carbohydrate Dict.--Alimentary rest being the therapeutic ideal, it appears evident that this can best be obtained by feeding minimal amounts of those food constituents which the small intestine fails adequately to deal with. Overloading of the stomach is also to be avoided, especially in ihe early stages, and this is best attained by non-bulky feeds at frequent intervals• Unless fat be restricted additional strain falls on an already over-taxed and failing absorption mechanism, while the resulting bulky fatty stools may result in further'entero-colonic irritation. In like manner, abnormal * Ratios advocated by Royal Society Committee during the war.

N. HAMILTON FAIRLE¥.

159

fermentation of the disaccharide residue with the production of organic acids and gas leads to gaseous distension and irritation of the already atrophied gut, and to further dysfunction. Under such circumstances it appears rational to make protein the chief constituent of the diet, commencing with one of a low calorie value, and gradually increasing the quantity while still maintaining the high protein ratio. This is the underlying principle on which this highprotein low-fat low-carbohydrate diet has been evolved, and in reinforcing the fat and carbohydrate moieties junket and custard (milk and eggs) have been largely used for the former, and glucose, fruit and fruit juice and rusks for the latter purpose. Care is also taken to see that both the calcium and vitamin content is adequate, though avitaminosis when it occurs is in my opinion always a secondary and never a primary factor in the production of the disease. During treatment, five diets are employed, the calorie value of which increases progressively from 770 in No. 1 to over 3,000 in No. 5. The ratio of protein : fat : carbohydrate is maintained at approximately 1 . 0 : 0 . 3 : 1.1 for Nos. 1 and 2 ; carbohydrate is increased to 1"3 in Nos. 3 and 4, the ratio of protein and fats remaining constant, while in No. 5 the ratios are 1.0 : 0.36 : 2.0. PROTOCOL N o . 7. THE CALORIE VALUE AND PROTEIN, FAT AND CARBOHYDRATE RATIOS IN DIETS N o s . 1 TO 5.

Diet.

Protein.

Fat.

Carbohydrate.

Calories.

No. 1

1.0

0"3

1.2

770

No. 2

1.0

0"3

1.0

1,280

No. 3

1.0

0 "32

1.3

1,820

No. 4

1.0

0 "34

1.3

2,200

No. 5

1.0

0"36

2.0

3,020

T h i s protocol is c o n s t r u c t e d o n t h e basis of tables g i v e n in PLIMMER'S Analyses a n d E n e r g y Values of F o o d s (1921). Available calorie values are u s e d t h r o u g h o u t , i.e., c a r b o h y d r a t e = 4.0 ; p r o t e i n = 4-0 ; fat = 9.0.

During convalescence a more liberal dietary is allowed, including certain vegetables like cauliflower, marrow, celery, asparagus, young peas and tomatoes, and fruits in quantity. Red meats, chicken, fish and eggs are advised, but where carbohydrate intolerance has been marked, small quantities of boiled potato and milk puddings are only gradually introduced after convalescence is well established. Details of the diets are appended.

( f ) Intestinal Features.--The rapidity with which diets are changed on such a r6gime is determined by the general condition of the patient, the

160

8PRUE,,

disappearance of abdominal distension and intestinal flatulence, and the character of the stools. The latter rapidly decrease in size and number, become brownish in colour, neutral or alkaline in reaction, and entirely lose their former 'gaseous qualities. At first the stools may be somewhat watery or loose in consistency, but even here evaporation demonstrates the dry weight of fmcal residue to be within normal limits. Chemical analysis also shows a definite decrease in the total f~ecal fat (Graph No. 3). The rapid amelioration of all intestinal symptoms and the return of the stools to a normal weight in the course of a few days is the rule under this dietetic r6gime, and one diet replaces another at short "intervals until in approximately three weeks No. 5 is established.

(g) Weight.--Owing to the specific dynamic action of protein, any diet which contains it in excess is not a good weight producer, and weight is commonly lost or little gained during the first three weeks of treatment. The objects of treatment, however, during this period are twofold--firstly, to rest the g u t ; and, secondly, to afford it a supply of blood richer in corpuscles and h~emoglobin. This being accomplished by combined liver extract and high protein dietary, the ratio of carbohydrate is increased, and a diet afforded whose calorie value is sufficient for a steady increase in weight without a return of intestinal distension or bulky gaseous stools. Mere increase in weight is of little benefit unless it be accompanied by normal stools, amelioration of abdominal symptoms, decrease in hypotension and relief of that asthenia which is so characteristic a feature of sprue cases which quiesce, but remain uncured. Capacity to do physical work, general increase in muscular tonus, and restitution of the blood pressure to a normal level are established at an earlier date in cases treated along these lines than by other modes of therapy. In my opinion, they constitute essential criteria in estimating clinical cure. Increase in weight is certainly desirable, but it must not be obtained by violating at too early a date the fundamental principle of treatment--alimentary rest. (h) Insulin and Glucose Therapy.--Should the patient be greatly emaciated or show little inclination to put on weight, I have found that the addition of more glucose to the diet (No. 5) and the administration of insulin in doses of 6 to 12 units daily is frequently followed by a marked increase in weight and a definite rise in blood pressure. THOMPSON (1925) found a certain degree of sugar intolerance during exacerbations of sprue which he attributed to a temporary inefficiency of the glycogenic function of the liver, and ASHFORD (1924) records, an average finding of 101 mg. per 100 c.cm. in forty-eight cases of sprue. REClO (1924) considers a high blood sugar level as peculiar to some cases of this disease, whereas FAIRLE¥, MACKIE and GOKHALE (1926) report the average in seventeen cases as only 84.6 rag. per 100 c.cm. On the other hand, in idiopathic steatorrhcea (sprue and Gee-Herter's disease) THAYSEN and NORGAARD (1929) have recently found that there is actually a subnormal

N.

HAMILTON

161

FAIRLEY.

rise in the blood sugar curve after the ingestion and absorption of glucose, and their findings indicate an active metabolism of glucose within the body. It should be noted that the beneficial effects here described are based on clinical observations in a limited series of cases. No definite evidence yet exists that insulin production is deficient in tropical sprue, and until further biochemical and clinical data are available a discussion of the significance of insulin administration would be premature. GRAPH No. 4. (Case No. 9.) Effect of dietary on weight.

I :I t v;

o

4-

+

t

7

k 1o

2o

30

40

~0

60

70

8o

90

100

t ii0

Days, The weight curve in the most emaciated patient of the present series is shown in Graph No. 4. It will be seen that 41 lbs. were gained over a period of fifty-eight days under this treatment, whereas under the earlier high protein diets only 4 lbs. had been added• It should also be noted that all effort to increase the weight of this patient was postponed for a period of forty-seven days until the blood had been improved by liver extract treatment, and the gastro-intestine adequately rested by a high-protein low-fat low-carbohydrate

120

162

SPRUE.

d i e t . T h e case h i s t o r y so t y p i c a l l y i l l u s t r a t e s t h e p r i n c i p l e s o f t r e a t m e n t as a d v o c a t e d in t h i s p a p e r t h a t i t is e p i t o m i s e d b e l o w . Case N o . 9.--Female, aged 40 years, was admitted to the Hospital for Tropical Diseases on 22nd February, 1930. Sore tongue, abdominal distension and diarrhoea with pale gaseous stools commenced in 1927, while in New York, though the condition was probably contracted in Salvador, where the patient had resided for many years. Recently exacerbation of sprue symptoms had occurred, and despite prolonged treatment for three months on milk and three blood transfusions, the p'atient was semi-starved and desperately ill on arrival at hospital. T h e loss of weight equalled 5 st. 5 lbs. On examination the patient was gravely anaemic, tremendously emaciated, and showed much abdominal distension, the coils of intestine being readily visible through the atrophied abdominal wall. T h e tongue was pale, glazed and atrophic, systolic bruits were present at both the apex and base of the heart, and there was (edema of the feet and a low blood pressure - - S/D = 90/50. T h e patient was fully investigated from a laboratory viewpoint. F~ecal examination, on 24th February, 1930, showed 43.6 per cent. of total fat, 29.5 per cent. being split. T h e blood picture was as follows : R.B.C.s = 1,100,000 per c.mm. H~emoglobin = 20 per cent. Colour Index = 1.0. Average diameter = 8.6 microns.

T h e blood picture showed numerous megalocytes and poikilocytosis, anisocytosis and polychromasia were evident. T h e reticulocytes = 0-2 per cent. Next day nasal h~emorrhage occurred, and the R.B.C.s fell to 900,000 per c.mm., and the hmmoglobin to 16 per cent. T h e blood coagulation time = 2 minutes 17 seconds. T h e Van den Bergh gave an indirect positive reaction of 1-5 units. T h e serum calcium = 7.3 rag. per 100 c.cm., and the blood chlorides = 597 rag. per cent. T h e blood cholesterol was only 46.0 mg. per 100 c.cm. T h e fractional test meal showed achlorhydria with a response to histamine. T h e patient was placed on a high protein diet (No. 1), and given liver extract in full dosage, calcium lactate per os and later vitamin D, and hydrochloric acid immediately after meals. Within a few days all abdominal distension had subsided, and semi-solid small residue stools were being passed. Nine days after commencing liver extract the reticulocytes equalled 410 per 1,000. A remarkable restitution of the blood followed (Graph No. 5). T h e rise in blood cholesterol, also the return of acid secretion may be studied in Graphs Nos. 1 and 2. On discharge, on 15th June, 1930, the blood cholesterol = 134 rag. per 100 c.cm., the blood calcium = 10.6 rag. per 100 c.cm., the f~ecal fat ~ 20.8 per cent., and the stomach was secreting acid normally. T h e patient had gained 3½ stones in weight, had normal stools, and showed no gastro-intestinal disturbances of any kind, T h e blood pressure was also normal - - S / D = 130/85. Clinically the case was cured. T h i s case, t h o u g h m u c h m o r e g r a v e l y ill t h a n t h e a v e r a g e , is t y p i c a l o f t h e r e s u l t s o b t a i n e d in t h e s e v e n t e e n cases c o m p r i s i n g t h e p r e s e n t series. A l l l e f t h o s p i t a l c l i n i c a l l y c u r e d as far as i m m e d i a t e s y m p t o m s w e r e c o n c e r n e d . T h e stools w e r e n o r m a l in e v e r y i n s t a n c e , a b d o n f i n a l d i s t e n s i o n a n d d y s p e p t i c features had disappeared, the tongue appeared normal, the blood pressure was r a i s e d , a s t h e n i a m a r k e d l y l e s s e n e d , a n d as s h o w n in t h e n e x t s e c t i o n , t h e b l o o d r e s t o r e d to a n o r m a l c o n d i t i o n . T h e w e i g h t v a r i e d . I n s o m e cases little h a d b e e n g a i n e d , i n o t h e r s , 30 to 40 Ibs. o r m o r e , b u t t h e o u t s t a n d i n g f e a t u r e in all was a n a p p e a r a n c e of fitness a n d p h y s i c a l v i g o u r c o n t r a s t i n g v e r y f a v o u r a b l y w i t h t h e f l a b b y a s t h e n i a s e e n in so m a n y s p r u e cases l e a v i n g h o s p i t a l . F u r t h e r , in p a t i e n t s r e c e n t l y r e p o r t i n g b a c k f o r e x a m i n a t i o n , c o n s i d e r a b l e g a i n i n w e i g h t has i n v a r i a b l y o c c u r r e d , s e v e r a l cases statiflg t h e y w e r e h e a v i e r t h a n

N. HAMILTON FAIRLEY.

163

ever previously. To date, only one ease out of seventeen has relapsed, and here the patient stated that his work had necessitated his being continually exposed to rain and damp, while at his boarding house he had been indulging in fried and fatty foods which he knew to be unsatisfactory. The response to a second course of treatment was prompt, and the patient was discharged clinically cured some three weeks after re-admission to hospital. GRAPH N o . 5. (Case No. 9.)

T h e effects of liver extract and high protein diet on the blood in Sprue. Liver Extract° (Eli Lilly) 1 s q u a r e = 3.5 oz. of raw liver. R,B,C,

Ret,

5

5o

4-

40

3

3o

~o

1

10

i0

2O

3o

~0

50 Day~

60

Red Blood C ~ p u s c l e s .

70

9o

80,

Retlc~iooytes. --". . . . . . . .

C,[, HIIIII]II',I',IIIII:II',IIHH+FFH+H+FFF:~', .............. ilJ

~ ~ 4 ! , l.a

8o

i,o

60

i : i I I ', : I ', ', i ', I I : 1 ~ I I I I+FHrI-FfH+H ,~-H

~

~

,"'@ ":

~'I ~'l lllII

H-I-H-~.

~ ~ ~ I I ,,: I ~'¢~'~C.~.L11 ,.~.~.~.

t [, .,.,,, '~ '' '' ~, ' ............. ~, ~,~,,,

I0

~'II " 1111111111111111 IIII ll"llIllll'

........

~

....................

0~

.

: ............ i . . . . . . io

~o

,

30

4o

y0 • Day~

60

7o

80

.

,

9

~0

.o

6

164

(3)

SPRUE.

Liver Treatment in Sprue.

I t is an i n t e r e s t i n g h i s t o r i c a l fact t h a t f o r m a n y y e a r s p r i o r to t h e i n t r o d u c t i o n o f liver t r e a t m e n t b y MINOT a n d MURPHY (1926), l i v e r s o u p was w i d e l y used by tropical physicians in sprue in the treatment of which it undoubtedly e n j o y e d a c o n s i d e r a b l e r e p u t a t i o n . MANSON-BAHR (1925) a d v o c a t e d one a n d one-half pounds of freshly minced calf's liver being simmered for three hours in a q u a r t o f b o i l i n g w a t e r , a n d a d m i n i s t e r i n g u p to 8 ozs. o f t h e s t r a i n e d s o u p d a i l y . U n t i l MINOT a n d MURPHY'S w o r k , h o w e v e r , n o n e o f t h e t r o p i c a l w o r k e r s h a d r e a l i s e d t h a t l i v e r e x e r t e d a n y specific a c t i o n o n s p r u e anaemia. P r o b a b l y t h e i n a d e q u a t e d o s a g e i n w h i c h t h e s o u p was a d m i n i s t e r e d as w e l l as t h e p r o l o n g e d h e a t i n g to w h i c h it was s u b j e c t e d r e d u c e d its e f f e c t i v e n e s s c o m p a r e d w i t h b o t h r a w l i v e r a n d m o d e r n liver e x t r a c t s , t h u s m a k i n g t h e r e c o g n i t i o n of its real m o d e o f a c t i o n difficult. BLOOMFIELD and WYCKOFF (1927) placed a case of sprue on the high liver diet of IVfINOT and MURPHY, no other drugs being used. There was a p r o m p t improvement. HC1 was also administered. There was decreased anaemia and diarrhoea and increase in weight within two months amounted to 25 lbs. Later the same authors (1929) reported recovery in two severe cases of sprue treated with liver extract (Lilly, No. 343) ; a characteristic reticulocyte response similar to that observed in pernicious anaemia was noted. Both cases had free HC1 in the stomach juice, typical sprue stools, and showed an absence of any neurological changes. ASHFORD(1928) tested fourteen cases of sprue before treatment with liver extract (Lilly, No. 343), ten showing a pernicious anaemia and four one of secondary type. Three to six vials were given daily. In 'addition, the patients received ASHFO~'S special diet, which consisted of vegetables and fruit and abundant animal protein, but was free from cane sugar and the cereals. Five cases responded with a reticulocyte shower on receiving liver extract, the average maximum rise being 16.2 per cent. After nine weeks' continuous treatment the red blood corpuscles showed an average rise of 47.6 per cent. and 47.2 per cent. respectively. In one of these patients two blood transfusions had been without effect. Of the five remaining patients with a pernicious blood picture receiving liver extract no reticulocyte shower was observed, the average percentage gain in erythrocytes and h~emoglobin over a period of forty days being 11 per cent. and 14-2 per cent, respectively. Four of these, however, had had liver treatment previously. Of the four patients with secondary anaemia none showed the slightest increase in reticulocytes. One control case treated with dietary alone showed a reticulocytic response of 10.4 per cent. on the tenth day of the disease. ASItFORDconcluded that secondary sprue anaemias show no reticulocyte response, that despite a high colour index the response is not appreciable if the erythrocyte count exceeds 3,000,000 per c.mm., and that it is certain to occur if the corpuscles are less than 2,000,000 per c.mm. Despite the fact that cases appear to proceed to clinical cure, ASttFORD found that for two months at least the colour index remained high. ASI-IFORD (1930) later recorded that reticulocyte rise may follow either his standard diet or the injection of monilia vaccine. I n t h e p r e s e n t series o f cases s e v e n t e e n w e r e t r e a t e d w i t h l i v e r e x t r a c t N o . 343, a large q u a n t i t y o f w h i c h was g e n e r o u s l y s u p p l i e d to us b y t h e Eli L i l l y Co. for t h i s p u r p o s e . T h e a m o u n t g i v e n c o n s i s t e d o f 6 vials d a i l y , e a c h vial b e i n g t h e e q u i v a l e n t o f 3½ ozs. of f r e s h liver. A s a r u l e , t h i s q u a n t i t y was a d m i n i s t e r e d for f o u r w e e k s , a f t e r w h i c h t h e d o s a g e was g e n e r a l l y r e d u c e d o r s t o p p e d a l t o g e t h e r , a c c o r d i n g to t h e r e q u i r e m e n t s o f t h e i n d i v i d u a l case. I n s e v e r e anaemia, l a r g e d o s e s w e r e c o n t i n u e d for l o n g e r p e r i o d s , a n d in cases o f

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achylia gastrica or anacidity a maintenance dose of one vial daily was advised until such time as acid again began to be secreted normally. In addition, all cases were placed on the high-protein low-fat low-carbohydrate diet as outlined. Haematological observations were made throughout the course of treatment, and initially sixteen out of seventeen suffered from a megalocytic anaemia. The average erythrocyte count on admission was 3,020,000 per e.mnl., the haemoglobin 63 per cent., the colour index 1"0, and the average diameter of the corpuscles 8.2 microns. Cases were discharged on an average fifty-three days later by which time the'average findings were : - Erythrocytes .. •. Haemoglobin .. .. Colour Index .. •. Diameter of Corpuscles ..

4,640,000 per c.mm. 80 per cent. 0"85

7.7 microns.

Thus, the gain in corpuscles amounted to 1,620,000 per c.mm. (32.4 per cent.), while the rise in haemoglobin amounted to 17 per cent. On an average, as a result of treatment, the corpuscles were smaller in diameter by 0.5 microns, and the colour index had fallen 0.15. Strangely, the only example of a low colour index (0.6) occurred in the first case of the series which was kindly transferred to me by Dr. MANSON-BAHR. She was a Parsi lady, who had been ill for fifteen years, and in whom numerous diets had been tried without avail. In addition she had just failed to respond to the milk and mixed diet treatment. Under the high protein, low-fat, lowcarbohydrate diet and liver extract administration, a remarkable clinical improvement occurred, and at the end of treatment all intestinal symptoms had disappeared, the stcols were normal, and there had been a 30 per cent. gain in haemoglobin, and an increase of 1,100,000 red cells (22 per cent.). The colour index had risen to 0.8. Since leaving hospital and returning to India, progress has continued, the patient now for the first time in fifteen years being free from all symptoms, and regarding herself as cured. Unfortunately, neither the reticulocyte response nor the corpuscular diameter was studied in this case, and it is not possible to determine to what extent liver extract was a factor in clearing up the anaemia. Continuous observation on the reticulocyte response was only possible in eight cases. T h e minimum before commencement was 0.1 per cent., and the maximum 2.0 per cent., the average being 1"0 per cent. The average maximum response equalled 8.4 per cent., the smallest being 2-0 per cent., and the greatest 41-0 per cent. The three cases with erythrocytic counts under 3,000,000 per c.mm. showed very definite reticulocytic peaks from the seventh to the eleventh day (Graphs Nos. 5, 6 and 7), but response was less evident in the five cases which showed counts varying from 3,000,000 to 3,800,000. The actual percentages were 5.8, 4.5, 4.5, 2.5 and 2.0. In all cases the reticulocytes were

166

SPRUE. Gm~PH N o . 6.

(Case No. 18.) T h e effects of liver extract and high p r o t e i n diet on the b l o o d in S p r u e R . B . C . Ret.

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increased above their original level, but it is doubtful whether this could be regarded as significant in the last two instances, as counts in ordinary individuals may reach 2 per cent. This, however, is in no way remarkable, for even in pernicious anaemia, MINOT, MURPHY and STETSON (1928) showed that an inverse relationship existed between the reticuloeyte count and the level of the erythrocytes, and that cases with more than three million red blood cells per c.mm. never exhibit more than a slight reticulocyte response. Our results in the present series therefore show no essential differences from those obtained in cases of pernicious anaemia suffering from a similar grade of anaemia. In the only case of secondary anaemia progressive improvement followed the combined liver extract and high protein dietary. High protein dietary has been given to all cases in the present series, and it is not possible to state what part it plays in blood regeneration. T h e fundamental work of WHIPPLE, ROBSCHEIT-ROBBINS and HOOPER (1920) on dogs, as well as that more recently reported by MOLLER (1927), indicate that it cannot be disregarded. MOLLER'S work on regeneration of the megaloblastic marrow in starved pigeons showed that red meat was actually superior to liver in maintaining though not necessarily in initiating normal blood production.

GRAPH No. 7. (Case No. 8.)

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Blood transfusion was employed by BARACH and MURRAY (1920), BAUMGARTNERand THOMAS (1925), and by other American observers in the treatment of sprue anaemia, and more recently its great utility has been favourably reported on by MANSON-BAHR,MAYBURY and MARTIN (1927) and L o w and COOKE (1927), at the London Hospital for Tropical Diseases. It has not been utilised in the present series of cases as our investigations were concerned with the effects of liver extract from a h~ematological point of view, and its application under these circumstances would only have confused the issue. Transfusion has undoubtedly been a measure of great practical value, both in the treatment of severe and moderate grades of sprue anaemia, and at times it is a life-saving procedure. Now, however, that potent liver extracts are available, its application should be limited to gravely anaemic patients in tiding them over the critical few days before liver extract can produce its extraordinary effect on megaloblastic bone marrow. (4)

Reinforcement of Demonstrable Deficiencies.

The third line of treatment adopted consists of the administration of HC1 and calcium salts where clinical and chemical investigations show them to be deficient.

(a) HCl Administration. HURST (1924) and his colleagues have emphasised the value of HC1 therapy in pernicious anaemia, and in sprue, where diminished or absent HC1 so often occurs, it is undoubtedly a reasonable procedure. In our series it was administered thrice daily in doses of ½ to 1 drachm, the acid hydrochloricum dilutum (B.P.) being given in diluted orange juice at the end of the meal, but its use was restricted to cases where secretory defect was shown in the fractional test meal. If this safeguard be not adopted, patients with a normal or excessive acid secretion will receive acid unnecessarily, and I have seen diarrhoea result in at least one such case. Again the duration of this treatment should be controlled by the fractional test meal findings, and in cases of achylia gastrica acid medication and a maintenance dose of liver extract should, in my opinion, be continued until normal secretion is established. Attention to therapeutic detail along such lines as these may do much to prevent relapse in chronic cases.

(b) Calcium Deficiency. Undoubtedly the essential measure in restoring blood calcium and relieving tetany is stoppage of the diarrhoea and the institution of a low fat dietary. This is the basic factor in treatment, and unless it be done no other measures are likely to lead to more than a temporary amelioration of the condition. I have observed a case which was treated by calcium and parathyroid per os, Collip's parathormone subcutaneously, and calcium intravenously, continue to have

N. HAMILTON FAIRLEY,

169

attacks of carpo-pedal spasm associated with a persistent low blood calcium over a period of several weeks while the diarrhoea continued. In other cases where the diarrhoea was controlled by dietetic measures, the administration of calcium salts and vitamin D. ted to rapid and progressive elevation of the blood calcium with complete disappearance of tetany and of Chvostek's and Trousseau's signs. In eight cases with serum calcium readings ayeraging 7.9 rag. pex 100 c.cm. treatment lead in every instance to a return to normal values, and prior to discharge the average for the series equalled 9-7 mg. per 100 c.cm. Four of these received no vitamin D., but their serum calcium also returned to normal.

(c) Commentary. These results indicate clearly that the serum calcium can be restored to its normal level by appropriate dietary combined with calcium salts, the absorption of which may have been assisted in certain of these cases by radiostol administration. From a dietetic point of view, the results are of interest, for though a low-fat diet is undoubtedly indicated in the treatment of any case of tetany associated with steatorrh~ea, the excess of protein in the present diet might on a priori grounds have been expected to increase the tendency to tetany. This, however, was not the case, as the results show. Another interesting point concerns the use of ultra-violet rays in treatment. For several years MANSON]~AHR (1929) has advocated ultra-violet rays in sprue on the grounds of its stimulating action in certain cases which did not respond readily to dietetic treatment. CAMPBELL'S(1926) experiments show that radiation has no effect upon the metabolism of healthy men, mice or rats, and I would suggest that the beneficial results obtained by this mode of therapy in sprue are dependent on the synthesis of vitamin D. locally in the skin. In one case of tetany (No. 8), ultra-violet rays were applied, but not until the nineteenth day, by which time the blood calcium was 8-0 rag. per 100 c.cm. In the next five days it rose to 10.0 rag. per 100 c.cm., a result which may have been related to this treatment. X.

SYMPTOMATIC TREATMENT.

Time will not permit a detailed survey of the remedial measures applicable to all the symptomatic complications of sprue, but reference may be made to the more common of them. The administration of an aperient at the commencement of treatment is always advisable, and the time-honoured remedy, Oleum ricini, in doses up to ii 3, has much to recommend it. For constipation later in the disease liquid paraffin proves most suitable. During the acute exacerbations watery diarrhoea may be very troublesome, and here tincture of opium, m.XV., twice or thrice daily, combined with pulv. Batavim Co. or chalky preparations may be of very real value. Attacks of acute abdominal distension sometimes prove very troublesome, and come on especially after excessive

170

SPRUE.

carbohydrate intake toward evening. If ambulatory, the patient should have a really hot bath to assist in the expulsion of flatus, and go straight to bed, the diet being subsequently modified by cutting down the sugary and starchy foods. A word or warning is necessary regarding the administration of drugs which are generally badly tolerated by the delicate gastro-intestinal mucosa. This holds particularly with aperients, including glycerine suppositories and enemata ; preparations of iron, arsenic, mercury, and the like, also frequently upset quiescent sprue cases, and if persisted in may precipitate relapse. Xl. SUMMARY. T h e views expressed in this paper are based on the conception that sprue is essentially an alimentary disease, and the clinical features and the pathological, h~ematological and biochemical findings are explained in terms of the resulting dysfunction of the gastro-intestine. Theoretical conceptions have of necessity formed an integral part of the paper, and the evidence on which certain views have been formulated is admittedly incomplete. Biochemical investigations are however being continued, and it is hoped at a later date to present fresh data having a material bearing on both the theoretical and practical issues involved. The pathological lesions which are primarily inflammatory and secondarily atrophic have a notoriously patchy distribution, and, in the later stages, implicate the whole tract. At times, however, the main brunt of the attack may fall on the ileum, the jejunum, the stomach or the tongue with corresponding modification of the clinical picture. It is suggested that derangement of the ileum specia!ly underlies defective fat, vitamin D and calcium absorption, and that jejunal involvement, leading to an inevitable decrease in the secretion of succus entericus, prevents normal splitting of cane sugar, lactose and maltose. Abnormal fermentation of the resulting disaccharide residue is largely responsible for abdominal distension, and the acid, gaseous stools so characteristic of sprue, while their increased fat content contributes largely to their bulkiness. Involvement of the stomach is indicated by the frequency of defective acid secretion, and, as in pernicious anmmia, deranged gastric secretion probably underlies the megaloblastic hyperplasia of the marrow and the megalocytic anmmia so characteristic of sprue. No essential relationship, however, exists between megalocytic anmmia and achylia gastrica, for several of the present series showed anmmia of this type associated with a free secretion of HC1. It is suggested that the aplasia which the megaloblastic marrow undergoes in sprue results from malnutrition, being analogous to the corresponding changes produced in the normal megaloblastic marrow of pigeons undergoing starvation. That grave nutritional disturbance exists in sprue is indicated by the great loss of weight, the practical disappearance of all subcutaneous fat and the extreme grade of atrophy of the viscera noted at autopsy. Hyper-bilirubin~emia is much less marked in sprue than in pernicious anaemia, and in doubtfuI

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171

cases both the indirect Van den Bergh reaction and gastric analysis, especially after histamine injections, afford information of considerable value. The acid response to histamine may also be used for estimating rejuvenescence of the oxyntic cells in cases of achylia gastrica.' The first indication of improvement is the reappearance of acid under such a stimulus ; later free acid appears in the ordinary fractional test meal. Investigations on the blood chemistry of sprue show that total as well as the ionic serum calcium is frequently reduced, and also that this reduction is not accompanied by an increase in the inorganic phosphorus. These findings indicate that tetany is due to a calcium deficiency caused by defective intestinal absorption in which the sterols (vitamin D) probably participate. Marked lowering of the serum cholesterol was a characteristic finding in the severer cases of sprue. Its return to normal closely followed clinical improvement and recovery from She anemia. The essential principles in the treatment of sprue may be summarised as follows :-(1) Alimentary rest. (2) Restoration of the blood to a normal condition. (3) Reinforcing demonstrable deficiencies such as lowered blood calcium and defective HCt secretion. Emphasis is placed on the fact that in sprue starchy foods and the disaccharides in the gut give rise to acid fermentation, while fat is poorly absorbed. Of the fundamental foodstuffs protein, especially in the form of minced underdone red meat, is well tolerated, leaving little residue, and it is submitted that the most rational method of obtaining alimentary rest under such conditions is by the administration of a high protein, low-fat, low-carbohydrate, adequate vitamin diet along the lines outlined in this paper. Glucose and milk are the best initial means of reinforcing the carbohydrate and fat moiety of the diet. The effects of a high protein diet are very obvious clinically since the stools show a fall in their fat content, become neutral or alkaline in reaction, rapidly decrease in bulk and number, while abdominal distension and intestinal flatulence disappear. During the first two or three weeks weight may be lost or little gained, but once the bowel has been adequately rested and the amemia rectified, higher calorie diets are well tolerated without the reappearance either of bulky stools or abdominal flatulence. Where patients are specially emaciated or the weight-curve fails to show the customary rise, insulin in doses of 6 to 12 units daily may be employed with striking benefit. In all cases of megalocytic anaemia liver extract in full dosage ( = 11 lb. daily) was administered daily. Steady improvement in the red cell counts and percentage of hmmoglobin followed, and generally a reticulocyte response was elicited, its intensity being directly related to the gravity of the anaemia. Simultaneously the colour-index and the average corpuscular diameter, as shown by halometer readings, progressively decreased toward normality.

172

SPRUE.

Anaemias not frankly megalocytic in type also improved under this high protein and liver extract rdgime, but in all types of cases it has not yet been ascertained to what extent p u r e l y dietetic measures were responsible. Where the total serum calcium was below 9.0 mg. per 100 c.cm., calcium lactate or calcium and sodium lactate were administered, and in special cases irradiated ergosterol (vitamin D) was also employed. In addition, in all instances a low fat diet was instituted. Restoration to a normal blood calcium level invariably followed treatment along these lines, and generally paralleled improvement in alimentation. HC1 was supplied in adequate dosage to all cases where its secretion was proved defective. After a prolonged experience of tropical sprue I am convinced that clinical observation should always be reinforced by biochemical and ha~matological data whenever possible, and also that in a disease so notoriously liable to relapse every patient should from time to time report for medical examination. Nor should treatment cease with discharge from hospital. Over-fatigue, extremes of temperature and cold and chill must be avoided ; and for many months, or even years, the diet may need careful supervision, especially in regard to carbohydrate excess. In cases of achylia gastrica and achlorhydria continued administration of HC1 and a maintenance daily dose of liver extract equal to } lb. of the fresh organ is advised until such time as normal gastric secretion be restored.

XII. CONCLUSIONS. I. Defective gastric secretion and malnutrition are suggested as the respective factors underlying megaloblasfic hypertrophy and aplasia of the red marrow in sprue. 2. In a series of twenty-two cases examined by Eve's halometer, nineteen presented an average corpuscular diameter varying between 7"8 to 8.6 microns. The mean diameter equalled 8-16 microns. 3. In eighteen out of twenty cases of sprue the indirect Van den Bergh reactions did not exceed 1"2 units or 0"6 rag. of bilirubin per I00 c.cm. 4. A megaloblastic anmmia associated with an indirect Van den Bergh reaction not exceeding 1-2 units (0.6 mg. per I00 c.cm.) is a very characteristic finding. 5. The study of the curve of acid secretion, especially after histamine injection, will frequently enable a clear-cut differentiation being made from pernicious anmmia. 6. The ~esponse to histamine affords one of the earliest indications of rejuvcnescence of the oxyntic cells in the achylia occasionally observed in sprue. 7. In twenty-one cases the total serum calcium averaged 8.8 mg. per 100 c.cm. Three were complicated by tetany, and here the values equalled 5-2, 5"8 and 6.4 mg. per 100 c.cm.

N. HAMILTON FAIRLEY.

178

8. Simultaneous observations on the inorganic serum phosphorus in fourteen instances showed normal values, the average being 3-2 rag., the minimum 2.2 rag., and the maximum 4.0 rag. per 100 c.cm. 9. Low total serum calcium unassociated with any abnormal rise in the inorganic phosphorus indicates that the tetany is arising from deficient calcium absorption. 10. The serum cholesterol in ten cases of sprue averaged only 72.8 rag. per 100 c.cm. Hypocholestera~mia was almost invariably present, but a rapid rise followed effective treatment. 11. Defective fat absorption and abnormal fermentation of disaccharide residues are regarded as underlying the chief intestinal manifestations of sprue. 12. The fundamental basis of treatment is alimentary rest; this is best attained by a high protein, low-fat, low-carbohydrate, adequate vitamin diet as detailed. 13. Simultaneously, the megalocytic aneemia should be treated by full dosage of liver extract (1¼ lb. daily). 14. Where fractional test meal analysis reveals deficient acid secretion, HC1 therapy is instituted. 15. Calcium deficiency is best controlled by a low-fat diet and the administration p er os of calcium salts, the absorption of which may in some cases be assisted by vitamin D administration or ultra-violet irradiation. 16. After a period of three weeks during which the intestine has been adequately rested and the blood restored, higher calorie diets are instituted (3,000 calories). 17. At this phase of treatment the administration of 6 to 12 units of insulin daily combined with glucose p e r os is frequently followed by a rapid rise in the weight curve and an elevation of the blood pressure. 18. In seventeen consecutive cases treated by this method, clinical cure was obtained ; one case of the series relapsed, but again rapidly responded to treatment. APPENDIX I. ROUTINE TREATMENT OF SPRUE CASES ON HIGH PROTEIN DIET AND LIVER EXTRACT.

General Instructions. 1. O n admission, cases are k e p t o n a m i l k dietary or a diet similar to t h a t w h i c h t h e y h a v e b e e n h a v i n g u n t i l p r e l i m i n a r y investigations are c o m p l e t e d . T h i s s h o u l d take a b o u t 24 h o u r s . 2. T h e r o u t i n e e x a m i n a t i o n s r e q u i r e d are : (1) Blood e s t i m a t i o n of calcium a n d p h o s p h o r u s . (2) V a n d e n B e r g h reaction. (3) S p e c i m e n of f~eces for fat analysis. (4) A fractional t e s t meal** a n d h i s t a m i n e response. (5) C o m p l e t e haematological investigation. I n severe cases it m a y b e c o n s i d e r e d advisable to p o s t p o n e or o m i t this p a r t i c u l a r examination.

174

SPRUE.

3. Then 61eum ricini, 2 drachms, is given as a routine, and the patient is put on Diet No. 1. 4. Acid HCldil. (½to13)is recommended to be taken with or immediately after the 8 a.m., 12 noon and 6 p.m. feeds where gastric analysis shows that there is a deficiency in acid secretion. 5. Where blood examination shows a deficiency of serum calcium, calcium lactate or calcium and sodium lactate, grs. XX t.d.s., should be given. Irradiated ergosterol (vitamin D) or ultra-violet irradiation may assist absorption in certain cases. 6. Water, ad. lib., may be drunk in between meals. No condiments or pepper are to be added to soup or meat. Salt is permitted. 7. If the patient becomes constipated, liquid paraffin in appropriate dosage is allowed, but no other aperient. Excessive diarrhoea is best checked by non-residue high protein diet, but in severe cases preparations of opium and Pulv. Batavia~ Co. may be utilised with benefit. 8. The patient must be kept warm and at rest in bed throughout the treatment. Weight will be lost on diets Nos. 1 and 2. No. 3 probably meets basal requirements. Nos. 4 and 5 are often associated with definite gain in weight. 9. Liver extract in full physiological dosage, i.e., equivalent to 1¼ lb. of fresh liver, is given either in ordinary or in liver soup whenever anaemia is present. APPENDIX I I .

High Protein, Low Fat, Low Carbohydrate Diets. T h e food values of these diets are based on PLIMMER'S tables (Analyses and Energy Values of Foods, H . M . Stationery Office, L o n d o n , 1921). Available calories were used for calculation throughout, i.e., 1 gram of carbohydrate ~--4 calories, 1 gram of protein - - 4 calories, and 1 gram of fat --- 9 calories. Protein is largely supplied in the form of lean r u m p steak, which must be of the first quality. I t is prepared b y cutting away all skin, fat and gristle, mincing, and then lightly cooking in a dry pan for two to three minutes without the addition of any grease or water. It is continually stirred with a fork until the exterior is greyish in colour, and then rapidly removed and served hot. M u c h of the meat fibre is still raw, being cooked only sufficiently to render it palatable, in which form it is more readily digested. T h e energy content of both ordinary and liver soup is ignored in these dietaries, as their calorie values are so low. T h e food value of the latter is under investigation. Rusks may be prepared from ordinary bread by baking t h o r o u g h l y in an oven until crisp. Before doing so, all crust is removed. It is found that 2{ ozs. of bread loses 1 oz. of moisture during the process. H e u d e b e r t unsweetened rusks--biscottes de pain grill6--are also excellent. W h e n available in the Tropics ripe papaya may be used either as a substitute for, or in addition to, orange juice in all these diets.

'

High Protein Diet, No. 1.

(Calorie value ~- 770.) 8 a.m.--Underdone beef, 3 ozs. ; rusks, ~ oz. ; juice of ½ orange; and glucose, 2 drachms. 12 a.m.--Soup, 4 ozs. + liver extract ( = ~ lb.) ; underdone beef, 3 ozs. ; rusks, ~ oz. ; juice of { orange ; and. glucose, 1 drachm. 6 p.m.--Ditto, 12 a.m.

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P r o t e i n : fat : c a r b o h y d r a t e = 1.0 : 0 . 3 : 1.2.

Note.--Where p a t i e n t s are v e r y ill, t w o h o u r l y feeds o f m e a t a n d b e e f j u i c e c a n b e substituted.

High Protein Diet, No. 2. ( C a l o r i e v a l u e = 1,280.) 8 a.m.--Underdone b e e f , 5 ozs. ; r u s k s , 1 oz. ; c a l v e s - f o o t jelly, 2 ozs. ; j u i c e o f 1 o r a n g e q- glucose, 2 d r a c h m s . 12 a . m . - - S o u p , 4 ozs. + l i v e r e x t r a c t ( = ~ l b . ) ; u n d e r d o n e b e e f , 5 ozs. ; r u s k s , 1 oz. ; j u i c e o f 1 o r a n g e q- g l u c o s e , 2 d r a c h m s . 4 p . m . - - T e a , 10 ozs. ; m i l k , 2 ozs. 7 p . m . - - D i t t o , 12 a . m . + c a l v e s - f o o t jelly, 2 ozs. P r o t e i n : fat : c a r b o h y d r a t e = 1.0 : 0 . 3 : 1 "0.

High Protein Diet, No. 3 ( C a l o r i e v a l u e = 1,820.) 6 a . m . - - T e a , 10 ozs. ; m i l k , 2 ozs. 8 a . r a . - - U n d e r d o n e b e e f , 6 ozs. ; r u s k s , 11- ozs. ; c a l v e s - f o o t jelly, 2 ozs. ; j u i c e o f 1 o r a n g e -}- glucose, 2 d r a c h m s . 10 a.ra.--1 b a k e d a p p l e ; c u s t a r d , 1 oz. 12 a . m . - - S o u p , 4 o z s . + l i v e r e x t r a c t ( ~ "~ lb.) ; u n d e r d o n e beef, 6 ozs. ; c a l v e s - f o o t jelly, 2 ozs. ; r u s k s , 1½ oz. ; j u i c e o f 1 o r a n g e -t- glucose, 2 d r a c h m s . 4 p . m . - - T e a , 10 ozs. ; m i l k , 2 ozs. ; b a k e d a p p l e , 1 oz. ; c u s t a r d , 1 oz. 7 p . m . - - D i t t o , 12 a.m. P r o t e i n : fat : c a r b o h y d r a t e ~ 1.0 : 0.32 : 1.3.

High Protein Diet, No. 4. ( C a l o r i e v a l u e = 2,200.) 6 a . m . - - T e a , 10 ozs. ; m i l k , 2 ozs. 8 a.m.--Underdone b e e f , 7 ozs. ; r u s k , 1½ ozs. ; c a l v e s - f o o t j e l l y 2 ozs. ; j u i c e o f 1 o r a n g e + glucose, 2 d r a c h m s . 10 a.m.--1 b a k e d a p p l e -+- c u s t a r d , 2 ozs. 12 noon.--Soup, 5 ozs. + l i v e r e x t r a c t ( = ~ lb), u n d e r d o n e beef, 7 ozs. ; c a l v e s - f o o t jelly, 2 ozs. ; r u s k s , 3 ozs. ; j u i c e o f 1 o r a n g e + glucose, 2 d r a c h m s . 4 p . m . - - T e a , 10 ozs. ; a n d m i l k , 2 ozs. ; 1 b a k e d a p p l e ; c u s t a r d , 3 ozs. 7 p . m . - - D i t t o , 12 a.m., b u t o n l y 1½ oz. o f r u s k allowed. P r o t e i n : fat : c a r b o h y d r a t e = 1-0 : 0 . 3 4 : 1.3.

High Protein Diet, No. 5. ( C a l o r i e v a l u e -~ 3,020.) 6 a . m . - - T e a , 10 o z s ; m i l k , 2 ozs. ; g l u c o s e , * 2 d r a c h m s ; r u s k , t ~ ozs. ; b u t t e r , 1 d r a c h m ; o n e s c r a p e d r i p e a p p l e o r o n e fully r i p e C a n a r y b a n a n a (yellow e n d s ) . 8 a.m.--Underdone b e e f , 7 ozs. ; r u s k s , 3 ozs. ; c a l v e s - f o o t jelly, 2 ozs. ; j u i c e o f 1 o r a n g e + glucose, ½ oz. ; h o n e y , 2 d r a c h m s ; b u t t e r , 1 d r a c h m . 10 a.m.--1 b a k e d a p p l e ; c u s t a r d , 3 ozs. 12 a . m . - - S o u p , 5 ozs. + l i v e r e x t r a c t ( = ~ lb) ; u n d e r d o n e b e e f , 7 ozs. ; c a l v e s - f o o t jelly, 2 ozs. ; r u s k s , 1½ ozs. ; j u i c e o f 1 o r a n g e + glucose, ½ oz. 4 p . m . - - T e a , 10 ozs. ; m i l k , 2 ozs. ; glucose, 2 d r a c h m s ; r u s k , 3 ozs. ; b a k e d a p p l e , 1 oz. ; c u s t a r d , 3 ozs. (egg b o i l e d o r p o a c h e d s o m e t i m e s s u b s t i t u t e d ) ; h o n e y , 2 d r a c h m s . 7 p . m . - - D i t t o , 12 a , m . P r o t e i n : fat : c a r b o h y d r a t e = 1.0 : 0"36 : 2.0. * O r d i n a r i l y 2 ozs. of g l u c o s e are g i v e n daily. I n s u l i n u p to 6 u n i t s t w i c e daily car~ b e i n j e c t e d w i t h t h i s diet, a n d g l u c o s e c a n b e i n c r e a s e d a c c o r d i n g to r e q u i r e m e n t s .

176

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APPENDIX I I I .

Convalescent Sprue Diet• Breakfast (8 to 9 a . m . ) . - - L i g h t l y boiled or poached eggs ; u n d e r d o n e lean chop or s t e a k ; filleted, boiled or steamed fish--whiting, sole, plaice, h a d d o c k ; thin toast, and butter in moderation ; weak tea ; stewed fruit : apples, rhubarb ; h o n e y or j a m in small q u a n t i t y ; also butter. 11 a.m.--½ p i n t of milk, if desired, and if it agrees. Lunch.--Chicken or vegetable soup ; u n d e r d o n e grilled steak ; roast or boiled chicken ; liver cooked in various ways ; cold beef or m u t t o n , but fat not to be eaten. Vegetables : spinach, marrow, cauliflower, F r e n c h beans, celery, young peas, boiled onions ; salad of lettuce and tomato ; boiled potatoes in small quantity. Custard, junket, milk jellies, and jelly w i t h fruit in, such as bananas, etc. Baked apples. Small quantity of cream allowed• F r e s h fruits such as oranges, Canary bananas, pears, peaches, grapes, raspberries, strawberries, melons, grape fruit. Rusks or toast allowed. Tea, 4 p . m . - - W e a k China tea, Madeira cake or sponge cake, dry toast and butter, Marie or water biscuits. Dinner, 7 p . m . - - C h i c k e n , rabbit, brains, sweetbread, tripe, cold lean meat ; lettuce and tomato salad or other vegetables mentioned, b u t no potatoes ; custard, junket, baked apple, stewed fruit or fruit in jelly, and a small quantity of fresh cream ; rusks or toast and butter allowed. General Advice. 1. T h e 7 o'clock meal should be the lightest in the day. T h e patient must watch his diet carefully, and if he has any idiosyncrasy, then he m u s t use c o m m o n sense and avoid an article of food that disagrees. 2. Vegetables m u s t be well cooked, and boiled, not fried. M e a t should be underdone. Sugar and starchy foods like boiled potatoes, milk puddings, such as rice, sago, tapioca and semolina, also cereals and bread should be taken at first in moderation, and the quantity not increased till the patient is sure that they agree• M i l k fat is the best tolerated of all fat in sprue, but milk, cream and butter are allowed only in very m o d e r a t e amounts at first• T h e y m a y be increased gradually in quantity. Patients are also instructed to cut out all obvious m e a t fat, whether it be m u t t o n or beef.

Articles to be Avoided. Avoid overdone and twice-cooked meat and articles fried or cooked in fat. Condiments, like pepper, mustard, chillies, sauces, chutneys, curries and spiced food. G a m e : duck and fat fish, such as salmon, trout, mackerel and herrings. Fresh bread, grease, fat, salad oil dressings and sauces of all kinds, suet puddings, cakes with icing, raisins and pastry• Sweets and chocolates. Alcoholic drinks and mineral waters. Note.--Smoking in m o d e r a t i o n is allowed once convalescence has been established.

REFERENCES. ASHFORD, B . K . (1915). A Monilia F o u n d in Certain Cases of S p r u e - - A Preliminary N o t e . Jl. Amer. Med. Assoc., lxiv, 810. ---. (1924). T r o p i c a l Sprue in Porto Rico. Proc. Internat. Conference on Health Problems ]i~ Trop. America, 686. U n i t e d F r u i t Co., Boston. • (1928). A n Evaluation of L i v e r Extract in the T r e a t m e n t of the Anmmias of Sprue. Jl. Amer. Med. Assoc., xci, 242. • (1930). T h e Anaemias of S p r u e - - T h e i r Nature and T r e a t m e n t . Arch. of Int. Med., xlv, 647-673. • (1930). T h e Anmmias of Sprue. Arch. Int. Med., xlv, 647. ----, and HERNANDEZ,L . G . (1926). Blood S e r u m Calcium in Sprue and other Pathologic States in the T r o p i c s . Amer. Jl. Med. Sci. clxxi, 575.

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BARACH, A. L., and MURRAY, H . A . (1920). Tetany in a Case of Sprue. yl. Amer. Med. Assoc., lxxiv, 786. BASSt~TT-SMITH,P. W. (1919). A Case of Sprue Associated with Tetany. 3~l. Trop. Med. ~ Hyg., xxii, 24 ; and Lancet, 1919, i, 178. BAUMGARTNER,E . A . (1927). Parathyroid in the Treatment of Tropical Sprue. Amer. yl. Trop. Med., vii, 181. - - - - - , and HUBBARD,R. S. (1927). The Effect of High Protein Diet on some Blood Constituents• Clifton Mecl. Bull•, xiii, 52. ----, and SMITH, G . D . (1927)• Pernicious Anaemia and Tropical Sprue. Arch. Int. Med., x!, 203. ----, and THOMAS, W. S. (1925). Case of Tropical Sprue with Autopsy. Clifton Med. Bull•, ii, 90. BLOOMFIELD,A. L•, and WYCKOFt~, H . A . (1927). Remission in Sprue following High Liver Diet--Case Report. California & Western Medicine, xxvii, 659. • (1929). The Treatment of Sprue with Liver Extract (343). Amer. Jl. Me& Sci., clxxvii, 209. BRINGS, A . P . (1922). A Modification of the Bell Doisey Phosphate Method. Jl. Biol. Chem., liii, 13. CAMMIDGE,P . J . (1914). The Feeces of Children ~.~ Adults, 255. Bristol : John Wright & Sons• CAMPBELL,J.A. (1926). Ultra-Violet Radiation and Metabolism with a New Method for Estimating Metabolism. Proc. Roy. Sou., B., xci, 451. CANTLIE, J. (1906). The Diet in Sprue. Jl. Trop. Med., lx, 277. • (1913). Some Recent Observations on Sprue. Brit. Med. Jl., ii, 1296. CARNOT, P., KOSKOWSKI, W., and LIBERT, E. (1922). Action de l'histamine sur les sucs digestifs chez l'homme. C.R. Soc. Biol., lxxxvi, 670. CASTLE, W . B . (1929). Observations on the Etiologic Relationship of Achylia Gastrica to Pernicious Anaemia. Amer. Jl. Med. Science, clxxviii, 748 and 764. DOAN, C. A., CUN2qINGHAM,R S., and SABIN, F . R . (1925). Contribution to Embryology. No. 82, Carnegie Publications, xvi, 127. ELDERS, C. (1919). Over Indische Spruw. Nederl. Tijdschr v. Geneesh. Part 2. No. 21. 1683-1690. • (1925). Tropical Sprue and Pernicious Anmmia. The Lancet, i, 75-77. ERLANGER,J., and HEWLETT,A . W . (1901). A Study of the Metabolism of Dogs with Shortened Small Intestines. Amer. Jl. of Physiol., vi, 1. EvE, F. C. (1928). Diagnosis of Pernicious Anaemia by Blood Haloes. The Lancet, i, 1070. FABt~R, K., and HOLST, J . E . (1928). Untersuchungen tiber die Ventrikel sekretion bei Achylia und Hypochylia gastrica. Acta Med. Scandinav., lxix, 46. FAIRLEY, N. H. and MACKIE,F. P. et al. (1926)• A Progress Report on Researches in Sprue. (1924-1925). Ind. ~l. Med. Res., xiv, 105. --, and BILLIMOItlA, H. S. (1929). Anmmia in Sprue. Ind. ~l. Med. Res., xvi, 831. GOMP]~RTZ, L. M., and VORHAUS, M. G. (1925). Studies on the Action of Histamin on Human Gastric Secretion• Jl. Lab. ¢J Clin. Med., ii, 14. HAMPSON, A. C., and SHACKLE, T. W. (1924). Megalocytic and Non-Megalocytic Anmmias. Guy's Hospital Reports, lxxiv, 193. HECHT JOHANSEN,A. (1929). Achylia in Pernicious Amemia after Liver Treatment. Jl. Amer. Med. Ass., xcii, 1728. HILLARY, W. (1766). Observations on the Changes of the Air and Concomitant Epidemical Diseases in the Island of Barbados. HOLT, L. E., COURTNEY,A. M., and FALES, H . L . (1919). A Method for the Determination of Fat in Dried Fmces and its Distribution as Soap, Free Fatty Acids and Neutral Fat. Amer. Jl. Dis. Child, xvii, 38, and xviii, 107. HUNTER, D. (1930). Goulstonian Lectures entitled, " T h e Significance to Clinical Medicine of Studies in Calcium and Phosphorus Metabolism. The Lancet, i, 897. HURST, H. F. (1924). Medical Essays and Addresses, 101. Wm. Heinemann, Ltd., London.

178

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HUTCHINSON, R.

(1923). Food and the Principles of Dietetics, 124. Arnold & Co., Quoted from " Nutrition Investigations at the University of Tennessee." United Stated Department of Agriculture Bull., liii, 43. JosHI, L . L . (1916). The Milk Problem of Indian Cities. D . B . Taraporevala, Sons & Co., Bombay. KI~MER, B., and TISDALL, F . F . (1921). A Simple Technique for the Determination of Ca. and Mg. in Small Amounts of Serum. Jl. Biol. Chem., xlvii, 475. (1923). A Note on the Kramer-Tisdall Method for the Determination of Ca. in "Small Amounts of Serum. Ibid., lvi, 439. KRJUKOFF, A. (1928). Anaemia bei Sprue. Folia hcematologlca, xxxv, 329. LINDER, G. C., and HARRIS, C. F. (1930). Calcium and Phosphorus Metabolism in Chronic Diarrhoea with Tetany. Quart. Jl. of Med., xxiii, 195. L o w , G. C. (1928). Sprue : A n Analytic Study of 150 Cases. Quart. J1. of Med., xxi, 523. ----, and COOKE, W, E. (1927). Blood Transfusion in Sprue. The Lancet, ii. MACKIE, F. P., and Go~n, S . N . (1928). A Note on an Unrecognised Bacillus Isolated from Sprue Cases. Ind. Jl. Med. Res., xvi, 275. - - - - - - , and FAIRLEY, N. H. (1929). T h e Morbid Anatomy of Sprue. Ind. Jl. Med. Res., xvi, 799. MANSON, P. (1879-1880). Notes on Sprue. China Imp. Marit. Cust. Med. Report, xlx, 33. (1907). Sprue. Allbrett and Rolleston's System of Medicine, ii, (2), 545. MANSON-BAHR, P. (1925). Manson's Tropical Diseases. 8th Ed., 431. L o n d o n : Cassell & Co., Ltd. (1929). Ibid., 9th Ed., 449. : MAYBURY, L. M., and MARTIN, P. H. (1929). On the Therapeutic Value of Blood Transfusion in Sprue Anaemia. Trans. Far East Ass. Trop. Med. Cong., 1927, ii, 258. McLEAN, H., GRIFFITHS,W. J., and WILLIAMS,B . W . (1928). Variations in the Acidity and Total Chloride contained in the Secretion from an Isolated Pavlov Pouch in the Dog. Jl. of Physiol., liv, 77. McNEE, J . W . (1923). J a u n d i c e - - A Review of Recent Work. Quart. ffl. Med., xvi, 390. ----, and KEEFER, C . S . (1925). T h e Clinical Value of the Van den Bergh Reaction for Bilirubin in Blood. Brit. Med. Jl., ii, 52. MINOT, G. R., and MURPHY, W . P . (1926). Treatment of Pernicious Anaemia by Special Diet. Jl. Amer. Med. Ass., lxxxvii, 470. , . (1927). Diet k i c h in Liver in Treatment of Pernicious Anaemia. ~l. Amer. Med. Ass., lxxxix, 759. and STETSON, R. P. (1928). T h e Response of the Reticulocytes to Liver T h e r a p y particularly in Pernicious Anaemia. Amer. o7l. Med. Sci., clxxv, 581. MOLLER, G. L. (1927). Experimental Bone Marrow Reactions. Amer. Jl. Physiol., Ixxxii, 269. MYERS, V. C., and WARDELL, E . L . (1918). T h e Colorimetric Estimation of Cholesterol in Blood with a Note in the Estimation of Coprosterol in Faeces. ~l. Biol. Chem., xxxvi, 147. NEWHAM, H. B., MORRIS, R. M., and MANSON-BAHR, P . H . (1926). A Study of Sprue and Addisonian Anaemia. Lancet, ii, 269. PASSI~y, R. D., and BRAINE, J. F. C. (1924). Measurements of the Red Cells in the Anaemias ,of Sprue and Dibotkriocepkalus latus Infection. Guy's Hospital Reports, lxxiv, 329: PijPlm, V . A . (1924). T h e Diagnosis of Pernicious Anaemia by a New Optical Method. The Lancet, ii, 367. PONDER, E., and MILLAR, W . G . (1924). T h e Measurement of the Diameters of Erythrocytes. Quart. ~l. Expt. Physiol., xiv, 67. PRAUSNITZ, W. (1889). U b e r die Ausniitzung der Kuhmilch im menschlichen Darmkanal. Zeit. f. Biologie, xxv, 533. London.

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PRICE-JONES, C. (1920)• The Diurnal Variations in the Size of Red Blood Cells. ffl. Path. ~.~ Bact., xxiii, 371. • (1922). The Diameters of Red Cells in Pernicious Anaemia and in Anmmia following Haemorrhage. Ibid., xxv, 487. REClO. (1924). Discussion on Tropical Sprue. Proc. Internat. Conference on Health Problems in Trop. America. United Fruit Co., Boston, 707. ROBSCHEIT-ROBBINS,F. S., and WHIPPLE, G . H . (1925). Blood Regeneration in Severe Anaemia ; Favourable Influence of Liver, Heart, and Skeletal Muscles in Diet. Amer. ffl. of Physiol., lxxii, 408. RYLE, J. A. (1924). Fatty Stools from Obstruction of the Lacteals. Guy's Hospital Reports, lxxiv, 1. SALVESEN, H . A . (1923). Studies on Physiology of Parathyroids. Acta Medics Scand., Stockholm, 1924, lx, Supplementum vi, 1. SAXON, G . J . (1914). A Method for the Determination of the Total Fats of Undried Fzeces and other Moist Masses. Jl. Biol. Chem., xvii, 99. SCHII~PS, L. (1927). Serum Bilirubin in Health and Disease. Arch. Int. Med., xt, 800. SCOTT, H . H . (1923). A New Theory as to the Causation of Sprue and the Results of Treatment based thereon. Tram• Roy. Soc. Trop. Med. C.@Hyg., xvi, (8), 475. • (1923). The Treatment of Sprue based on a New Theory of Causation• Lancet, ii, 876. (1923). Recent'Advances in the Treatment of Sprue. Brit. Med. Jl., ii, 305. • (1925). On the Value of the Estimation of the Ionic Ca. of the Serum in the Diagnosis of, and as a Gauge of Progress in Sprue. Ann. of Trop. Med. ~ Parasit., xix, 23. SOKHEY, S. S., and MALANDKHAR,M.A. (1928). Pancreatic ~unctions in Sprue. Indian ~l. Med. Res., xv, 921. THAYSEN,T. E. H., and NORGAARD,A. (1929). Regulation of Blood Sugar in Idiopathic Steatorrhcea (Sprue and Gee-Herter's Disease). I. Low Blood Sugar Curve. Arch. Intern• Med., xliv, 17• THOMPSON, S. D. (1925). Some Analysis of Materials Obtained from Sprue Cases. Trans. Roy. Soc. of Trop. Med. ~ Hyg., xviii, 381. VAN DERBURG, C.C. (1879-1880). China Imp. Customs Med. Report to Shanghai, xix, 33. • (1883-1884). China Imp. Marit. Customs Med. Report, xxvii, 55. VAUCHAN, J . M . (1930). Critical Review : The Liver Treatment of Anaemias. Quart. ft. Med., xxiii, 213. VINES, H. W.C. (1921). The Coagulation of the Blood. Part I. The R61e of Calcium. Jl. PhysioL, lv, 86. WHIPPLE, S. H., ROBSCHEIT-ROBmNS,F. S., and HOOPER,C.W. (1920). Blood Regeneration following Simple Anaemia. Influence of Meat, Liver and Various Extractives, alone or combined with Standard Diets. Amer. ~l. of Physiol., liii, 236.

DISCUSSION. Lieut.-C01. F. P. Maokie said that he would like to congratulate Dr. FAIRLEY most heartily, not only on the extremely able and scientific paper with which he had provided us, but on the admirable m a n n e r in which it had been presented. He had referred to their work in Bombay, and it was true that the foundations of a great deal of that which he had been describing tonight were laid there when Dr. FAIRLEY and he were in close association. But since Dr. FAIRLEY had come to L o n d o n he had been able to reinforce the evidence they had obtained in Bombay.

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DISCUSSION,

He might say, perhaps, that as a result of their close association for several years in this disease they had decided to write a book, but that the clinical aspects of the disease, the biochemistry, the h~ematology, and more particularly the treatment, would be in the able hands of Dr. FAIRLEY. He himself had been more particularly interested in the historical aspect of sprue, the distribution, the epidemiology, the etiology, regarding which there were various conflicting theories, and, lastly, the morbid anatomy and pathology. To introduce any one of those subjects tonight would be to draw a red herring across the track. He would content himself with acknowledging that he was entirely with Dr. FAIRLEY in his conclusions. They were both agreed on one or two fundamentals which might perhaps be emphasised. They believed that sprue was a disease sui generis, and that by certain tests and laboratory methods and other means which Dr. FAIRLEY has described, they were able to distinguish between conditions which have hitherto been liable to be confusing, such conditions as coeliac disease, steatorrhcea, pernicious anmmia, chronic dysentery, pellagra, and such like. In the next place, he thought they were also entirely agreed that sprue was fundamentally an infective disease. What the specific infection was, of course, they were not able to say ; their surveys had not led them to any finality on that issue. But they agreed that it was a specific disease which attacked the small intestine, especially the ileum, or sometimes perhaps the jejunum. From there it probably spread upwards, involving the stomach, and producing those various alterations in the acid content and other changes which Dr. FAIRLE¥ had described. It also produced manifest lesions in the tongue. But whatever the cause was, the results were very evident, as would be seen from the microscopic preparations which had been shown this evening. The main alterations were a profound atrophy and degeneration affecting principally--probably almost entirely--the secretory and absorptive elements of the intestinal canal. The result of the interference with absorption and secretion was ultimately to produce a condition resembling chronic starvation, and there were certain parallels with that condition as first described by CUNNINGHAMin India in 1880, which showed that the lesions found in conditions of chronic starvation were not dissimilar from those in sprue. The result of this semi-starvation and this lack of absorption was evidenced by other changes which were probably secondary. The organs responsible for the production of hormones, for example, commonly underwent the same changes or showed the same lack of vitality that the other tissues exhibit, and it was probable, or at least possible, that hormonic deficiencies might add to the clinical complex of sprue. In the same way, a vitamin deficiency undoubtedly existed, but they did not consider that vitamin deficiency was in any sense a primary or necessary condition to the onset of the sprue. When it occurred, it was probably due to lack of absorption of vitamins rather than lack of opportunity for absorption.

DISCUSSION.

181

Dr. FAIRLEY had indicated that there was a large number of different theories as to the etiology of sprue. One of the most prominent up to a few years ago was the theory of ASHFORDthat sprue was due to the combination of several factors causing glandular insufficiency, to which was added the organism Monilia psilosis. But their Bombay experiments were sufficient to disprove the theory that Monilia psilosis was the causative factor, and that theory was losing ground even in the country of its birth, As to other etiological factors, they were not in a position to say anything definitely. Dr. FAIRLEY had referred to some bacteriological observations made in Bombay by the speaker, but the part played by bacteria was still undecided. He hoped that the discussion would follow the interesting line of the scientific procedure which underlies the treatment of sprue, and which Dr. FAIRLEY had so admirably introduced.

Dr. P. Manson-Bahr said that although he had in the past been wandering in the dark from the biochemical point of view until the advent of Dr. FAmLE¥, a certain amount of work had been done. Guided by clinical signs and experience, he had just completed, and would shortly publish a review of 200 cases of sprue which had been under his care in the Hospital for TropicaI Diseases. He had never been for the last ten years an out-and-out advocate of the. milk treatment of sprue. He had rather sat on the fence, and had adopted a diet which in some respects and in calorie value approximated to that which Dr. FAIRLE¥ had described this evening. His cases had been started n-tore or less on the old lines for the first week, and gradually a protein dietary had been introduced. For many years he had been treating sprue cases by means of the liver soup treatment, which dated from MANSON in 1881, who, in his turn, assured him that he got it from Chinese doctors in Amoy and Hongkong. Then came Sir JAMES CANTLTEwith his meat treatment, and it was noted from a clinical point of view that those cases with the greatest anaemia did the best on this meat treatment. He showed some of the graphs of cases in the series he had mentioned, and would give one or two examples of some of the remarkable recoveries on this mixed milk and protein diet. There had been some most striking recoveries, but everybody who had treated a large series of sprue cases could point to cases of the kind. The graphs indicated in a large series of cases the increase in weight per week shown by the patient, together with the average decrease in the size of the stools and the average increase in the red corpuscles. As the stool decreased in size, so the weight of the patient increased. The curve of increase in the red blood corpuscles ran fairly parallel to the increase of body weight. That brought, in a rough way, some confirmation of what Dr. FAIRLE¥ has stated this evening. Another graph reduced from a whole series of cases indicated that during the first weeks of treatment there was a

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DISCUSSION.

gradual decrease in the weight of the patient. This curve showed again that the increase of body weight was very marked at about the fifth week of treatment, when the size of the stool decreased as rapidly as the body weight increased. Therefore the problem of treatment of sprue resolves itself into one of absorption of the diet. The next curve was a little bit more ambitious. It was an attempt to correlate the amount of food taken in by the patient, with the increase of the patient's weight and the decrease of the size of the stool. It would be seen that with the increase of the diet there was a great decrease in the size of the stools, showing, therefore, that the convalescence.of the patient began at about the time when the two points meet. Another curve showed in one particular case the very rapid rise in the weight of the patient, and the rapid decrease in the size of the stool. As a result of this work, he had formulated a few conclusions. In the first place, he thought that sprue was a specific disease sui generis. Wherever sprue occurred it was especially liable to effect Europeans, and it was more prevalent in these Europeans the nearer the Equator was approached. But in its distribution sprue tended to miss the whole of the Central African continent. Wherever it occurred in widely separated localities, the nature and symptoms of sprue were identical, that was to say, the sprue from South America Was exactly the same as the sprue from India. The European victims of sprue were for the most part, those who had been living in close contact with natives in the endemic area of the disease. It possibly existed in association with other diseases to an extent not recognised. To his mind the probability of sprue being an infective disease contracted from the native population, as in the case of the other tropical diseases could be supported by other considerations. Sprue had a definite incubation period, which he had calculated at three months. It was subject to latency and recrudescence. There was evidence of inflammation ranging throughout the whole of the intestinal tract. It had to be assumed that the virus of sprue was capable of lying dormant in the human body for a number of years. In the series which he had quoted there were quite a number of cases in which sprue began seven years after residence in this country, and in one case, after 25 years of apparent good health in England, the symptoms of sprue made themselves manifest. Improvement depended on restoring the functions of absorption. There were two kinds of anmmia in sprue, as Dr. FAIRLEY has already explained. There was a secondary anaemia, and a true pernicious ah~emia, due to atrophy of the blood-forming.elements in the bone marrow. There was evidence that cases of sprue with the most severe type of anaemia had been completely restored to health when the blood picture was brought back to normal. Some of his very worst cases, dating back now for more than seven years, cases which were dying from this sprue anaemia, had been restored to perfect health so far as one could see, by blood transfusion. He saw these people from time to

DISCUSSION.

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time, and they appeared to be in perfectly good health, without evident intestinal symptoms. Dr. G. M. Harston said there was one practical point which had been raised with regard to the treatment of sprue, namely, treatment by ultra-violet rays. He could confirm the effect of ultra-violet rays in sprue, but he woutd like to ask Dr. MANSON-BAHRwhat particular type of apparatus he used in the production of ultra-violet rays. It is well known to physicists that the ordinary carbon arc apparatus only emitted 5 per cent. of ultra-violet rays. The mercury vapour lamp might be emitting none at all, and one might be wasting one's own and the patient's time. The best form of apparatus for the treatment of sprue was the open Tungsten arc. He had used that in his own practice in Hongkong. He had not used it in this country yet, but he could confirm what has been said about the improvement which followed treatment with ultra-violet rays. Some cases seem to stand still until they were put under ray treatment, when the improvement which immediately followed was very striking. This point in therapeutics was interesting, because of the blood condition. He would like to add that the " Scott treatment " of sprue, as they called it in China, has been most enthusiastically received in that country by every medical man out there. Personally, he had not had a single case of sprue which had not yielded to the Scott treatment. I-Ie was not a pathologist, and had been absolutely overwhelmed with the monumental mass of detail presented by Dr. FAIRLEY. But he would state it as a practical fact that the Scott treatment of sprue had been found most successful in Chinese cases, and he could not help thinking that the fact that lesions were not found in the parathyroid gland was no valid argument; that had very little to do with the case, as one would not expect to find much in the way of pathological lesion in so small a gland. He did not look upon that consideration as an argument against the Scott treatment. Dr. G. W. Goodhart said that the cases of sprue described by Dr. FAIRLEY did not appear to gain weight during the initial period of treatment, although they were on very large doses of liver extract. If one took the analogy of pernicious anmmia, the result of liver treatment was very different, for it produced immediate gain in weight. Patients with pernicious anmmia go up in weight as a result of the liver treatment. They go up beyond anything that could be explained simply on the nutritional effect. He recalled one case in which a woman treated with liver originally weighed 8{ stones. Her weight increased to 15 stones, so that means had to be adopted for bringing the weight down. It seems to him rather strange that that did not occur with sprue eases. He had had to do with one case to which Dr. FAIRLEY had referred. He

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DISCUSSION.

diagnosed sprue on the condition of the skin, which was crinkled and obviously wasting, a condition quite different from that seen in pernicious anaemia, where the patients appear well covered with rather a good skin. T h a t seemed to him to exclude the diagnosis of pernicious anaemia in that particular case. H e would like to ask whether there was any familial incidence of sprue. Were there any cases on record of sprue and pernicious a n e m i a occurring in the same families ? A patient who came to him f r o m India brought with her the definite diagnosis f r o m India that she was not suffering from sprue. She had a pernicious anaemia count. She responded to liver treatment, and made, as far as he knew, a perfect recovery. But her father had died of sprue ; he was an old Indian civil servant, and sprue had been diagnosed in his case by Sir PATRICK MANSON himself. T h e patient herself was perfectly convinced that she had not had sprue, because of the absence of stools showing anything like the condition in the case of her father. But this was a case of pernicious a n e m i a in the child of a man who died of sprue.

Dr. Manson-Bahr said that a question had been asked about treatment by ultra-violet rays. T h e apparatus which was used at the Hospital for Tropical Diseases was a T u n g s t e n lamp. A n u m b e r of cases do very well, as Dr. FAIRLEY himself could corroborate, u n d e r heliotherapy and sun baths. Lieut.-Col. F. P. Mackie said that with regard to the question about the familial incidence of sprue, he did not know of any instance in literature where it had been suggested that sprue was a farnilial disease. N o t infrequently a n u m b e r of cases occurred together in the same family, or, what was still more common, there occurred a succession of cases in the same house ; but as far as he knew, t h e r e was no predisposition to sprue as a familial condition, and he took it that the predisposition to pernicious anaemia was not to the pernicious anaemia itself, but to a hereditary tendency towards achylia gastrica. In sprue the condition was quite different. T h e acid content of the gastric juice disappeared as the result of atrophy of the gastric mucous membrane. T h u s the problem was rather different in the two diseases. The President, Dr. G. Carmichael Low, said that he had now over thirty years' experience of sprue, and that he was in the unique position of having seen most of Sir PATRICK MANSON'S cases and also those of Sir JAMES CANTLTE. He had thus b6en able to watch the results ot their different methods of treatment. Sir PATRICK MANSON chiefly used milk as the basis of the treatment, other things such as carbohydrates, sago, rice and fruit, gradually being added. Strawberries in some instances acted with great efficiency, and bananas were also useful. Sir JAMES CANTLIE, on the other hand, relied more on the meat

DISCUSSION.

185

treatment, raw or partially cooked beef being the basis of his treatment. He thought that on the whole the results of Sir PATRICK'S cases were best. There were certain cases of sprue, which, provided they were carefully rested in bed with simple diet, would do well, and one knew that they would do well. On the other hand, there were other cases which would do badly from the beginning, and one knew that they would do badly whatever diet was adopted. One had always to use a certain amount of caution in estimating dietetic results. The outstanding feature of Dr. FAIRLEY'S paper was that the subject was now being approached on biochemical lines, and in some of the cases which he had handed over to Dr. FAIRLEY to try on the high protein diet, the patients had done very well indeed. The value of this biochemical work was undoubted, and having a proper hospital with well-equipped laboratories rendered it possible to use the material to its best advantage. At present the work had not been going on very long, but when more results were obtained, one would be in a better position to judge if the high protein diet was better than the so-called milk diet. It would be well to have a series of cases on the latter diet also biochemically examined, and then the results of the two would be comparable. He thought that Dr. FAIRLEY'S paper was an extremely valuable one, and wished to congratulate him very heartily on the excellent work he had put into it.

Dr. Fairley, in reply, said : At this late hour there are just a few points on which I would comment, but first of all I should like to say how much I appreciate having had the critical opinion of Dr. L o w in regard to this treatment. It has been a very great asset to be able to talk things over with him and to get a critical opinion regarding its efficacy. When Dr. L o w says a case has improved you can rest assured that definite improvement has taken place. DR. GOODHART has raised the very interesting question why these cases of sprue do not gain in weight during the initial period of treatment, although they are on very large doses of liver extract pushed to the physiological limit. In the first place, these patients are all on low diets varying from 800 to 1,800 calories, and they are bound to lose weight initially. Then there is the specific dynamic action of a high protein diet in increasing metabolism, and the limited absorption which handicaps the patient until the intestine recuperates. Defective absorption, the low calorie value and the high protein content of the diet are the factors responsible for failure to put on weight in the early stages of treatment. Many cases of course recover under milk diet, and many cases also have recovered under meat diet and fruit diet. One thing which I should have emphasised is that in this treatment fruit plays a prominent part. The great virtue of fruit lies, in my opinion, in its hexose content. Glucose and levulose are monosaccharides. They are quite different from the starches, as there is

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DISCUSSION.

no necessity for them to be digested in any way before absorption. Similarly, maltose, lactose and saccharose have to be disintegrated into monosaccharides before absorption. I would like to point out that this high protein, low fat, low carbohydrate diet is not the same as CANTLIE'S original treatment. Pure meat has certain deficiencies. It is very defective in calcium and vitamins, and, of course, in carbohydrate also. All these deficiencies have been rectified in this diet, the composition of which is appended at the end of the paper. With regard to liver soup which has b e e n u s e d for so long in China, several interesting problems arise. The liver soup has been boiled for a period of one and a half hours to three hours. What is the effect of that on the blood regenerating principle concerned ? Secondly, soup is not a standardised product, and I have no doubt that in the past the dosage has been very inadequate, and in no way comparable to big quantities of liver which MINOT, MURPHY, CASTLE and others insist are necessary in order to get a maximum response in a megaloblastic bone marrow. Still, it is very remarkable that through all these years liver extract treatment has been used clinically, and that at so late a date we should find by scientific methods the underlying basis of the improvement. It is only just, however, to point out that tropical physicians failed to appreciate its specific effect on the anmmia of sprue, this action probably being masked by inadequate dosage.

The meeting was preceded at 7.45 by a Demonstration prepared by Dr. HAMILTON FAIRLEY and Colonel F. P. MACKIE, I.M.S., to illustrate the

Pathology of Sprue.