A note on the treatment of sprue with special reference to a high protein milk powder

~97 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. VO]. X X V . No. 4. January, 1932.

A

NOTE

ON

THE

TREATMENT

OF

SPRUE

WITH

SPECIAL

REFERENCE TO A H I G H P R O T E I N M I L K POWDER.* BY

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

Evidence is steadily accumulating that sprue is a disease of the gastrointestine characterised by the deficient gastric secretion of both H C L and Castle's bone marrow stimulating factor as well as by mal-absorption of fats, glucose, and calcium in the small intestine. The basis of the gastro-intestinal derangement remains unknown ; it may represent either a metabolic breakdown such as is encountered in diseases with deranged internal secretion or, as certain epidemiological facts suggest, it may originate from some obscure infective agency involving the alimentary tract. The theory of vitamin deficiency or monilia infection as the primary etiological factor is no longer tenable. Being essentially an alimentary disease sprue is best treated by measures designed to rest the gastro-intestine. The essentials of treatment as suggested by the writer (1930) are :-(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 H C L , calcium and vitamin D. Both in the initial attack and during relapses these emaciated, poorly insulated patients must be put to bed under conditions which ensure mental as well as physical rest, while the avoidance of chill is essential especially in patients recently returned from the tropics. * T h i s w o r k was u n d e r t a k e n u n d e r a special g r a n t for i n v e s t i g a t i o n s o n s p r u e given

by the Colonial Medical Research Council. I wish to thank Dr. CARMmHAELLow and Dr. MANSON-BAHRfor placing their clinical material at my disposal, and also Mr. J. TAVROGES,B.Sc., for his co-operation and advice during this investigation. Cow and Gate Ltd., have very generously assisted by supplying large quantities of high protein milk powder for purposes of therapeutic trial, and this is now available under the trade-name of Sprulac. G

298

TREATMENT OF SPRUE WITH HIGH PROTEIN MILK POWDER. DIETARY.

Alimentary rest being the therapeutic ideal, it appears obvious that this can best be obtained by bed rest combined with feeding minimal amounts of those foodstuffs with which the small intestine fails to deal adequately. Overloading of the stomach must be avoided, and this is best effected by non-bulky feeds at short intervals. Unless fat be restricted additional strain falls on an already overtaxed and failing absorption mechanism, and bulky, fatty stools, involving increased enterocolonic work, result. Carbohydrate intolerance also is marked in most cases, starchy and sugary foods undergoing abnormal fermentation with the production of organic acids and gas leading to abdominal distension, excessive flatus and acid gaseous stools. Dietic indiscretions, especially excess of carbohydrate, may precipitate attacks of acute enteritis which so often initiate severe relapses. Probably deficiency of the di-saccharide enzymes in the succus entericus associated with malabsorption of glucose leads to abnormal mono- and di-saccharide residues in the gut and so affords a basis for the excessive carbohydrate fermentation so characteristic of this disease. Under these circumstances it appears rational to make protein the chief constituent of the diet commencing with one of low calorie value, and gradually increasing its quantity while still maintaining as a constant the high protein ratio. These are the underlying principles on which the high protein, low fat, low carbohydrate diet has been evolved. The successful results which have followed the employment of a high meat protein, low fat, low carbohydrate have been already reported on by the writer (1930), and subsequent experience in a much larger series of cases has fully confirmed its great therapeutic value. In the present paper the results obtained with a dried high protein milk powder, containing a similar ratio of protein (140, fat (0.3) and carbohydrate (1.3), are recorded. LIQUID M I L K .

During the war, the Royal Society Committee advised that the desirable ratios of protein, fat and carbohydrate in a normal diet was 1 : 0 : 1 : 0 : 5 : 0, the actual amounts advocated for a man of average weight doing light work being 100, 100, and 500 grams respectively. In the accompanying table (No. 1) the ratios of these various constituents in cows' milk, buffalo milk and sprulac are compared. TABLE I.

Protein.

Type of Diet.

Fat.

Carbohydrate.

Normal diet

....

1.0

1'0

5.0

Cows' milk

....

1 "0

1.1

1.5

Buffaloes' milk . . . .

1.0

1-75

1-1

0.3

1-3

Sprulac

....

,..

1"0

.

9,99

N. HAMILTONFAIRLEY.

It will be seen that both cows' milk and buffaloes' milk which is widely used in the tropics contain relatively a larger proportion of fat than obtains in a normal diet, and when once the patient reaches five pints of cows' milk daily the absolute quantity of fat present is actually in excess of the 100 grams advocated for a healthy active man on a balanced diet of 3,300 calories. AGGARWALA (1929) gives the following analysis of Indian buffalo milk :-Water .. Total protein Fat . . . . . Sugar .. Ash . . . . . Total solids Specific gravity

-= =

82.22 per cent. 4.37 7.65 --= 4.82 0 -94 -~: 17.78 --:- 1.0300 ,, ,,

~t

,,

It is evident that with buffaloes' milk even three pints may contain excess of fat. Thus in the later stage of Manson's classical milk treatment, especially in the Far East, the sprue patient, despite his incapacity to absorb fat adequately may be given more fat than the physiologists advocate for a man of average weight doing a moderate amount of muscular work. This can hardly be regarded as the ideal dietary for a patient suffering from a disease characterised by defective fat absorption. Milk is a bland food containing all the essential food elements : its fat has a low melting point, is present in a state of fine emulsion and in consequence is readily absorbed. Its two disadvantages, especially in the tropics, are its high fat content, and its almost invariable contamination with micro-organisms and dirt. Meat protein is by no means always obtainable in a satisfactory condition in hot climates and these facts led, after consultation with Dr. CARMICHAEL Low, to my approaching the firm of Cow and Gate Ltd., regarding the possibility of their producing a stable dried high protein milk powder with a minimal bacterial content and with a ratio of protein : fat : carbohydrate of approximately 1 . 0 : 0.3 • 1.3 for experimental trial in the treatment of cases of sprue in the wards of the Hospital for Tropical Diseases, Endsleigh Gardens. Should it prove successful we felt that the product would have a special sphere of usefulness in the tropics and on board ship when the sprue patient was returning to Europe. DRIED HIGH PROTEIN MILK POWDER (SPRULAC).

This powder is prepared from fresh milk which is first treated by passage through a gauze and wire filter and subsequently chilled and centrifuged to get rid of inorganic and organic debris. Thence it passes through mechanical mixing vats where its chemical composition is determined and the necessary modifications regarding its protein, fat and carbohydrate content are made. Subsequently it is dessicated by the improved roller process at 120 ° C., the actual time of contact with the metal rollers being two and a half seconds. The temperature

~00

T R E A T M E N T OF S P R U E W I T H

HIGH

PROTEIN MILK POWDER.

o f t h e m i l k , h o w e v e r , is s t a t e d n o t to rise a b o v e 98 ° C. N e x t , t h e d r i e d flaky m i l k is p o w d e r e d , s i f t e d a n d p u t u p in a i r t i g h t tins. I f for u s e in t h e t r o p i c s t h e a i r is e x h a u s t e d a n d s u b s e q u e n t l y r e p l a c e d b y a n a t m o s p h e r e o f C O 2 b e f o r e s e a l i n g . T h e final b a c t e r i a l c o n t e n t d o e s n o t e x c e e d 150 o r g a n i s m s p e r c . c m . , w h e r e a s a h i g h g r a d e l i q u i d m i l k (certified T . T . ) c o n t a i n s f r o m 3,000 t o 30,000 organisms per c.cm. Chemical analysis of the powder shows :-Moisture . . . . . Fat . . . . . . . . Protein . . . . Lactose . . . . Mineral matter . . Total

. . --~ . . .

..

T h e calorie v a l u e p e r o u n c e ~ c a r b o h y d r a t e 1 . 0 : 0 . 3 : 1.3.

--

3 . 0 p e r cent. 10.6 34.0 )) 45.0 )) 7.4 100"0

125, a n d t h e r a t i o o f p r o t e i n , fat a n d

DIET ADVOCATEDIN SPRUE. After admission cases have been kept on an ordinary mixed dietary until preliminary investigations have been completed, and then a dose of oleum ricini (2 drachms) is administered and diet No. I instituted. The patient must be kept warm and at rest in bed throughout the treatment. Weight will be lost on diets Nos. I and 2. No. 3 approximates to basal requirements, while a gain of weight may be associated with Nos. 4 and 5. Liver extract is given in full dosage (i.e., equivalent to 11 Ibs. of fresh liver daily) whenever megalocytic anaemia is present, and acid hydrochlor, dil. (half to one drachm) and calcium lactate (grains xxx t.d.s.) are administered if biochemical investigations indicate their deficient production. T h e d i e t a d v o c a t e d is as f o l l o w s : - Diet N o .

1.

(Calorie value =

697).

I oz. of sprulac made up to 8 oz. with water every 2½ hours for six feeds (7.30 a.m. to 7.30 p.m.). Protein : fat : carbohydrate = 1.0 : 0"3 : 1.3. Diet N o . 2.

(Calorie value ~- 1,117).

1½ oz. of sprulac made up to 12 oz. with water every 2½ hours for six feeds (7.30 a.m. to 7.30 p.m.). The juice of one orange ; calves foot jelly (1 oz.). Protein: f a t : carbohydrate ~ 1 . 0 : 0 . 3 : 1 . 4 . Diet N o . 3.

(Calorie value =

1,536).

2 oz. of sprulac made up with 16 oz. of water are given every 2½ hours for six feeds (7.30 a.m. to 7.30 p.m.). T h e juice of two oranges ; calves foot jelly (2 oz.). Protein : fat : carbohydrate ~ 1.0 : 0.3 : 1.5.

N. HAMILTON FAIRLEY.

80I

Diet No. 4. (Calorie value = 2,001). Sprulac--ditto diet No. 3. Juice of two oranges ; calves foot jelly (3 oz.) : two baked apples ; custard (2 oz.) ; underdone beef = 4 oz. ; ½ rusk (~ oz.). Protein : fat : carbohydrate = 1 . 0 : 0 " 3 : 1.5. Diet No. 5. (Calorie value = 2,516). Sprulac--ditto diet No. 3. Juice of two oranges : calves foot jelly (3 oz.) ; two baked apples ; custard (2 oz.) ; two rusks (3 oz.) ; underdone meat (10 oz.). Protein : fat : carbohydrate = 1.0 : 0-3 : 1.4.

The food value of these diets are based on Plimmer's tables (Analysis and Energy Values of Foods, H.M. Stationery Office, London, 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. Where it is considered desirable to increase the ratio of carbohydrate in any diet, glucose (1 oz. ~ 113.6 calories) may be added to the orange drinks or used in any other manner. As far as possible the sprulac feeds should be given at two and a half hourly intervals, and the other constituents mainly taken at the 9 a.m., 1 p.m., and 5 p.m. meals. A certain latitude is permissible in this respect and in some patients, especially when very debilitated the feeds may be given in smaller quantities more frequently and during the night. T h e rapidity with which the diets are changed is determined by the progress of the patient as indicated by the disappearance of intestinal flatulence and abdominal distension, and the characteristics of the stools. W h e n progress is satisfactory the latter decrease in bulk and n u m b e r , become progressively more solid, and lose their gaseous features. Chemical analysis also shows a decrease in the total f~ecal fat. Not infrequently it is possible to pass from No. 1 to No. 5 diets within a period of three or four weeks. During convalescence a more liberal dietary including fresh fruit and well cooked vegetables such as celery, marrow and cauliflower are allowed. Lean steak, chicken, fish, and eggs are also permitted, and carbohydrate such as boiled potatoes and milk puddings are gradually introduced. CLINICAL OBSERVATIONS.

In this preliminary report the results of treatment with sprulac and liver extract are considered in ten consecutive cases, the average stay in hospital equalling 54-5 days. In one case admitted with b r o n c h o - p n e u m o n i a the response was particularly gratifying, and in all cases the end results were good. Intestinal features such as abdominal distension and fluid fatty stools did not appear to be always as rapidly relieved as with high meat protein, low fat, low carbohydrate diet and occasionally the m o n o t o n y of the dietary was complained of. With a little encouragement, however, this difficulty was invariably overcome, and not infrequently the patients later stated they really enjoyed it. New sprulac recipes are now on trial in the form of egg custard and milk jelly in which the high protein, low fat and low carbohydrate ratios are maintained, and these should prove a welcome addition in future cases.

802

TREATMENT OF SPRUE WITH HIGH PROTEIN MILK POWDER.

Effect on W e i g h t . - - D u r i n g t h e early stage of t r e a t m e n t w e i g h t was g e n e r a l l y lost, a n d u n t i l diets Nos. 4 a n d 5 were r e a c h e d little w e i g h t w a s ' g a i n e d . O w i n g to t h e specific d y n a m i c a c t i o n of p r o t e i n a n y diet c o n t a i n i n g this c o n s t i t u e n t i n excess is n o t a good w e i g h t p r o d u c e r , b u t despite this fact t h e gain i n w e i g h t d u r i n g t h e stay i n h o s p i t a l a v e r a g e d eight p o u n d s . W h e n these p a t i e n t s have b e e n seen at a later date, h o w e v e r , a c o n s i d e r a b l e f u r t h e r gain i n w e i g h t has been invariably found. T h e f o l l o w i n g case histories m a y b e cited as t y p i c a l of t h e series. Case I. Male, aged 65 years, had resided in India for twenty-seven years, and later was in China from 1908 to 1929. The onset commenced in the winter of 1929 and passed off during the summer when he went to the hills. Relapse followed on returning to the plains. Generally he had two or three pale or putty coloured motions each morning, and had lost about one and a half stones in weight. The lips but not the tongue had been sore, and lately pallor had developed ; he readily became fatigued. Physical Examination.--The tongue was clean, but not inflamed or ulcerated ; the mucous membranes were pallid and the skin dry and yellow. There was a blowing systolic m u r m u r at the apex ; the abdomen was somewhat distended, while the abdominal parietes were markedly thinned in the fashion so characteristic of sprue. The liver appeared to be of normal size and the spleen was just palpable. Special Investigations.--Analysis of the stool showed fatty acids =19-9 per cent., neutral fat = 1 4 . 3 per cent. ; the total fats = 34.2 per cent., of which 58.1 per cent. was split and 41.9 per cent. unsplit. The serum calcium equalled 8.5 rag. and the cholesterol 105 rag. per 100 c.cm. The Van den Bergh test yielded a negative direct and a strongly positive indirect reaction of 4-0 units which is an exceptionally high reading for sprue. H~ematological investigations showed that the R.B.C.'s =1,480,000, h~emoglobin= 30 per cent., colour index = 1 . 0 . The blood picture presented marked anisocytosis, poikilocytosis and numerous megalocytes ; while the average diameter of the corpuscle measured by diffraction micrometry (Eve's halometer)=8"6 microns. Under treatment with sprulac the stools rapidly became normal, and the intestinal features cleared up. Liver extract therapy was instituted on the 4th May, 1931, and it resulted in a reticulocytosis six days later of 24.3 per cent. The bilirubin value had decreased on the 1lth May, 1931, to 1"75 units, and by the 3rd June, 1931, the serum calcium= 10-0 rag. per 100 c.cm. H~ematological investigations before dis charge (26th June, 1931 ) showed the R.B.C.'s 4,500,000 per c.mm., h~emoglobin=70 per cent., and the colour i n d e x = 0 ' 8 . The average diameter of the corpuscle had diminished from 8.6 to 7.8 microns, but as the normal value had still not been reached the indication was to continue with a maintenance dose of liver extract. The gain of weight in hospital equalled nine pounds.

Case H. J. C., an Irish soldier, aged 41 years, was admitted to the hospital on 26th February, 1931, having lost thirty-two pounds in weight. He stated that his trouble commenced in the Bermudas in January, 1928, with a quite unexpected and disappointing intolerance for beer, which induced vomiting. Later tea had the same effect. He rapidly lost weight and the motions became soft, whitish, frothy and very frequent, being passed especially i n the early morning. T h e tongue and mouth became sore shortly after the onset c.f the illness. He developed petechi~e on the back of the wrists and bruised readily. Three months ago generalised oedema developed. Clinical Examination.--On examination the patient appeared somewhat anaemic, while the skin was wrinkled and dry ; petechial h~emorrhages were present on the back of the right hand. T h e tongue was not typical of sprue, but the abdomen was distended and the abdominal parietes atonic and wasted. There was a blubbery oedema of the scrotum and the left leg was swollen and oedematous, the latter condition being due to a local throm-

N. HAMILTON FAIRLEY.

808

bosis involving the femoral vein. T h e cardio-vascular system and lungs were normal and the blood pressure S / D = 148/102. T h e faeces were typical of sprue. Special Investigations.--Faecal analysis showed neutral f a t = 2 6 - 9 per cent. and fatty a c i d s = 2 6 . 4 per cent. ; the total fat----53.1 per cent., of which 49.4 per cent. was split and 50.6 per cent. unsplit. T h e s e r u m c a l c i u m = 7 . 4 mg. and the s e r u m c h o l e s t e r o l = 59 rag. per 100 c.cm., b o t h v a l u e s being decidedly low. T h e Van den Bergh reaction was negative. T h e glucose tolerance test (50 grams) showed a minimal rise of blood sugar which at its m a x i m u m did not exceed 10 mg. per 100 c.cm., while the fractional test meal revealed an achlorhydria not responding to histamine. Haematological investigations showed that the R.B.C.'s =3,000,000 per c.mm., h a e m o g l o b i n = 4 0 per cent. and the colour i n d e x = 0 " 7 . T h e average corpuscular diameter measured by diffraction m i c r o m e t r y (Eve's h a l o m e t e r ) = 7.8 microns. U n d e r treatment w i t h sprulac and liver extract the patient m a d e a very satisfactory recovery, gaining fifteen pounds in weight, and losing all stigmata of sprue before leaving hospital on the 4th May, 1931. W h e n seen six months later the patient was in robust health ; there had been an additional gain in weight of two stones, and the blood picture and faeces were quite normal. In addition the glucose tolerance test showed a normal curve, b u t the oxyntic cells of the stomach still failed to secrete H C L after histamine. T h e patient was living a normal life, the only complaint being swelling of the left leg related to the femoral thrombosis referred to above.

In severely ulcerated lesions of the tongue and mouth sprulac has proved a valuable asset combining as it does the bland properties of liquid milk with the advantages of a high protein diet. In intractable cases of this nature I have found alkaline medication of considerable service, sodium bicarbonate and citrates being administered in a dosage sufficient to keep the urine continuously alkaline. Amemia.--Suitable dietaryby instituting alimentary rest and gradually restoring the function of the gastro-intestine assists in blood restoration but in whole liver, commercial liver extracts and ventriculin ~ we possess specifies to which the megalocytic anzemia, so characteristic of this disease, rapidly responds. In a case at present under treatment with sprulac, liver extract has lead to a reticulocytic response of 42 per cent. The case is of interest as hepatex P.A.F. quite unexpectedly failed to elicit any effective reticulocytosis when given intravenously in quantities of 5 c.cm. daily for a period of five consecutive days, yet later a high grade response followed feeding six tubes of ex-hepa daily ( = one and a half pounds fresh liver). In the present series the average stay in hospital was 54.5 days and the hzematological data on admission and discharge are included in the following table : TABLE I I . H.ZEMATOLOGICALFINDINGS IN CASES TREATED WITH LIVER EXTRACT (EX-HEPA) AND SPRULAC. Average diaR.B.C. per Haemoglobin Colour m e t e r of R.B.C. c.mm. per cent. index. (microns). Admission Discharge

2,734,000 4,484,000

Gain

1,750,000

I

51-5 71.7

0'94 0"8

7-9 7.6

20-2

0.2

0-3

* Sometimes cases of sprue respond less readily to ventriculin than to liver extract, while on two occasions its administration has coincided w i t h an increase in the diarrhoea. F o r these reasons we glve preference to liver extract in the treatment of this anaemia.

804

TREATMENT OF SPRUE WITH HIGH PROTEIN MILK POWDER.

It will be seen that the average gain in R.B.C.'s ~- 1,750,000 per c.mm. and in haemoglobins20.2 per cent. The average diameter of the corpuscle decreased from 7.9 to 7-6 microns (normal) while the colour index changed from 0.94 to 0.8. These findings compare very favourably with those reported by the writer (1930) in a series of seventeen cases staying fifty-three days in hospital treated with high meat protein, low fat, low carbohydrate diet and liver extract (Eli Lilly, No. 343). The reticulocyte response was also similar in the two series of cases. Provided adequate supplies of liver extract are available it would therefore appear immaterial from the standpoint of blood restoration whether meat or milk protein constitutes the chief element of the dietary. SUMMARY AND CONCLUSIO N S .

(1) A preliminary report is made on the dietetic value of a high protein milk powder (sprulac) in the treatment of sprue. (2) This powder has been specially prepared so that the ratios of protein : fat : carbohydrate--1.0 : 0.3 : 1.3. (3) Though the alimentary features are not always as dramatically relieved as with a high meat protein, low fat, low carbohydrate diet, the end results have been uniformly satisfactory in all cases. (4) Provided adequate quantities of liver extract are administered blood restoration proves equally rapid whether a high milk protein or a high meat protein dietary is adopted. (5) Sprulac should have a special field of usefulness in the tropics where good quality meat in a satisfactory condition is often unprocurable, and where milk owing to its high fat and bacterial content frequently proves an unsuitable diet for sprue cases. REFERENCES. AGGARWALA,A. C. (1929). .4 Laboratory Manual of Milk Inspection, 1st Ed., p. 9. Gulab Chand Kapur & Sons, Lahore. FAIRLEY, N . H . (1930). Sprue: its applied Pathology, Biochemistry and Treatment. Trans. Roy. Soc. Trop. Med. ~ Hyg., xxiv, 131-179.