an experimental study of the effect of the thyroid on the motility of the gastro-lntestinal tract

~ I O R R I S O N A N D F E L D M A N - - T H Y R O I D A N D G A S T R O - I N T E S T I N A L I ~ I O T I L 1 T Y 5 4 9

in hyper thyro id i sm and Page t ' s disease, account ing for cer ta in "diabet ic" symptoms seen in these diseases; (b) is decreased in myxedema and Addison 's disease, exp la in ing a b n o r m a l i t i e s of carbohydra te metabol ism in these condit i(ms; and (c) is usually un- impaired by hypermot i l i ty of the in tes t ine or by chronic passive congest ion of cardiac origin.

6. The fundamen ta l con t r ibu t ion of our work with the galactose absorpt ion test is in t roduc t ion of the concept tha t in tes t ina l absorpt ion may be abnormal ly increased in cer ta in diseases.

R E F E R E N C E S 1. Verz~r , F . : Abso rp t i on f r o m the In tes t ine . I , o n g m a n s , Green and

Co., London, N e w Y o r k and Toronto . 1936. 2. Al thausen . T. L. and Stockholm. M , : Inf luence of the Thyro id

Gland on Abso rp t i on in the D iges t ive T rac t . Am. J. Physiol., 123:577, 1938.

3. He lmer , O. M. and Fouts , P. J . : G a s t r o - I n t e s t i n a l Studies. V I I . The E x c r e t i o n of Xylose in Pe rn i c ious A n e m i a . d. Cli~. h~vest., 16:343. 1937.

4. H e a t h , C. W. and Ful le r ton , I t . W . : The R a t e of Abso r p t i on of Iodide and Glycine f r o m the G a s t r o - I n t e s t i n a l T r a c t in N o r m a l P e r sons and in Disease Condi t ions . J. Clin. Invest.. 14:475, 1935.

5. R a y m o n d , A. L. and Blanco, J . C . : Blood S u g a r D e t e r m i n a t i o n s and S e p a r a t i o n of S u g a r s w i t h L i v e Yeas t . J. Biol. Chem., 79:649. 1928.

6. A l t h a u s e m T. L., Basse t t . A. M. and Coltr in. G . : Ut i l i za t ion of I n t r a v e n o u s l y In j ec ted Galactose as a L i v e r Func t ion Test . ( In p r e p a r a t i o n ).

7. Moehlig, R. C. and Murphy , J . M. : P a g e t ' s Disease (Os te i t i s De- f o r m a n s ) . Endocrinology, 19:515, 1935.

D I S C U S S I O N DR. JOHN L. KANTOR (New York): I t is too bad

that Dr. Althausen did not have, in his clinical material, some cases of idiopathic steatorrhea. It would have been interesting to see what results his galactose test would give in such definite cases of failure of absorption by the small intestine.

I missed the reason why Dr. Althausen selected galactose and hope he will repeat this in his closing remarks.

DR. A. C. IVY (Chicago): I should like to ask if Dr. Althausen has followed the blood sugar curve as related to ur inary elimination. Dr. Althausen h~s introduced a new concept and it may explain some of the apparent de- creases in sugar tolerance in certain diseases. Heretofore, we have said that a decrease in sugar tolerance may be due to a liver disturbance. The diseased liver may not store the absorbed sugar in the form of glycogen and thus a hyperglycemia and perhaps a glyeosuria will result.

Is that question clear? DR. ALTHAUSEN: Yes, it is.

DR. GEORGE B. EUSTERMAN (Rochester, Minn.) : This appears to be an important contribution to our increasing knowledge of the normal and morbid physiologic processes of the small intestine. The important role of the vitamins in cellular metabolism was emphasized in a recent presentation by E. S. Guzman-Baron, of Chicago. He summarized the collective observations emphasizing the fundamental importance of the vitamins in the di- gestion and absorption of carbohydrates, proteins, fats and minerals because of their powerful oxidasie and catalytic properties. T h i s e x p l a i n s the rationale of adequate vitamin therapy in disorders of nutrition, especially in disease or dysfunction of the small bowel. The ap- pellation "vitamin" is surely a euphemistic one in view of its powerful chemical attributes.

DR. THEODORE L. ALTHAUSEN (San Francisco): To answer the question asked by Dr. Kantor, galactose was chosen because it is typical of the group of substances the absorption of which is accelerated by phosphorylation, and because it does not occur normally in the blood. For the latter reason, the concentration of galactose in the blood indicates with fair accuracy the rate of its absorption from the intestine. Glucose cannot be used for a test of absorption because the absorbed glucose loses its identity by becoming mixed with the glucose of the blood.

Dr. Ivy correctly pointed out the most important con- clusion to be derived from the results of this test in patients with thyroid disease--namely that the so-called "diabetic" type of glucose tolerance curve in patients with hyperthyroidism is in reality due to accelerated intestinal absorption. The same is true of Paget's disease. The finding of accelerated intestinal absorption of galactose has been so constant in our series of patients with Graves' disease that the galactose absorption test is regarded in our clinic as equal in reliability to determinations of the basal metabolism. In addition, the galactose test possesses certain advantages which are indicated in the paper.

As far as the avitaminoses are concerned, we had a single patient with typical pellagra whose intestinal absorption was very much reduced during the active stage of the disease. Three weeks later, after successful treatment with nicotinic acid, the absorptive ability of this patient was better than normal. This is probably another instance in which newly regenerated tissue temporarily exhibits a higher than normal activity.

An Experimental Study of the Effect of the Thyroid on the Motility of the Gastro-lntestinal Tract

By

SAMUEL MORRISON, M.D.

and MAURICE FELDMAN, M.D.

B A L T I M O R E , M A R Y L A N D

S T U D I E S on the re la t ionship between endocrine and gas t ro- in tes t ina l func t ions has become a ma t t e r of

increas ing in teres t . Un fo r tuna t e ly our knowledge of this re la t ionship is very incomplete. Al though the endocrine problem is g radua l ly be ing unfolded there is a dear th of scientific work on its effect upon gas t ro- in-

Read a t t he A n n u a l 1939 Sess ion of the A m e r i c a n Gas t ro -En te ro log ica l Assoc ia t ion a t A t l an t i c City.

F r o m the Resea rch Sect ion of the Clinic of Gas t ro -En te ro logy . School of Medicine, U n i v e r s i t y of Mr ry l and .

T h i s w o r k was m a d e possible by a g r a n t f r o m The Ju l iu s F r i e d e n w a l d Resea rch Fund.

tes t ina l moti l i ty. As a consequence of the lat ter , m a n y of our ideas are at best mere conjectures. However, a good deal has a l ready been accomplished toward the solution of this difficult problem but obviously, much more remains to be understood and explained. The effect of the thyro id on the digest ive t r ac t var ies widely depending upon the degree of involvement and the effect of the associated hormonal d is turbances . Nevertheless, there is some u n a n i m i t y of opinion in respect to some of its actions. There can be no quest ion

550 AMERICAN JOURNAL OF DIGESTIVE DISEASES

that the thyroid gland exerts some influence on gastro- intestinal physiology.

When consideration is given to the relation of dysfunctions of the endocrine system to gastro-intestinal disease the problem becomes even more intricate. For example, definite knowledge is still lacking as to w h e t h e r t he gastro-intestinal disturbances so frequently observed in the endocrinopathies are actually due to the latter or are secondary to changes in the autonomic nervous system. Our work comprises only one phase of this problem and is more in the nature of a preliminary study.

The purpose of our communication in brief is to determine through what mechanism the abnormally act-

lationship there could not be a better understanding of the problem.

Certain suggestions have appeared in the literature concerning the cause and effect of the relationship of thyroid gland to gastro-intestinal m o t i l i t y . The direct effect of thyrotoxicosis on the musculature, the hormonal-metabolic effects and the effects by way of the vagus have been considered as possible methods of action. It is believed by Crotti and others that the endocrine and the autonomic nervous systems ~are so intimately related that they cannot be studied separately. It is also maintained by Deusch that the thyroid hormone acts only through the nervous mechanism of the gastro-intestinal tract.

Fig. 1 Right: Six hour roentgen motility study in the normal dog, The stomach is completely empty. Most of the barium is in lower bowel; the small intestine is empty. Left: Motility study in the bilateral vagotomized dog, showing a large gastric retention (at arrow) in six hours.

ing thyroid gland exerts its effect upon the digestive tract. In an effort to answer the simple query whether or not the effect is through the vagus nerves or due to general metabolic changes which secondarily involve the digestive tract, a group of experiments were undertaken on dogs. Gastric acidity studies were not made although we have reported on them in other communications. It was primarily because the literature on this subject is so meagre, confusing and un- satisfactory that it seemed to us advisable to attempt to establish experimentally the relation of the vagus nerve and thyroid gland to gastro-intestinal motility. It also seemed that without a clarification of this re-

Although there are reports of the influence of thyroid action upon the vagus nerve with respect to gastro-intestinal motility considerable academic controversy has arisen concerning this exact mechanism of action and an appraisal of the literature leads only to fur ther confusion and controversy ra ther than easy evaluation. As early as 1900 Eppinger and Hess had attributed the gastro-intestinal hypermotility in hyperthyroidism to overactivity of the vagus nerve and as recently as 1936 Richieri also believed that the most important pathogenic factor in hyperthyroid gastro-intestinal motility is vagotony produced by direct stimulation of the vagus by ' the hyperfunction-

MORRISON AND FELDMAN--THYROID AND GASTRO-INTESTINAL MOTILITY 551

ing thyroid gland. Moreover, Rehfuss has reported that small doses of thyroid gland medication exert a stimulating effect on gastro-intestinal function which he believed probably acted through the vagus nerve. In excessive doses, however, it seemed to him that an inhibitory effect was exerted. In several reports, the e x p l a n a t i o n of gastro-intestinal motor activity in hyperthyroid states has been attributed to a change in gastric secretion. Moreover, the possible involve- merit of nervous mechanisms in the gastro-intestinal dysfunctions a s s o c i a t e d w i t h hyperthyroidism de- serves consideration. The explanation of an increased gastro-intestinal activity is obviously not immediately at hand.

However, in 1932 Fetter and Carlson studied the effect of induced hyperthyroidism on gastro-intestinal

The relationship of the secretion of the ductless glands and the functions of the vegetative nerves have not as yet been explained with entire satisfaction even with the newer chemical studies. Certain facts, however, have been established, as for example, the influence of the adrenal glands and perhaps also the pituitary thyrotropic hormone in increasing the tonus of the autonomic system. On the other hand, in con- sidering the thyroid some maintain that it acts only through the sympathetic while others suggest that it produces its effect through the vagus, and still others attribute to it both sympathetic and vagotonic actions. Fogelson is under the impression that the thyroid itself does not initiate the increased activity, that the stimulation comes through the sympathetic nervous system and that the most powerful control of the

Fig. 2. Lef t : Normal motility of the gastro-intestinal tract in six hours. The stomach is completely empty. The barium is scattered through the lower ileum and large intestine. Center: Same animal, thyroidectomized, illustrating the effect of thyroid medication on the intestinal tract. Roentgenogram after seven days treatment during which time 350 grains of desiccated thyroid had been administered shows the stomach empty and very little change in the motility of the intestines. Right : Roeut- genogram after ten days of thyroid medication (500 grains of desiccated thyroid) shows some acceleration of motility of the intestinal tract.

motility in the non-vagotomized dog and found that the motility was increased. Later Fetter, Barron and Carlson sectioned the vagus nerves below the diaphragm and then fed sufficient thyroid to produce hyper- activity of the gland and found that gastro-intestinal motility was again accelerated. Their experiments indicated that thyroid activity apparently did not take place through the vagus nerve and they therefore regarded it as clear that the influence of the thyroid on gastro-intestinal motility is largely, if not wholly, independent of the possible influence of the thyroid hormone on the gastro-intestinal vagus mechanism. This work raises the question as to the part played by the stimulated intact thyroid gland and especially by what mechanism such action takes place.

sympathetic system is in the adrenal glands. Fur ther- more, the need for the elaboration of the action of the thyrotropic pituitary hormone in connection with this problem is manifest.

Timme recently re-emphasized his belief that the thyroid rarely functions alone and that any disturbance of this gland always induces a change in the function of other glands. He points out in general, that whenever thyroid dysfunction exists the involvement no longer remains entirely confined to it but becomes a multiglandular disturbance. Again, it is evi- dent that our knowledge regarding the action of the endocrines upon the gastro-intestinal functions is still far from c l e a r l y established, especially since the


problem of polyglandular involvement is so difficult of approach.

It seemed to us that the removal of the thyroids (and parathyroids) would interrupt the so-called endocrine chain and thus interfere with interglandular communications. Such a procedure was one of our ap- proaches to our problem which may now be stated as follows: in hypermotility of the digestive tract does the thyrogenic effect of the thyroid upon the autonomic nervous system play a significant role or is it the effect of gastric secretory changes or is it simply the result of the greatly heightened metabolic rate?

In this introductory presentation we are concerned only with the relationship of the thyroid gland to the vagus nerve and their effect upon gastro-intestinal motility. As will be pointed out, the work of others was repeated but in addition we have performed total thyroidectomy (and parathyroidectomy) so as to re- move any effect through a pluriglandular mechanism either by way of nerve or through a purely thyroid or secondary endocrine gland stimulation.

A group of dogs with suitable controls were utilized in these experiments. Total thyroidectomies were performed in each animal. Both vagus nerves were severed at the lower end of the esophagus below the diaphragm. In the feeding of desiccated thyroid rela- tively large doses were administered. The dosage was 0.4 gm. (and in some instances, more) per kilo of body weight. All the animals so fed lost weight. After the cessation of treatment the animals regained their weight. A number of our dogs developed parathyroid spastic states which necessitated the injection of para- thormone as well as the administration of calcium for a brief time. The parathyroid deficiency was con- trolled in this way and therefore could not have had any significant influence on the final results.

NORMAL MOTILITY STUDIES

In a series of eight dogs in which normal gastro- intestinal motility was studied, the stomach was found completely empty in the six hour examinations following the administration of barium; a small amount of barium was frequently noted in the lower ileum and the head" of the barium meal was usually observed in the descending colon. Desiccated thyroid administered to normal dogs produced an acceleration of gastro-intestinal motility. The small intestine was completely emptied and most of the barium meal had been evacuated with only a small amount remaining in the colon.

MOTILITY STUDIES FOLLOWING BILATERAL VAGOTOMY

Bilateral vagotomy was performed in a series of thirteen animals. In eight of these the normal motility had been previously studied. After a post-oper- ative recuperative period of from 10 to 21 days, studies were made on the effect of vagotomy on gastro- intestinal motility. In the 6 hour examination of this group a gastric retention was invariably found in almost every instance. The barium was scattered through both small and large intestines and the head of the barium meal was usually found to be in the descending colon. I t is interesting to point out that

the motility of the intestines was not significantly affected by the bilateral vagotomy.

EFFECTS OF THE ADMINISTRATION OF DESICCATED THYROID IN VAGOTO-

MIZED ANIMALS In a series of five vagotomized dogs, desiccated

thyroid was administered orally. Subsequent study showed a definite thyroid action on the motility of the gastro-intestinal tract in that the motility was greatly accelerated in every instance. In the 6 hour examination, following vagotomy, there was a g a s t r i c residue whereas, af ter a period of thyroid medication there was complete emptying. The small intestine was completely empty and the colon had evacuated most of the barium. However, a small amount of barium still remained in the colon. This demonstrates conclusively that thyroid action is independent of the vagus nerves, an observation which is in accord with the findings of Fetter, Barron and Carlson.

STUDIES OF MOTILITY IN THYROIDECTO- MIZED ANIMALS

In a series of six animals total resections of the thyroid were performed in order to determine what effect the removal of the thyroid alone had upon the motility of the gastro-intestinal tract. It was observed that the removal of the thyroid had no immediate effect upon gastro-intestinal motility. In the six hour roentgen examination, the stomachs were completely empty. Within a period of from 10-21 days following thyroidectomy, the motility of the intestines was not significantly affected. In several animals a sluggish motility of the intestines was noted. This experiment gave conclusive evidence that the removal of the thyroid gland alone did not in any way significantly affect the normal motor physiology of the digestive tract in the immediate studies. However, in two addi- tional dogs observed over a period of 5 months, there was a constant gain in weight and the development of myxedematous features. With this development, which in itself produced sluggish motility with loss of tone of the digestive tract, a superimposed bilateral sub- diaphragmatic vagotomy was followed by gastric dila- tation resulting in a greater gastric retention than was observed in the animals which had only been vagotomized. The injection of one cc. of thyroid ex- t ract administered daily for 16 days decreased the retention by two-thirds and it was clear that if sufficient thyroid extract was given the retention could be entirely overcome.

MOTILITY STUDIES IN VAGOTOMIZED AND THYROIDECTOMIZED DOGS

In six vagotomized dogs, all of which showed a gastric retention, a total thyroidectomy was done. A gastro-intestinal roentgen study revealed a similar picture to that obtained in the vagotomized animals. In every instance a gastric residue was still observed. In the immediate examination, between 10 and 18 days postoperatively, the motility of the intestines was variable but on the whole showed no significant change from that of the normal. These findings gave definite proof that the removal of the thyroid gland in vagotomized animals did not have any immediate effects upon the gastro-intestinal motility other than those seen following vagotomy alone.

~IOI~RISON AND FELDMAN--THYROID AND GASTRO-INTESTINAL ~IOTILITY 553

T H E E F F E C T OF D E S I C C A T E D THYROID AD- M I N I S T E R E D TO COMBINED VAGOTOMIZED

AND T H Y R O I D E C T O M I Z E D A N I M A L S

In six an imals in which a bi la tera l vagotomy and thyroidectomy were done desiccated thyroid was ad- min is te red orally. Af te r 7 days of thyroid medicat ion

the mot i l i ty was s l ight ly increased wi th a reduct ion in gas t r ic re ten t ion but va r y i ng periods a f t e r 10 days the stomach was completely emptied and all of the a_~imals presented marked hypermot i l i ty of the ent i re gas t ro - in tes t ina l t r a c t w i t h the product ion of a n u m b e r of bowel movements. F o u r weeks la ter a f t e r

Fig. 3. Upper Left: Thyroidectomized animal revealing a sluggish motility of the intestinal tract in the six hour roentgen examination. The stomach is completely empty, all of the barium is in the small intestine, and none in the colon. Upper Right.: Same animal, 29 hour examination reveals expulsion of the barium with most of the meal in the lower left colon. Lower Left: Same thyroidectomized dog following double vagotomy. Note the large (6 hour) gastric retention with sluggish motility of the intestinal tract. Lower Center: Same animal, 31 hours after administration of barium showing an unusually large gastric retention. Lower Right: Same animal, 55 hours Jater, still showing a large gastric retention. This latter is not the usual finding.

5 5 4 A M E R I C A N J O U R N A L OF D I G E S T I V E D I S E A S E S

cessation of thyroid medication re-examination of these animals revealed a return of the gastric retention.

CONTROLS As a check and control to these experiments the

above procedures were reversed, i.e., in four animals thyroidectomies were p e r f o r m e d first. Subsequent roentgen studies on motility revealed no immediate effect upon the g a s t r o - i n t e s t i n a l tract. Bilateral vagotomies were then performed on these animals, with the result that a gastric retention occurred in each instance. The above findings were exactly similar to those observed in the original experiments de- scribed.

SUMMARY The physiologic mechanism of thyroid action upon

the gastro-intestinal tract has not been clearly established in the past. A preliminary study was made to determine the effect of the thyroid and the vagus nerves on gastro-intestinal motility in dogs. Our studies yielded the following results:

1. Desiccated thyroid administered to normal dogs showed an acceleration of gastro-intestinal motility.

2. Motility of the stomach is invariably affected by section of the vagus nerves. This procedure causes a six hour retention in almost every instance.

3. Motility of the intestines is not significantly affected by section of the vagus nerves. The immediate effect of vagotomy on the digestive tract is mainly on gastric motility with very little, if any, effect upon the intestines.

4. Desiccated thyroid administered to vagotomized dogs revealed an acceleration of gastro-intestinal motility thus demonstrating conclusively that thyroid action is independent of the vagus nerves.

5. Removal of the thyroid glands alone had no immediate effect upon gastro-intestinal motility. After a lapse of months, however, it did produce some loss of tone and sluggish motility.

6. Thyroid gland extract given subcutaneously or desiccated thyroid administered orally to the thyroidectomized a n i m a l s accelerated gastro-intestinal motility.

7. In the combined vagotomized and thyroidectomized dogs, motility studies revealed no immediate changes other than those noted in the vagotomized animals (6 hour gastric retention) indicating that thyroid removal did not influence the changes noted following vagotomy.

8. Desiccated thyroid administered to the animals with combined vagotomy and thyroidectomy revealed a hypermotility of the gastro-intestinal t ract with the return of retention af ter cessation of thyroid medication.

9. Thyroid medication in adequate dosage produced an acceleration of motility of the intestines as well as the stomach.

CONCLUSIONS The administration of adequate doses of desiccated

thyroid gland to dogs with and without the removal of the thyroid gland produces the same effect whether the vagus nerve is intact or not. In other words, induced hyperthyroidism increases gastro-intestinal motility with or without sectioning of the vagus nerve.

Removal of the normal thyroid gland has no immediate effect upon the motility of the gastro-intesti-

hal tract but when myxedema supervenes there is evidence of loss of tone throughout the gastro-intestinal tract.

Bilateral section of the vagus nerve produces a gastric retention which can be overcome by thyroid medication.

A combination of a thyroidectomy and a bilateral vagotomy in the same animal is followed by an immediate picture which duplicates that of bilateral vagotomy alone.

Therefore, it has been definitely Shown that the effect of increased thyroid action upon gastro-intestinal motility does not occur through the vagus nerve but is entirely independent of it.

Since thyroid medication in amounts adequate to produce the hyperthyroid syndrome in the absence of the thyroid gland, is followed by increased gastro-intestinal motility it would seem that heightened basal metabolic activity probably accounts for the change. Since pluriglandular action has been disturbed by thyroidectomy it would seem likely that any other hormonal action through the thyroid gland is im- probable though by no means impossible.

In this report we make no effort to evaluate the possible roles played by the pi tui tary thyrotropic hormone nor the adrenal glands nor have we sufficient data to clarify the mechanism of pluriglandular activity in its relation to gastro-intestinal motility. In fur ther studies we hope to clear up some of these in- volved problems.

R E F E R E N C E S Crotti, A . : "Thyrotoxicosis and the Autonomic Nervous System."

Canad. M. A. J., 30:479, 1934. Deusch, G.: "Die Hyperthyreosen Handb. d. inn. Sekretion yon

Hirsch ," pp. 1-70, 1917. " T h y r o i d a n d Motility of Intes t ines ." Deutsches arch. f. klin. Med., 142:1, 1923.

Eppinger , H. and Hess, L . : "Die V a g o t o n i e . " Trans. Hirschwald, Berlin. 1910.

Fetter , D. and Carlson, A. J . : I. "The Effect of Exper imenta l Hyper- thyroidism on Gr~stro-Intestinal Motility." Am. J. Physiol., 101:598, 1932.

Fetter , D., Barren, L. and Carlson, A. J . : II . "The Effect of Induced Hypothyroidism on the Gastro-Intest inal Motility of Vagotomized Dogs." Am. J. Physiol., 101:605, 1932.

Friedenwald, J . , Morrison, T. H. and Morrison, S. : "Clinics on Second- a ry Gastro-Intest inal D i s o r d e r s ; Reciprocal Relationships." Win. Wood & Co., Baltimore, p. 104, 1938.

Friedenwald, J . and Morrison, S . : "Gastro-Intes t inal Disturbances Assbciated with the Endocrinopathies. Endocrinology, 17:393, 1933.

Friedenwald, J . and Feldman, M. : "Exper imenta l Studies on the Effect of Section of the Vagus Nerve on Gastric Secretion." Arch. Int. Med., 49:234. 1932.

Fogelson, S. J . : "Gastr ic and Duodenal Ulcer." Intcrnat. Abst. of Surg., 55:297, 1932.

Meyerson, A. : " H u m a n Antonomic Pharmacology. XII . Theories and Results of Antonomic Drug Administrat ion. '" J . A. M. A., 110:101, 1938.

Rehfuss, M.: "Diseases of the Stomach." W. B. Saunders Co., Phila- delphia, p. 1063, 1937.

Richieri, A. : " F o r m s and Diagnosis of Hyperthyroid Diar rhea ." Prensa Medico Argentina, Buenos Aires, 22:2317, 1935.

Timme, W . : "Discussion on Thyroid Dis turbances ." J. A. M. A., 97:515, 1931.

DISCUSSION DR. JULIUS FRIEDENWALD (Baltimore): For a

long time considerable interest has been manifested in the relation of the endocrines to gastro-intestinal function. It is well known that certain digestive symptoms are produced by disturbances of these glands. Inasmuch as the thyroid is one of the most important of the endocrines, the digestive symptoms manifested as the result of its dysfunction have been carefully studied and their clinical significance has become more clearly recognized. It is well known, for instance, that hyperthyroidism is frequently associated with diarrhea and hypothyroidism with consti- pation; but the exact mechanism by means of which these manifestations are brought about have by no means as yet been fully established.

In an attempt to unravel this intricate problem, Doctor Morrison and Doctor Feldman have conducted their experiments, which tend to indicate that the changes in me-

!V[0RRISON AND FELDMAN--THYROID AND GASTRO-INTESTINAL ~IOTILITY 555

Fig. 4. Upper Left: Demonstrates a (six hour) gastric retention (at arrow) in a bilateral vagotomized dog. All of the barium is in the small intestine and none in the colon. Upper Right: Combined double vagotomy and thyroidectomy in the same animal i l lustrating a gastric retention in six hours with barium scattered through the small and large intestine. Lower Left: Thyroid medication in the combined vagotomized, thyroidectomized dog, treated for seven days (280 grains desiccated thyroid), showing a small gastric retention (at arrow) with most of the barium in the colon. Lower Center: Same animal treated for ten days (400 grains desiccated thyroid) revealed complete emptying of the stomach with marked hypermotility of the intestinal tract in the six hour roentgen examination. Lower Right: Same animal, showing a return of the gastric retention (at arrow) after a rest period (no medication) of 25 days.


tility of the gastro-intestinal tract, induced by thyroid action, are not influenced by way of the vagus or sympathetic nervous system.

But the problem is not simple for, as Timme and others have also pointed out, the thyroid rarely functions alone and the disturbance of this gland induces a change in the functions of the other glands, such as the parathyroids and pituitary, in other words, a multi-glandular endocrine involvement occurs.

In a further study of this larger problem, which is being conducted, Doctors Morrison and Feldman will attempt more fully to clear up the significance of this multiglandular relationship to the associated digestive dysfunction.

Thank you !

DR. THEODORE ALTHAUSEN (San Francisco): I was very much interested in the observations of Drs. Morrison and Feldman on the increased emptying rate of the stomach and increased motility of the intestine under the influence of the thyroid hormone. In working with hyperthyroid rats, we made similar observations and were able to determine quantitatively the acceleration of the gastric discharge. Normal and hyperthyroid rats were given by stomach tube a 20 per cent solution of glucose or or xylose. One hour later the rats were sacrificed and the amount of residual sugar determined separately in the

stomach and in the intestine. In normal rats, 72 per cent of the unabsorbed glucose was found in the stomach and 28 per cent in the intestine. In hyperthyroid rats, only 51 per cent of the remaining glucose was in the stomach, whereas 49 per cent of it was in the intestine. This effect of the thyroid hormone was even more pronounced when we fed to rats xylose, which has a slightly i r r i ta t ing action. Normal rats had 50 per cent of the residue in the stomach and 50 per cent in the intestine, while in hyperthyroid rats only 11 per cent of the residue was found in the stomach and 89 per cent in the intestine. These findings are rendered more significant by the fact that the rate of intestinal absorption for these two sugars is ap- proximately doubled in hyperthyroid rats.

I t is of interest that the slowing of gastric emptying in hyperthyroid rats with benzedrine did not significantly reduce the rate of intestinal absorption of glucose.

An increase of intestinal motility in our hyperthyroid rats was manifested by a tendency to develop diarrhea after the feeding of such slightly i r r i ta t ing substances as xylose or oleic acid. This tendency was entirely absent ;n normal animals.'

DR. SAMUEL MORRISON (Baltimore) : I thank those who have discussed the paper, and I have nothing further to add, thank you.

Editorials N E W R E S E A R C H E S ON T H E M E C H A N I S M

U N D E R L Y I N G H E A D A C H E

O NE of the remarkable pecul iar i t ies of medical pract ice is tha t a lmost n o t h i n g is known about

the mechanics of the commonest symptoms, and usually b u t l i t t le research is ever done on the subject . Who ever heard of anyone ' s ge t t ing large sums of money f rom a founda t ion to s tudy mucous colitis, or o rd ina ry headaches, or backaches, or nervousness , I t i sn ' t done. Eno rmous sums are spent commonly for research on ra re diseases, s imply because they excite most in teres t . F o r instance, recent ly all the public heal th forces of a grea t s tate were marshal led to fight an epidemic of fourteen cases of a r a re type of en- cephalit is. Large sums of money were obtained f rom the state and the federal gove rnmen t ; a large n u m b e r of W P A workers were ass igned to make surveys of mosquitoes and birds, and every effort was to be made to wipe out the disease. As we sat in a mee t ing and heard this g rea t campaign be ing explained to the phy- s icians ga thered for the s tate medical convention, we could not help wonde r ing how many hundreds of thousands of inval ids there were in t ha t state, crippled and suffer ing and kept on re l ief rolls or in char i ty hospitals because of such common t roubles as consti- tu t iona l inadequacy, psychopathy, c o n s t a n t f a t igue and weakness, backache, headache, hyper tens ion, and a r th r i t i s . We wondered if anyone could ever get much money wi th which to s tudy these t remendous ly impor t an t and common scourges of civilized man.

Because of thoughts along this line, we were par- t icu lar ly pleased to see recent ly a repor t of a paper by George Schumacher and Harold Wolff on exper imenta l s tudies on headaches and the pa thways over which pMn travels. I t is to be found on page 488 of the July n u m b e r of the Journa l of Clinical Inves t iga t ion .

Us ing volunteers, these inves t iga tors r egu la r ly pro-

duced a b i la tera l type of headache by i n j ec t i ng 0.1 mg. of h i s t amine phosphate in t ravenously . They could see, then, what difference was made by the previous section or des t ruc t ion of one or more nerves of the face or scalp or neck. Some of the volunteers s tudied had sub- mi t ted to surgica l opera~ions on one of these nerves, and others had suffered some i n j u r y to the b r a i n stem or to dorsal roots which resul ted in par t ia l or incomplete analges ia of one side of the back of the head.

I t has been shown tha t h i s t amine produces headache by caus ing di la t ion of crania l ar ter ies , hence the or ig in of the nerve s t imul i was known. I t was found tha t four pa t i en t s who, as a resu l t of incomplet~e section of the t r i gemina l sensory nerve root, had un- i la teral loss of sensat ion over the lower pa r t of the face, still had headache on both sides of the face and head. Five pa t ien ts who, as the resul t of complete section of the t r i gemina l sensory nerve root, had -~n addi t ion to hemi-analges ia of the lower hal f of the face, un i la te ra l loss of sensa t ion over the frontal , temporal , and par ie ta l areas, did not get a h i s tamine headache in these regions, a l though they did get it elsewhere over the head.

Tha t l iga t ion of the middle meningea l and temporal ar ter ies , done at the t ime of a t r i gemina l root section, was not the cause of the absence of the h i s tamine type of headache was shown by the appearance of a his tamine headache a f t e r l iga t ion of the vessels and only par t ia l t r ansec t ion of the nerve root.

Two pa t ien ts who had a un i la te ra l loss of sensat ion in the occipital region did not have headaches induced in th is region by h is tamine . They did, however, have headaches elsewhere in the head.

Other observat ions indicated tha t there were ad- dit ional, though less impor tant , afferent pathways. In short, pa in fu l messages coming f rom dis tended crania l a r te r ies of the f ron t of the head and t r ave l ing along

an experimental study of the effect of the thyroid on the motility of the gastro-lntestinal tract

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