The celiac syndrome

The Journal of Pediatrics V o L 35

JuL-z, I949

No. I

Original Communications TIIE CELIAC SYNDROME ~PACTOIIS I N F L U E N C I N G ITS ])EVELOPMENT W I T H

PARTICULAR REFEIgENCE

TO HYPOTIIYROIDISM AS A C()Nq'RIBUTING (ji USI"

J. A. ,JOHNSTON, M.D., ANI) P. J. }IowaRD, M.D. ])ETROIT, M I C H .

H E t e r m cdia, c sy~tdrome has been suggested to describe a group of digesdisturbances eharaeterized b y intoleranee to f a t or starch, either or both, with no implication of a uniform etiology. The excretion of bulky, foul stools, and enlarged abdomen, malnutrition, retarded growth, and evidence of deficiency of one or more vitamins and minerals are p a r t of the picture. The classification suggested b y Andersen and ]Iodges ~ is as follo.ws: (1) "celiac disease," in which the p r i m a r y defect is in the absorption of f a t t y acids f r o m the intestine; (2) eases in which there is d i e t a r y intolerance of starch but not of fat; (3) congenital pancreatic insuf~ciency; (4) chronic mechanical obstruction of the p a t h w a y s of digestion and absorption; and (5) eases presenting o.r suggesting the celiac syndrome but which do not fall into the above groups. I n a more recent contribution, Andersen ~ states her %cling that the presenee of s t e a t o r r h e a is not required for the first group, since it was only transiently present in treated patients. Nine of her patients who showed it on first examination failed to show it on a normal diet including' whole milk a few weeks later. Increasingly, there is a tendency to attribzlte a n u m b e r of the findings in these chronic digestive disturbances to defieieney states resulting f r o m f a u l t y absorption and not basically a p a r t of the f u n d a m e n t a l disturbanee. No single etiologic factor has been found in the celiac syndrome which explains satisfactorily its pathogenesis, except in the group of pancreatic fibrosis eases. Nasopharyngeal in%etion is said to be the eomnionest finding in the experience of Holt and MeIntosh, ~ and in twelve o.f our f o r t y patients infeetion of the u p p e r r e s p i r a t o r y tract was p r o m i n e n t at the onset of the illness and during exacerbations. The f r e q u e n c y of this finding in children of the age g'roup in whieh the syndrome is seen, and the r a r i t y of the syndrome itself, ea]l for a seareh for some other u n d e r l y i n g conditio,nin~ factor which causes these children to react differently to such an infection than do otherwise normal children. A similar line of reasoning applies to t!le attributing of the symptoms to allergy; 4, ~ there are undoubted instances in which the failure of abso.rption

T tive

F r o m the D e p a r t m e n t of Pediatrics, l~enry For.d 1-[osp~tal. 1R.ead before t h e A m e r i c a n i~ediatric Society in Ma.y, 19"t8. 1

2

THE JOURNAL OF PEDIATRICS

seems referable to sensitivity, and yet a very small percentage of allergic individuals show the celiac syndrome. F i v e of our f o r t y patients gave histories or findings suggesting allergy; though in none did it, seem to be the entire explanation of the difficulty. None showed skin reactions to foods, though in two the introduction of an item f o u n d not to be tolerated would provoke abnormal stools. A third factor that we feel m a y well co.ntribute to digestive difficulties, the psychogenic, is well accepted as a cause for a v a r i e t y of gastrointestinal difficulties in older children and in adults, but seems not to have been considered seriously in this group. In the histories of eleven of our patients we were impressed b y the possibilities o.f the role of insecurity, p a r e n t a l overanxiety, and frank, m i s m a n a g e m e n t as c o n t r i b u t i n g to the disturbance. I t has been our experience in a n u m b e r of instances t h a t the use of t h y r o i d has been valuable in p r o m o t i n g a n o r m a l rate of g r o w t h when this has not been achieved b y diet alone, and in some instances it has been valuable in s h o r t e n i n g m a r k e d l y the d u r a t i o n of the digestive s y m p t o m s also. F u r t h e r more, there are a n u m b e r of f e a t u r e s in some eases of celiac disease which suggest h y p o t h y r o i d i s m . ]it is the purpose of this p a p e r to discuss t h y r o i d deficiency as a f a c t o r contributing' to the etiology of chronic intestinal indigestion. A f o u r t h f a c t o r always e x p l o r e d in the search for and e x p l a n a t i o n of a disturbance of g r o w t h is an endoerine one, and the following experiences are offered in s u p p o r t of the thesis t h a t in a condition t h a t m a y have nmltiple eauses, t h y r o i d deficiency is a conditioning f a c t o r in its development. Anders e n ' s 2 recent hypothesis is t h a t the condition is " b e l i e v e d to result f r o m a deficiency of multiple nutritional factors c o m p l i c a t i n g a n d resulting' f r o m a basic constitutional d i s e a s e " and t h a t " t h e r e is suggestive evidence t h a t the difficulty in protein metabolism, shown b y the high r e q u i r e m e n t for d i e t a r y p r o t e i n a n d a t e n d e n c y to h y p o p r o t e i n e m i a on a n o r m a l diet, m a y be an expression of the basic d i s e a s e . " I t is our t h o u g h t t h a t this " b a s i c constitutional d i s e a s e " m a y in some instances involve a t h y r o i d deficiency on which is superimposed some other t r i g g e r m e e h a n i s m such as infection, allergy, or emotion. One of the o u t s t a n d i n g findings in the eondition is the d i s t u r b a n c e of growth, and as we have w a t c h e d the d e v e l o p m e n t of the condition in children whom we have followed from birth, we are impressed with the frequency with which a flattening of the curves of height and weight has preceded the abnormal stools. There has always been accepted as a p a r t of the picture a retardation in the time of a p p e a r a n c e of the centers of ossification, b u t this has been dism.issed, s o m e w h a t g r a t u i t o u s l y it seems to us, as a result of the fecal losses r a t h e r t h a n as an i n t e g r a l p a r t of the metabolic difficulty. I n m a n y of our eases it would a p p e a r t h a t digestive s y m p t o m s have a p p e a r e d l a t e r t h a n would explain the r e t a r d a t i o n of bone age. Studies were done on t h i r t y - t w o eases and showed delay in twenty-six, as judged b y the s t a n d a r d s of V o g t and Viekers ~ f r o m the H a r v a r d G r o w t h Study. W e w e r e impressed with T o d d ' s ~ s t a t e m e n t t h a t these have g r e a t e r value w h e n studied serially t h a n

JOLINSTON

AND HOWARD:

THE

CELIAC SYNDROiV[E

3

when a t t e m p t was made at a single assessment. Seventeen cases of p a n c r e a t i c fibrosis are not considered here other t h a n to point out t h a t in seven of these in w h o m " b o n e a g e " was determined, in six it was f o u n d normal. ]f delay in the a p p e a r a n c e of the centers of ossification were to be explained as a result of the digestive difficulty r a t h e r t h a n au u n d e r l y i n g cause, we should expect this group to show it in inore e x t r e m e fashion than any. Osteoporosis was marked, but in only one was the a p p e a r a n c e of centers delayed. I t seems to us significant t h a t the commonest time of a p p e a r a n c e of bowel symptoms, the l a t t e r half of the first y e a r and the first half of the second (in t w e n t y - t h r e e o~ our cases s y m p t o m s a p p e a r e d between, the seventh and eighteenth m o n t h of age), coincides with a decelerating phase and a falling rate of metabolism, lit recalls a similar period in adolescence when the n o r m a l falling r a t e which follows the onset of p u b e r t y , physiologic though it be, carries with it a m a r k e d increase in the incidence of h y p o t h y r o i d i s m . There is a n o r m a l t e n d e n c y to recover from this fall; in W e t z e l ' s s calculations an accelerating phase a p p e a r s at 31/~ years. T o p p e r and Muller ~ agree t h a t the p o s t p u b e r t y fall likewise will be r e c o v e r e d fi'om in the adolescent girl. The response of the anemia, the lassitude, the hypotension, low metabolism, and the m e n s t r u a l i r r e g u l a r i t y to t h y r o i d is so brilliant t h a t to withhold this t h e r a p y would seem like poor j u d g m e n t . B r a i l s f o r d R o b e r t s o n ~~ in p a r t i c u l a r stressed the v u l n e r a b i l i t y of the decelerating phase of g r o w t h n o t e d in the latter p a r t of the first year. Again, the i n f r e q u e n e y with which it is seen in the first few months suggests the situation seen in the cretin, whose failure to show the effects o:f his deficiency in the first few months results f r o m the influences of his m o t h e r ' s hormone, However in seven cases there was a history of pylorospasm or enterospasm in the first few months. K y p o t h y r o i d i s m and the celiac s y n d r o m e have in eoniinon abnormalities in the m e t a b o l i s m of protein, fat, c a r b o h y d r a t e , and calcium, and in gastrointestinal motility. The effect of t h y r o i d on p r o t e i n is covered in two studies f r o m this clinic. 11, ~ The high r e q u i r e m e n t for p r o t e i n of which A n d e r s e n speaks is characteristic of the child with t h y r o i d deficiency because this h o r m o n e is essential for the anabolie processes involving n i t r o g e n in growth. The flat oral tolerance curve noted in the celiac, a d m i t t e d l y nonspecific and common to a n u m b e r of conditions, is seen in the h y p o t h y r o i d 2 a Svensg a a r d ~4 r e p o r t s a series of studies with the oral tolerance curve on subjects t h a t included cretins and eeliacs. Both showed flat curves, those of the cretin beconiing erect with thyroid. She did not give t h y r o i d to ee]iaes. An a v e r a g e of the d a t a on four of her ct'etins before and a f t e r t r e a t m e n t with t h y r o i d is shown in Table I. TABLE I.

:Before After

AVERAGE OF SVENSGAARD 'S [DATA ON ]~OUR CRETINS FASTING SUGAR 74 79

I ]

MAXI35AL VALUE 133 229

DURATION OF HYPERGLYCEMIA 110 minutes 125 minutes

TI:IE J O U R N A L

OF P E D I A T R I C S

That the defect; in the utilization of glucose in celiac disease involves a failure of absorption is generally conceded. '~ May and McCreary 'G coneluded that their low blood s u g a r curves seem to be " m e r e l y a reflection of the inactivity in gastro-intestinal m o t i l i t y " and confirmed the findings of similar curves in the cretin. A similar failure is shown in the thyroidectomized animal in whom A l t h a u s e n t7 shows a reduction in absorption of 50 per cent. This he attributes to a failure of the normal f u n c t i o n of the t h y r o i d in stimulating phosphoryiation in the intestinal mucosa. A d e q u a t e replacement was shown to correct the deficiency r a p i d l y and effectively. Imt)aired fat absorption in the h y p o t h y r o i d as measured by the vitamin A absorption test is of a degree comparable to t h a t f o u n d in the celiac (Clausen and MeCoord, ~s May and MeCrearyl*~), but whereas in the celiac carotene is also r e p o r t e d low, the h y p o t h y r o i d is said to have an a b n o r m a l l y high level, his defect involving a failure of conversion of carotene to vitamin A. 7It could be expected, however, that when a eondition characterized by poor absorption arid steatorrhea is superimposed on one in which a hormone defect results in poor conversion, the carotene level would not be helpful. When it was f o u n d high, it was not at a time when d i a r r h e a was prominent. Using the single dose four- or five-hour test, ~~ ten of our eases showed a level of vitamin A of less than 30 ~g, seven from 31 to 50 ~g, and six higher than 50 ~g. Carotene was below 100 ) g in twelve, between 100 and 200 ~g in four, and in seven it was over 200 ~g'. There were two a b n o r m a l l y high figures of 410 t~g and 510 ~g. The last figure was obtained on a subject who had had an adequate celiac diet b u t had not yet had thyroid. I n these studies a factor of 7.38 was used for the conversion of out' values on carotene recorded in m i c r o g r a m s to the " u n i t s " of M a y and M c C r e a r y and 2.05 for' converting' micrograms of vitamin A to their units. According15% the normal standards wouhl be as shown in Table II. *' TAm,~ ZI

AGE GROUP 4 d a y s - 5 too. 9 too.-2 y r . 3 yr.-5 yr. 6 yr.-10 yr. 1] y r . - 1 2 y r .

CAROTENE MAY UNITS [ #a 3 . J - 7.5 22.0- 55 34.8-72.4 256.0-534 36.4-75 268.0-553 1 9 . 4 59 143.0-435 10.5-56 77.4 4 1 3

VITAMIN A MAY 6 2 0 UNITS I ~a 7.1-13 14-26.6 13.1-19.9 26-40 10.1-19.2 20-39 8.1-21.5 16 44 9.4-20.9 ]942

Rickets and t e t a n y have both been seen in eeliae disease and the failure to absorb calcium n o r m a l l y has been noted in balance observations. 2~, 2~ I t was the negative calcium balance of the cretin made positive by thyroid that led us to use it in t r e a t i n g the obstinate t e t a n y in the ease of J. M. I n a previous study, ~ we had shown t h a t normal retentions of ealcimu could be expected only with a normal level of t h y r o i d activity and that the cretin failed to store until he received thyroid, his losses being referable to large fecal excretions, the h y p e r t h y r o i d 's negative balances being the result of excessive losses both t h r o u g h the urine and the stool. 'For

t h e s e c a l c u l a t i o n s w e a r e i n d e b t e d to D r . George H, 3 ~ a n g u n ,

J O I t N S ! I ! O N AND

HOWAIgl):

THI~] CELIiAC SYNDROME

5

I t n p a i r m e u t of tone and sluggish peristalsis, held responsible for the clumping noted in celiac disease, arc f o u n d in h y p o t h y r o i d i s m , t h o u g h I[amilton and associates ~ also d e m o n s t r a t e d h y p e r m o t i l i t y of the stomach in adult h y p o t h y r o i d s becoming n o r m a l u n d e r t r e a t m e n t with thyroid. Titus a n u m b e r of the findings seen in the one condition are duplicated in the other, save the abnormal stools. I t is our t h o u g h t t h a t a certain percentage of infants have their digestive disorder pt'ecipitated by infection, emotion, and allergy, but t h a t its d e v e l o p m e n t is conditioned by ~m u n d e r l y i n g t h y r o i d deficiency and t h a t the c o m p l e m e n t i n g of the high protein diet with thy~'oid would n o t a b l y shorten the d u r a t i o n of the mild case and in tile severe ease would correct an otherwise irreplaceable deficit. The question will arise as to the confusion of a true p r i m a r y hyl)othyroid state with the " h y p o n t e t a b o l i s m " seen as a result, for example, of a low protein intake ~5 or p r o l o n g e d inactivity. I n a s t u d y of two children '~ whose metabolic rate had fallen as a result of a y e a r ' s inactivity, we showed t h a t small amounts of thyroid were anabolic, as j u d g e d b y the f a c t t h a t t h e y produced increased storage of n i t r o g e n and calcium, l~a.rger amounts became katabolie unless the intake were increased, llt was possible to achieve an increased intake, however, only w h e n the metabolic r a t e had been elevated with thyroid. The mechanism of the lowered rate of oxidation m a y be qui~e different in the two conditions, b u t there would seem to be the same usefulness in t h y r o i d as a t h e r a p e u t i c agent, p r o v i d e d the dose is k e p t smalh The first experience leading to this t h o u g h t was the d e m o n s t r a t i o n (}11the effectiveness of t h y r o i d in the correction of a failure to absorb calcium nerreally in two conventionally t r e a t e d celiacs. CASE 1.--T. IV[.,~:~a male child, was seen at 5 year's of age with a history of onset of bo.wel disturbance at lt/~ years. Abdominal enlargement and failure to gain had been noted for three years, and, although a high protein diet had been followed by a reduction in the n u m b e r of stools f r o m ten to two, the stools had eontifmed to be large and frothy. The family histo,ry showed that one sibling has eeliae disease and one a history suggestive of it. D u r i n g the p a t i e n t ' s first year his feeding history had not been unusual, t i e was breast-fed for three months, followed by ]aetic acid milk with K a r o formula; cod liver oil was later' replaced by 10 drops of viosterol; orange juice had been given since 3 months of age, cereal from 5 months, vegetables from 6, and eggs and meat a f t e r one year. Infection played no p r o m i n e n t role until the age of 3 years, when he had chicken pox, followed by pertussis at 4 and measles at 5 years. Stools showed a f a t v a r y i n g f r o m 37 per cent to 63 per cent. Glucose tolerance (oral) was 55 ntg'., 50 mo.., 61.5 rag., and 60 rag. at 8 9 1, 2, and 3 hours. I n t r a v e n o u s pyelograms showed a double kidney pelvis, good excretion of the dye, and no dilata.tion of the pelves. W r i s t plates showed a delay in ossification of at ]east two years. X - r a y s of the chest were negative. Blood ealcimn was 12.4 and pho.sphorus 3.0 rag. per cent. Blood[ showed 11.8 Gm. hemoglobin; white blood cells 3,800 with 64 per cent polymorphonuelears. Urine was negative. B a r i u m meal showed the " e h m p i n g and segmentation noted in vitamin defieiency and celiac disease." Treated in another hospital front ,July, 1938, to, August, 1938, he was discharged to a convalescent home until November, i1938, and to his home * F o r t h e c a s e of 'r, ~ . we a r e i n d e b t e d tO Dr, J a m e s W i l s o n , Ann A r b o r ,

()

TtlE

JOURNAL

OF PEDIATRICS

'{5 ~S r35 i

r ~c v~

Co.trol

[nt&Ee

"Th/~'o~dCo~'~olTh~o~aControlTh~'~ola

II.4~ 11.55 1,5~0 I.~68 1.64o ~.65~

Urine 5tool

T.Ti 8.35 0.040 o.obt 0599o.TzL i.~9 146 1~5o 1.~tk o.q'26 o.T~,5

~Sga,=ce

~.S& [.~& ~

0,355 0.280

A.

B.

C,

~'ig. 1.--T. McI'., 6 years of age. I t h a d b e e n p o s s i b l e to c o n t r o l t h e c h a r a c t e r of this boy's stools reasonably well with the celiac diet, but growth was unsatisfactory and he was B, X - r a y a t 5 y e a r s , subject to frequent relapses. Bone age was grossly delayed~ A, Chart. 4 months of age. C, X - r a y a t 9 y e a r s , 4 m o n t h s of a g e . Note: I n A, a n d t h e f o l l o w i n g c h a r t s t h e s i l h o u e t t e s w e r e t r a c e d d i r e c t l y f r o m t h e x - r a y films. In all of these weight charts the "normal zone" represents the sixteenth and eightyf o u r t h p e r c e n t i l e s of t h e I o w a s t a n d a r d s .

JOHNSTON

AND ItO~VARD:

THE

CELIAC SYNDROME

7

after that. He was readmitted in March, 1939, with a history again of large, gray, foul stools. These improved in the hospital, though they remained quite large. Data on his growth are given in Table III. TABLE

I

DATE

IIl.

I)ATA ON GROWTII

AQE

I

OF T. M.

(INC~IES) I

~EmIIT

J u l y , 1.938 N o v e m b e r , 1938 M a r c h , 1939 April~ 1939

5 5 6 6

yr., 4 mo. y r , 8 mo. yr. yr., 1 too.

33a~ 37 37

J u n e , 1939

6 yr., 3 too.

38

WE~I~ (LB.) 23 321/2 29 30 Thyroid begun M a y 7, 1939 37

Balance studies for thirty-six days (significant figures for calcium require between fifteen and twenty days when the intake is not restricted) showed a negative balance for calcium entirely referable to fecal excretion, becoming positive with one grain of Burroughs-Wellcome thyroid for nine days and then two grains for eightecen days, which resulted in a rise in basal calories f r o m 763 to 887 per twenty-four hours. I n t e r p r e t a t i o n of the "basal r a t e " is confused by the child's dwarfism; by the Boothby surface area standards these determinations would be minus 7 and plus 18, respectively. A negative calcium balance of 20 rag. per day was converted with t h y r o i d to a positive balance of 126 mg. per day. Phosphorus and nitrogen retention fell slightly (Macy's ~ normal mean r e t e n t i o n of calcium at 5 years was 172 rag. per day). TABLE i V . NITROGEN (G3s PER BAY)

CONTROLITHYROID Intake Urine Stool Balance

11.46 7.71 1.39 2.36

11.55 8.33 1.46 1.76

CALCIUiV[ (GNI. PER DAY)

CONTROL] THYROID 1.550 0.040 1.530 -0.020

1.568 0.031 1.411 +0.11.26

T.M.

PHO SP}tORUS (G~{. PEg BAY)

CONTROL 1.640 0.559 0.726 0.355

BASAL CALORIES IN (2~ ItR.)

ITIIYROID 00NTROL 1.656 0.721 0.715 0.280

763 . . . . . .

ITHYROID

B.?cER. (BOOTtIBY)

CONTROL

887 . . . . . . . . .

. . .

-7 . . . . . .

ITIIYI%OID +18

CASE 2.--J. M.,* a male child born weighing 5 pounds a p p a r e n t l y at term, did well n u t r i t i o n a l l y the first y e a r on a diet of e v a p o r a t e d milk, w a t e r and Dextri-Maltose, orange juice, cod-liver oil, cereal, vegetables, and meat. History was u n e v e n t f u l until the age of 21/2 y e a r s ; he stood at 10 months but did not walk until 18 months of age. F r o m 21/2 to 3 years of age, he lost weight, the abdomen became distended, and the stools, at first yellow and watery, became large, foul, and frothy. T w o months before admission the hands were noted to be held in spasm and there was some stiffening of the body. At this time, aged 3 years, he a p p e a r e d severely malnourished, with little subcutaneous fat, s h r u n k e n buttocks, and a large abdomen. His measurements were as follows: length, 37 inches; weight, 23 pounds; head, 183~ inches; and chest, 18 inches. He was showing definite tetany. The blood calcium was 7.3, phosphorus 2.1, phosphatase 0.8 units. The glucose tolerance curve was flat. He was t r e a t e d for six weeks with calcium chloride, viosterol, and a celiac diet. Ue was r e f e r r e d to this clinic for balance studies, and at admission, aged 3 years, 3 months, the blood calcium was 5.0 rag. per cent, phosphorus 2.84 rag., and phosphatase 2.72 units. The wrist showed two * F o r the ease of ft. M. w e a r e i n d e b t e d to Dr. C l e m e n t A. Smith, Boston.

T/:IE JOURI'qAL

OF PEDIATRICS

~

J. ~1. 5~ Age a

5i

~

41

5

Cont~o .l %y~oicl 18- aa V to- d~y C a lc~m l~ittoge n Ca[ clain llit~o~ea ].nta~e U~ltte 5tool ~al~nce %

955 ~[ e tz 5zi 5

1.5.6o S. ,5 z 1.45 5.~o

6,.36 4[ 4.96 29~ ~5

t4_,36 Y.36 1.53 5"it

A.

2~

2Fig. 2 . - - J . M . ' s c o n d i t i o n w a s c o m p l i c a t e d by recurrent letany. Thyroid o r ' e a s i n g h i s r e t e n t i o n o f c a l c i u m f r o m 5 p e r c e n t o f t h e i n t a k e to :t5 p e r c e n t . X-ray at 3 years of age.

r e s u l t e d in inA, Chart. 2,

JOHNSTON

AND t [ O W A R D :

THE

CELIAC SYNDROME

earpa] centers at 3 y e a r s of age. Serum albumin 11.64. A balance s t u d y was conducted 12or thirty-six eighteen of which he received thyroid. The intake in the celiac diet and was a n a l y z e d in duplicate % r

was 3.18 and globulin days, during the l a t t e r was derived f r o m items nitrogen and calcium.

TA m,~: V 18-DAY CONTR()T~ CALCIUS{ Intake Urine Stool Balance

953 rag. 87 812 54

[

NITRO(~EN 15.6 gin. 8.52 1.48 5.60

. THYI%0ID 1~ GEAIN PER DAY. 18 DAYS CALCIUI~i

]

836 rag. 47 496 293

NITROGEN 14.36 gin. 7.36 1.53 5.47

Seven months later he r e t u r n e d with the history o12 doing well until three months previous, when the stools became a b n o r m a l and he lost weight. A t this time an ~ntensive eourse of v i t a m i n B p a r e n t e r a l l y was given following M a y ' s suggestion without m e a s u r a b l e effeet. H o m e cooperation on diet and medieation was completely u n t r u s t w o r t h y and he had several setbacks whieh the m o t h e r explained b y the dropping' of both t h y r o i d and the diet and increasing of the starch intake. A 3-year-old plate showed m a r k e d osteoporosis and only two carpal centers. A t 4 y e a r s the wrists showed only two centers oil either side, with the radial head on one side. A t 4t/~ y e a r s he had a r e c u r r e n c e of tetany. A t this time his p r o t h r o m b i n was f o u n d to be 20 per cent of normal. A t 5 and 51/2 y e a r s there were recurrences o12 tetany, the blood on the last admission showing calcium of 7.4, phosphorus 6.3, and p h o s p h a t a s e o12 3.2. I t could be concluded from this ease t h a t hypoea]cemic t e t a n y was correctable b y r e p l a c e m e n t t h e r a p y with thyroid. Diet alone had been tried for three months. T h y r o i d was d r o p p e d for considerable periods be12ore each of these readmissions. CASE 3.--Ru. B., a %male child, was seen at 6 years for dwarfism and f a i l ure to develop m e n t a l l y ; celiac stools were observed only i n t e r m i t t e n t l y . She was first studied in another institution at 2 years of age, unable to stand and weighing 13 lb. Stools were large but %treed, save on occasions when they became loose and foul. She showed a marked r e t a r d a t i o n o12 bone age, a flat oral glucose tolerance curve, normal caleimn and phosphorus, a phosphatase of 2 units, a n d cholesterol of 201. During' the n e x t two years she gained well while on a high protein, high vitamin diet but she entered the hospital f o u r times, each time with a sharp loss o12 weight. A t 4 y e a r s of age she weighed ]5 lb. and was 303~ inches in height, t i e r r e c o v e r y a f t e r the diet was s u p p l e m e n t e d b y t h y r o i d was started as measured b y height, weight, and bone d e v e l o p m e n t is r e c o r d e d on the chart, but is not n e a r l y so d r a m a t i c as her m e n t a l progress. The his[ory of her twin, obtained 12tom a n o t h e r institution, follows. CaSE 4.--Ro. B., ~:~ a p r e m a t u r e male t w i n o f Ru. B., was hospitalized because of the complaint o12 slow m e n t a l d e v e l o p m e n t and dwarfism, l i e was 2 y e a r s old, weighed 11 pounds, 15 ounces, and was 261~ inches in height. The five other children were normal, as were the parents, lie sat up at the age of 2 years, l i e did not a p p e a r ill, but was inactive. W i t h a good diet the child gained one p o u n d in seven days and seemed i m p r o v e d ; D u r i n g the following five months the child failed to i m p r o v e at home, and was r e a d m i t t e d at the age of 2 years, 9 months, weighing il:l pounds, 9 ounces, l i e still did not talk, walk or stand alone. A t this time bowel m o v e m e n t s were stated to be large * F o r t h e c a s e of Ro. B. we a r e i n d e b t e d to Dr. P a u l V. W o o l l e y , D e t r o i t .

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Fig. 3.--Ru. B. She was treated sporadically as a celiac for four years. No growth occurred until thyroid was started, although her stools could be controlled by a celiac diet. Her twin died with an identical history shortly before thyroid deficiency was apprecia,ted in Ru. .4, Chart. B, X-ray at 2 years, 9 months of age. O, X-ray at 7 years of age.

JOHNSTON

AND H O W A R D :

THE

CELIAC SYNDROME

11

and foul. The x - r a y s of the long bones showed i r r e g u l a r i t y of the diaphyseal ends and patches of periostitis. The blood p h o s p h o r u s was 5.5 rag. per cent, and p h o s p h a t a s e 0.9 B o d a n s k y units. The blood cholesterol was 349 rag. per cent. The oral dextrose tolerance c u r v e was 83, 90, 72, 75, and 67 rag. per 100 c.e. at f a s t i n g and 30, 60, 120, 180 minutes, l i e was placed in a convalescent home, and u n d e r careful feeding his weight increased to 24 pounds, .1.2 ounces, and he was sent home to convalesce further. A g a i n u n d e r home care the child progresMvely failed and died. This child would, in retrospect, a p p e a r to have duplicated his s i s t e r ' s course and to have h a d as g r e a t a need for t h y r o i d as she. CASE 5.--R. K., a male child, was born at t e r m of a mother said to have t h y r o i d deficiency and arthritis. B i r t h weight was 8 pounds. G r o w t h and d e v e l o p m e n t were f a i r l y n o r m a l for a y e a r ; he w a l k e d at 13 months of age, and said several words at 17 months. F r o m age one to 2 years he had grossly a b n o r m a l stools, six to ten a day, f e r m e n t a t i v e and greasy, and the abdomen became distended. He i m p r o v e d on a high protein diet. One hand became swollen at 2 years, one foot at 4 y e a r s of age. A t a b o u t this time he a p p e a r e d edematous, with f r a n k puffiness of the eyes, and he was r e f e r r e d for s t u d y w i t h a question of nephrosis, a l t h o u g h studies in a n o t h e r hospital had shown a n o r m a l urine b u t a v e r y low s e r u m protein. A t 4 8 9 y e a r s the weight was 39 pounds, the height 39 inches. He a p p e a r e d pale and puffy. There was f r a n k swelling of the p h a l a n g e a t joints of the r i g h t h a n d and the left ankle. W r i s t studies showed only two c a r p a l centers. T h y r o i d was begun and i m p r o v e m e n t was m a r k e d . The following observations were m a d e eight months l a t e r : cholesterol 143; p h o s p h a t a s e 5.7 units: v i t a m i n A absorption 13.8 /,g p e r cent; carotene 54.2 t~g per cent. A l l e r g y tests showed reaction to alternaria, dust, and several b a c t e r i a l proteins. A l b u m i n was 2.05, globulin 1.46. Urine was negative. Cephalin eholesterol was negative. Stool f a t was 19.3 per cent d r y weight. An i n t e r c u r r e n t r e s p i r a t o r y infection in March, 1948, was followed b y a r e e u r r e n c e of celiaelike stools and a loss of 3 pounds of weight. TABLE

Birth 4 yr., 4 too. 5 y r . , 6 too.

39 41

V I~

8 39 ( t h y r o i d b e g u n ) 40

CASE 6 . - - T h e case of J. S. is offered as an example of the occurrence of the intestinal difficulty in a child in w h o m h y p o t h y r o i d i s m had been suggested clinically four months before the stools became abnormal. B o r n n o r m a l l y and fed on an e v a p o r a t e d milk f o r m u l a w i t h a d d e d cereal and vegetables, his hist o r y was u n e v e n t f u l for % u r t e e n months. A general check w h e n he was 10 months of age occasioned the r e m a r k t h a t he seemed an u n u s u a l l y placid b a b y a n d was not t r y i n g to pull himself erect. A t t h a t time he weighed 19 pounds, and the height was 281/2 inches. A t 14 months he r e t u r n e d with the complaint of five or six stools a day, m a r k e d irritability, an(l a flattening of the w e i g h t curve. The oral tolerance was 72, 76, 74, 54 rag. p e r .100 e.e. V i t a m i n A absorption was 31.0 ~g and 180 t~g carotene. Red blood count was 3,800,000; hemoglobin 10.9 Gin. Stool f a t was 11 per cent d r y weight. W r i s t plate showed a single carpal bone at 16 months. Thyroid, grain 1~, was started, with a high protein diet; he was s y m p t o m - f r e e in two months. On J a n u a r y , 1948, his height was 36 inches and weight, 27 pounds. The bone age in this ease was sufficiently d e l a y e d to w a r r a n t the assumption t h a t a re-

12

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JOHNSTON AND IIOWARD:

1 o()

THE CEI,IAC SYNDROME

larding influence antedated the gastrointestinal symptoms. In addition, there were clinical signs of hypothyroidism, lethargy, and slowness in development a t 10 m o n t h s o f a g e . T h e role of i n f e c t i o n of t h e l y m p h o i d be understood

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~ig'. 5.--Chart showing the effect on the nitrogen balance of the removal of infected tonsils and adenoids. (l~rom Johnston, J. A., and Maroney, J. ~vV.: iFoeaI Infection 'and 2d[etabolisra, J. PNDIA~P. 1~: 563, J.938. A, F. S., a boy 9 years old, height 50 inches, estimated weight, 58 pounds. Tensill.ectomy was performed on the first day, fifth period. Nitrogen balance and basal metabolism were deter~ mined before and 'after removal of tonsils and adenoids. In this and subsequent charts the balances are continuous; each bar represents a three-day balance, and the average of all balances before and after is indicated by crosshatching. B, S. R., a boy 13 years old. height 56 inches and estimated weight 78 pounds. Tonsilleetomy was on the first day, sixth period. Nitrogen balance and basal metabolist~ were before and after' removal of tonsils and adenoids. The balances, are continuous, a.nd the diet constant. Each bar represents a three-day ba.Ianee and the average of all periods before and after tonsillectomy is shown by erossh~atehing~

14

T H E J O U R N A L OF PEDIATRICS

eight we felt we had. I n twelve of the f o r t y cases infection of the tonsils and adenoids, or the adenoids alone, seemed to have etiologic significance. I n one (Case No. 12), our concern w i t h it p e o b a b l y led to our overlooking the possibility of its being s u p e r i m p o s e d on a t h y r o i d deficiency, and a bone plate was not t a k e n until the age of 41/2 years, w h e n only two centers were f o u n d in the wrist and t h y r o i d was started. Nevertheless, we fee] t h a t in some instances chronic infection of the adenoids and tonsils alone m a y constitute both the u n d e r l y i n g metabolic flaw and the conditioning factor, and the usefulness of the p r o c e d u r e of tonsillectomy a n d a d e n o i d e e t o m y should be borne in mind constantly. I t would be well to stress a g a i n the f a c t t h a t if t h y r o i d is used, its anabo]ic effect will not be n o t e d un]ess an increase in the intake of p r o t e i n can be effeeted. I n our original studies on the cretin, the increased storage was largely r e f e r a b l e to an increase in intake. R e c e n t l y in a juvenile m y x e d e m a no such increased storage occurred w h e n we restricted the intake to the a m o u n t t a k e n w h e n the metabolism was at its lowest. I n this series we were f u r t h e r impressed with the p r o b a b l e role p l a y e d b y emotional factors in the etiology of the d i s t u r b e d bowel function. Overa n x i e t y on the p a r t of parents, e n g e n d e r i n g fears in e a r l y infancy, the lack of affection and of normal handling a t t e n d a n t or prolonged institutional stays in the ease of two illegitimate children, and the i n s e c u r i t y in several instances r e l a t e d to the instability of a r m y camp life, all m u s t h a v e left their marks, and several instances are s u m m a r i z e d out of the eleven eases in which we felt t h a t emotional disturbances m a d e an etiologic c o n t r i b u t i o n to the digestive disturbance. I t would be desirable to have some more q u a n t i t a t i v e assessment of the hypometabolie state t h a n the bone age. The weakness of cholesterol is widely accepted, unless it be d e t e r m i n e d before, during, and a f t e r the a d m i n i s t r a t i o n of thyroid. The response of the g r o w t h curve is highly suggestive. W e have felt t h a t the suggestion of Talbot a n d associates, 2s who f o u n d the basic phosp h a t a s e consistently below 4 units in the cretin, and of Hill and Webber, =9 whose low metabolism d e t e r m i n a t i o n s and c]inical evidences of h y p o t h y r o i d i s m were a c c o m p a n i e d b y low phosphatase, was highly useful and we include in Table V I I , t h r o u g h the courtesy of Dr. Sidney F a r b e r , figures (in addition to those quoted in the protocols) on three eases f r o m the C h i l d r e n ' s I t o s p i t a l of Boston. I n two of these cases the bone was one-half the ehrono]ogieal age. TABLE VII CALCIUM 7.8 mg. 7.7 7.0

I

P~OSPHORUS 4.7 mg. 6.4 4.4

[

PHOSPHATASE 3.5 u n i t s 3.6 2.3

Kowever, in a controlled series of our own we have found, in a g r o u p of orphans f r o m poor homes, phosphatase levels below 4 when there was no other evidence of h y p o t h y r o i d i s m . W e feel, however, t h a t the d e m o n s t r a t i o n

JOHNSTON AND HOWARD:

THE CELIAC SYNDROMZE

15

of improved calcium absorption in the two cases in whom balance determinations were reported, the acceleration of growth, and the shortening of the average time duration of symptoms, are all adequate reasons for considering that in a certain percentage of cases the hypometabolie state of the i n f a n t with celiac s y n d r o m e is improved with t h y r o i d medication. The addition of thyroid to the other items in the m a n a g e m e n t of this condition has seemed notably to shorten the duration of symptoms, in eighteen cases the average being nine months, in contrast to seventeen in those t r e a t e d with diet Mone, and five children were symptom-free in less than two months, A n u m b e r of patients whose t h y r o i d t h e r a p y was not instituted until after several years of symptoms are not included. In a condition complicated by the development of deficiency states, it is not suggested that there be any dep a r t u r e from the practice of utilizing the high protein, high vitamin diet. SUi~MARY

In summary, we snggest t h a t chronic intestinal indigestion may be p r e c i p i t a t e d by a n u m b e r of factors, infections, emotional, allergic, but, t h a t since all of those suggested do not commonly produce the disorder in otherwise normal children, Andersen's 4 assumption of an u n d e r l y i n g constitutional defect seems valid, and that in some instances this defect is a t h y r o i d deficiency, while in others it is in the n a t u r e of a secondary hypothyroidism resulting f r o m nitrogen and caloric deficits, in which cases t h y r o i d in small doses is indicated for its anabolic effect. W e do not feel that t h y r o i d deficiency explains all cases but t h a t a number will be f o u n d in whom the defect will he referable to other mechanisms relating to protein synthesis. The role of the liver in these cases w a r r a n t s f u r t h e r study. Dr. l~rank ~ I a r t m a n supervised the metabolism determinations. Dr. Oliver tI. Gaebler supervised t h e balance determinations. REFERENCES 1. Andersen, D. H., and I-Iodges, R. G.: The Celiac S y n d r o m e , B r e n n e m a n n ' s Practice of P e d i a t r i c s I, tIagerstown~ W. F. P r i o r Company, Inc., p. 29. 2. Andersen, D. I~.: Celiac Syndrome: Relationship of Celiac Disease, Starch Intolerance, and Steatorrhea, J. PEDIAT. 30: 564, 1947. 3. Holt, L. E., and McIntosh, R.: H o l t ' s Diseases of I n f a n c y and Childhood~ ed. l l , New York~ 1940~ D. A p p l e t o n - C e n t u r y Co., p. 274. 4. Kun.stadte% R. H.: G a s t r o i n t e s t i n a l Allergy and Celiac Syndrome~ J. PEI)I2.'~'. 21: 193, 1942. 5. Mct~hann, C. Y., Spector~ S , and ZV[eserve~ E. R.: Association of Gastro-Intestinal Allergy w i t h Celiac Syndrome, J. PEDIAT. 22: 362, 1943. 6. Vogt, E. C., and Vickersj V . S . : Osseous Growth and Development, Radiology 31: 441, 1938. 7. Todd, T. W i n g a t e : Atlas of Skeletal M a t u r a t i o n , St. Louis, The C. V. Mosby Company, p. 17. 8. Wetzel, N. C.: On the Motion of Growth; X V I . : Clinical Aspects of I t u m a n Growth w i t h Special Reference to I n f a n c y and Pre-sehool Life, J. PEDIAT. 4: 465, 1934. 9. T~)pper, A., and ~ u l i e r , H.: Basal 1V~etabolism of Normal Children: P u b e r t y Reaction, Am. J. Dis. Child. 43: 327, 1932. 10. Robertson~ T . B . : The Chemical Basis of Growth and Senescence, Philadelphia, 1923, J. B. Lippineott Co.

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THE JOURNAL OF PEDIATRICS

11. Joh~tston, J. A.: h~actors Affecting Retention of Nitrogen and Calcium in Period of Growth; II. Effect of Thyroid on Nitrogen Retention, Am. J. Dis. Child. 58: 965, 1939. 12. Johnston, J . A . : Factors Influencing Retention of Nitrogen and Calcium ~n Period of Growth; V. ]!~urther Evidence of the Auabolic Effect of Thyroid on Calcimn ~Ietabolism, Am. J. /)is. Child. 62: 1172, 194]. 113. Januey, N. W., and ]saaeson~ V.: I. Blood Sugar in Endocrine Diseases, Arch. Int. Med. 22: 160, 1924. 14. Svensgaard, F.: The Blood Sugar in the Sick Child, Acta. Pediat. 12: Supp. 1-6, p. 83, ]93]. ]5. Crawford, T.: Causation of Low Blood Sugar Curve in Celiac Disease. Quart. ,I. 3/[(~. 8: 251, 1939. 16. May, C. D., and McCreary, J. ]~'.: Glucose Tolerance Test in Celiac Disease, Significance of Low Blood Sugar Curves, J. PEmAT. 17: 143, 1940. 17. Althausen, T. L., and Stockholm, M.: Influence of Thyroid Gland ca Absorption in Digestive Tract, Am. J. Physiol. 123: 577, 1938. 18. Clausen, S. W., and 3/s A. B.: The Carotinoids and Vitamin A of the Blood, il. PEDIAT. 13: 636, 1938. ]9. May, Charles ])., and McCreary, . I . F . : The Absorption of Vitamin A in Celiac Disease, ft. PEDIAT. 18: 200, ]941. 20. Pratt, E. L., and Fahey~ D. R.: Clinical Adequacy of Single Measurement of VRamin A Absorption, Am. J. Dis. Child. 68: 83, ]944. 21. McCrudden, ~'. H., and Fales, K . L . : Complete Balance Studies of Nitrogen~ Sulphur, Phosphorusj Calcium, and Magnesium in I n t e s t i n a l Infantilism, J. Exper. Med. 15: 450, 1912. 22. Bennett, T. I., Itunter, D., and Vaughn, J. M.: Idiopathic Steatorrhoea (Gee's Disease) a Nutritional Disturbance Associated with Tetany, Osteomalacia, and Anaemia, Quart. J. 5Ied. 1: 603, ]932. 23. /lohnsto~b J. A., and 5~aroney, J. W.: ?'actors Aft'eeting Retention of Nitrogen and Calcium in Period of Growth; I[. Effect of Thyroid on Calcium :Retention, Am. J. Dis. Child. 58: 1186, 1939. 24. t[amiRon, F. E., MacQuigg, R. E., and Curtis, G. M.: Hypothyroidism, The Gastric Motility in Certain P a t i e n t s wRh Thyroid Deficiency, J. Clin. Endocrinol. 1: 24, 1941. 25. Johnston, J. A , and [v[aroney, J . W . : Relationship of Basal Metabolism to ,Dietary Yntake, Am. J. Dis. Child. 51: 2939, ]936. 26. Maey, I. G.: Nutrition and Chemical Growth ]n Childhood, VoL I, p. 161. Baltimore, 1942, C. G. Thomas. 27. Johnston, ft. A., and Maroney, J. W.: Focal Infection and Metabolism: The Effect of the Removal of Tonsils and Adenoids on the Nitrogen Balance and the Basal Metabolism, J. P~ZD~AT. 12: 563, 1938. 28. Talbot, N. B., Hoeffel, G, and Tuohy, E. L.: Serum P h o s p h a t a s e as Aid in Diagnosis of Cretinism and Juvenile Hypothyroidism, Am. J. Dis. Child. 62: 273, 1941. 29. Hill, It. M., and Webber, J. E.: Serum Phosphatase Values in Children Showing R e tardation i~ Osseous Development and Low Metabolic l~ates, J. PEDIAT. 22: 325, 1943.