CELIAC DISEASE

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CELIAC

DISEASE

Kenneth

D. Blackfan

Memorial

Lecture*

By Wilfrid Sheldon, C.V.O., M.D., F.R.C.P.

Hospital for Sick Children, Great Ormond Street, London

0 Delivered at the Children’s Medical Center, Boston, on March 12, 1958. These Lectures are niade

possible by gifts from the Children’s Hospital Alumni Club.

ADDRESS: 46 Harley Street, London Wi, England.

PEDIATRICS, January 1959

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ARTICLES

132

M

FIRST duty is to express my

appreci-ation of the honor accorded me by

the invitation to deliver this lecture,

dedi-cated to the memory of one of America’s great pediatricians. Dr. Kenneth Blackfan

was a man who, by his high endeavor,

in-tegrity of character and devotion to his call-nig, not only added lustre to this Medical

School, but was enabled so to enrich

pedi-atric knowledge that his name is respected far beyond the confines of his own country.

It is a comfort to reflect that he might well have approved of the subject of today’s lecture, for his long association with Dr.

John

Howland did not fail to rouse his

in-terest in celiac disease, and this was in fact

the topic of his last publications. In 1940,

in conjunction with Charles May, John

McCreary and Fred Allen1 he described the vitamin A absorption test and its relation to

celiac disease in an article which can stand

as a perfect model, not only as to the

methodology of clinical research, but also as to its presentation. In the following year,

and only 6 months before he died, a

com-munication bearing his name2 was given to

the 1941 meeting of the American Pediatric

Society concerning the pathogenesis of celiac disease. It would therefore be fitting

if today’s lecture might be regarded as a

humble attempt to quest further along the trail already illuminated by Dr. Blackfan.

The original description of “The Celiac

Affection” by Gee3 in 1888, although of

commendable brevity, was so perfect a pen

picture that there has been little to add to his clinical account. It is therefore worth

recalling the symptoms he described; they

were, first an(l foremost, the passage of

loose, pale, bulky and offensive motions,

as-sociated with wasting, muscular atony,

anemia, abdominal distention and cessation

of growth. These symptoms remain today

the essential criteria for making the

dfag-nosis, for despite the passage of 70 years there is no laboratory procedure by which

the diagnosis can be given the stamp of

proof. Perhaps during these years we have been made more aware of the psychologic disturbances that may accompany physical

disease; certainly the unhappiness of the

celiac child is a very typical feature of the fully developed disease. Another very

common finding, first pointed out by

Still,4 is the smallness of the liver, which

sometimes cannot be felt at all. This is

of some clinical importance, for normally in the young child the liver edge is easily palpable, nor is its size reduced in those other digestive disorders which figure in the differential diagnosis, while, with the

exception of massive necrosis, disease of the liver in the young child produces an

en-larged organ.

The first descriptions of a disease entity almost invariably depict the condition in

its maturity; only later comes the account of the earlier manifestations that point the way to the fully developed illness. Today

we can recognize that Gee’s description was

that of an illness that had reached a severe

degree. What of the milder and earlier

cases? It is here that diagnosis presents its

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well be a matter for dispute. For example,

is the temporary steatorrhea that may

follow an acute infection, often gastro-intestinal, in a young child and that

re-sponds to reducing the fat intake for a few weeks to be regarded as incipient celiac

disease? I do not propose to attempt an answer, but surely the history of children

with celiac disease reveals as an early

feature the passage of pale loose stools

typical of steatorrhea, the impaired fat

ab-sorption being demonstrable by fat balances

or by estimating the daily excretion of fat. This, so it seems to me, makes it difficult

to accept the view of Boyer and Andersen5 that early celiac disease is synonymous with

starch intolerance, and that at this stage of the illness there may be little or no steator-rhea. It is however necessary at this point to

remark that the impact of gluten on the

celiac story makes it imperative to be pre-cise when we use the term starch; we should

limit it to pure polysaccharide, and not

confuse the picture by speaking of starch if we really mean flour, for it is now realized

that the protein component and the starch

component of flour can have quite

differ-ent effects on the child with celiac disease.

Starch intolerance and flour intolerance are not synonymous terms.

Of the etiologic causes of the disease,

in-creasing interest is being given to the ques-tion of a family predisposition since Ebbs in 1950 suggested that the incidence among relatives was too high to be a matter of

chance; he also suggested that the incidence of diabetes mellitus in families of children with celiac disease was sufficiently high to

link the condition with the diabetic gene.

Boyer and Andersen5 in their study of these

aspects concluded that there was a

sig-nificantly higher incidence of celiac disease,

recurrent unexplained diarrhea, and

intol-erance to fats and other foods in the

pedi-gree of children with celiac disease than

in a control group, but they were unable to

confirm the relationship with diabetes

mel-litus.

A comparable investigation is at present

being conducted on a large group of

chil-dren afflicted with celiac disease by the

Medical Research Council’s Genetic Unit

at the Hospital for Sick Children in

Lon-don. The details are not yet available, but it can be sai(l that a low but definite family

concentration of the disease can be

dis-cerned, confirming the work already

re-ferred to. Although the London figures show

a somewhat lower family incidence, this

may well be due to different criteria being

required for the diagnosis. So far, it has not

been possible to establish any significant

relationship between celiac disease and

di-abetes mellitus.

Unfortunately, and in spite of many

op-portunities, morbid anatomical studies have

failed to throw any light on the

patho-genesis of the disease, but a recent report

(the first of its kind) by Sakula and Shiner7

of a duodenal biopsy performed on a boy

aged 7 years with celiac disease revealed a

considerable degree of mucosal atrophy;

the lining membrane showed a flattened

surface, with virtual disappearance of the villi. Dr. Shiner had previously reported

similar changes in biopsy material from 11

cases of idiopathic steatorrhea in adults, a

condition now widely accepted as the adult

form of celiac disease and often

represent-ing a hangover from childhood. The

changes in the adult cases had extended in patches throughout the small intestine. The

exact significance of these findings must

await further biopsy studies, for the child

with celiac disease had had his illness for

some years, and there is no telling at what

stage of his disease these changes appeared.

There can however be little doubt that such

alterations would greatly reduce the

absorb-ing area of the gut, and they would also

destroy the feathery pattern of the small

intestine which is normally seen in

roent-genographic examination using barium. It

seems more doubtful whether they could account for the clumping of barium, which

is so typical a feature of the malabsorption

syndrome, and which Frazer8 has attri-buted to excessive secretion of mucus, but this must await further study.

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already well known, but in order to

real-ize its impact tPon affected children in

Great Britain, their plight prior to this new

knowledge must be appreciated. Had the

teaching of John lowland and his pupils,

to the effect that restriction of starches was of primary importance, been more widely

accepted, the children would undoubtedly

have been much better off, but there was a

persistent and universal adherence to the

view that intolerance of fat was the primary

defect. Although Parsons1#{176} had found that

fat absorption in spite of the obvious

steatorrhea could be as high as 84%, and

Macrae and Iorris,” also using fat

bal-ances, had demonstrated that increased

feeding of fat to children with celiac dis-ease led to increased absorption,

neverthe-less complete removal of fat from the diet

was regarded as fundamental, with

limi-tation of flours as a secondary necessity. Under this regimen the stools

undoubt-edly improved, but the principle underly-ing the treatment was the therapy of

avoid-ance of fat rather than the therapy of

use-expressive terms of which Holt12 has

re-cently reminded us. The severe limitation

of calorie intake which the treatment

in-flicted not only rendered satisfactory growth

almost impossible, but tended to make the

acute stage of the illness a long and tedious affair sometimes stretching over years,

dur-ing which time the outcome remained

un-certain, while for those who survived this

stage there was a fair prospect of eventual

stunting of stature, as well as episodic

re-lapses of diarrhea in later years.

The P5iti0n was so unsatisfactory that in 1947 the question of whether fat intolerance

was really the primary difficulty, and

die-tetic restriction of fat absolutely essential,

was reopened by feeding a group of these children a normal fat intake, over periods

when starches were either given or

com-pletely withheld, and by means of fat

hal-ances it was conclusively shown that

withholding starches led to a considerable

rise in fat absorption, often restoring it to normal. This finding, which was soon con-firmed in this country by Lowe and May,14

not only converted the “therapy of

avoid-ance” of fat to the “therapy of use,” but was

accompanied, in a manner quite unforeseen,

by a dramatic and rapid improvement in

the state of the children. It was at this

stage that Dicke,’ and Weijers and van de

Kamer16 narrowed the problem of starches by demonstrating that their harmful effect

lay in the protein fraction (gluten) of wheat

and rye flour, but that the remaining por-tion of wheat flour, namely wheat starch,

was harmless in the absence of gluten. Con-firmation of their work came quickly from

Birminghaml7 and London,18 and has since

received widespread approval. It now seems

clear that the previous experiments, in

which improvement in fat absorption came

about when starch-containing foods were

completely withheld, owed their success to

the elimination from the diet of wheat

pro-tein rather than to the avoidance of

polysac-charide, and it is equally likely that much of the benefit ascribed by previous writers

to the omission of starches arose in fact from the coincident withdrawal of certain cereal proteins.

The consequence of this new understand-ing has been to revolutionize our attitude towards treatment, the object of which is now to give a diet normal in all respects except for the strict avoidanec of

gluten-containing foods. It has also altered the

prognosis greatly for the better, for whereas

in 1939 Hardvick19 had to report an over-all mortality of some 15%, the death rate has now receded to vanishing point, while

the long-term outlook as regards both

growth and health has greatly improved.

The details of the management with a

gluten-free diet need not here detain us, for they have been fully described else-where,#{176} but three points deserve emphasis.

Firstly, if a child is already severely ill with celiac disease, a month or two of

ex-pert nursing care, usually in a hospital, may

be required before the diet can be gradually

built up from such simple beginnings as

high-protein skimmed milk, glucose and

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patient build-up is carried out,

disappoint-ment can be expected. It is only in the

milder cases that simple withdrawal of

gluten may be all that is necessary.

Second, the avoidance of gluten must be

absolute, for it only needs traces of it in the diet to produce unsatisfactory results. It is

very easy for such traces to reach the child

in proprietary feeding stuffs. Obviously the

co-operation of the parents is essential, and they must be supplied with an up-to-date

list of those proprietary foods that contain gluten, but given these conditions, the diet

can be easily managed in the child’s own

home. Many of the children treated by us

have their mid-day meal at school, the co-operation of the school authorities being in-variably forthcoming.

Third, the length of time for which gluten

restriction must be maintained probably varies from patient to patient. This point

is discussed later.

The mechanism by which gluten exerts its effect is not understood, nor has it been

established that this substance is able to initiate celiac disease de novo. When the ill-ness has already developed, the adverse

role of gluten can be demonstrated beyond

any doubt, at any rate in the great majority

of cases. The progress towards recovery can

be made to wax or wane by withholding or

giving gluten.

The fact that so few children who receive

wheat in their diet develop the disease sug-gests that one or more predeterminng fac-tors must be present. In this respect the

probability of an inherited tendency has

already been pointed out; but it seems

likely that other influences may also be

operative, for the clinical history often

in-dicates that gluten has been tolerated quite satisfactorily for several months and some-times for years before the disease has ap-peared. In some children, an acute infection seems to have been the activating trigger;

in some the disease has dated from the time of removal from home to a residential insti-tution; in others the onset has been so in-sidious as to provide no clue to an initiating event. It may be that the final eruption of

the disease can be set off by a variety of fuses.

There is as yet no evidence to indicate

that gluten intolerance is attributable to a

state of allergy, and therefore this term is

better avoided. Children with celiac disease

show no particular tendency towards other

well-known allergic phenomena, nor is there

an eosinophilia. Skin tests performed with gluten, using both scratch and intradermal

techniques, have been uniformly negative in my hands, and Alvey et al.23 have had the

same experience.

Meanwhile the partition of gluten has

carried our knowledge further. Gluten con-sists of two proteins, glutenin and gliadin,

and it is generally thought that the harmful factor resides mainly in the gliadin fraction. Incidentally oat flour also contains a gliadin,

which differs a little from wheat gliadin by

possessing a higher content of cystine, and

Dicke2’ and his co-workers have considered oat flour to be also harmful to children with

celiac disease. This has not been the gen-eral experience in Britain. Investigation of

this point in six of our cases showed that

the addition of 1 or 2 ounces of oat flour daily to an otherwise gluten-free diet did not affect the level of fat absorption, which remained at 91%.

By a series of skillful analyses carried

out in Professor Frazer’s laboratory at

Birmingham,22 it has been shown that chil-dren with celiac disease and normal chil-dren digest gluten equally efficiently. After fractionation of the enzymic hydrolysate

obtained from gluten, it was shown that a water-soluble peptide fraction possessed the same harmful properties as the original gluten, but further digestion of this

frac-tion with an extract of pig’s intestinal mucosa caused the toxic effects to disap-pear. These investigations offer a link with

the demonstration by Weijers and van de

Kamer24 that in children with celiac

dis-ease a meal of gliadin is followed by a much

higher rise in the amount of bound-gluta-mine in the blood than takes place in nor-mal children (averaging 100% in celiac

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136

a control group), although pure glutamine does not provoke any symptoms.

At this stage it seemed possible that

determining the rise of glutamine in the

blood following the administration of gli-adin might offer a positive laboratory method of confirming the diagnosis. Alvey

et al.,’ while finding that gliadin

pro-duced a rise in blood-glutamine, were led

to conclude that the test vas IR)t to be

relied upon. This question has also been

investigated on 40 cases at the Hospital for Sick Children in London; a full report is in

course of preparation, but it can be stated

here that although the average rise of

glu-tamine in the blood after giving gliadin was

higher in celiac disease than in a control group, this was not as marked as the Dutch workers had reported, and the scatter was too wide to make the test of diagnostic

value. In one typical and severe case in a

boy of 2 years, who responded well to a gluten-free diet as indicated by an improve-ment in fat absorption from 73% to 92%, the gliadin test gave a rise of blood-glutamine as little as 3% (Fig. 1).

The position has been reached where it

would seem that the effect of gluten is not

dependent upon the whole protein

mole-cule, but is attributable to the absorption of

a glutamine-containing peptide formed dur-ing the digestion of gluten. It has been sug-gested that the absorption of this peptide

may depend upon a defective enzymic

ac-tion within the intestinal cells.

Hitherto it has been generally accepted

that all the manifestations of celiac disease

arise from malabsorption. If in fact the

circulation contains a noxious peptide, this

may exert a toxic effect upon the nervous

FIG. 1. Child with celiac disease described in text (left, June 29, 1957, before

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137

system and on the mechanisms that control

growth, and indeed on other parts of the

body. In this way one could account

di-rectly for some of the symptomatology,

in-stead of the entire picture being due to

either general or specific starvation.

Whilst it has seemed unnecessary in this

lecture to catalogue all the well-known symptoms and complications of celiac

dis-ease, in the light of our knowledge of gluten,

a re-grouping of them under three headings may have certain advantages. The first

group comprises those referable to the ali-mentary system, such as diarrhea, typical

stools, abdominal distension, loss of weight,

and perhaps anemia. The second group

in-eludes the psychologic disturbances,

char-acterized by depression, contrariness and perhaps anorexia. The third group is con-cerned with the interference with growth. The symptoms in the first group may well be directly due to malabsorption; whereas

it is conceivable that those of the two latter groups may be caused by a circulating

pep-tide, and therefore may be said to exist in their own right, independent of malabsorp-tion. Further, although the disease is not

likely to be misdiagnosed when the

au-mentary symptoms are presented to us,

there may be occasions when the psycho-logic disturbances or the interference with growth are the outstanding features. Their

relation to celiac disease might then be

easily overlooked.

With regard to the emotional disorders, we may recall that Daynes25 has recently drawn attention to children brought to him

because of such behavior problems as

naughtiness, negativism, spitefulness, and

sometimes momentary blank turns, coming

on within a week or two of some acute in-fection, and which were sometimes

accom-panied by abdominal distention or pale

stools. His description also included adults

complaining of headache, insomnia or

de-pression. Left to themselves these patients,

whether children or adults, may recover

spontaneously in a few months, but do so

with promptitude as soon as gluten is

re-moved from the diet, though they may

re-lapse if a normal diet is resumed too

quickly. Are we not seeing here the psycho-logic manifestations of gluten-intolerance

playing the predominant clinical role?

A case reported by Frazer22 illustrates that failure to grow may be the presenting,

and virtually isolated, symptom. The

pa-tient, a girl, was noticed to be failing in her growth when she was 8 years of age.

Men-tally she was normal, and apart from an

occasional loose stool there had been no

alimentary symptoms. Investigation when

she was 13 years old, and only 127 cm in

height, showed no endocrine abnormality, but fat absorption was reduced to 82%. On

removal of gluten from the diet, the fat

absorption became normal and she grew

rapidly.

Were the interference with growth in

celiac disease due solely to malabsorption,

we might expect it to be made good as the

acute symptoms subside, and a more varied

diet becomes tolerated. The fact is that growth often remains unsatisfactory,

in-deed stunting of growth has been described

as a legacy of the disease by many writers.

Nor is a lag in growth the only stigma that

may remain. Gerrard’s2 follow-up study of 32 children treated by the older methods

led to the conclusion that not one had com-pletely recovered; a liability to diarrhea

and a significant reduction in height and

weight were the most common failings,

while in the glucose tolerance test a normal

rise was attained in only six of them. A late follow-up of 30 cases of celiac disease at

the Hospital of Sick Children in London7 showed that a flat curve in the glucose

tol-erance test was still present in 20. All these findings indicate that survival

after the acute phase is by no means

synonymous with a return to normal, and

we may do well to remind ourselves of the description given many years ago to these

children by Sir James Goodhart,28 to the

effect that they had been made “safe, but not sound.”

However, the observation has frequently

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tol-RESULTS OF GLUTEN FREE DIET

:

95 CASES

1

ON RETURN TO GLUTEN

RMAL PROGRESS

CASES.

OF THE 72 CASES 28 WERE

INHERENTLY SMALL CHILDREN.

RELAPSE IN 23 CASES.

OF THE 23 CASES VI SHOWED RETURN

OF COELIAC SYMPTOMS.

OF THE 23 CASES 12 SHOWED RETARDATION OF GROWTH ONLY.

erance test tends to become more

nor-Illal, :;u mu that this is accompanied by

illlprovelllen t ill the chylomicron curve,i 1

ail(1 by a return towards normal of tile radiographic 11liet1rt1ice of tile small

in-testine. At such times the small liver may

also return to a iire normal size.

These varying statements concerning

prognosis may seem at first sight to be

con-tradictory, but surely the story they tell is

that celiac disease does not easily let go its

hold, and that although improvement is

demonstrable so long as treatment is

care-fully controlled, there is a decided tendency for relapse to take place when the patient is later allowed to fend for himself. In this

ililase the illness may not be so likely to

endanger life, but laboratory tests

fre-quently indicate that real recovery has not come about. This is confirmed by the

Ii-ability to persistent interference with

growth and the possible re-emergence of

symptoms in adult life.

Under these circumstances the question of the length of treatment is clearly one of

importance. In an attempt to find the

an-swer, since 1952 a follow-up clinic for

chil-dren with celiac disease, treated on a

gluten-free diet, has been established at the Hospital for Sick Children, London.

Particular attention has been given to growth, as it was thought that any

ten-dency to relapse would be reflected in a

failing-off of the rate of growth. Each child

has his own height and weight chart on

which these measurements are regularly

recorded. In this way the gradient of

growth, and the effect of restoring gluten

to the diet, can be closely watched.

In terms of averages, our studies have indicated the following:

1) Before giving a gluten-free diet the

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40’

30

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T,f C1 cCK C,lOPF4 (rAT OMONfl sTr (INflON w

2 3 4 5 6 7 8 9 0 II 2

FIG. 3. In this child a gluten-free diet from 1 to 33 years of age gave an accelerated rate of growth, and satisfactory growth was maintained during the subsequent 4 years with a normal diet.

(In this and the following figures the upper line records height, the lower, weight. The broken line indicates the period on a gluten-free diet. The continuous line indicates a normal diet.)

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children were below their expected height and weight.

2) During the first 6 months of treatment,

height increased at a rate of some 30% above

the normal rate, and weight at a rate of

some 300% above the normal.

3) When treatment continued beyond 6

months, the rate at which height was gained

tended to persist, but weight, which by

then was catching up to normal, dropped to a rate of gain about 10% above the normal.

4) On restoring gluten to the diet, the

average

rate of growth became slightly less

than that of normal children. Statements of

averages can however be misleading, for

some of the children with celiac disease

when given a normal diet grew at a

nor-mal rate, while others slowed down

con-siderably. This latter group were therefore

restored to a gluten-free diet, and again

their rate of growth accelerated to surpass that of normal children.

Our most recent analysis was made in

January, 1958. There were at that time 95

children attending the clinic, all of whom had experienced a gluten-free diet. Of these,

44 continued to grow satisfactorily when

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140

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4(

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Tf NOPITAL FOQ CK CMIIDP(N GREAT OMON9 STREE ONDON W C I.

FIG. 4. This child did hot begin a gluten-free diet until 83 years of age. 11cr growth had previously been unsatisfactory. During 2 years of gluten-free diet her rate of growth improved, and this WaS maintained

when a normal diet was subsequently resumed.

gluten-free treatment having varied

be-tween 1 and 3 years. A further 28 children,

who were persistently more than one stand-ard deviation below the average

measure-ments appropriate to their age, were given

a second course of treatment for not less than a year, but their rate of growth did not

accelerate. After measuring their parents it was concluded that their small stature was inherent to them, for the parents were small people, their fathers averaging 66% inches in height, their mothers 62 inches.

The remaining 23 children underwent a

relapse when gluten was restored to their diet. In 11 of these, the relapse involved a

return of all the typical symptoms; in some

this occurred at once, in others not until several months had elapsed, and it was

then often provoked by some acute

infec-tion. In the other 12, the only evidence of

relapse consisted of a definite decline in their rate of growth, which would have

been very easily overlooked had

growth-charts not been niaintained. All 23 children

quickly improved when gluten was again taken out of their diet, but when a year or

so later this protein was restored, only 7 of

them continued to do well, in 8 others it is as

yet too soon to form a judgment, the

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141

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Tc wO5PTAL FO SICKC’IILDP(N . GREAT ORMOND STR(ET #{149}LONDON W C I

FIG. 5. This child grew satisfactorily from 23 to 6L years of age while receiving a gluten-free diet. During the next 2 years, with a normal diet, the rate of growth fell away, but improved when gluten was again

removed fronl the diet.

are once again receiving a gluten-free diet,

which will be continued until puberty

(Figs. 2-7).

It has been suggested that children with

celiac disease ought to receive a

gluten-free diet until they reach maturity. If the

disease can reappear in adult life, it might equally well be thought that the diet should

persist much longer. Our studies do not su)port sucil views, for roughly three out

of four of the children who responded to

a gluten-free diet eventually tolerated

gluten satisfactorily and continued to grow

at a normal speed. The difficulty lies in

foretelling how any individual child is

likely to respond to a return to gluten, for

there is no laboratory test that can be

applied. It would seem that the answer to

the question of how long a gluten-free diet

should be maintained cannot be given in

terms of months or years. It is clearly

neces-sary to maintain a most careful observation

of a child’s progress for several years after

tile restoration of a normal diet. This is

greatly facilitated by employing some form

of growth chart, bearing in mind that a

slowing down of growth may be the only

evidence to indicate that gluten intolerance is still present.

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to-DC HOSPVTAL FO SICK CHUOR(N GAT ORMOND STET LONDON w C I

61

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I-FIG. 6. Beginning at 15 months of age, a 2-year period with a gluten-free diet was accompanied by a satisfactory rate of growth, but growth ceased during tile subsequent year with a normal diet. Gluten

was therefore removed again from the diet for a further 21 months with improvement in the rate of growth, and this improvement is now being maintained with a normal diet.

wards gluten offers a complete explanation

of celiac disease. Gerrard et ai.32 have re-ported two patients with celiac disease

whose symptoms had dated from the

neo-natal period, before tiley had received any

gluten, and who did not respond to a

gluten-free diet. One of these was shown

later to he deficient in bile-salt production.

Chaptal et have recently given an

ac-count of an infant whose illness began at 14 days of age, and in whom improvement

eventually came about only when

cow’s-milk protein, as well as wheat and oat

protein, was avoided. Even then growth

remained so defective that intolerance to

J.

F., and Allen, F. H., Jr. : Clinical studies of vitamin A in infants and in children. Am.

J.

Dis. Child., 59:1167, 1940.

2. May, C. D., McCreary,

J.

F., and Blackfan, K. D. : Notes concerning the cause and treatment of celiac disease.

J.

Pediat., 21:289, 1942.

3. Gee, S. : On the coeliac affection. St. Barth. Hosp. Rep., 24:17, 1888.

4. Still, G. F. : On celiac disease. Lancet, 2: 163, 1918.

5. Boyer, P. H., and Andersen, D. H. : Celiac disease: genetic study. Am.

J.

Dis. Child., 91:131, 1956.

6. Ebbs,

J.

H., Thompson, M., and Stein,

w.

0. : Etiologic factors in celiac dis-ease. Am.

J.

Dis. Child., 79:936, 1950. 7. Sakula,

J.,

and Shiner, M. : Coeliac disease

with atrophy of the small-intestine mu-cosa. Lancet, 2:876, 1957.

8. Frazer, A. C., French,

J.

M., and Thomp-son, M. D. : Radiographic studies show-ing induction of segmentation pattern in small intestine in normal human subjects. Brit.

J.

Radiol., 22: 123, 1949.

9. Howland,

J.

: Prolonged intolerance to carbohydrates. Tr. Am. Pediat. Soc., 33:

11, 1921.

10. Parsons, L. G. : Celiac disease: Rachford Memorial Lecture. Am.

J.

Dis. Child.,

43:1293, 1932.

11. Macrae, 0., and Morris, N.: Metabolism studies in celiac disease. Arch. Dis. Childhood, 6:75, 1931.

12. Holt, L. E., Jr. : Celiac disease-what is it?

J.

Pediat., 46:369, 1955.

13. Sheldon, W. : Celiac disease; relation be-tween dietary starch and fat absorption.

Arch. Dis. Childhood, 24:81, 1949. 14. Lowe, C. U., and May, C. D. : Metabolic

studies in patients with intolerance to

complex carbohydrates. Am.

J.

Dis.

Child., 81:81, 1951.

15. Dicke, W. K. : Celiac disease: a study of the damaging effect of some cereals, es-pecially wheat, caused by a factor out-side of their starch, on the fat absorp-tioii of children with celiac disease. Zu-rich Internat. Cong. Paediat., 1950, p. 117.

16. Weijers, H. A., and van de Kamer,

J.

H.: The probable cause of excretion of satu-rated fatty acid in celiac disease. Ibid.,

p. 118.

17. Anderson, C. M., et al.: Coeliac disease: gastrointestinal studies and effect of dietary wheat flour. Lancet, 1:836, 1952.

18. Sheldon, W., and Lawson, D. : Manage-ment of celiac disease. Lancet, 2:902, 1952.

19. Hardwick, C. : Prognosis in celiac disease. Arch. Dis. Childhood, 14:279, 1939. 20. Sheldon, W. : Celiac disease. Postgrad.

Med., 15:79, 1954.

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ill cases of celiac disease. Acta paediat., 42:34, 1953.

22. Frazer, A. C. : On the growth defect in celiac disease. Proc. Roy. Soc. Med., 49:

1009, 1956.

23. Alvev, C., Anderson, C. M., and Freeman,

M. : Wheat gluten and coeliac disease. Arch. Dis. Childhood, 32:434, 1957. 24. van de Kamer,

J.

H., and Weijers, H. A.:

Celiac disease; some experiments on cause of harmful effect of wheat gliadin

(

preliminary communication). Acta pae-diat., 44:536, 1955.

25. Davnes, G. : Bread and tears. Naughtiness, depression and fits due to wheat sensi-tivitv. Proc. Roy. Soc. Med., 49:391, 1956.

26. Gerrard,

J.

W., Ross, C. A. C., Astley, R., French,

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M., and Smeilie,

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M. : Celiac disease: is there natural recover? Quart.

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Med., 24:23, 1955.

27. Sheldon, W. : Coeliac disease. Lancet, 2: 1097, 1955.

28. Goodhart,

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: Quoted by Still.

29. May, C. D., McCreary,

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F., and Black-fan, K. D. : Notes concerning cause and

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21:289, 1942.

30. Sheldon, W., and MacMahon, A. : Studies in celiac disease : glucose absorption. Arch. Dis. Childhood, 26:446, 1951. 31. Sheldon, W., and MacMahon, A. : Studies

in celiac disease; fat absorption. Arch.

Dis. Childhood, 24:245, 1949.

32. Gerrard,

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W., Ross, C. A. C., and Smellie,

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M. : Celiac disease; results of late treatment with gluten-free wheat diet. Lancet, 1:587, 1955.

33. Chaptal,

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et al.: Maladie coeliaque par intolerance

a

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34. Emery,

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ANNUAL REVIEW OF MEDICINE, Vol. 9,

edited by David Rytand and William P.

Creger. Palo Alto, California, Annual

Re-views, Inc., 1958, 530 pp., $7.00.

It is difficult to prepare a revealing review of

a review. The reputation of the entire series

of Annual Reviews of basic sciences and

clini-cal medicine hardly calls for elaboration by detailed comment on each volume as it

ap-pears. Suffice it to say that here in the present volume one finds once again a superior collec-tion of contributions written by authoritative

illdividuals on a wide variety of topics of

cur-rent interest. The pediatrician will find a

com-petent section on pediatrics by Harold K.

Faber and associates in which they were

obliged to cover the many developments in this major branch of medicine in 17 pages,

including a biblography of 150 papers.

One of the most helpful sections, which was included in some of the recent issues of the

Annual Review of Medicine, unfortunately has

not been included in the 1958 issue, namely an annotated list of review articles which had appeared in the literature of the world during the preceding year. It may be that the editors believe this has been supplanted by the

Bibli-ography of Medical Reviews from the world

literature, which has begun a regular annual appearance and is compiled by the National Library of Medicine (available from the Su-perintendents of Documents, U.S. Govern-ment Printing Office, Washington 25, D.C.). The latter list will be less useful to those who do not have an extensive medical library read-ily available, and who would not be able to

examine review articles on a given topic to

select one most suitable for the purpose in hand. The annotations on review articles

pre-viously published in the Annual Review of

Medicine gave the general reader the benefit

of an authoritative and critical appraisal of the coverage of review articles on major topics.

(15)

1959;23;132

Pediatrics

Wilfrid Sheldon

CELIAC DISEASE: Kenneth D. Blackfan Memorial Lecture

Services

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(16)

CELIAC DISEASE

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1959;23;132

Pediatrics

Wilfrid Sheldon

CELIAC DISEASE: Kenneth D. Blackfan Memorial Lecture

Services

Updated Information &

http://pediatrics.aappublications.org/content/23/1/132

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or in its

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

1959;23;132

Pediatrics

Wilfrid Sheldon

CELIAC DISEASE: Kenneth D. Blackfan Memorial Lecture

http://pediatrics.aappublications.org/content/23/1/132

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.