CLINICAL
CONFERENCE
The
Celiac
Syndrome
By Murray Davidson, M.D.
Department of Pediatrics, New York Hoital-Cornell Medical Center
This presentation was part of a Clinical Confereice conducted under the chairmanship of Dr. Samuel
Z. Levine at the New York Hospital, New York City, for the Annual Meeting of the Academy, October
11, 1956.
508
PEDIAmIcs, March 1958
DR. LEVINE : The patient to be presented is
an infant who had chronic diarrhea. Studies
performed on this patient by Dr. Murray
Davidson, Assistant Professor of Clinical
Pedi-atrics, suggest that there are multiple factors
involved in the production of the celiac
syn-drome. Dr. Davidson will discuss the patient’s
illness and observations made.
DR. MURRAY DAVIDSON: To many
pediatri-cians the diagnosis of celiac syndrome means
difficulty in absorption of nutrients. According
to this concept the diagnosis cannot be made
unless there is evidence of excessive stool loss
of ingested material. An important contribution
to our understanding of the condition has been
made by the Dutch and British workers who
have demonstrated steatorrhea related to the
ingestion of gluten in patients with the celiac syndrome.
On the other hand, to some, celiac syndrome
merely implies a state of chronic diarrhea.
Thus, some cases of diarrhea related to milk
ingestion have been called celiac syndrome
because of chronicity of symptoms. To the best
of our knowledge there are no published
re-ports of such patients in whom detailed study
has revealed evidence of malabsorption or a
relationship to a specific protein in milk as
has been shown in the studies with gluten.
In this paper it is our intention first to report
a patient who fulfilled the criteria for celiac
syndrome upon ingestion of a specific milk
pro-tein, and then to examine the current cI
issifica-tion of the conditions which make up the celiac
syndrome.
D.B., a 5-week-old infant, was admitted to
the New York Hospital with a history of severe
and chronic diarrhea from birth, manifested
while receiving evaporated and skim milk
formulae as well as Nutramigen#{174}.
Stool cultures failed to reveal any pathogens.
Study of the urinary tract, gastrointestinal tract
and adrenal function revealed no cause for
diarrhea. Examination of the sweat and
du-odenal fluid ruled out cystic fibrosis of the
pancreas.
When fed a formula prepared from Sobee#{174}
the infant responded with cessation of diarrhea
and demonstrated a weight gain for the first
time since birth. Accordingly, various diets
were fed in approximately isocaloric amounts,
and 48-hour stool collections were examined
for fat according to the method of Wejers and
Van der Kamen, nitrogen by the Kjeldahl
tech-nique, and an estimate was made of the fluid
content. The intake of each diet ranged from
950 to 1200 ml daily and the dietary protein
from a low of 18 gin to a high of 41 gm; the
fat intake was held more constant, fluctuating
only between 29 and 33 gm/day.
While receiving Nutramigen#{174} the patient’s
total stool output per 24 hours weighed over
150 gm and the stool fat content was 13 gin.
When the formula consisted of whole milk the
total stool output per 24 hours increased in
excess of 200 gin and the stool fat content to
46 gin. However, with Sobee#{174} feedings the
total stool output fell to about 75 gm/day
and the fat content of 5 gm/day.
Since the only difference between Sobee#{174}and
Nutramigen#{174} is the source of protein, the
pro-tein in the latter being derived from hydrolyzed
Casee#{174}, the patient was fed the same Sobee#{174}
feeding as before with the addition of 9 gin
of Casec#{174}per day, or one-third the amount
which would furnish the prot&n derivatives
contained in the Nutramigen#{174} formula. With
this feeding the 24-hour stool output rose to
approximately 150 gin and the stool fat
con-tent to 17 gin. During two subsequent control
collections, one composed of Sobee#{174} feedings,
the other a formula containing fibrinogen
hydrolysate in amounts comparable to those
present in Nutramigen#{174}, the stools returned to
normal.
AMERICAN ACADEMY OF PEDIATRICS-PROCEEDINGS 509
purified casein preparation with a refeeding of
Casec#{174}, both providing 9 gin of casein per day,
revealed normal stool values while receiving
the purified casein preparation and abnormal
values similar to those previously obtained
with Casec#{174}feedings.
At this point it appeared that the steatorrhea
was not due to casein but to an impurity of
Casec#{174},probably a fraction of whey protein.
Essenamine#{174}, a purified whey powder, 250 mg,
was therefore added to Sobee#{174}.This represents
approximately one-third the amount contained
in a quart of milk. While receiving this diet
the patient’s stool output rose to approximately
100 gin per 24 hours. This is not a dramatic
increase but the stool fat content of 12 gin
per 24 hours during this period represented
definite steatorrhea.
Two fractions of whey protein, crystalline
alpha lactalbumin and beta lactoglobulin, have
been prepared. These were fed in very small
amounts. A formula of Sobee#{174}with 3 mg of
lactalbumin (or 1/20 of the normal daily
in-take) resulted in a total stool output per 24
hours of 80 gin and stool fat content only
5gm.
Next a study was made of the stools during
which only 8 mg/day (or 1/100 the amount
contained in a quart of milk) of beta
lacto-globulin was added to the patient’s daily
ra-tion of Sobee#{174}.Even with this minute amount
of beta lactoglobulin in the diet the 24-hour
stool output rose to over 150 gin, and the
24-hour fat content to 15 gin. These findings were
confirmed in a repeat study. A control collection
using Sobee#{174} alone was within the normal
range, and a collection using Sobee#{174}plus 4 gin
daily of gluten-enriched flour produced no
diar-rhea or steatorrhea.
At no time did the subject lose excessive
nitrogen. The total stool nitrogen never
ex-ceeded 1 gin/day.
Clinical demonstration of the exquisiteness
of the child’s sensitivity is illustrated by his
weight curve. On arrival at New York Hospital
at 5 weeks of age the child weighed less than
at birth. Although diarrhea continued during
the period of Nutramigen#{174} feedings there was
some weight gain, and then while receiving
evaporated milk and whole milk a loss of
weight again occurred. After starting Sobee#{174},
there was a general tendency toward consistent
weight gain for the rest of the patient’s stay.
However, whenever the child was fed one of
the foods producing steatorrhea, there was
an immediate cessation of this tendency to
gain. Often there was an actual loss of weight,
even when these foods were fed in small
amounts for only a few days.
The Dutch workers have indicated that the
coefficient or percentage of ingested fat which
is absorbed is a more valid approach to the
problem of steatorrhea than simple
measure-ment of stool fat. In our laboratory as in theirs,
the lowest values obtained for absorption in the
normal individual range from 80 to 85% of the
ingested fat. We have been interested also in
a measure of the wetness or fluidity of the
stool as an expression of the magnitude of
diarrhea. Therefore, a weighed aliquot of the
fresh stool is dried and reweighed. The per
cent or coefficient of wetness is calculated in
the same manner as is the coefficient of fat
absorption. In 30 normal controls studied, this
value did not exceed 80%.
A decreased per cent fat absorption (that
is, values below 80%), occurred when this child
received Nutrainigen#{174}, whole milk,
Casee#{174},Es-senamine#{174}, and lactoglobulin. However, only
when diets of Nutramigen#{174} and whole milk
were fed, during which there was marked
diarrhea, were there very high coefficients of
wetness. As the quantity of substances to which
the child was intolerant was lowered in the
diet, the degree of wetness returned to
approxi-mately normal. This was also noted during
Casec#{174} feedings. Formulas containing small
amounts of whey protein and lactoglobulin
re-suited in normal values for the coefficient of
wetness. This illustrates the fallacy of relying
entirely on the clinical picture for the diagnosis
of celiac disease and therefore implying that
there is malabsorption. It is possible to have
steatorrhea and poor fat absorption with little
or no abnormality in the number, frequency
and size of stools. The reverse is also true.
The diagnosis of celiac disease should be made
only after careful stool examinations.
One of the problems raised here is the
ex-planation of the mechanism underlying the
de-feet. Is it allergy? Certainly if very small
quantities of protein can cause such a major
upheaval in the absorptive mechanism, allergy
should be considered. On the other hand, this
might be a specific enzymatic defect. Perhaps
the fact that steatorrhea occurred with
Nutra-migen#{174}, which is a digest, indicates that it is
product resulting from its digestion, that is at
fault.
In an effort to answer these questions further
studies were done:
Intracutaneous skin tests using .04 ml of a
1: 1000 solution of three different milk proteins
were performed. With Casein#{174}there was a mild
transitory reaction which represents a
non-specific effect. There was no reaction to
lactal-bumin. An area of reddening 7 mm in diameter
and persisting 45 minutes developed with
lactoglobulin. The child was fed lactoglobulin
in small amounts the day following the skin
test; 6 hours after taking the first formula the
site in which the skin test with lactoglobulin
had been performed the previous day became
reddened and a wheal measuring 1.5 cm in
diameter developed. This delayed reaction
per-sisted for the next 36 hours while the feedings
of lactoglobulin were continued and slowly
faded thereafter.
However, Dr. Bret Rather tried
unsuccess-fully to demonstrate antibodies in the patient’s
serum by means of passive immunization in adult volunteers.
After an interval of 5 months, the child’s diet
was again altered during four study periods. In
each of these, he received what is a normal full
diet for him-that is, a cow’s-milk-free diet
con-taining Sobee#{174},meat, cereals, vegetables and
fruits. The diet was supplemented during one
period with 8 mg/day of beta lactoglobulin as
before, and during two periods with the
prod-ucts of digestion for 3 days of like amounts of
beta lactoglobulin. The first was digested by
pancreatin, the second digested by acid. The
fourth study was a control period using the
basic diet only.
There was a clear-cut increase in 24-hour
stool weight and fat content over the control
period following the ingestion of undigested
lactoglobulin. There was also an apparent
tendency toward increased stool weight and
fat excretion when the two digests were
fed.
When the results of these studies were
trans-lated into coefficients of fat absorption and
wet-ness, it was noted that the patient had normal
fat absorption and a normal, relatively dry
stool while receiving the regular diet without
supplements. Because of the small amounts
of upsetting material which were fed during
all of the periods, the coefficients of wetness
displayed the normal nondiarrheal pattern and
were below 80%. The most significant finding
however was that, not only did the unmodified lactoglobulin feeding result in an abnormal
fat absorption, but even with the digests, the
absorption of fat was abnormal. Whether this
is due to incomplete digestion of lactoglobulin
in our preparations, or whether this illustrates
that the fundamental defect is due to a peptide
or other breakdown product of beta
lacto-globulin, only further studies will tell.
At this point I would like to present the
child, who is now 1 year of age. He has been
fed throughout this year on a diet normal in
all respects except that it is a milk-free diet.
The child now weighs approximately 9 kg,
and appears to be in good health. His appetite
is good, and he has four semi-formed stools
per day.
QUESTION: Is there any history of allergy?
DR. DAVIDSON : There is no history of allergy
in the immediate family. However, a cousin
of this child was also sensitive to milk, and is
now about 14 years old.
In summary, then, we can say that this
patient represents a case of celiac disease
be-ginning at birth, apparently due to the
inges-tion of beta lactoglobulin in cow’s milk. It has
been demonstrated that steatorrhea may occur
without excessively watery stools and therefore
only by careful balance studies should the
diag-nosis of celiac disease be made. In this patient
there is tenuous evidence favoring both the
concept of allergy and of a breakdown product
of beta lactoglobulin as the cause. Further
studies may provide the answer.
It might be profitable to review the current
classification of celiac syndrome, in the light
of some of the newer reports. The classification
is outlined on the next page.
The clinical picture termed celiac syndrome
may be manifested by an all-inclusive group
of patients in whom chronic diarrhea is a
coin-mon symptom. They should be divided into
two general categories : Those patients with
evidence of malabsorption, that is, steatorrhea
with or without loss of other nutrients, and
those with nonspecific diarrhea associated
pri-manly with water loss but with little evidence
of malabsorption or malnutrition.
In the first group are patients with enzyme
deficiencies as found in cystic fibrosis of the
pancreas. Included also are patients with
lymphatic obstruction in which there is
L -Starch intolerance
(Starch “loss”)
AMERICAN ACADEMY OF PEDIATRICS-PROCEEDINGS 511
CELIAC SYNDROME
MALABSORPTION SYNDROME
(
Steatorrhea)1. Enzymatic defect
2. Lymphatic obstruction
3. Anatomic defects
4. ? Adrenal insufficiency
5. Specific protein intolerance 6. Idiopathic steatorrhea
long-chain fatty acids usually absorbed by this
route. This has been reported in giardiasis and
tuberculosis of the small bowel and presumably
can occur with other granulomatous or
inflain-matory lesions of this area. Patients having
cer-tam anatomic defects such as fistulous tracts,
reduplications, malrotations and stenoses, and
operative removal of segments of the small
bowel will manifest disturbed motility and
absorption. Some patients with the syndrome of
malabsorption may have a questionable
rela-tionship to the endocrine axis, as suggested by
animal data and the clinical response to adrenal
corticoids.
Finally we must include in the
malabsorp-tion syndrome the specific protein intolerances,
as in the case presented and exemplified in the
Dutch reports with gluten. Whether the
addi-tion of “idiopathic steatorrhea” is justified, or
whether these patients will ultimately be
shown to have a sensitivity to protein, only
time will tell. For the present it is probably
wise to include such a classification.
I personally prefer to consider patients with
specific protein intolerance and idiopathic
steatorrhea as having celiac disease; that is,
these patients make up a specific part of the
more diffuse celiac syndrome. Others may not
agree with this terminology.
The second group of patients, those having
primary water loss with chronic nonspecific
diarrhea, is a much larger group in our
experi-ence and represents most of the patients
diag-nosed clinically as having celiac syndrome. It
is our belief that the majority of them have
hyperirritability of the large bowel with
dis-CmioNlc NONSPECIFIC DIARRHEA
(Primary Water Loss)
1. Irritable colon syndrome a) Emotional
b) Infectious c) Constitutional
2. Large bowel allergy
3. Anatomic defects
ordered motility and resultant episodes of
diarrhea. Furthermore we believe that they
represent a familio-hereditary group and are
constitutionally disposed to these symptoms for as yet undiscovered reasons. Recently
Shwach-man and Prugh have indicated that the
symp-toms of some of these patients may be based
on emotional factors. Cohlan has suggested
that they may suffer from a chronic low grade
infectious or inflammatory process amenable
to treatment with Diodoquin#{174}.
In this group must also be included the large
bowel counterparts of small bowel
disturb-ances. Either on the basis of allergy or
ana-toinic defects, hypermotility of the large bowel
may result in lack of water absorption with
subsequent diarrhea.
Finally the problem of starch intolerance as
manifested by the demonstration of undigested
starch in the stool must be considered. There
is no counterpart of the careful chemical
analy-sis for fat which can be applied to stool starch.
Amylorrhea is determined by the finding of
starch granules microscopically. If, as
Ander-sen believes, this is evidence of starch
intoler-ance, then these patients belong in the group
having malabsorption syndrome. On the other
hand, it is our impression that they merely
represent cases of large bowel hypermotility.
If a child has frequent stools and there is not
enough time for bacterial digestion of the
starch which normally is delivered undigested
to the colon, then it will be found in the stool.
Therefore, this condition is shown at the
bot-torn of the chart with tentative connections to
