occult celiac disease: a common cause of short stature - GGH Journal

Vol. 5 No.2 June 1989
Asaria Ashkenazi, M.D.
Associate Professor of Pediatrics
Director, Department of
Pediatrics B
Kaplan Hospital, Rehovot
Affiliated with the Medical School
of the Hebrew University and
Hadassah
Jerusalem, Israel
Failure to thrive in association with
gastrointestinal (GI) symptoms is
common in children with active celiac
disease (CD). In two studies 1,2
of patients with GI symptoms due
to CD, 36% and 55% were below
the third centile for height, and
40% and 60% were below it forweight.
A small proportion (-5%)
of CD patients with short stature,
however, have no GI symptoms.
They are considered to have occult
CD, which is quite important in
the differential diagnosis of short
stature.
Although gliadin-toxic peptides
damage the intestinal mucosa in
genetically susceptible individuals,
the exact mechanism is not
completely understood.3-S Current
opinion favors the hypothesis that
the harmful effects of gluten are
mediated by immunologic processes.
Immunologic reactions
appear to playa part in the pathogenesis
of CD, but the distinct
mechanism-be it cellular immunity,
humoral immunity, or a combination
of the two-remains
elusive.6
Short Stature as the
Presenting Symptom of CD
Several investigators have reported
short stature as the only
manifestation in some cases of CD
(Table).7-11 In one cohort7 of 796
children and adolescents seen for
growth retardation, 14 had CD
(1.8%). Although the children with
CD had no current GI symptoms,
eight had a history of diarrhea during
Etiology and Pathogenesis
infancy. In another study, 34
of CD
patients with short stature of unde-
Wheat gluten, specifically its gliadin
fraction, is toxic to genetically
susceptible individuals. In recentstudies,
we demonstrated the In This Issue
toxic effects of purified gliadin derived
The Remarkable Catch-up
from peptides; it was ob-
Growth of American
tained from intestinal mucosa cultures
of CD patients ingesting a
normal gluten-containing diet. The
Slaves
Letters to the Editor
Editorial Comment
page 4
page 7
page 10
smallest toxic peptide had a molecular
mass of 6,129 daltons and
Abstracts ".".",."."..".., page 11
Meeting Calendar page 16
contained 53 amino acids.
termined origin, but no GI symptoms,
underwent jejunal biopsy for
exclusion of celiac disease.8 Eight
patients (24%) had subtotal or severe
partial villous atrophy; seven
of these patients showed signifi.,
cant increases in height and
weight velocity after switching to a
gluten-free diet.
In a group of 108 children with
short stature of undetermined etiology
referred to an endocrine clinic
in Italy, 9 (8%) had CD.9 All
patients with CD were diagnosed
by a biopsy of the small intestine,
and the specimen was obtained
via the oral route. The investigators
found that although no single
screening test or combination of
tests identified all of these patients,
an abnormal xylose test, the
presence of anti reticular and/or
antigliadin antibodies, and a history
of diarrhea in the first 2
years of life identified most cases
of CD. In a similar study,1O 87
children with short statlife (height
> 2 SO below the mean for age
and sex) underwent biopsy of the
small intestine after other causes
of growth retardation had been
ruled out. Although none had GI
symptoms, four (5%) had CD.
Another study, conducted in Israel,
described short stature as a
major manifestation of CD in older
children.11 In 11 of 23 (48%) patients
referred to a gastroenterologist
after an extensive negative
endocrine evaluation, CD was diagnosed
by small-bowel biopsy.
continued on page 2

Occult Celiac Disease
continued from page 1
No clinical or laboratory clues enabled
the investigators to differentiate
between the cases of short
stature due to occult CD and those
due to other causes. Equally unhelpful
in differential diagnosis
was the age at diagnosis, length of
follow-up prior to referral to the GIservice,
and degree of bone-age
retardation. Although abnormal
stool-fat excretion was found only
in children with CD, sensitivity waslow,
and abnormal results were
found in only four of nine patients
tested. However, testing for the
presence of microcytic anemia revealed
that all of the children with
CD, but none without the disease,
were anemic. A positive history of
past GI problems, particularly diarrhea,
during early childhood
also was very helpful.
The prevalence of CD is low in
some studies (1.8%,7 8%,9 and
5% 1°) but high in others (24%8 and
48%11). This disparity may indicate
that CD can be recognized
and treated in some areas of the
world at a younger age, when
the malabsorption symptoms are
more clear-cut and before severe
stunting of growth occurs; in other
regions, however, it tends to be
diagnosed later, when short stature
is the more obvious problem.
This varying prevalence may also
reflect a real disparity between the
incidence of CD and its mode of
presentation.
Is CD-Induced Short Stature
Occult?
Detecting occult CD as a cause of
short stature is a function of professional
alertness insofar as the
clinician considers this condition
in a differential diagnosis. Data in
the medical literature. as well as
from our own experience, show
that many CD patients with short
stature have a history of diarrhea at
an early age and/or have microcytic
anemia. Other diagnostic
clues that may indicate CD include
increased stool fat, antigliadin and
antiendomysial antibodies. and
low folate and serum ferritin
levels.3-S In a few cases, however,
there may be no clue to CD other
than abnormal intestinal mucosa
diagnosed by an orally obtained
jejunal biopsy.
Pathogenesis of Growth
Retardation
The cause of growth failure in children
with CD has been the focus of
many investigations. Initial studies
suggested secondary hypopituitarism
might be the basis for
the retarded growth.1, 12-14 Subsequent
assessments, however,
failed to substantiate growth hormone
(GH) deficiency in most
growth-impaired children with CD.
On continued investigation, it became
increasingly evident that a
gluten-free diet could reverse this
complication. This finding further
emphasized the importance of
adequate and appropriate nutrition
in maintaining normal linear
growth.
The effect of gluten ingestion on
the growth pattern of CD patients
is still unresolved. Is growth retardation
induced by the effect of
the disease on the general nutritional
status? That is, does malabsorption
lead to malnutrition,
which, in turn, leads to a decrease
in weight and failure to gain
height? Or, in addition, is there a
direct effect of gliadin peptides on
the GH-secreting apparatus, as
well as on other hormones affecting
growth, such as somatomedin?
GH and CD
Inadequate response of serum GH
levels to insulin stimulation was re-
ported by Hamilton in 1969 in one
of five CD patients examined. 1 We
have examined the plasma GH
levels in response to insulin stimulation
in CD patients on a normal
gluten diet, in patients on a glutenfree
diet, and in normal children
of comparable age who served
as controls (Figure).12 The CD
children showed a lower GH response,
as a group, than the normal
controls. Also, serum GH response
to insulin stimulation in the
CD group consuming a normal
gluten diet was significantly lower
than in the CD group on the glutenfree
diet. Similar results have been
reported in other studies.1,7,13,14
Somatomedin-C (Sm-C), a GHdependent
growth factor modulated
by nutrient status, is variable
in CD patients.1s-17 We were unable
to find a correlation between
serum Sm-C levels in CD children
and the diet consumed. As would
be expected, some CD patients
who had low Sm-C levels while on
the normal gluten diet had increased
levels while on a glutenfree
diet. On the other hand, other
patients had normal serum Sm-C
levels while consuming a normal
gluten diet. Data are accumulating
to suggest that Sm-C may be a
useful marker of nutritional adequacy
in patients with inflammatory
bowel disease 18,19 but not in
patients with CD.
Enhanced Enteric Losses and
Nutritional Dwarfism
Anyone or a combination ot the
nutritional alterations may lead to
nutritional dwarfing in CD patients.This
may occur even in patients

who have an increased body
weight/height ratio (i.e., short and
plump patients).
The basic defect in CD is destruction
of the intestinal epithelial
cell layer, with reactive production
of intestinal cells up to seven times
the normal rate. The net result is
flattening of the intestinal mucosa;
immature and damaged epithelial
cells cover the surface. This blunting
of the villi is instrumental in
decreasing the absorptive surface
of the intestine and producing
malabsorption and malnutrition.3-s
The nutritional status of these patients
is further impaired by the
defects in the intestinal epithelium
that cause protein-losing enteropathy,
and is aggravated by the
desquamation of the epithelial
cells and shedding of lymphocytes.
The resultant loss of protein,
DNA, and lymphocytes leads to
hypoproteinemia and lymphopenia.
CD patients also experience
intestinal loss of zinc. There
is a tendency toward lower serum
zinc levels in the CD patients. but
these levels are not low enough to
produce clinical symptoms.
Children with CD have impaired
iron balance as well. Serum ferritin
levels in CD patients are often sig-
nificantly lower than in controls,
and a gluten-free diet produces a
definite rise toward normal levels.
The low ferritin levels reflect impairment
of iron absorption, as well
as increased iron losses in the
desquamating epithelial cells and
lymphocytes. Additionally, the serum
folate levels are significantly
lower in the untreated CD patients
and may result from a decrease in
the folate absorption caused by
the impairment of the deconjugase
enzyme present in the brush border
of the intestinal epithelial cells.
This enzyme facilitates absorption
by splitting glutamic acid residues
from the folate heptaglutamate in
foods and reducing them to monoor
diglutamates. However, it is well
known that there is a sevenfold
increase of cell turnover and in
DNA synthesis in patients with CD.
This regenerative effort by the
crypt cells in active CD requires
folic acid, an essential component
of the enzymes involved in the synthesis
of DNA. Thus, there is a
decrease in folic acid absorption
that parallels an increase in folic
acid requirements for DNA synthesis
in patients with active CD.
The net result is decreased serum
folate levels.
3
Diagnosis of CD
Two factors are important to remember
when considering occult
CD in the differential diagnosis of
short stature: 1) Studies show an
increased incidence of CD among
children hospitalized for examination
of short stature; and 2) CD may
be present even in the absence of
GI symptoms. A small-bowel bi-opsy,
"the gold standard" for the
diagnosis of CD, should be performed
in all children examined for
short stature who show a decrease
in the body weight/height ratio,
have a history of diarrhea during
the first year of life, or present with
hematologic abnormalities such
as anemia.
Summary
CD is more common than idiopathic
GH deficiency as a cause of
short stature. Thus, it is important
to rule out this disease in children
in whom there is no endocrinologic
cause of short stature. CD should
be suspected in patients who 1)
fail to grow at normal rates and
have a bone age that is delayed,
particularly if by more than 4 years;
or 2) have a bone age below that
expected for height. Because abnormal
absorption may not be detected
by common tests even in
known CD patients, an intestinal
biopsy may be needed for diagnosis.
Confirmation of CD as the
cause of delayed growth should
come from documentation of
catch-up growth in weight and
height after institution of a glutenfree
diet, the only treatment"-now
available for CD.
The original work was supported by a grant
from DFG, West Germany.
Editor's comment-One of the
greatest enigmas in pediatrics today
is why celiac disease is so
prevalent in Europe and the Middle
East (Israel, for example) but
not in North America. There are
many descendants of Europeans
in North America, but the disease
is rare. Readers who have a tenable
theory, particularly one with
supporting data, are encouraged
to write to the editors of Growth,Genetics,
and Hormones.
continued on page 4

Occult Celiac Disease
continued from page 3
Even though celiac disease is
less frequent in our clinics than in
those of Europe, we must remain
alert to the possibility that any child
with short stature of unexplained
etiology may have celiac disease.
Robert M. Blizzard, M. D.
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