Selections from Current Literature Gluten-free diets, coeliac disease and associated disorders
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Family Practice Vol. 20, No. 5 © Oxford University Press 2003, all rights reserved. Printed in Great Britain
Doi: 10.1093/fampra/cmg520, available online at www.fampra.oupjournals.org
Selections from Current Literature
Gluten-free diets, coeliac disease and
associated disorders
Lorraine Danowski, Lauren Garguila Brand and
Josephine Connolly
Danowski L, Garguila Brand L and Connolly J. Gluten-free diets, coeliac disease and associated
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disorders. Family Practice 2003; 20: 607–611.
Introduction The endomysial antibody (EMA) test has become a
simple reliable screening tool. This test has enabled
Coeliac sprue is a life-long inflammatory condition of accurate determination of prevalence.5 Silent coeliac
the gastrointestinal tract that affects the small intestine disease has been found to be more frequent in patients
of genetically susceptible individuals. This condition is with type I diabetes mellitus than in controls. First-
a chronic malabsorptive disorder caused by exposure to degree relatives of diabetic patients also showed a higher
dietary gluten. Villous atrophy, a lowering of the villous incidence of coeliac disease. The higher prevalence of
height to crypt depth ratio, an increase in intraepithelial other autoimmune diseases in subjects with both coeliac
lymphocytes and extensive surface cell damage and disease and type I diabetes may be related to delayed
infiltration of the lamina propria with inflammatory cells diagnosis of coeliac disease.6 Evidence supports the fact
are characteristic of the disease.1 Prompt improvement that coeliac disease should be considered in cases of
of nutrient absorption and healing of the intestinal mucosa ‘unexplained’ female infertility and as a possible risk
is seen upon withdrawal of gluten from the diet.2 factor for an adverse pregnancy outcome.7
Dermatitis herpetiformis is considered an extrain-
testinal manifestation of coeliac sprue. This condition Martinelli P, Troncone R, Paparo F et al. Coeliac disease
presents as a pruritic, blistering rash. Treament involves and unfavourable outcome of pregnancy. Gut 2000; 46:
dapsone and a gluten-free diet, which, if strictly followed, 332–335.
may allow for withdrawal of the medication.1 In children, Coeliac disease has been connected with adverse out-
the onset of coeliac disease occurs within the first or come of pregnancy. The goal of this study was to estimate
third years of life after introduction of gluten into the the prevalence of untreated coeliac disease in women
diet. These children present with a classic syndrome attending the obstetric/gynaecological department of a
of chronic diarrhoea, failure to thrive and abdominal major city hospital, in an attempt to determine its effect
distention.3 Atypical coeliac disease is seen in older on the reproductive status of these women. Serum col-
children or adolescents, who display no overt features lections from 845 pregnant woman were screened for
of malabsorption. In addition to recurrent abdominal EMAs. Patients with positive results were offered a
pain, hypertransaminasaemia, stomatitis, arthralgia and small intestinal biopsy to confirm the diagnosis.
defects in dental enamel, children may also experience Twelve of 845 samples were positive. Three of these
depression, irritability or poor school performance.4 12 women had a diagnosis of coeliac disease from
Adult presentation is increasingly common and can childhood which was confirmed by biopsy. They did not
occur at any age. The prevalence varies widely in differ- report the disease on admission and had not received
ent countries. European studies show a prevalence rate treatment for 10–25 years. This was a first pregnancy
of between 1:152 and 1:300. In the USA, this condition for all three women, and two had a breech presentation
may affect 1:250.1 of the baby. None of the three reported gastrointestinal
symptoms or were underweight.
Nine patients without a history of coeliac disease who
had positive results underwent small intestine biopsy.
Received 7 May 2003; Accepted 19 May 2003. The pathologist was blinded to serum results. In all
Department of Family Medicine, State University of New York
at Stony Brook, Stony Brook, NY 11794-8461, USA. Corres- cases, severe to total villous atrophy, crypt hyperplasia
pondence to Lorraine Danowski; E-mail: ldanowski@notes. and lymphocyte infiltration were found. Of the newly
cc.sunysb.edu diagnosed patients, three babies died, one had a breech
607608 Family Practice—an international journal
presentation, one experienced pre-eclampsia, and pre- This article did not report the length of gestation at
mature deliveries were expected in two. An adverse neo- the time of diagnosis or when the gluten-free diet was
natal outcome occurred in seven of the newly diagnosed initiated for the 12 cases identified. Follow-up results
cases: five small for gestational age and three preterm were promising for a simple, inexpensive screening and
deliveries. Depressed haemoglobin was reported in four adherence to a gluten-free diet.
of the 12 newly diagnosed women with coeliac disease.
A control group was obtained by randomly selecting Abdulkarim A, Burgart L, See J, Murray J. Etiology
206 women with negative results from the coeliac of nonresponsive celiac disease: results of a systematic
screening. Age was similar in both groups, but menarche approach. Am J Gastroenterol 2002; 97: 2016–2021.
occurred later in the patients with coeliac disease. A Non-responsive coeliac disease (NCD) is a lack of
history of previous miscarriage was more common in response to a gluten-free diet (GFD) or recurrence of
coeliac patients than in controls. Two of the 206 controls symptoms in a patient despite adherence to the diet after
had a stillbirth and another two infants suffered from initial positive response to these restrictions. Clinical
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severe perinatal disease; no babies died after birth. improvement is usually seen within the first few weeks
Three out of the 13 babies born to women with coeliac of a GFD. Intestinal mucosa restoration may take up to
disease died during the first week of life. All 12 women 2 years. The goals of this study were to determine the
with coeliac disease went to delivery. The mean gestation aetiology of persistent and relapsing symptoms in
was similar in coeliac patients and controls, but 33% coeliac patients referred to a tertiary care centre for
terminated before the 37th week in coeliac patients evaluation of NCD and to characterize further those
versus 11.6% in controls. Breech presentation occurred patients identified as having true refractory sprue (RS).
in 25% of the coeliac patients and 1.4% in controls. NCD was defined as persistence or recurrence of
Mean birth weight was also lower in patients with coeliac symptoms for up to a year, despite presumed adherence
disease than controls. In this study, 41% of the 12 patients to a GFD. RS was defined as persistent symptoms and
diagnosed with coeliac disease had unfavourable out- evidence for histological injury despite adherence to a
come of pregnancy or low birth weight babies. GFD, as evaluated by a dietitian with clinical expertise,
for up to a year. Fifty-five patients with a presumed diag-
Comment nosis of NCD from a single referral centre underwent
These data imply that with minimal expense, ~US$100 a systematic sequential evaluation which included a
per test, a negative outcome of pregnancy might be reduced detailed dietary review, serological testing for coeliac
or eliminated. In a case–control study, a comparison of disease, repeat small intestine and colonic biopsies, small
94 untreated and 31 treated coeliac women indicated intestine aspirates for quantitative culture, 72 h fecal fat
that the relative risk of abortion was 8.90 times higher measurement, small intestine radiographic studies and
and the relative risk of a low birth weight baby was computed tomography (CT) body imaging. All tests
5.84 times higher in untreated mothers. In the before– were not completed on all patients if a cause was identi-
after study, 12 of the treated and untreated women were fied and treatment was successful. A comprehensive
compared. Results indicated that adherence to a gluten- assessment of dietary compliance was the initial step of
free diet reduced the relative risk of abortion by 9.18 times evaluation and was comprised of three parts: physician
and the number of low birth weight babies from 29.4% interview of the patient to determine their perspective of
to zero.12 The 12 cases that were identified are slightly the GFD, interview and detailed evaluation by an expert
higher than in the general population. The authors point dietitian about dietary compliance and serological tests
out that this disease is more common in women than (EMAs and gliadin antibodies).
in men and accounts for this higher percentage. They Forty-nine cases were not diagnosed at the inves-
also stated that the 12 cases had no overt signs of mal- tigators’ facility. In thirty-two of these cases, the original
nutrition and no one was underweight. This led to the biopsy slides were retrieved and reviewed by the same
conclusion that nutritional factors were probably not of pathologist. The remaining cases confirmed diagnosis
major importance in the negative outcomes reported. by original biopsy report, repeat biopsy, serological
Follow-up was as follows: one was lost to follow-up; markers and response to GFD. Fifty-five patients were
three had no further pregnancies and were complying studied in total. After extensive evaluation, six patients
with the gluten-free diet; eight patients were pregnant, proved to be negative for coeliac disease. Nine of the
with one still to deliver, and the other seven reached remaining 49 were identified as RS. Four of these
term. Six of these patients gave birth to healthy babies patients had RS alone and the other five had RS in
and the seventh patient gave birth to a baby with a major addition to another condition. Twenty-five patients had
cardiac malformation. Notably, the seventh patient was gluten contamination of their diet. The source of con-
the only subject on a gluten-containing diet. tamination was found to be commercially packaged corn
Perhaps it is the dysregulation of the immune system or rice cereals that contained malted barley, or frequent
that may account for an unfavourable outcome of preg- dining out. Once the diet was strictly followed, symptoms
nancy despite only minor nutritional abnormalities.8,9 resolved or improved in all 25 patients. Other causes forGluten-free diets, coeliac disease and associated disorders 609
unresolved symptoms included: seven bacterial over- and vitamin B12 status. Additionally, these latter sub-
growth; six pancreatic insufficiency; five lymphocytic jects underwent jejunal biopsy, and women with con-
colitis; four collagenous colitis; four irritable bowel firmed coeliac disease were advised to start a gluten-free
syndrome; two ulcerative jejunitis; one lymphoma; one diet. A control group for the determination of the
pancreatic cancer; one fructose intolerance; one T-cell prevalence of silent coeliac disease was obtained from a
receptor gene rearrangement; one tropical sprue; and previous screening conducted on school children from
one protein-losing enteropathy. the same geographical area.10
Seven out of the nine patients diagnosed with RS had None of the 99 female subjects had abnormal levels
improvement or remission of symptoms once the cause of IgA-class AGA. Four women had IgG-class AGAs
was identified, treated or eliminated. Two patients were and were EMA positive. Three of these women had
lost to follow-up. histological features of coeliac disease on jejunal biopsy.
Two of the newly diagnosed coeliac patients belonged to
Comment the group of patients with unexplained infertility. The
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The investigators conclude that in 10% of cases, the patient who tested positive for IgG, AGA and EMA, but
original diagnosis was incorrect. Gluten contamination had a normal jejunal biopsy, also belonged to the unex-
was the most frequent cause of NRD despite dietary plained infertility group. This patient was considered to
counselling. Gluten contamination should be considered have latent coeliac disease. The other woman with coeliac
first in patients with suspected RS. They also found that disease was the partner of a man with azoospermia. One
despite the sensitivity for gliadin antibody and high sen- male partner was positive for histological features of
sitivity and specificity of EMAs, five of the 25 patients coeliac disease which is not different from that of the
with known gluten contamination had no detectable general population.
antibodies. This may further complicate the issue of
compliance with the GFD. Comment
The RS was a small group and tended to be older than In this study, the observed frequency of histologically
the NCD group. Twelve patients received steroids for the confirmed silent coeliac disease is 3.03% in the female
treatment of RS. Only three of these patients, however, group. This represents a 3-fold higher prevalence than in
had RS and the rest were treated for a variety of diseases the general population of this region. These data support
in which steroids may have been potentially harmful. the hypothesis that silent coeliac disease may represent
a risk factor for infertility. The underlying mechanisms
Meloni GF, Dessole S, Vargiu N, Tomasi PA, Musumeci S. remain unclear. No study subject displayed overt mal-
The prevalence of coeliac disease in infertility Hum absorption, folic acid or vitamin B12 deficiency which
Reprod 1999; 14: 2759–2761. could have an adverse effect on fertility. One subject
Sardinia is an island where the prevalence of coeliac proved to be iron deficient. None of the newly diagnosed
disease in the general population is high, 10.6 per 1000.10 coeliac patients displayed the usual delayed menarche.
This region was selected by investigators to correlate Approximately half the male subjects in this study had
silent coeliac disease with infertility. The study group abnormalities of sperm morphology and motility, but only
was comprised of 99 women and their partners who were one was diagnosed with coeliac disease. This is similar to
examined for infertility. The following protocol was the incidence in the general population. Female subjects
followed to determine the aetiology of the infertility. The appear to be more affected by coeliac disease than their
presence of ovulation was detected by serial pelvic male counterparts; why this happens remains unknown.
ultrasonography and serial serum progesterone meas- The investigators used a group of schoolchildren as
urements during the mid-luteal phase. Endocrine status their control group for prevalence. This group may not
included determination of pituitary gonadotrophins, represent a similar sample population. Although adult
prolactin, androstenedione, testosterone and thyroid patients may be diagnosed at any age, there appears to
hormones. Tubal patency and uterine morphology were be a bimodal peak noted in the 30s and 40s for women.11
also evaluated, and diagnostic laparoscopy was per- The mean age of the women was 33.04 with a range of
formed as indicated. Post-coital testing was performed 26–45 years.
to screen for cervical factors. Male partners underwent The authors point out that further screening studies
semen analysis and testicular sonography. The infertility are needed in other populations of infertile women
was considered unexplained if no obvious cause could to establish whether the prevalence of coeliac disease
be found after evaluation. Venous blood samples were depends on a genetically determined predisposition.
obtained from all study participants. These samples were
tested for antigliadin antibody (AGA) assays for IgA Kemppainen T, Kroger H, Janatuninen E et al. Osteo-
and IgG. All samples that tested positive for IgA- and/or porosis in adult patients with celiac disease. Bone 1999;
IgG-class AGA were tested for IgA-class anti-EMAs. 24: 249–255.
Subjects who tested positive for at least two of the three The investigators of this cross-sectional study looked at
markers underwent assessment of serum ferritin, folate the data on the severity of coeliac disease and bone610 Family Practice—an international journal
mineral density (BMD) of 77 coeliac patients, and BMD coeliac patients than in coeliac patients in remission.
results were compared with control subjects matched for None of the men had osteoporosis at the femoral neck.
age, gender and menopausal status. The study group Male patients experienced osteopenia at the lumbar
was comprised of seven woman who had not reached spine in 39% of patients in remission, 63% with newly
remission despite adherence to a gluten-free diet for diagnosed coeliac disease and 14% in controls. Osteo-
at least a year, and 19 men and 23 women in remission. penia at the femoral neck was found in 26% of patients
Each coeliac patient was matched with two age, gender in remission, 67% of newly diagnosed coeliac patients
and menopausal status controls from a separate study of and 5% of the control population. BMDs were lower at
volunteers. The anthropometric and BMD data of each the lumbar spine, femoral neck, trochanter and Ward’s
coeliac patient were compared with two control subjects. triangle for age in the coeliac patients.
A questionnaire was used to obtain information on drug Low 25-hydroxyvitamin D concentrations were
and calcium supplements, symptoms and menopausal typically found in coeliac patients; 64% of the men and
status. Each participant also underwent a physical exam- 71% of women showed abnormally low values, and some
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ination. Coeliac subjects completed four day food were pathologically depressed values. Five out of seven
records which were checked by a nutritionist. Height, patients with elevated PTH values also had low 25-
weight, body mass index (BMI) calculations and upper hydroxyvitamin D values. Ten percent of women and
endoscopy were performed, with duodenal biopsies to 14% of men showed low serum calcium values. Fourteen
verify diagnosis and degree of severity. Endoscopies were female coeliac subjects displayed elevated alkaline
not carried out on subjects if villous atrophy had been phosphatase levels. In male subjects, the serum calcium
verified within the last 6 months via duodenal biopsies. and phosphorus values were related to the severity of
BMD was measured at the spine, left femoral neck, the disease. Elevated PTH levels were only found in
trochanter and Ward’s triangle. newly diagnosed female patients. Men in the lowest
BMD results were reported as absolute values, and tertile of BMD at the lumbar spine had lower serum
the percentage variation from the mean normal value 25-hydoxyvitamin D and higher serum PTH levels com-
was calculated using values from control subjects. The pared with men in the other tertiles. Women displayed
subjects were divided into tertiles based on the BMD no significant differences in biochemical measurements
at the lumbar spine and femoral neck to examine the between tertiles of BMD. Regression analysis was used
relationship of calcium intake and serum biochemical to determine if an association between calcium intake,
values to BMD. Serum calcium, alkaline phosphatase, age, weight, height, menopausal status or other putative
parathyroid hormone (PTH), 25-hydroxyvitamin D, factors and BMD of lumbar spine and femoral neck could
cross-linked C-terminal telopeptide of human type I be shown. In male subjects, a clear association between
collagen (ICTP) and C-terminal extension peptide of BMD and age, weight and serum 25-hydroxyvitamin D
type I procollagen (PICP) were measured. values at the lumbar spine was shown. Low BMD values
Height and weight for female coeliac and control sub- were related to age and weight at the femoral neck. In
jects showed no significant difference. Post-menopausal female subjects, post-menopausal status was the main
coeliac subjects showed a lower mean menopausal age determinant factor of low BMD at the lumbar spine and
than controls. Male coeliac subjects weighed less and femoral neck. Weight and depressed serum vitamin D
were shorter than controls. The BMD of the lumbar values were associated with BMD at the femoral neck
spine, femoral neck and trochanter region were signifi- in female subjects. No association was found between
cantly lower in female celiac subjects than controls. Male calcium intake and BMD in either sex.
coeliac subjects showed significantly lower BMD of the
lumbar spine and femoral neck than controls. BMDs Comment
of newly diagnosed and previously diagnosed patients The results of this study show that many coeliac patients
showed no differences at any sites in both sexes. are prone to reduced BMD at the lumbar spine and
World Health Organization (WHO) criteria was used femoral neck. Women with coeliac disease not in remis-
to classify patients with osteoporosis. Twenty-six percent sion and newly diagnosed males had osteopenia and
of all coeliac subjects were shown to have osteoporosis osteoporosis more often than controls. The investigators
at the lumbar spine compared with 5% in the control state that a slight bias may have occurred in this study
group. The presence of osteoporosis at the femoral neck as control subjects with osteoporotic fractures were
was rare in both groups. Osteopenia at the lumbar spine excluded from the control group. In this study, untreated
in women was related to the severity of the disease. patients did not have a significantly lower mean BMD
Osteoporosis at the lumbar spine was found more often when compared with treated patients.
in patients with previously diagnosed disease not in The authors felt that the pathogenesis of bone mineral
remission than those newly diagnosed or in remission. loss in coeliac patients may not be the same for all
The presence of osteoporosis at the femoral neck also patients. A defect in the vitamin D transporter protein
followed this same trend. In men, osteoporosis at the present in coeliac patients may account for the low
lumbar spine was found more often in newly diagnosed values observed in this study. Four day diet records wereGluten-free diets, coeliac disease and associated disorders 611
checked by a nutritionist, but the level of compliance populations. The diet requires a high level of motivation
with the diet was not considered in the data collection. and knowledge about gluten-free products and is an on-
Despite the fact that calcium and BMD were not going process. Beneficial results are seen rapidly when
related, 31% of patients did show depressed calcium in- gluten is removed from the diet of affected individuals.
take, which was attributed to secondary lactose intoler- Some practical points remain. Is the diet palatable and
ance. Restriction of milk and milk products should be easy to follow? Yes; the diet can be appealing and some
re-evaluated once the recovery of villous atrophy has excellent products have been developed. There are a
been shown. wide variety of products and cookbooks on the market;
The authors conclude that complete reversal of many can be shipped to your home. Some companies will
metabolic bone disease may not be possible in coeliac send a free sample pack to patients so they can taste test
subjects. Prevention and management of osteoporosis in the products before purchase. Websites are available to
these patients is needed to restore the intestinal mucosa obtain reliable information on brand-specific products
to normal so that calcium and vitamin D absorption can available for coeliac patients. Not all products will be
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take place. Untreated or poorly treated coeliac subjects acceptable to all patients. However, not all patients
seem to be at increased risk for the development of respond well to all medications.
osteoporosis. Is it more costly? Yes; a loaf of tapioca bread costs
~US$4.39 and coconut macaroons ~US$7.75 per package.
Some of the rice pasta and other products are available
Conclusions in a regular supermarket and may be more reasonably
priced. Below are helpful websites for patients getting
It may be argued that if patients do not present with started on a gluten-free diet.
symptoms of malabsorption or malnutrition why would
testing for coeliac disease be necessary. Simply because www.gluten.net
it can be? The anti-EMA test is safe and simple and www.csaceliacs.org
has an acceptable sensitivity and specificity. But what www.celiac.org
situations warrant testing? www.celiac.com
The literature reviewed here shows that with minimal www.glutenfreeinfo.com
expense and compliance with a gluten-free diet, certain
adverse consequences of this disease may be eliminated
or reduced. Compliance with the diet may enable couples References
who were unable to conceive to become fertile. Negative 1 American Gastroenterological Association. Medical Position
outcomes of pregnancy may be minimized/eliminated Statement: celiac sprue. Gastroenterology 2001; 120: 1522–1525.
simply by following a gluten-free diet. 2 Abdulkarim A, Burgart L, See J, Murray J. Etiology of nonrespon-
A closer look at diet composition is necessary in cases sive celiac disease: results of a systematic approach. Am J
Gastroenterol 2002; 97: 2016–2021.
of refractory coeliac disease as inadvertent gluten 3 Nehra V. New clinical issues in celiac disease. Gastroenterol Clin
contamination is most often the culprit. Once dietary North Am 1998; 27: 453–465.
compliance is established, other causes of symptoms 4 Farrell R, Kelly C. Current concepts: celiac sprue. N Engl J Med
should be addressed. Incorrect diagnosis may cause con- 2002; 346: 180–188.
5 James M, Scott B. Coeliac disease: the cause of the various associated
tinued symptoms, needless suffering by patients and use disorders? Eur J Gastroenterol Hepatol 2001; 13: 1119–1121.
of medications that are potentially harmful. 6 Not T, Tommasini A, Tonini G et al. Undiagnosed celiac disease and
Metabolic bone disease appears to be a more complex risk of auto immune disorders in subjects with type I diabetes
issue. BMDs of coeliac subjects were lower at the lumbar mellitus. Diabetologia 2001; 44: 151–155.
7 Stazi A, Mantovani A. A risk factor for female fertility and preg-
spine and femoral neck in both sexes and also lower in nancy: celiac disease. Gynecol Endocrinol 2000; 14: 454–463.
females at the trochanter region. However, newly diag- 8 Sher KS, Mayberry JF. Female fertility, obstetrics and gynaeco-
nosed and previously diagnosed subjects showed no logical history in coeliac disease. Digestion 1994; 55: 243–246.
9 Stewart K, Willoughby JM. Postnatal presentation of celiac disease.
differences of BMD at any sites. Subjects with previously
Br Med J 1988; 297: 1245.
diagnosed disease or disease of longer duration would be 10 Meloni GF, Dore A, Fanciulli G et al. Subclinical celiac disease in
expected to have lower BMDs. This was not true of schoolchildren from northern Sardinia. Lancet 37: 353.
11 Swinson C, Levi J. Is coeliac disease underdiagnosed? Br Med J
the reviewed study. The precise relationship between bone
1980; 281: 1258–1260.
disease and coeliac disease remains to be elucidated. 12 Ciacci C, Cirillo M, Auriemma G, Di Dato G, Sabbatini F, Mazzacca G.
Routine screening is not practical or necessary; how- Celiac disease and pregnancy outcome. Am J Gastroenterol 1996;
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