Clinical benefit of gluten-free diet in screen-detected older celiac disease patients
© Vilppula et al; licensee BioMed Central Ltd. 2011
Received: 23 September 2011
Accepted: 16 December 2011
Published: 16 December 2011
The utility of serologic screening for celiac disease is still debatable. Evidence suggests that the disorder remains undetected even in the older population. It remains obscure whether screening makes good or harm in subjects with long-standing gluten ingestion. We evaluated whether older subjects benefit from active detection and subsequent gluten free dietary treatment of celiac disease.
Thirty-five biopsy-proven patients aged over 50 years had been detected by serologic mass screening. We examined the disease history, dietary compliance, symptoms, quality of life and bone mineral density at baseline and 1-2 years after the commencement of a gluten-free diet. Symptoms were evaluated by gastrointestinal symptom rating scale and quality of life by psychological general well-being questionnaires. Small bowel biopsy, serology, laboratory parameters assessing malabsorption, and bone mineral density were investigated.
Dietary compliance was good. The patients had initially low mean serum ferritin values indicating subclinical iron deficiency, which was restored by a gluten-free diet. Vitamin B12, vitamin D and erythrocyte folic acid levels increased significantly on diet. Celiac patients had a history of low-energy fractures more often than the background population, and the diet had a beneficial effect on bone mineral density. Alleviation in gastrointestinal symptoms was observed, even though the patients reported no or only subtle symptoms at diagnosis. Quality of life remained unchanged. Of all the cases, two thirds would have been diagnosed even without screening if the family history, fractures or concomitant autoimmune diseases had been taken carefully into account.
Screen-detected patients benefited from a gluten-free diet. We encourage a high index of suspicion and active case-finding in celiac disease as an alternative to mass screening in older patients.
Evidence suggests that the incidence of celiac disease increases with age [1, 2]. Physicians' lack of alertness in the older people may result in a significant delay in diagnosis, as celiac disease is widely deemed to be a condition affecting younger subjects. Indeed, the majority of older celiac disease patients have remained undetected, often due to the absence of symptoms [3, 4]. It is reasonable to assume that, due to long gluten exposure, older patients with untreated celiac disease may be disposed to severe nutritional deficiencies, even when they are seemingly asymptomatic. In particular, the rate of bone loss is accelerated in women after the menopause, likewise in men at the same age. We know that even young and asymptomatic patients with celiac disease may have reduced bone mineral density while untreated , and the condition might be even more evident in older .
On the other hand, a lifelong gluten-free diet is restrictive and may also increase the burden of illness and impairs quality of life [7, 8]. Especially in the older subjects the diet may not be well tolerated, as patients will have adopted lifetime dietary habits which may be hard to break. Moreover, if a gluten-free diet does not necessarily produce any clinical improvement, screen-detected cases may not be motivated to adhere strictly to it. Therefore, to clarify the benefit of serologic screening for celiac disease in older population, a follow-up of the previously undiagnosed patients identified by screening is required .
In this prospective study we evaluated the benefits of active serologic population-based mass screening for celiac disease and subsequent dietary treatment in subjects over 50 years of age. The aim was to establish whether celiac disease should be rigorously searched for in the older people.
Patients and study design
We identified screen-detected new celiac disease patients enrolled from a cohort representing the older Finnish population. The original study population comprised 4272 randomly selected individuals born in the years 1946-50, 1936-40 and 1926-30, and was defined for a 10-year research project on ageing and well-being (Good Ageing in the Lahti region = GOAL) http://www.palmenia.helsinki.fi/ikihyva/InEnglish.html. In 2002, altogether 2815 subjects (66%) consented to participate and serum samples were drawn and stored at -20°C until used. Anti-tissue transglutaminase antibodies were tested from the stored sera in 2004, and 48 new seropositive cases were identified; their diagnostic work-up has been published elsewhere . Four had started a gluten-free diet before enrolment, 39 of the remainder consented to a small bowel biopsy, and villous atrophy with crypt hyperplasia compatible with celiac disease was found in 35. These 35 comprised the current study group; their median age was 61 years (range 52-76) and 57% were female.
At baseline the patients were interviewed for their family history, associated disorders and symptoms of celiac disease. Nutritional condition and quality of life were evaluated. The patients were advised to start a gluten-free diet, and dietary counseling was carried out by a gastroenterologist and a dietician. To ensure dietary response and adherence to a gluten-free diet, an interview by the dietitian, small bowel biopsies and celiac disease antibodies were investigated after a median of one year; nutritional condition and quality of life were assessed after a median of two years on a gluten-free diet. The diet was considered strict when there were no signs of dietary transgressions upon the interview. Occasional gluten-free diet was defined as a gluten intake occurring less often than once in the month.
Small bowel mucosal biopsy
Small bowel mucosal biopsy samples were taken by upper gastrointestinal endoscopy from the distal part of the duodenum. Three samples were paraffin-embedded, processed, stained with hematoxylin-eosin and studied under light microscopy. The villous height/crypt depth ratio (Vh/CrD) was calculated from well orientated biopsy specimens as previously described ; a ratio < 2 was considered abnormal and indicative of active celiac disease. The densities of intraepithelial lymphocytes (IELs) were counted from randomly selected surface epithelium and expressed as IELs per 100 epithelial cells .
Celiac serology and HLA
IgA-class tissue transglutaminase antibodies (TGA) were investigated by enzyme-linked immunosorbent assay (Celikey; Phadia, Freiburg, Germany) according to manufacturer's instructions; values ≥5.0 arbitrary units (U) were considered elevated. TGA-positive sera were further analyzed for IgA-class endomysial antibodies (EMA) by an indirect immunofluorescence method using human umbilical cord as substrate; a dilution of 1:5 or more was considered positive .
The study patients were genotyped for HLA-DQB1*02, DQB1*0302 and DQA1*05 alleles using the DELFIA Coeliac Disease Hybridization Assay (Perkin-Elmer Life and Analytic Sciences, Wallac Oy, Turku, Finland) according to manufacturer's instructions; DQB1*02 and DQA1*05 corresponding to associated alleles for HLA DQ2 and DQB1*0302 for HLA DQ8.
The clinical symptoms were classified into three different subgroups: (i) no symptoms, (ii) subtle symptoms with occasionally one or more of the following: abdominal pain, flatulence, belching, loose stools, tiredness, joint pain or oral blisters, and (iii) classical symptoms with constant abdominal complaints, diarrhea or excessive weight loss. Abdominal complaints were additionally evaluated by the Gastrointestinal Symptom Rating Scale (GSRS), which denotes the total score derived from five different gastrointestinal symptoms; diarrhea, indigestion, constipation, abdominal pain and gastro-esophageal reflux; a higher score indicates more severe symptoms . Quality of life was appraised by the Psychological General Well Being (PGWB) questionnaire . This is a 22-item questionnaire including both negative and positive affective states divided into six parts: anxiety, depressed mood, positive well-being, self-control, health and vitality; here a higher score denotes better quality of life. Both questionnaires have been widely employed in celiac disease. A total of 110 subjects served as non-celiac controls for GSRS and PGWB. The controls for GSRS and PGWB were collected form the general population. We asked celiac members of the Finnish celiac society to recruit an individual living in their neighbourhood and not suffering from celiac disease. They had similar age and sex distribution as the study subjects. Celiac disease was not systematically excluded in controls, but the subjects reported no symptoms and had no relatives with celiac disease.
Assessment of nutritional condition
Body mass index was computed as weight/height2 (kg/m2). Blood hemoglobin, erythrocyte folic acid levels, serum iron, ferritin, ionized calcium, phosphate and vitamin A, B-12, D-25 and E concentrations were measured using routine laboratory methods.
Bone mineral density and history of fractures
Bone mineral density was measured by dual-energy X-ray absorptiometry (GE Medical Systems, LUNAR, UK) in the spine (L1 to L4) and right femoral neck. Values were expressed as standard deviation (SD) scores, which compare individual values to the mean bone mineral density of sex-matched young adults (T score) or of the age- and sex-matched population (Z score). T scores above -1.0 SD represented normal values, scores between -1.0 and -2.4 osteopenia and scores ≤ -2.5 SD osteoporosis. When indicated, bisphosphonate medication together with supplementary calcium and vitamin D were recommended, since it was considered unethical to postpone medical treatment and wait for the effect of a gluten-free diet.
The number of low-energy bone fractures was extracted from the questionnaires of the original GOAL study, equally in the total (n = 2815) series and in study subjects.
The study was accepted by the Ethical Committee of Päijät-Häme Central Hospital, and written informed consent was obtained from all participants. Research is in compliance with the Helsinki Declaration.
Data were given as means with 95% confidence intervals (CI) or medians with lower and upper quartiles and range when appropriate. Chi-square or Fisher's tests were used in cross tabulations Wilcoxon signed or paired rank test to compare changes within the study group. A p value < 0.05 was considered statistically significant. We calculated that, for the statistical power of 0.80 at a significance level of 0.05, 30 subjects would be sufficient. We estimated that the difference of > 0.5 in the Vh/CrD and that of 0.5 in GSRS were clinically significant [13, 14].
Diagnostic clues for detecting celiac disease
Vitamin B12 deficiency
Fracture of hand
Pernicious anemia, hypothyroidism
Blisters in mouth, family history
Sarcoidosis, family history
Fracture of vertebra, osteomalacia hypothyroidism
Fracture of ankle, psoriasis
Sjögren's syndrome, psoriasis
Type I diabetes mellitus, hypothyroidism
Depression, vitamin B12 deficiency
Hyperthyroidism, family history
Fracture of ribs and sternum, osteoporosis
Fracture of wrist
Hypothyroidism, family history
Hypothyroidism, family history
Fracture of foot, family history
Fracture of ribs, osteoporosis blisters in mouth
Fracture of ribs, family history
Symptoms and quality of life
Screen-detected celiac patients
At the diagnosis After gluten-free diet
Gluten-free dietary treatment
Thirty-two (91%) of the 35 screen-detected older celiac disease patients consented to start a gluten-free diet. Twenty-seven maintained a strict diet, and five had occasional transgressions less often than once in the month; three patients did not commence gluten-free diet.
Clinical symptoms resolved in 14 out of the 15 who reported symptoms at the time of diagnosis. One with initially subtle abdominal complaints developed diarrhea despite small bowel mucosal normalization on a strict gluten-free diet; colonoscopy showed no abnormal findings or inflammation. In accordance with the clinical history, alleviation in gastrointestinal symptoms was observed both by GSRS total score and by subscores, and was statistically significant, except in the case of constipation (Table 2).
At the diagnosis
After gluten-free diet
M: 13.4-16.7 g/dl
F: 11.7-15.5 g/dl
M: 20-275 μg/l
F: 7-205 μg/l
Serum vitamin B12
Erythrocyte folic acid
Serum vitamin D25
Serum vitamin A
Serum vitamin E
Serum ionized calcium
Bone density and body mass index
At the diagnosis
After gluten-free diet
Mean; 95% confidence intervals
Mean; 95% confidence intervals
Lumbar spine Z-score (SD)
0.0 - 1.1
0.1 - 1.5
Femoral Z-score (SD)
-0.5 - 0.2
-0.2 - 0.6
Lumbar spine T-score (SD)
-1.2 - -0.1
-1.2 - 0.1
Femoral T-score (SD)
-1.5 - -0.6
-1.5 - -0.5
Body mass index (kg/m2)
An increasing number of patients with celiac disease will be diagnosed among the older people [1–3]. The correct diagnosis may have been missed even when the patients had contacted their physicians for many years due to unexplained symptoms or abnormalities in blood tests . Altogether, older patients may have more symptoms than younger ones , and may have an increased risk of malabsorption or enteropathy-associated T-cell lymphoma. Anemia, iron, vitamin B12, folic acid, and calcium deficiency have been the major malnutrition findings in older celiac disease patients [3, 16]. It would thus, appear desirable to detect the disease as early as possible.
On the other hand, it is of crucial importance to know what the overall implications of the diagnosis are in older people. Mortality has not increased among older undiagnosed celiac disease patients  and the effect of the diagnosis on well-being has not been investigated. In this prospective follow-up study we evaluated the consequences of dietary treatment in a definite celiac disease patient series obtained by population-based mass screening in the older . Since neither celiac disease nor any abdominal disease was the target of the original GOAL project, there was no selection bias towards individuals suffering from gastrointestinal symptoms. Of note, the rate of detection of celiac disease in Finland is relatively high, and in the present series, 0.9% of individuals already had the diagnosis of celiac disease established before the screening program . This notwithstanding, even here the majority of older celiac disease patients would have remained undiagnosed without active screening or case finding.
In these screen-detected patients an improvement in GSRS was evident under dietary treatment, both in total score and in virtually in all subscores, displaying an alleviation in gastrointestinal symptoms. The effect of the treatment on quality of life (PGWB) was not so evident, but it is of note that the diet did not worsen it. A comparable finding was obtained in our recent study where celiac patients detected by screening at risk groups were investigated . An improvement in laboratory values was seen almost invariably. This was most evident in serum mean ferritin indicating the presence of subclinical iron deficiency, as the serum iron levels remained within normal range. A low ferritin level was similarly observed in a series from Godfrey and colleagues . Apart from gluten-free diet, iron or vitamin supplementation was given to some of our patients, but the beneficial effect was evident also in those subjects, who did not receive any substitution. There was a slight but statistically significant decrease in blood hemoglobin levels in females (Table 3), but none of the patients suffered from severe anemia. A regular follow-up of hemoglobin values is in any case indicated in celiac patients.
A risk of low bone mineral density is possible in screen-detected apparently asymptomatic celiac disease patients . In the present study, Z-scores, reflecting the values in the age- and sex-matched population, were within reference levels at baseline, but a significant improvement was observed on a gluten-free diet. As Z-score reference values usually decrease with age, we concluded that this process was slowed down by dietary treatment. Though no improvement was observed in T-scores in the total series, such an effect was seen in subjects with osteoporosis or osteopenia, even when subjects treated with bisphosphonates were excluded. The analysis would have been impossible if also subjects receiving vitamin D or calcium substitution were excluded. On the other hand, in the randomized study carried out by Mautalen et al. , strict gluten-free diet promoted a significant increase in bone mineral density, but calcium and vitamin D supplementation did not provide additional benefit. We will further point out, that the medical management for bone disease of malabsorption would not have been possible without our active screening. There was a small but significant decrease in serum calcium levels. This may be due to ongoing bone restoration, which implies that calcium substitution is indicated after the commencement of a gluten-free diet. Our results further suggest that low-energy fractures may be a risk in untreated celiac disease. Larger prospective studies are however needed to confirm this finding.
Compliance with a gluten-free diet does not seem to be a problem in older patients with celiac disease, as compliance rates have been more than 90% . Accordingly, the histological or serological recovery in the 32 patients adhering to a gluten-free was virtually complete. However, our results cannot directly be applied in every country, as the availability of gluten-fee diet may not be as good as in Finland. Another limitation of the study was that we did not have laboratory or bone mineral density values for the control group. Nevertheless, we emphasize that a favorable outcome can be achieved by screening older population for celiac disease.
None of our celiac disease patients suffered from severe malabsorption syndrome, and they did not have refractory sprue or any other severe complications. Ten (29%) of these 35 screen-detected celiac patients had had relatives with celiac disease and 10 autoimmune diseases, which should both alert to celiac disease. Katz and associates  concluded that symptoms do not predict who will have celiac disease, making case-finding ineffective, and they therefore suggested that general population screening may be needed to find the disorder. To the contrary, we believe that in this older population case finding will be effective as long as symptoms and risk-groups are taken into account. Altogether, 29 out of 35 of our celiac patients would have been detected without serologic mass-screening if family history, bone fractures or concomitant diseases (Table 1) had alerted the physicians (in patient 35 routine duodenal biopsy would have detected celiac disease). We therefore recommend screening in groups, where the costs are lower than in mass-screening, and as shown here, the patients benefit from dietary treatment.
Screen-detected, apparently asymptomatic older celiac disease patients may suffer from subclinical malabsorption, gastrointestinal symptoms or bone disease, which are alleviated during gluten-free dietary treatment. No deterioration in quality of life was seen in our series, and dietary compliance was excellent. Despite this, we consider that there is still insufficient evidence to advocate mass screening, until the costs and benefits of the approach have been thoroughly evaluated. Instead, as the majority of patients had a family history or associated conditions known to occur with celiac disease, we recommend active case finding in older people belonging to at-risk groups.
This study and the Celiac Disease Study Group were supported by the Competitive Research Funding of the Pirkanmaa Hospital District and Päijät-Häme Hospital, the Academy of Finland research Council for Health, the Sigrid Juselius Foundation, and the Research Fund of the Finnish Celiac Society. We thank Robert MacGilleon for the revision of the English language.
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