Coeliac DiseaseSynonyms: gluten-sensitive enteropathy, celiac disease, celiac sprue

This is an immune-mediated, inflammatory systemic disorder provoked by gluten and related prolamines ingenetically susceptible individuals. [1] Gluten is a protein found in wheat, rye and barley.

GeneticsIt is a multigenetic disorder, associated with HLA types HLA-DQ2 (90%) or HLA-DQ8, plus other genetic orenvironmental factors. HLA typing indicating lack of DQ2 or DQ8 has a high negative predictive value, which maybe useful if trying to exclude coeliac disease. [2]

There is a familial tendency (10-15% of first-degree relatives will also be affected), and identical twins'concordance is 70%. It is theoretically possible, by HLA testing, to provide more accurate information to parentswith a child with coeliac disease (CD) about the real risk for another child having the disease, including anantenatal assessment. [3]

EpidemiologyPrevalence is approximately 1 in 100 people in the UK. [2] Prospective birth cohort studies suggest 1% of childrenhave immunoglobulin A (IgA) endomysial antibodies by 7 years of age. [4] However, only 10-20% will have beendiagnosed as having coeliac disease (CD). [5]

The disorder is thought to be rare in central Africa and East Asia. [6]

PresentationIt may present at any age. [1] [2] Coeliac disease (CD) can be difficult to recognise because of the wide variationin symptoms and signs. Many cases may be asymptomatic.

Babies and young children present any time after weaning (peak 9 months to 3 years):Malabsorption generally presents with diarrhoea (frequent paler stools), weight loss andfailure to thrive.Vomiting, anorexia, irritability and constipation are also common.The abdomen may protrude, with eversion of the umbilicus.

Older children and adults may present with:Anaemia (folate or iron deficiency).Nonspecific symptoms of abdominal discomfort, arthralgia, anaemia, fatigue and malaise.Diarrhoea, steatorrhoea and malabsorption.Mouth ulcers and angular stomatitis are common (85% have asymptomatic iron/folatedeficiency, 15-30% have vitamin D deficiency and 10% vitamin K deficiency).Deficiencies of vitamin E also occur.B12 deficiency can also occur (mechanism unknown).

Some CD patients are identified at infertility clinics. CD is associated with subfertility in both men andwomen, miscarriage, low-birthweight children and increased infant mortality. [7]

Dermatitis herpetiformis is the classic skin manifestation of CD - almost all patients with the rash have eitherdetectable villous atrophy (approximately 75%) or minor mucosal changes. Lamellar ichthyosis has also beenreported in association with CD. [8]

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InvestigationsSpecific auto-antibodiesCD-specific antibodies include auto-antibodies against tissue transglutaminase type 2 (tTGA2), includingendomysial antibodies (EMAs), and antibodies against deamidated forms of gliadin peptides (DGPs). These aremeasured in blood.

IgA anti-tissue transglutaminase antibodies (tTGAs) is the preferred investigation. EMAs are used if thetTGA test is not available or equivocal. The tTGA is a newer test (tTGA is the auto-antigen of EMA) andis gradually replacing the latter, but both are highly specific and sensitive for untreated CD, providedthe patient is still on gluten. tTGA should not be performed on children younger than 2 years. [1]

False negatives occur if the patient has selective IgA deficiency, as occurs in approximately 0.4% ofthe general population and in 2.6% of patients with CD (laboratories should test for IgA deficiency onnegative samples). Use IgG tTGA and/or IgG EMA serological tests for people with confirmed IgAdeficiency.Antibodies frequently become undetectable after 6-12 months of a gluten-free diet (GFD) and thus canbe used to monitor the disease.

Positive antibodies should prompt a referral to a gastroenterologist. In children and adolescents with signs orsymptoms suggestive of CD and high anti-tTGA titres (levels ≥10 times the upper limit of normal), the likelihoodfor villous atrophy is high. The paediatric gastroenterologist may discuss with the parents and patient (asappropriate for age) the option of performing further laboratory testing (EMA, HLA) to make the diagnosis of CDwithout biopsies.

Referral should also be made where the serology is negative, but there is strong clinical suspicion of CD.

HLA-DQ2 and HLA-DQ8 typingA negative result for these makes a diagnosis of coeliac disease (CD) highly unlikely. If available, it can be offeredto:

Patients with an equivocal diagnosis of CD.Asymptomatic patients - as a screening tool for, for example, first-degree relatives, patients withDown's syndrome or known associated autoimmune or other conditions.

In the community for example, a GP may request HLA testing in a young patient with Down's syndrome, toobviate the need for annual screening.

Biopsy confirmationPatients will need to stay on gluten until after the biopsy. The biopsy is obtained by upper gastrointestinalendoscopy or by suction capsule.

Histological examination of the mucosa classically shows 'subtotal villous atrophy' and results inmalabsorption - however, mucosa is of normal thickness, the villous atrophy is compensated by crypthyperplasia. There should be full clinical remission on excluding gluten from the diet.Under these circumstances, tTGA or EMA antibodies found at the time of diagnosis and theirdisappearance after gluten exclusion, means that it is only necessary to perform a further biopsy (andeven a further gluten challenge and more biopsies) if there are still doubts.

Other investigationsFBC shows anaemia in 50%; iron and folate deficiency are both common (microcytes andmacrocytes), hypersegmented leukocytes and Howell-Jolly bodies (splenic atrophy). Also check B12,folate, ferritin, LFTs, calcium and albumin.LFTs may show elevated transaminases which should return to normal on a GFD. If they don't,consider associated autoimmune disease, ie primary biliary cirrhosis, autoimmune hepatitis or primarysclerosing cholangitis.Small bowel barium studies are occasionally needed to exclude other causes of malabsorption anddiarrhoea, and to diagnose rare complications such as obstruction or lymphoma.

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Target case finding for serological testingConsider the diagnosis and perform serological testing in all patients who present with: [4]

Chronic or intermittent diarrhoea.Failure to thrive or faltering growth in children (including short stature and delayed puberty). [6]

Persistent or unexplained gastrointestinal symptoms, including nausea and vomiting.Prolonged fatigue ('tired all the time').Recurrent abdominal pain, cramping or distension.Sudden or unexpected weight loss.Unexplained iron-deficiency anaemia, or other unspecified anaemia.

Also, offer testing to patients with known associated conditions: [4]

Autoimmune thyroid disease.Dermatitis herpetiformis.Irritable bowel syndrome (IBS). [9]

Type 1 diabetes (3-12% have coeliac disease (CD)) [6] - screen children every 2-3 years untiladulthood, and subsequently if adults have a low body mass index (BMI) or develop unexplainedweight loss. [1]

First-degree relative (parents, siblings or children) with CD.

The National Institute for Health and Clinical Excellence (NICE) also suggests considering serological testing inpatients with: [4] Addison's disease, amenorrhoea, aphthous stomatitis (mouth ulcers), autoimmune liverconditions, autoimmune myocarditis, chronic thrombocytopenia purpura, dental enamel defects, depression orbipolar disorder, Down's syndrome, epilepsy, lymphoma, metabolic bone disease (such as rickets orosteomalacia), microscopic colitis, persistent or unexplained constipation, persistently raised liver enzymes withunknown cause, polyneuropathy, recurrent miscarriage, reduced bone mineral density and/or low-traumafracture, sarcoidosis, Sjögren's syndrome, Turner syndrome, unexplained alopecia and unexplained subfertility.

Differential diagnosisIBS, lactose or other food intolerances, colitis (including inflammatory bowel disease), and other causes ofmalabsorption.

ManagementStarting a gluten-free diet (GFD) rapidly induces clinical improvement, which is mirrored by the mucosa. The dietconsists of no wheat, barley, rye, or any food containing them (eg bread, cake, pies). [2] Moderate quantities ofoats (free from other contaminating cereals) can be consumed, as studies suggest that they do not damage theintestinal mucosa in most coeliac patients, although a small number of patients remain unwell if oats are includedin the diet. British Society of Gastroenterology (BSG) guidelines suggest oats be excluded at least for the firstyear while patients get used to a GFD but then can be cautiously introduced. Rice, maize, soya, potatoes, sugar,jam, syrup and treacle are all allowed. Gluten-free flour, bread and pasta are NHS prescribable. There is a gluten-free food prescribing guide available for health professionals and Coeliac UK produces a prescribable productlist. [10] GPs are responsible for the appropriate prescription of gluten-free products.

Arrange a dietitian appointment (with regular reviews). [2] Even minor dietary lapses may cause recurrence. AGFD should be lifelong, as relaxation of diet generally brings a return of symptoms and increased incidence ofcomplications. Add supplements as necessary (eg fibre, folic acid, iron, calcium and vitamin D). Serial tTGA orEMA antibodies can be used to monitor response to diet.

Research is looking at how gluten could be detoxified in the intestine by oral endopeptidases. They are enzymesthat break the gluten peptides into small chunks with fewer adverse effects. [6]

Follow-upPatient compliance with a gluten-free diet (GFD) is poor, particularly in adolescents. [6] The long-term

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Patient compliance with a gluten-free diet (GFD) is poor, particularly in adolescents. [6] The long-termhealth risks for patients who comply poorly with a GFD include nutritional deficiency and reduced bonemineral density. About a quarter of patients with coeliac disease (CD) have osteoporosis of the lumbarspine compared with 5% of matched controls. Bone mineral density improves significantly with a GFD.Dietary compliance positively correlates with regular follow-up and knowledge of the condition.Many coeliac patients have an inadequate energy intake. Poor absorption often leads to inadequateintake of calcium and vitamin B6 and vitamin D.Regular follow-up is an opportunity to provide patient-centred care that is sensitive to the individual'slife circumstances.

How often should patients be reviewed?Patients should be followed up throughout their lifetime.After diagnosis, the patient should be reviewed at the gastroenterology clinic after three months andsix months to ensure they are making satisfactory progress and managing the diet.If well, they should be reviewed annually or sooner if problems arise - follow-up assessments arecurrently being carried out by dietitians, nurses, general practitioners and gastroenterologists inprimary and secondary care.

The annual assessment [2]

Disease statusGeneral: weight, height, and BMI.Symptom assessment: bowel function (stool frequency, stool consistency, blood in stool) abdominalpain.

InvestigationsFBC, LFTs, calcium and albumin, B12, folate, serum ferritin. Patients with coeliac disease (CD) whoadhere to a gluten-free diet (GFD) often eat inadequate intakes of folic acid and iron. Lowhaemoglobin, red cell folate, and serum ferritin may suggest persisting malabsorption warrantingfurther assessment.Antibody tests can be used to monitor significant dietary gluten ingestion.

Complication preventionOsteoporosis risk assessment and management:

Consider measuring bone mineral density with a dual energy X-ray absorptiometry (DEXA)scan at the time of diagnosis (depending on age), and the test should then be repeated:

After three years on a GFD (only if the baseline DEXA is abnormal). [2]

At the menopause for all women.At the age of 55 years for all men.At any age if a fragility fracture is suspected (follow osteoporosis guidelines).

Calcium and/or vitamin D supplements can be prescribed if dietary intake is inadequate(<1,500 mg/day) or the patient is housebound. Checking vitamin D levels and parathyroidhormone levels may be appropriate in at-risk individuals. [2]

Hyposplenism - some degree of splenic atrophy is present in most patients with CD, and is sufficientlysevere to cause peripheral blood changes in about a quarter (Howell-Jolly bodies, target cells andelevated platelet count). Patients should be considered for:

Vaccination against pneumococcus and Haemophilus influenzae type b.Vaccination against influenza.Guidance about the increased risks attached to tropical infections, eg malaria.

Lifelong prophylactic antibiotics are not recommended.

Management of disease and associated medical problemsDiscussion of familial risk if required. First-degree relatives of people with CD have a 1 in 10 chance ofdeveloping the disease, and should be screened.

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Review prescription items - prescribing guidelines suggest minimum monthly prescriptionrequirements, so discuss prescribable items with any patients using fewer than theserecommendations.Self-care:

Discuss GFD compliance and advice.Discuss membership of the Coeliac Society.Discuss use of the Coeliac Society's Gluten-free Food and Drink directory.Provide dietary advice on weight, macronutrients, calcium, vitamin D, iron and fibre intakeas required.

ReferralYou should consider specialist referral if:

There is poor response to a gluten-free diet (GFD).There is weight loss on a GFD.There is blood in stools.There is onset of unexplained abdominal pain.There are other clinical concerns.

ComplicationsDelayed diagnosis of coeliac disease (CD) may result in continuing ill health, osteoporosis, miscarriage and amodest, increased risk of intestinal malignancy (in adults); also, growth failure, delayed puberty and dentalproblems (in children). [4]

Osteoporosis. [11]

Cancer risk - there is conflicting research on this subject. Some research shows a small increase inoverall risks of developing malignancy, eg gastrointestinal cancers and some types of lymphoma. [6]

Intestinal lymphoma usually presents with the return of bowel symptoms, although it usually respondspoorly to treatment.

Further reading & referencesGuideline for the diagnosis and management of coeliac disease in children, British Society of Paediatric Gastroenterology,Hepatology and Nutrition with Coeliac UK (Sept 2013)Coeliac Disease; NICE CKS, May 2010Karpati S; Dermatitis herpetiformis. Clin Dermatol. 2012 Jan;30(1):56-9. doi: 10.1016/j.clindermatol.2011.03.010.

1. Guidelines for the Diagnosis of Coeliac Disease, European Society for Pediatric Gastroenterology Hepatology andNutrition (January 2012)

2. The Management of Adults with Coeliac Disease; British Society of Gastroenterology (2010)3. Bourgey M, Calcagno G, Tinto N, et al; HLA related genetic risk for coeliac disease. Gut. 2007 Aug;56(8):1054-9. Epub 2007

Mar 7.4. Coeliac disease; NICE Clinical Guideline (May 2009)5. Steele R; Diagnosis and management of coeliac disease in children. Postgrad Med J. 2011 Jan;87(1023):19-25. Epub

2010 Dec 3.6. Di Sabatino A, Corazza GR; Coeliac disease. Lancet. 2009 Apr 25;373(9673):1480-93.7. Pellicano R, Astegiano M, Bruno M, et al; Women and celiac disease: association with unexplained infertility. Minerva Med.

2007 Jun;98(3):217-9.8. Nenna R, D'Eufemia P, Celli M, et al; Celiac disease and lamellar ichthyosis. Case study analysis and review of the Acta

Dermatovenerol Croat. 2011 Dec;19(4):268-70.9. Ford AC, Chey WD, Talley NJ, et al; Yield of diagnostic tests for celiac disease in individuals with symptoms Arch Intern

Med. 2009 Apr 13;169(7):651-8.10. Prescribable Product List, Coeliac UK11. Guidelines for Osteoporosis in Inflammatory Bowel Disease and Coeliac Disease, British Society of Gastroenterology

(2007)

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medicalconditions. EMIS has used all reasonable care in compiling the information but make no warranty as to itsaccuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions.For details see our conditions.

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Original Author:Dr Huw Thomas

Current Version:Dr Hayley Willacy

Peer Reviewer:Dr Helen Huins

Last Checked:13/06/2012

Document ID:1975 (v25)

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