Coeliac disease: investigation and management

Coeliac disease is a gluten-sensitive enteropathy

Coeliac disease is a chronic inflammatory condition of the small intestine that causes flattening of the villi and results in nutrient malabsorption.¹ Coeliac disease occurs in genetically susceptible people and involves an autoimmune response to gluten – the major protein found in varieties of wheat, rye and barley.^{1, 2} It is not an allergy to gluten. A small proportion of people with coeliac disease may also be affected by avenin, the protein found in oats (see: “The role of oats in a gluten-free diet”). Coeliac disease is associated with an increased risk of long-term health problems, e.g. osteoporosis, infertility, lymphoproliferative disorders (e.g. T-cell lymphoma) and gastrointestinal malignancy.^{1, 3 ,4} However, this risk reduces in people who, after diagnosis, adhere to a strict gluten-free diet (see: “Complications of coeliac disease”).^{1, 3, 4}

The prevalence of coeliac disease has increased over time

The prevalence of coeliac disease is increasing, which may partially reflect increased awareness and testing.^{2, 5} It is estimated that 1.2% of adults in Australasia have coeliac disease; exact prevalence data are unavailable for children, however, rates are reportedly increasing.⁶ Worldwide, prevalence data range from 0.6 – 1.9% and risk varies according to several factors:^{1, 2, 6–9}

• Genetics. People with human leukocyte antigen (HLA) haplotypes, HLA-DQ2 or HLA-DQ8, or people with a family history of coeliac disease – particularly first-degree relatives, have the strongest genetic predisposition to developing coeliac disease. People with an autoimmune condition, e.g. type 1 diabetes, autoimmune thyroid or liver disease, trisomy 21, Turner or Williams syndrome and those with IgA deficiency are also at greater risk of coeliac disease than the general population.^{1, 9, 10}
• Ethnicity and geographic location. Coeliac disease occurs in people living in any geographic area and of any ethnicity, however, it predominantly affects European populations.^{3, 4, 11} In New Zealand, children of Indian ethnicity are reportedly disproportionately affected.
• Age. A diagnosis of coeliac disease can be made at any age; however, most people are diagnosed as adults, often between the ages of 40 and 45 years.^{1, 7, 12}
• Sex. Studies report that a higher proportion of females have coeliac disease than males (approximately 1.3 to 1.5 females are affected for every one male).^{1, 7}

N.B. There is no evidence that breastfeeding duration or timing of gluten introduction influences the development of coeliac disease.¹

Recognising coeliac disease in patients with vague and non-specific symptoms

Coeliac disease is often under-recognised because of the wide range and non-specific nature of symptoms with which people present.^{10, 13}

The ‘classical’ presentation of coeliac disease reflects its effect on the small intestine causing gastrointestinal symptoms, e.g. diarrhoea, abdominal distension and discomfort, weight loss or in children, failure to gain weight (Figure 1).¹ Symptoms of coeliac disease may be difficult to distinguish from those found in irritable bowel syndrome or inflammatory bowel disease.¹ People may also present with other gastrointestinal symptoms such as constipation, nausea and vomiting, or extra-intestinal manifestations, e.g. chronic fatigue, dermatitis herpetiformis, anaemia secondary to iron deficiency, or they can be asymptomatic.^{1, 14} Children may display additional symptoms and signs, e.g. faltering growth, pubertal delay, emotional distress/changes in mood.^{1, 5}

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Figure 1. Coeliac disease – symptoms, signs and associated conditions.^{1, 9, 10, 14}

N.B. Not all people with coeliac disease will display these symptoms and signs, some people can also be asymptomatic.

Appropriate initial tests are serum anti-tTG and total IgA levels, with the patient consuming gluten

Coeliac disease is an immune-mediated response to gluten; therefore, antibody testing has an important role in the diagnosis. The reliability of these tests has improved over time.¹ Serum testing for coeliac-specific antibodies is indicated for all patients in whom coeliac disease is suspected, including those who are asymptomatic but at high risk of coeliac disease, e.g. due to family history, a genetic condition or other associated condition (e.g. unexplained infertility, autoimmune thyroid disease, type 1 diabetes).^{1, 9}

Which laboratory tests to request

Coeliac disease is associated with elevated tissue transglutaminase (tTG), endomysial (EMA), deamidated gliadin peptide (DGP) and anti-gliadin (AGA)^* antibodies.¹

Request a “coeliac screen” on the laboratory form and advise the patient to continue with their usual diet, i.e. containing gluten (see: “Patients should be consuming gluten in the lead up to testing for coeliac disease”).

The specific antibody tests performed by the laboratory when a request is made for a “coeliac screen” varies. Generally, the laboratory will begin by testing serum anti-tTG and total IgA. If anti-tTG is positive (and IgA levels are sufficient), EMA-IgA is usually then tested automatically. Testing the total IgA level is necessary as up to 2.6% of people with coeliac disease have IgA deficiency that can give a misleadingly low anti-tTG result.^{4, 9} If IgA levels are deficient, DGP-IgG is usually then tested automatically.⁹ DGP is not as reliable as tTG in people with normal IgA titres, therefore, use outside of IgA deficiency is not recommended.⁴ If results are uncertain and clinical suspicion of coeliac disease remains for a patient with IgA deficiency, discuss with or refer to a gastroenterologist.

^*N.B. AGA antibodies are no longer used in the testing panel for coeliac disease due to low specificity.¹²

Request additional laboratory tests, as indicated

Additional laboratory tests may be requested to investigate differential diagnoses, e.g. inflammatory bowel disease, or associated conditions, e.g. autoimmune hepatitis or thyroid disease. Also consider testing for and treating any nutritional deficiencies or abnormal biochemistries as the inflammatory changes associated with coeliac disease can disrupt intestinal absorption.¹

Laboratory tests may include:¹

• Full blood count
• Ferritin
• LFTs
• TSH (as higher risk of autoimmune thyroid disease)
• Folate
• Vitamin B12
• Calcium and phosphate
• CRP (as indicated)
• Faecal calprotectin (if inflammatory bowel disease suspected)

A duodenal biopsy may no longer be essential for the diagnosis of coeliac disease

Following positive coeliac-specific serology results, advise the patient to continue eating a gluten-containing diet and organise referral to a gastroenterologist for further assessment (Figure 2).¹ In the past, duodenal biopsy was regarded as the gold standard investigation for the diagnosis of coeliac disease, but due to advancements in the reliability and accuracy of serological testing over time, some gastroenterologists now consider strongly suggestive serology results to be sufficient for diagnosis, particularly in children (see: “A diagnosis of coeliac disease can be made in some children without a duodenal biopsy”) and now increasingly in selected adults, e.g. those aged under 50 years without red flag symptoms and signs.¹⁵ Some gastroenterologists also diagnose coeliac disease without duodenal biopsy in people with confirmed dermatitis herpetiformis.

In some cases, genetic testing may be considered if the diagnosis of coeliac disease is uncertain (see: “HLA typing may be requested by a gastroenterologist to exclude coeliac disease in selected patients”).¹

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Figure 2. Diagnostic overview of coeliac disease in adults.¹²

A duodenal biopsy can still be useful for some patients

Histological changes characteristic of coeliac disease include flattening of the villi, crypt hyperplasia, a thickened basement membrane, raised intraepithelial lymphocytes and inflammatory cell infiltrate of the lamina propria.^{4, 5}

A biopsy may still be recommended for a patient for the following reasons:^14–16

• For diagnostic certainty as:
  • Elevated anti-tTG titres could represent a false-positive result
  • Some patients find reassurance in having a histologically confirmed diagnosis
  • Adherence to a gluten-free diet is a lifelong commitment and usually has a significant effect on the patient’s quality of life, including financial implications
• To assess mucosal damage. Serological testing may not always correlate with mucosal damage, and it is important to accurately determine the degree of inflammation and villous changes in the small intestine as well as excluding other small intestinal diseases.
• Due to implications for future medical care, e.g. increased risk of malignancy
• For Special Authority approval of partly funded gluten-free products.^* N.B. A biopsy is not required for Special Authority approval in children where a biopsy-free diagnosis has been made by a paediatric gastroenterologist.

^*Funding of these products is no longer actively managed by PHARMAC (i.e. no access, product or funding changes will occur), therefore, the range of funded items will decrease over time¹⁷

Although rare, false negative and false positive results can still occur with duodenal biopsy, e.g. if the sample is taken in an area without damage, or if medicine-related adverse effects or an infection produces histological changes consistent with those of coeliac disease.^14–16

If clinical suspicion for coeliac disease remains despite normal histological findings, consider re-referral to a gastroenterologist for further assessment if this has not already been organised.¹

HLA typing may be requested by a gastroenterologist to exclude coeliac disease in selected patients

Susceptibility genes, HLA-DQ2 and HLA-DQ8, are present in almost all people with coeliac disease.¹ If the patient tests negative for HLA-DQ2/8, coeliac disease is very unlikely.¹ A positive HLA typing result indicates that coeliac disease is possible, however, it does not provide diagnostic certainty as these haplotypes are also present in up to 40% of the general population who do not have coeliac disease.^{4, 13} The positive HLA test must be followed up with coeliac-specific antibody testing (if not already performed) with the patient still consuming gluten, and managed according to the results.¹⁹

HLA typing has a limited role in the diagnosis of coeliac disease because of its high negative predictive value, however, it may be requested by a gastroenterologist to exclude coeliac disease (if the result is negative) if the diagnosis is uncertain, e.g. discrepant findings in a patient who is symptomatic.^{1, 12}

Expert tip: “HLA testing to exclude coeliac disease is not helpful in people with type 1 diabetes as the HLA associations are the same, so they will invariably be positive by virtue of having type 1 diabetes.”

What to do after negative coeliac-specific serology results

If the results of coeliac-specific antibody testing are negative, but the patient remains symptomatic, reconsider differential diagnoses, e.g. irritable bowel syndrome or inflammatory bowel disease. Alternatively, discuss with or refer to a gastroenterologist for further assessment. Check local HealthPathways for specific referral criteria.

A lifelong gluten-free diet is the only effective treatment for coeliac disease

Adherence to a gluten-free diet, i.e. exclusion of all foods containing wheat, rye and barley, is key for the management of coeliac disease.¹ Following a confirmed diagnosis, offer referral to a dietitian if this has not already been organised by the gastroenterologist.¹ Also recommend that patients or their parents/caregivers join local support groups and register with Coeliac New Zealand; a range of resources, advice and assistance is available on their website: coeliac.org.nz

Educate, support and encourage patients transitioning to a gluten-free diet

Patients should be provided with ongoing support, education and reassurance when changing to and sustaining a gluten-free diet.¹ Adherence to a strict gluten-free diet is challenging, even in ideal circumstances and can be complicated by family and professional commitments as well as fears of social isolation or being different.¹ Food is also often a significant aspect of family and cultural traditions.

With the help of Coeliac New Zealand, peer support groups, a dietitian and their general practice team, people with coeliac disease should be educated and advised on:

How to eat a balanced, varied, gluten-free diet

Strict adherence to a gluten-free diet generally corrects any initial nutritional deficiencies that were due to malabsorption. However, some gluten-free diets can be low in nutrients including, fibre, calcium, vitamin D, vitamin B12, folate or iron; advise patients to eat a balanced and varied diet (e.g. high-fibre with whole-grain rice, corn, potatoes and vegetables) with appropriate substitutions, and consider supplementation as required.^{1, 3}

The role of oats in a gluten-free diet

Oats contain high levels of some vitamins, minerals and fibre which can improve the nutritional adequacy and variety of a gluten-free diet. Some people with coeliac disease, however, do not tolerate oats (possibly due to avenin toxicity/sensitivity), and there can also be cross contamination with gluten during production; there is no reliable source of gluten-free oats available in New Zealand.¹⁹ For these reasons, Coeliac New Zealand does not recommend the consumption of oats for people with coeliac disease. However, this is still somewhat of a “grey area”, for example, some paediatric gastroenterologists may recommend that oats can be re-introduced for children under medical supervision after tTG has normalised, with monitoring of serology. Flaked buckwheat, quinoa or other gluten-free grains may be suitable alternatives in those who cannot tolerate oats.

Product availability

Gluten-free foods are usually widely available in supermarkets and via gluten-free food supplier websites. A small selection of gluten-free products, e.g. flour, baking mix, bread mix and pasta, are available on prescription (partly funded with Special Authority approval^*).¹⁷ N.B. The funding of these products is no longer actively managed by PHARMAC (i.e. no access, product or funding changes will occur), therefore, the range of funded items will decrease over time.¹⁷ Prescription gluten-free products may not be less expensive than supermarket equivalents when consultation and other prescription-associated fees are considered. Some people with coeliac disease (or caregivers) may also be eligible to receive a disability allowance; for further information, see: coeliac.org.nz/winz-info

^*Partly funded for patients with a biopsy-proven diagnosis of coeliac disease (or for children with a biopsy-free diagnosis of coeliac disease according to ESPGHAN criteria) or if the patient has dermatitis herpetiformis. Prescription gluten-free products are only available at hospital pharmacies (home delivery may be available in some areas).

How to interpret food labels

It can be difficult for people newly diagnosed with coeliac disease to establish which food products are gluten-free as many contain ingredients made from gluten-containing grains that may not be immediately obvious. The Australia New Zealand Food Standards Code established under The Food Standards Australia New Zealand (FSANZ) Act 1991 requires that food labels must declare if the product contains an ingredient derived from a cereal containing gluten, e.g. wheat, rye, barley (and malt derived from barley), spelt and oats.²¹ A full list of gluten-containing grains is available from: coeliac.org.nz/common-sources-of-gluten

Foods labelled as “low gluten” or “contains traces of gluten” are not usually suitable for a person with coeliac disease.

Many product labels state “may contain gluten” but are gluten-free by ingredient. Although these foods may not necessarily produce symptoms related to gluten exposure, there is a risk that intestinal damage can occur, especially if eaten frequently or in large quantities. This labelling is not a FSANZ requirement, and usually means that the manufacturer cannot guarantee that the product does not contain gluten, e.g. there may be a risk of cross-contamination because it was processed in a manufacturing plant that also produces gluten-containing products. In practice, many people with coeliac disease choose to consume “may contain” foods so that their diet is not too restrictive; encourage these patients to be vigilant for any symptoms, and have a low threshold for serology testing if symptoms are reported.

Cross contamination and hidden sources of gluten

Common examples include foods containing additives or thickeners derived from wheat, some confectionery, desserts, coated oven fries, processed meats, sauces (including some soy sauces), dressings and soups. Some medicines may contain gluten as an excipient but usually only in small amounts; continued use, however, can cause ongoing mucosal damage and symptoms in some people with coeliac disease. Before prescribing a medicine to a patient with coeliac disease, check the excipient list for gluten. Certain children’s play materials may also contain gluten, e.g. synthetic modelling doughs and plasticines. Involvement of caregivers and teachers can help to prevent “cheating” or experimentation with the diet, sharing lunchboxes at school, parties or other accidental exposure to gluten.

Smartphone apps are available to support people living gluten-free with coeliac disease. These apps range from enabling food and symptom tracking, to providing gluten-free recipes and food substitutions. For further information, see: www.healthnavigator.org.nz/apps/c/coeliac-disease-apps

A gluten-free diet improves symptoms and long-term health for people with coeliac disease

A strict lifelong gluten-free diet usually resolves the majority of symptoms associated with coeliac disease, normalises coeliac-specific antibody titres and heals the small intestinal mucosa.¹²

After 6 – 12 months of adherence to a gluten-free diet, approximately 80% of people with coeliac disease will test negative for coeliac antibodies or show a considerable reduction in tTG titre, and by five years of adherence, this increases to more than 90%.¹ The rate of histological improvement is comparatively slower; studies show that mucosal healing can take up to two years for children and up to eight years for adults.^{1, 14}

Eliminating gluten from the diet also lowers the risk of complications associated with coeliac disease, e.g. osteoporosis, infertility (see: “Complications of coeliac disease”).^{1, 3, 4}

It is estimated that fewer than one in 100 people with coeliac disease will not respond to a strict gluten-free diet and require further gastroenterology review (see: “Consider the possibility of non-responsive or refractory coeliac disease”).⁴

Regular follow-up is recommended

Follow-up is typically more frequent in the first year following a diagnosis of coeliac disease, e.g. ideally every three to six months, while the patient is becoming established on a gluten-free diet.^{1, 28} Initially, this may be with the gastroenterologist, but for most patients, ongoing follow-up occurs in primary care. Once the patient is successfully established on a gluten-free diet and symptoms have resolved, reviews can be conducted annually.¹ People with coeliac disease should also be reviewed during pregnancy.

Suggested approach to follow-up appointments:^{1, 9}

• Check BMI or monitor growth in children
• Ask about any persistent or new symptoms. If indicated, perform a physical examination, e.g. abdominal palpation for any tenderness, mass or another abnormality.
• Check how the patient is coping with the gluten-free diet. If there are concerns about inadvertent exposure, repeat coeliac serology and consider re-engagement with a dietitian. Coeliac serology should be repeated after 12 months of a gluten-free diet regardless of symptoms.
• Repeat laboratory tests, e.g. ferritin, folate and vitamin B12, particularly if there were abnormal biochemistries at diagnosis and if symptoms suggest, check for other laboratory evidence of autoimmune conditions, e.g. with LFTs, TSH. If nutritional deficiencies have not normalised or improved after one year of a gluten-free diet (or earlier as appropriate, e.g. older age), consider supplementation.
• Discuss ways to optimise bone health. Bone densitometry scans can be requested on a case-by-case basis, e.g. aged > 55 years or with additional risk factors for osteoporosis.²³

Vaccination: People with coeliac disease should be vaccinated against pneumococcus (not funded) due to the increased risk of hyposplenism; the benefit of other vaccinations such as Haemophilus influenzae type b (not funded), meningococcus (not funded) and annual influenza vaccine (funded) to people with coeliac disease are less clear, although may be considered.^{1, 28}

Consider the possibility of non-responsive or refractory coeliac disease in patients who have had an inadequate response to a gluten-free diet after 12 months, i.e. persistent symptoms, if other diagnoses have been excluded.^{1, 9} Refer the patient to a gastroenterologist for further assessment. Check local HealthPathways for specific referral advice.

“Tighten up your glute-n facts!” with a podcast from The Curbsiders. Dr Amy Oxtentenko discusses coeliac disease from an American perspective, covering the recognition of classical and non-classical features of coeliac disease, diagnostic testing, management and follow up. Listen to it here: thecurbsiders.com/podcast/300 (skip ahead to ‘12.57’ for the main content). Don’t have time to listen to the whole podcast? Click here for a quick summary.

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