https://www1.racgp.org.au/ajgp/2018/january-february/interpreting-tests-for-coeliac-disease-1

• Coeliac disease is a chronic immune-mediated small bowel disorder triggered by dietary gluten in genetically susceptible people.
• Gluten is found in:
  • Wheat
  • Barley
  • Rye
  • Triticale
• Oats contain proteins similar to gluten and may trigger symptoms or immune activity in some patients.
• Gluten exposure causes small bowel mucosal inflammation, villous atrophy and reduced absorptive surface area.
• It can present with gastrointestinal symptoms, extra-intestinal features, or minimal/no symptoms.
• It can develop at any age; median age of diagnosis is around 40 years.
• Coeliac disease should not be excluded based on sex, age, ethnicity, or body habitus. Around one-third of patients may be overweight or obese at diagnosis.

Epidemiology / risk

• Australian prevalence is approximately 1.5%.
• Around 80% of Australians with coeliac disease remain undiagnosed.
• Female predominance is seen, but men are often underdiagnosed.
• Older patients can be affected; patients aged >60 years represent a significant minority of cases.
• Family history is a strong risk factor:
  • First-degree relatives: approximately 10% risk
  • Risk may increase to 20% if multiple family members are affected
  • Second-degree relatives: lower risk, but screening may be considered if multiple family members are affected
• Monozygotic twins have high concordance.
• Population screening is not routinely recommended, but active case-finding in at-risk groups is recommended.

Pathophysiology

• Coeliac disease occurs in genetically susceptible individuals, usually with HLA-DQ2 and/or HLA-DQ8.
• Gluten, particularly gliadin, triggers an abnormal immune response in the small bowel.
• Immunological mechanisms include:
  • T-cell mediated inflammation
  • IgA and IgG antibody responses
  • Inflammation in the lamina propria
  • Villous injury and atrophy
• Histological changes reduce absorptive surface area, causing malabsorption and micronutrient deficiencies.
• Typical biopsy findings:
  • Increased intraepithelial lymphocytes
  • Crypt hyperplasia
  • Villous atrophy

Associated conditions

Consider coeliac disease in patients with associated autoimmune or chromosomal conditions, including:

• Type 1 diabetes mellitus
• Autoimmune thyroid disease
• Dermatitis herpetiformis
• Selective IgA deficiency
• Sjögren syndrome
• Primary biliary cholangitis
• Autoimmune hepatitis
• Addison disease
• Systemic lupus erythematosus
• Alopecia areata
• Vitiligo
• Psoriasis
• Down syndrome
• Turner syndrome
• Williams syndrome

Clinical presentation

Gastrointestinal features

• Chronic or intermittent diarrhoea
• Loose bowel motions
• Abdominal pain
• Bloating
• Flatulence
• Nausea
• Weight loss
• Failure to thrive in infants/children
• Irritable bowel syndrome-like symptoms in adults

Extra-intestinal features

• Fatigue / lethargy
• Iron deficiency
• Folate deficiency
• Vitamin B12 deficiency
• Anaemia
• Headaches
• Osteopenia / osteoporosis
• Dental enamel defects
• Raised transaminases
• Infertility or subfertility
• Recurrent miscarriage
• Oligomenorrhoea
• Dermatitis herpetiformis
• Neurological symptoms, especially peripheral neuropathy or ataxia
• Behavioural or mood symptoms in children, including anxiety, depression, aggression or sleep disturbance

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When to test for coeliac disease

Offer coeliac serology if any of the following are present

• Persistent unexplained abdominal or gastrointestinal symptoms
• Faltering growth
• Prolonged fatigue
• Unexpected weight loss
• Severe or persistent mouth ulcers
• Unexplained iron, vitamin B12 or folate deficiency
• Type 1 diabetes, at diagnosis
• Autoimmune thyroid disease, at diagnosis
• Irritable bowel syndrome in adults
• First-degree relative with coeliac disease

Consider coeliac serology if any of the following are present

• Reduced bone mineral density or osteomalacia
• Unexplained neurological symptoms, especially peripheral neuropathy or ataxia
• Unexplained subfertility or recurrent miscarriage
• Persistently raised liver enzymes of unknown cause
• Dental enamel defects
• Down syndrome
• Turner syndrome

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Initial testing

Important pre-test requirement

• The patient must be eating a normal gluten-containing diet before testing.
• A gluten-free diet can make both serology and histology falsely negative.
• Immunosuppression can also reduce diagnostic sensitivity.

Preferred serology options

Option	Tests	Notes
Option 1: preferred one-step approach	tTG-IgA + DGP-IgG	DGP-IgG is useful if IgA deficiency is present.
Option 2	tTG-IgA + total IgA	If total IgA is low, add DGP-IgG.

Serology interpretation

• tTG-IgA and DGP-IgG both have sensitivity >85% and specificity >90% in practice.
• False-negative rate is approximately 10–15%.
• False negatives are more likely if:
  • Patient is already gluten-free
  • Patient is immunosuppressed
  • Patient has IgA deficiency
  • Child is under 3 years and DGP-IgG was not included
• Higher antibody titres increase the positive predictive value.
• Positive serology alone is not sufficient to diagnose coeliac disease.
• Negative serology does not fully exclude coeliac disease in high-risk patients.
• Persistently positive serology with normal biopsy may represent potential/latent coeliac disease and requires follow-up.

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Confirmation of diagnosis

Gastroscopy with small bowel biopsies

• Small bowel biopsy is the diagnostic cornerstone.
• Biopsy should be performed while the patient is eating gluten.
• Coeliac disease can be patchy, so multiple biopsies are recommended:
  • Two biopsies from the first part of the duodenum
  • Four biopsies from the second part of the duodenum
• Diagnostic histology includes:
  • Raised intraepithelial lymphocytes
  • Crypt hyperplasia
  • Villous atrophy

Important caveat

• Villous atrophy is suggestive but not pathognomonic for coeliac disease.

Other causes of villous atrophy include:

• Giardia
• Common variable immunodeficiency
• Crohn’s disease
• Tropical sprue
• Autoimmune enteropathy
• Cow’s milk protein intolerance
• Medication-related enteropathy, especially olmesartan

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HLA-DQ2/DQ8 genotyping

Role

• HLA-DQ2/DQ8 testing is mainly useful to exclude coeliac disease.
• HLA-DQ2/DQ8 is present in approximately 99% of patients with coeliac disease.
• However, these genes are common in the general population.
• A positive HLA result does not diagnose coeliac disease.
• Absence of HLA-DQ2/DQ8 makes coeliac disease very unlikely, with likelihood <1%.

When HLA testing is useful

• Equivocal or inconclusive serology or biopsy
• Patient has already started a gluten-free diet before testing
• Patient is unwilling or unable to undertake gluten challenge
• Persistent symptoms despite gluten-free diet
• Higher-risk patients where a negative HLA result would avoid further repeat testing
• Family screening where clarifying future risk is useful

Practical points

• HLA testing is a once-only test because genotype does not change.
• HLA results are not affected by a gluten-free diet.
• It should be used selectively because it is relatively expensive.

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Patient already on gluten-free diet

• This is a common diagnostic problem.
• Gluten-free diet for more than a few months can make:
  • Serology falsely negative
  • Histology falsely normal
• Two diagnostic options:

Option 1: HLA-DQ2/DQ8 genotyping

• If HLA-DQ2/DQ8 negative:
  • Coeliac disease is very unlikely.
  • Investigate other diagnoses.
• If HLA-DQ2/DQ8 positive:
  • This does not confirm coeliac disease.
  • Gluten challenge and objective testing are needed for definitive diagnosis.

Option 2: Gluten challenge followed by testing

• Recommended gluten intake:
  • 3–6 g gluten daily
  • Ideally for 6 or more weeks
• Practical equivalent:
  • 2–4 slices of wheat bread daily, or
  • 2–4 Weet-Bix daily, or
  • 0.5–1 cup cooked pasta daily
• Symptom relapse during gluten challenge is common but does not confirm coeliac disease.
• Objective serology and/or biopsy is still required.
• Some patients reporting “gluten sensitivity” may actually be reacting to wheat FODMAPs rather than gluten.

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Paediatric considerations

• Children may present with more classical symptoms:
  • Diarrhoea
  • Abdominal distension
  • Poor growth
  • Failure to thrive
  • Weight loss
• Extra-intestinal and behavioural symptoms can also occur.
• tTG-IgA has lower sensitivity in children under 3 years.
• In children under 3 years, include:
  • tTG-IgA
  • DGP-IgG
• Some European paediatric guidelines allow non-biopsy diagnosis in selected children, but in Australia this should only be done with specialist paediatric input.

Possible non-biopsy criteria include:

• Characteristic symptoms
• tTG-IgA >10 times upper limit of normal
• Positive endomysial antibody on a separate sample
• Positive HLA susceptibility

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Management after diagnosis

Core treatment

• Strict lifelong gluten-free diet.
• Refer to an experienced dietitian.
• Provide education on:
  • Gluten-containing foods
  • Cross-contamination
  • Label reading
  • Eating out
  • Nutritional adequacy
• Encourage patient support resources, such as Coeliac Australia.
• Explain that first-degree relatives should be screened.

Baseline assessment after diagnosis

Consider checking:

• FBC
• Ferritin / iron studies
• Folate
• Vitamin B12
• Vitamin D
• Calcium, phosphate, magnesium
• LFTs
• UEC/eGFR
• TSH ± free T4
• Fasting glucose or HbA1c if clinically indicated
• Zinc if malabsorption suspected
• Bone mineral density, particularly in adults or those with risk factors

Follow-up

• Annual review is recommended.
• Review:
  • Symptoms
  • Weight and nutritional status
  • Dietary adherence
  • Ongoing gluten exposure
  • Micronutrient deficiencies
  • Associated autoimmune disease
  • Bone health
  • Vaccination status

Serology follow-up

• Repeat coeliac serology can be used to monitor response.
• Antibody titres usually start to fall by 3–6 months.
• Titres generally normalise by around 12 months on a strict gluten-free diet.
• Persistently positive titres suggest ongoing gluten exposure.
• In adults, serology correlates poorly with mucosal healing.
• In children, normalising tTG titres correlate better with mucosal recovery.

Repeat gastroscopy

• In adults, repeat gastroscopy after approximately 18–24 months may be considered to assess mucosal healing.
• This is particularly relevant if:
  • Symptoms persist
  • Serology remains positive
  • Diagnosis was uncertain
  • There are complications or red flags
• Children who improve clinically and normalise serology generally do not require repeat endoscopy.

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Complications of untreated or poorly treated coeliac disease

Nutritional / malabsorptive

• Iron deficiency anaemia
• Folate deficiency
• Vitamin B12 deficiency
• Vitamin D deficiency
• Calcium deficiency
• Vitamin K deficiency with bleeding tendency
• Zinc deficiency
• Poor growth in children
• Fatigue and reduced exercise tolerance

Bone health

• Osteopenia
• Osteoporosis
• Osteomalacia
• Increased fracture risk

Reproductive

• Subfertility
• Recurrent miscarriage
• Pregnancy complications

Malignancy

• Increased risk of lymphoma, especially non-Hodgkin lymphoma / enteropathy-associated T-cell lymphoma
• Increased risk of small bowel adenocarcinoma

Other

• Secondary lactose intolerance
• Functional hyposplenism
• Increased risk of some infections
• Neurological complications, including neuropathy and rarely seizures

Vaccination

• Review immunisation status.
• Consider pneumococcal vaccination, particularly due to increased infection risk, possibly related to functional hyposplenism.

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Practical approach

1. Suspect coeliac disease in patients with GI symptoms, fatigue, iron/B12/folate deficiency, autoimmune disease, osteoporosis, infertility, abnormal LFTs, or family history.
2. Confirm gluten intake before testing.
3. Request tTG-IgA + DGP-IgG or tTG-IgA + total IgA.
4. If serology positive, refer for gastroscopy and duodenal biopsies.
5. Do not start a gluten-free diet before diagnostic testing unless unavoidable.
6. If already gluten-free, consider HLA-DQ2/DQ8 and/or gluten challenge.
7. After diagnosis, treat with lifelong strict gluten-free diet and dietitian input.
8. Monitor symptoms, serology, nutritional deficiencies, bone health and associated autoimmune disease.
9. Screen first-degree relatives.
10. Reconsider diagnosis, adherence, complications, or alternate pathology if symptoms persist.

Key pitfalls

• Do not diagnose coeliac disease on symptoms alone.
• Do not diagnose coeliac disease on serology alone.
• Do not test after gluten has been removed without recognising false-negative risk.
• Do not exclude coeliac disease in overweight patients.
• Do not exclude coeliac disease in men, older patients, or non-European patients.
• Do not assume negative serology excludes disease in high-risk patients.
• Do not rely on symptom relapse during gluten challenge as diagnostic.
• Do not forget IgA deficiency.
• Do not forget other causes of villous atrophy.
• Point-of-care coeliac antibody tests are not recommended for primary care diagnosis.

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Patient explanation — Coeliac disease

What is coeliac disease?

Coeliac disease is a lifelong condition where your immune system reacts abnormally to gluten.

Gluten is a protein found in:

• Wheat
• Barley
• Rye
• Triticale

In people with coeliac disease, eating gluten causes inflammation and damage to the lining of the small bowel. This lining normally absorbs nutrients from food. When it is damaged, the body may not absorb nutrients properly.

Is it an allergy?

No. Coeliac disease is not a food allergy and it is not simply “gluten intolerance”.

It is an autoimmune condition, meaning the immune system mistakenly attacks the body’s own small bowel lining when gluten is eaten.

What symptoms can it cause?

Symptoms vary a lot. Some people have bowel symptoms, while others mainly have tiredness or low vitamin/iron levels.

Common symptoms include:

• Diarrhoea or loose stools
• Bloating
• Abdominal pain
• Excess wind
• Nausea
• Weight loss, although some people are overweight
• Fatigue or lethargy
• Iron deficiency or anaemia
• Low B12, folate or vitamin D
• Mouth ulcers
• Headaches
• Osteopenia or osteoporosis
• Infertility or recurrent miscarriage
• Itchy blistering rash called dermatitis herpetiformis

Some people have very mild symptoms or no obvious symptoms.

Why is diagnosis important?

Untreated coeliac disease can lead to:

• Ongoing tiredness and poor wellbeing
• Iron, B12, folate, calcium or vitamin D deficiency
• Osteoporosis
• Poor growth in children
• Fertility or pregnancy issues
• Increased risk of some bowel-related cancers, especially lymphoma
• Ongoing bowel inflammation

The good news is that treatment with a strict gluten-free diet usually allows the bowel lining to heal and reduces these risks.

How is it tested?

The first step is usually a blood test called coeliac serology.

This often includes:

• tTG-IgA
• DGP-IgG
• Sometimes total IgA

It is very important that you are still eating gluten before the test. If you have already stopped gluten, the blood test may be falsely normal.

If the blood test is positive, the diagnosis is usually confirmed with a gastroscopy and small bowel biopsies. This means a specialist looks at the small bowel lining and takes tiny samples.

Should I stop gluten before testing?

No — not unless your doctor has told you to.

Stopping gluten before testing can make the blood test and biopsy look normal, even if you actually have coeliac disease.

If you have already stopped gluten, your doctor may discuss:

• HLA-DQ2/DQ8 genetic testing, or
• A supervised gluten challenge before repeat testing

What is the treatment?

The treatment is a strict lifelong gluten-free diet.

This means avoiding gluten from wheat, barley, rye and triticale. You will usually be referred to a dietitian to learn how to:

• Identify gluten-containing foods
• Read food labels
• Avoid cross-contamination
• Maintain good nutrition
• Replace any vitamin or mineral deficiencies

Most people feel better after starting a gluten-free diet, but bowel healing can take months to years.

Do family members need testing?

Yes, close family members have a higher risk.

First-degree relatives, such as parents, siblings and children, should consider screening even if they feel well.

Key message

Coeliac disease is a serious but very manageable condition. The main treatment is a strict lifelong gluten-free diet, but it is important to confirm the diagnosis properly before removing gluten from the diet.