- Coeliac disease is a disorder of the proximal small intestine.
- It can occur at any age.
- Diarrhoea is the most common presenting symptom in adults.
- Lifelong avoidance of dietary gluten is an austere yet effective
- Non-adherence to a gluten-free diet causes most ongoing symptoms.
1. AETIOLOGY AND EPIDEMIOLOGY
Coeliac disease was first described by Samuel Gee in 1888, although a similar description of a chronic, malabsorptive disorder reaches as far back as the 2nd century AD. Until recently it was considered to be a rare childhood affliction, although is now recognised to occur at any age, with a wide range of clinical manifestations.
The Dutch paediatrician, Willem K Dicke, was the first to recognise an association between the consumption of bread and cereals and the onset of diarrhoea. This observation was corroborated by the Dutch famine during the Second World War, when the symptoms of those affected improved with the introduction of non-cereal containing foods. The toxic agent, gliadin, was subsequently found to be present in gluten, the alcohol-soluble fraction of wheat protein.
The histological lesion in the proximal small intestine was first described in 1954. The primary findings are mucosal inflammation, crypt hyperplasia and villous atrophy.
In a dose-dependent fashion, the wheat proteins induce a T-cell mediated inflammatory response in genetically predisposed individuals. The putative auto-antigen is tissue transglutaminase (TTG), a ubiquitous intracellular enzyme that is released by inflammatory cells and fibroblasts. It acts on gliadin to promote antigen presentation to intestinal T-cells, which provoke inflammation and villous atrophy.
Coeliac disease mainly affects white Europeans, primarily of Celtic ancestry.
Coeliac disease was previously thought to be rare, on the basis of clinical frequency, affecting one in 3,000 people worldwide. However, the advent of serological testing has shown the worldwide prevalence to be 1 in 266.
Thus, a vast population of patients exist, previously thought to be asymptomatic, but now recognised to have non-specific symptoms and be subject to the same risks and complications as those with 'classical' disease.
Coeliac disease can also affect non-European populations if they have an appropriate genetic background. Punjabi and Gujarati migrants living in England develop the disorder 2.7 times more commonly than Europeans when on a gluten-rich diet. A disorder named 'summer diarrhoea' has long been known in India, which occurs when wheat replaces maize during the summer season.
The mortality rate in coeliac disease exc-eeds that of the general population by a factor of 1.9-3.8, which is mainly due to malignant disease.
The reduction in excess mortality after one to five years on a gluten-free diet suggests that such a diet is protective against malignancy.
This notion is lent support by a Finnish study that showed patients on a strict gluten-free diet had no greater frequency of death than the general population.
- Patients with coeliac disease are intolerant to gliadin, which is present in gluten.
- Coeliac disease mainly affects white Europeans, primarily of Celtic ancestry.
- The mortality rate in coeliac disease exceeds that of the general population by a factor of 1.9-3.8, mainly due to malignant disease.
- After one to five years on a gluten-free diet, this excess mortality is reduced to that of the general population.
2. CLINICAL MANIFESTATIONS
Coeliac disease is a disorder of the proximal small intestine that can involve the entire small intestine. This location often results in malabsorption of iron, folic acid, calcium and fat-soluble vitamins, with resultant nutrient deficiencies and reduced bone density. Diarrhoea, the hallmark of 'classical' disease, is a result of progression of disease to the distal small bowel.
If only the proximal small bowel is involved, then the distal small bowel is able to compensate and absorb the products of fat and carbohydrate digestion. Pregnancy, traveller's diarrhoea, gastroenteritis or gastrointestinal surgery can act as a trigger for the development of symptoms.
Infants and young children present with diarrhoea, abdominal distension and failure to thrive. However, vomiting, irritability, anorexia and constipation are also common.
Diarrhoea remains the most common presenting symptom in adults, but accounts for less than half of all presentations. Patients frequently have a long duration of symptoms, with a mean time to diagnosis of 11 years. In the interim, patients often receive an alternate diagnosis, such as irritable bowel syndrome (IBS).
Extra-intestinal manifestations are frequently the presenting complaints.
These include dermatitis herpetiformis and neurological symptoms.
Dermatitis herpetiformis is an intensely pruritic vesicular rash, occurring anywhere on the body but especially on the extensor surfaces and the scalp.
The diagnosis is confirmed by the demonstration of granular IgA on the subepidermal basement membrane. Dapsone controls these skin lesions, although the majority resolve on a gluten-free diet.
The neurological presentations are varied, from peripheral neuropathy or ataxia to neuropsychiatric syndromes such as depression, anxiety or epilepsy. The frequency of this association appears to be under-recognised.
For example, in one series of patients with idiopathic ataxia, 68 per cent had serological markers of coeliac disease.
The subclinical form of coeliac disease has become apparent since the development of serological testing. These patients experience mild, non-specific symptoms such as fatigue, unexplained iron-deficiency, unexplained elevations in serum transaminases or no symptoms at all.
Establishing the diagnosis of subclinical coeliac disease is important for four reasons: the risk of potential malignancy, the presence of unsuspected nutritional deficiencies, the association with low-birth weight infants in affected mothers, and the occurrence of autoimmune disorders.
The risk of malignancy in patients with subclinical coeliac disease is not known, although it appears to be lower than in patients who present with malabsorption symptoms. However, once the disease is in remission, with the patient on a gluten-free diet, the risk approaches that of the normal population. The prevalence of autoimmune disease, such as type-1 diabetes mellitus and autoimmune thyroiditis, appears to be related to the duration of undetected coeliac disease.
- Malabsorption of iron, folic acid, calcium and fat-soluble vitamins is present, with resultant nutrient deficiencies and reduced bone density.
- Infants and young children present with diarrhoea, abdominal distension and failure to thrive.
- Patients with the subclinical form of coeliac disease experience mild, non-specific symptoms such as fatigue, unexplained iron-deficiency, unexplained elevations in serum transaminases or no symptoms at all.
3. DIAGNOSIS OF COELIAC DISEASE
Coeliac disease is diagnosed by the presence of characteristic changes on a small intestinal biopsy sample, and improvements in clinical symptoms or histology after four to six months on a gluten-free diet. Positive serological tests lend support to the diagnosis, but are not essential.
The detection of IgA antibodies against TTG antibodies has a sensitivity of 95 per cent and specificity of 96 per cent for the diagnosis of coeliac disease. However, this should not replace small intestinal histology, which is required both to confirm the diagnosis, and as a baseline from which to monitor improvement.
Selective IgA deficiency occurs in 2.6 per cent of patients with coeliac disease, 10-fold higher than that in the general population. Thus, individuals with selective IgA deficiency and coeliac disease will not have anti-TTG antibodies. These patients will, nevertheless, have a raised total IgG concentration.
The diagnosis therefore rests upon measuring the serum IgA, and specific anti-endomysial and anti-TTG IgG antibody tests. The combination of IgA deficiency and a positive IgG test should prompt a biopsy.
The amount of dietary gluten, the presence of symptoms, the degree of villous atrophy and the concomitant use of immunosuppressants influence titres of anti-TTG antibodies. Therefore, serological testing alone will significantly underestimate the prevalence of coeliac disease.
Antibody titres are usually undetectable after six to 12 months on a gluten-free diet, but can take up to 31 months if the initial titres are high. Seroconversion precedes histological improvement.
The major pitfall of histological diagnosis is biopsy interpretation.
Adequate numbers of biopsies are required, since the disease is patchy and the biopsies need to be oriented correctly to interpret the crypt-to-villous ratio. As a rule, at least three well-oriented crypts need to be identified to interpret villous atrophy.
The differential diagnosis of villous atrophy includes post-gastroenteritis, giardiasis, peptic duodenitis, tropical sprue and Crohn's disease. Negative serological tests or poor response to a gluten-free diet should prompt review of the biopsy to ensure that the original interpretation was correct.
When to consider a biopsy:
- Gastrointestinal symptoms including chronic diarrhoea, malabsorption,
weight loss and abdominal distension.
- Iron-deficiency anaemia.
- Short stature.
- Delayed puberty.
- Elevation of serum transaminases.
- Recurrent foetal loss and infertility.
- Peripheral neuropathy and cerebellar ataxia.
- Coeliac disease is diagnosed by the presence of characteristic changes on a small intestinal biopsy sample, and improvements in clinical symptoms or histology after four to six months on a gluten-free diet.
- Positive serological tests lend support to the diagnosis, but are not essential.
- The major pitfall of histological diagnosis is biopsy interpretation.
- Negative serological tests or poor response to gluten-free diet should prompt biopsy review.
4. DIETARY COUNSELLING AND SUPPLEMENTATION
Lifelong avoidance of dietary gluten is an austere yet effective therapy. Adherence to such a diet should follow a definitive, biopsy-proven, diagnosis.
Dietary counselling is the cornerstone of treatment. Gluten is a common constituent of the western diet, and complete avoidance is a significant challenge.
Written information and dietary counselling are essential to promote compliance. Further resources include patient groups such as Coeliac UK, internet sites, gluten-free cook books and gluten-free prepared foods.
Gluten-free products are available on prescription, which should be on FP10 forms clearly marked ACBS, an abbreviation for 'according to the borderline substances act'. Specialist products include bread, biscuits, flour, pasta, crackers, pizza bases and cakes. Luxury items can be obtained from supermarkets and health food shops.
Oats are of a different taxonomy to wheat, barley and rye, and do not have gliadin as their major protein. They are considered safe in coeliac disease. However, many patients experience symptoms on eating oats, due to contamination of commercially available oats with other grains.
Potatoes, rice, fruits, vegetables, maize, corn, soya, eggs and dairy produce are all safe. Attention should be given to food labels and also to additives, since stabilisers and emulsifiers can also contain gluten.
A gluten-free diet can induce constipation due to the lack of roughage.
This usually responds to dietary rice bran and ispaghula husk.
Nutritional and calorific deficiencies must be sought and appropriately supplemented. Specific dietary deficiencies such as iron, folic acid, calcium, vitamin D and, rarely, vitamin B12, should be corrected.
Bone loss is common in coeliac disease, and can occur in patients without gastrointestinal symptoms. Much of this is related to secondary hyperparathyroidism, a consequence of vitamin D deficiency. It is only partly corrected by a gluten-free diet, and can persist despite normal serum calcium and alkaline phosphatase values.
All patients should have their bone mass assessed by dual energy X-ray absorptiometry at diagnosis. All patients should receive calcium and vitamin D supplementation, and appropriate osteoporosis treatment as determined by their bone density.
Coeliac disease is also associated with hyposplenism, hence patients should be immunised with pneumococcal vaccination.
- Lifelong avoidance of dietary gluten is an austere yet effective therapy.
- Oats are considered safe.
- Bone mass assessment by dual energy X-ray absorptiometry at diagnosis is essential.
- All patients should receive calcium and vitamin D supplementation, and appropriate osteoporosis treatment.
5. FOLLOW-UP AND NON-RESPONDERS
Non-adherence is the most common cause of ongoing symptoms after the introduction of a gluten-free diet. Many patients consider their symptoms to be sufficiently mild as to not warrant gluten avoidance and lifestyle change.
This opinion is even more common among asymptomatic patients, in whom coeliac disease was diagnosed following antibody testing. However, regardless of clinical symptoms, the previously stated arguments favour the strict adherence to a gluten-free diet in patients with established coeliac disease.
Despite feeling clinically well, patients can have a variety of micronutrient deficiencies that might have clinical sequelae, such as bone loss or anaemia.
These patients also have increased mortality compared to the general population, predominantly due to gastrointestinal malignancy, which recedes with adherence to a gluten-free diet.
The likelihood of developing associated autoimmune disease can also be related to the duration of exposure to gluten. Furthermore, mothers with untreated coeliac disease are at increased risk of having children of low birth weight or with neural tube defects.
Further counselling with an experienced dietitian, and meticulous food diary monitoring, are appropriate at this stage.
In patients who do not respond to gluten avoidance a secondary diagnosis, refractory coeliac disease or intestinal lymphoma should be considered.
IBS, lactose intolerance or small bowel bacterial overgrowth are frequent secondary diagnoses. Refractory disease or suspected lymphoma often requires inpatient assessment by a gastroenterology multidisciplinary team.
Coeliac disease has undergone a metamorphosis from a rare disorder of infancy to a silent epidemic with lifelong consequences. The cornerstones of management are a long-term relationship with physicians and dietitians, patient education and lifelong support.
- Non-adherence is the most common cause of ongoing symptoms.
- Counselling and food diary monitoring are appropriate.
- Mothers with untreated coeliac disease are at increased risk of having children of low birth weight or with neural tube defects.
Furse R M, Mee A S. Atypical presentation of coeliac disease. BMJ 2005;
See Medicine on the Web, page 32.
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