Coeliac disease is a common disorder of the small intestine in which storage proteins in dietary wheat, rye, and barley (gliadin, secalins, hordeins, usually referred to as ‘gluten’) induce T-cell responses restricted by HLA DQ2 or DQ8. This immune response drives intestinal inflammation and loss of villous architecture and can lead to a wide spectrum of clinical manifestations.

The condition presents most commonly either in early childhood or in the third or fourth decade of life. A ‘classical’ malabsorption syndrome characterized by diarrhoea, steatorrhoea, weight loss, fatigue, and anaemia may occur in severe cases, but is now rare: most patients have a milder constellation of symptoms such as abdominal discomfort, bloating, indigestion or nongastrointestinal symptoms (e.g. dermatitis herpetiformis), and many have no symptoms at all.

Diagnosis is made by serological testing for antitissue transglutaminase/antiendomysial antibodies, which have excellent sensitivity and specificity. About 1% of the (white European origin) population have positive coeliac serology, but many are undiagnosed. Positive serological tests should be followed by small intestinal biopsy, whilst a normal (gluten containing) diet is continued, looking for histological features of intraepithelial lymphocytosis, chronic immune cell infiltration of the lamina propria, loss of villous height (villous atrophy), and crypt hyperplasia.

Treatment is by strict avoidance of dietary wheat, rye, and barley (a gluten-free diet), which is safe and usually effective, but constitutes a major challenge for some people. Most patients (but not all) can eat pure oats. Screening for osteoporosis, vitamin D deficiency, and osteomalacia is advised, with treatment if indicated.

Intestinal complications include enteropathy-associated T-cell lymphoma, which should be considered particularly in older patients experiencing a clinical relapse in symptoms, despite effective gluten exclusion, after a prolonged period of clinical response. The overall prognosis of coeliac disease is excellent, but requires lifelong commitment to a gluten-free diet to reduce the risk of complications.

Coeliac Disease in great detail

Introduction

Coeliac disease is a common (c.1% prevalence) inflammatory disorder of the small intestine occurring in both children and adults. Specific proteins in dietary wheat, rye, and barley (gliadin, secalins, hordeins, usually referred to as ‘gluten’) induce T cell responses restricted by HLA DQ2 or DQ8. These responses are central to the subsequent intestinal inflammation and loss of villous architecture that characterizes the disease. Now that serological testing is widespread, symptoms observed in diagnosed individuals vary greatly and are often absent. Classical malabsorption is now infrequent, and only the most florid of the spectrum of presentations seen in coeliac disease. Strict avoidance of dietary wheat, rye, and barley (a gluten-free diet) usually induces remission. Disease reappears on re-challenge and dietary treatment is lifelong.

Historical perspective

Aretaeus (2nd century AD) gave the first recognizable account of coeliac disease (Greek: koiliakos, abdominal) describing steatorrhoea, that disease occurred in both children and adults, and that it was more common in women than men. Samuel Gee presented the first clear modern description of coeliac disease in 1888. Willem Dicke (1950) in his doctoral thesis entitled ‘Investigation of the harmful effects of certain types of cereal on patients suffering from coeliac disease’ outlined the modern treatment of a gluten-free diet. Dicke came to these observations in part by noticing that when wheat flour (i.e. bread) became scarce in the wartime Netherlands, children with coeliac disease paradoxically improved. John Paulley (1954) demonstrated using surgical operative specimens that villous atrophy occurs in the small-intestinal mucosa in coeliac patients. A technique enabling small-bowel biopsy by the oral route was first developed by Margot Shiner (1956), refined as the ‘Crosby capsule’ (1957), and subsequently replaced in the 1980s by fibre optic endoscopy. Shiner and Doniach (1960) were then able to show using light and electron microscopy the identical histology of adult idiopathic steatorrhoea and childhood coeliac disease. Marsh described the sequence of changes in small-intestinal histology, and a classification system. Duhring (1884) was the first to describe dermatitis herpetiformis, and the often coexisting coeliac small bowel changes were described by Marks and Watson (1966).

The cultivation of wheat in Europe began about 5000 years ago, and (with rye) it became more common in the diet with the introduction of crop rotation in the Middle Ages. Serological diagnostic tests became available in the 1960s (antigliadin antibodies) and 1970s (antireticulin antibodies), although they lacked specificity until the development of the antiendomysial antibody test (1984). The HLA association was recognized in 1972. Dieterich and colleagues (1997) identified tissue transglutaminase as the endogenous target of antiendomysial antibodies and the key autoantigen in coeliac disease.

Aetiology (Causes)

Many of the immunological mechanisms by which dietary wheat (and to a lesser extent rye and barley) induce coeliac disease are now understood. Wheat gluten is partially digested, but key toxic protein sequences are resistant to intestinal proteases—in part due to high proline (P) and glutamine (Q) content. Tissue transglutaminase in the intestinal epithelium deamidates critical peptide sequences such as the dominant HLA DQ2 restricted wheat epitope sequence PQPQLPY to PQPELPY, and (cross-linked to critical wheat peptides during the deamidation step) is the antigen detected by current diagnostic serological tests such as the antiendomysial or tissue transglutaminase antibody assays. It is unclear if these antibodies have a pathological role in coeliac disease. Work using intestinal T cell clones, intestinal biopsy culture, and peripheral blood T cells in wheat antigen challenged coeliac patients, has shown that wheat peptides are presented by HLA DQ2 (or in a few patients DQ8) to CD4+ helper T cells. Immunodominant wheat (and rye, barley) epitopes that are capable of inducing T cell responses in almost all coeliac patients have been defined, and the crystal structure of these epitopes bound to HLA DQ2 or DQ8 has been elucidated. Activated T cells secrete interferon-γ, and other cytokines. Interleukin-15, expressed by intestinal epithelial cells and lamina propria macrophages, appears to activate intraepithelial lymphocytes and leads to epithelial cell killing. Multiple pathways lead to intestinal inflammation, villous atrophy and subsequent malabsorption.

The full HLA DQ2 heterodimer (encoded at the DNA level by the combination of HLA DQA1*0501 and DQB1*0201) is found in around 90% of coeliac disease patients, compared to around 30% of white European population controls. The remaining 10% of coeliac disease individuals either carry HLA DQ8, or part of the HLA DQ2 heterodimer. Carriage of one of these HLA types is therefore necessary but not sufficient to develop coeliac disease.

The HLA only explains around 30% of the heritable risk of coeliac disease; other genetic and environmental risk factors play a major role. Genetic risk variants on chromosome 4 (in a region containing the genes for the T-cell cytokines interleukin-2 and interleukin-21) as well as variants in other immune system genes have recently been identified. Several of these have independently been shown to influence risk to other autoimmune diseases, especially type 1 diabetes mellitus. The timing of the introduction of wheat during infant feeding is probably important, some studies suggesting that continued breastfeeding while weaning is protective. Whether gastrointestinal infections (e.g. rotavirus) in infancy are important triggers remains unclear.

Epidemiology

Prevalence estimates of clinically diagnosed coeliac disease (i.e. where symptoms lead to diagnostic testing) should be distinguished from population prevalence studies that employ serological screening. Most studies have been performed in populations of mainly white European origin, and used combined serological and intestinal biopsy testing. In these studies the prevalence of clinically diagnosed disease is around 0.1% (range 0.05 to 0.3%), whereas seroprevalence (including previously undiagnosed cases) in the general population is around 0.5 to 1% in both children and adults. Prevalence is even higher in close relatives of affected individuals; about 10% in first degree relatives. A large proportion of coeliacs in most populations remain undiagnosed—recently estimated at four out of five affected individuals in the United Kingdom. The highest population prevalence of 5% was found in Saharawi refugees living in Algeria. Coeliac disease occurs in Asians, but is extremely rare in individuals of tropical African, Japanese, and Chinese descent.

The similar United Kingdom population seroprevalence found in studies of children (1.0% in 5470 7-year-olds) and adults (1.2% in 7550 over-45-year-olds), suggests the coeliac trait is present from childhood in all cases, even those subsequently diagnosed as adults. Environmental trigger factors resulting in breakdown of oral tolerance to wheat, rye, and barley are therefore likely to occur in the first few years of life. The clinical observation that some adults suddenly develop symptoms in later life remains unexplained, but may reflect a later event in the control of immunological tolerance.

Clinical Features

Although coeliac disease can be diagnosed at any age, it presents most commonly either in early childhood (between 9 and 24 months) or in the third or fourth decade of life. Coeliac disease is more common in females, with an approximately 2:1 sex ratio. Although the ‘classical’ gastrointestinal malabsorption syndrome characterized by diarrhoea, steatorrhoea, weight loss, fatigue, and anaemia may occur in severe cases, most patients nowadays have a milder constellation of symptoms such as abdominal discomfort, bloating, indigestion, or nongastrointestinal symptoms (or no symptoms at all). The clinical manifestation appears to be changing, with increasing numbers being diagnosed as a result of the investigation of iron deficiency (anaemia), fatigue and/or ‘nonclassical’ symptoms. See bullet point list below:

Although the natural history of the disease may be changing (possibly due to environmental factors), a more likely explanation for the current clinical manifestations is that the ability to make the diagnosis has improved (both better tests, and greater test accessibility) throughout the last 20 years with the development of accurate serological markers of the disease and increasing use of endoscopic biopsy techniques. Therefore a much broader spectrum of individuals are being investigated for coeliac disease and consequently being diagnosed.

Intestinal complications

Refractory coeliac disease

This term is used for the small minority of patients (<5%) who show persistent histological features of coeliac disease with villous atrophy, despite apparently strict exclusion of gluten. In some individuals, this occurs due to the development of an aberrant, premalignant intraepithelial lymphocyte population. Immunohistochemistry is helpful in distinguishing these patients (see below) from those with persistent villous atrophy without aberrant lymphocytes, who have a very low risk of progression to lymphoma.

Enteropathy-associated T cell lymphoma (EATL)

This is a rare complication of coeliac disease but should be considered particularly in older patients experiencing a clinical relapse in symptoms, despite effective gluten exclusion, after a prolonged period of clinical response. Symptoms may include anorexia, weight loss, abdominal pain, fever, night sweats, and diarrhoea.

Ulcerative jejunitis

This presents with small intestinal ulcerations and stricturing—a high index of suspicion should be maintained for the presence of an EATL, as lymphoma may also cause similar appearances, including benign-appearing ulcerations.

Small-bowel adenocarcinoma

The risk of small-bowel adenocarcinoma is increased in coeliac disease, but the absolute risk of this rare cancer is still very small.

Extraintestinal manifestations and associated conditions

Coeliac disease shares similarities with autoimmune diseases, even though the trigger for inflammation in the intestine is not an autoantigen, but dietary gluten. Coeliac disease may have multisystemic effects, thought to be immune-mediated phenomena, although the pathophysiology is unproven in most cases.

Skin

Dermatitis herpetiformis is an inflammatory skin condition characterized by pruritic papules and vesicles over extensor surfaces and IgA deposition in the dermal papillae adjacent to lesions. Histological features of coeliac disease are present on intestinal biopsy in nearly all patients, but only 20% have intestinal symptoms. Dermatitis herpetiformis responds to gluten exclusion, but this may take months to years. Dapsone provides relief of the intense pruritus associated with dermatitis herpetiformis within 2 or 3 days and can lead to healing of the skin lesions, but not cure, as lesions recur rapidly on discontinuation of therapy.

Article about dermatitis herpetiformis

Liver

Mild elevations of hepatic transaminases are common in untreated coeliac disease, which resolve in most cases within 6–12 months of starting a strict gluten-free diet. Separately, there are also associations between coeliac disease and autoimmune liver disorders including autoimmune hepatitis and primary biliary cirrhosis. The progression of these autoimmune disorders in the presence of coeliac disease is unaffected by subsequent gluten exclusion. Although accounting for a small minority of coeliac patients with abnormal liver function tests, these diagnoses should be considered in patients whose abnormal liver function tests do not improve despite prolonged gluten exclusion.

Neurological

Malabsorption may rarely lead to neurological sequelae from vitamin deficiency: vitamin B₁₂ deficiency may cause peripheral neuropathy and myelopathy; vitamin E deficiency can cause cerebellar ataxia or myopathy. Tetany may be seen with severe hypocalcaemia or hypomagnesaemia. Associations with coeliac disease have also been reported for several neurological disorders, notably cerebellar ataxia, peripheral neuropathy, and epilepsy, although most studies have been small or inconsistent. A large Swedish study that retrospectively compared the frequency of several neurological diseases in 14 000 coeliac cases and population controls, found an increased risk of polyneuropathy, but not of other neurological diseases including ataxia.

Other immune-mediated diseases

There is an approximately fivefold increased risk of autoimmune disorders in coeliac disease. Definite associations include type 1 diabetes mellitus, autoimmune thyroid disease, Sjögren’s syndrome, and Addison’s disease.

Miscellaneous

Several cross-sectional studies have shown that the prevalence of coeliac disease is increased (approximately fivefold) in individuals with Down’s syndrome. In untreated coeliac disease, rates of miscarriage and infertility are increased, possibly due to undernutrition, but rates return to near normal following diagnosis and institution of a gluten-free diet.

Differential diagnosis

Several other small-intestinal diseases can cause villous atrophy. See bullet point list below: 

• ◆ Autoimmune enteropathy
• ◆ Common variable immunodeficiency
• ◆ Crohn’s disease
• ◆ Eosinophilic gastroenteritis
• ◆ Giardiasis
• ◆ Graft-vs-host disease
• ◆ HIV enteropathy
• ◆ Ischaemic enteritis
• ◆ Nonsteroidal anti-inflammatory drug enteropathy
• ◆ Peptic duodenitis
• ◆ Post-chemotherapy intestinal mucositis
• ◆ Radiation enteritis
• ◆ Tropical sprue

However, most conditions bear only partial resemblance to coeliac disease and can usually be distinguished either through the clinical history or histologically on careful review. Response to treatment (gluten exclusion) plays an important part in confirming the diagnosis of coeliac disease and excluding other causes. Patients who do not show a clinical or histological response to a strict gluten-free diet warrant consideration of alternative diagnoses and complications of coeliac disease. As well as other causes of villous atrophy, many comorbid conditions may mimic symptoms of coeliac disease and other causes of malabsorption should be excluded. Conditions occurring more frequently in coeliac disease, that may have similar symptoms, include small intestinal bacterial overgrowth, secondary lactase deficiency, microscopic colitis, Crohn’s disease, and ulcerative colitis.

Clinical investigation

Pathology

The coeliac lesion occurs predominantly in the proximal small intestine, reflecting the distribution of gluten encounter. Changes may be mild and patchy and for this reason it is recommended that multiple (>4) biopsies are taken from separate sites, usually by upper gastrointestinal endoscopy from the second part of the duodenum. The classic histological features are intraepithelial lymphocytosis, chronic immune cell infiltration of the lamina propria, loss of villous height (villous atrophy), and crypt hyperplasia. These features may be graded according to a commonly used classification proposed by Marsh. Intraepithelial lymphocytosis is the earliest change, but specificity for the diagnosis of coeliac disease increases with the presence of the other accompanying features, particularly villous atrophy.

Immunohistochemistry for T-cell markers (CD3, CD8) and the epithelial integrin CD103 are of value in refractory coeliac disease in detecting an aberrant intraepithelial T cell population that can precede the development of overt lymphoma.

An approach to duodenal biopsies - detailed and very technical article 

Haematological abnormalities

A variety of haematological abnormalities may occur, arising from haematinic deficiencies, hyposplenism, and autoimmune phenomena. IgA deficiency (2–3%) and non-Hodgkin’s lymphoma (see below) are also more common in coeliac disease.

Anaemia occurs frequently with microcytosis due to iron deficiency, but folate deficiency is also common and may cause macrocytosis. Vitamin B₁₂ levels are usually preserved, except in severe, long-standing disease with involvement of the whole small intestine. Pancytopenia may occur in these cases as a result of folate or vitamin B₁₂ deficiency.

Leucopenia and thrombocytopenia may also occur rarely as an autoimmune phenomenon.

Thrombocytosis is common in coeliac disease and can occur as a result of iron deficiency or hyposplenism, but usually resolves with gluten exclusion.

Morphological red cell changes characteristic of functional hyposplenism (Howell–Jolly bodies, target cells, acanthocytosis) may be apparent on blood film. Hyposplenism (based on sensitive research techniques, such as pitted red cell counting) is common in adult coeliac disease, but is rare in children and may be more frequent in patients with associated autoimmune disorders. The cause of hyposplenism in coeliac disease is unknown. Most studies suggest hyposplenism does not revert after treatment with a gluten-free diet. The risk of infection due to hyposplenism in coeliac disease is likely to be increased, but to date there have been only a few studies. A modest increased risk of infections in all patients with coeliac disease has been suggested by a large Swedish cohort study examining hospital inpatient episodes. The increased risk is partly accounted for by a 2.5-fold increase in the rate of pneumococcal infections. Immunization against the encapsulated organisms Haemophilus influenza type b, Streptococcus pneumonia, and Neisseria meningitidis should be considered in those with blood film evidence of hyposplenism. However, as yet no studies evaluating the effectiveness of this approach in coeliac disease have been performed. Immunization against influenza should also be considered in older patients because of the risk of secondary bacterial infections.

IgA deficiency

This occurs more commonly in coeliac disease, affecting 2 to 3% of patients. Conversely, the prevalence of coeliac disease in IgA deficiency is also increased and may be as high as 8%. IgA deficiency is important in coeliac disease as it may be a cause of false negative IgA endomysial or tissue transglutaminase tests.

Biochemistry

Fat malabsorption occurs in classical coeliac disease, leading to steatorhoea and malabsorption of vitamins A, D, E, and K. Hypocalcaemia and hypomagnesaemia may occur due to vitamin D deficiency. Rarely coagulopathy with prolonged prothrombin time is seen due to vitamin K malabsorption. Serum albumin can be low in the setting of intestinal inflammation, but systemic inflammatory markers such as C-reactive protein or ESR are not usually raised.

Antibody tests

Antiendomysial antibody (EMA) and human recombinant tissue transglutaminase (TTG) antibody tests have about 95% sensitivity and specificity in untreated coeliac disease. These tests have superseded both antigliadin and antireticulin antibody tests which have much lower diagnostic accuracy. The sensitivity and specificity estimates for EMA and TTG antibody tests were obtained in studies with patients with classical histological changes on biopsy including villous atrophy. Diagnostic difficulties therefore may arise in patients with mild disease, who may have negative serology and only mild inflammatory (infiltrative) changes on biopsy. Such patients may still have clinical manifestations that respond to gluten exclusion. Intestinal biopsy should therefore be obtained in all patients with unexplained features consistent with coeliac disease even if antibody tests are negative. EMA is assayed by indirect immunofluorescence (most commonly against monkey oesophagus) whereas TTG antibody titres are measured by ELISA and provide a quantitative measure that may be useful in assessing patients’ compliance with a gluten-free diet.

Radiology

Barium radiology (barium follow-through, enteroclysis) lacks sensitivity in coeliac disease and is rarely used in diagnosis, but is of value when complications are suspected (lymphoma, ulcerative jejunitis) or alternative diagnoses such as Crohn’s disease need to be excluded. Intestinal lymphoma usually has a diffuse pattern of bowel involvement and can be particularly difficult to diagnose. Barium studies in uncomplicated disease may show thickening of mucosal folds and flocculation, segmentation or clumping of barium. CT or MR cross-sectional imaging with enteroclysis is superior when complications are suspected, enabling assessment of the intestinal wall but also regional lymphadenopathy and extra-intestinal disease.

Wireless capsule enteroscopy

This technique has good sensitivity and specificity for the diagnosis of coeliac disease and may be considered where upper gastrointestinal endoscopy and duodenal biopsies are nondiagnostic, but suspicion of small-bowel pathology remains (e.g. iron deficiency). Wireless capsule enteroscopy also has a role in investigation of patients with refractory sprue to help exclude complications such as lymphoma, small-bowel adenocarcinoma, and ulcerative jejunitis. This may lead on to targeted biopsies of suspicious areas by laparoscopy or double balloon enteroscopy.

HLA DQ typing

Genetic testing for HLA DQ2/8 is valuable, but only as an exclusionary test. The absence of genes encoding subunits of the HLA DQ2 or DQ8 heterodimers has almost 100% negative predictive value. However, local laboratories vary greatly in the format in which results are reported, making this a confusing area, and clinicians without experience are advised to refer back to the laboratory to ensure correct interpretation. The test is particularly useful in those in whom the diagnosis remains uncertain after serological testing and intestinal biopsy.

Criteria for diagnosis

Definitive diagnosis is based on intestinal biopsy and the finding of characteristic histological features of coeliac disease, together with clinical improvement on a gluten-free diet. Published guidelines on diagnosis (including NICE guidance) and treatment are listed below (see ‘Further reading’). Upper gastrointestinal endoscopy and distal duodenal biopsy can be undertaken as an outpatient with local throat anaesthetic spray or intravenous sedation. An improvement in symptoms and nutritional parameters, including micronutrient deficiencies, occurs in most patients within months after commencing a gluten-free diet and provides important confirmatory support for the diagnosis. Repeat intestinal biopsy after gluten exclusion to observe recovery of the intestinal mucosa is no longer considered necessary for diagnosis in adults, provided other objective indicators of response to gluten exclusion are observed (e.g. disappearance of positive coeliac antibody titres).

In patients with suspected coeliac disease who have commenced a gluten-free diet before a small-intestinal biopsy has been obtained and in whom serological tests and biopsies are nondiagnostic, biopsy after prolonged gluten challenge (equivalent to 4 slices of bread per day for at least 2 weeks) is helpful to confirm the diagnosis.

Treatment

Strict, lifelong gluten exclusion is the cornerstone of therapy and is effective in most individuals. The gluten-free diet is safe and usually effective, but constitutes a major challenge for some people because of the pervasiveness of these grains in modern diets and the paucity of palatable alternatives. Resolution of symptoms and nutrient deficiencies are the earliest markers of response. Bone density and other nutritional parameters such as body mass index and fat mass also increase, predominantly in the first year after starting a gluten-free diet. Subjective indices of well-being, such as self-reported vitality, may also improve. In children histological recovery is usually complete within a few months, but recovery in adults may be slower. The bullet point list below summarizes a typical course of treatment and additional investigation after diagnosis of coeliac disease.

Action after diagnosis of coeliac disease

Resolution of positive EMA and TTG antibody titres provides a useful objective marker of response to gluten exclusion and usually occurs within 6 to 12 months. However, it should be remembered that these antibodies are commonly negative in the presence of low-grade histological abnormalities and are therefore insensitive markers of the extent of disease response. Monitoring of antibody tests, particularly quantitative TTG antibodies, is useful in patient follow-up to assess compliance. Major dietary indiscretions can lead to a rise in antibody levels, and can be helpful to reinforce efforts to improve compliance.

Compliance is also aided by joining a local coeliac society and by review with a dietitian with coeliac expertise. In the United Kingdom, Coeliac UK provides direct patient support and a comprehensive directory of gluten-free and gluten-containing food products. In general, wheat, rye, and barley should be avoided entirely. Feeding studies have established that pure oats are safe for most patients, but contamination of oat products with wheat gluten during harvesting or production is a common problem. A small number of patients appear to have a true coeliac intolerance to gluten-related avenins in oats. T-cell lines reactive to avenins in oats can be generated from the intestinal mucosa of some of these patients.

It is unclear whether there is a safe amount of gluten that may be consumed without adverse effects, although for the majority even small amounts of gluten (50 mg/day) appear sufficient to cause ongoing intestinal inflammation. Individuals appear to vary considerably in their sensitivity to gluten. A few are exquisitely sensitive and even minimal amounts of gluten may provoke gastrointestinal symptoms and histological abnormalities. At the opposite end of the spectrum, some patients have no symptoms despite a normal gluten-containing diet.

Patients with coeliac disease show a modestly increased risk of osteoporosis and fractures. Hip fractures are increased nearly twofold, a significant concern given the high incidence of these fractures in ageing populations. The most effective intervention is the gluten-free diet, which improves bone density in coeliac disease, predominantly in the first year. Patients should be encouraged to undertake regular weight-bearing exercise, and advised on consuming adequate dietary calcium (c.1000 mg/day). Calcium supplements may be prescribed to meet these targets. Screening for osteoporosis with bone densitometry scanning should be considered, particularly in older patients who have the greatest risk of fractures and in those with other risk factors (low body mass index, weight loss, poor adherence to gluten-free diet). Patients at high risk of fractures, with osteoporosis determined by bone densitometry scanning, should receive appropriate supplementary therapies for osteoporosis including bisphosphonates.

Patients should be screened for vitamin D deficiency and osteomalacia. This may be suggested by hypocalcaemia, hypophosphataemia and raised alkaline phosphatase and is confirmed by serum 25-hydroxyvitamin D (calcidiol) assay. The British Society of Gastroenterology have produced guidelines on the management of low bone mineral density in coeliac disease. These guidelines recommend screening for secondary hyperparathyroidism as a surrogate marker of vitamin D deficiency, by measuring serum calcium and parathyroid hormone. Patients with a high parathyroid hormone level and normal calcium should receive supplementation with calcium and vitamin D (800–1000 units/day).

Persistent clinical symptoms

The commonest reason for recurrent or persistent clinical manifestations in coeliac disease is inadequate adherence to a gluten-free diet. This may be inadvertent, and a careful dietary review should be undertaken to assess presence of gluten in the diet. Symptoms may also commonly persist or recur due to the presence of comorbidities, which should be carefully sought and treated (see above).

Rarely patients have true refractory coeliac disease, if symptoms and histological features persist despite strict gluten exclusion over several months. Intestinal complications of coeliac disease, including enteropathy-associated T-cell lymphoma, should be considered and excluded in these patients (see above). It is worth remembering that the incidence of several gastrointestinal conditions that are not connected to coeliac disease, e.g. sporadic colorectal carcinoma greatly exceeds that of enteropathy-associated T-cell lymphoma and should also be excluded in patients with persisting symptoms.

Prognosis

Prognosis in coeliac disease is excellent, provided a prompt diagnosis is made and treatment instituted with strict adherence to a gluten-free diet. In long-term treated coeliac disease mortality is comparable to that of population controls.

The largest cohort studies point to an increased risk (c.twofold) of malignancy and mortality occurring within the first 2 or 3 years after diagnosis, although there is evidence for a sustained (c.sixfold) increased risk of lymphoproliferative disorders beyond this. It should be noted that absolute risks (i.e. at an individual patient level) of malignancy are small. See table below: 

Table: Estimates of relative and absolute risks in coeliac disease

	Relative risk	Absolute risk (incidence per 100 000 person-years)
		General population	Coeliac
Any sepsis	2.6	58	139
Hip fracture	2.2	128	197
Any fracture	1.5	444	600
Lymphoma	5.9	8	45

Comparisons of events in the cohort of coeliacs (>10 000 cases) in the Swedish inpatient register with the general population. Includes first year after diagnosis. Adapted from the analysis of Walters JRF, et al. (2008). Coeliac disease and the risk of infections. Gut, 57, 1034–5

The increased risk appears to correlate with disease severity as it is highest in those with overt malabsorption but not detected in studies of patients with asymptomatic disease.

Screening

Screening for coeliac disease in asymptomatic individuals (including those at higher risk, e.g. with a family history or coexisting type 1 diabetes) remains controversial. The natural history of disease (especially risk of complications) in asymptomatic screening-detected cases is currently unknown, hence clear guidance on whether such individuals should commence a gluten-free diet cannot be given.

Likely developments over the next 5 to 10 years

Understanding of the heritable genetic risk factors predisposing to coeliac disease is rapidly increasing, driven by advances in genetics. Several new approaches to therapy are currently being developed or in early clinical trials. These include oral peptidase supplements designed to breakdown toxic cereal peptides, small molecules to inhibit various steps in pathogenesis (e.g. directed against transglutaminase, HLA DQ2, zonulin), and cereals genetically modified to reduce antigenicity.

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