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Coeliac disease
MALABSORPTION
Coeliac disease
What’s new?
Jeremy Woodward C
Abstract C
Coeliac disease is a common condition that affects as many as 1 in 100 Caucasians and may present at any age after weaning with a spectrum of symptoms ranging from none to all, through mild irritable bowel type complaints, to weight loss and diarrhoea. Patients with coeliac disease are at increased risk of autoimmunity. The majority of patients express either HLA DQ2 or DQ8 haplotypes, but it is likely that a large number of genes (some of which have recently been identified) are implicated in disease expression. IgA antibodies against tissue transglutaminase have a high specificity but sensitivity as low as 80% for detection of the condition and intestinal biopsy remains the diagnostic standard. Treatment with a strict gluten-free diet is mandatory and leads to a reduced risk of associated complications that include low bone mineral density and intestinal malignancy. The majority of patients thought to be ‘refractory’ to dietary treatment are found to have gluten sources in the diet, but a small proportion harbour atypical monoclonal intraepithelial lymphocytes and are at risk of developing intestinal lymphoma. Non-dietary treatments are currently under investigation.
Pathology The enteropathy of coeliac disease is predominantly proximal. The characteristic lesion is described as ‘villous atrophy’. However, except in very severe disease, the intestinal mucosa is far from atrophic, being expanded by a chronic inflammatory infiltrate in the lamina propria and hyperplasia of the crypts, in which stem cells are stimulated to divide in order to replenish surface enterocytes. Intraepithelial lymphocytes (IELs) are increased in number and may persist after resolution of other changes (Figure 1).3
Keywords anaemia; coeliac disease; enteropathy-associated T-cell lymphoma; gluten; malabsorption; osteoporosis; refractory; sprue; tissue transglutaminase
Pathogenesis The toxic factor ‘Gluten’ is the generic term used for the protein fraction of cereal grains that causes coeliac disease, being present in wheat, barley and rye. Many different gluten proteins have been identified and characteristically contain a large amount of proline and glutamine residues.4 This may confer unique properties on gluten peptides including resistance to luminal proteolysis. Gluten is not found in rice, maize or millet. However, the toxicity of oats remains controversial e cross-contamination with other cereals at the time of milling may account for most reports of oats causing coeliac disease.5
Coeliac disease results from damage to the small intestinal mucosa due to an inappropriate immune response to a cereal protein. The term ‘coeliac’ derives from the Greek ‘koiliakos’, meaning ‘belly’.
Epidemiology
Host factors The ability to mount an immune response to gluten depends on the presentation of gluten peptides to T cells. This requires prior deamidation of the glutamine residues of the peptide by tissue transglutaminase (TTG), a ubiquitous connective tissue enzyme.6 Few class II major histocompatibility (MHC) proteins are capable of presenting gluten peptides e hence, of patients with coeliac disease over 90% express HLA DQ2, and 5e10% express HLA DQ8.7 As approximately 12% of Caucasians express HLA DQ2, other factors must be required in order to develop coeliac disease. HLA haplo-identical siblings have a concordance rate of 40%8 compared to around 75% for identical twins,9 suggesting a large non-HLA genetic component. Recent large-scale genome-wide association studies have identified over 20 regions harbouring candidate genes.10 The majority of these affect immune functions and include genes such as interleukin 2 and 21, interleukin 18 receptor and others with innate immune functions, such as SH2B3. Many such loci are shared with other autoimmune conditions including type I diabetes and rheumatoid disease, explaining a shared propensity.
Coeliac disease is a common condition that affects 0.3e1% of Caucasians.1 A high prevalence also occurs in North African and Middle Eastern populations. It is largely confined to the Northwest of the Indian subcontinent and is rarely reported in oriental or black African peoples. A slightly higher incidence in females than males possibly relates to the likelihood of detection as a result of iron deficiency, or associated autoimmunity. Coeliac disease can present at any age after weaning. Whilst commonly diagnosed in early childhood, it can remain subclinical or ‘latent’ for considerable periods of time. Approximately 10e15% of first-degree relatives are affected.2
Jeremy Woodward MA MRCP PhD is a Consultant Gastroenterologist at Addenbrooke’s Hospital in Cambridge, UK. He has clinical and research interests in nutrition and small intestinal diseases. Competing interests: none declared.
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Recent studies have investigated innate immune recognition of gliadin peptides that may trigger or enhance adaptive T-cell responses. Epithelial production of interleukin-15 appears pivotal in this role Novel non-dietary therapies are being explored including: C the use of oral endopeptidases to digest gliadin peptides C ‘blocking’ peptides to prevent TTG deamidation of gluten or binding of peptides to HLA DQ2 C ‘immunization’ by systemic exposure to immunodominant gliadin peptides C immunomodulation by monoclonal antibodies
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a
b
a This 47-year-old man who was being investigated for osteomalacia and weight loss also complained of steatorrhoeic motions, abdominal bloating and discomfort. The blood count revealed a slightly low haemoglobin (11.3 g/dl) with normal mean cell volume (91.2 fl). Red blood cell folate, serum vitamin B12 and ferritin levels were within normal range. The serum albumin was normal at 35 g/dl, but the corrected calcium level was 1.88 mmol/l (normal range 2.1–2.5 mmol/l), serum alkaline phosphatase was elevated at 299 u/l (normal range 30–135 u/l) and the alanine aminotransferase at 180 u/l (normal range 0–50 u/l). The serum parathyroid hormone level was 284 ng/l (normal range 9–54 ng/l) and the vitamin D level was 8.1 µg/ml (normal seasonal range 9–47). The IgA anti-TT G titre was >100 iu/l (normal 0–3 iu/l). b Following initiation of a gluten-free diet his body weight increased from 50 kg to 70 kg over four months with resolution of the diarrhoea and abdominal symptoms. The liver enzymes and parathormone levels returned to normal ranges. Figure 1 The profound potential consequences of coeliac disease
Neurological presentations, including peripheral neuropathy, epilepsy and ataxia,14 are uncommonly described. Vitamin D deficiency causes rickets in childhood and osteomalacia in adults and may present with fractures, or proximal muscle pains and weakness.
End organ damage T-cell activation following recognition of the gluten peptide results in damage to the intestinal mucosa by the direct action of inflammatory mediators and by matrix metalloproteinase enzymes secreted by stimulated fibroblasts.11 The ensuing reduction in absorptive capacity can result in malabsorption of fat- and lipid-soluble vitamins (A, D, E and K), as well as iron, folate and calcium.
Investigations Routine laboratory investigations may reveal a low haemoglobin with microcytosis, and HowelleJolly bodies may be present on the blood film. Serum folate and vitamin B12 may be low. A reduced serum calcium and raised serum alkaline phosphatase may result from vitamin D deficiency. An elevated serum transaminase (ALT or AST) is common at presentation.15 Quantification of serum IgA antibodies against tissue transglutaminase (TTG) has a very high specificity for the diagnosis of coeliac disease (>95% depending on the cut-off level), but a sensitivity that may be as low as 80%.16,17 It may also aid the monitoring of dietary compliance. TTG has superseded endomysial antibody testing owing to ease of assay. Intestinal biopsy is mandatory for the diagnosis of coeliac disease, and is usually obtained by gastroscopy, during which scalloped, thickened duodenal folds may be seen.
Clinical features Coeliac disease is frequently asymptomatic, but patients without symptoms may notice increased well-being on treatment.12 The classical presentation in early childhood is with profuse diarrhoea and failure to thrive after weaning, but subtle features may occur in older children, such as reduced growth velocity or impaired performance at school. Diarrhoea may be clearly steatorrhoeic owing to fat malabsorption. However, gastrointestinal symptoms may be minimal, and bloating and discomfort may be misdiagnosed as irritable bowel syndrome.13 Weight loss may be significant (see Figure 1), but is frequently absent and obesity does not exclude the diagnosis. Fatigue and depression are common. Iron deficiency may result in symptomatic anaemia but is frequently detected coincidentally (for instance, at blood donor sessions). Anaemia may also be the result of folate or vitamin B12 deficiency.
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Differential diagnosis Cow’s milk protein allergy is the only other enteropathy induced by dietary protein. Unlike gluten sensitivity, affected children usually develop tolerance over time. Intestinal villous atrophy
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MALABSORPTION
may also occur with tropical sprue, HIV enteropathy, enteroviral or noroviral infection and infestation with Giardia lamblia. An enteropathy associated with common variable immunodeficiency (CVID) is identical in appearance to coeliac disease but may not respond to gluten withdrawal.18
European directive, any food labelled as ‘gluten free’ after January 2012 must contain less than 20 ppm gluten. Other interventions Until intestinal recovery has occurred it is appropriate to supplement identified deficiencies such as iron, folate and calcium. Calcium absorption may be reduced despite good dietary compliance and a higher than normal intake is recommended (1500 mg/day).
Associated conditions Up to 30% of patients with coeliac disease also have another autoimmune condition, such as thyroid disease or type 1 diabetes, compared to 3% in the general population.19 Dermatitis herpetiformis (DH) is an uncommon intensely itchy vesicular rash that may occur on limb extensor surfaces and buttocks. As few as 1% of patients with coeliac disease have this condition, but all patients with DH have some degree of enteropathy. The severity of the rash is unrelated to the degree of intestinal damage.20 DH responds slowly to gluten withdrawal. Oral dapsone at 50e100 mg/day also heals the skin lesions but has no effect on the enteropathy. Approximately 5% of patients with IgA deficiency have coeliac disease.21 In such cases, the IgG, rather than the IgA, antiTTG antibody test may be diagnostic.
Complications Malignancy The increased risk of mortality in coeliac disease (the average standardized mortality ratio is approximately 2) is largely attributable to malignancy.22 The risk is greatest for poorly compliant patients and within 1e2 years of diagnosis, but falls to normal levels after strict gluten withdrawal. B- and T-cell intestinal lymphomas arise with increased frequency in coeliac disease. Enteropathy-associated T-cell lymphoma (EATL) occurs in approximately 1 per million population per year in the UK and is associated with approximately 20% survival at 2 years.23 EATL occurs predominantly in older patients, often with presumed long-standing and undiagnosed coeliac disease, and may present with haemophagocytic syndrome. The risk of duodenal adenocarcinoma is also increased, but only around 10% of patients with this tumour are coeliac.24
Treatment Dietary measures The intestinal damage and associated symptoms are reversed by removal of gluten from the diet (Figure 2). Gluten is present in a wide variety of foodstuffs, including bread, biscuits, cakes, pizzas, pasta, sauces and gravy. Immunological assays now provide a reasonable estimate of the gluten content of food and, by law, all foods must be clearly labelled. ‘Eating out’ and foreign travel may result in accidental gluten exposure. Whilst individual sensitivity to gluten varies, it is important to exclude all dietary gluten. A wide range of commercial gluten-free products is now available from supermarkets and also on FP10 prescription. By
Osteoporosis Impaired calcium absorption leads to low bone density and increased fracture risk. Significant increases in bone density often occur on a gluten-free diet, and DEXA scanning should be delayed until after diet initiation (Figure 3). Whilst an increased risk of bone fractures has been found before diagnosis, it is difficult to demonstrate an increased risk for diet-compliant patients.25
a
b
a At the time of initial diagnosis. There is loss of villous height with evidence of crypt hyperplasia and expansion of the lamina propria with chronic inflammatory cells. There are increased numbers of lymphocytes within the epithelial layer. b Following 9 months of treatment by gluten-free diet. Whilst the biopsies have not returned completely to normal, there is clear architectural improvement with tall slender villi present, and resolution of the chronic inflammation within the lamina propria. There are still increased numbers of lymphocytes present within the epithelium. Figure 2 Mucosal biopsies taken by endoscopy from the second part of the duodenum of the patient in Figure 1 (low power).
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Ó 2010 Elsevier Ltd. All rights reserved.
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Hyposplenism Splenic function may be impaired and may translate into an increased risk for some bacterial infections. This impairment responds to dietary treatment.26
rearrangement. This finding is considered pre-malignant as there is a high progression in such patients to frank EATL.27 Other patients with coeliac disease refractory to diet may respond to treatment with corticosteroids and azathioprine.28
Refractory coeliac disease Some patients with coeliac disease experience symptomatic relapse and intestinal damage despite gluten withdrawal. Positive anti-TTG antibodies generally indicate dietary indiscretion and in most cases of ‘refractory’ disease gluten sources can be identified in the diet. However, a few patients harbour an atypical population of intraepithelial T-cells that lack cell surface CD3 or CD8 expression and share a clonal T-cell receptor
Follow-up Some authorities advocate further intestinal biopsy after a few months of gluten withdrawal. Resolution of pathological changes helps reinforce the diet and demonstrates the effect of treatment. Lack of improvement may lead to careful dietary analysis or alterations, including the removal of oats- or wheat-starch-based products. Further biopsies may be required if there is symptomatic relapse. Support and regular review by a specialist dietitian is essential and, once established on a stable diet, annual review with a hospital gastroenterology team is appropriate. Routine biochemistry and full blood count can be checked, associated autoimmune conditions screened for and repeated anti-TTG antibody titres can give some measure of dietary compliance.A
Graphs showing the effect of gluten restriction on the titre of anti-tissue transglutaminase antibodies and bone mineral density measured by DEXA scan for the patient in Figure 1 a
120
REFERENCES 1 Cook HB, Burt MJ, Collett JA, Whitehead MR, Frampton CM, Chapman BA. Adult coeliac disease: prevalence and clinical significance. J Gastroenterol Hepatol 2000; 15: 1032e6. 2 Pittschieler K, Gentili L, Niederhofer H. Onset of coeliac disease: a prospective longitudinal study. Acta Paediatr 2003; 92: 1149e52. 3 Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiological approach to the spectrum of gluten sensitivity. Gastroenterology 1992; 102: 330e54. 4 Kasarda DD, Okita TW, Bernardin JE, et al. Nucleic acid (cDNA) and amino acid sequences of a-type gliadins from wheat (Triticum aestivum). Proc Natl Acad Sci USA 1984; 81: 4712e6. 5 Janatuinen EK, Kemppainen TA, Julkunen RJ, et al. No harm from five year ingestion of oats in coeliac disease. Gut 2002; 50: 332. 6 Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997; 3: 797e801. 7 Marguerite-Jeannin P, Babron MC, Bourgey M, et al. HLA DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on Coeliac Disease. Tissue Antigens 2004; 63: 562e7. 8 Bevan S, Popat S, Braeggar CP, et al. Contribution of the MHC region to the familial risk of coeliac disease. J Med Genet 1999; 36: 687. 9 Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut 2002; 50: 624e8. 10 Hunt KA, van Heel DA. Recent advances in coeliac disease genetics. Gut 2009; 58: 473e6. 11 Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 1997; 158: 1582e90. 12 Johnston SD, Watson RG, McMillan SA, Sloan J, Love AH. Coeliac disease detected by screening is not silent e simply unrecognised. QJM 1998; 91: 853e60. 13 Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling RO ME II criteria referred to secondary care. Lancet 2001; 358: 1504e8.
IgA anti-TTG titre (u/ml)
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Age (years) Figure 3
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14 Sander HW, Magda P, Chin RL, et al. Cerebellar ataxia and coeliac disease. Lancet 2003; 362: 1548. 15 Dickey W, McMillan SA, Collins JS, Watson RG, McLoughlin JC, Love AH. Liver abnormalities associated with celiac sprue. How common are they, what is their significance, and what do we do about them? J Clin Gastroenterol 1995; 20: 290e2. 16 Fabiani E, Catassi C. The serum 19A class anti-tissue transglutaminase antibodies in the diagnosis and follow up of coeliac disease. Results of an international multi-centre study. International working group on Eu-Ttg. Eur J Gastroenterol Hepatol 2001; 13: 659e65. 17 Rostami K, Kerckhaert J, Blomberg BME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiacs: disappointing in clinical practice. Am J Gastroenterol 1999; 94: 888e94. 18 Teahon K, Webster AD, Price AB, Weston J, Bjarnason I. Studies on the enteropathy associated with primary hypogammaglobulinaemia. Gut 1994; 35: 1244e9. 19 Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223e43. 20 Fry L, McMinn RM, Cowan JD, Hoffbrand AV. Effect of gluten-free diet on dermatological, intestinal and haematological manifestations of dermatitis herpetiformis. Lancet 1968; I: 557e61. 21 Cataldo F, Marino V, Ventura A, Bottaro G, Corazza GR. Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study. Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and “Club del Tenue” Working Groups on Coeliac Disease. Gut 1998; 42: 362e5. 22 Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001; 358: 356e61. 23 Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 2000; 18: 795e803. 24 Howdle PD, Jalal PK, Holmes GKT, Houlston RS. Primary small bowel malignancy in the UK and its association with coeliac disease. QJM 2003; 96: 345e53. 25 West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with coeliac disease: a population-based cohort study. Gastroenterology 2003; 125: 429e36. 26 O’Grady JG, Stevens FM, Harding B, et al. Hyposplenism and glutensensitive enteropathy. Natural history, incidence, and relationship to diet and small bowel morphology. Gastroenterology 1984; 87: 1326e31. 27 Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease and enteropathy-associated T-cell lymphoma. Lancet 2000; 356: 203e8.
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28 Goerres MS, Meijer JW, Wahab PJ, et al. Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther 2003; 18: 487e94. FURTHER READING Celiac Disease. Proceedings of the NIH Consensus Conference on Celiac Disease. Gastroenterology 2005; 128(suppl 1). Coeliac disease. In: Howdle PD, ed. Baillieres Clinical Gastroenterology International Practice and Research 9. No 2. London: Bailliere Tindall, 1995. Green PH, Jabri B. Coeliac disease. Lancet 2003; 362: 383e91. Kagnoff MF. Celiac disease pathogenesis: the plot thickens. Gastroenterology 2002; 123: 939e43. National Institute for Health and Clinical Excellence. Coeliac disease: recognition and assessment of coeliac disease. London: National Institute for Health and Clinical Excellence. Available from: www.nice. org.uk/CG86; 2009. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002; 2: 647e55.
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Coeliac disease can present at any age after weaning; symptoms may be absent, mild or severe. Patients with a range of conditions including irritable bowel syndrome, autoimmune conditions, unexplained low bone mineral density, hyposplenism or immunoglobulin A deficiency should be tested for coeliac disease. Serological testing for IgA anti-TTG antibodies has a high specificity for coeliac disease but a sensitivity as low as 80% and is of no value in IgA deficiency. Distal duodenal biopsy remains the diagnostic standard and demonstration of histological resolution on diet is beneficial. Patients with coeliac disease require advice and support from a dietitian in order to maintain a strict gluten-free diet. Oats are considered safe for coeliac patients if from a verified contamination-free source. Significant complications of coeliac disease, including bone fractures owing to low bone mineral density, and malignant lymphoma and adenocarcinoma of the intestine, are unlikely to occur in long-term diet-compliant patients. Annual follow-up provides opportunities for assessing dietary compliance and surveillance for associated conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Coeliac disease
What’s new?
Jeremy Woodward C
Abstract C
Coeliac disease is a common condition that affects as many as 1 in 100 Caucasians and may present at any age after weaning with a spectrum of symptoms ranging from none to all, through mild irritable bowel type complaints, to weight loss and diarrhoea. Patients with coeliac disease are at increased risk of autoimmunity. The majority of patients express either HLA DQ2 or DQ8 haplotypes, but it is likely that a large number of genes (some of which have recently been identified) are implicated in disease expression. IgA antibodies against tissue transglutaminase have a high specificity but sensitivity as low as 80% for detection of the condition and intestinal biopsy remains the diagnostic standard. Treatment with a strict gluten-free diet is mandatory and leads to a reduced risk of associated complications that include low bone mineral density and intestinal malignancy. The majority of patients thought to be ‘refractory’ to dietary treatment are found to have gluten sources in the diet, but a small proportion harbour atypical monoclonal intraepithelial lymphocytes and are at risk of developing intestinal lymphoma. Non-dietary treatments are currently under investigation.
Pathology The enteropathy of coeliac disease is predominantly proximal. The characteristic lesion is described as ‘villous atrophy’. However, except in very severe disease, the intestinal mucosa is far from atrophic, being expanded by a chronic inflammatory infiltrate in the lamina propria and hyperplasia of the crypts, in which stem cells are stimulated to divide in order to replenish surface enterocytes. Intraepithelial lymphocytes (IELs) are increased in number and may persist after resolution of other changes (Figure 1).3
Keywords anaemia; coeliac disease; enteropathy-associated T-cell lymphoma; gluten; malabsorption; osteoporosis; refractory; sprue; tissue transglutaminase
Pathogenesis The toxic factor ‘Gluten’ is the generic term used for the protein fraction of cereal grains that causes coeliac disease, being present in wheat, barley and rye. Many different gluten proteins have been identified and characteristically contain a large amount of proline and glutamine residues.4 This may confer unique properties on gluten peptides including resistance to luminal proteolysis. Gluten is not found in rice, maize or millet. However, the toxicity of oats remains controversial e cross-contamination with other cereals at the time of milling may account for most reports of oats causing coeliac disease.5
Coeliac disease results from damage to the small intestinal mucosa due to an inappropriate immune response to a cereal protein. The term ‘coeliac’ derives from the Greek ‘koiliakos’, meaning ‘belly’.
Epidemiology
Host factors The ability to mount an immune response to gluten depends on the presentation of gluten peptides to T cells. This requires prior deamidation of the glutamine residues of the peptide by tissue transglutaminase (TTG), a ubiquitous connective tissue enzyme.6 Few class II major histocompatibility (MHC) proteins are capable of presenting gluten peptides e hence, of patients with coeliac disease over 90% express HLA DQ2, and 5e10% express HLA DQ8.7 As approximately 12% of Caucasians express HLA DQ2, other factors must be required in order to develop coeliac disease. HLA haplo-identical siblings have a concordance rate of 40%8 compared to around 75% for identical twins,9 suggesting a large non-HLA genetic component. Recent large-scale genome-wide association studies have identified over 20 regions harbouring candidate genes.10 The majority of these affect immune functions and include genes such as interleukin 2 and 21, interleukin 18 receptor and others with innate immune functions, such as SH2B3. Many such loci are shared with other autoimmune conditions including type I diabetes and rheumatoid disease, explaining a shared propensity.
Coeliac disease is a common condition that affects 0.3e1% of Caucasians.1 A high prevalence also occurs in North African and Middle Eastern populations. It is largely confined to the Northwest of the Indian subcontinent and is rarely reported in oriental or black African peoples. A slightly higher incidence in females than males possibly relates to the likelihood of detection as a result of iron deficiency, or associated autoimmunity. Coeliac disease can present at any age after weaning. Whilst commonly diagnosed in early childhood, it can remain subclinical or ‘latent’ for considerable periods of time. Approximately 10e15% of first-degree relatives are affected.2
Jeremy Woodward MA MRCP PhD is a Consultant Gastroenterologist at Addenbrooke’s Hospital in Cambridge, UK. He has clinical and research interests in nutrition and small intestinal diseases. Competing interests: none declared.
MEDICINE 39:3
Recent studies have investigated innate immune recognition of gliadin peptides that may trigger or enhance adaptive T-cell responses. Epithelial production of interleukin-15 appears pivotal in this role Novel non-dietary therapies are being explored including: C the use of oral endopeptidases to digest gliadin peptides C ‘blocking’ peptides to prevent TTG deamidation of gluten or binding of peptides to HLA DQ2 C ‘immunization’ by systemic exposure to immunodominant gliadin peptides C immunomodulation by monoclonal antibodies
173
Ó 2010 Elsevier Ltd. All rights reserved.
MALABSORPTION
a
b
a This 47-year-old man who was being investigated for osteomalacia and weight loss also complained of steatorrhoeic motions, abdominal bloating and discomfort. The blood count revealed a slightly low haemoglobin (11.3 g/dl) with normal mean cell volume (91.2 fl). Red blood cell folate, serum vitamin B12 and ferritin levels were within normal range. The serum albumin was normal at 35 g/dl, but the corrected calcium level was 1.88 mmol/l (normal range 2.1–2.5 mmol/l), serum alkaline phosphatase was elevated at 299 u/l (normal range 30–135 u/l) and the alanine aminotransferase at 180 u/l (normal range 0–50 u/l). The serum parathyroid hormone level was 284 ng/l (normal range 9–54 ng/l) and the vitamin D level was 8.1 µg/ml (normal seasonal range 9–47). The IgA anti-TT G titre was >100 iu/l (normal 0–3 iu/l). b Following initiation of a gluten-free diet his body weight increased from 50 kg to 70 kg over four months with resolution of the diarrhoea and abdominal symptoms. The liver enzymes and parathormone levels returned to normal ranges. Figure 1 The profound potential consequences of coeliac disease
Neurological presentations, including peripheral neuropathy, epilepsy and ataxia,14 are uncommonly described. Vitamin D deficiency causes rickets in childhood and osteomalacia in adults and may present with fractures, or proximal muscle pains and weakness.
End organ damage T-cell activation following recognition of the gluten peptide results in damage to the intestinal mucosa by the direct action of inflammatory mediators and by matrix metalloproteinase enzymes secreted by stimulated fibroblasts.11 The ensuing reduction in absorptive capacity can result in malabsorption of fat- and lipid-soluble vitamins (A, D, E and K), as well as iron, folate and calcium.
Investigations Routine laboratory investigations may reveal a low haemoglobin with microcytosis, and HowelleJolly bodies may be present on the blood film. Serum folate and vitamin B12 may be low. A reduced serum calcium and raised serum alkaline phosphatase may result from vitamin D deficiency. An elevated serum transaminase (ALT or AST) is common at presentation.15 Quantification of serum IgA antibodies against tissue transglutaminase (TTG) has a very high specificity for the diagnosis of coeliac disease (>95% depending on the cut-off level), but a sensitivity that may be as low as 80%.16,17 It may also aid the monitoring of dietary compliance. TTG has superseded endomysial antibody testing owing to ease of assay. Intestinal biopsy is mandatory for the diagnosis of coeliac disease, and is usually obtained by gastroscopy, during which scalloped, thickened duodenal folds may be seen.
Clinical features Coeliac disease is frequently asymptomatic, but patients without symptoms may notice increased well-being on treatment.12 The classical presentation in early childhood is with profuse diarrhoea and failure to thrive after weaning, but subtle features may occur in older children, such as reduced growth velocity or impaired performance at school. Diarrhoea may be clearly steatorrhoeic owing to fat malabsorption. However, gastrointestinal symptoms may be minimal, and bloating and discomfort may be misdiagnosed as irritable bowel syndrome.13 Weight loss may be significant (see Figure 1), but is frequently absent and obesity does not exclude the diagnosis. Fatigue and depression are common. Iron deficiency may result in symptomatic anaemia but is frequently detected coincidentally (for instance, at blood donor sessions). Anaemia may also be the result of folate or vitamin B12 deficiency.
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Differential diagnosis Cow’s milk protein allergy is the only other enteropathy induced by dietary protein. Unlike gluten sensitivity, affected children usually develop tolerance over time. Intestinal villous atrophy
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Ó 2010 Elsevier Ltd. All rights reserved.
MALABSORPTION
may also occur with tropical sprue, HIV enteropathy, enteroviral or noroviral infection and infestation with Giardia lamblia. An enteropathy associated with common variable immunodeficiency (CVID) is identical in appearance to coeliac disease but may not respond to gluten withdrawal.18
European directive, any food labelled as ‘gluten free’ after January 2012 must contain less than 20 ppm gluten. Other interventions Until intestinal recovery has occurred it is appropriate to supplement identified deficiencies such as iron, folate and calcium. Calcium absorption may be reduced despite good dietary compliance and a higher than normal intake is recommended (1500 mg/day).
Associated conditions Up to 30% of patients with coeliac disease also have another autoimmune condition, such as thyroid disease or type 1 diabetes, compared to 3% in the general population.19 Dermatitis herpetiformis (DH) is an uncommon intensely itchy vesicular rash that may occur on limb extensor surfaces and buttocks. As few as 1% of patients with coeliac disease have this condition, but all patients with DH have some degree of enteropathy. The severity of the rash is unrelated to the degree of intestinal damage.20 DH responds slowly to gluten withdrawal. Oral dapsone at 50e100 mg/day also heals the skin lesions but has no effect on the enteropathy. Approximately 5% of patients with IgA deficiency have coeliac disease.21 In such cases, the IgG, rather than the IgA, antiTTG antibody test may be diagnostic.
Complications Malignancy The increased risk of mortality in coeliac disease (the average standardized mortality ratio is approximately 2) is largely attributable to malignancy.22 The risk is greatest for poorly compliant patients and within 1e2 years of diagnosis, but falls to normal levels after strict gluten withdrawal. B- and T-cell intestinal lymphomas arise with increased frequency in coeliac disease. Enteropathy-associated T-cell lymphoma (EATL) occurs in approximately 1 per million population per year in the UK and is associated with approximately 20% survival at 2 years.23 EATL occurs predominantly in older patients, often with presumed long-standing and undiagnosed coeliac disease, and may present with haemophagocytic syndrome. The risk of duodenal adenocarcinoma is also increased, but only around 10% of patients with this tumour are coeliac.24
Treatment Dietary measures The intestinal damage and associated symptoms are reversed by removal of gluten from the diet (Figure 2). Gluten is present in a wide variety of foodstuffs, including bread, biscuits, cakes, pizzas, pasta, sauces and gravy. Immunological assays now provide a reasonable estimate of the gluten content of food and, by law, all foods must be clearly labelled. ‘Eating out’ and foreign travel may result in accidental gluten exposure. Whilst individual sensitivity to gluten varies, it is important to exclude all dietary gluten. A wide range of commercial gluten-free products is now available from supermarkets and also on FP10 prescription. By
Osteoporosis Impaired calcium absorption leads to low bone density and increased fracture risk. Significant increases in bone density often occur on a gluten-free diet, and DEXA scanning should be delayed until after diet initiation (Figure 3). Whilst an increased risk of bone fractures has been found before diagnosis, it is difficult to demonstrate an increased risk for diet-compliant patients.25
a
b
a At the time of initial diagnosis. There is loss of villous height with evidence of crypt hyperplasia and expansion of the lamina propria with chronic inflammatory cells. There are increased numbers of lymphocytes within the epithelial layer. b Following 9 months of treatment by gluten-free diet. Whilst the biopsies have not returned completely to normal, there is clear architectural improvement with tall slender villi present, and resolution of the chronic inflammation within the lamina propria. There are still increased numbers of lymphocytes present within the epithelium. Figure 2 Mucosal biopsies taken by endoscopy from the second part of the duodenum of the patient in Figure 1 (low power).
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Hyposplenism Splenic function may be impaired and may translate into an increased risk for some bacterial infections. This impairment responds to dietary treatment.26
rearrangement. This finding is considered pre-malignant as there is a high progression in such patients to frank EATL.27 Other patients with coeliac disease refractory to diet may respond to treatment with corticosteroids and azathioprine.28
Refractory coeliac disease Some patients with coeliac disease experience symptomatic relapse and intestinal damage despite gluten withdrawal. Positive anti-TTG antibodies generally indicate dietary indiscretion and in most cases of ‘refractory’ disease gluten sources can be identified in the diet. However, a few patients harbour an atypical population of intraepithelial T-cells that lack cell surface CD3 or CD8 expression and share a clonal T-cell receptor
Follow-up Some authorities advocate further intestinal biopsy after a few months of gluten withdrawal. Resolution of pathological changes helps reinforce the diet and demonstrates the effect of treatment. Lack of improvement may lead to careful dietary analysis or alterations, including the removal of oats- or wheat-starch-based products. Further biopsies may be required if there is symptomatic relapse. Support and regular review by a specialist dietitian is essential and, once established on a stable diet, annual review with a hospital gastroenterology team is appropriate. Routine biochemistry and full blood count can be checked, associated autoimmune conditions screened for and repeated anti-TTG antibody titres can give some measure of dietary compliance.A
Graphs showing the effect of gluten restriction on the titre of anti-tissue transglutaminase antibodies and bone mineral density measured by DEXA scan for the patient in Figure 1 a
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REFERENCES 1 Cook HB, Burt MJ, Collett JA, Whitehead MR, Frampton CM, Chapman BA. Adult coeliac disease: prevalence and clinical significance. J Gastroenterol Hepatol 2000; 15: 1032e6. 2 Pittschieler K, Gentili L, Niederhofer H. Onset of coeliac disease: a prospective longitudinal study. Acta Paediatr 2003; 92: 1149e52. 3 Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiological approach to the spectrum of gluten sensitivity. Gastroenterology 1992; 102: 330e54. 4 Kasarda DD, Okita TW, Bernardin JE, et al. Nucleic acid (cDNA) and amino acid sequences of a-type gliadins from wheat (Triticum aestivum). Proc Natl Acad Sci USA 1984; 81: 4712e6. 5 Janatuinen EK, Kemppainen TA, Julkunen RJ, et al. No harm from five year ingestion of oats in coeliac disease. Gut 2002; 50: 332. 6 Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997; 3: 797e801. 7 Marguerite-Jeannin P, Babron MC, Bourgey M, et al. HLA DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on Coeliac Disease. Tissue Antigens 2004; 63: 562e7. 8 Bevan S, Popat S, Braeggar CP, et al. Contribution of the MHC region to the familial risk of coeliac disease. J Med Genet 1999; 36: 687. 9 Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut 2002; 50: 624e8. 10 Hunt KA, van Heel DA. Recent advances in coeliac disease genetics. Gut 2009; 58: 473e6. 11 Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 1997; 158: 1582e90. 12 Johnston SD, Watson RG, McMillan SA, Sloan J, Love AH. Coeliac disease detected by screening is not silent e simply unrecognised. QJM 1998; 91: 853e60. 13 Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling RO ME II criteria referred to secondary care. Lancet 2001; 358: 1504e8.
IgA anti-TTG titre (u/ml)
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Age (years) Figure 3
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14 Sander HW, Magda P, Chin RL, et al. Cerebellar ataxia and coeliac disease. Lancet 2003; 362: 1548. 15 Dickey W, McMillan SA, Collins JS, Watson RG, McLoughlin JC, Love AH. Liver abnormalities associated with celiac sprue. How common are they, what is their significance, and what do we do about them? J Clin Gastroenterol 1995; 20: 290e2. 16 Fabiani E, Catassi C. The serum 19A class anti-tissue transglutaminase antibodies in the diagnosis and follow up of coeliac disease. Results of an international multi-centre study. International working group on Eu-Ttg. Eur J Gastroenterol Hepatol 2001; 13: 659e65. 17 Rostami K, Kerckhaert J, Blomberg BME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiacs: disappointing in clinical practice. Am J Gastroenterol 1999; 94: 888e94. 18 Teahon K, Webster AD, Price AB, Weston J, Bjarnason I. Studies on the enteropathy associated with primary hypogammaglobulinaemia. Gut 1994; 35: 1244e9. 19 Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223e43. 20 Fry L, McMinn RM, Cowan JD, Hoffbrand AV. Effect of gluten-free diet on dermatological, intestinal and haematological manifestations of dermatitis herpetiformis. Lancet 1968; I: 557e61. 21 Cataldo F, Marino V, Ventura A, Bottaro G, Corazza GR. Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study. Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and “Club del Tenue” Working Groups on Coeliac Disease. Gut 1998; 42: 362e5. 22 Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001; 358: 356e61. 23 Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 2000; 18: 795e803. 24 Howdle PD, Jalal PK, Holmes GKT, Houlston RS. Primary small bowel malignancy in the UK and its association with coeliac disease. QJM 2003; 96: 345e53. 25 West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with coeliac disease: a population-based cohort study. Gastroenterology 2003; 125: 429e36. 26 O’Grady JG, Stevens FM, Harding B, et al. Hyposplenism and glutensensitive enteropathy. Natural history, incidence, and relationship to diet and small bowel morphology. Gastroenterology 1984; 87: 1326e31. 27 Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease and enteropathy-associated T-cell lymphoma. Lancet 2000; 356: 203e8.
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28 Goerres MS, Meijer JW, Wahab PJ, et al. Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther 2003; 18: 487e94. FURTHER READING Celiac Disease. Proceedings of the NIH Consensus Conference on Celiac Disease. Gastroenterology 2005; 128(suppl 1). Coeliac disease. In: Howdle PD, ed. Baillieres Clinical Gastroenterology International Practice and Research 9. No 2. London: Bailliere Tindall, 1995. Green PH, Jabri B. Coeliac disease. Lancet 2003; 362: 383e91. Kagnoff MF. Celiac disease pathogenesis: the plot thickens. Gastroenterology 2002; 123: 939e43. National Institute for Health and Clinical Excellence. Coeliac disease: recognition and assessment of coeliac disease. London: National Institute for Health and Clinical Excellence. Available from: www.nice. org.uk/CG86; 2009. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002; 2: 647e55.
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Coeliac disease can present at any age after weaning; symptoms may be absent, mild or severe. Patients with a range of conditions including irritable bowel syndrome, autoimmune conditions, unexplained low bone mineral density, hyposplenism or immunoglobulin A deficiency should be tested for coeliac disease. Serological testing for IgA anti-TTG antibodies has a high specificity for coeliac disease but a sensitivity as low as 80% and is of no value in IgA deficiency. Distal duodenal biopsy remains the diagnostic standard and demonstration of histological resolution on diet is beneficial. Patients with coeliac disease require advice and support from a dietitian in order to maintain a strict gluten-free diet. Oats are considered safe for coeliac patients if from a verified contamination-free source. Significant complications of coeliac disease, including bone fractures owing to low bone mineral density, and malignant lymphoma and adenocarcinoma of the intestine, are unlikely to occur in long-term diet-compliant patients. Annual follow-up provides opportunities for assessing dietary compliance and surveillance for associated conditions.
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