Celiac Disease: Beyond Bowels, Blood, & Bones

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Celiac disease. One in 132 Americans has it. We know about the malabsorption, the anemia, the osteoporosis associated with celiac disease. But what of associations with neurological disease, reproductive health, and other organ systems? What DON'T you know about this common condition?

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  • Figure 3. Endoscopic and biopsy findings in patients with and without celiac disease. (A) High-definition endoscopic photo of normal small intestine. The villi are clearly visible with no evidence of atrophy or scalloping of the folds. (B) Biopsy specimen of normal small intestine (hematoxylin-eosin; original magnification, × 100). (C) PillCam image of small intestine in a patient with celiac disease, showing scalloping of the mucosal folds (arrows) characteristic of a malabsorption pattern. There is also evidence of villous atrophy compared with normal. (D) Biopsy specimen of small intestine in a patient with celiac disease (hematoxylin-eosin; original magnification, × 100). Note the loss of villous architecture.
  • 8% Ackerman Study
  • BMD is low in patients with clinically silent untreated coeliac disease, but it can be substantially improved by dietary treatment even within a year. With a view to the prevention of osteopenia screening for silent coeliac disease is thus warranted. The study group consisted of 19 consecutive patients with coeliac disease; six women and 13 men, median age 45 years, range 23–69 years. In all cases the disease was diagnosed through our routine screening programmes with the IgA-class endomysial antibody test as screening method; the risk groups were those having a 4–10% risk for coeliac disease. 15 were healthy family members of coeliacdisease patients, and four had disorders not indicative of coeliac disease—ie, two from oral ulcers, one from nonspecific arthritis, and one from ataxia. None of the clinically silent coeliac-disease patients had symptoms of malabsorption or anaemia, but two had mild abdominal symptoms. For comparison, data for 30 symptomatic untreated coeliac disease patients (23 women and seven men, median age 44 years, range 21–68 years) were used. 13 of these had abdominal distension, five loose stools, three weight loss, and nine anaemia as presenting symptoms. All coeliac patients were positive for endomysial antibodies, and had small-intestinal villous atrophy and crypt hyperplasia, which subsequently improved on a gluten-free diet. BMD was measured by dual-energy radiograph absorptiometry (Norland XR 26, Norland Corp, Fort Atkinson, WI, USA) in the lumbar spine and femoral neck before the start of gluten-free diet and 1 year thereafter. The baseline BMD data were expressed as t-scores with reference to data for sex-matched young individuals. The percentage change in BMD was calculated, and in individual change was judged significant if its magnitude exceeded 2Ö2 times the short-term in-vivo precision of the given measurement. In our laboratory, the significance levels were thus SD 2·0% for spine and SD 1·4% for f e m u r .5 At diagnosis, the median t-scores in symptom-free patients were –1·9 (95% CI –2·4 to –1·4) in the spine and – 0·9 (–1·5 to –0·7) in the femoral neck, and in patients with symptoms –1·1 (–1·5 to –0·7) and –0·8 (–1·1 to –0·5), respectively. Surprisingly, BMD was even lower in clinically silent than in symptomatic coeliac patients. This indicates that silent cases may have had a manifest mucosal lesion for a long time. After 1 year on a gluten-free diet, the spinal BMD increased significantly in eight out of 19 clinically silent coeliac disease patients (figure). In the femoral neck, ten patients showed significant increases in BMD.
  • La¨hteenoja H, Toivanen A, Viander M, Ma¨ki M, Irjala K, Ra¨iha¨ I, Syrja¨nen S: Institute of Dentistry, University of Turku, Oral mucosal changes in coeliac patients on a gluten-free diet. Eur J Oral Sci Turku, Finland 1998; 106: 899–906. © Eur J Oral Sci, 1998 Oral mucosal lesions or dental enamel defects may be the only presenting features of coeliac disease. A series of 128 patients with coeliac disease (CD) on a gluten-free diet (GFD), 8 patients with a newly diagnosed CD, and 30 healthy controls participated in a clinical and histopathological study of their oral mucosa. Oral mucosal lesions occurred in 71/128 GFD-treated CD patients, in 4/8 untreated and in 10/30 controls, and oral symptoms in 85/128, in 6/8 and in 10/30, respectively. Five CD patients had aphthous ulcers. Moderate
  • La¨hteenoja H, Toivanen A, Viander M, Ma¨ki M, Irjala K, Ra¨iha¨ I, Syrja¨nen S: Institute of Dentistry, University of Turku, Oral mucosal changes in coeliac patients on a gluten-free diet. Eur J Oral Sci Turku, Finland 1998; 106: 899–906. © Eur J Oral Sci, 1998 Oral mucosal lesions or dental enamel defects may be the only presenting features of coeliac disease. A series of 128 patients with coeliac disease (CD) on a gluten-free diet (GFD), 8 patients with a newly diagnosed CD, and 30 healthy controls participated in a clinical and histopathological study of their oral mucosa. Oral mucosal lesions occurred in 71/128 GFD-treated CD patients, in 4/8 untreated and in 10/30 controls, and oral symptoms in 85/128, in 6/8 and in 10/30, respectively. Five CD patients had aphthous ulcers. Moderate
  • Cronin study: 1 in 20 pts c insulin dependant diabetes has celiac
  • Ludvigsson, Sweedon
  • Selective IgA deficiency was observed in 12 of 688 (1.7%) patients with celiac disease who were clinically undistinguishable from patients with celiac disease with normal IgA levels. This high prevalence of IgA deficiency in patients with celiac disease makes serum IgA assay advisable when screening for celiac disease is performed by measurement of antigliadin antibodies or anti-IgA endomysium antibodies. Similarly, subjects with IgA deficiency should be considered at risk ofceliac disease. (J Pediatr 1997;l31 :306-8) Selective IgA deficiency is the most common primary immunodeficiency, with a prevalence of 1 case in 500 to 700 subjects, I It is an important risk factor for recurrent infections and for diseases with autoimmune response, although many subjects seem to have no sequelae of IgA deficiency.e Selective IgA deficiency is significantly increased in celiac disease, but its prevalence and clinical and pathogenetic implications in patients with celiac disease are still unclear,3.& We report the prevalence and the clinical features ofsubjects with IgA deficiency in a group of 688 children with CD who were the object of a recent multicenterstudy.
  • Celiac Disease: Beyond Bowels, Blood, & Bones

    1. 1. Celiac Disease: Beyond Bowels, Blood & Bones   Patricia Raymond MD FACP FACG
    2. 2. Objectives <ul><li>Identify the prevalence of celiac disease, nationally and worldwide </li></ul><ul><li>Summarize what is known about the pathophysiology of the disease </li></ul><ul><li>Describe the comorbitities found with celiac disease </li></ul><ul><li>Explain the limitations of conventional management and advances in the future </li></ul>
    3. 3. Prevalence in the US <ul><li>Healthy Individuals 1:133 </li></ul><ul><li>Symptomatic Subjects 1:40 </li></ul><ul><li>1 st Degree Relative with Celiac 1:22 </li></ul><ul><li>2 nd Degree Relative with Celiac 1:39 </li></ul><ul><li>Projected number Celiacs in US 2,115,954 </li></ul><ul><li>Known Celiacs in US 40,000 </li></ul><ul><li>For each known Celiac, there are 53 undiagnosed patients </li></ul>Arch Int Med 2003; 163: 286-292
    4. 4. Celiac Disease Globally Prevalence on Screening Data http://www.istockphoto.com/janrysavy Worldwide 1:266 Brazil 1:400 Denmark 1:500 Finland 1:130 Germany 1:500 Italy 1:184 Netherlands 1:198 Norway 1:250 Sahara 1:70 Sweden 1:190 United Kingdom 1:112 USA 1:133
    5. 5. Objectives <ul><li>Identify the prevalence of celiac disease, nationally and worldwide </li></ul><ul><li>Summarize what is known about the pathophysiology of the disease </li></ul><ul><li>Describe the comorbitities found with celiac disease </li></ul><ul><li>Explain the limitations of conventional management and advances in the future </li></ul>
    6. 6. Pathophysiology <ul><li>Allergy to the protein ‘gluten’, found in wheat, rye, barley </li></ul><ul><li>Leads to lymphocytic infiltrate in small intestinal mucosa, villous atrophy </li></ul><ul><li>Diagnosis </li></ul><ul><ul><li>History </li></ul></ul><ul><ul><li>Serology </li></ul></ul><ul><ul><li>Endoscopic gross appearance </li></ul></ul><ul><ul><li>Endoscopic biopsy </li></ul></ul><ul><li>Treatment is “only” GFD </li></ul>http://www.aafp.org/afp/20071215/1795.html
    7. 7. Bowels , Blood, and Bone <ul><li>Diarrhea </li></ul><ul><ul><li>From 45-85% of patients </li></ul></ul><ul><ul><li>Diarrhea persisting despite GFD </li></ul></ul><ul><ul><ul><li>Microscopic colitis </li></ul></ul></ul><ul><ul><ul><li>Steatorrhea secondary to pancreatic exocrine insufficiency </li></ul></ul></ul><ul><ul><ul><li>Secondary lactose or fructose malabsorption </li></ul></ul></ul><ul><ul><ul><li>Anal sphincter dysfunction causing fecal incontinence </li></ul></ul></ul><ul><ul><ul><li>Irritable bowel syndrome </li></ul></ul></ul><ul><ul><ul><li>Small bowel bacterial overgrowth </li></ul></ul></ul><ul><li>Constipation </li></ul><ul><ul><li>due to low fiber intake with avoidance of common whole grains </li></ul></ul><ul><ul><li>responds to dietary rice bran and ispaghula husks (psyllium) </li></ul></ul>
    8. 8. Bowels, Blood , and Bone <ul><li>Anemia </li></ul><ul><ul><ul><li>10-15% of celiac patients </li></ul></ul></ul><ul><ul><ul><li>Due to impaired absorption of iron and/or folate from the proximal small intestine. </li></ul></ul></ul><ul><li>In celiac disease with ileal involvement </li></ul><ul><ul><ul><li>Impaired absorption of vitamin B-12 </li></ul></ul></ul><ul><ul><ul><li>Macrocytic anemia, elevated MCV </li></ul></ul></ul><ul><li>Who has the highest yields on small bowel biopsy? </li></ul><ul><ul><ul><li>6- 12% of iron deficient patients have celiac disease </li></ul></ul></ul><ul><ul><ul><li>20% of nonresponders to supplemental iron have celiac disease </li></ul></ul></ul>www.istockphoto.com/vladm
    9. 9. Bowels, Blood, and Bone <ul><li>Osteopenia, rarely osteoporosis. </li></ul><ul><ul><li>Due to secondary hyperparathyroidism, likely from due to vitamin D deficiency </li></ul></ul><ul><ul><li>Partial reversal with a gluten-free diet </li></ul></ul><ul><ul><li>Peripheral bone loss may persist despite normalization at axial skeletal sites </li></ul></ul><ul><li>Advanced disease may have bone pain, </li></ul><ul><li>pseudofractures, or deformity </li></ul><ul><ul><li>May occur without gastrointestinal symptoms </li></ul></ul><ul><ul><li>Most patients are asymptomatic or have only raised serum levels of alkaline phosphatase or hypocalcemia </li></ul></ul><ul><li>Evaluation of people with celiac </li></ul><ul><ul><li>Baseline DEXA (dual energy x-ray absorptiometry) scan </li></ul></ul><ul><ul><li>Repeat DEXA scan after one year </li></ul></ul>www.istockphoto.com DoctorKan
    10. 10. Objectives <ul><li>Identify the prevalence of celiac disease, nationally and worldwide </li></ul><ul><li>Summarize what is known about the pathophysiology of the disease </li></ul><ul><li>Describe the comorbitities found with celiac disease </li></ul><ul><li>Explain the limitations of conventional management and advances in the future </li></ul>
    11. 11. <ul><li>CAUTION needed! </li></ul><ul><ul><li>Case reports and small series </li></ul></ul><ul><ul><li>Many international, not directly applicable to US population </li></ul></ul><ul><ul><li>Do not assume causal </li></ul></ul><ul><ul><li>In some cases, but not all, comorbidity improves with GFD </li></ul></ul><ul><li>Recognition of celiac comorbidities may lead to diagnosis </li></ul><ul><ul><li>Time from symptom onset to diagnosis in US as long as 10 years </li></ul></ul>There’s a lot to celiac disease beyond bowels, blood, and bones http://www.istockphoto.com/LajosRepasi C L E I A C
    12. 12. <ul><li>Depression </li></ul><ul><ul><li>60% vs 10% controls </li></ul></ul><ul><li>Anxiety </li></ul><ul><ul><li>62% vs 31% controls </li></ul></ul><ul><li>Epilepsy </li></ul><ul><ul><li>1 in 44 </li></ul></ul><ul><ul><li>Advocate celiac screen in all epileptics </li></ul></ul><ul><li>Neuropathy </li></ul><ul><ul><li>Sensory or motor neuropathies </li></ul></ul><ul><ul><li>Check for celiac in unexplained advocated </li></ul></ul>Cerebral http://www.istockphoto.com/hidesy C L E I A C
    13. 13. <ul><li>Gluten ataxia </li></ul><ul><ul><li>Small series of 28 patients found to have celiac disease </li></ul></ul><ul><ul><li>Gait and some limb ataxia, 19 with peripheral neuropathy </li></ul></ul><ul><ul><li>16 of 28 without bowel symptoms </li></ul></ul><ul><li>Cognitive impairment in elderly </li></ul><ul><ul><li>Newly diagnosed celiac disease </li></ul></ul><ul><ul><li>Dementia responsive to GFD </li></ul></ul><ul><li>Episodic headache </li></ul><ul><li>Down syndrome </li></ul><ul><ul><li>Prevalence of biopsy proven celiac disease up to 16 % </li></ul></ul><ul><ul><li>20-fold increase compared to the general population </li></ul></ul>Cerebral http://www.istockphoto.com/mpabild C L E I A C
    14. 14. <ul><li>Autoimmune myocarditis and idiopathic dilated cardiomyopathy </li></ul><ul><ul><li>5 percent of patients with autoimmune myocarditis or idiopathic dilated cardiomyopathy have celiac disease </li></ul></ul><ul><ul><li>In one report of nine patients, none had classic GI symptoms of celiac disease (recurrent abdominal pain, diarrhea, and weight loss), but all had iron deficiency anemia refractory to oral iron replacement </li></ul></ul><ul><ul><li>Cardiac function improved with GFD +/- immunosuppressive therapy. </li></ul></ul>Cardiac www.istockphotp.com/dny59i C L E I A C
    15. 15. Cutaneous <ul><li>Dermatitis Herpetiformis </li></ul><ul><ul><li>95% extensor elbows </li></ul></ul><ul><ul><li>66% buttocks </li></ul></ul><ul><ul><li>Also at extensor knees, sites of clothing pressure (belt, bra) </li></ul></ul><ul><li>2/3 have celiac disease </li></ul><ul><li>Likely all have some degree gluten sensitivity </li></ul><ul><li>Rapid response to dapsone, slow response to GFD </li></ul>http://www.nlm.nih.gov/medlineplus/ency/imagepages/2791.htm C L E I A C
    16. 16. <ul><li>Atrophic glossitis </li></ul><ul><ul><li>Erythema or atrophy </li></ul></ul><ul><ul><li>Soreness or burning sensation of the tongue </li></ul></ul><ul><ul><li>Responds to gluten free diet </li></ul></ul><ul><li>Ask your dentist! </li></ul><ul><ul><li>71/128 (55%) with celiac disease have oral aphthous ulcers or dental enamel ‘pits’ </li></ul></ul>Cutaneous www.istockphoto.com/shironosov C L E I A C
    17. 17. <ul><li>Diabetes mellitus type 1 </li></ul><ul><ul><li>2.6 % have EMA IgA and 7.8 % have TTG IgA </li></ul></ul><ul><ul><li>Most positive patients will have positive small bowel biopsy for celiac disease </li></ul></ul><ul><ul><li>3.5 % of children of parents with type 1 diabetes have celiac disease, prevalence increases with age </li></ul></ul><ul><li>Human studies unclear on GFD & modulation of diabetes </li></ul><ul><ul><li>Animal studies suggest that the interplay between gluten exposure and the intestinal immune system can modulate the development of type 1 diabetes </li></ul></ul>Endocrine www.istockphoto.com/laures C L E I A C
    18. 18. <ul><li>Autoimmune thyroid disease </li></ul><ul><ul><li>14% of people with celiac </li></ul></ul><ul><ul><ul><li>Hypothyroidism 10% </li></ul></ul></ul><ul><ul><ul><li>Hyperthyroidism 4% </li></ul></ul></ul><ul><li>Pancreatitis </li></ul><ul><ul><li>Celiac disease patients have </li></ul></ul><ul><ul><ul><li>3.3 HR (Hazard Risk) pancreatitis of all kinds </li></ul></ul></ul><ul><ul><ul><li>19.8 HR chronic pancreatitis </li></ul></ul></ul><ul><ul><li>Risk of subsequent diagnosis of celiac disease </li></ul></ul><ul><ul><ul><li>Pancreatitis of any type (OR 3.2) </li></ul></ul></ul><ul><ul><ul><li>Chronic pancreatitis (OR 7.3.) </li></ul></ul></ul>Endocrine www.istock.com/angelhell C L E I A C
    19. 19. <ul><li>Kidney disease </li></ul><ul><ul><li>Glomerular IgA deposition is common </li></ul></ul><ul><ul><li>Occurs in up to 33% </li></ul></ul><ul><ul><li>Most with no clinical manifestations of renal disease </li></ul></ul><ul><ul><ul><li>Felt to be because of no associated activation of complement </li></ul></ul></ul>Elimination (Kidney) www.istockphoto.com/eraxion C L E I A C
    20. 20. <ul><li>Elevated liver tests </li></ul><ul><ul><li>Up to 40% adult patients with celiac </li></ul></ul><ul><ul><li>Nonspecific mild chronic elevation in serum aminotransferase levels </li></ul></ul><ul><ul><ul><li>AST ranging from 29 to 80 </li></ul></ul></ul><ul><ul><ul><li>ALT ranging from 60 to 130 </li></ul></ul></ul><ul><ul><ul><li>ALT usually slightly greater than AST </li></ul></ul></ul><ul><ul><li>Celiac disease accounts for 4 % of abnormal liver function tests of unexplained etiology </li></ul></ul>Liver Tests www.istockphoto.com/eraxion C L E I A C
    21. 21. <ul><li>Primary biliary cirrhosis </li></ul><ul><ul><li>PBC in people with celiac 3% </li></ul></ul><ul><ul><li>Celiac disease in patients with PBC 6% </li></ul></ul><ul><li>Primary sclerosing cholangitis </li></ul><ul><ul><li>Celiac in 3% patients with PSC </li></ul></ul><ul><li>Advanced liver disease </li></ul><ul><ul><li>One report focused on four patients with severe liver disease (due to congenital liver fibrosis, massive steatosis, and progressive hepatitis of unclear origin) and untreated celiac disease. Hepatic dysfunction reversed in all patients following a gluten-free diet </li></ul></ul>Liver Tests http://www.istockphoto.com/eraxion C L E I A C
    22. 22. <ul><li>Idiopathic pulmonary hemosiderosis </li></ul><ul><li>Lane-Hamilton syndrome </li></ul><ul><ul><li>Coexistence of celiac disease and idiopathic pulmonary hemosiderosis </li></ul></ul><ul><ul><li>Gluten-free diet has been associated with remission of pulmonary symptoms in several patients </li></ul></ul>Lungs www.istock.com/eraxion C L E I A C
    23. 23. <ul><li>Increased frequency of menstrual abnormalities </li></ul><ul><ul><li>later menarche </li></ul></ul><ul><ul><li>earlier menopause </li></ul></ul><ul><li>Infertility </li></ul><ul><ul><li>Prevalence 1 in 96 with fertility problems </li></ul></ul><ul><ul><li>15% miscarriage vs 6% controls </li></ul></ul><ul><li>IUGR </li></ul><ul><ul><li>Threefold higher risk of intrauterine growth restriction among infants of mothers with undiagnosed celiac disease compared with controls </li></ul></ul><ul><li>GFD prevents/corrects these issues </li></ul>Infertility, female Females with untreated celiac disease C L E I A C
    24. 24. Infertility, male <ul><li>Abnormalities in sperm motility and morphology </li></ul><ul><li>Androgen resistance </li></ul><ul><ul><li>high serum testosterone and high LH concentrations </li></ul></ul><ul><ul><li>GFD led to normalization of the biochemical abnormalities and sperm </li></ul></ul>C L E I A C
    25. 25. <ul><li>Hyposplenism </li></ul><ul><ul><li>Several case reports </li></ul></ul><ul><ul><li>Prophylactic pneumococcal vaccination has been suggested </li></ul></ul><ul><li>Selective IgA deficiency </li></ul><ul><ul><li>In up to 8 % of celiac patients </li></ul></ul><ul><ul><li>Compares with one in 500-700 control population </li></ul></ul><ul><ul><li>May render serologic testing inaccurate </li></ul></ul>Immune System C L E I A C
    26. 26. <ul><li>Osteoarthritis </li></ul><ul><ul><li>26% patients </li></ul></ul><ul><ul><li>7.5% controls </li></ul></ul><ul><ul><li>Not very responsive to GFD </li></ul></ul>Arthritis www.istockphoto.com/aceshot C L E I A C
    27. 27. <ul><li>Risk of malignancy overstated </li></ul><ul><ul><li>Standardized incidence ratio {SIR} 1.3 </li></ul></ul><ul><ul><li>Suggests that the overall increase in cancer risk is modest </li></ul></ul><ul><li>Lymphoma </li></ul><ul><ul><li>Most common malignancy </li></ul></ul><ul><ul><li>SIR 5.9 </li></ul></ul><ul><li>Digestive tract cancers increased </li></ul><ul><ul><li>including squamous cell esophagus, small intestinal, colorectal, and hepatocellular </li></ul></ul><ul><li>Breast & lung reduced! Why? </li></ul>Cancer www.istockphoto.com/eraxion C L E I A C
    28. 28. <ul><li>Cerebral </li></ul><ul><li>Cardiac </li></ul><ul><li>Cutaneous </li></ul><ul><li>Endocrine </li></ul><ul><li>Elimination (Kidney) </li></ul><ul><li>Liver </li></ul><ul><li>Lungs </li></ul><ul><li>Infertility </li></ul><ul><li>Immune System </li></ul><ul><li>Arthritis </li></ul><ul><li>Cancer </li></ul>Pop quiz: CCCEELLIIAC? Name some associated comorbidities! C L E I A C
    29. 29. Objectives <ul><li>Identify the prevalence of celiac disease, nationally and worldwide </li></ul><ul><li>Summarize what is known about the pathophysiology of the disease </li></ul><ul><li>Describe the comorbitities found with celiac disease </li></ul><ul><li>Explain the limitations of conventional management and advances in the future </li></ul>
    30. 30. Celiac now, and in the future? <ul><li>How much flour is ‘gluten free’? </li></ul><ul><li>Oats have been removed from the forbidden list, but have they been processed in a gluten free environment? </li></ul><ul><li>Inconsistent labeling of processed foods </li></ul><ul><li>How do you eat out at restaurants or friends’ homes? </li></ul><ul><li>Find the hidden gluten </li></ul>www.istockphoto.com/snokid
    31. 31. Research is underway to change the future of celiac disease <ul><li>Enzyme therapy (Stanford Chemical Engineering Dept) Two-enzyme cocktail detoxifies grocery store gluten within 10 minutes under simulated duodenal conditions </li></ul><ul><li>Probiotic therapy (VSL3)- decreased toxicity of gliadin in long term fermentation in test tube </li></ul><ul><li>Oral budesenide (locally active steroid) for RS (9 patients- 2 failed to respond </li></ul><ul><li>Encapsulated enzyme extract (based on animal digestive tract) (RMIT Melbourne) 21 CD challenged with gluten daily over 2 weeks. Reduced symptoms on enzyme vs placebo, no TTG increase </li></ul>
    32. 32. Objectives <ul><li>Identify the prevalence of celiac disease, nationally and worldwide </li></ul><ul><li>Summarize what is known about the pathophysiology of the disease </li></ul><ul><li>Describe the comorbitities found with celiac disease </li></ul><ul><li>Explain the limitations of conventional management and advances in the future </li></ul>
    33. 33. References 1 of 4 <ul><li>Holmes, GK. Non-malignant complications of coeliac disease. Acta Paediatr Suppl 1996; 412:68. </li></ul><ul><li>Addolorato, G, Stefanini, GF, Capristo, E, et al. Anxiety and depression in adult untreated celiac subjects and in patients affected by inflammatory disease: A personality &quot;trait&quot; or a reactive illness? Hepatogastroenterology 1996; 43:1513. </li></ul><ul><li>Hadjivassiliou, M, Chattopadhyay, AK, Davies-Jones, GA, et al. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997; 63:770. </li></ul><ul><li>Cronin, CC, Jackson, LM, Feighery, C, et al. Coeliac disease and epilepsy. QJM 1998; 91:303. </li></ul><ul><li>Hu, WT, Murray, JA, Greenaway, MC, et al. Cognitive impairment and celiac disease. Arch Neurol 2006; 63:1440. </li></ul><ul><li>Hadjivassiliou, M, Grunewald, RA, Chattopadhyay, AK, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998; 352:1582. </li></ul><ul><li>Hadjivassiliou, M, Grunewald, RA, Lawden, M, et al. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001; 56:385. </li></ul><ul><li>Hadjivassiliou, M, Maki, M, Sanders, DS, et al. Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 2006; 66:373. </li></ul><ul><li>Lubrano, E, Ciacci, C, Ames, PR, et al. The arthritis of coeliac disease: Prevalence and pattern in 200 adult patients. Br J Rheumatol 1996; 35:1314. </li></ul><ul><li>Ackerman, Z, Eliakim, R, Stalnikowica, R, Rachmilewitz, D. Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia. Am J Gastroenterol 1996; 91:2099. </li></ul>
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