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F. Schweiger MD Moncton, May 27, 2007. Celiac sprue - Definiton Intolerance to gluten proteins from wheat and to related proteins from barley or rye Intolerance.

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Presentation on theme: "F. Schweiger MD Moncton, May 27, 2007. Celiac sprue - Definiton Intolerance to gluten proteins from wheat and to related proteins from barley or rye Intolerance."— Presentation transcript:

1 F. Schweiger MD Moncton, May 27, 2007

2 Celiac sprue - Definiton Intolerance to gluten proteins from wheat and to related proteins from barley or rye Intolerance to gluten proteins from wheat and to related proteins from barley or rye Presents with characteristic histopathological changes of the jejeunal mucosa Presents with characteristic histopathological changes of the jejeunal mucosa Consequences: from asymptomatic to global malabsorption and an increased risk to develop GI malignancies Consequences: from asymptomatic to global malabsorption and an increased risk to develop GI malignancies Manifestation by genetic, environmental,and immunological factors Manifestation by genetic, environmental,and immunological factors

3 Mortality of celiac sprue Before introduction of gluten-free diet: 544 children 12 % Hardwick children 12 % Hardwick 1939 (malabsorption and infection) (malabsorption and infection) After introduction of gluten-free diet (Dickie 1951): 485 children 0.4 % Sheldon children 0.4 % Sheldon adults 2 x increased Logan et al adults 2 x increased Logan et al adults on GFD no increase Collin et al adults on GFD no increase Collin et al 1994

4 Prevalence of Celiac Disease USA / Canada 1 in 100 Irish 1 in 152 Italians with “dyspepsia” 1 in 103 Swedish blood donors 1 in 256 Brazilians 1 in 680 Baltimore (USA) 1 in 300 Rare in Afro-Caribbean, Chinese, Japanese Rare in Afro-Caribbean, Chinese, Japanese Mild female preponderance (2:1 at most) Mild female preponderance (2:1 at most)

5 Triggers of celiac disease Infectious (viral bacterial) Diatetic (gluten) Genetic HLA-DQ2 Autoimmunity Immune-maturation Th2 Th1 Sprue

6 Family Gramineae Subfamily Festucoideae Panicoideae Tribe Triticeae Aveneae Oryzeae Andropogoneae Paniceae Subtribe Triticineae Hordeinae Tripsacinae Anthrxoninae Genus Triticum Secale Hordeum Avena Oryza Zea Sorghum Pennisetum Wheat Rye Barley Oats Rice Corn Sorghum Millet Wheat Rye Barley Oats Rice Corn Sorghum Millet

7 Toxic wheat proteins Glutelins (glutenins of wheat) Soluble in acids and bases Soluble in acids and bases 45 % Glu 45 % Glu Prolamines (gliadins of wheat) Soluble in 50 – 70 % ethanol Soluble in 50 – 70 % ethanol 30 – 56 % Glu, 15 – 30 % Pro 30 – 56 % Glu, 15 – 30 % Pro Alpha, beta, gamma, delta gliadins Alpha, beta, gamma, delta gliadins Toxic peptides: PSQQ, QQQP Toxic peptides: PSQQ, QQQP Gluten

8 Environmental Factors OATS Oats may be tolerated by patients Oats may be tolerated by patients Oats contain less QQQPF (toxic fraction in wheat gliadin) Oats contain less QQQPF (toxic fraction in wheat gliadin) Prolamines in oats have less glutamine and proline Prolamines in oats have less glutamine and proline Tolerance to oats depends on the amount consumed (less than 40 gm) Tolerance to oats depends on the amount consumed (less than 40 gm)

9 Genetic factors Concordance in monozygotic twins : 75 % Concordance in monozygotic twins : 75 % Risk to first degree relatives : 2 – 15 % (10 %) Risk to first degree relatives : 2 – 15 % (10 %) Risk to 2 nd degree relatives : 3 – 5 % Risk to 2 nd degree relatives : 3 – 5 %

10 Familial clustering of celiac disease/dermatitis herpetiformis 1.degree relatives number sprue/DH prevalence Parents % Sisters/brothers % Offspring % 2.degree relatives % Total %

11 Relatives: Who and How to Screen ? Index case has proven celiac disease Index case has proven celiac disease Relative is interested in being screened Relative is interested in being screened Relative is willing to undergo diagnostic testing Relative is willing to undergo diagnostic testing Relative is willing to undergo treatment Relative is willing to undergo treatment Relative will derive benefit from treatment Relative will derive benefit from treatment If relative is symptomatic, approach is diagnostic not screening If relative is symptomatic, approach is diagnostic not screening S. Crowe, DDW 2007

12 Classical presentation of celiac disease 1960-ies, Helsinki, Finland Number 53 Age at initial symptoms (months) 7.7 Duration of gluten ingestion (months) 4.3 Age at admission (months) 10.2 Diarrhea 87 % Vomiting 74 % Growth retardation 98 % Weight below 2.5 percentile 70 % Distended abdomen 64 % Acta Ped Scand 1967

13 Celiac Disease in Adults 20 % over age % over age 60 Often mistaken for Irritable Bowel Syndrome Often mistaken for Irritable Bowel Syndrome 50 % do not have diarrhea 50 % do not have diarrhea Iron deficiency anemia most common presentation Iron deficiency anemia most common presentation Unmasking by gastric surgery Unmasking by gastric surgery May present as recurrent “canker sores” May present as recurrent “canker sores” Significant fatty stools uncommon Significant fatty stools uncommon Abdominal pain uncommon Abdominal pain uncommon

14 Atypical Presentations (1) Nonspecific Weight loss, lethargy, fatigue Nonspecific Weight loss, lethargy, fatigue Hematological bruising (Vitamin K), anemia Hematological bruising (Vitamin K), anemia (iron,folate,B12) (iron,folate,B12) hyposplenism (thrombocytosis) hyposplenism (thrombocytosis) Neurological cerebellar ataxia, peripheral Neurological cerebellar ataxia, peripheral neuropathy,post/lateral column neuropathy,post/lateral column abnormalities, neuromyopathies, abnormalities, neuromyopathies, epilepsy (+/-cerebral calcifications) epilepsy (+/-cerebral calcifications) demyelinating CNS lesions demyelinating CNS lesions

15 Atypical Presentations (2) Musculoskeletal Osteoporosis, osteomalacia, #s Musculoskeletal Osteoporosis, osteomalacia, #s osteoarthropathy,tetany,weakness osteoarthropathy,tetany,weakness dental enamel hypoplasia, dental enamel hypoplasia, Gynecologic primary or secondary amenorrhea Gynecologic primary or secondary amenorrhea infertility, recurrent abortions infertility, recurrent abortions Dermatologic alopecia, follicular keratosis Dermatologic alopecia, follicular keratosis Psychiatric depression, psychosis, Psychiatric depression, psychosis, schizophrenia schizophrenia

16 Atypical Presentations (3) Endocrine : pubertal delay, short stature, 2 nd hyperparathyroidism, infertility, 2 nd hyperparathyroidism, infertility, impotence, amenorrhea impotence, amenorrhea

17 Dietary Response -? Diagnostic Placebo response in IBS up to 70 % Placebo response in IBS up to 70 % Gluten (increased prolamines) is hard to digest Gluten (increased prolamines) is hard to digest GFD often eliminates other dietary factors GFD often eliminates other dietary factors Symptomatic response to GFD, especially a transient response, does not imply the diagnosis of celiac disease Symptomatic response to GFD, especially a transient response, does not imply the diagnosis of celiac disease

18 Laboratory tests Protein: Albumin, globulins, Liver tests Protein: Albumin, globulins, Liver tests Carbs : glucose, Lactose-H breath test, (D-Xylose) Carbs : glucose, Lactose-H breath test, (D-Xylose) Fats : (stool for fat), lipid profile, carotene Fats : (stool for fat), lipid profile, carotene Minerals : Ca, Mg, P, Fe, ferritin,zinc Minerals : Ca, Mg, P, Fe, ferritin,zinc Vitamins : RBC folate, B12, Vit A, 25-OH Vitamin D, PT Vitamins : RBC folate, B12, Vit A, 25-OH Vitamin D, PT

19 Serologic Tests for Celiac Disease Serologic Test Sensitivity Specificity PPV NPV percent percent Anti-EMA (IgA) IgA antigliadin IgG antigliadin tTg (IgA)

20 Epidemiology of Celiac Disease the sprue iceberg Healthy individuals Latent CD Silent CD Clinical CD Normal mucosa Abnormal mucosa EMA present Asymptomatic

21 The asymptomatic patient Advantages of screening: Advantages of screening: Reduction in risk of enteropathic T-cell lymphoma Reduction in risk of enteropathic T-cell lymphoma Reversal of unrecognized nutritional deficiences Reversal of unrecognized nutritional deficiences Resolution of mild or unrecognized symptoms Resolution of mild or unrecognized symptoms Avoidance of other autoimmune disorders Avoidance of other autoimmune disorders Improvement of general well-being Improvement of general well-being Disadvantages of screening: Disadvantages of screening: Lack of motivation to adhere to GFD Lack of motivation to adhere to GFD Adverse psychological effects Adverse psychological effects Mass screening currently not advocated Mass screening currently not advocated

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23 Pathology of celiac disease Length of SB involvement correlates with clinical severity Length of SB involvement correlates with clinical severity GFD results in marked improvement beginning distally GFD results in marked improvement beginning distally Histology is not specific Histology is not specific

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28 Causes of villous atrophy Cow’s milk protein intolerance (children) Cow’s milk protein intolerance (children) Post-gastroenteritis Post-gastroenteritis Giardiasis Giardiasis Peptic duodenitis (including ZES) Peptic duodenitis (including ZES) Crohn’s disease Crohn’s disease Small intestinal bacterial overgrowth Small intestinal bacterial overgrowth Eosinophilic enteritis Eosinophilic enteritis Radiation or cytotoxic therapy Radiation or cytotoxic therapy Tropical sprue Tropical sprue Severe malnutrition Severe malnutrition Diffuse small intestinal lymphoma Diffuse small intestinal lymphoma Graft versus host disease Graft versus host disease Hypogammaglobulinemia Hypogammaglobulinemia Alpha chain disease Alpha chain disease

29 Prevalence of autoimmune disease in celiac disease

30 Celiac disease and associated disorders Definite Association Dermatitis herpetiformis Dermatitis herpetiformis Insulin-dependent Diabetes Insulin-dependent Diabetes Thyroid disease Thyroid disease IgA deficiency IgA deficiency Epilepsy with cerebral calcifications Epilepsy with cerebral calcifications Inflammatory bowel disease Inflammatory bowel disease Microscopic colitides Microscopic colitides IgA mesangial nephropathy IgA mesangial nephropathy Chronic autoimmune hepatitis Chronic autoimmune hepatitis Sclerosing cholangitis Sclerosing cholangitis Primary biliary cirrhosis Primary biliary cirrhosis Down syndrome (3-12%) Down syndrome (3-12%) Turner syndrome Turner syndrome Rheumatoid arthritis Rheumatoid arthritis Sarcoidosis Sarcoidosis Bird fancier’s lung Bird fancier’s lung Fibrosing alveolitis Fibrosing alveolitis Recurrent pericarditis Recurrent pericarditis Idiopathic pulmonary hemosiderosis Idiopathic pulmonary hemosiderosis

31 Dermatitis herpetiformis Papulovesicular lesions of extensor surfaces, buttocks, trunk, neck and scalp Papulovesicular lesions of extensor surfaces, buttocks, trunk, neck and scalp Intensely pruritic Intensely pruritic Early or middle adult life; M = F Early or middle adult life; M = F 2/3 have patchy enteropathy; tends to be less severe 2/3 have patchy enteropathy; tends to be less severe Less than 10 % have intestinal symptoms Less than 10 % have intestinal symptoms 10 – 40 fold increased risk of lymphoma 10 – 40 fold increased risk of lymphoma

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33 Dermatitis herpetiformis Frequency of Abs to tTG only about 75 % Frequency of Abs to tTG only about 75 % More than 80 % of pts with DH have sprue More than 80 % of pts with DH have sprue 10 % of celiacs have DH 10 % of celiacs have DH Tx: Dapsone 1 – 2 mg/kg (does not improve SB) Tx: Dapsone 1 – 2 mg/kg (does not improve SB) GFD allows most patients to reduce/stop Dapsone GFD allows most patients to reduce/stop Dapsone

34 Celiac disease and type 1 DM Patients (n) Pos (%) Patients (n) Pos (%) Finland children (776) 2.4 Finland adults (195) 4.1 Italy children (498) 3.2 Italy adults (383) 2.6 Italy adults (639) 7.8 Sweden children (436) 4.6 Ireland adults (101) 4.9 UK adults (767) 2.0 Germ/Switz children (1032) 1.2 Australia children (273) 1.8 USA children (211) 1.4

35 Celiac disease and Osteoporosis Prevalence of CD is increased in osteoporosis (1.5-3%) Especially in premature osteoporosis/osteomalacia Prevalence of CD is increased in osteoporosis (1.5-3%) Especially in premature osteoporosis/osteomalacia Newly diagnosed CD : spine 28 % & hip 15 % Newly diagnosed CD : spine 28 % & hip 15 % Patients with asymptomatic CD have increased risk Patients with asymptomatic CD have increased risk Postmenopausal females are at greatest risk Postmenopausal females are at greatest risk

36 Celiac disease and Osteoporosis Vitamin D deficiency is common in CD Vitamin D deficiency is common in CD Bone mineral density increases with GFD, especially in the first year of treatment Bone mineral density increases with GFD, especially in the first year of treatment Axial bone mass increases more then appendicular BMD Axial bone mass increases more then appendicular BMD

37 Celiac disease and Osteoporosis  Adequate calcium and vitamin D intake  Regular weight bearing exercises  Smoking cessation; avoid alcohol  Correction of hypogonadism

38 Celiac Disease and Osteoporosis

39 Celiac disease and associated conditions Possible association Congenital heart disease Congenital heart disease Lung cavities Lung cavities Sjogren’s syndrome Sjogren’s syndrome Systemic and cutaneous vasculitis Systemic and cutaneous vasculitis SLE SLE Polymyositis Polymyositis Schizophrenia Schizophrenia Myasthenia gravis Myasthenia gravis Iridocyclitis or choroiditis Iridocyclitis or choroiditis Cystic fibrosis Cystic fibrosis Macroamylasemia Macroamylasemia Addison’s disease Addison’s disease Autoimmune thrombocytopenic purpura Autoimmune thrombocytopenic purpura Autoimmune hemolytic anemia Autoimmune hemolytic anemia

40 Celiac Disease and Malignancies 44/105 deaths during 13.5 years in 653 (untreated) patients from Edinburgh, Scotland Risk Risk All malignancies 3 x Lymphoma 30 x Intestinal carcinoma 3 x Esophageal carcinoma 8 x Logan et al, Gastroenterology 1989

41 Cancer and Celiac Disease 12, 000 celiac patients in Sweden over 30 years: 6-fold increased risk of lymphoma (18% of all Ca) 6-fold increased risk of lymphoma (18% of all Ca) Oropharyngeal Ca (SCC) Oropharyngeal Ca (SCC) Esophageal Ca (SCC) Esophageal Ca (SCC) Small bowel Ca Small bowel Ca Colon Ca - confined to subjects older than 60 Colon Ca - confined to subjects older than 60 Primary liver Ca Primary liver Ca Reduced occurrence of breast Ca Reduced occurrence of breast Ca Askling et al. Gastro 2002 Askling et al. Gastro 2002

42 Celiac Disease and cancer Strict adherence to a GFD probably reduces the risk of enteropathy-associated T cell lymphoma as well as the other malignancies Strict adherence to a GFD probably reduces the risk of enteropathy-associated T cell lymphoma as well as the other malignancies

43 Treatment of Celiac Disease Dietary counseling and strict avoidance of gluten Dietary counseling and strict avoidance of gluten Initial avoidance of dairy products Initial avoidance of dairy products Replacements of micronutrients in case of deficiencies Replacements of micronutrients in case of deficiencies Corticosteroids/azathioprine for celiac crisis or refractory sprue Corticosteroids/azathioprine for celiac crisis or refractory sprue

44 Treatment of Celiac Disease Non-compliance is an issue - eating out of home Non-compliance is an issue - eating out of home - peer pressure for children - peer pressure for children - less acceptable taste - less acceptable taste - accidental ingestion of G. - accidental ingestion of G. - cost, availability, labelling - cost, availability, labelling Use of oats, wheat starch controversial Use of oats, wheat starch controversial GFD reduces risk of malignancy GFD reduces risk of malignancy Unclear how much gluten if any is safe Unclear how much gluten if any is safe - new FDA guidelines up to 10 mg/day safe ? - new FDA guidelines up to 10 mg/day safe ? S. Crowe, DDW 2007 S. Crowe, DDW 2007

45 Response to Treatment Clinical improvement in 2 weeks in 70 %, by 6 weeks in most Clinical improvement in 2 weeks in 70 %, by 6 weeks in most Serological improvement by 4 – 6 weeks Serological improvement by 4 – 6 weeks Histological improvement in up to 2 years Histological improvement in up to 2 years Gaining weight above ideal BMI Gaining weight above ideal BMI Constipation Constipation Falling off the diet and getting ill again Falling off the diet and getting ill again S. Crowe, DDW 2007 S. Crowe, DDW 2007

46 Patient on GFD – no Biopsy! Celiac disease is possible and patient Celiac disease is possible and patient willing to undergo a gluten challenge willing to undergo a gluten challenge YES, ideally get NO, but wants no further testing if YES, ideally get NO, but wants no further testing if genetic testing genetic testing wants to stay on GFD genetic testing genetic testing wants to stay on GFD regardless of testing regardless of testing Challenge if DQ2 or DQ8 Positive; check Abs q 2 m EGD + Bx, if Ab +ve, +ve, increases -ve – not celiac dis. Symptoms develop or likelyhood of CD ? Use GFD for By 6 months suggest G challenge symptom control only S.Crowe, DDW 2007

47 Gluten Challenge Gradual increase of gluten in diet up to target (typically 4 slices of bread/day) Gradual increase of gluten in diet up to target (typically 4 slices of bread/day) Check tTG at 4-6 weeks and at intervals thereafter until positive Check tTG at 4-6 weeks and at intervals thereafter until positive Biopsy if diarrhea develops and/or become seropositive Biopsy if diarrhea develops and/or become seropositive Management if sero-negative at 3-6 months needs to be individualized Management if sero-negative at 3-6 months needs to be individualized S.Crowe, DDW 2007

48 Treatment of celiac disease Histology may not recover completely despite clinical normalization Histology may not recover completely despite clinical normalization Negativation of IgA anti-TTG after 4 – 6 months of a strictly gluten-free diet (GFD) Negativation of IgA anti-TTG after 4 – 6 months of a strictly gluten-free diet (GFD) Diagnosis to be reconsidered when no clinical improvement is reached after 6 – 9 months of a GFD Diagnosis to be reconsidered when no clinical improvement is reached after 6 – 9 months of a GFD Risk of malignancy approaches baseline after 5 years of a GFD Risk of malignancy approaches baseline after 5 years of a GFD

49 Why a Gluten Free Diet ? Benefits overall cancer risk Benefits overall cancer risk Improves unexplained infertility Improves unexplained infertility Improves osteoporosis Improves osteoporosis Corrects iron deficiency Corrects iron deficiency Improved QOL even for those detected by screening Improved QOL even for those detected by screening GFD is beneficial for preventing, reversing and/or treating some complications

50 Summary Celiac disease is not rare (1 in ) Celiac disease is not rare (1 in ) It can present in many ways It can present in many ways iron deficiency anemia, depression, osteoporosis, abnormal liver tests, non- specific or IBS-like symptoms, dyspepsia, DH, recurrent miscarriages, microscopic colitis iron deficiency anemia, depression, osteoporosis, abnormal liver tests, non- specific or IBS-like symptoms, dyspepsia, DH, recurrent miscarriages, microscopic colitis Associated with autoimmune diseases Associated with autoimmune diseases Screening with tTG IgA is best Screening with tTG IgA is best Confirm diagnosis with duodenal biopsy Confirm diagnosis with duodenal biopsy Cornerstone of treatment is avoidance of gluten Cornerstone of treatment is avoidance of gluten

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