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celiac sprue (gluten-sensitive enteropathy)

Etiology: - sensitivity to wheat gluten & related rye & barley proteins [3] - may coexist with autoimmune liver disorders including - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis [3,38] - association with: - diabetes mellitus type 1 - autoimmune thyroiditis - microscopic colitis - small intestinal lymphoma - enterovirus may be associated with early development of celiac disease [50] * introduction of gluten < 4 month of age or > 6 months of age not associated with increased incidence of celiac disease * higher gluten intake early in life is associated with increased risk for celiac disease in children genetically at risk [52] Epidemiology: 1) more frequent in patients with diabetes mellitus type-1 2) more frequent in patients with autoimmune thyroid disease 3) 19 cases in 22,000 children by 5 years of age [6] - 2.6 years of age youngest patient with diagnosis 4) prevalence of 1% at 7 years of age [7] 5) overall prevalence of positive celiac serology is 0.8% [22] 6) 2-fold higher rate of celiac disease in Sweden (vs. U.S.) [33] 7) prevalence of 1.4% of women vs 0.8% of men avoid gluten without evidence of celiac disease [43] 8) prevalence higher in northern U.S. lattitudes [44] - globally, prevalence higher in northern lattitudes [44] 9) make present (as initial presentation) in elderly [51] Pathology: 1) villus blunting & atrophy of small bowel mucosa 2) crypt elongation 3) submucosa, muscular layers & serosa are spared 4) histopathologic changes resolve when dietary gluten is withdrawn 5) autoantibody to tissue transglutaminase 6) intraepithelial lymphocytes, CD3+ T-cells [17] 7) duodenal villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis [55] Genetics: - associated with HLA-DR3 & HLA-DQ2 or HLA-DQ8 [3] - alleles common in the general population - most useful for ruling out celiac disease [3] - homozygosity for HLA haplotype DR3-DQ2 confers 5.7 fold risk [30] - susceptibility linked to CTLA4, myosin-9b Clinical manifestations: 1) majority of cases are probably asymptomatic (7:1) [6] 2) variable presentation & age of onset 3) typical features include: diarrhea, bloating, weight loss - children with irritable bowel syndrome 4-fold more likely to have celiac disease than general population [29] 4) growth retardation in children [34] 5) hematologic a) iron deficiency anemia in adults unresponsive to oral iron b) vitamin B12 deficiency, folate deficiency [3] c) splenic atrophy, functional asplenia d) elevated PT/INR & bleeding may occur secondary to vitamin K deficiency 6) GI symptoms in 1/2 of newly diagnosed cases [6] a) diarrhea b) steatorrhea, malodorous stools [3] c) abdominal cramping: constant abdominal pain is unusual [5] d) bloating [18] 7) musculoskeletal a) osteomalacia (may be present without steatorrhea with proximal small bowel involvement) b) osteopenia, osteoporosis c) arthropathy 8) neurological manifestations [5] a) peripheral neuropathy (RR=2.5, AR=0.4%) [35] b) paresthesias c) sensory abnormalities d) muscle weakness, myopathy, & ataxia less common e) seizures [3] 9) dermatitis herpetiformis - pruritic papulovesicular rash on extensor surfaces 10) glomerular IgA deposition 11) infertility, recurrent miscarriages [3] 12) tooth enamel defects [3] * see Differential diagnosis Diagnostic criteria: - positive tissue transglutaminase IgA - small intestine biopsy consistent with diagnosis of celiac disease (absence of mucosal villi) Laboratory: 1) serology a) tissue transglutaminase IgA in serum (most reliable) [41] - titers >= 10X upper limit of normal diagnostic [53,56] - repeat titers determine effectiveness of diet therapy/compliance [3] b) if patient is on a gluten-free diet, testing is less specific - if tissue transglutaminase IgA in serum is normal, repeat testing after resuming gluten-containing diet - consider genetic testing for HLA-DQ2 &/or HLA-DQ8 - nearly all patients with celiac disease carry HLA-DQ2 or HLA-DQ8 haplotype - 40% of general population carries one of these haplotypes - only useful for exclusion [3] c) IgA in serum - patients with IgA deficiency may have false-negative serology - if IgA deficiency - tissue transglutaminase IgG in serum - anti-deamidated gliadin peptide IgG in serum - antigliadin antibodies (IgA &/or IgG) (poor sensitivity & specificity, not recommended) [3] d) reticulin antibody in serum e) commercial assays not standardized; diagnoses may be missed [16] 3) complete blood count: iron deficiency anemia 4) peripheral smear may show Howell-Jolly bodies (10-15%) 5) serum chemistries a) serum calcium & serum albumin; hypocalcemia may be present b) serum magnesium: hypomagnesemia c) serum albumin: hypoalbuminemia (correct serum calcium for low serum albumin, see Misc Tools) d) serum vitamin B12 & serum folate: vitamin B12 deficiency & folate deficiency e) serum 25-OH vitamin D may be diminished f) serum iron, TIBC suggestive of iron deficiency g) serum transaminases, serum AST & serum ALT, may be elevated [3,15,18] h) serum lipase may be elevated [32] i) serum PTH may be elevated if serum 25-OH vitamin D is low 6) PT/INR may be prolonged due to vit K deficiency 7) see ARUP consult [23] Special laboratory: 1) upper GI endoscopy a) biopsy of the proximal small intestine b) gold standard for diagnosis c) indicated if antiendomysial antibody IgA (tissue transglutaminase IgA in serum) is positive d) histopathology shows absence of villi 2) repeat upper GI endoscopy with biopsy indicated if initial upper GI endoscopy & colonoscopy are negative for source of GI bleed [3] Radiology: 1) barium enema 2) abdominal CT - lymphadenopathy may be seen [32] 3) bone mineral density in newly diagnosed patients Differential diagnosis: 1) tropical sprue 2) graft versus host disease 3) irritable bowel syndrome - celiac disease needs to be ruled out prior to diagnosis of irritable bowel syndrome [55] 4) primary hyperparathyroidism - celiac disease is a cause of secondary hyperparathyroidism - elevated serum PTH with normal serum calcium 5) small intestinal bacterial overgrowth - vitamin B12 deficiency; serum folate high 6) lactose intolerance Complications: 1) microscopic colitis is the most common cause of diarrhea in a patient adherent to a gluten-free diet [55] 2) increased risk of lymphoproliferative cancer (RR = 4.8) [9] a) small bowel lymphoma is a late complication - incidence peaks 50-60 years - usually develops in the jejunum - recurrent malabsorption in a compliant patient [3] - relapse of celiac disease symptoms [55] b) T-cell lymphoma*, Hodgkins lymphoma c) well-controlled disease lowers risk [24] 3) increased risk of other cancers: a) oropharyngeal cancer b) esophageal cancer c) breast cancer d) small bowel adenocarcinoma 4) increased risk of gastrointestinal cancer (RR = 1.8) [9] 5) most cancers occur during 1st year after diagnosis of celiac sprue [9] 6) cerebellar ataxia [49] 7) neuropathic pain associated with gluten neuropathy [49] 8) fat soluble vitamin deficiencies: vitamin D deficiency, vitamin K deficiency 9) osteoporosis due to vitamin D deficiency & secondary hyperparathyroidism [55] * if symptoms worsen in patient in their 50's, T-cell lymphoma most likely diagnosis (despite lack of corroborating evidence) [55] Management: 1) gluten-free diet a) response is diagnostic b) of benefit for children with serologic evidence of celiac disease regardless of small bowel biopsy [19] c) only symptomatic patients benefit [36] d) strict gluten-free diet may protect from neuropathic pain associated with gluten neuropathy [49] e) lifelong avoidance of wheat, rye & barley [3] 2) gluten-free medications &/or supplements may be necessary for some patients [21] - consult pharmacist for possible sources of gluten, such as dextrin, pregelatinized starch, or sodium starch glycolate - if a starch is listed, the manufacturer may need to be contacted to find out what the starch is derived from 3) prednisone for refractory disease NOT responding to a gluten-free diet 4) vitamins, iron, vitamin D, & calcium, vitamin K - untreated disease is unresponsive to oral iron - for vitamin D deficiency, 50,000 IU vitamin D orally weekly for 6-12 weeks [51] 5) dapsone may facilitate resolution of dermatitis herpetiformis - check G6PD in erythrocytes for G6PD deficiency prior to initiation of dapsone 6) most common cause of recurrence is dietary indiscretion - assess recurrence for dietary indiscretion (1st step) [3] - patients adherent to diet should be evaluated for microscopic colitis & small intestinal lymphoma [3] 7) screening unlikely to be of benefit [20] - insufficient evidence to recommnend for or against screening asymptomatic individuals [40,45] (USPSTF) 8) prevention: - early introduction (4-6 months) of gluten into diets of high-risk infants does not appear to reduce risk of celiac disease [31] 9) experimental tranglutaminase-2 inhibitor ZED1227 attenuates gluten- induced duodenal mucosal damage [54]

Related

dermatitis herpetiformis; Duhring-Brocq disease food allergy gluten gluten-free diet tropical sprue

General

autoimmune disease intestinal disease food intolerance

Database Correlations

OMIM 609753

References

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