REVIEW CME EDUCATIONAL OBJECTIVE: Readers will recognize that celiac disease can affect more than just CREDIT the gastrointestinal system GURSIMRAN SINGH KOCHHAR, MD, TAVANKIT SINGH, MD ANANT GILL, MBBS DONALD F. KIRBY, MD, FACP, FACN, CNSC, FACP Department of Internal Medicine, Saraswathi Institute of Medical FACG, AGAF, CNSC, CPNS Department of Gastroenterology and Hepatology, Cleveland Clinic Sciences, Anwarpur, Center for Human Nutrition, Digestive Disease Digestive Disease Institute, Cleveland Clinic Uttar Pradesh, India Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH Celiac disease: Managing a multisystem disorder ABSTRACT eliac disease is an autoimmune disorder C that occurs in genetically predisposed in- Celiac disease is a multisystem autoimmune disorder that dividuals in response to ingestion of gluten. Its can cause symptoms involving the gastrointestinal tract prevalence is about 0.7% of the US population.1 and other organ systems such as the skin and bones. This paper reviews the pathogenesis, diagnosis, and manage- See related editorial, page 228 ment of celiac disease and associated diseases. The gold standard for diagnosis is duode- KEY POINTS nal biopsy, in which the histologic features may include varying gradations of flattening Besides gastrointestinal symptoms, celiac disease is as- of intestinal villi, crypt hyperplasia, and infil- sociated with a variety of diseases, including dermatitis tration of the lamina propria by lymphocytes. herpetiformis, malabsorption of several nutrients (poten- Many patients have no symptoms at the time tially leading to osteoporosis, iron deficiency anemia, and of diagnosis, but presenting symptoms can other disorders), and intestinal malignancies. include diarrhea along with features of mal- absorption,2 and, in about 25% of patients (mainly adults), a bullous cutaneous disorder While serologic testing for immunoglobulin A antibod- 3,4 ies to tissue transglutaminase can be used as an initial called dermatitis herpetiformis. The patho- screening test for this condition, the confirmatory tests genesis of celiac disease and that of dermati- tis herpetiformis are similar in that in both, are invasive, involving upper endoscopy for duodenal ingestion of gluten induces an inflammatory biopsy in celiac disease and skin biopsy in dermatitis reaction leading to the clinical manifesta- herpetiformis. tions. The mainstay of treatment of celiac disease The only effective treatment is lifelong adherence to a remains avoidance of gluten in the diet. gluten-free diet, and nonadherence is a common cause of refractory disease. ■ GENETIC PREDISPOSITION AND DIETARY TRIGGER Concomitant conditions such as anemia and vitamin The pathogenesis of celiac disease has been deficiency often require nutritional supplements. In addi- well studied in both humans and animals. The tion, patients with dermatitis herpetiformis often require disease is thought to develop by an interplay of treatment with dapsone. genetic and autoimmune factors and the inges- tion of gluten (ie, an environmental factor). Celiac disease occurs in genetically pre- disposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.5 Ingestion of gluten is necessary for the disease doi:10.3949/ccjm.83a.14158 to develop. Gluten, the protein component of CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 3 MARCH 2016 217 CELIAC DISEASE TABLE 1 by both the innate and adaptive immune sys- tems that can ultimately result in flattening of Diseases associated villi and crypt hyperplasia (Figure 1).7 with celiac disease Tissue transglutaminase also plays a cen- tral role in the pathogenesis, as it further Endocrine deaminates gliadin and increases its immu- Hashimoto thyroiditis Type 1 diabetes mellitus nogenicity by causing it to bind to receptors Addison disease on antigen-presenting cells with stronger af- Osteoporosis finity. Furthermore, gliadin-tissue transgluta- Osteopenia minase complexes formed by protein cross- linkages generate an autoantibody response Dermatologic Dermatitis herpetiformis (predominantly immunoglobulin A [IgA] Alopecia areata type) that can exacerbate the inflammatory process.8,9 Hepatic Certain viral infections during childhood, Autoimmune hepatitis such as rotavirus and adenovirus infection, Primary biliary cirrhosis 10–13 Primary sclerosing cholangitis can increase the risk of celiac disease. Nonalcoholic fatty liver disease Although earlier studies reported that breast- feeding seemed to have a protective effect,14 as Obstetric and gynecologic did introducing grains in the diet in the 4th to Amenorrhea 6th months of life as opposed to earlier or lat- Delayed menarche er,15 more recent studies have not confirmed Early menopause 16,17 Recurrent spontaneous abortion these benefits. Infertility Loss of libido ■ CLINICAL FEATURES Neurologic Most adults diagnosed with celiac disease are Celiac disease Cerebellar ataxia in their 30s, 40s, or 50s, and most are women. Peripheral neuropathy Diarrhea remains a common presenting occurs in Epilepsy symptom, although the percentage of patients carriers of Dementia with celiac disease who present with diarrhea 18,19 HLA-DQ2, Psychiatric has decreased over time. Depression Abdominal pain and weight loss are also HLA-DQ8, Schizophrenia common.20 or both Oncologic Pallor or decreased exercise tolerance can Intestinal T-cell lymphoma develop due to anemia from iron malabsorp- Adenocarcinoma of small intestine tion, and some patients have easy bruising due to vitamin K malabsorption. Cardiac Autoimmune myocarditis Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abor- tion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.21,22 Pa- wheat, barley, and rye, contains proteins called tients who follow a gluten-free diet tend to prolamins, which vary among the different have a lower incidence of intrauterine growth types of grain. In wheat, the prolamin is gliadin, retardation, preterm delivery, and low-birth- which is alcohol-soluble. In barley the prolamin weight babies compared with untreated pa- is hordein, and in rye it is secalin.4 The prolamin tients.21,22 content in gluten makes it resistant to degrada- Osteoporosis and osteopenia due to mal- tion by gastric, pancreatic, and intestinal brush absorption of vitamin D are common and are border proteases.6 Gluten crosses the epithelial seen in two-thirds of patients presenting with barrier and promotes an inflammatory reaction celiac disease.23 A meta-analysis and position 218 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 3 MARCH 2016 KOCHHAR AND COLLEAGUES Pathogenesis of celiac disease Gluten Villi flattening Crypt hyperplasia Gliadin Apoptosis of enterocytes Transcytosis Inflammatory Lamina propria response Deamination Secretion of Fibroblast tTG proinflammatory activation cytokines Deaminated gliadin IgA Presentation of Activated T cell autoantibody deaminated peptides response by antigen-presenting cell to T cell Antigen- presenting B cell cell T cell CCF ©2016 Medical Illustrator: David Schumick FIGURE 1. Celiac disease is an autoimmune disorder that, in genetically susceptible individuals, is triggered by ingestion of foods containing gluten. IgA = immunoglobulin A; tTG = tissue transglutaminase. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 3 MARCH 2016 219 CELIAC DISEASE Dermatitis herpetiformis Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.30 The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the ex- tensor surfaces of the upper and lower extremi- ties, elbows, knees, scalp, nuchal area, and but- tocks31 (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa32 or purpura on the palms and soles.33–35 The pathogenesis of dermatitis herpetifor- mis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplo- type. In the skin, there is an analogue of tissue transglutaminase called epidermal transgluta- minase, which helps in maintaining the integ- rity of cornified epithelium.36 In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the FIGURE 2. Eroded and crusted erythematous plaques with basement membrane.37–39 These deposits then scalloped borders on the elbow of a patient with dermati- initiate an inflammatory response that is pre- tis herpetiformis. dominantly neutrophilic and results in forma- 40 Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic. tion of vesicles and bullae in the skin. Also supporting the linkage between celiac disease statement from Canada concluded that dual- and dermatitis herpetiformis, if patients ad- energy x-ray absorptiometry should be done at here to a gluten-free diet, the deposits of im- the time of diagnosis of celiac disease if the mune complexes in the skin disappear.41 patient