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Celiac Disease

      Abstract

      Celiac disease (CD) affects approximately 1% of the general population, although most cases remain unrecognized. Because CD is a multisystem disorder with protean clinical manifestations, a high index of suspicion is needed to make an appropriate diagnosis. A diagnosis of CD is made in a patient who is genetically predisposed based on the presence of compatible clinical features, positive highly specific celiac serologic findings, duodenal biopsies that document enteropathy, and improvement with a gluten-free diet. The differential diagnoses for the clinical features and the histologic findings seen in patients with CD are numerous and need to be considered; because the management of celiac disease consists of a lifelong gluten-free diet, ensuring that the diagnosis is correctly established is of utmost importance. The aim of this review is to provide practicing clinicians with the most current information on the diagnosis and management of CD, including new developments and the approach to controversial issues.

      Abbreviations and Acronyms:

      CD (celiac disease), EMA (endomysial antibody), RCD (refractory CD), TTG (tissue transglutaminase)
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      Learning Objectives: On completion of this article, you should be able to (1) identify the protean manifestations of celiac disease, (2) describe the testing used to screen for and diagnose celiac disease, including in patients already consuming a gluten-free diet, and (3) detail the appropriate management of the patient with newly diagnosed celiac disease both at diagnosis and follow-up.
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      Celiac disease (CD) is an immune-mediated multisystem disorder characterized by the presence of enteropathy after the ingestion of gluten in genetically susceptible persons. Gluten is a water-insoluble protein present in wheat, barley, and rye. Circulating antibodies to tissue transglutaminase (TTG) are detectable in the serum of most patients. Treatment requires strict adherence to a gluten-free diet and routine medical follow-up for life. A gluten-free diet is very effective in most patients; however, recurrent or persistent symptoms are common in clinical practice. Nonresponsive CD is an umbrella term for persistent or recurrent symptoms despite attempted adherence to a gluten-free diet, with the most common cause being inadvertent gluten contamination. Refractory CD (RCD) is a severe complication defined by persistent or recurrent symptoms and villous atrophy despite proven strict adherence to a gluten-free diet and exclusion of malignancy or other causes of nonresponsiveness.

      Pathogenesis of CD

      A detailed discussion of CD pathogenesis is beyond the scope of this article but is reviewed elsewhere.
      • Kupfer S.S.
      • Jabri B.
      Pathophysiology of celiac disease.
      • Jabri B.
      • Sollid L.M.
      T cells in celiac disease.
      • Sollid L.M.
      The roles of MHC class II genes and post-translational modification in celiac disease.
      In susceptible persons, exposure to immunogenic gliadin peptides originating from gluten in the diet leads to a cascade of changes in both the surface epithelium and the lamina propria through immune-mediated mechanisms involving both the innate and adaptive immune systems.
      • Green P.H.
      • Cellier C.
      Celiac disease.
      Intestinal microbiota is recognized as an emerging new player in modulating immune responses in patients with CD after ingestion of gluten.
      • Caminero A.
      • Galipeau H.J.
      • McCarville J.L.
      • et al.
      Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity.
      • Verdu E.F.
      • Galipeau H.J.
      • Jabri B.
      Novel players in coeliac disease pathogenesis: role of the gut microbiota.
      Gliadin can be injurious to the surface epithelium, which results in an increase in cytotoxic intraepithelial lymphocytes in response to overexpression of interleukin 15.
      • Abadie V.
      • Jabri B.
      IL-15: a central regulator of celiac disease immunopathology.
      Once gliadin reaches the lamina propria, it becomes more immunogenic after being deaminated by TTG, with facilitation of interaction between deamidated peptides and the permissive celiac haplotypes on antigen-presenting cells. Immune cell activation and cytokine release cause the histologic changes that are a hallmark of CD.
      • Jabri B.
      • Sollid L.M.
      T cells in celiac disease.
      Additionally, B lymphocytes produce CD-specific autoantibodies, which allows for serologic detection of CD.

      Epidemiology of CD

      Celiac disease is a global disease of both children and adults, and although the mean age at diagnosis is 38 years in the United States, approximately 20% of patients are diagnosed after age 60 years.
      • Ludvigsson J.F.
      • Rubio-Tapia A.
      • van Dyke C.T.
      • et al.
      Increasing incidence of celiac disease in a North American population.
      The diagnosis is more common in women (ratio 1.3-3:1), a pattern typically seen with autoimmune disorders. The availability of highly specific celiac serology has been crucial to understanding the epidemiology of CD. It is widely accepted that CD is a common problem based on prevalence studies, but most cases remain undiagnosed (“iceberg phenomenon”). Celiac disease has a wide geographic distribution and affects persons from multiple ethnic and racial backgrounds.
      • Singh P.
      • Arora A.
      • Strand T.A.
      • et al.
      Global prevalence of celiac disease: systematic review and meta-analysis.
      The overall prevalence of CD in Europe has been reported at 1%, but the prevalence varies widely among countries (eg, 0.3% in Germany and 2.4% in Finland).
      • Mustalahti K.
      • Catassi C.
      • Reunanen A.
      • et al.
      Coeliac EU Cluster, Project Epidemiology
      The prevalence of celiac disease in Europe: results of a centralized, international mass screening project.
      One of the higher prevalence rates reported to date is 5.6% among the Saharawi people of northwest Africa.
      • Catassi C.
      • Rätsch I.M.
      • Gandolfi L.
      • et al.
      Why is coeliac disease endemic in the people of the Sahara?.
      The prevalence of CD in the general population of the United States is 0.8%
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • et al.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      • Rubio-Tapia A.
      • Ludvigsson J.F.
      • Brantner T.L.
      • Murray J.A.
      • Everhart J.E.
      The prevalence of celiac disease in the United States.
      and has increased 4-fold in the past 40 years.
      • Rubio-Tapia A.
      • Kyle R.A.
      • Kaplan E.L.
      • et al.
      Increased prevalence and mortality in undiagnosed celiac disease.
      A larger proportion of persons living at latitudes of 35° north or higher have CD compared with persons living in the south.
      • Unalp-Arida A.
      • Ruhl C.E.
      • Choung R.S.
      • Brantner T.L.
      • Murray J.A.
      Lower prevalence of celiac disease and gluten-related disorders in persons living in southern vs northern latitudes of the United States.
      Although less is known about the incidence of CD globally, an increasing incidence in both men and women has been clearly documented in Olmsted County, Minnesota, over the past 30 years (Figure 1). In fact, the adjusted incidence of CD between 2000 and 2010 was 17.4 per 100,000 person-years.
      • Ludvigsson J.F.
      • Rubio-Tapia A.
      • van Dyke C.T.
      • et al.
      Increasing incidence of celiac disease in a North American population.
      Hypotheses to explain this trend include increased awareness of CD, changes in wheat processing and intake, route of delivery, timing of introduction of gluten into the diet during infancy, case finding, availability of serologic tests, a true increase in people affected, and innate changes to the microbiome. Elucidation of the underlying reason(s) remains a relevant challenge with the potential goal to implement effective preventive measures. However, modification of timing of introduction into or amount of gluten in the diet and breastfeeding failed to reduce the overall risk of CD compared with placebo.
      • Vriezinga S.L.
      • Auricchio R.
      • Bravi E.
      • et al.
      Randomized feeding intervention in infants at high risk for celiac disease.
      • Lionetti E.
      • Castellaneta S.
      • Francavilla R.
      • et al.
      SIGENP (Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition) Working Group on Weaning and CD Risk
      Introduction of gluten, HLA status, and the risk of celiac disease in children.
      Figure thumbnail gr1
      Figure 1Incidence of clinical diagnosis of celiac disease in Olmsted County, Minnesota, 1950-2010. There is increasing incidence in both women (blue line) and men (green line) in the past 30 years. The red line represents overall incidence.
      Interestingly, the frequency of classic CD among incident cases has decreased over time, while those presenting with nonclassic features has increased.
      • Ludvigsson J.F.
      • Rubio-Tapia A.
      • van Dyke C.T.
      • et al.
      Increasing incidence of celiac disease in a North American population.
      Similar trends in the presentation of CD have been reported in referral populations.
      • Rampertab S.D.
      • Pooran N.
      • Brar P.
      • Singh P.
      • Green P.H.
      Trends in the presentation of celiac disease.
      Based on National Health and Nutrition Examination Survey data, less than 20% of patients with CD have been officially diagnosed, whereas greater than 80% of patients with CD remain undiagnosed and untreated.
      • Rubio-Tapia A.
      • Ludvigsson J.F.
      • Brantner T.L.
      • Murray J.A.
      • Everhart J.E.
      The prevalence of celiac disease in the United States.
      However, the proportion of people with undiagnosed CD may be decreasing in a more recent National Health and Nutrition Examination Survey (2013-2014) despite stable overall prevalence.
      • Choung R.S.
      • Unalp-Arida A.
      • Ruhl C.E.
      • Brantner T.L.
      • Everhart J.E.
      • Murray J.A.
      Less hidden celiac disease but increased gluten avoidance without a diagnosis in the United States: findings from the National Health and Nutrition Examination Surveys from 2009 to 2014.

      CD-Related Definitions

      Celiac disease is a multisystem disease and may present a diagnostic challenge given the numerous associated ways that a patient may seek medical attention and the varying terms used to label individuals with gluten-related disorders. The 2011 Oslo definitions consensus, although not without controversy, summarizes currently accepted terminology for common terms related to CD.
      • Ludvigsson J.F.
      • Leffler D.A.
      • Bai J.C.
      • et al.
      The Oslo definitions for coeliac disease and related terms.
      Understanding the terminology helps the clinician to fully appreciate the wide spectrum of the clinical manifestations of CD. Asymptomatic CD is used to define patients who do not have symptoms at the time of the initial diagnosis of CD, even in response to direct questioning. Symptomatic CD is used to characterize those who have clinically evident gastrointestinal and/or extraintestinal features attributable to gluten intake. Classic CD is the term used to describe patients with CD who present with features of a malabsorption syndrome; a combination of diarrhea, steatorrhea, weight loss, or growth failure is usually required. This clinical presentation predominated before the 2000 but may explain only about 30% of diagnosed cases in the past decade.
      • Ludvigsson J.F.
      • Rubio-Tapia A.
      • van Dyke C.T.
      • et al.
      Increasing incidence of celiac disease in a North American population.
      Nonclassic CD is the term used to describe the most common clinical manifestations of CD at the present time, characterized by a predominance of extraintestinal features, often monosymptomatic (eg, iron deficiency anemia, premature metabolic bone disease, infertility, elevated transaminase levels) in the absence of clinical malabsorption. Potential CD is used to describe patients with normal small intestinal mucosa who are at increased risk for development of CD as indicated by positive CD serologic findings.
      • Biagi F.
      • Trotta L.
      • Alfano C.
      • et al.
      Prevalence and natural history of potential celiac disease in adult patients.
      • Mandile R.
      • Discepolo V.
      • Scapaticci S.
      • et al.
      The effect of gluten-free diet on clinical symptoms and the intestinal mucosa of patients with potential celiac disease.
      Celiac disease autoimmunity is characterized by increased TTG antibody or endomysial antibody (EMA) on at least 2 occasions when the status of the duodenal histology is unknown. This feature could be the clinical presentation of potential CD (if the biopsy result is negative), vs actual CD (if the biopsy result is positive). Finally, the use of latent CD has been discouraged because of the multiple definitions in the literature.
      • Ludvigsson J.F.
      • Leffler D.A.
      • Bai J.C.
      • et al.
      The Oslo definitions for coeliac disease and related terms.

      Diagnosis of CD

      A diagnosis of CD is based on the presence of compatible clinical features, positivity of CD-specific serology, small bowel biopsy specimens with characteristic histologic features, and response to a gluten-free diet (Figure 2). Clinical suspicion of CD is based on symptoms, associated conditions, or the presence of at-risk conditions.
      • Lebwohl B.
      • Rubio-Tapia A.
      • Assiri A.
      • Newland C.
      • Guandalini S.
      Diagnosis of celiac disease.
      For persons with a low pretest probability of CD, serology followed by biopsy, if serologic result is positive, is the most reasonable and cost-effective approach. The preferred initial serology is TTG IgA with measurement of total IgA to rule out IgA deficiency.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      Persons with a high pretest probability of CD require both serologic testing (including total IgA level) and intestinal biopsy to substantiate the presence or absence of the diagnosis. The diagnostic accuracy of serologic testing and small intestinal histology for CD is severely affected by elimination of gluten from the diet (eg, sensitivity of 16% for IgA TTG after a median of 11 months on a gluten-free diet).
      • Rashtak S.
      • Ettore M.W.
      • Homburger H.A.
      • Murray J.A.
      Comparative usefulness of deamidated gliadin antibodies in the diagnosis of celiac disease.
      Therefore, testing for CD should be done when patients are consuming a gluten-containing diet.
      Figure thumbnail gr2
      Figure 2Clinical algorithm to assess for celiac disease. EMA = endomysial antibody; GFD = gluten-free diet; HLA = human leukocyte antigen; NEG = negative; POS = positive; TTG = tissue transglutaminase antibody.

      Clinical Features

      Patients with CD may present with classic features such as short stature, failure to thrive in childhood, delayed puberty, lethargy, and weight loss. However, more than 10% of patients with CD are obese, so this population of patients should not be overlooked. In terms of gastrointestinal symptoms, diarrhea, flatulence, bloating, abdominal discomfort, and nausea may be seen.
      • Murray J.A.
      • Watson T.
      • Clearman B.
      • Mitros F.
      Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease.
      It should be noted that approximately 20% of patients with CD may actually report constipation.
      • Murray J.A.
      • Watson T.
      • Clearman B.
      • Mitros F.
      Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease.
      Rarely, CD may present as a life-threatening diarrheal illness or “celiac crisis” with multiple electrolyte disturbances.
      • Jamma S.
      • Rubio-Tapia A.
      • Kelly C.P.
      • et al.
      Celiac crisis is a rare but serious complication of celiac disease in adults.
      Although previously termed atypical CD, the term nonclassic CD is more appropriate, given that these manifestations are currently the typical presenting features. Patients with CD may be anemic and due to iron, folate, or vitamin B12 deficiency; therefore, patients may present with microcytic, macrocytic, or normocytic anemia based on a combination of one or more deficiencies.
      • Halfdanarson T.R.
      • Litzow M.R.
      • Murray J.A.
      Hematologic manifestations of celiac disease.
      Iron deficiency anemia is the most common extraintestinal feature of CD.
      • Mahadev S.
      • Laszkowska M.
      • Sundström J.
      • et al.
      Prevalence of celiac disease in patients with iron deficiency anemia—a systematic review with meta-analysis.
      In a patient with iron deficiency anemia without any gastrointestinal symptoms, the prevalence of CD ranges from 3% to 9%, whereas those with gastrointestinal symptoms may have prevalence rates as high as 10% to 15%.
      • Grisolano S.W.
      • Oxentenko A.S.
      • Murray J.A.
      • Burgart L.J.
      • Dierkhising R.A.
      • Alexander J.A.
      The usefulness of routine small bowel biopsies in evaluation of iron deficiency anemia.
      Celiac disease may be most overlooked in the population of menstruating women, which is the demographic more likely to get CD. Therefore, CD should be considered in all patients undergoing a work-up for iron deficiency anemia, and small bowel histology should be obtained in any patient being evaluated for iron deficiency anemia who is undergoing upper endoscopy.
      • Goddard A.F.
      • James M.W.
      • McIntyre A.S.
      • Scott B.B.
      British Society of Gastroenterology
      Guidelines for the management of iron deficiency anaemia.
      Metabolic bone disease is a leading cause of morbidity in patients with CD, with a fracture risk that may be 2 to 3 times higher than in the general population.
      • Jafri M.R.
      • Nordstrom C.W.
      • Murray J.A.
      • et al.
      Long-term fracture risk in patients with celiac disease: a population-based study in Olmsted County, Minnesota.
      • Vasquez H.
      • Mazure R.
      • Gonzalez D.
      • et al.
      Risk of fractures in celiac disease patients: a cross-sectional, case-control study.
      Chronic inflammation and malabsorption of calcium and/or vitamin D can lead to osteopenia, osteoporosis, or osteomalacia. Therefore, CD should be considered in any patient with premature metabolic bone disease, and conversely, all patients with newly diagnosed CD should undergo an assessment of bone health.
      Patients with untreated CD commonly have abnormal liver biochemistry results.
      • Castillo N.E.
      • Vanga R.R.
      • Theethira T.G.
      • et al.
      Prevalence of abnormal liver function tests in celiac disease and the effect of a gluten-free diet in the US population.
      Elevation of alanine aminotransferase and/or aspartate aminotransferase may be seen because of a reactive hepatitis (“celiac liver”), autoimmune hepatitis, or nonalcoholic fatty liver disease.
      • Rubio-Tapia A.
      • Murray J.A.
      The liver in celiac disease.
      Alkaline phosphatase elevation may be seen because of vitamin D deficiency, but levels may also be elevated in the setting of concomitant primary sclerosing cholangitis or primary biliary cholangitis. Liver biopsy is rarely necessary in patients with CD. However, in a subgroup of patients with CD who underwent liver biopsy, more than half were found to have an autoimmune cause of liver disease, with autoimmune hepatitis being the most common. Interestingly, those with autoimmune disease were less likely to have gastrointestinal symptoms related to their underlying CD.
      • Mounajjed T.
      • Oxentenko A.
      • Shmidt E.
      • Smyrk T.
      The liver in celiac disease: clinical manifestations, histologic features, and response to gluten-free diet in 30 patients.
      All patients with elevated liver biochemistry results of unknown etiology should undergo assessment for CD. Conversely, all patients with known CD who have persistent elevation of serum transaminases should be assessed for autoimmune liver disease.
      Dermatitis herpetiformis is the cutaneous manifestation of CD.
      • Zone J.J.
      Skin manifestations of celiac disease.
      Interestingly, dermatitis herpetiformis is more common in men. The primary skin lesion includes pruritic papulovesicular lesions most often located in the extensor surfaces of elbows, knees, and buttocks (Figure 3 A and B). The secondary skin lesion consists of scratched papules and macules with superficial bleeding due to intense itching. A definitive diagnosis requires a biopsy of healthy-looking skin adjacent to the affected area. Direct immunofluorescence reveals granular deposits of IgA at the level of the basal membrane between the dermis and epidermis junction. Antibodies against epidermal transglutaminase (transglutaminase type 3) are present in 80% of the cases but are not necessary to confirm the diagnosis.
      • Salmi T.T.
      • Hervonen K.
      • Laurila K.
      • et al.
      Small bowel transglutaminase 2-specific IgA deposits in dermatitis herpetiformis.
      A rapid clinical response to dapsone (25-50 mg daily) strongly supports the diagnosis. Long-term prognosis is excellent with consumption of a gluten-free diet, although clinical response is slow and most patients require dapsone initially to control rash-related symptoms.
      • Reunala T.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Collin P.
      Dermatitis herpetiformis: a common extraintestinal manifestation of coeliac disease.
      Iodine ingestion may cause flares of the disease and should be discouraged.
      Figure thumbnail gr3
      Figure 3Dermatitis herpetiformis. A, Typical distribution of the skin lesion with scratched macules and papules on the elbows. B, Direct immunofluorescence showing granular IgA deposits at the basal membrane zone. Images courtesy of T. T. Salmi, MD, and K. Kaukinen, MD, University of Tampere, Tampere, Finland.
      Other associated features of CD include functional asplenia, enteropathy-associated arthropathy, seizures, peripheral neuropathy, ataxia, infertility, recurrent aphthous stomatitis, dental enamel defects, headaches, and “brain fog.”
      • Green P.H.
      • Cellier C.
      Celiac disease.

      Serology

      The presence of antibodies directed against gluten and connective tissue proteins is a hallmark of CD. Several antibodies have clinical relevance because of good sensitivity and/or specificity among patients presenting with abdominal symptoms or clinical suspicion of CD (Table). IgA TTG, along with measurement of total IgA, is the serology of choice for screening patients for CD. A result that is 3 times the upper limit of normal is strong evidence for a diagnosis of CD.
      • Li M.
      • Yu L.
      • Tiberti C.
      • et al.
      A report on the International Transglutaminase Autoantibody Workshop for Celiac Disease.
      False-positive results are more likely when lower titers are found, especially in the presence of other conditions such as cirrhosis, heart failure, or concurrent autoimmune disease. Sensitivity may vary among clinical laboratories.
      • Li M.
      • Yu L.
      • Tiberti C.
      • et al.
      A report on the International Transglutaminase Autoantibody Workshop for Celiac Disease.
      A negative TTG result is not sufficient to rule out CD in patients when there is a high suspicion for the disease. False-negative results are usually explained by initiation of a gluten-restricted diet before testing, coexistent IgA deficiency, or mild enteropathy. Seronegative CD should be considered in patients with a high pretest probability of CD, enteropathy on small bowel biopsies, serologic tests that are negative (in the absence of IgA deficiency), and permissive celiac haplotyping, as long as other mimickers of CD have been ruled out (eg, medication effect).
      • Schiepatti A.
      • Sanders D.S.
      • Biagi F.
      Seronegative coeliac disease: clearing the diagnostic dilemma.
      TableSummary of Diagnostic Accuracy of Available Serologic Tests for Celiac Disease
      TestSensitivity (%)Specificity (%)Clinical comment
      Tissue transglutaminase89 (82-94)98 (95-99)Test of choice
      Endomysial antibody90 (80-95)99 (98-100)Operator dependent, requires immunofluorescence
      Deamidated gliadin peptides88 (85-90)94 (92-95)Comparable to tissue transglutaminase
      Gliadin80 (57-100)90 (47-94)No longer recommended
      Data from JAMA
      • van der Windt D.A.
      • Jellema P.
      • Mulder C.J.
      • Kneepkens C.M.
      • van der Horst H.E.
      Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review.
      and Aliment Pharmacol Ther,
      • Lewis N.R.
      • Scott B.B.
      Meta-analysis: deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease.
      and adapted from Am J Gastroenterol,
      • Leffler D.A.
      • Schuppan D.
      Update on serologic testing in celiac disease.
      with permission.
      The use of celiac serologic panels is discouraged; although such panels may increase the sensitivity of case finding, it comes at the expense of decreased specificity, leading to unnecessary testing. All of the celiac serologies come in both an IgA- and IgG-based assay, with the exception of the EMA, which is an IgA-based test. Although IgA deficiency may be seen in approximately 2% to 3% of patients with CD, it is inappropriate to solely use IgG-based serology for testing for all patients.
      • Pallav K.
      • Xu H.
      • Leffler D.A.
      • Kabbani T.
      • Kelly C.P.
      Immunoglobulin A deficiency in celiac disease in the United States.
      Although IgG-based serology has excellent sensitivity and specificity for patients with CD and known IgA deficiency, such serology has very low sensitivity in patients with CD who are not IgA deficient.
      • Gould M.J.
      • Brill H.
      • Marcon M.A.
      • Munn N.J.
      • Walsh C.M.
      In screening for celiac disease, deamidated gliadin rarely predicts disease when tissue transglutaminase is normal.
      • Absah I.
      • Rishi A.R.
      • Gebrail R.
      • Snyder M.R.
      • Murray J.A.
      Lack of utility of anti-tTG IgG to diagnose celiac disease when anti-tTG IgA is negative.
      In a patient with suspected IgA deficiency, clinicians could either measure the IgA level or use a combination IgA and IgG serology.
      • Rashid M.
      • Lee J.
      Serologic testing in celiac disease: practical guide for clinicians.

      Histology

      Histopathologic documentation of small intestine enteropathy is considered the criterion standard method to confirm the diagnosis of CD in adult patients. Endoscopic findings such as loss of folds, scalloping, fissuring, or cobblestone mucosa lack sensitivity but when present are strongly suggestive of enteropathy, although not specific for CD
      • Oxentenko A.S.
      • Grisolano S.W.
      • Murray J.A.
      • Burgart L.J.
      • Dierkhising R.A.
      • Alexander J.A.
      The insensitivity of endoscopic markers in celiac disease.
      (Figure 4 A, B, and C). Therefore, in patients with a clinical suspicion of CD, biopsies are recommended regardless of the presence or absence of endoscopic findings. Multiple duodenal biopsies are suggested for assessment of CD because of the patchy nature of the disease.
      • Lebwohl B.
      • Kapel R.C.
      • Neugut A.I.
      • Green P.H.
      • Genta R.M.
      Adherence to biopsy guidelines increases celiac disease diagnosis.
      Ideally, 4 biopsy specimens should be obtained from the distal (postbulbar) duodenum and 2 specimens from the duodenal bulb, ideally at the 9- and 12-o'clock positions.
      • Kurien M.
      • Evans K.E.
      • Hopper A.D.
      • Hale M.F.
      • Cross S.S.
      • Sanders D.S.
      Duodenal bulb biopsies for diagnosing adult celiac disease: is there an optimal biopsy site?.
      • Robert M.E.
      • Crowe S.E.
      • Burgart L.
      • et al.
      Statement on best practices in the use of pathology as a diagnostic tool for celiac disease: a guide for clinicians and pathologists.
      Figure thumbnail gr4
      Figure 4Endoscopic and pathologic findings in celiac disease. Endoscopy shows loss of mucosal folds (A) and scalloping, nodularity, and mosaic pattern (B). C, Duodenal biopsy specimen showing increased intraepithelial lymphocytosis, villous atrophy, crypt hyperplasia, and a chronic inflammatory infiltrate in the lamina propria (hematoxylin-eosin, original magnification ×200). Pathologic image courtesy of T. T. Wu, MD, Mayo Clinic, Rochester, Minnesota.
      There is incremental evidence to support making a diagnosis of CD without the need for biopsies in both children and adults.
      • Werkstetter K.J.
      • Korponay-Szabó I.R.
      • Popp A.
      • et al.
      ProCeDE Study Group
      Accuracy in diagnosis of celiac disease without biopsies in clinical practice.
      Currently, a nonbiopsy approach to the diagnosis is recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition for selected pediatric cases with classic symptoms, presence of TTG antibody (>10 times the upper normal limit), presence of HLA-DQ2 or HLA-DQ8, and a separate blood sample with a positive EMA result,
      • Husby S.
      • Koletzko S.
      • Korponay-Szabó I.R.
      • et al.
      ESPGHAN Working Group on Coeliac Disease DiagnosisESPGHAN Gastroenterology Committee
      European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.
      although HLA-DQ2/HLA-DQ8 testing may not be necessary for all.
      • Werkstetter K.J.
      • Korponay-Szabó I.R.
      • Popp A.
      • et al.
      ProCeDE Study Group
      Accuracy in diagnosis of celiac disease without biopsies in clinical practice.
      Characteristic histologic features include a combination of increased tip-predominant intraepithelial lymphocytes (>25 per 100 enterocytes), partial or total villous atrophy, crypt hyperplasia, and chronic inflammation in the lamina propria.
      • Rostami K.
      • Marsh M.N.
      • Johnson M.W.
      • et al.
      ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.
      Multiple CD histologic classification systems are available (Marsh, Oberhuber-Marsh, Corazza, and Ensari) to improve communication between pathologists and clinicians.
      • Corazza G.R.
      • Villanacci V.
      • Zambelli C.
      • et al.
      Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease.
      Although the utility of grading of villous atrophy has been challenged recently,
      • Biagi F.
      • Vattiato C.
      • Burrone M.
      • et al.
      Is a detailed grading of villous atrophy necessary for the diagnosis of enteropathy?.
      • Rostami K.
      • Ensari A.
      • Ciacci C.
      • et al.
      Coeliac biopsies: numbers are valid, alphabets not [letter].
      a complete histopathologic report is mandatory in everyday clinical practice.
      • Robert M.E.
      • Crowe S.E.
      • Burgart L.
      • et al.
      Statement on best practices in the use of pathology as a diagnostic tool for celiac disease: a guide for clinicians and pathologists.
      There are a number of conditions that may histologically mimic CD.
      • Jansson-Knodell C.L.
      • Hujoel I.A.
      • Rubio-Tapia A.
      • Murray J.A.
      Not all that flattens villi is celiac disease: a review of enteropathies.
      • Murray J.A.
      • Rubio-Tapia A.
      Diarrhoea due to small bowel diseases.
      There has been an increase in the number of duodenal biopsies reported to have elevated intraepithelial lymphocyte levels with normal villous architecture, ranging from 3.0% of all duodenal biopsies in 2000 to 10.9% in 2010.
      • Shmidt E.
      • Smyrk T.C.
      • Boswell C.L.
      • Enders F.T.
      • Oxentenko A.S.
      Increasing duodenal intraepithelial lymphocytosis found at upper endoscopy: time trends and associations.
      Although known or newly diagnosed CD may account for some cases, others were thought to be related to nonsteroidal anti-inflammatory drug use, small intestinal bacterial overgrowth, Helicobacter pylori infection, and known or newly diagnosed inflammatory bowel disease, but many cases remained unexplained.
      • Shmidt E.
      • Smyrk T.C.
      • Boswell C.L.
      • Enders F.T.
      • Oxentenko A.S.
      Increasing duodenal intraepithelial lymphocytosis found at upper endoscopy: time trends and associations.
      • Kakar S.
      • Nehra V.
      • Murray J.A.
      • Dayharsh G.A.
      • Burgart L.J.
      Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture.
      • Mahadeva S.
      • Wyatt J.I.
      • Howdle P.D.
      Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant?.
      Similarly, there are entities known to cause villous atrophy besides CD, such as medications (eg, olmesartan, mycophenolate mofetil), autoimmune enteropathy, combined variable immunodeficiency, tropical sprue, and collagenous sprue.
      • Malamut G.
      • Verkarre V.
      • Suarez F.
      • et al.
      The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.
      • Rubio-Tapia A.
      • Talley N.J.
      • Gurudu S.R.
      • Wu T.T.
      • Murray J.A.
      Gluten-free diet and steroid treatment are effective therapy for most patients with collagenous sprue.
      • Rubio-Tapia A.
      • Herman M.L.
      • Ludvigsson J.F.
      • et al.
      Severe spruelike enteropathy associated with olmesartan.
      Endoscopic and/or histologic findings that should make one question the diagnosis of CD include mucosal erosions/ulcerations, neutrophilic-predominant infiltrate, loss of goblet or plasma cells, crypt abscesses, or a thickened collagen band.
      • Robert M.E.
      • Crowe S.E.
      • Burgart L.
      • et al.
      Statement on best practices in the use of pathology as a diagnostic tool for celiac disease: a guide for clinicians and pathologists.

      Haplotyping

      Celiac disease is strongly associated with HLA-DQ2 (DQA1*05/DQB1*02) and HLA-DQ8 (DQA1*03/DQB1*03).
      • Sollid L.M.
      • Markussen G.
      • Ek J.
      • Gjerde H.
      • Vartdal F.
      • Thorsby E.
      Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer.
      The permissive genes are present in approximately 30% of the general white population, so a test revealing permissive celiac genes has limited diagnostic value. The absence of both of these permissive genes is helpful to rule out CD in clinical practice and therefore has strong negative predictive value. Genetic testing is not affected by a gluten-free diet, so this test can be considered in patients who are consuming a gluten-free diet with no prior work-up for CD before embarking on a gluten challenge. Haplotyping may also be considered in selected clinical scenarios, such as patients with discordance between serologic and pathologic results, as well as those with certain at-risk conditions (eg, Down or Turner syndrome).
      • Kaukinen K.
      • Partanen J.
      • Mäki M.
      • Collin P.
      HLA-DQ typing in the diagnosis of celiac disease.

      Screening for CD

      Active screening in persons with conditions at risk for CD (case finding) is a proposed strategy to increase clinical detection (Figure 5).
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      However, recent evidence strongly suggests that case finding may not be effective to distinguish between persons with undiagnosed CD and referent individuals at a population level.
      • Hujoel I.A.
      • Van Dyke C.T.
      • Brantner T.
      • et al.
      Natural history and clinical detection of undiagnosed coeliac disease in a North American community.
      Therefore, more evidence is needed related to screening for CD in asymptomatic individuals.
      • Chou R.
      • Bougatsos C.
      • Blazina I.
      • Mackey K.
      • Grusing S.
      • Selph S.
      Screening for celiac disease: evidence report and systematic review for the US Preventive Services Task Force.
      Moreover, the strength of evidence supporting the recommendation for testing is variable among the accepted indications for clinical testing. Currently, case finding is recommended for the following: first-degree family members of an index case or both first- and second-degree relatives of sibling pairs with CD,
      • Rubio-Tapia A.
      • Van Dyke C.T.
      • Lahr B.D.
      • et al.
      Predictors of family risk for celiac disease: a population-based study.
      autoimmune thyroid disease,
      • Roy A.
      • Laszkowska M.
      • Sundström J.
      • et al.
      Prevalence of celiac disease in patients with autoimmune thyroid disease: a meta-analysis.
      Down or Turner syndrome,
      • Mårild K.
      • Stephansson O.
      • Grahnquist L.
      • Cnattingius S.
      • Söderman G.
      • Ludvigsson J.F.
      Down syndrome is associated with elevated risk of celiac disease: a nationwide case-control study.
      unexplained elevation of serum transaminases, type 1 diabetes mellitus, diarrhea-predominant irritable bowel syndrome, IgA deficiency, growth stunting in children, unexplained iron deficiency anemia,
      • Mahadev S.
      • Laszkowska M.
      • Sundström J.
      • et al.
      Prevalence of celiac disease in patients with iron deficiency anemia—a systematic review with meta-analysis.
      unexplained ataxia or neuropathy, premature metabolic bone disease, and infertility.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      Figure thumbnail gr5
      Figure 5Currently accepted indications for testing for celiac disease include classic, nonclassic, and associated/high-risk conditions.

      Gluten Challenge for Patients Consuming a Gluten-Free Diet

      A gluten challenge consists of a medically supervised exposure to gluten (usually 3-10 g/d) with close monitoring for symptoms and subsequent serologic and/or histologic testing for CD.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      • Leffler D.
      • Schuppan D.
      • Pallav K.
      • et al.
      Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.
      A gluten challenge is more helpful to make or exclude the diagnosis of CD in patients with permissive genes for CD who have been consuming a gluten-free diet without a prior definitive diagnostic evaluation.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      It is unnecessary for the patient who does not have either permissive gene because the diagnosis will already have been excluded.
      There is no consensus about the best way to conduct a gluten challenge. A kinetic study suggests that serologic and histologic changes of clinical significance are present as early as day 14 of a gluten challenge with more than 3 g/d in the majority of patients with CD.
      • Leffler D.
      • Schuppan D.
      • Pallav K.
      • et al.
      Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.
      Better tolerance and an ability to endure a longer challenge may be additional advantages of a lower-dose gluten challenge. The duration of a gluten challenge may vary from 2 to 8 weeks, depending on clinical circumstances (Figure 6). Given that a slice of wheat bread typically contains 2 g of gluten (range of 2-5 g based on product), a reasonable approach would be to have the patient consume the equivalent of 2 slices of wheat bread daily (or other gluten-containing product when amount of gluten is known) for 2 weeks, assess tolerability, and, if able, continue the daily gluten consumption for 6 additional weeks before testing is performed.
      Figure thumbnail gr6
      Figure 6Proposed modified gluten challenge. From Gut,
      • Leffler D.
      • Schuppan D.
      • Pallav K.
      • et al.
      Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.
      with permission. HLA = human leukocyte antigen.

      Management of CD

      Strict, lifelong adherence to a gluten-free diet, avoiding wheat, barley, and rye, is the most effective treatment for CD (Figure 7).
      • See J.A.
      • Kaukinen K.
      • Makharia G.K.
      • Gibson P.R.
      • Murray J.A.
      Practical insights into gluten-free diets.
      • See J.
      • Murray J.A.
      Gluten-free diet: the medical and nutrition management of celiac disease.
      A baseline visit and subsequent follow-up with an experienced dietitian is essential and cost-effective in order for patients to obtain accurate information about the gluten-free diet. Moreover, patients may prefer to see a dietitian for long-term follow-up.
      • Bebb J.R.
      • Lawson A.
      • Knight T.
      • Long R.G.
      Long-term follow-up of coeliac disease—what do coeliac patients want?.
      Although pure oats are typically safe for patients with CD to consume,
      • Pinto-Sánchez M.I.
      • Causada-Calo N.
      • Bercik P.
      • et al.
      Safety of adding oats to a gluten-free diet for patients with celiac disease: systematic review and meta-analysis of clinical and observational studies.
      • Lionetti E.
      • Gatti S.
      • Galeazzi T.
      • et al.
      Safety of oats in children with celiac disease: a double-blind, randomized, placebo-controlled trial.
      • Aaltonen K.
      • Laurikka P.
      • Huhtala H.
      • Mäki M.
      • Kaukinen K.
      • Kurppa K.
      The long-term consumption of oats in celiac disease patients is safe: a large cross-sectional study.
      there is the concern for potential cross-contamination,
      • Koerner T.B.
      • Cléroux C.
      • Poirier C.
      • Cantin I.
      • Alimkulov A.
      • Elamparo H.
      Gluten contamination in the Canadian commercial oat supply.
      and it may be reasonable to recommend that oats be withheld for the first year after CD is diagnosed in patients with features of severe malabsorption.
      • Laurikka P.
      • Salmi T.
      • Collin P.
      • et al.
      Gastrointestinal symptoms in celiac disease patients on a long-term gluten-free diet.
      Active membership in a CD support group is recommended because it may be beneficial to improve adherence to a gluten-free diet.
      • Leffler D.A.
      • Edwards-George J.
      • Dennis M.
      • et al.
      Factors that influence adherence to a gluten-free diet in adults with celiac disease.
      Figure thumbnail gr7
      Figure 7Benefits and challenges of the gluten-free diet for treatment of celiac disease.
      Adult patients with newly diagnosed CD should undergo bone densitometry either at the time of diagnosis or 1 year after starting treatment because the frequency of osteoporosis may be as high as 34% in patients with malabsorption
      • Meyer D.
      • Stavropolous S.
      • Diamond B.
      • Shane E.
      • Green P.H.
      Osteoporosis in a North American adult population with celiac disease.
      ; if normal at baseline, bone densitometry would not need to be repeated until other risk factors for metabolic bone disease are present (eg, menopause, corticosteroid exposure). Those with osteopenia or osteoporosis at baseline should be advised about the recommended replacement of calcium and vitamin D according to age, with consideration of rechecking bone densitometry after 2 years of initiation of a gluten-free diet.
      • Duerksen D.
      • Pinto-Sanchez M.I.
      • Anca A.
      • et al.
      Management of bone health in patients with celiac disease: practical guide for clinicians.
      Although there is no universal agreement on the type of laboratory work-up that should ensue in patients with newly diagnosed CD,
      • Pietzak M.M.
      Follow-up of patients with celiac disease: achieving compliance with treatment.
      it is reasonable to do some basic blood work, including a complete blood cell count (to assess for anemia) and measurement of ferritin, vitamin B12, folate, 25-hydroxyvitamin D, both alkaline phosphatase and alanine aminotransferase (to assess for cholestatic or hepatitis conditions associated with CD), and thyrotropin levels. If the patient has features of malabsorption, additional testing should include serum albumin, vitamins A and E, international normalized ratio, copper, and zinc measurements. Other laboratory studies should be individualized based on the patient's presentation. Some patients with CD may be functionally asplenic (as evidenced by Howell-Jolly bodies on a peripheral smear), and consideration should be given to vaccinating against encapsulated organisms in that situation. Patients should be instructed to have first-degree family members undergo testing for CD, which can be done with an IgA TTG antibody test.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      • Ludvigsson J.F.
      • Bai J.C.
      • Biagi F.
      • et al.
      BSG Coeliac Disease Guidelines Development Group
      Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology.
      There are a number of conditions that are seen with increased frequency in those with CD, so clinicians should have a high index of suspicion for these associated disorders during follow-up visits. These conditions include autoimmune thyroid disease, type 1 diabetes mellitus, adrenal insufficiency, various connective tissue disorders such as rheumatoid arthritis, lupus, and Sjögren syndrome, selective IgA deficiency, inflammatory bowel disease, microscopic colitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and IgA nephropathy.

      Follow-up

      Symptom relief is typically quite fast in patients with CD once a gluten-free diet has been commenced.
      • Murray J.A.
      • Watson T.
      • Clearman B.
      • Mitros F.
      Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease.
      The mean time to symptom improvement is 4 weeks, with two-thirds of patients noting complete relief at 6 months. Celiac serologic titers also decline quickly after a gluten-free diet is started, with a notable decrease by 6 months.
      • Sugai E.
      • Nachman F.
      • Váquez H.
      • et al.
      Dynamics of celiac disease-specific serology after initiation of a gluten-free diet and use in the assessment of compliance with treatment.
      Historically, clinical follow-up after diagnosis has been inadequate.
      • Herman M.L.
      • Rubio-Tapia A.
      • Lahr B.D.
      • Larson J.J.
      • Van Dyke C.T.
      • Murray J.A.
      Patients with celiac disease are not followed up adequately.
      We recommend follow-up 3 to 6 months after the initial diagnosis of CD to assess the clinical response to the gluten-free diet and to recheck serologic titers at that time. If the patient is struggling to follow a gluten-free diet, they should be offered another visit with the dietitian for further review. At the initial follow-up visit, any vitamin or mineral levels that were abnormal at the time of diagnosis should be rechecked to see if replacement has been adequate. After clinical improvement, routine follow-up every year with serology may be sufficient for most patients. Small bowel histology is slower to improve after initiation of a gluten-free diet, and time to healing increases with patient age.
      • Rubio-Tapia A.
      • Rahim M.W.
      • See J.A.
      • Lahr B.D.
      • Wu T.T.
      • Murray J.A.
      Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.
      Although not without controversy, given the absence of accurate noninvasive methods, we recommend that adult patients undergo upper endoscopy with small bowel biopsies in follow-up to prove there has been histologic healing in view of the excess comorbidity in patients without healing.
      • Lebwohl B.
      • Michaëlsson K.
      • Green P.H.
      • Ludvigsson J.F.
      Persistent mucosal damage and risk of fracture in celiac disease.
      • Lebwohl B.
      • Granath F.
      • Ekbom A.
      • et al.
      Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study.
      If follow-up biopsy is considered, it should be done no sooner than 1 year after the gluten-free diet has been started and most ideally at 2 years to ensure the possibility for full healing before reassessment.
      • Rubio-Tapia A.
      • Rahim M.W.
      • See J.A.
      • Lahr B.D.
      • Wu T.T.
      • Murray J.A.
      Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.

      Nonresponsive CD

      Nonresponsive CD is a common clinical problem characterized by persistent or recurrent symptoms after starting a gluten-free diet.
      • Rubio-Tapia A.
      • Barton S.H.
      • Murray J.A.
      Celiac disease and persistent symptoms.
      The most common symptoms are diarrhea, abdominal pain, weight loss, fatigue, and bloating.
      • Abdulkarim A.S.
      • Burgart L.J.
      • See J.
      • Murray J.A.
      Etiology of nonresponsive celiac disease: results of a systematic approach.
      The first step in the work-up of patients with persistent or recurrent symptoms is a meticulous review of the evidence that supported the initial diagnosis of CD, including reviewing the initial serology and having the pathologic material reexamined if necessary to make sure that the diagnosis of CD is solid. The most common etiology for nonresponsive CD is gluten contamination, either blatant or inadvertent.
      • Abdulkarim A.S.
      • Burgart L.J.
      • See J.
      • Murray J.A.
      Etiology of nonresponsive celiac disease: results of a systematic approach.
      Deliberate ingestion of gluten is an obvious reason for persistent or recurrent symptoms but is infrequent. Those who may be less compliant with the gluten-free diet include those who were asymptomatic or had nonclassic features at presentation, teenagers, those who are diagnosed later in life, frequent travelers or socialites, and those with any change in social situation (eg, starting college).
      • See J.
      • Murray J.A.
      Gluten-free diet: the medical and nutrition management of celiac disease.
      • Leffler D.A.
      • Edwards-George J.
      • Dennis M.
      • et al.
      Factors that influence adherence to a gluten-free diet in adults with celiac disease.
      A dietitian consultation may be useful for the patient to obtain additional education about the gluten-free diet and to investigate sources of accidental contamination. The most frequent reason for inadvertent gluten consumption is cross-contamination in packaged foods, at restaurants, or during social events or with medications or supplements.
      • Abdulkarim A.S.
      • Burgart L.J.
      • See J.
      • Murray J.A.
      Etiology of nonresponsive celiac disease: results of a systematic approach.
      Overlooked sources of gluten include beer and other alcohol, sauces, lipstick or lip balm, medications, and over-the-counter supplements.
      Persistently positive serologic results after 12 months of consuming a gluten-free diet is unexpected and strongly supports gluten contamination. Conversely, negative serologic findings do not exclude gluten contamination as the cause of persistent symptoms. Upper endoscopy with duodenal biopsies is often recommended to clarify the etiology of persistent symptoms, and in the presence of ongoing diarrhea and negative serologic results, colonoscopy (or flexible sigmoidoscopy) with random biopsies should also be considered to rule out microscopic colitis given the strong association between microscopic colitis and CD.
      • Stasi E.
      • Marafini I.
      • Caruso R.
      • et al.
      Frequency and cause of persistent symptoms in celiac disease patients on a long-term gluten-free diet.
      Other diagnoses commonly found in patients with persistent symptoms include irritable bowel syndrome, small intestinal bacterial overgrowth, pancreatic insufficiency, lactose or fructose intolerance, inflammatory bowel disease, gastroesophageal reflux disease, and peptic ulcer disease (Figure 8).
      • Leffler D.A.
      • Dennis M.
      • Hyett B.
      • Kelly E.
      • Schuppan D.
      • Kelly C.P.
      Etiologies and predictors of diagnosis in nonresponsive celiac disease.
      Figure thumbnail gr8
      Figure 8Clinical approach to nonresponsive celiac disease. CD = celiac disease; consult = consultation; c/w = consistent with; dx = diagnosis; GFD = gluten-free diet; meds = medications; NSAIDs = nonsteroidal anti-inflammatory drugs; Psych = psychiatric; SBBXs = small bowel biopsies. From Clin Gastroenterol Hepatol,
      • Rubio-Tapia A.
      • Barton S.H.
      • Murray J.A.
      Celiac disease and persistent symptoms.
      with permission.

      Refractory CD

      Refractory CD is an uncommon cause of persistent or recurrent symptoms, but it is a relevant diagnosis due to the clinical severity and mortality risk.
      • Rubio-Tapia A.
      • Murray J.A.
      Classification and management of refractory coeliac disease.
      Patients with RCD should be treated in a dedicated celiac center with expertise.
      • van Gils T.
      • Nijeboer P.
      • van Wanrooij R.L.
      • Bouma G.
      • Mulder C.J.
      Mechanisms and management of refractory coeliac disease.
      Refractory CD is characterized by persistent or recurrent symptoms and enteropathy despite strict adherence to a gluten-free diet for at least 12 months after exclusion of other causes of nonresponsive CD and malignancy.
      • Cellier C.
      • Delabesse E.
      • Helmer C.
      • et al.
      French Coeliac Disease Study Group
      Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma.
      There are 2 recognized types of RCD: type 1, with normal intraepithelial lymphocyte morphology, and type 2, with aberrant intraepithelial lymphocytes and T-cell receptor clonality.
      • Patey-Mariaud De Serre N.
      • Cellier C.
      • Jabri B.
      • et al.
      Distinction between coeliac disease and refractory sprue: a simple immunohistochemical method.
      Survival is reduced in patients with both types but worse in patients with type 2 (5-year survival, 80% vs 50%, respectively).
      • Malamut G.
      • Afchain P.
      • Verkarre V.
      • et al.
      Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II.
      • Al-Toma A.
      • Verbeek W.H.
      • Hadithi M.
      • von Blomberg B.M.
      • Mulder C.J.
      Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience.
      Low serum albumin concentration is an independent risk factor for mortality.
      • Rubio-Tapia A.
      • Malamut G.
      • Verbeek W.H.
      • et al.
      Creation of a model to predict survival in patients with refractory coeliac disease using a multinational registry.
      Refractory CD type 1 responds well to therapy with corticosteroids (including open-capsule budesonide) alone or in combination with azathioprine.
      • Mukewar S.S.
      • Sharma A.
      • Rubio-Tapia A.
      • Wu T.T.
      • Jabri B.
      • Murray J.A.
      Open-capsule budesonide for refractory celiac disease.
      There is no consensus on the best treatment for RCD type 2.
      • Rubio-Tapia A.
      • Kelly D.G.
      • Lahr B.D.
      • Dogan A.
      • Wu T.T.
      • Murray J.A.
      Clinical staging and survival in refractory celiac disease: a single center experience.
      Some treatments proposed for RCD type 2 include corticosteroids, immunosuppressants, cyclosporine, alemtuzumab, cladribine, or autologous stem cell transplant.
      • van Gils T.
      • Nijeboer P.
      • van Wanrooij R.L.
      • Bouma G.
      • Mulder C.J.
      Mechanisms and management of refractory coeliac disease.
      • Rishi A.R.
      • Rubio-Tapia A.
      • Murray J.A.
      Refractory celiac disease.
      Aggressive nutritional support, together with open-capsule budesonide, is a common preferred initial therapy for RCD type 2.
      • Rubio-Tapia A.
      • Kelly D.G.
      • Lahr B.D.
      • Dogan A.
      • Wu T.T.
      • Murray J.A.
      Clinical staging and survival in refractory celiac disease: a single center experience.
      Other therapies should be discussed in a case-by-case manner in patients without response to nutritional support and budesonide.

      Future Possibilities in CD

      Celiac disease awareness has improved over the past decade. There is emerging evidence to support a nonbiopsy diagnosis of CD in children (and possibly for adults) that may facilitate detection of new cases in the appropriate clinical scenario. Currently, there is limited access to specialty CD care centers across the world, and this problem needs to be improved in the coming years. There is also an unmet need for nondietary therapies in CD.
      There are several nondietary therapies under different stages of development and/or clinical trials. The best outcome measures for CD trials are evolving.
      • Ludvigsson J.F.
      • Ciacci C.
      • Green P.H.
      • et al.
      Outcome measures in coeliac disease trials: the Tampere recommendations.
      More nondietary options are likely to become available as our understanding of the pathophysiology of CD increases.
      • Schuppan D.
      • Junker Y.
      • Barisani D.
      Celiac disease: from pathogenesis to novel therapies.
      Different targets in the pathophysiology of CD have been identified in clinical and preclinical trials as potential nondietary therapies (reviewed elsewhere
      • Veeraraghavan G.
      • Leffler D.A.
      • Kaswala D.H.
      • Mukherjee R.
      Celiac disease 2015 update: new therapies.
      • Plugis N.M.
      • Khosla C.
      Therapeutic approaches for celiac disease.
      • Mukherjee R.
      • Kelly C.P.
      • Schuppan D.
      Nondietary therapies for celiac disease.
      ). The potential to induce tolerance to gluten in patients with CD with epitope-specific immunotherapy targeting T cells is exciting and a potentially remarkable discovery.
      • Goel G.
      • King T.
      • Daveson A.J.
      • et al.
      Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.
      Other potential targets for nondietary therapies include oral proteases for gluten detoxification, zonulin antagonist to modulate tight junctions, gluten-sequestering polymers, transglutaminase type 2 inhibitors, and HLA-DQ2 blockers. These novel strategies provide promise of alternative or adjunctive treatment options beyond the gluten-free diet.
      There are evolving tools to allow patients to assess their food for gluten contamination including portable handheld gluten detection devices,
      • Taylor S.L.
      • Nordlee J.A.
      • Jayasena S.
      • Baumert J.L.
      Evaluation of a handheld gluten detection device.
      and both urine and stool tests are under development to detect gluten immunogenic peptides that may help to gauge gluten ingestion.
      • Syage J.A.
      • Kelly C.P.
      • Dickason M.A.
      • et al.
      Determination of gluten consumption in celiac disease patients on a gluten-free diet.
      • Moreno M.L.
      • Rodríguez-Herrera A.
      • Sousa C.
      • Comino I.
      Biomarkers to monitor gluten-free diet compliance in celiac patients.
      The specific role of these tools in clinical practice will require further study.
      There is an increased interest in other wheat/gluten-related disorders, but validation of diagnostic criteria and mechanistic insight are urgently needed. New therapies for RCD type 2 are also needed. Interleukin 15 inhibitors are under active investigation to avoid expansion and activation of aberrant intraepithelial lymphocytes.

      Conclusion

      Celiac disease has a wide geographic distribution across the world and affects 1% of non-Hispanic whites in the United States. A high index of clinical suspicion is needed for early diagnosis. The diagnosis is strongly supported on the basis of serologic testing, and duodenal histology is recommended to confirm the diagnosis in most clinical situations. Lifelong adherence to a gluten-free diet remains the only effective therapy for CD. Persistent or recurrent symptoms of CD are not uncommon after starting a gluten-free diet, and this situation requires a systematic evaluation to rule out gluten contamination and other associated conditions, including RCD.

      Supplemental Online Material

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