Celiac Disease
Celiac Disease
Authors: Erica Boettcher, MD, Chief, Gastrointestinal Fellow, University of California, San Diego
Sheila E. Crowe, MD, Professor of Medicine, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA
Peer Reviewer: Ramesh K. Gandhi, MD, FACG, Associate Clinical Professor of Medicine, WSU Boonshoft School of Medicine, Dayton, OH
Authors’ Note
During the past 50 years, tremendous progress has been made in understanding the pathogenesis, clinical spectrum, and treatment of celiac disease. Once considered a rare childhood disease, recent advances have been made in the technology of diagnosing celiac disease and the disease is estimated to affect approximately 1% of the population. Presently, the gold standard for the diagnosis of celiac disease is a small intestinal biopsy based on the most recent American Gastroenterological Association1 and National Institutes of Health2 guidelines. Recent European Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines, however, challenge this notion, suggesting that at least among children, there is a possibility of diagnosis without biopsy. This article will review the spectrum of celiac disease in clinical practice, and will include an overview of the classification of celiac disease, clinical presentations, evaluation, treatment, complications, and controversies.
Introduction
Celiac disease (CD), also known as gluten-sensitive enteropathy as well as two older and no longer recommended terms,3 nontropical sprue and celiac sprue, is a chronic immune-mediated disorder induced by dietary gluten in genetically susceptible individuals. In CD patients, the ingestion of gluten results in the development of small intestinal mucosal villous atrophy with crypt hyperplasia and mucosal inflammation. Patients may be asymptomatic or may manifest classic malabsorptive symptoms of abdominal pain, bloating, weight loss, diarrhea, and steatorrhea. They also may present along a spectrum with more subtle gastrointestinal and/or extraintestinal symptoms and signs of the disease; virtually every body system can be affected.
In CD patients, a gluten-free diet (GFD) leads to healing of small bowel mucosa and amelioration of symptoms. Healing of the small intestinal mucosa is important as ongoing villous damage with inflammation may predispose patients to complications or associated disorders.
Epidemiology
Overview. Articles describing individuals suffering from diarrhea, most likely due to what we now call CD, first appeared more than 2000 years ago. It was not until the late 19th century, however, that the English physician Samuel Gee offered the first modern description of CD when he lectured to medical students “On the Coeliac Affection.” In his description, he reported “if the patient can be cured at all, it must be by means of diet.”4 He did not, however, uncover the underlying cause of the disorder. Roughly 50 years went by before the Dutch pediatrician, Willen-Karel Dicke, established a link between wheat exposure and CD.4 Dicke noticed that during the bread shortages in the Netherlands caused by World War II, children with CD improved. He also saw that when Allied planes dropped bread into the Netherlands, the patients quickly deteriorated. A few years later, with others, he produced a series of landmark papers, documenting for the first time the role that gluten plays in CD.4
Once considered a rare childhood disease, recent advances in the understanding of CD have refuted this notion. Prevalence is estimated in the range 1:100 to 1:300 in genetically susceptible populations,5-10 and variability exists both across and within countries, likely reflecting true population differences in the risk of CD as well as differences in study design and screening strategy.11 It is estimated that fewer than 10-15% of current cases of CD have been diagnosed in the United States compared to some other countries, where rates of diagnosis are greater than 50%,8,10,12,13 highlighting the challenge of diagnosing the disorder.
A large U.S. multicenter study by Fasano et al of a predominantly Caucasian population observed a prevalence of 0.95% (1:105) and 0.31% (1:322) in not-at-risk adults and children, respectively, with an overall prevalence of 0.75% (1:133) in not-at-risk groups.7 A retrospective U.S. study by Rubio-Tapia et al using stored serum reported that CD is 4-4.5 times more prevalent than 50 years ago8 and an increase in prevalence has been reported in other studies.14-17 The cause of this increase is unknown and may be related to environmental factors such as changes in cereal processing and other yet to be identified environmental factors.8
Genetic susceptibility. A role for genetic susceptibility in CD was first demonstrated in clinical observations of multiple cases of CD within families and the estimated 70-75% concordance for CD among monozygotic twins.18 Based on studies using a varying study design, the prevalence of CD among first-degree relatives of CD patients is around 10%.6,11 The prevalence among second-degree relatives is in the range of 2.6-5.5%.6,11
There is an established association between CD and specific human leukocyte antigen (HLA) class II genes, known as HLA-DQ2 and HLA-DQ8, located on chromosome 6p21. Most CD patients express genes encoding the major histocompatibility complex (MHC) class II protein HLA-DQ2; the remainder usually are HLA-DQ8 positive. The HLA-DQ2 and –DQ8 haplotypes are common and are carried by approximately 30-40% of Caucasian individuals, implying that the presence of such alleles are necessary for disease development but not sufficient on their own to cause CD19 (see Figure 1). Roughly 2-5% of HLA-DQ2 and –DQ8 gene carriers develop CD; thus, there are other undetermined genetic factors that are necessary for phenotypic expression. Candidate genetic regions have been identified through genomewide screening approaches, but the mechanisms by which they contribute to disease susceptibility currently are not known.20
Figure 1: Venn Diagram Depicting Distribution of HLA-DQ2 and HLA-DQ8 in General U.S. Population and in CD
It is also apparent that environmental factors play a role in the development of CD. Contributing environmental factors include early exposure of infants to dietary gluten21 and a change of bacterial gut flora,22-24 which could favor the evolution of CD in childhood. There are also reports addressing the possible role of enteric infections in the pathogenesis of CD. Case series and reports suggest an association in which patients with CD attribute the onset of symptoms to an episode of gastroenteritis25 or where CD is diagnosed after a confirmed gastrointestinal infection.26-29 Beyond these case descriptions, a recent study looking at infectious gastroenteritis as a trigger for CD was reported by Riddle et al,30 who found that medical visits for infectious gastroenteritis were twice as high among CD cases compared with matched controls. While these findings are interesting, the potential for misclassification of infection exposure given overlapping symptoms for infectious diarrhea and CD confounds their potential association. The emerging data warrant further prospective studies linking pathogen-specific infectious diarrhea to incident CD and antibody development or initiation of disease in those who previously were asymptomatic. Such studies, however, would require exclusion of at least serological CD markers before the infection.31 The study of the complex relationship between immunologic, genetic, environmental, and other triggering factors in susceptible individuals will help enhance our understanding on the recently reported increase in prevalence in CD.
Mortality and malignancy. Overall, studies have shown a small increased risk of death in CD. For instance, a retrospective U.S. study by Rubio-Tapia et al indicates that the mortality of untreated CD is increased four-fold over control populations.8 Similarly, a recent meta-analysis found an increased all-cause mortality odds ratio (OR) of 1.24.32 There was an excess risk of death from cardiovascular disease (OR, 1.19; 95% confidence interval [CI], 1.01-4.01) and lymphoproliferative disease or malignancy (OR, 2.53; 95% CI, 1.59-4.04). It has been proposed that mortality in CD is increased if gluten intake is high both before and after the diagnosis.33 The greatest risk of malignancy is for non-Hodgkin’s lymphoma including enteropathy-associated T-cell lymphoma (EATL),34 but increased rates of malignancy including head and neck cancers (primarily squamous cell carcinoma of the esophagus), hepatocellular, and small bowel adenocarcinoma35 also have been reported. However, whether there is a true and significant increased risk for these non-EATL malignancies in all populations and in current times has not been studied fully.
Etiology
Causative factors. The key components leading to CD are a specific genetic background (HLA-DQ2 or –DQ8) and exposure to gluten. Gluten is the commonly used term for the complex of proteins from wheat, rye, barley, and other grains that are harmful to patients with CD. Wheat gluten consists of glutenin and the prolamin gliadin. The corresponding prolamin fractions in barley and rye are called hordein and secalin, respectively. Gliadin, as well as the analogous proteins of rye and barley, serve as the nidus of the cascade of events that cause CD.
Predisposing conditions/risk factors. Several conditions are associated with an increased risk of CD. Patients with such disorders (see Table 1) should be screened if they are willing to undergo further testing and treatment, even if they do not have symptoms to suggest CD. First- and second-degree family members of biopsy-proven CD patients are at increased risk of CD, as are patients with autoimmune conditions including autoimmune endocrinopathies such as type 1 diabetes mellitus,36-40 autoimmune thyroid disease, and autoimmune adrenal disease;41-43 autoimmune connective tissue disorders including Sjogren’s syndrome,44,45 juvenile rheumatoid arthritis,46 and systemic lupus erythematosus;47 autoimmune dermatological disorders including psoriasis48 and alopecia areata;49 and autoimmune hepatobiliary disorders including autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.50 Some data suggest that the longer the exposure to gluten in undiagnosed CD, the higher the risk of certain autoimmune disorders,51,52 but other prospective long-term studies are necessary to clarify the role of untreated CD and autoimmune disorders.
Table 1: Conditions/Disorders to Consider in CD Diagnosis
Two of the autoimmune conditions, type 1 diabetes mellitus (T1DM) and autoimmune thyroid disease, necessitate further discussion as they share the same HLA-DQ2/8 susceptibility alleles. In regards to T1DM, the majority of studies cluster prevalence of CD among patients with T1DM in the range of 2%-5% for adults and 3%-8% for children.11,53-62,37 The prevalence of CD in patients with autoimmune thyroid disease has been assessed in multiple studies63-73 with a pooled prevalence of 3%.11 Reports have found an increased prevalence of DQ2/DQ8;74 however, a recent genetic linkage study did not demonstrate a single major locus suggesting a genetically heterogeneous disease.75
Other miscellaneous disorders warranting screening for CD in asymptomatic individuals include IgA deficiency,76 IgA nephropathy,77 Down syndrome,78 and Turner syndrome.79
Pathophysiology
Mechanism of disease process. In CD, the ingestion of gluten induces inflammatory and morphological changes such as an increase in intraepithelial lymphocytes (IELs), villous atrophy, and crypt hyperplasia in small intestinal mucosa (See Figure 2). Gliadin and the analogous proteins of rye and barley are not intrinsically toxic but are poorly digested, reaching the intestinal lumen as large polypeptides. In normal individuals, the intestinal epithelial barrier controls entry of foreign particles to the lamina propria, enabling the passage of useful nutrients while preventing harmful agents. In untreated CD, the tight junctional integrity contributing to epithelial barrier function is compromised and thus gliadin peptides are able to pass into the lamina propria and launch a harmful immunological cascade. In the lamina propria, the immunogenic gliadin peptides are modified by the enzyme transglutaminase (tTG),80,81 a CD autoantigen,82 and then bind with higher affinity to HLA antigen DQ4 and DQ8 molecules on antigen-presenting cells, stimulating both cell-mediated and humoral immune reactions.80,81 In addition to adaptive immune system activation, the innate immune system is also involved in the pathogenesis of CD.83 Simultaneously with immune cell activation, ingested gluten induces, in addition to gliadin antibodies, the production of disease-specific autoantibodies against the self, tTG, which may also contribute to the pathogenesis of the disease.
Figure 2: Pathogenesis of Celiac Disease
Target organ. The inflammatory sequence eventually leads to extensive remodeling of the small bowel mucosal architecture known as the “flat” lesion. This is the normal behavior of small intestinal mucosa when protecting itself against an environmental insult, in this case ingested gluten. When the insult is removed, the autoimmune process ceases, inflammation passes, and the mucosa reverts to its normal architecture without scarring.
Clinical Features
Chief complaint, presenting symptoms, key historical and physical exam findings. There are varying forms and many clinical presentations of CD, which can pose a serious challenge for clinicians. CD can present as “classical” disease in childhood, “non-classical” or atypical disease with non-specific gastrointestinal or extraintestinal manifestations, dermatitis herpetiformis, silent/asymptomatic disease, or latent/potential disease.84 Classical CD presents in childhood with symptoms of malabsorption and dramatic response to GFD. Non-classical CD presents later in life with a potential myriad of symptoms, including less severe gastrointestinal symptoms or extraintestinal manifestations. Asymptomatic/silent CD patients do not manifest any symptoms commonly associated with CD and have no symptoms that respond to gluten withdrawal. These patients are often diagnosed through testing of populations enrolled in screening programs or in case-finding strategies. Latent CD refers to patients with normal small intestinal biopsies who are at risk of developing CD as indicated by genetic susceptibility and positive CD serology.
Digestive system manifestations and associations with CD. The classical symptomatic presentation of CD is relatively rare in current times and includes malabsorptive symptoms of diarrhea, steatorrhea, failure to thrive, weight loss, bloating, abdominal pain, and vitamin or other nutrient deficiencies. Some non-specific physical exam findings can include muscle wasting, loss of adipose tissue, edema, protuberant abdomen, and short stature. More commonly, CD presents later in life, with an average age of diagnosis in the fifth decade. Non-specific presenting gastrointestinal symptoms include altered bowel habits with diarrhea, constipation, or a combination of both, abdominal pain, flatus, bloating, dyspepsia,85 and heartburn.86
Some studies suggest that a subset of patients diagnosed with irritable bowel syndrome (IBS) may in fact have CD87,88 and decision analysis studies suggest that there is an acceptable cost of testing patients with diarrhea-predominant IBS.89,90
In support of this, a recent systematic review and meta-analysis of 14 studies found that the likelihood of biopsy-proven CD in patients meeting criteria for IBS was increased more than four-fold compared with non-IBS controls.91 Another study, however, reported a prevalence of CD in non-IBS-constipation predominant patients similar to controls.92 Whether findings truly reflect an increased association between these two common clinical entities, therefore, is a matter of debate.
CD can present with a variety of other digestive system manifestations. Disorders that warrant testing for CD and generally improve with GFD include a pattern of asymptomatic cryptogenic transaminitis with nonspecific histologic changes on liver biopsy;93 disturbances of the oral cavity, including recurrent aphthous ulcers;94 and atrophic glossitis (sore/burning mouth).95,96 There are digestive disorders that can coexist with CD and merit consideration but, in general, they do not improve with GFD. These include eosinophilic esophagitis,97 microscopic colitis,98,99 lymphocytic gastritis,100,101 and inflammatory bowel disease102,103 (See Table 1). However, screening for CD in individuals with these conditions is indicated.
CD has a reported association with pancreatic dysfunction as well, including pancreatic insufficiency104,105 and recurrent acute pancreatitis,106,107 but further studies are necessary to determine whether testing patients for CD with such conditions is warranted.
Non-digestive manifestations and associations with CD. While gastrointestinal symptoms are a dominant feature of CD, virtually any body system can be affected, with dermatologic, hematologic, reproductive, musculoskeletal, and neurologic systems most commonly involved (see Table 1). Many of the non-digestive conditions improve or resolve with a GFD emphasizing the importance of early diagnosis and treatment.
The most common dermatologic manifestation of CD is dermatitis herpetiformis (DH). DH is a blistering, intensely pruritic papulovesicular rash typically located on the elbows, forearms, buttocks, knees, and scalp (see Figure 3). The disease can be distinguished from other sub-epidermal blistering disorders by histological and immunological characteristics. Histopathological findings of the lesional skin of patients with DH are characterized by subepidermal blisters with predominantly neutrophil infiltrates at the tip of the papillary dermis. Direct immunofluorescence reveals granular IgA deposition in the papillary dermis. DH is considered pathognomonic for CD and does not require an intestinal biopsy to confirm the diagnosis. Although DH is highly associated with CD, the gastroenterological symptoms in DH are generally mild or are clinically completely absent. DH is the result of intestinal gluten sensitivity as opposed to a direct dermal response, and treatment with a GFD resolves both the intestinal and skin manifestations.108
Figure 3: Dermatitis Herpetiformis
Anemia is the most common hematologic disorder in CD and may be the only presenting feature. Most often, the anemia is caused by iron deficiency but it can also be due to folate or B12 deficiency or a combination of several deficiencies. The iron deficiency in CD primarily results from impaired absorption of iron in the proximal small intestine. Coagulopathy from a deficiency in vitamin K can occur and hyposplenism has also been reported.109,110 Restriction of gluten typically improves the hematologic manifestations of CD. CD should be considered in menstruating women as well as in individuals younger than 50 years with unexplained iron deficiency, especially if they are resistant to oral iron supplementation. Patients older than 50 years with unexplained iron deficiency anemia should be referred for endoscopic evaluation, including upper endoscopy with duodenal biopsies.
Patients with untreated CD can suffer a wide range of reproductive manifestations and this may be the only manifestation of CD. Delayed menarche, early menopause, secondary amenorrhea, infertility, recurrent miscarriages and intrauterine growth restriction, low birth weight, or preterm deliveries have all been reported.111,112 Treating CD seems to improve fertility in women and men, and improve pregnancy outcomes, although systematic follow-up studies are lacking. Women and men with unexplained infertility and women with recurrent miscarriages should be considered for CD testing.
CD can result in vitamin D and calcium malabsorption and can impact the musculoskeletal system at any age; it can affect the developing bones of infants and children, compromise bone accretion during adolescence and young adulthood, and add to the effects of menopause and aging in the elderly.113 Patients with unexplained metabolic bone disease or severe osteoporosis should be assessed for CD.114 Conversely, screening for osteopenia and osteoporosis is recommended for all newly diagnosed CD patients. A GFD corrects bone loss in patients with mild disease and provides significant improvement in patients with severe malabsorption.113 Diminished bone mineral density is associated with increased risk for fractures in patients with CD.115 GFD reduces the risk of fracture, underscoring the importance of early diagnosis and treatment. In contrast, CD influences the mineralization of permanent teeth and can lead to dental enamel defects including discoloration and structural changes of teeth94 that do not respond to a GFD.
There are several links between neuropsychiatric and behavioral disorders and CD.116 Classic associations that should prompt serologic assessment of CD include cerebellar ataxia117,118 and idiopathic peripheral neuropathy.119,120 These disorders have a variable response to a GFD. Neuropsychiatric syndromes have been reported both as complications of prediagnosed CD and as initial manifestations of CD including cerebral calcifications, seizures, myelopathy, schizophrenia, depression, migraines, irritability, cognitive deficits, and chronic fatigue, although there is no proof that CD is causal in most of these conditions.114
Diagnostic Studies
Indications and recommendations for evaluation. Deciding when to test a symptomatic patient or screen an asymptomatic patient for CD is challenging. Furthermore, the decision of when to refer a patient for further evaluation is equally difficult. These clinical challenges contribute to an average of 11 years of symptoms prior to diagnosis121,122 and often, a complete failure to test for the disease.
Based on the available data, it is recommended that patients with gastrointestinal or extraintestinal symptoms (see Table 1) suggestive of CD should be tested. In addition, asymptomatic individuals with an associated autoimmune or other condition, as well as those with first-or second-degree family member(s) with biopsy-confirmed CD, should be screened for CD (see Table 1). The strategy for testing and screening varies depending on the clinical scenario and is described below.91,123,124
Both screening and testing for CD in asymptomatic patients with associated conditions and in symptomatic older children and adults who have been consuming gluten for more than 1 year is performed using serum IgA antibodies to tissue transglutaminase (tTG), an enzyme that is increased in most cases of active CD.125 The tTG IgA serum antibody marker has high sensitivity (89%) and very high specificity (98%) for CD in patients with abdominal symptoms.126 A related antibody, antiendomysial IgA antibody (EMA), which detects the same tTG protein as tTG antibodies by immunofluorescence assay, has a similar sensitivity (90%) and specificity (99%).126 However, this test is more expensive, complex, and operator dependent with larger interobserver variation.127 In a meta-analysis of both symptomatic and asymptomatic patients, both EMA IgA and tTG IgA had high sensitivities (93% for both) and specificities (> 99% and > 98% respectively) and again, due to cost and ease of administration, tTG IgA is recommended as the preferred test.128 Anti-gliadin (AGA) IgG and IgA previously were used to screen for CD but are no longer recommended in adults due to low sensitivities and specificities of both tests.129 Recently available tests for IgG and IgA antibodies to deamidated gliadin peptide (DGP) were initially reported to match the performance of tTG and EMA antibody tests.130 In a recent meta-analysis; however, DGP was found to be less sensitive and specific than tTG IgA.131
Although the absence of HLA-DQ2 or –DQ8 makes CD highly unlikely, adding this test to either tTG IgA or EMA IgA antibody measurement in this clinical scenario does not change test performance.132 Thus, genetic (HLA) testing is not recommended. If tTG IgA antibodies are negative, serum total IgA is recommended, and if this is normal, then CD is unlikely to be the cause of the symptoms. If tTG is positive or if results are negative but clinical suspicion is high, patients should be referred to a gastroenterologist for upper endoscopy with duodenal biopsies.
For an asymptomatic individual at increased risk of CD due to family history, the recommended screening test is genetic testing for HLA-DQ2 or HLA-DQ8. If positive for either HLA-DQ2 or HLA-DQ8, the family member should have serum tTG IgA screening, which should begin after 2 years of age and following at least 1 year of a gluten-containing diet. Since CD can develop at any age, identifying family members who are actually at risk for CD by using HLA DQ testing is recommended to prevent unnecessary tTG IgA testing in those with no risk.114 The interval at which family members should be screened is not clear, but recent European Society for Pedatric Gastroenterology, Hepatology and Nutrition (ESPGHN) guidelines suggest every 2 to 3 years.133 However, given that the average age of diagnosis occurs in the 5th decade, screening of family members may be carried out throughout adult life.
A caveat to the above recommendations includes patients with IgA deficiency in whom serum tTG IgA testing is not helpful. Selective IgA deficiency affects 2% of CD patients, which can cause false-negative results on serologic testing.134 While routine total IgA serum levels are not recommended in screening for CD, in the case of a low tTG IgA, total IgA levels should be obtained and if IgA deficiency is confirmed, an IgG-based serologic test such as tTG IgG is recommended.134,135
If a patient has positive serologic testing or if there is high clinical suspicion for CD, endoscopic biopsies of the duodenum are needed to confirm the diagnosis based on American Gastroenterological Association1 and National Institutes of Health2 guidelines. A pattern on endoscopic examination, including scalloping or notching mucosal folds, is highly specific for the disease (see Figure 4). However, endoscopic changes have low sensitivity and biopsies should be obtained regardless of gross appearance. Small intestinal biopsies can reveal varying degrees of villous blunting and lymphocytic and plasma cell infiltrates (see Figure 5). Biopsies must be carefully evaluated, ideally by a pathologist with expertise in gastrointestinal pathology to help differentiate CD from other conditions. Other disorders that can masquerade as CD with increased intraepithelial lymphocytes and/or villous atrophy include peptic duodenitis, nonsteroidal anti-inflammatory drug damage, food protein-mediated conditions (hypersensitivity, protein enteropathies), eosinophilic gastroenteritis, collagenous sprue, tropical sprue, radiation damage, recent chemotherapy, graft-versus-host disease, chronic ischemia, small intestinal bacterial overgrowth, severe giardiasis, acute viral gastroenteritis, tuberculosis, Crohn’s disease, common variable immunodeficiency, and autoimmune and other enteropathies.114,136,137
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Figure 4: Endoscopic Appearance of CD
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Figure 5: Histologic Appearance of CD
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Recently the notion of mandatory confirmatory intestinal biopsies for the diagnosis of CD has been contested in both the pediatric and adult literature. ESPGHN published guidelines that offer the option of a serological diagnosis without intestinal biopsies in the case of a tTG IgA level ≥ 10 times the upper limit of normal. In the case of a tTG < 10 times the upper limit of normal, intestinal biopsies are still recommended.133 Similarly, in a recent review, Sapone et al propose that a quantitative approach described as the “four out of five rule” be utilized for the diagnosis of CD in an adult population. Using this method, the diagnosis is confirmed if at least four of the following five criteria are fulfilled: “1) typical symptoms of CD; 2) positivity of CD IgA class autoantibodies at high titer; 3) HLA-DQ2 and/or HLA-DQ8 genotypes; 4) celiac enteropathy found on small bowel biopsy; and 5) response to a GFD.”138 This method has not been validated and, for now, the gold standard for diagnosis of CD remains small intestinal biopsies.
Note that continued consumption of gluten-containing products is necessary in the diagnosis of CD as described and recommended.
Increasingly, however, patients present for diagnosis and treatment having already initiated a GFD. Furthermore, an empiric trial of GFD without a biopsy-established diagnosis of CD is not recommended because a beneficial response may be seen in other disorders. Many dietary components in addition to gluten are eliminated in a GFD, which also may provide relief in such functional gastrointestinal disorders such as IBS, gastroesophageal reflux, functional dyspepsia, and a newly described condition termed non-celiac gluten sensitivity (NCGS). In one study, the positive predictive value of a beneficial response after gluten withdrawal resulting from CD was only 36%.139 Differentiating between CD and other disorders that may respond to a GFD is important to help determine if a lifelong GFD is required to understand the implications for long-term management and risk assessment of relatives if CD is present.
In the case of the patient who is already on a GFD, the effect of gluten withdrawal on the accuracy of diagnostic serologic testing or small intestinal biopsies is dependent on the duration of GFD, the degree to which gluten has been avoided, and the severity of underlying disease. In severe malabsorptive CD, the histologic abnormalities can take months to years to return to normal on a GFD.140,141 For this reason, it is recommended to obtain serologic studies for CD on first visit, even if a patient reports a GFD. If tTG IgA is elevated, an intestinal biopsy should be obtained. If tTG IgA is not elevated (and IgA deficiency has been ruled out), further diagnostic testing may be deferred until gluten has been reintroduced into the diet for a sufficient duration to reproduce the serologic abnormality and characteristic intestinal damage. In this case, HLA-DQ2/-DQ8 testing is recommended, and a gluten challenge is initiated for those genetically susceptible to CD.114 Since the gluten challenge may induce a severe reaction in rare instances, a gradual increase in gluten is advised. Patients should be challenged for 4 weeks with enough gluten to produce symptoms, on average, the equivalent of 3 to 4 slices of whole wheat bread (8-10 g of gluten) per day. If symptoms do not recur, development of antibodies may be used to guide the timing of intestinal biopsy. If there are no clinical symptoms or characteristic serology with the initial gluten challenge, it should be continued for at least 3 to 6 months and intestinal biopsies should be obtained. Patients who have followed a GFD for prolonged periods may take up to several years to relapse after gluten is reintroduced.142
Among patients who improve on a GFD but are not genetically susceptible to CD or those who have HLA susceptibility genes but do not develop antibodies or intestinal lesions after a gluten challenge, referred to as non-celiac gluten sensitivity, there are no current management guidelines. This group of patients is heterogeneous and not well characterized because currently there are no criteria to define this disorder. To what degree NCGS patients should adhere to a GFD is also not known. The common practice is to advise such patients without the HLA genes that can predispose to CD to remain on a GFD to an extent sufficient to control symptoms. Further studies are needed to guide medical practice for this emerging clinical entity.143-146
Differential Diagnosis
Many different conditions can be confused with or can occur with CD. These include intolerance to lactose and other carbohydrates, functional gastrointestinal disorders including irritable bowel syndrome, non-celiac gluten sensitivity, inflammatory bowel disease, microscopic colitis, eosinophilic gastroenteritis, pancreatic insufficiency, other food protein-mediated conditions (hypersensitivity, protein enteropathies), peptic duodenitis, anti-inflammatory drug damage, collagenous sprue, tropical sprue, radiation damage, recent chemotherapy, graft-versus-host disease, chronic ischemia, small intestinal bacterial overgrowth, giardia infection, acute viral gastroenteritis, tuberculosis, intestinal lymphoma, IgA deficiency, common variable immunodeficiency, and autoimmune and other enteropathies.114,136,137
Management
Initial treatment. The mainstay of treatment for CD is a lifelong GFD; removal of gluten from the diet nearly always reverses disease manifestations. Although dapsone may manage the skin manifestations of dermatitis herpetiformis, it does not ameliorate intestinal mucosal injury; thus, GFD is the only effective treatment of both CD and DH. Secondary lactose intolerance is very common with newly diagnosed CD due to intestinal damage and a lactose-free diet is recommended for a minimum of a few weeks after initiation of GFD. For most individuals, once the intestine heals, lactose intolerance resolves. In the case of continued lactase insufficiency, low-lactose dairy products and lactase supplements are required long-term.
The GFD is complex and difficult to adhere to and patient motivation and education are paramount, particularly because there is no alternative treatment. Non-adherence is common and ingestion of even small amounts of gluten may result in the return of symptoms and histologic changes of the small bowel.147 Once a GFD is initiated, symptoms may resolve in days to weeks and patients may incorrectly believe that the absence of symptoms when eating gluten-containing foods indicates that it can be consumed without harm. Accordingly, patients should be actively encouraged to strictly adhere to the diet to avoid such complications as bone loss and increased risk for cancer.
A recent systematic review provides evidence that adherence to a GFD and mucosal healing prevent the complications of CD.148 The authors suggest that long-term follow-up is essential, but they acknowledge that the evidence is limited. In general, outcome studies of CD are limited due to their retrospective nature and the inherent difficulty of assessing adherence.114
Indications for hospitalization. Currently, in most cases, untreated CD is characterized by an indolent course with gastrointestinal and extraintestinal manifestations and nutritional abnormalities but no severe or life-threatening symptoms. In rare cases, however, patients may present in “celiac crisis” which is clinically characterized by severe diarrhea, dehydration, and metabolic disturbances including hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, and hypoproteinemia149 either at the initial diagnosis or in times of severe stress such as the perioperative period. In these cases, hospitalization is required for close monitoring and electrolyte and nutritional support. In turn, hospitalization may be required in severely malnourished patients when enteral feeding is resumed to avoid the complications of the refeeding syndrome.150
Specific dietary recommendations. Upon diagnosis, patients should be referred to a dietitian, preferably one with clinical expertise in CD and the GFD. Current recommendations focus on choosing naturally gluten-free products of high nutritional value (see Tables 2, 3, and 4). Eating processed gluten-free foods combined with gluten-free flours that are not vitamin-enriched can contribute to nutritional deficiencies, for example, in iron, vitamin B or D, or fiber.114 Other important topics for counseling include hidden sources of gluten and the increased costs of prepared gluten-free foods.
Table 2: Grains, Seeds, Flours, Ingredients Containing Gluten (Must Be Avoided)
Table 3: Gluten-free Grains, Seeds, and Flours (Safe to Eat)
Table 4: Nutritional Advice for Patients with Celiac Disease
Vitamin supplementation. Untreated CD can lead to malabsorption of fat-soluble vitamins (D, E, A, and K) as well as folic acid and iron, which are preferentially absorbed through the proximal small intestine. Deficiencies of thiamine, B6, and B12 may occur but are less common. Certain minerals including magnesium, copper, zinc, and selenium can be low depending on disease severity and dietary intake. A multivitamin is recommended until the intestine has healed. In addition, vitamin D levels should be monitored, and if levels are low, additional supplemental vitamin D is necessary.114
Monitoring response of GFD. Achieving compliance with a GFD poses a considerable challenge and adherence can by monitored, with varying degrees of accuracy, by four methods: dietitian interview, serology, validated surveys, and mucosal biopsy. Although evidence-based guidelines for follow-up and lifelong management are lacking, the need for long-term follow-up evaluation to improve adherence with the GFD has been well established.151 Both the 2004 National Institutes of Health consensus statement and the 2006 American Gastroenterological Association technical review on CD recommends that patients be evaluated “at regular intervals”11 or with “periodic visits” by a “physician and dietitian.”2 Following a diagnosis of CD, it is suggested that patients be followed up within a few weeks to discuss the results of intestinal biopsies and other tests. A visit with an expert dietitian is scheduled for the same day or very soon thereafter. From there, patients should be monitored at regular intervals by a health care team, including a physician and a dietitian. The frequency of the visits should be individualized to the patient. In general, lifelong follow-up is recommended, although health care visits may be as infrequent as those in a normal population for those who have returned to normal health on a GFD.114 Herman et al recently reported on the long-term follow-up practices in a non-referral patient population of CD patients from Olmsted County, Minnesota, and found that only 35% received follow-up consistent with AGA recommendations. By 1 and 5 years after diagnosis with CD, 41.0% and 88.7% of the patients had follow-up visits, 33.6% and 79.8% were assessed for adherence with GFD, and 3.3% and 15.8% met with a dietitian151 — underscoring the need for practice improvement.
In most cases, patients can be monitored based on symptom resolution, improved laboratory abnormalities, and declining levels of celiac antibodies. Antibodies that are initially elevated are typically measured every 3 to 6 months until they fall into the normal range, although this practice is not based on scientific studies. Higher antibody titers can take longer to return to normal and if antibodies remain elevated or become positive after 6 to 12 months of treatment, repeated endoscopy with biopsies should be considered. Conversely, even in the setting of normalized antibodies, intestinal healing can lag behind serologic response, and histology may remain abnormal for years with persistent inflammation even in the setting of a GFD. This has been proposed to be the result of low levels of gluten contamination, a persistent immune response independent of gluten, or other unknown mechanisms.152 The clinical consequences of such low-grade inflammation are unknown in seemingly healthy, asymptomatic patients, and as such, there are few data to support repeated biopsies in the routine monitoring of CD patients.
Complications
Nonresponsive CD. While most patients rapidly respond to a GFD, a minority of patients have persistent symptoms.153,154 The most common cause of ongoing symptoms is continued intentional or accidental ingestion of gluten; thus, the first step is to carefully review the dietary history with the assistance of an expert dietitian. If strict adherence to GFD is confirmed, the patient should be referred to a gastroenterologist, preferably one with expertise in CD, for further evaluation. One important consideration in nonresponsive CD is determining whether the original diagnosis of CD is correct. An incorrect diagnosis may result from false-positive serologic results, particularly antigliadin IgG antibodies, or false interpretation of intestinal biopsy specimens. Other reasons for lack of response include co-existing conditions such as lactose or other carbohydrate intolerances, pancreatic insufficiency, microscopic colitis, small intestinal bacterial overgrowth, gastroparesis, functional gastrointestinal disorders, or inflammatory bowel disease.137,114
One of the most feared causes of nonresponsive CD is refractory CD. This uncommon disease is defined as persistent or recurrent malabsorption and villous atrophy despite strict adherence to a GFD for 6 to 12 months in the absence of other causes of nonresponsiveness or the presence of overt cancer,137 and it is a diagnosis of exclusion. The complications of refractory CD include ulcerative jejunitis and low-grade and ultimately high-grade T-cell lymphoma, termed enteropathy-associated T-cell lymphoma (EATL), arising from clonal intraepithelial lymphocytes.137
Refractory CD is sub-classified based on the immunophenotype of intraepithelial lymphocytes as type I, in which the IEL phenotype is normal, and type II, in which there is a clonal aberrant phenotype of the IELs.155 Most patients with type I refractory CD can be managed, under the care of a gastroenterologist, with immunosuppressive therapy, usually beginning with corticosteroids and maintained with immunomodulators including thiopurines (azathioprine, 6-mercaptopurine), cyclosporine, and other immunosuppressive agents. Data on such therapies are limited and there are no randomized trials to guide management. Type II refractory CD is usually resistant to any known therapy.156
Lymphoma. Patients with type I and especially type II refractory CD are at risk for EATL and in such patients, as well as those who develop new or recurrent symptoms of malabsorption, abdominal pain, fever, and weight loss despite adherence with GFD, should be evaluated for small intestinal cancer. CT enterography and capsule endoscopy are recommended. Upper endoscopy with multiple biopsies should be obtained from the duodenum and more distal small intestine, depending on the findings of radiographic and capsule studies. Biopsy specimens should be evaluated with immunohistochemistry and molecular diagnostic studies to assess for abnormal lymphoid cells. Molecular genetic studies for rearrangement of T-cell genes are used to categorize refractory CD into type I (without gene rearrangement) and type II (with gene rearrangement). Several retrospective studies indicate that the 5-year mortality rate of patients with type II refractory CD is approximately 45%.155,156 Causes of death in patients with refractory CD include severe malnutrition, lymphoma, and infection.
When lymphoma is suspected, consultation with a hematologist/oncologist is indicated. Full-thickness surgical biopsies of the small intestine may be necessary. Management is complex and only small case series are available for guidance in this rare cancer. Given the complexity, patients with refractory CD are typically referred to tertiary care centers.
Additional Aspects
Is it ever safe to discontinue the GFD? There are few studies to indicate when, if ever, a GFD can be relaxed or discontinued. Most studies addressing this topic have a small sample size and/or a relatively short duration of follow-up after gluten reintroduction.157-159 In one of the few relatively large retrospective analyses of a cohort of adult patients with CD diagnosed in childhood, who after initial gluten challenge remained asymptomatic and continued to consume gluten until adulthood, Matysiak-Budnik et al found that among 61 patients, 60% had osteopenia or osteoporosis. While nearly half of the patients presented with minor clinical symptoms such as abdominal pain or bloating, these symptoms were not intense enough to prompt a return to GFD indicating that bone disease is frequent in clinically asymptomatic or mildly symptomatic CD.160 Given the risk of bone demineralization, the increased risk of lymphoma, other malignancies,35 and the proposed increase in mortality in untreated CD,8 as well as the notion that mortality in CD is increased if gluten intake is high both before and after the diagnosis,33 it is recommended that the GFD be maintained for life.
When to refer to a gastroenterologist. Patients with an elevated celiac serology should be referred to a gastroenterologist for upper endoscopy with intestinal biopsies to confirm the diagnosis. A gastroenterologist should also be consulted for evaluation of unexplained iron deficiency anemia, chronic diarrhea, malabsorption, weight loss, and other abnormalities including unexplained osteoporosis or infertility.114 Referral to a gastrointestinal celiac specialist is indicated in patients with biopsyproven CD who do not respond to a GFD or if relapse occurs despite continuation of the GFD.
Myths, Misconceptions and Controversies
CD is rare. The prevalence of CD is 1:100 to 1:300 in most genetically susceptible populations populations.5-10
You cannot have CD if you are overweight or obese. It is well established that many CD patients have a high or normal body mass index at diagnosis.161-164 Diagnosis of CD can be delayed by a low suspicion in patients with a normal or high body mass index on initial presentation.
You cannot use gluten-containing beauty products if you have CD. The only way to trigger an immune response in CD, including dermatitis herpetiformis, is by ingesting gluten so as long as shampoos, creams, lotions stay out of the mouth they will not cause problems! Since lipsticks and chapsticks may be ingested, albeit in small amounts, patients can be instructed to choose a gluten-free product.
The consumption of oats can trigger CD. At one time, the consensus was that oats were immunogenic to those with CD, but a large number of studies in adults and children have demonstrated that oats can be safely consumed.165-169 However, only pure oats are safe to eat and until recently, most food manufacturers milled oats in the same facility as gluten-containing grains, leading to gluten contamination of commercial oat products.170 Fortunately, pure-oat containing food products are becoming increasingly available, both at specialty food stores and larger grocery chains.
Cost. Much of the economic literature on CD has focused on estimating costs associated with CD screening or diagnosis171-174 and dietary costs to the patient.175-177 From these studies it is evident that gluten-free foods are generally more expensive than their gluten-containing counterparts. Research on the effect that detecting and treating CD has on health care resource use and overall economic burden of illness is emerging and suggests that there is a cost benefit to early diagnosis and treatment.178 In one recent population-based study assessing the effect of diagnosis on direct medical costs of care as well as the incremental costs associated with CD prior to diagnosis, they found that direct medical outpatient and total costs were significantly reduced for patients in the year following diagnosis.179
Tax deductions. Having CD can be considered for a tax deduction in the United States,180 but the eligibility requirements and the amount you can deduct vary depending on the jurisdiction in which you live. To qualify, patients need a letter or complete form from a physician certifying the diagnosis of CD. Eligibility for a possible tax benefit typically only applies to the individuals in the household who have CD, not the other family members.180
Summary
Recent advances have led to an increasing understanding of the pathogenesis and clinical spectrum of CD. Diagnosis and treatment of the disease, however, remain challenging. Aside from recognizing both classical and atypical presentations of the disease and associated conditions, clinicians can arm themselves with an understanding of the recommended diagnostic testing as well as appropriate treatment and follow-up care for CD patients. Clinicians have a pivotal role in educating, motivating, and supporting CD patients to achieve lifelong adherence to a GFD with the assistance of an experienced dietitian, referral to a support group, clinical follow-up.
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Celiac disease (CD), also known as gluten-sensitive enteropathy as well as two older and no longer recommended terms,3 nontropical sprue and celiac sprue, is a chronic immune-mediated disorder induced by dietary gluten in genetically susceptible individuals. In CD patients, the ingestion of gluten results in the development of small intestinal mucosal villous atrophy with crypt hyperplasia and mucosal inflammation. Patients may be asymptomatic or may manifest classic malabsorptive symptoms of abdominal pain, bloating, weight loss, diarrhea, and steatorrhea. They also may present along a spectrum with more subtle gastrointestinal and/or extraintestinal symptoms and signs of the disease; virtually every body system can be affected.Subscribe Now for Access
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