The recognition of celiac disease may be quite challenging due to the wide range of presenting symptoms, which includes patients who are asymptomatic.4 Clinical manifestations of celiac disease also significantly vary according to age group (Table 49–3). Infants and young children generally experience diarrhea, abdominal distention, and failure to thrive. Vomiting, irritability, anorexia, and even constipation are also common in these young patients. Extraintestinal manifestations such as short stature, neurologic findings (e.g., peripheral neuropathy, ataxia, seizure, migraine, and dementia24), or anemia are often found in older children and adolescents. The classic presenting symptom in adults is diarrhea, which may be accompanied by abdominal pain or discomfort; however, it is noteworthy that during the last decade it has been reported that diarrhea has been the main presenting symptom of celiac disease in less than 50% of cases. Adults may be found to exhibit what are sometimes characterized as silent manifestations of this disease such as iron-deficiency anemia or osteoporosis. Less common but important presentations of celiac disease in adults include abdominal pain, constipation, weight loss, neurologic symptoms, dermatitis herpetiformis, hypoproteinemia, hypocalcemia, and elevated liver enzymes. Some adults may be diagnosed as a result of having an endoscopy performed in response to their complaints of symptoms associated with gastroesophageal reflux.20 Prior to age 65 years, the disease is two to three times more common in adult women than adult men.4 Regrettably, patients with celiac disease often experience symptoms for a long period of time and may experience multiple hospitalizations and undergo surgical procedures before celiac disease is diagnosed.20
Dermatitis herpetiformis is a skin manifestation of the intestinal response to ingested gluten (Figs. 49–1 and 49–2). It occurs in approximately 15% to 25% of patients with celiac disease.27 This extremely pruritic, bullous skin rash is generally found on the elbows, knees, buttocks, and scalp but can occur anywhere on the body.24,27 Although dermatitis herpetiformis is most frequently observed in patients who are 30 to 40 years of age, it can also be found in children and elderly patients.28 Patients with dermatitis herpetiformis often do not have the typical gastrointestinal symptoms that are associated with celiac disease; however, they are at risk for developing intestinal damage.29 Although dermatitis herpetiformis was once considered to be a skin disease that was often found in patients with celiac disease, current evidence supports that it is actually a cutaneous manifestation of the disease.30 Although every patient with celiac disease does not develop dermatitis herpetiformis, every individual with dermatitis herpetiformis has celiac disease.29
The diagnosis of celiac disease is based upon clinical suspicion and confirmation with laboratory tests and duodenal biopsy.31 When suspected, the diagnosis of celiac disease is easily established.20 Although the frequency of diagnosis of patients with celiac disease has increased, the majority of patients (an estimated 97%) with this condition remain undiagnosed.24 This is particularly concerning as undiagnosed celiac disease has been associated with a nearly fourfold increased risk of death compared with subjects without serologic evidence of disease.32
Perhaps the most important initial step in making this diagnosis is for healthcare providers to recognize its many and diverse possible symptoms.33 Only 11% of celiac disease cases are diagnosed in a timely manner, with an average reported period of 5.8 to 11.7 years from the onset of symptoms to the diagnosis.34 Clinicians can help reduce the time from the onset of symptoms to the diagnosis of celiac disease by being aware of the common diseases with which many celiac patients are misdiagnosed (Table 49–4). Although these disorders may be mistakenly diagnosed instead of celiac disease, they may also coexist with celiac disease.34
Clinicians should also note that individuals with certain disorders are more likely to have celiac disease than the general population. Examples include other autoimmune diseases, such as diabetes mellitus (type 1), multiple sclerosis, myasthenia gravis, Raynaud disease, rheumatoid arthritis, Addison disease, chronic active hepatitis, cystic fibrosis, scleroderma, and Sjögren syndrome; Down syndrome; neurologic conditions such as ataxia, epilepsy, and cerebral calcifications; and primary biliary cirrhosis. Although patients with these disorders are more frequently found to have celiac disease than the general population, these associated conditions are not believed to cause celiac disease.29
Diagnostic testing for celiac disease must be performed while the patient continues to consume gluten.35 A confirmed diagnosis of celiac disease requires both a positive finding on duodenal biopsy and a positive response to a gluten-free diet.20 The identification of villous atrophy with small bowel endoscopy and biopsy is generally regarded as the diagnostic gold standard.36 Although villous atrophy is associated with celiac disease, clinicians must consider that this may also be found in other diseases, including giardiasis, autoimmune enteropathy, tuberculosis, Crohn disease, intolerance to food other than gluten, intestinal lymphoma, and Zollinger-Ellison syndrome.3,20 Positive findings on biopsy include increased intraepithelial lymphocytes (i.e., >30/100 enterocytes), loss of nuclear polarity, change from columnar to cuboid cells, lamina propria cellular infiltration, crypt elongation and hyperplasia, increased crypt mitotic index, and progressive villous flattening or blunting. These findings lead to a presumptive diagnosis that is followed by placing the patient on a gluten-free diet. A definitive diagnosis can only be made after the patent's symptoms clearly improve while maintaining the special diet. Clinicians have noted that a second biopsy to confirm histologic improvement is not required except in cases when the clinical symptoms of celiac disease were absent.36 Other clinicians have suggested that a repeat biopsy after dietary intervention may have merit to demonstrate histologic improvement that will support the diagnosis, assess the patient's dietary compliance, and reassure the patient. A second biopsy can be useful for patients whose initial biopsy demonstrated ambiguous histological changes, whose serology was negative or discrepant, or who continue to have symptoms after initiating the gluten-free diet.4
Dermatitis herpetiformis is diagnosed by taking a small skin biopsy from normal skin that is next to the blister site.29 The characteristic skin biopsy finding in this disorder is the deposition of IgA granules at the dermal–epidermal junction.27 The 2004 National Institutes of Health (NIH) Consensus Development Conference on Celiac Disease reported that patients with skin biopsy–proven dermatitis herpetiformis generally are not required to have small bowel biopsies.33
Serologic test results provide clinicians with a useful noninvasive tool that helps to determine if symptomatic patients, or patients who are at risk for celiac disease, require a biopsy.2,18,37 Available tests include those for antigliadin antibodies, connective-tissue antibodies (antireticulum and antiendomysial antibodies), and antibodies against tissue transglutaminase.20 The most common serologic markers that are used for screening patients are serum IgA endomysial antibodies and IgA tissue transglutaminase antibodies.35 Both of these tests have over 90% sensitivity; therefore, a test for either marker is considered to be the best means of screening for celiac disease.20 Antiendomysial antibody testing is operator dependent, rather time consuming, and more expensive than the test for IgA tissue transglutaminase antibodies, which is operator independent.2 A rapid test for anti–tissue transglutaminase antibodies that only requires a sample of fingertip blood may be a convenient point-of-care test to aid with diagnosis and dietary monitoring.20 Testing for gliadin antibodies is no longer utilized because of its low sensitivity and specificity for celiac disease.31,35 Although serology is a good method to identify patients who will benefit from endoscopy and biopsy, negative serology should not preclude a biopsy examination in individuals for whom disease is suspected on clinical grounds.3,4
Genetic testing can be performed as a means of confirming the diagnosis of celiac disease or to determine which family members of a diagnosed patient may develop the disease (the prevalence of celiac disease has been reported to be 10% to 12% in first-degree relatives and is also higher than that found in the general population in second-degree relatives).24 Patients and their family members can be tested for HLA-DQ2 and HLA-DQ8 as the HLA-DQ2 is found in up to 95% of celiac disease patients, with most other patients being HLA-DQ8 positive.2,31 Although nearly all celiac disease patients carry one of these alleles, they are also found on 30% to 40% of the general population. Therefore when these alleles are absent it is extremely unlikely that the individual has celiac disease (i.e., the test has a high negative predictive value [NPV]).33 A patient-administered saliva-based test for HLA-DQ2/DQ8 was released for direct sale to consumers.38 It will be interesting to observe how the availability of this test will impact upon the already rather strong interest of those patients who seek self-diagnostic methods.39
Sidebar: Clinical Controversy
The diagnosis of celiac disease in children under 2 years of age is based upon the demonstration of small-bowel enteropathy when the patient is consuming a gluten-containing diet; normalization of the mucosa while observing a gluten-free diet; and then relapse of the mucosal enteropathy during a subsequent gluten challenge. Although the gluten challenge followed by biopsy is generally not utilized in adults and children over 2 years of age, it has been recommended for children under 2 years of age because these young patients have an increased incidence of mucosal enteropathy due to other transient disorders. Researchers recently found that utilizing a gluten challenge had a very low therapeutic yield in children under 2 years of age in their study who presented with suspected celiac disease.25,26
Treatment: Celiac Disease
Overall goals of treatment include relieving symptoms, healing the intestine, and reversing the consequences of malabsorption while enabling the patient to adhere to a healthy, interesting, and practical gluten-free diet.21,40
Table 49–5 presents a mnemonic that summarizes the major principles of the treatment of celiac disease. Strict lifelong adherence to a gluten-free diet is the only proven treatment for celiac disease.4 Patients must recognize that adhering to a gluten-free diet includes not ingesting anything that contains gluten, has been contaminated with gluten, or has come in contact with gluten. Wheat, barley, and rye must be avoided.21 Although oats are in a different plant family, they have also been regarded to be problematic; however, the ingestion of certified pure gluten-free oats appears to be safe.4 Due to the continued difference of opinion regarding the safety of oats, patients are generally advised to discuss the risks and benefits associated with consuming oats with their healthcare provider before they include oats in their diet. Patients must also commit to avoiding the ingestion of gluten found in nonfood items such as toothpaste, lip balm, lipstick, etc. A list of gluten-free grains can be found in Table 49–1.
Table 49-5 Mnemonic for Celiac Disease |Favorite Table|Download (.pdf)
Table 49-5 Mnemonic for Celiac Disease
|C||Consultation with a skilled dietician|
|E||Education about the disease|
|L||Lifelong adherence to a gluten-free diet|
|I||Identifying and treating nutritional deficiencies|
|A||Access to an advocacy group|
|C||Continuous long-term follow-up by a multidisciplinary team|
Oral prescription drugs, nonprescription drugs, vitamin and mineral supplements, and health and beauty aids and cosmetics that have oral ingestion potential must not be overlooked as sources of gluten due to its presence in their formulation or due to contamination or contact.41,42 Although clinicians have concluded that as little as 30 to 50 mg/day of gluten is the minimum dose required to produce measurable damage to the small intestinal mucosa it is difficult to set a universal threshold given the individual variability among patients.24,30,37 Therefore, healthcare providers must check to determine whether prescription drugs contain gluten in their formulation or have been contaminated with or have come in contact with gluten before these drugs are provided to the patient with celiac disease. Patients should also be assisted with determining whether nonprescription drugs and health and beauty aids are safe for their use.43 Lack of reliable information may lead individuals with celiac disease to mistakenly assume that their prescription or nonprescription drugs contain gluten and therefore refuse to take newly recommended or prescribed medications, or stop taking previously prescribed and needed medications without conferring with their healthcare provider.44 Although there are published lists of gluten-free drugs, it is often difficult to obtain information about the gluten content of medications.45,46
It is extremely important that patients become thoroughly knowledgeable about celiac disease. Although there are an increasing number of articles, reference materials, and other sources of information readily available to patients and their families, patients should still be advised to obtain advice and guidance from their healthcare providers. Consultations with a knowledgeable dietician will assist the patient to understand and effectively adhere to the gluten-free diet.47
Newly diagnosed patients should be evaluated for nutritional deficiencies associated with vitamin and mineral malabsorption. This assessment should include assuring that the patient does not have deficiencies of folic acid, vitamin B12, fat-soluble vitamins, iron, and calcium.20 Iron-deficiency anemia may be the only presenting sign of disease in patients without diarrhea.48 Monitoring for potential nutritional deficiencies should also continue during subsequent follow-up visits.
Most adults with celiac disease are found to have some degree of bone loss, therefore, all patients must be screened for osteoporosis or osteopenia. A dual-energy x-ray absorptiometry (DEXA) scan is often performed to assist with this evaluation.24,40 Supplementing a calcium-rich gluten-free diet with calcium, magnesium, and vitamin D may arrest or reverse celiac decrease–related bone loss. Although their use has not been extensively studied in patients with celiac disease, bisphosphonates, selective estrogen receptor modulators, anabolic agents, and other drugs have been prescribed for patients with bone disease.21 Antiresorptive drugs have been utilized in some instances when patients do not adequately improve after at least 1 year of observing an appropriate diet and taking calcium supplements. These drugs have also been used sooner in patients with low bone mineral density and little or no intestinal malabsorptive problems. Clinicians must note that these drugs can cause serious adverse effects if they are administered before the intestine properly heals. Excessive dangerous drops in blood calcium can lead to cardiac dysrhythmias, muscle weakness, and seizures.24
Implementing a gluten-free diet presents some challenges. A dietician will be helpful, particularly when the patient is newly diagnosed. Patients are advised to initiate a complete gluten-free lifestyle immediately after diagnosis. Partial adherence to this diet is not adequate. In order to accomplish this objective, patients must be aware of what foods are gluten-free and when in doubt must know how to confirm whether a food contains gluten. Reading labels is extremely important; however, it may be difficult to identify hidden sources of gluten listed among the ingredients. Patients with celiac disease must also determine whether products were processed on equipment shared with wheat, barley, or rye. It may be necessary to call the manufacturers or check their website to obtain the needed information.29
Patients must also be advised to maintain a gluten-free kitchen. A dedicated toaster, bread maker, waffle iron, and other appliances should be obtained for use in preparing gluten-free meals. Utensils and dishes must be carefully cleaned to avoid gluten contamination. Care must also be taken when dining in restaurants and homes of family and friends. The individuals who prepare and serve the food must be knowledgeable about gluten-free foods and food preparation.24 Patients with celiac disease will often eat before leaving home and will bring gluten-free food with them when dining out.29
Sidebar: Clinical Controversy
Approximately 75% of patients with newly diagnosed celiac disease have some degree of bone loss, and up to 35% of newly diagnosed adults have established osteoporosis. Although low bone density affects both men and women with celiac disease, men often develop more severe osteoporosis.24 This high rate of osteoporosis has led some experts to recommend that all patients with celiac disease be screened for osteoporosis.20 Some clinicians have also suggested that the frequency of celiac disease in patients with osteoporosis is so high that serologic screening for celiac disease may be prudent for all patients with osteoporosis.49 These recommendations have been disputed by others who have stated that universal screening for osteoporosis in patients with celiac disease, or vice versa, is premature until evidence is available that demonstrates an increased risk of fracture and the safety, efficacy, and cost-effectiveness of screening.50–52
Dietary avoidance of gluten remains the mainstay of treatment of celiac disease. Novel pharmacologic treatment modalities are under investigation. Most reports related to pharmacotherapy for celiac disease focus on the treatment of refractory disease.
In case reports, corticosteroids, azathioprine, cyclosporine, tacrolimus, infliximab, and alemtuzumab have been reported as effective treatments for refractory celiac disease.53–56 Patients were characterized to have refractory celiac disease when they strictly adhered to the gluten-free diet and yet continued to experience malabsorption in the presence of persisting or recurrent severe inflammatory infiltration of the epithelium and lamina propria, hyperplasia of the crypts, and partial villous atrophy. Less than 5% of adult patients are found to have refractory celiac disease.57
Based on the pathophysiology of celiac disease, novel targets for the treatment of the disease have been identified. These novel approaches may be divided into two categories: decreasing the antigenic load and modulation of the immune response.
Methods of decreasing the antigenic load include blocking the activity of tissue transglutaminase, gastrointestinal destruction of proline peptides via enzyme therapy, blocking the binding of deaminated proteins to HLA-DQ2 and HLA-DQ8, detoxification of gluten peptides, and decreasing intestinal permeability in patients with celiac disease, in particular through inhibition of zonulin.58–60 Investigational tissue transglutaminase inhibitors have been developed; however, their safety is questioned due to the presence of the enzyme throughout the body and its role in many functions necessary for homeostasis.61 In the area of gluten detoxification, gluten proteins were developed in which the proline residues were replaced by azidoprolines; these azidoproline residues bound to HLA-DQ2 but did not stimulate an autoimmune response.62 A zonulin inhibitor was shown to be well tolerated and effective in a small study and is currently being studied in larger populations.61
Methods of modulating the immune response include the neutralization of inflammatory cytokines and regulation of T cells.59 All of these methods are currently investigational but may offer new hope in the future.
The frequency of diagnosis of celiac disease is increasing; however, celiac disease is still grossly underdiagnosed in the United States.63 This is particularly concerning as diagnosis and observance of a gluten-free diet lead to improvement in the patient's quality of life even in those individuals who are asymptomatic at diagnosis.63,64 The underdiagnosis observed in the United States may be attributed to a lack of awareness of the wide clinical spectrum of the disease as well as underutilization of serologic tests by healthcare providers.63
When the diagnosis of celiac disease increased, expenditures increased substantially at the time of diagnosis and for the 12-month period after diagnosis (attributed mainly to an increase in facility inpatient services). This was not a surprising finding as patients are often screened for comorbid conditions following diagnosis. A particularly important observation of this study was that, over time, mean medical expenditures decreased due to a decrease in facility inpatient and emergency room expenditures. Therefore, an increase in the frequency of diagnosis of celiac disease was associated with a reduction in direct standardized relative value–based medical costs and utilization of selected healthcare services (office visits and laboratory, diagnostic, imaging, and endoscopic procedures) over the study's 3-year follow-up period.63
Researchers reviewed the cost implications associated with diagnostic strategies, which included screening with serology for IgA anti–tissue transglutaminase alone; screening for IgA anti–tissue transglutaminase and HLA-DQ2/8 and performing endoscopy and biopsy; screening for IgA anti–tissue transglutaminase and performing endoscopy and biopsy; and screening for IgA anti–tissue transglutaminase and IgA deficiency and performing endoscopy and biopsy. They concluded that screening with serology for IgA anti–tissue transglutaminase alone was the least costly strategy and that it demonstrated a high negative predictive value (NPV = 99.8%) and a low positive predictive value (PPV = 63.4%). Performing endoscopy and biopsy to confirm the diagnosis in patients who were positive for IgA anti–tissue transglutaminase increased the PPV to 100%. Restricting the use of endoscopy and biopsy to patients who were positive for both IgA anti–tissue transglutaminase and HLA-DQ2/8 slightly reduced cost while maintaining the same PPV and NPV. Screening patients who were negative for IgA anti–tissue transglutaminase for IgA deficiency increased the NPV to 99.9%. These researchers also noted that costs must be weighed against the consequences of a false-positive diagnosis.65
More accurate diagnostic measures will assist with the management and hopeful reduction of comorbid conditions (correcting deficiencies of iron, folic acid, vitamin B12, fat-soluble vitamins; diagnosing and treating osteoporosis; etc.) and complications (a gluten-free diet may reduce the increased mortality related to risk of malignancy) that are associated with celiac disease.35 Preventing additional comorbid conditions and/or celiac disease complications will not only improve the patient's quality of life but may also avoid the costs that are associated with treating these other disorders.
Patients may have difficulty coping with the economic burden associated with maintaining a gluten-free diet.40,66,67 The relatively low availability and high cost of these foods contributes to the challenges associated with adhering to the required strict diet and may lead to varying degrees of noncompliance.66,67 Patients also find that the extra cost associated with the special diet is not reimbursed by healthcare plans, and most policies do not pay for consultations with a dietician.68 These challenges with compliance are particularly concerning as noncompliance with the gluten-free diet is associated with an increased mortality rate and compromised quality of life.66 Patients are also encouraged to investigate their personal circumstances as to whether some of the costs of maintaining a gluten-free diet are eligible for approval as a tax deduction.68
Evaluation of Therapeutic Outcomes
Clinical improvement will often be observed within days or weeks of instituting the required diet.20 Although dermatitis herpetiformis is also treated with the prescribed diet, these cutaneous lesions may not completely resolve for 1 to 2 years after initiating strict dietary measures.48
Healthcare providers must also be mindful of conditions that are related to celiac disease and that are potential complications of the disease, including certain forms of cancer, neurologic manifestations, osteoporosis, depression, diabetes, infertility, as well as other autoimmune and related illnesses. Cancers that are of particular concern include thyroid cancer, adenocarcinoma of the small intestine, lymphoma (predominantly non-Hodgkins lymphoma of any type), esophageal cancer, melanoma, and malignancies found in childhood.24 Patients with celiac disease have also been found to have an increased risk of developing certain infectious diseases that include pneumococcal or staphylococcal sepsis and tuberculosis.69 The immune system of celiac patients is not compromised as it is actually overactive. The risk of infections due to encapsulated organisms (pneumococcal pneumonia, meningococcal infections) arises from hyposplenism, which is common in active celiac disease. Therefore patients over 50 years of age are advised to receive pneumococcal vaccine.24 Annual influenza vaccine is advisable as this will reduce the incidence of secondary bacterial infections.69
Increased hazard ratios (HRs) for death were found in individuals with biopsy-verified celiac disease, inflammation, and latent celiac disease (the absolute risks were small). Individuals undergoing small-intestinal biopsy in childhood had increased HRs for death. These researchers concluded that the main causes of death in patients they studied were cardiovascular disease and malignancy.70