In the 1970s, gastrointestinal (GI) endoscopic techniques were introduced. This provided the opportunity to obtain routine biopsy samples, which in turn provided improved opportunities in CD case finding and diagnosis. In the 1980s and 1990s, two human leukocyte antigen molecules (HLA-DQ2 and HLA-DQ8) typically associated with CD were identified, which led to more specific diagnosis [4]. In 1990, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) published guidelines to achieve higher diagnostic accuracy of CD. A panel of experts established that CD is an autoimmune disease associated with specific genes (DQ2 and DQ8) and identified the autoantigen in CD as the enzyme tissue transglutaminase [2,135]. In 2012, a working group within ESPGHAN established new guidelines as well as a new definition of CD based on scientific and technical developments; these evidence-based guidelines were further updated and expanded in 2020 [2,135].

The ESPGHAN guidelines define CD as "an immune-mediated systemic disorder elicited by gluten and related prolamins in genetically susceptible individuals and characterized by the presence of a variable combination of gluten-dependent clinical manifestations and CD-specific antibodies" [2,135]. CD, also known as gluten intolerance, gluten-sensitive enteropathy, nontropical sprue, and celiac sprue, is an immune-mediated response to gluten (e.g., wheat, rye, barley) in genetically predisposed individuals [5]. When an individual with CD consumes gluten, it damages the small intestines and results in difficulty absorbing nutrients from foods. As previously noted, approximately 1 in 133 individuals in the United States (or about 1%) have CD. The risk is greater (i.e., 1 in 22) in individuals with a first-degree relative with CD [10].

The ESPGHAN guidelines define CD as "an immune-mediated systemic disorder elicited by gluten and related prolamins in genetically susceptible individuals and characterized by the presence of a variable combination of gluten-dependent clinical manifestations and CD-specific antibodies" [2,135]. CD, also known as gluten intolerance, gluten-sensitive enteropathy, nontropical sprue, and celiac sprue, is an immune-mediated response to gluten (e.g., wheat, rye, barley) in genetically predisposed individuals [5]. When an individual with CD consumes gluten, it damages the small intestines and results in difficulty absorbing nutrients from foods. As previously noted, approximately 1 in 133 individuals in the United States (or about 1%) have CD. The risk is greater (i.e., 1 in 22) in individuals with a first-degree relative with CD [10].

The ESPGHAN guidelines define CD as "an immune-mediated systemic disorder elicited by gluten and related prolamins in genetically susceptible individuals and characterized by the presence of a variable combination of gluten-dependent clinical manifestations and CD-specific antibodies" [2,135]. CD, also known as gluten intolerance, gluten-sensitive enteropathy, nontropical sprue, and celiac sprue, is an immune-mediated response to gluten (e.g., wheat, rye, barley) in genetically predisposed individuals [5]. When an individual with CD consumes gluten, it damages the small intestines and results in difficulty absorbing nutrients from foods. As previously noted, approximately 1 in 133 individuals in the United States (or about 1%) have CD. The risk is greater (i.e., 1 in 22) in individuals with a first-degree relative with CD [10].

Individuals with CD often have an inherited predisposition influenced by environmental factors [15]. An estimated 5% to 22% of individuals with CD have an immediate family member (i.e., first-degree relative) who also has the disease [3]. CD affects two to three times as many women as men and is most commonly seen among relatives, especially siblings [16,17].

CD originates as a result of a combined action that involves both adaptive and innate immunity [18,21]. Four presentations are recognized (Table 1) [18,21]:

Destruction of mucosal cells instigates inflammation. Water and electrolytes are secreted, causing diarrhea. Potassium loss leads to muscle weakness. Magnesium and calcium malabsorption can cause seizures or tetany [19]. Unabsorbed fatty acids combine with calcium, and secondary hyperparathyroidism increases phosphorus excretion, resulting in bone reabsorption. Calcium is no longer available to bind oxalate in the intestine and is absorbed, producing hyperoxaluria [23]. The function of the gallbladder may be abnormal, and bile salt conjugation may be decreased [19]. Vitamin K malabsorption leads to hypoprothrombinemia. In one-third of cases, iron and folic acid malabsorption is manifested as cheilosis, anemia, and a smooth, red tongue. Vitamin B12 absorption is impaired in those with extensive ileal disease, and folate and iron deficiencies are common [19]. Failure to thrive is noted, and hypotonia is common [24]. Extraintestinal manifestations of CD include dermatitis herpetiformis, dental enamel hypoplasia, aphthous ulcers, delayed tooth eruption, and arthritis/arthralgia [18].

As noted, the single most important risk factor for CD is having a first- or second-degree relative (particularly a sibling) in whom the disease is already diagnosed. An incidence of up to 20% has been noted in this population. The risk is greater in families in whom two siblings are affected, especially if one is a man who carries HLA-DQ2 [25]. The presence of another autoimmune disorder (e.g., thyroid disease, type 1 diabetes) may also increase the risk of developing CD [3]. Women appear to be at greater risk than men [26]. Other environmental factors include a high number of gastrointestinal infections before 6 months of age and frequent rotavirus infections in children younger than 4 years of age [27].

Adults with CD commonly present with weight loss, diarrhea, lassitude, and anemia. Very young children (9 to 24 months of age) often present with failure to thrive, vomiting, chronic diarrhea, muscle wasting, anorexia, abdominal distension, and irritability. Symptoms may begin at various times after the introduction of gluten-containing foods. Older children present with nausea, recurrent abdominal pain, bloating, constipation, and intermittent diarrhea [18]. Other symptoms in both children and adults may include itchy skin rash, headache, depression, and bone and/or joint pain [3,36]. Symptoms may vary widely from patient to patient; some patients are asymptomatic or minimally symptomatic, especially older children and adults [18]. Many symptoms of CD mimic those of other diseases, leading to a high rate of misdiagnosis [37]. Dermatitis herpetiformis may be an extraintestinal manifestation of gluten-sensitive enteropathy, manifesting as a pruritic, blistering rash [36]. The reversible nature of CD makes prompt diagnosis important [38].

Three antibodies commonly appear in patients with CD: antibodies to tissue transglutaminase (tTG), antiendomysial antibodies, and antigliadin antibodies. The American Gastroenterological Association and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommend using serologic markers to screen patients with either nonspecific symptoms of CD or medical conditions that increase the risk of CD; small intestinal biopsy should be performed to confirm the diagnosis [38]. The ESPGHAN recommends foregoing the confirmatory duodenal biopsy in selected cases of children and adolescents to reduce the burden on patients and their families [2,135].

Esophagogastroduodenoscopy (EGD) with duodenal biopsy is considered the criterion standard to confirm the diagnosis of CD. During EGD, a small flexible endoscope is introduced through the mouth or nose and advanced through the pharynx, esophagus, stomach, and duodenum. Most endoscopes use a video chip, which provides the best imaging. Moderate sedation and topical anesthesia are used in the United States to ensure patient comfort and cooperation. Benzodiazepines (e.g., midazolam, diazepam) and opioids (e.g., meperidine, fentanyl) are the most commonly used sedative agents. EGD is contraindicated in patients who are medically unstable or unwilling. Possible complications (occurring in 1 in 1,000 procedures) include bleeding, infection, perforation, and cardiopulmonary problems caused by the sedation agent [41,42]. Diagnostic criteria include abnormal small intestinal mucosa, usually accompanied by increased intraepithelial lymphocytosis, followed by objective clinical response and unequivocal improvement in villous architecture on a gluten-free diet [36,43]. Experts recommend that six biopsy samples be obtained from the distal and proximal areas of the small intestine to protect against missed diagnoses [96]. In the past, repeat biopsy was the standard of care, but this is now often avoided [36].

Esophagogastroduodenoscopy (EGD) with duodenal biopsy is considered the criterion standard to confirm the diagnosis of CD. During EGD, a small flexible endoscope is introduced through the mouth or nose and advanced through the pharynx, esophagus, stomach, and duodenum. Most endoscopes use a video chip, which provides the best imaging. Moderate sedation and topical anesthesia are used in the United States to ensure patient comfort and cooperation. Benzodiazepines (e.g., midazolam, diazepam) and opioids (e.g., meperidine, fentanyl) are the most commonly used sedative agents. EGD is contraindicated in patients who are medically unstable or unwilling. Possible complications (occurring in 1 in 1,000 procedures) include bleeding, infection, perforation, and cardiopulmonary problems caused by the sedation agent [41,42]. Diagnostic criteria include abnormal small intestinal mucosa, usually accompanied by increased intraepithelial lymphocytosis, followed by objective clinical response and unequivocal improvement in villous architecture on a gluten-free diet [36,43]. Experts recommend that six biopsy samples be obtained from the distal and proximal areas of the small intestine to protect against missed diagnoses [96]. In the past, repeat biopsy was the standard of care, but this is now often avoided [36].

The histologic lesions characteristic of CD may be missed in some cases, even with multiple duodenal biopsies [44,45]. Also, some patients with clinical presentation highly suggestive of CD may have a normal EGD and nondiagnostic biopsy [41]. These patients may benefit from video capsule endoscopy (VCE). VCE, also referred to as physiologic endoscopy, is a noninvasive procedure that provides high-resolution magnified views of the small intestinal mucosa, with a reported sensitivity of 76% to 99% and specificity of 56% to 100% [46]. It is mainly used to evaluate patients with CD in whom the disease course after diagnosis has been unfavorable and a diagnosis of adenocarcinoma, lymphoma, or refractory CD is suspected [36,43,96]. Other indications for the use of VCE include iron-deficiency anemia, chronic diarrhea, and abdominal pain due to suspected Crohn disease [43]. No well-designed trial has tested for noninferiority or equivalence between VCE and EGD with biopsy [43].

Two theories have been proposed to explain the association between CD and other autoimmune disorders [49]. The first suggests that untreated CD leads to the onset of another disorder in genetically susceptible individuals. This theory is supported by the prevalence of autoimmune disorders in patients with CD in relation to the duration of gluten exposure and by an increased prevalence of comorbid autoimmune disorders in first-degree relatives of individuals with CD [50,51,52]. The second theory suggests that the association is secondary to a more frequent than expected, simultaneous occurrence of genes that predispose individuals for both the autoimmune disorder and CD [49]. Authors of one study screened for the presence of autoimmune disorders in 605 healthy controls and 422 patients with CD. Both groups included individuals 16 to 84 years of age who had been on a gluten-free diet for at least one year. A three-fold higher prevalence of autoimmunity was found in patients with CD as compared to the controls [53]. The autoimmune disorders associated with CD were both organ-specific (e.g., type 1 diabetes, thyroid disease) and nonorgan-specific (e.g., rheumatoid arthritis) [49].

The close association between CD and type 1 diabetes may be due to the same HLA pattern, specifically HLA-DQ2 and/or HLA-DQ8, which predisposes individuals to both disorders. Consumption of gluten may also be a causative factor, and undiagnosed CD may favor the onset of type 1 diabetes [54]. Because symptoms (e.g., bloating, diarrhea) of the two disorders are similar, diagnosis of CD may be missed unless screening is performed [18].

Dermatitis herpetiformis is a severe, itchy, blistering skin manifestation of CD. It occurs in approximately 10% of people with CD, affecting men more frequently than women and generally presenting in adults 20 to 55 years of age [63]. It may occur in children, although this is uncommon. Approximately 80% of individuals with dermatitis herpetiformis have some degree of villous atrophy, and approximately 20% have intestinal symptoms of CD. A small percentage of patients with CD will develop dermatitis herpetiformis despite adherence to a gluten-free diet [3,131].

The disease-causing mechanism of liver damage in patients with CD is poorly understood, and the spectrum of liver abnormalities associated with CD is wide [87]. The most frequent occurrence, present in approximately 50% of patients with untreated CD, expresses as mild liver impairment (i.e., celiac hepatitis), which reverts to normal after a few months of gluten withdrawal [87,88]. More severe liver injury (chronic hepatitis or liver cirrhosis) presents in only a few cases of patients with CD and may improve after gluten withdrawal. Autoimmune liver dysfunction is rare and usually does not improve after gluten withdrawal [87].

Medical nutrition therapy provided by a registered dietitian as part of a team-based approach is strongly recommended for the individual with CD [96]. The dietitian can assess the individual's food- and nutrition-related history (e.g., intake, medication/supplement use, patient knowledge/willingness to change behaviors) to effectively determine nutritional needs and appropriate dietary interventions [98]. The dietitian can also help monitor the patient's compliance with the diet and can identify dietary nutrient deficiencies, inadequate fiber intake, and excess weight gain, each of which may be associated with adherence to the gluten-free diet [96]. Research on individuals with CD reports that long-term compliance with a gluten-free diet improves outcomes related to bone density, iron-deficiency anemia, villous atrophy, GI and neurologic symptoms, pregnancy outcomes, and quality of life [98].

Adherence to a gluten-free dietary pattern involves all foods containing or derived from wheat, barley, and rye (Table 2). This may result in a diet that is low in carbohydrates, iron, folate, niacin, zinc, and fiber. Individuals with CD often suffer from malabsorption and can develop vitamin and mineral deficiencies despite adequate intake. Age-specific gluten-free vitamin and mineral supplements are an important addition to the diets of persons with CD [98]. Iron supplements are recommended for iron-deficiency anemia, and folic acid and vitamin B12 should be taken to avoid anemia due to folate or B12 deficiencies. Vitamin K is necessary for individuals with abnormal PT times. Calcium and vitamin D supplements should be encouraged for individuals with low blood calcium levels or osteoporosis.

The treatment of CD also includes the management of complications. Dapsone can be used to treat dermatitis herpetiformis until the gluten-free diet has had effect; the drug typically relieves symptoms within one to three days [37,99]. Because of the potential for dapsone to cause hemolysis in some individuals, a baseline blood count and periodic follow-up testing are recommended [99]. The use of bisphosphonates for osteoporosis may be appropriate, although their use for osteoporosis related to CD has not been studied extensively [34].

Refractory CD is a malabsorption syndrome defined by villous atrophy and usually an increase of intraepithelial lymphocytes in the small bowel despite strict adherence to a gluten-free diet [103]. The real prevalence of refractory CD is unknown but likely rare; however, it may be the cause of underlying persistent or recurrent symptoms in 10% to 18% of patients treated for CD. It affects two to three times more women than men [104]. Common symptoms include persistent diarrhea, abdominal pain, and involuntary weight loss. Vitamin deficiencies, anemia, fatigue, and malaise are also frequent. Refractory CD is most often diagnosed following development of new symptoms or recurrence of diarrhea after initial clinical response to a gluten-free diet for years.

Refractory CD can be subdivided into types I and II, with phenotypically normal and aberrant intraepithelial T lymphocytes in the small intestinal mucosa, respectively [105,106]. Type II can be complicated by ulcerative jejunitis or enteropathy-associated lymphoma. The five-year survival rates are 80% to 96% for type I and 44% to 58% for type II, which carries a higher risk of developing lymphoma [106].

Aggressive nutritional support is an important component of the treatment of refractory CD. Total parenteral nutrition is frequently necessary [103,107,108]. Correction of trace element deficiencies (e.g., zinc, copper) should also be included. Strict adherence to a gluten-free diet is widely recommended [107,108,109]. Depending on the severity of refractory CD, alternative therapies may include prednisone, budesonide, or a combination of prednisone and azathioprine to induce clinical remission and recovery of mucosa [106,107,109,110,111,112,113]. Type II refractory CD is usually resistant to any known therapy. Alternative therapies being investigated include cladribine, autologous stem cell transplantation, and interleukin-15-blocking antibodies [106,114].

Healthcare practitioners who treat the individual with CD should be knowledgeable about the importance of a gluten-free diet and should understand the factors (e.g., cost concerns, social stress, feelings of isolation) that contribute to patient noncompliance [121]. Individuals with CD require ongoing education and support that address the physical and psychologic concerns associated with the disease [122]. Sources of gluten may be difficult to detect. Dining at a restaurant or friend's home, attending social gatherings at which food is served, and routine grocery shopping can be stressful events if the individual is not equipped with appropriate management strategies. Patient education should include information about how to create and maintain a gluten-free lifestyle for both adults and children with CD (Table 4).

Healthcare practitioners who treat the individual with CD should be knowledgeable about the importance of a gluten-free diet and should understand the factors (e.g., cost concerns, social stress, feelings of isolation) that contribute to patient noncompliance [121]. Individuals with CD require ongoing education and support that address the physical and psychologic concerns associated with the disease [122]. Sources of gluten may be difficult to detect. Dining at a restaurant or friend's home, attending social gatherings at which food is served, and routine grocery shopping can be stressful events if the individual is not equipped with appropriate management strategies. Patient education should include information about how to create and maintain a gluten-free lifestyle for both adults and children with CD (Table 4).