Celiac disease, also known as gluten-sensitive enteropathy, is a chronic disease of the digestive tract that interferes with the digestion and absorption of food nutrients. People with celiac disease cannot tolerate gliadin, the alcohol-soluble fraction of gluten. Gluten is a protein commonly found in wheat, rye, and barley. Most patients with celiac disease tolerate oats, but they should be monitored closely. When people with celiac disease ingest gliadin, the mucosa of their intestines is damaged by an immunologically mediated inflammatory response, resulting in maldigestion and malabsorption. Patients with celiac disease can present with failure to thrive and diarrhea (the classical form). However, some patients have only subtle symptoms (atypical celiac disease) or are asymptomatic (silent celiac disease).[5]
Celiac disease has a strong hereditary component. The prevalence of the condition in first-degree relatives is approximately 10%.
A strong association exists between celiac disease and two human leukocyte antigen (HLA) haplotypes (DQ2 and DQ8).[6] Damage to the small intestinal mucosa occurs with the presentation of gluten-derived peptide gliadin, consisting of 33 amino acids, by the HLA molecules to helper T cells. Helper T cells mediate the inflammatory response. Endogenous tissue transglutaminase deamidates gliadin into a negatively charged protein, increasing its immunogenicity. Autoantibodies to type 2 transglutaminase (TG2) is a hallmark of celiac disease.[7] Absence of intestinal villi and lengthening of the intestinal crypts characterize the mucosal lesions in untreated celiac disease. More lymphocytes infiltrate the epithelium (intraepithelial lymphocytes). Destruction of the absorptive surface of the intestine leads to a maldigestion and malabsorption syndrome.[8]
Celiac disease results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors.[9, 10, 11]
The interaction of alcohol-soluble gliadin in wheat, barley, and rye with the mucosa of the small intestine is crucial to the pathogenesis of celiac disease. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in the enteric epithelial cells, stimulating the proliferation of the natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes.[12]
Gliadin (a complex mixture of proline- and glutamine-rich polypeptides obtained by alcohol extraction of wheat gluten) can produce symptoms and the histologic changes in the small intestine when administered to patients with asymptomatic celiac disease. Antigliadin antibodies can frequently be identified in untreated patients.
Immunoglobulin A (IgA) antibodies to smooth muscle endomysium and tissue transglutaminase (the most commonly used test) are used for serological diagnosis. However, 3-5% of all patients with celiac disease are IgA deficient. Therefore, determining total IgA prior to antibody testing is appropriate in patients with celiac disease.
Cell-mediated immune responses are also important for the pathogenesis of celiac disease, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium.
Genetics play an important role in celiac disease. The incidence of celiac disease in relatives of patients with celiac disease is significantly higher than in the general population. The prevalence in first-degree relatives of patients with celiac disease is approximately 10%. Concordance for the disease in monozygotic twins approaches 75% and is approximately 30% for first-degree relatives.
Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to the expression of the proinflammatory cytokine interferon gamma and the activation of CD4+ T lymphocytes.
The frequency of celiac disease in the United States is relatively low, about 1 case in 3000 persons. Estimates suggest that approximately 1% of the Western population is affected, but celiac disease is underdiagnosed in most affected people.[9, 10]
Because the historical prevalence and long-term outcome of undiagnosed celiac disease were unknown, Rubio-Tapia et al collected serologic information on three cohorts[13] : 9133 healthy young adults from whom sera were collected between 1948 and 1954, and 12,768 gender-matched subjects from two recent cohorts, one whose years of birth were similar to those of members of the first cohort, and the other whose age at sampling was similar.
The sera were first tested for tissue transglutaminase, then, if abnormal, for endomysial antibodies. During 45 years of follow-up in the older cohort, all-cause mortality was nearly 4-fold greater in persons with undiagnosed celiac disease than among those who were seronegative (hazard ratio = 3.9; 95% confidence interval, 2.0-7.5; P< 0.001).[13] Comparison of the older and more recent cohorts suggested that undiagnosed celiac disease in the United States has increased dramatically in the past half century: 0.2% of the older cohort had undiagnosed celiac disease compared with 0.8% of the cohort with similar years of birth and 0.9% of those with similar age at sampling (P ≤ 0.0001).[13]
A 2018 systematic review and meta-analysis noted that celiac disease is a global public health concern.[14] The overall prevalence of this condition is 1.4% on the basis of serologic findings and 0.7% on the basis of biopsy findings.[11, 14] However, specific national population-based prevalence studies are needed because the prevalence of celiac disease varies with factors such as sex, age, and location.[14]
Approximately 3 million people in Europe and another 3 million people in the United States are estimated to be affected by celiac disease. Celiac disease is prevalent in European countries with temperate climates. The highest prevalence of celiac disease is in Ireland and Finland and in places to which Europeans emigrated, notably North America and Australia. In these populations, celiac disease affects approximately 1 in 100 individuals. The incidence of celiac disease is increasing among certain populations in Africa (Sahrawi population), Asia (India),[15, 16] and the Middle East.
Celiac disease is most prevalent in Western Europe and the United States, with an increasing incidence in Africa and Asia. Females are affected slightly more than males.
The age distribution of patients with celiac disease is bimodal, the first at 8-12 months and the second in the third to fourth decades. The mean age at diagnosis is 8.4 years (range, 1-17 y).
Celiac disease might become apparent in infants when gluten ingestion begins. Symptoms of celiac disease might persist throughout childhood if untreated but usually diminish in adolescence. Symptoms often reappear in early adulthood, between the third and fourth decades of life.
Approximately 20% of patients with celiac disease are older than 60 years.[17]
Adolescents with celiac disease frequently present with extraintestinal manifestations, including short stature, behavioral problems, fatigue, and skin problems. The diagnosis of celiac disease is often not established until middle age or old age.
The prognosis for patients with correctly diagnosed and treated celiac disease is excellent. The prognosis for patients with celiac disease who are not responding to gluten withdrawal and corticosteroid treatment is generally poor.
Although rarely lethal, celiac disease is a significant and often debilitating maldigestion and malabsorption syndrome affecting multiple organ systems.
Patients with celiac disease are at an increased risk for complications, such as lymphomas and adenocarcinomas of the intestinal tract.
Untreated pregnant women are at risk of miscarriage and at risk of having a baby with a congenital malformation.
Short stature often results when celiac disease prevents nutrient absorption during the childhood years when nutrition is critical to growth and development.
Symptoms of celiac disease malabsorption can include one or more of the following (see History):
The risk for malignant disease is increased in patients with celiac disease. These malignancies include adenocarcinoma of the oropharynx, esophagus, pancreas, small and large bowel, and hepatobiliary tract. Other malignancies with an increased incidence in patients with celiac disease are enteropathy-associated T-cell lymphoma, which has a poor prognosis, and T- and B-cell non-Hodgkin lymphoma.
A study in Sweden reported increased cataract risk (hazard ratio = 1.28) in patients with celiac disease compared with age-matched and sex-matched controls.[18]
Refractory celiac disease occurs in approximately 5% of patients despite strict adherence to a gliadin-free diet. Refractory celiac disease is characterized by symptoms of malabsorption, weight loss, diarrhea, abdominal distention, and anemia.
Refractory celiac disease is subdivided into two types: Type 1 is characterized by a normal intraepithelial lymphocyte phenotype, and type 2 is characterized with an increased number of intraepithelial lymphocytes, possibly due to an increase in epithelial interleukin 15 expression.
The manifestations of untreated celiac disease (celiac sprue) can be divided into gastrointestinal symptoms and extraintestinal symptoms.
Diarrhea is the most common symptom in untreated celiac disease and is present in 45-85% of all patients. Diarrhea caused by celiac disease is due to the maldigestion and malabsorption of nutrients. The stools might be watery or semiformed, light tan or gray, and oily or frothy. The stools have a characteristic foul odor. In infants and young children, extensive diarrhea can lead to severe dehydration, electrolyte depletion, and metabolic acidosis.
Malabsorption of ingested fat (steatorrhea) results in the delivery of excessive dietary fat to the large bowel. This results in the production of hydroxy fatty acids by bacteria, which causes secretion of fluids into the intestinal lumen.
Flatulence (28% of patients) and borborygmus (35-72% of patients) results from the release of gas by the intestinal bacterial flora feasting on undigested and unabsorbed food materials and often becomes excessive or even explosive.
Weight loss (present in 45% of all patients) is variable because some patients might compensate for the malabsorption by increasing their dietary intake. In infants and young children with untreated celiac disease, failure to thrive and growth retardation are common.
Weakness and fatigue (prevalence 78-80%) are usually related to the general poor nutrition. In some patients, severe anemia can contribute to fatigue. Occasionally, severe hypokalemia due to the loss of potassium in the stool can cause muscle weakness.
Severe abdominal pain (prevalence 34-64%) is unusual in patients with uncomplicated celiac disease. However, abdominal bloating or cramps with excessive malodorous flatus is a common complaint.
Anemia (10-15% of patients) is usually due to the impaired absorption of iron or folate from the proximal small intestine. In severe celiac disease with ileal involvement, absorption of vitamin B-12 may also be impaired.
A bleeding diathesis is usually caused by prothrombin deficiency due to the impaired absorption of fat-soluble vitamin K.
Osteopenia and osteoporosis (prevalence 1-34%) may develop for several reasons, including defective calcium transport by the diseased small intestine, vitamin D deficiency, and binding of luminal calcium and magnesium to the unabsorbed dietary fatty acids.
Neurologic symptoms (frequency 8-14%) that result from hypocalcemia include motor weakness, paresthesia with sensory loss, and ataxia. Seizures might develop because of cerebral calcifications.[1]
Psychological symptoms include anxiety, depression, and brain fog due to cognitive impairment.[19]
Skin disorders, including dermatitis herpetiformis (a pruritic papulovesicular skin lesion involving the extensor surfaces of the extremities, trunk, buttocks, scalp, and neck), is associated in 10-20% of patients with celiac disease.
Hormonal disorders, such as amenorrhea, delayed menarche, and infertility in women and impotence and infertility in men, have been described.
Physical examination findings may reveal the following:
A review that compared seven guidelines for celiac disease (celiac sprue) in reputable organizations of various geographic areas found that the main points of dispute among them include the nonbiopsy approach, genetic human leukocyte antigen testing, and follow-up protocols.[53]
The diagnosis of celiac disease (celiac sprue) is confirmed via histopathologic evaluation of duodenal biopsy specimens.[10] Corroboration comprises evidence of small intestinal villous atrophy in the presence of celiac autoantibodies and/or an unequivocal response to a gluten-free diet.[11] Controversy exists regarding making the diagnosis without biopsy in specific cases, particularly in the pediatric population.[10]
In 2013, the American College of Gastroenterology (ACG) issued clinical guidelines regarding the diagnosis and treatment of celiac disease, including the following[2] :
The 2018 College of Family Physicians of Canada released their recommendations for managing bone health in adult and pediatric patients with celiac disease, including the following[26] :
Adults
Children and adolescents
The College of Family Physicians of Canada also noted that "the role of antiresorptive medications in reducing the risk of fractures in patients with CD also remains unclear," and that the decision regarding use of hormone replacement therapy in perimenopausal women be individualized.[26] Therefore, clinicians should follow the guidelines from major gastroenterology, endocrinology, and dietetic associations. In patients adhering to 1-2 years of a gluten-free diet with adequate calcium and vitamin D supplementation who show persistent signs of osteoporosis, consider adding specific osteoactive therapies.[26]
The European Society for the Study of Coeliac Disease (ESsCD) guidelines indicate the following individuals should be treated for celiac disease[27, 28] :
The ESsCD indicate the following for diagnostic confirmation of CD[27, 28] :
The American College of Gastroenterology (AGA) guidelines do not recommend detecting devices for food or biosamples in patients with celiac disease.[3] The ESsCD indicate video capsule endoscopy (VCE) is not used for the initial diagnosis of CD except for patients with positive celiac-specific serology who are unwilling/unable to undergo endoscopy with biopsy; VCE is important in detecting complications associated with CD.[27, 28] In addition, intestinal-permeability tests are neither sensitive nor specific and are not recommended for CD diagnosis, but serum intestinal fatty acid binding protein (I-FABP) might be useful in identifying dietary nonadherence and unintentional gluten intake.[27, 28]
More recent screening guidelines for detecting undiagnosed cases of celiac disease using questionnaire-based, case-finding strategies failed to identify the majority of pediatric cases in a Swedish population-based screening study.[30, 31] The study consisted of prediagnosis questionnaire responses about celiac disease–associated symptoms and conditions from 7054 children aged 12 years and 6294 of their parents.
Celiac disease was confirmed by small-bowel biopsy in 153 (2.1%) children from a group of 192 (2.7%) with elevated levels of tissue transglutaminase–immunoglobulin A or tissue transglutaminase–immunoglobulin G.[31] The frequency of celiac disease detected was similar among children with and those without any associated celiac disease symptoms (2.1% in both groups) or celiac disease–associated conditions (3.6% vs 2.1%, respectively).[30, 31] The sensitivity of this case-finding questionnaire was 38%, the specificity was 63%, the positive predictive value was 2%, and the negative predictive value was 98%.[31]
Patients with type 1 diabetes mellitus, Down syndrome, or Turner syndrome have an increased incidence of celiac disease. The mean prevalence ratio for coexisting type 1 diabetes and celiac disease is an estimated 8%, although this is likely an underestimation owing to subclinical or asymptomatic celiac disease.[32]
European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHN) guideline
The ESPGHN recommendations include the following in the workup and diagnosis of celiac disease (CD)[29]
Electrolyte imbalances, such as hypokalemia, hypocalcemia, hypomagnesemia, and metabolic acidosis, can develop. Evidence of malnutrition, such as hypoalbuminemia, hypoproteinemia, hypocholesterolemia, and a low serum carotene level, might be present.
Anemia due to deficiency in iron, folate, and, rarely, vitamin B-12 might be present. A low serum iron level is common. A systematic review of 18 studies comprising 2998 patients with iron-deficiency anemia found that the prevalence of biopsy-confirmed celiac disease in these patients was about 1 in 31.[33]
The prothrombin time (PT) might be prolonged and the international normalized ratio (INR) may be elevated because of malabsorption of vitamin K.
The typical bulky, greasy appearance and rancid odor of stools suggests malabsorption of fat. Findings from a Sudan stain of the stool might reveal fat droplets.
For a more quantitative measurement of fat absorption, a 72-hour fecal fat collection is frequently helpful in documenting steatorrhea.
Excretion of breath hydrogen, a product of bacterial fermentation of unabsorbed lactose, is often elevated in celiac disease.
The oral D-xylose tolerance test can reveal carbohydrate malabsorption. D-xylose is absorbed preferentially in the proximal small intestine and excreted unmetabolized in the urine. In untreated celiac disease, urinary D-xylose excretion and peak blood xylose levels are depressed.
Lactose tolerance is another oral tolerance test.
The most sensitive and specific antibodies for the confirmation of celiac disease are TTG IgA, endomysial IgA, and reticulin IgA and correlate with the degree of mucosal damage. As the incidence of selective IgA deficiency is higher among patients with celiac disease, total IgA serum concentrations should be determined. If the patient is IgA deficient, tissue transglutaminase IgG can be measured.
The presence of serum IgA antibody to endomysium in untreated celiac disease has higher sensitivity and higher specificity than antigliadin antibodies. However, serum IgA antiendomysial antibody often becomes undetectable after 6-12 months of gluten withdrawal. Persistently elevated IgA endomysial and tissue transglutaminase antibodies for 12 months usually indicate poor compliance with a gliadin-free diet.
Seronegative celiac disease has been reported in 6.4-9.1% of patients with normal IgA serum concentrations; however, these patients are either elderly or have severe disease.[34]
The American College of Gastroenterology (ACG) recommends that antibody testing, especially TTG IgA, is the best first test for suspected celiac disease, although biopsies are needed for confirmation; in children younger than 2 years, the IgA TTG test should be combined with testing for IgG-deamidated gliadin peptides.[2] The 2022 AGA recommendations note that the TTG IgA and endomysial antibody tests have lower accuracy in children younger than 2 years.[3]
The ESsCD has the following recommendations for serology[27, 28] :
A 2024 meta-analysis showed that in selected adult patients with celiac disease, a nonbiopsy approach using TTG antibody levels of at least 10-fold the normal level has moderate to high pretest probability in making the diagnosis (100% specificity, 51% sensitivity, and 83% area under the curve).[35]
Many new promising biomarkers have been studied (eg, citrulline, interleukin-2, high mobility group box 1 [HMBG1] protein, gluten immunogenic peptide [GIP], nitric oxide, regenerating islet-dervied 1 alpha [REG 1α] protein, fatty acid binding proteins); however, they still require further validation for use in clinical practice.[36]
Genetic testing with confirmatory serology may streamline the diagnosis of celiac disease. In a study that included 1494 women and 1540 men from the general Australian population, along with 356 volunteers who had biopsy-confirmed celiac disease, Anderson et al assessed the ability of HLA-DQ genotyping and serology to estimate the prevalence of celiac disease.[37, 38] Of those with biopsy-confirmed celiac disease, 91.3% had HLA-DQ2.5, 5.3% had HLA-DQ8 but not HLA-DQ2.5, and 2.0% had HLA-DQ2.2 but not HLA-DQ2.5 or HLA-DQ8; 5 patients lacked all 3, but 4 were found to have normal small bowel histology despite prolonged gluten challenge.
The prevalence of celiac disease in the general community, on the basis of the presence of 1 of these HLA-DQ types and positive tissue transglutaminase (TG)-2 serology, was approximately 1.3% in both women and men.[38] Confirmatory testing yielded positive results in 26 subjects (13 women and 13 men) with elevated TG-2 IgA levels, all of whom had HLA-DQ2.5. In addition, test results were positive in all 21 subjects (10 women and 11 men) with raised levels of TG-2 IgA, deamidated gliadin peptide (DGP) IgG, and DGP IgA, all of whom had HLA-DQ2.5.[38]
The authors developed a series of diagnostic algorithms to compare costs and resource utilization.[38] In the most cost-effective one, biopsies are reserved for patients with positive results on composite TG-2/DGP IgA/DGP IgG screening who are confirmed to be genetically susceptible to celiac disease and show abnormalities on confirmatory TG-2 IgA, DGP IgG, or DGP IgA testing. With this model, cost per case diagnosed is reduced by 38% in women and 25% in men, and gastroscopies are reduced by 38% in women and 65% in men.[38]
Avoid routine use of HLA-DQ2/DQ8 testing in the initial diagnosis of CD. Include the results of such testing with a caution that patients at risk should be serologically tested for CD without changing their diet.
Use HLA-DQ2/DQ8 testing to rule out CD in selected clinical situations, including: (a) Marsh 1-2 histology in seronegative patients; (b) evaluation of patients not tested for CD before initiation on a gluten-free diet (GFD); (c) discrepant results of celiac-specific serology and histology.
Radiographic evaluation of the small bowel after barium ingestion is helpful in making a diagnosis of untreated celiac disease. Abnormal radiographic findings can include dilatation of the small intestine, a coarsening or obliteration of the normally delicate mucosal pattern, and fragmentation or flocculation of the barium in the gut lumen. However, barium studies are no longer commonly used in celiac disease.[39]
Small bowel ultrasonography gained popularity due to its high-resolution devices and noninvasiveness. Moreover, the diagnostic criteria for celiac disease have become more familiar to clinicians. While they are not incorporated in the diagnostic guidelines, diagnostic features of small bowel ultrasonography include increased peristalsis, increased intraluminal fluids, a dilated small intestine, enlarged mesenteric lymph nodes, and a "reversed jejunal-ileal pattern" (in which the number of mucosal folds is increased in the intestinal ileal segments more than in the jejunal parts relative to the normal pattern). The role of small intestinal ultrasonography is unclear, but this imaging modality offers use as a good noninvasive follow-up tool.[39]
Upper endoscopy with at least six duodenal biopsies is considered the criterion standard to help establish a diagnosis of celiac disease. Serology and endoscopy should be considered, especially in patients presenting with classic symptoms, evidence of malabsorption, and endoscopic findings, including mucosal fold scalloping, reduced mucosal folds, and a mosaic pattern.
The ESsCD recommends the following for endoscopy and histopathology in cases of suspected celiac disease (CD)[27, 28] :
In 2022, the AGA updated the diagnostic nonbiopsy recommendations for pediatric patients at least aged 2 years. Pediatric patients aged 2 years and old who have elevated tissue transglutaminase (TTG) immunoglobulin A (IgA) (TTG IgA) levels (>10-fold the normal level) in addition to another blood sample that shows positive endomysial antibody do not need a biopsy.[3] However, if these criteria are not fulfilled, then a duodenal biopsy is mandatory for confirmation of celiac disease. TTG IgA and endomysial antibody tests have lower accuracy in children younger than 2 years.[3]
Celiac disease primarily involves the mucosa of the small intestine. The submucosa, muscularis, and serosa are usually not involved. The villi are atrophic or absent with a decreased villous-to-crypt ratio (normal ratio, 4-5:1) and crypts are hyperplastic. The cellularity of the lamina propria is increased with a proliferation of plasma cells and lymphocytes. The number of intraepithelial lymphocytes per unit length of absorptive epithelium is increased (normal intraepithelial lymphocyte to epithelial cell ratio, 1:10).
Historically, duodenal biopsies have been graded into the following five stages, according to Marsh-Oberhuber (1999); however, the last stage is now considered obsolete:
The milestone treatment of celiac disease (celiac sprue) is the removal of gluten from the diet. Unfortunately, there is a financial burden on society that is associated with this disease and rarely considered. A 2024 review noted that a gluten-free diet is only the tip of the iceberg of the costs to be considered. Other costs that burden the healthcare system include undiagnosed cases of celiac disease with atypical presentations, comorbidities in diagnosed cases, as well as the loss of productivity of the affected population, in terms of either education or work.[40]
In children and adolescents, the European Society for the Study of Coeliac Disease (ESsCD) recommends introducing a gluten-free diet (GFD) only when the CD diagnosis has been made conclusively.[27, 28] In addition, a gradual, structured transfer of medical care of an adolescent with CD to adult care is recommended. Include as the minimum written information on the base of diagnosis, follow-up, anthropometric data, comorbidities, and dietary adherence.[27, 28]
Consider consultations with a dietitian and nutritionist.
The primary management of celiac disease is dietary, but research into novel nondietary therapy is ongoing.[9, 10] Complete elimination of gluten-containing grain products (including wheat, rye, and barley) is essential to treatment.[26, 41, 42] Although the majority of patients will celiac disease respond to a gluten-free diet, persistent/recurrent symptoms affect up to 20%.[11] Moreover, complete avoidance of gluten-containing grain products is relatively difficult for patients to achieve and maintain because certain products, such as wheat flour, are virtually ubiquitous in the American diet.
To facilitate elimination of gluten from the diet, the US Food and Drug Administration (FDA) has released rules providing uniform food-label definitions of "gluten-free."[43, 44] By these rules, foods so labeled—as well as those that claim to contain "no gluten" or to be "free of gluten" or "without gluten"—must contain fewer than 20 parts of gluten per million. The European Union and Canada have implemented the same standards.[43]
After an initial period of avoidance, oats might be reintroduced into the diet of patients with celiac disease. These patients should be monitored carefully for recurrent symptoms. Careful and extensive indoctrination of the patient by the physician and the dietitian is often necessary to achieve full compliance.
The European Society for the Study of Coeliac Disease (ESsCD) recommends the following[27, 28] :
Timing of gluten introduction
Two studies have suggested that the timing of gluten exposure does not affect the likelihood of developing celiac disease in children at high risk for the condition.[45, 46, 47] The first study, which examined whether early exposure to gluten was protective against celiac disease, involved 944 children who were positive for the human leukocyte antigen (HLA) haplotype DQ2 or DQ8 and had at least one first-degree relative with celiac disease. Starting at age 16 weeks and continuing daily for 8 weeks, the infants received either 200 mg of vital wheat gluten mixed with 1.8 g lactose (the equivalent of 100 mg of immunologically active gluten) or placebo.[45, 46]
The children were followed up at age 3 years, at which time the cumulative incidence of celiac disease was 5.9% in the gluten group and 4.5% in the placebo group. It was also found that among girls, the cumulative incidence of celiac disease was higher in the gluten group than in the placebo group (8.9% vs 5.5%, respectively), although no such difference was found between boys in the two groups. Another finding was that the duration of breastfeeding (ie, whether the breastfeeding was exclusive or whether it was continued during gluten introduction) had no significant effect on the development of celiac disease.[45, 46]
The second study looked at whether delayed timing of gluten introduction was protective. More than 550 children who were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative with celiac disease were randomized to be introduced to gluten-containing food at either age 6 months or age 12 months. By age 2 years, the incidence of overt celiac disease was 12% in the early gluten group and 5% in the late group, but by age 5 years, the incidence in both groups was 16%. Celiac disease autoimmunity was also more prevalent by age 2 years in the early gluten group than in the late group (16% vs 7%, respectively), but again evened out (21% vs 20%, respectively) by age 5 years.[45, 47]
Thus, the later introduction of gluten in this study did not seem to affect the risk of celiac disease but may have delayed its onset, with the median age of diagnosis being 26 months in the early group and 34 months in the late group. Similar to the first study, the duration of breastfeeding did not appear to affect the risk of celiac disease in either group.[45, 47]
A small percentage of patients with celiac disease fail to respond to a gluten-free diet. In some patients who are refractory, corticosteroids might be helpful. In patients who fail to respond to corticosteroids, other comorbid conditions, such as lymphomas of the small intestine, have to be ruled out.
The microbiota gut composition is changed in celiac disease infants at risk of developing this condition from the early stages as compared to control subjects; this is associated with genetic and epigenetic changes as well.[48] The main imbalance is in the reduction of the Bacteroides species, and the abundance of the Firmicutes and Proteobacteria spp.
Through targeted probiotic use, many clinical trials have investigated the restoration of the balance of the microbiota composition. In addition, early stages of research into postbiotics (active or proactive components that are extracted from nonliving organisms and help the host; also known as ghost probiotics) show promise in the prevention of the inflammatory process to gliadin through improving the intestinal barrier function of the gut.[48]
The use of probiotics has also been proposed in multiple pilot randomized controlled trials on children with only a small sample size. The 2022 American Gastroenterology Association (AGA) guidelines have presented this as an important area of future research and a potential therapeutic approach. The concept behind these is the restoration of bacterial dysbiosis in patients with celiac disease and thus symptomatic improvement. However, investigators have raised concerns regarding the safety of administering probiotics over the long term, as all these trials were only short term and there was the presence of gluten in the probiotic drugs.[3]
In a study comprising 170 children (ages 8-10 years) with celiac disease, the efficacy of probiotics in stopping celiac disease-associated diarrhea was higher in the probiotics group (91%) than the control group (64%) over a 28-day period.[49]
Newly considered treatment approaches for managing celiac disease that are in preclinical and clinical trials include gluten-sequestering agents, wherein patients can eat gluten and the drug sequester specifically, rendering gluten unharmful to the patient.
In murine studies, BL-7010 is a modified polystyrene that specifically binds to gluten in the gut, showing attenuated sensitization to gluten upon ingestion.
Oral egg yolk antigliadin antibody (AGY) hinders the absorption of gliadin from the gut lumen. Another approach is the enzymatic degradation of gliadin. Other clinical trials are evaluating the reintroducion of tolerance or immune modulation to gliadin.[50]
Latiglutenase is composed of two enzymes. When orally administered with meals, latiglutenase will reduce celiac disease symptoms and mucosal damage.
Nonresponsive celiac disease is commonly encountered in clinical practice, occurring in most cases due to nonadhernce to a gluten-free diet. However, refractory celiac disease is rare; it is caused by gluten-independent autoimmunity (type I) or low grade lymphoma in the epithelium (type II).[51]
The ESsCD recommends the following for slow responders and refractory CD[27, 28] :
Monitor CD patients regularly for persistent or new symptoms, adherence to a GFD, and assessment for complications. Base monitoring of GFD adherence on a combination of history and serology. Monitoring of CD patients should include verification of the normalization of laboratory abnormalities detected during the initial investigation.[27, 28]
Dietary revision should be performed by a dietitian with special expertise in CD especially in slow-responders to exclude gluten contamination.[27, 28]
A normal anti-TG2 level at follow-up does not predict recovery of villous atrophy (VA).[27, 28]
A follow-up duodenal biopsy is recommended for monitoring in cases of lack of clinical response or relapse of symptoms despite a GFD.[27, 28]
CD patients who are known to be hyposplenic should receive the pneumococcal vaccine.[27, 28]
Measure bone density in those at high risk of osteoporosis at diagnosis, especially in those with malabsorption or those at high risk if there is a long delay in diagnosis, or there are clinical presentations suggestive of bone disease. In others, not later than age 30-35 years and then to be repeated at 5-year intervals. Use a shorter interval (2-3 years) in case of low bone density on index measurement, evidence of ongoing VA, or poor dietary adherence.[27, 28]
A brief discussion of conventional and newer markers for monitoring celiac disease in patients is outlined below.[52]
Conventional markers
Fecal gluten immunogenic peptides (GIPs) have been used to monitor adherence to gluen-free diets. These markers can be detected following voluntary or involuntary ingestion of gluten, correlating with the quantity of gluten ingestion. Levels of GIPs have no relation to patient symptoms.
Serum anti-TTG has been used to monitor patients' immune response. Typically, levels are elevated at the time of diagnosis and then the serum anti-TTG levels decrease or normalize with a gluten-free diet. The anti-TTG levels will rise with gluten challenge testing. More investigation for the use of this marker for surveilling immune response in patients with celiac disease is needed.
Newer markers
Fecal calprotectin is not a new marker, but it has not traditionally been used to monitor inflammation in individuals with celiac disease. Those with untreated celiac disease have been shown to have elevated levels of fecal calprotectin relative to control subjects, and higher levels are also seen in complicated celiac disease. More investigation to validate and promote the use of this marker for monitoring inflammation in patients with celiac disease is needed.
Serum intestinal fatty acid binding protein (I-FABP) is not typically used to monitor tissue damage in celiac disease. However, I-FABP levels are elevated at the time of diagnosis and they decrease or normalize with a gluten-free diet. Higher levels also result with gluten challenge testing. Additional investigation is needed to validate and promote the use of this marker for monitoring tissue damage in patients with celiac disease.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Corticosteroids might be indicated in patients with refractory celiac disease.
Clinical Context: Can be used in patients with refractory celiac disease. Might decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. The usual starting dose of its metabolite prednisolone is 40 mg to 60 mg daily.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.