Celiac disease overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2], Syed Hassan A. Kazmi BSc, MD [3]
Overview
About 8,000 years ago, Aretaeus, a Greek physician from Cappadocia, wrote a total of 8 books on medicine. In one of his books, he described a patient with celiac disease and called it 'koiliakos'. It came from Greek word of 'koelia' (abdomen), explaining diarrhea as the inability to retain food and the passage of undigested material through the gastrointestinal tract. This later formed the basis of explanation of various diseases presenting as chronic malabsorptive diarrhea, including celiac disease. Celiac disease (CD) may be classified according to the symptoms and laboratory findings into 5 sub groups as, classical, atypical, asymptomatic, latent, and potential CD. The etiology of the celiac disease is known to be multifactorial, both in that multiple factors can lead to the disease and that multiple factors are necessary for the disease to manifest in a patient. Gluten triggers autoimmunity and results in the inflammation of the gastrointestinal mucosa. Gluten in wheat, rye, and barley may trigger the autoimmunity to develop celiac disease. Gluten peptides cross the epithelium into the lamina propria where they are deamidated by tissue transglutaminase. The peptides are then presented by DQ2+ or DQ8+ antigen-presenting cells to pathogenic CD4+ T cells. The CD4+ T cells trigger the T-helper-cell type 1 response which results in the infiltration of inflammatory cells into the lamina propria and epithelium. This inflammatory process ultimately leads to crypt hyperplasia and villous atrophy. Celiac disease must be differentiated from other diseases presenting as chronic diarrhea. Common differentials of celiac disease include lactose intolerance, cystic fibrosis, Crohns disease, laxative overuse, hyperthyroidism and irritable bowel syndrome. The prevalence of celiac disease in 2017 is estimated to be 500 to 1000 per 100,000 individuals worldwide. The incidence of celiac disease is approximately 10-13 per 100,000 individuals worldwide. The symptoms of celiac disease usually develop in the first decade of life, and start with symptoms suggestive of malabsorption such as abdominal pain and distension, diarrhea, malnutrition, and failure to thrive within the first few years of life. The diagnosis of celiac disease is made when at least four of the following five or three out of four (if the HLA genotype is not performed) diagnostic criteria are met: typical symptoms (chronic diarrhea, chronic abdominal pain, malabsorption, bloating, constipation, failure to thrive/weight loss, anorexia, vomiting, GERD), serum positivity for Ig A autoantibodies at high titer, HLA-DQ2 or HLA-DQ8 genotypes, celiac enteropathy at the small intestinal biopsy, and response to gluten-free diet. Laboratory findings consistent with the diagnosis of celiac disease include electrolyte abnormalities such as hypokalemia, hypocalcemia, hypomagnesemia, metabolic acidosis,hypoalbuminemia, hypoproteinemia, hypocholesterolemia and low serum carotene level. Hematologic findings include low folate and vitamin B-12 levels, low serum ironlevel and prothrombin time (PT) prolongation. Stool examination may show fat droplets on Sudan stain and a 72-hour fecal fat collection may be used for documentation of steatorrhea. Features present on CT enteroclysis consistent with the diagnosis of celiac disease may include, jejunoileal fold pattern reversal, ileal fold thickening, vascular engorgement, prominent mesenteric lymph nodes may cavitate with a fluid-fat level, submucosal fat deposition may be observed in long standing cases, and features suggestive of splenic atrophy may be present. Preferred therapy for celiac disease is dietary modification which includes gluten-free diet. Patients with celiac disease should be referred to a dietitian once the diagnosis of celiac disease is made. A minority of patients suffer from refractory disease, which means that they do not improve with a gluten-free diet. Pharmocotherapy is used if alternative causes are eliminated and dietary modification is not beneficial. Pharmacotherapy include steroids, azathioprine, cyclosporin, and monoclonal antibodies. Effective measures for the primary prevention of celiac disease include breastfeeding, delayed introduction of gluten-including diet, and preventing GI infections.
Historical Perspective
Since the advent of human life on the earth, human beings have met their nutritional demands through hunting. In times of scarce supply of food from animal sources humans used to turn to fruits, seeds, and nuts for their nutritional needs. About 8,000 years ago, Aretaeus, a Greek physician from Cappadocia, wrote a total of 8 books on medicine. In one of his books, he described a patient with celiac disease and called it 'koiliakos'. It came from Greek word of 'koelia' (abdomen), explaining diarrhea as the inability to retain food and the passage of undigested material through the gastrointestinal tract. This later formed the basis of explanation of various diseases presenting as chronic malabsorptive diarrhea, including celiac disease. In October 1887, Samuel Gee, an English pediatrician, comprehensively explained celiac disease in one of his lectures. Gee was of the opinion that if a patient affected by celiac disease can be cured at all, it must be by means of diet. He also added that the percentage of farinaceous food intake in celiac patients must be low. Gee also introduced the concept of gluten-free diet for the relief of symptoms.
Classification
Celiac disease (CD) may be classified according to the symptoms and laboratory findings into 5 sub groups as, classical, atypical, asymptomatic, latent, and potential CD.
Pathophysiology
The etiology of the celiac disease is known to be multifactorial, both in that multiple factors can lead to the disease and that multiple factors are necessary for the disease to manifest in a patient. Gluten triggers autoimmunity and results in the inflammation of the gastrointestinal mucosa. Gluten in wheat, rye, and barley may trigger the autoimmunity to develop celiac disease. Gluten peptides cross the epithelium into the lamina propria where they are deamidated by tissue transglutaminase. The peptides are then presented by DQ2+ or DQ8+ antigen-presenting cells to pathogenic CD4+ T cells. The CD4+ T cells trigger the T-helper-cell type 1 response which results in the infiltration of inflammatory cells into the lamina propria and epithelium. This inflammatory process ultimately leads to crypt hyperplasia and villous atrophy. It is suggested that the gliadin may be responsible for the primary manifestations of celiac disease whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune disease. Over 95% of celiac patients have an isoform of DQ2 (encoded by DQA1*05 and DQB1*02 genes) and DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), which is inherited in families. The reason these genes produce an increased risk of celiac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process. Celiac disease is associated with other autoimmune diseases such as type 1 diabetes mellitus, IgA deficiency, IgA nephropathy, insulin dependent diabetes mellitus (IDDM), Sjogren’s syndrome, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, Hashimoto's thyroiditis, Graves Disease, and dermatitis herpetiformis.
Causes
The common causes of celiac disease are autoantibodies to gluten and certain genetic factors.
Differentiating Celiac Disease from other Diseases
Celiac disease must be differentiated from other diseases presenting as chronic diarrhea. Common differentials of celiac disease include lactose intolerance, cystic fibrosis, Crohns disease, laxative overuse, hyperthyroidism and irritable bowel syndrome.
Epidemiology and Demographics
Celiac disease is more prevalent than previously thought. The prevalence of celiac disease in 2017 is estimated to be 500 to 1000 per 100,000 individuals worldwide. The incidence of celiac disease is approximately 10-13 per 100,000 individuals worldwide. Celiac disease affects children and adults alike. Celiac disease usually affects individuals of the non-Hispanic whites (1000 per 100,000 individuals), Hispanics (300 per 100,000 individuals) and non-Hispanic blacks (200 per 100,000 individuals). Like other autoimmune disorders, women are more commonly affected by celiac disease than men. In Africa, Algerian refugees have the highest number of prevalence rate at 5600 per 100,000 individuals.
Risk Factors
Common risk factors in the development of celiac disease include a positive family history, HLA genes, other autoimmune diseases, infections, and certain drugs.
Screening
Screening with tissue transglutaminase (tTG) IgA test is recommended for symptomatic high risk celiac disease patients.
Natural History, Complications and Prognosis
The symptoms of celiac disease usually develop in the first decade of life, and start with symptoms suggestive of malabsorption such as abdominal pain and distension, diarrhea, malnutrition, and failure to thrive within the first few years of life. The classic malabsorption manifestation of disease is just the tip of the iceberg, and other more specific manifestations are invisible below the waterline. Natural history of celiac disease variations is not completely understood but if left untreated it may result in serious complications, such as malignancy. Complications of celiac disease may include vitamin deficiencies related syndromes, essential nutrient deficiencies, enamel hypoplasias, neurological abnormalities, gastrointestinal malignancies, hyposplenism, ulcerative jejunitis, and infertility. Depending on the extent of the celiac disease at the time of diagnosis and also extent of complications and dietary deficiencies, the prognosis may vary. However, the prognosis is generally regarded as good. The presence of gastrointestinal malignancies is associated with a particularly poor prognosis among patients with celiac disease.
Diagnosis
Diagnostic Criteria
The diagnosis of celiac disease is made when at least four of the following five or three out of four (if the HLA genotype is not performed) diagnostic criteria are met: typical symptoms (chronic diarrhea, chronic abdominal pain, malabsorption, bloating, constipation, failure to thrive/weight loss, anorexia, vomiting, GERD), serum positivity for Ig A autoantibodies at high titer, HLA-DQ2 or HLA-DQ8 genotypes, celiac enteropathy at the small intestinal biopsy, and response to gluten-free diet.
History and Symptoms
Celiac disease can present with typical symptoms such as diarrhea, steatorrhea, weight loss, and growth failure or non-typical symptoms not involving the gastrointestinal tract. The classic presentation of celiac disease is more common in young children, consisting primarily of gastrointestinal symptoms. In adults, the presentation of celiac disease is often more subtle and can be mistaken for irritable bowel syndrome. Some patients lack any evident gastrointestinal symptom and instead present with nutritional deficiencies (most commonly iron deficiency) or extra-intestinal symptoms, or are asymptomatic.
Physical Examination
Patients with celiac disease usually appear tired. Common physical examination findings of celiac disease include hepatosplenomegaly, abdominal tenderness with distention and scaly rash on extensor surfaces.
Laboratory Findings
Laboratory findings consistent with the diagnosis of celiac disease include electrolyte abnormalities such as hypokalemia, hypocalcemia, hypomagnesemia, metabolic acidosis,hypoalbuminemia, hypoproteinemia, hypocholesterolemia and low serum carotene level. Hematologic findings include low folate and vitamin B-12 levels, low serum ironlevel and prothrombin time (PT) prolongation. Stool examination may show fat droplets on Sudan stain and a 72-hour fecal fat collection may be used for documentation of steatorrhea. Genetic testing is usually positive for HLA-DQ2 and HLA-DQ8. Serologic markers include IgA endomysial antibody (IgA EMA), IgA tissue transglutaminase antibody(IgA tTG), IgG tissue transglutaminase antibody (IgG tTG), IgA deamidated gliadin peptide (IgA DGP), and IgG deamidated gliadin peptide (IgG DGP). Serum IgA EMA and IgAtTG have the highest diagnostic accuracy. The IgA and IgG antigliadin antibody (AGA) are not recommended for establishing diagnosis because they have low accuracy and give more false positive results when compared with IgA tTG and IgA DGP assays.
Electrocardiogram
There are no ECG findings associated with celiac disease.
Chest X Ray
Abdominal x-ray findings that are suggestive for celiac disease include small bowel dilatation, stack of coin appearance (hidebound sign), segmentation, mucosal atrophy, and transient intussusception.
CT Scan
Features present on CT enteroclysis consistent with the diagnosis of celiac disease may include, jejunoileal fold pattern reversal, ileal fold thickening, vascular engorgement, prominent mesenteric lymph nodes may cavitate with a fluid-fat level, submucosal fat deposition may be observed in long standing cases, and features suggestive of splenic atrophy may be present.
MRI
There are no MRI findings associated with celiac disease.MRI has a great specificity among all imaging modalities for celiac disease diagnosis, but the sensitivity of MRI differs based on the finding. MRI may be normal in less than 20% of cases. The most important intestinal findings of MRI include: Bowel dilatation, increased number of ileal folds, reversed fold pattern abnormality, increased intestinal wall thickness, intussusception, mesenteric lymphadenopathy, mesenteric vascular changes, ascites.
Echocardiography or Ultrasound
There are no ultrasound abnormalities associated with celiac disease.
Other Imaging Findings
Features of small bowel barium studies are not sensitive enough for confident diagnosis, but the following changes may be seen: Small intestinal dilatation due to excess fluid, dilution of contrast, multiple non-obstructing intussusceptions, jejunoileal fold pattern reversal, moulage sign, mosaic pattern, flocculation, and segmentation.
Other Diagnostic Studies
Endoscopy may be helpful in the diagnosis of celiac disease especially when the biopsies of luminal wall are obtained for microscopic evaluation. Most patients with celiac disease have a small bowel that appears normal on endoscopy; however the following findings are more suggestive of celiac disease: Scalloping of the small bowel folds, paucity in the folds, mosaic pattern of the mucosa, prominence of the submucosal blood vessels, and Nodular pattern to the mucosa.
Treatment
Medical Therapy
Preferred therapy for celiac disease is dietary modification which includes gluten-free diet. Patients with celiac disease should be referred to a dietitian once the diagnosis of celiac disease is made. A minority of patients suffer from refractory disease, which means that they do not improve with a gluten-free diet. Pharmocotherapy is used if alternative causes are eliminated and dietary modification is not beneficial. Pharmacotherapy include steroids, azathioprine, cyclosporin, and monoclonal antibodies.
Surgery
Primary Prevention
Effective measures for the primary prevention of celiac disease include breastfeeding, delayed introduction of gluten-including diet, and preventing GI infections.
Secondary Prevention
Effective measures for the secondary prevention of celiac disease include avoiding gluten-containing diet and vaccination against encapsulated organisms in individuals with hyposplenism.
Future or Investigational Therapies
Various approaches are being studied that would reduce the need of dietary modification (gluten-free diet). Most of them are still under development and include genetically engineered wheat species, enzymes, gluten vaccination, biological agents, and inhibition of endogenous signaling protein.