Celiac disease

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]

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.

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.

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. 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.

The common causes of celiac disease are autoantibodies to gluten and certain genetic factors.

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.

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.

Common risk factors in the development of celiac disease include a positive family history, HLA genes, other autoimmune diseases, infections, and certain drugs.

Screening with tissue transglutaminase (tTG) IgA test is recommended for symptomatic high risk celiac disease patients.

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.

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.

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.

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 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.

There are no ECG findings associated with celiac disease.

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.

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.

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.

There are no ultrasound abnormalities associated with celiac disease.

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.

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.

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.

Effective measures for the secondary prevention of celiac disease include avoiding gluten-containing diet and vaccination against encapsulated organisms in individuals with hyposplenism.

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

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.

Here is the historical perspective of celiac disease at a glance

Beginning of the mankind

2.5 million years ago

Hunting and eating meat, fruits, seeds, and nuts

10,000 years ago

Neolithic period

Discovery of agriculture. New antigens have been introduced to human diet (protein from cow, goat, and donkey milk, bird eggs, and various cereals). First cases of celiac disease.

Discovery

2,000 years ago

Aretaeus A Cappadocian physician

Described celiac disease, calling it koiliakos. It came from Greek word ‘koelia (abdomen), representing a “suffering abdomen”

1812

Mathew Baillie A Scottish physician

Described some adult patients experiencing malnutrition and bloating along with chronic diarrhea

1887

Samuel Gee A famous English pediatrician

Gave a detailed explanation of celiac disease, presenting a lecture on “Celiac affection”

1924

Sidney Haas A New York city pediatrician

Used a new dietetic therapeutic option for 10 children with celiac disease, the banana diet

1949

Wood An Australian gastroenterologist

Invented a simple flexible biopsy tube which could be used for GI biopsies without requiring X-ray or gastroscope assistance

1950

Wim Dicke A Dutch pediatrician

Suggested in his doctoral thesis that elimination of wheat, rye, and oats from diet would result in cure of celiac disease

1950

Wim Dicke’s colleagues, Weijers and Van de Kamer

Presented stool fat measurement as a method to diagnose celiac disease

1954

John Paulley An English pathologist from Ipswich

Discovered the pathophysiology of celiac disease, that is histological abnormalities in small intestine lining

Diagnosis

1955

Marcelo Royer An Argentinian gastroenterologist from Buenos Aires

Developed a technique for duodenal biopsy under fluoroscopic vision

1956

Margot Shiner A German-British gastroenterologist

Developed another technique for duodenal biopsy under fluoroscopic vision

1964

Berger A Switzerland immunologist

Detected and reported anti gliadin antibodies in children with celiac disease

1969

European Society of Pediatric Gastroenterology (now ESPGHAN)

Gave the diagnostic tool of “Interlaken criteria”, which was used for about 20 years

1971

Seah A British physician

Discovered an auto-antibody, the anti-reticulin; showing that antibody is not necessarily an anti-food protein

1983

Chorzelski A Polish dermatologist from Warsaw

Discovered anti-endomysium antibodies and dermatitis herpetiformis in celiac disease patients

Treatment

Recently

Main guidelines

• Agency for Healthcare Research and Quality (AHRQ, 2004)[1] • American Gastroenterological Association (AGA, 2006)[2] • North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NSPGHAN, 2005)[3] • European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN, 2012)[4] • National Institute for Health and Clinical Excellence (NICE, 2015)[5]

• At the beginning of human life on the earth, nutritional demands were met through hunting. In severe circumstances, inability to hunt for a while, encouraged the utilization of fruits, seeds, and nuts.^[6]
• 10,000 years ago the mankind learnt to cultivate and grow agriculture. Humans have utilized foods that were not been known for 2.5 million years.^[7]
• During Neolithic period, some new foods such as milk from cow, goat, and donkey, along with bird eggs, and various cereals were introduced for daily utilization of human beings.^[6]
• Amongst agricultural products, wheat showed a higher rate of growth and resistance to environmental changes. It became the main food source of human beings related to agriculture.^[8]
• There were no problems until some members of the tribe suffered from abdominal discomfort, after eating wheat based products.
• About 2,000 years ago, Aretaeus, a physician from Cappadocia, wrote a total of 8 books on medicine. In one of his books, he described a patient with celiac disease and named it ‘koiliakos‘, derived from a Greek word ‘koelia‘ (abdomen). This was represented as “if the stomach be irretentive of the food and if it pass through undigested and crude, and nothing ascends into the body, we call such persons coeliacs”.^[6]
• 17 centuries later, in 1812, Mathew Baillie, a Scottish physician, probably unaware of Aretaeus, presented his point of view about some adult patients experiencing malnutrition and bloated abdomen along with chronic diarrhea due to specific diet, “some patients have appeared to derive considerable advantage from living almost entirely upon rice.” Unfortunately, his work was not considered much.^[6]
• In October 1887, Samuel Gee, an English leading authority in pediatrics, gained the full credit of explanation of celiac disease, presenting a lecture named “celiac affection” to medical students; which was published next year. Gee mentioned that “If the patient can be cured at all, it must be by means of diet”.^[9] He also added that “the allowance of farinaceous food must be small”.^[10] He also found gluten-free diet relieved symptoms, which relapsed when gluten was introduced again.^[6]
• In 1920s, Sidney Haas, a New York city pediatrician, used a new dietetic therapeutic option for 10 children with celiac disease, the banana diet; owing to his success in treating a child with anorexia nervosa by the diet. 8 of those children were “clinically cured” and the remaining 2 died.^[11]
• In 1949, Wood, an Australian gastroenterologist, invented a simple flexible biopsy tube which could be used for GI biopsies without requiring X-ray or gastroscope.^[12]
• In 1950, Wim Dicke, a Dutch pediatrician, suggested in his doctoral thesis that elimination of wheat, rye, and oats from diet would result in reasonable cure of celiac disease. He found the pathological factor to be gluten.^[13]
• At the same time, Wim Dicke’s colleagues, Weijers and Van de Kamer, presented a way to diagnose celiac disease by using stool fat measurement.^[14]
• In 1954, John Paulley, a pathologist from Ipswich in England, discovered the histological abnormalities in small intestinal lining as the main pathophysiology of celiac disease.^[15]

• In 1955, Marcelo Royer, a gastroenterologist from Buenos Aires, developed a technique for duodenal biopsy under fluoroscopic vision. He was inspired by Wood’s instrument.^[16]
• In 1956, Margot Shiner, a German-British gastroenterologist, also developed a technique for duodenal biopsy under fluoroscopic vision. He was also inspired by Wood’s instrument.^[17]
• In the mid to late 60’s, it was understood that a jejunal biopsy, showing villus atrophy was the best way to diagnose celiac disease. Since atrophy of villi may also have some other causes, the diagnosis could not be approved until gluten was proven to be the cause of atrophy.
• In 1964, Berger, a Switzerland immunologist, detected and reported anti-gliadin antibodies in children with celiac disease.^[18]
• In 1969, European Society of Pediatric Gastroenterology (now ESPGHAN), presented “Interlaken criteria” as a diagnostic tool, which was used for about 20 years. The criteria consisted of full remission of the symptoms on using gluten-free diet, along with curing the atrophic lesions in GI lumen, and finally recurrence of the disease, once gluten was reintroduced in diet.^[6]
• In 1971, Seah, a British doctor, found that the antibody is not necessarily an anti-food protein, but it is actually an auto-antibody, the anti-reticulin.^[19]
• In 1983, Chorzelski, a dermatologist from Warsaw, discovered anti-endomysium antibodies and dermatitis herpetiformis in celiac disease.^[20]
• In 1986, the Coeliac society on United Kingdom was founded. Similar societies were also founded around the world.

• The main management guidelines are issued by Agency for Healthcare Research and Quality (AHRQ, 2004)^[1], the American Gastroenterological Association (AGA, 2006)^[2], the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NSPGHAN, 2005)^[3], the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN, 2012)^[4], and National Institute for Health and Clinical Excellence (NICE, 2015)^[5].

• There has just been one outbreak of celiac disease in Sweden. The details of this outbreak are summarized below:^[21]
  • It was established that since celiac disease has genetic, immune-mediated, and chronic features, it rarely contributes to an outbreak.
  • This outbreak was quite unique for celiac disease, suggesting evolution of causal factors or environmental influences on Swedish children.
  • It is assumed that an outbreak can be caused by introducing large amounts of gluten containing foods to the diet of children, immediately after withholding breast milk.
  • At the beginning of outbreak more girls were affected with celiac disease than boys.
  • Children that were born in summer had higher rate of celiac disease, due to high gluten containing foods during winter, when the infections are more common.

• In October 1887, Samuel Gee, an English leading authority in pediatrics, completely explained celiac disease, presenting a lecture named “celiac affection” to medical students; which was published the year later. Gee mentioned that “If the patient can be cured at all, it must be by means of diet“.^[9] He also added that “the allowance of farinaceous food must be small”.^[10] He also found that the gluten-free diet relieved symptoms, which relapsed when gluten was reintroduced.^[6]

• The following are a few famous cases of celiac disease:
  • Drew Brees: Star quarterback for the Saints
  • Justin Morneau: Twins first baseman Justin Morneau
  • Chelsea Clinton: Bill Clinton’s daughter
  • Zooey Deschanel: Star of the show “New Girl”
  • Novak Djokovic: World renowned tennis player
  • Victoria Beckham: Wife of soccer star, David Beckham
  • Jessica Simpson: Actress
  • Amy Yoder Begley: Olympic runner
  • Ryan Phillippe: MacGruber star
  • Susie Essman: Mostly known for her role on the show “Curb Your Enthusiasm”
  • Rachel Weisz: Appeared in films such as “Constantine” and “The Mummy”
  • Heidi Collins: A news anchor for CNN
  • Robin McGraw: Dr. Phil’s wife
  • Keith Olbermann: A broadcaster for Fox and ESPN
  • Cedric Benson: Cincinnati Bengals running back
  • Josh Turner: Famed country singer
  • Elisabeth Hasselbeck: Member of “The View”
  • Emmy Rossum: Known for her glamorous acting
  • Dana Vollmer: U.S. swimmer
  • James Starks: Green Bay Packers running back

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

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.

Celiac disease (CD) may be classified according to burden of symptoms into five sub groups:^{[1][2][3][4][5][6]}

• Classical CD
• Atypical CD
• Asymptomatic CD
• Latent CD
• Potential CD

Type	Characteristics
Classical	Classic CD has typical features of gastrointestinal upset (eg, chronic diarrhea) in addition to extraintestinal symptoms and signs (eg, anaemia, neuropathy, decreased bone density, increased risk of fractures)
Atypical	Atypical CD presents with minor gastrointestinal symptoms and signs and is rarely associated with anemia, dental enamel defects, osteoporosis, arthritis, increased transaminases, neurological symptoms, or infertility.
Asymptomatic	Silent CD is defined as the presence of positive CD-specific antibodies, HLA, and small-bowel biopsy findings that are compatible with CD but without sufficient symptoms and signs to warrant clinical suspicion of CD.
Latent	Latent CD is defined by the presence of compatible HLA but without enteropathy in a patient who has had a gluten-dependent enteropathy at some point in his or her life. The patient may or may not have symptoms and may or may not have CD-specific antibodies.
Potential CD	Potential CD is defined by the presence of CD-specific antibodies and compatible HLA but without histological abnormalities on duodenal biopsies. The patient may or may not have symptoms and signs and may or may not develop a gluten dependency enteropathy later.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ;Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

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.

The etiology of the celiac disease is known to be multifactorial, both in that more than one abnormal factor can lead to the disease and also more than one factor is necessary for the disease to manifest in a patient. Gluten triggers autoimmunity and results in the inflammation of the gastrointestinal mucosa.^[1][2]

• Prolamines are storage proteins with a similar amino acid composition to the gliadin fractions of wheat. Prolines have been identified in barley (hordeins) and rye (secalines), and are related closely to the properties of wheat cereal that affect people with celiac disease.
• Wheat varieties or sub-types containing gluten such as spelt and the rye/wheat hybrid triticale may also trigger the symptoms of celiac disease.
• Gluten is mainly found in wheat. Gluten consists of storage proteins that remain after starch is washed from wheat-flour dough.
• These storage proteins have different solubilities in alcohol–water solutions and are usually separated into two fractions:
  • Gliadins
  • Glutenins
• Gluten proteins are grouped into four main types (ω5-, ω1,2-, α/β-, γ-gliadins).
• Several gliadin epitopes are immunogenic and also have direct toxic effects.

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.^{[3][3][4][5][6]}

The gluten peptides can be translocated through the gastric epithelium via these mechanisms:

• Paracellular transport
• Transcytosis transport
• Retrotranscytosis transport

The gluten peptides are deaminated by the tissue transglutaminase (tTG) to glutamic acid molecules. Tissue transglutaminase is cross linked to the deaminated gluten.

The glutamic acid molecules cross-linked with tTG are presented to CD4+ T cells.

The activation of CD4+ T cell produces several proinflammatory cytokines which may trigger the secretion of tissue-damaging matrix metalloproteinases and activation of lymphocytes against the enterocytes which result in enterocyte apoptosis and villous flattening.

• Alternative causes of this tissue damage have been proposed and involve the release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This triggers the killing of enterocytes by lymphocytes in the epithelium.

Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.^[7]

• Endomysial component of antibodies (EMA) to tTG are believed to be directed towards cell surface transglutaminase.^[8]

• 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 diseases.^[9]

• Stored biopsies from suspected celiac patients have revealed that autoantibody deposits in the subclinical gastrointestinal mucosal lining of celiacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anemia or malabsorption phenomena at an increased rate compared to the normal population.^[10]

• In a large percentage of celiac patients, the anti-tTG antibodies also recognize a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation. Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.^[11][12]

• This suggests that viral proteins may take part in the initial flattening and stimulate self-reactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin mediated tTG presentation provides a second source of self-reactive antibodies.

HLA and non-HLA genes are involved in the pathogenesis of the celiac disease^[3].^[13]

• HLA genes are a part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguish between self and non-self antigens for the immune system. There are 7 HLA DQ variants (DQ2 and DQ4 through 9).
• DQ2 and DQ8 are associated with celiac disease. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage, this locus has been labeled as CELIAC1.

• 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.

• Most celiac patients bear a two-gene HLA-DQ haplotype referred to as DQ2.5 haplotype. This haplotype is composed of 2 adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α⁵ and DQ β². In most individuals, the DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents. Most celiacs inherit only one copy of the DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk of celiac disease, as well as being more susceptible to severe complications.^[15]
• Some individuals inherit DQ2.5 from one parent and portions of the haplotype (DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent, called a trans-haplotype association, and these individuals are at similar risk for the development of celiac disease as those with a single DQ2.5 bearing chromosome 6, but in this case, the disease tends to be non-familial.^[16]

• In addition to the CELIAC1 locus, CELIAC2 (5q31-q33 – IBD5 locus), CELIAC3 (2q33 -CTLA4 locus), CELIAC4 (19p13.1 – MYOIXB locus), have been linked to coeliac disease. The CTLA4 and myosin IXB and gene have been found to be linked to celiac disease and other autoimmune diseases.^[17][18] Two additional loci on chromosome 4, 4q27 (IL2 or IL21 locus) and 4q14, have been found to be linked to coeliac disease.^[19][20]

Celiac disease is associated with other autoimmune diseases which include:^{[21][22][23][24][25][3][26]}

• 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
• Dermatitis herpetiformis
• Primary sclerosing cholangitis
• Autoimmune hepatitis
• Irritable bowel syndrome
• Down’s syndrome
• Turner syndrome

On gross pathology, duodenum usually shows:^[27]

• Scalloping of duodenal folds
• Mosaic mucosal pattern
• Mucosal atrophy

The classic pathological changes of celiac disease in the small bowel are categorized by the “Marsh classification”:^[27][28]

• Marsh stage 0: normal mucosa
• Marsh stage 1: increased number of intraepithelial lymphocytes, usually exceeding 20 per 100 enterocytes
• Marsh stage 2: proliferation of the crypts of Lieberkuhn
• Marsh stage 3: partial or complete villous atrophy
• Marsh stage 4: hypoplasia of the small bowel architecture

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

The common causes of celiac disease are autoantibodies to gluten and certain genetic factors.

The common causes of celiac disease are autoantibodies to gluten and certain genetic factors.^[1][2]

Celiac disease is usually caused by:

• Autoantibodies against gluten which is found in:
  • Wheat
  • Barley
  • Rye

• Celiac disease is linked to the HLA genes usually HLA DQ2 and HLA DQ8.
  • CELIAC1 (6p21)
• Non-HLA genes are also thought to be related to celiac disease:
  • CELIAC2 (5q31-33)
  • CELIAC3 (2q33)
  • CELIAC4 (19p13·1)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

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.

Celiac disease must be differentiated from other diseases presenting as chronic diarrhea (diarrhea for more than 2 weeks) and abdominal pain and discomfort.^{[1][2][3][4][5][6][7]}

The table below summarizes the diseases that cause malabsorption, diarrhea and abdominal pain.

Abbreviations: WBC: White blood cells; Plt: Platelets, Hgb: Hemoglobin, IgE: Immunoglobulin E, IgA: Immunoglobulin A Abbreviations: WBC: White blood cells; Plt: Platelets, Hgb: Hemoglobin, IgE: Immunoglobulin E, IgA: Immunoglobulin A

Cause	Peak age of onset	History					Physical exam	Lab findings				Additional findings	Cause/Pathogenesis	Gold standard diagnosis
		Fever	Abdominal pain	Diarrhea		Weight loss
				Watery	Fatty			WBC	Hgb	Plt	Other lab findings
Celiac disease	Childhood Adult	–	+	+/-	+/-	+	Abdominal distention Tetany Mouth ulcers	–	↓	–	IgA endomysial antibody Anti-tissue transglutaminase antibody Anti-gliadin antibody	Signs of the fat-soluble vitamins A, D, E, and K deficiency Dementia Hepatosplenomegaly Ascites Dermatitis herpetiformis Must follow Gluten-free diet	HLA-DQ2 HLA-DQ8 Innate responses to wheat proteins	IgA endomysial antibody IgA tissue transglutaminase antibody
Whipple’s disease	40-60	±	+	+	+	+	Abnormal extraocular movement Lymphadenopathy Hyperpigmentation Decreased breathing sound	↓	↓	↓/↑	Hypoalbuminemia	Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Ascites Pleural effusion	Tropheryma whipplei HLA-B27	Small intestine biopsy for Tropheryma whipplei testing PCR testing
Cystic fibrosis	Childhood Adult	±	+	–	+	+	Digital clubbing Abnormal breathing sounds Cyanosis	–	↓	–	Positive DNA analysis for CFTR Evaluated nasal transepithelial potential difference (NPD)	Diabetes Recurrent upper and lower respiratory tract infections Infertility	Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein	Elevated sweat chloride ≥60 mmol/L
Crohns disease	Young adults (20th)	+	+	+	+	+	Abdominal tenderness Tachycardia Hypotension	↑	↓	↑	Iron deficiency Vitamin B12 deficiency Elevated ESR Elevated CRP	Blood seen on rectal exam	Abnormal immune response to self antigens	Colonoscopy with biopsy
Irritable bowel syndrome	30-50	–	±	±	±	–	Abdominal tenderness Flatulence Hard stool in the rectal vault	–	–	–				Diagnosis of exclusion
VIPoma	30-50	–	+	+	+	+	Tachycardia Rash Facial flushing Abdominal distention Abdominal RUQ tenderness	–	–	–	Elevated VIP level Hypokalemia Hypochlorhydria or achlorhydria Low osmotic gap (<50 mOsm/kg)	Dehydration Lethargy Muscle weakness Nausea Vomiting	Primary secretory tumor	Elevated VIP levels Followed by imaging
Zollinger-Ellison syndrome	20-50	–	+	+	+	+	Abdominal tenderness	–	↓	–	Positive secretin stimulation test Elevated serum chromogranin A	Heartburn	Gastrin producing tumor mainly in duodenum	Elevated basal or stimulated serum gastrin> 120 pg/mL
Lactose intolerance	Any age	–	+	+	–	–	Abdominal tenderness Hypotension Tachycardia Nausea and vomiting	–	–	–	Hydrogen breath test	Bloating Flatulence Symptoms begin mainly after ingestion of lactose	Reduction of lactase enzyme activity or inability to produce persistent lactase Congenital lactase deficiency	Lactase activity assay
Eosinophilic gastroenteritis	30th	–	+	+	+	+	Abdominal distention	↑	–	–	Elevated serum IgE levels Eosinophilia Elevated ESR Hypoalbuminemia	Other allergic disorders Associated with an identifiable dietary antigen	Autoimmune allergic response to food antigens	Eosinophilic infiltration of the gastrointestinal tract on biopsy
Primary bile acid malabsorption	Childhood Adult	–	+	+	+	+		–	↓	–	Low vitamins A, D, E, and K		Genetic defects in SLC10A2 (solute carrier family 10 member 2 gene)	Elevated total and specific bile acids in stool Positive SeHCAT
Abetalipoproteinemia	Infancy Adult	–	+	+	+	+	Abdominal distension Visual field defect Dysarthria	–	–	–	Low triglyceride Low total cholesterol levels  Acanthocytes Low vitamin E levels	Visual impairment Ataxia	Autosomal recessive disorder caused by mutations encoding the microsomal triglyceride transfer protein (MTP)	Clinical findings and low triglyceride and cholesterol level
Microscopic colitis	50-70	–	+	+	–	+	Abdominal tenderness	–	↓	–	Elevated autoantibodies include: RF ANA AMA ANCA	Fecal urgency Fecal incontinence Arthralgia Arthritis Uveitis	Mucosal immune responses to luminal factors in a genetically predisposed individual	Colonoscopy with mucosal biopsy with mononuclear infiltrates: Collagenous colitis is characterized by a colonic subepithelial collagen band >10 micrometers in diameter Lymphocytic colitis is characterized by ≥20 intraepithelial lymphocytes (IEL) per 100 surface epithelial cells
Hyperthyroidism	Any age	±	+	+	–	+	Lump in the neck Proptosis Tremor Increased DTR	–	–	–	Elevated T4 Elevated T3 Decreased TSH	Lid lag Sweating Hyperpigmentation	Graves’ disease Hashimoto’s thyroiditis Toxic adenoma	TSH
Grain allergy	Childhood	–	+	+	–	+	Vomiting Abdominal distension	–	–	–	Elevated IgE	Atopic dermatitis Dysphagia	Abnormal immune response to wheat antigens	Measurement of grain-specific immunoglobulin E (IgE)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Celiac disease is more prevalent than previously thought. The prevalence of celiac disease in 2017 has been 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 white race (1000 per 100,000 individuals), Hispanics (300 per 100,000 individuals) and non-Hispanic blacks (200 per 100,000 individuals). Women are more commonly affected by celiac disease than men. In Africa, Algerian refugees have the highest prevalence rate of 5600 per 100,000 individuals.

• The incidence of celiac disease is approximately 10-13 per 100,000 individuals worldwide.^[1]
• In United States the incidence of celiac disease is approximately 10 per 100,000 individuals.
• The incidence of celiac disease has been increasing over the years. This can be attributed to increasing use of serologic screening, leading to more accurate results and early diagnosis in cases of mild disease. A general trend in incidence of celiac disease over the years is as under:^[2]
  • In 1950, the incidence of celiac disease was estimated to be 1 case per 100,000 individuals worldwide.
  • In 1960-1980, the incidence of celiac disease was estimated to be 2 cases per 100,000 individuals worldwide.
  • In 1990, the incidence of celiac disease was estimated to be 3-5 cases per 100,000 individuals worldwide.
  • In 2000, the incidence of celiac disease was estimated to be 9 cases per 100,000 individuals worldwide.

• Worldwide, the prevalence of celiac disease is estimated to be 500 to 1000 per 100,000 individuals.^[3]
• In United States, the prevalence of celiac disease is approximately 710 per 100,000 individuals.^[4]
• The overall prevalence of celiac disease has been increasing in United States from 170 per 100,000 individuals in 1988 to 440 per 100,000 individuals in 2012.^[5]
• In Europe the prevalence of celiac disease is estimated to be 1000 per 100,000 individuals. The Scandinavian countries, Ireland, and the United Kingdom population tended to show a higher prevalence of celiac disease of approximately 1000 to 1500 per 100,000 individuals.^[6]
• In Australia the prevalence of celiac disease is estimated to be 400 per 100,000 individuals.^[7]
• In New Zealand the prevalence of celiac disease is estimated to be 1200 per 100,000 individuals.^[7]
• In India the prevalence of celiac disease is estimated to be 300 per 100,000 individuals.^[8]
• In North Africa, Algeria with its refugees in the Sahara desert have the highest prevalence of celiac disease at 5600 per 100,000 individuals.^[9]

• The risk for celiac disease is higher for people with diabetes, autoimmune disorder and relatives with celiac disease individuals because of shared HLA typing.^[10]

• Celiac disease affects children and adults alike.
• In children celiac disease peaks in early childhood.
• In adults celiac disease is usually diagnosed around fourth and fifth decades of life.

• Celiac disease usually affects individuals of the non-Hispanic white race (1000 per 100,000 individuals), Hispanics (300 per 100,000 individuals) and non-Hispanic blacks (200 per 100,000 individuals).
• HLA-DQ2 associated celiac disease is frequently found in white populations located in Western Europe.

• Women are more commonly affected by celiac disease than men.^[11]
• The female to male ratio is approximately 3:1.
• In contrast, patients over the age of 60 who are diagnosed with celiac disease are most commonly males.^[12]

• Tthe highest prevalence of celiac disease has been reported in Algerian refugees. These individuals have a high rate of consanguinity and high frequencies of HLA-DQ2.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]Seyedmahdi Pahlavani, M.D. [3]

Common risk factors in the development of celiac disease include a positive family history, HLA genes, other autoimmune diseases, infections, and certain drugs.

Common risk factors in the development of celiac disease may be environmental, genetic, infections and certain drugs.^[1]

• Common risk factors in the development of celiac disease include:^{[2][3][4][5][6][7][8][9][10][11][12][13][14][10][15]}
  • Family history
  • HLA DQ2 and DQ8 genes
  • Other autoimmune diseases
    • 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
    • Dermatitis herpetiformis
    • Primary sclerosing cholangitis
    • Autoimmune hepatitis
    • Irritable bowel syndrome
    • Down’s syndrome
    • Turner syndrome
  • Interferon-alpha
  • Rotavirus
  • Rod shaped bacteria^[2]

• Less common risk factors in the development of celiac disease include:^[16]
  • Non-recommended infant feeding practices:
    • Introduction of large amounts of gluten diet
    • Exclusive gluten diet
    • No breastfeeding
    • Exposure to wheat, barley, or rye before the gut barrier is fully developed (three months after birth)^[17]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Screening with tissue transglutaminase (tTG) IgA test is recommended for symptomatic high risk celiac disease patients.

• Screening in asymptomatic celiac disease patients is not recommended.^[1]
• Screening is recommended for symptomatic and high risk patients with positive family history in first and second degree relatives as well as in patients with other autoimmune diseases such as, type 1 diabetes mellitus, inflammatory luminal gastrointestinal disorders, Down syndrome, Turner syndrome, IgA deficiency, and IgA nephropathy.^[1]
• Screening method for celiac disease is tissue transglutaminase (tTG) IgA test.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

• B12 deficiency
• Iron deficiency
• Folate deficiency
• Anemia
• Hypoalbuminemia
• Osteoporosis
• Osteomalacia
• Increased risk of small bowel lymphoma

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