Condition

Celiac Disease in Adults

Editors: Joseph A. Murray MD; Dawn Ebach MD; Amir Qaseem MD, PhD, MHA, MRCP (London), FACP; Katharine DeGeorge MD, MS

American College of PhysiciansProduced in collaboration with American College of Physicians
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Background Information

Description

  • Celiac disease is a chronic, multiorgan autoimmune disease that develops in genetically predisposed individuals of any age who, in response to unknown factors, develop an inappropriate immune response to dietary gluten (a storage protein found in wheat, rye, barley, spelt, and kamut) exposure.
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  • Inappropriate immune responses to ingested gluten cause inflammation-mediated injury primarily to the small intestinal mucosa, followed over time by malabsorption. However, clinical manifestations may occur with gastrointestinal symptoms, extraintestinal signs and symptoms, or both.
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  • See also Extraintestinal Manifestations of Celiac Disease and Celiac Disease in Children.

Also Called

  • Coeliac disease
  • Celiac sprue
  • Gluten sensitive enteropathy (GSE)
  • Nontropical sprue

Types

  • Clinical symptom types of celiac disease can be categorized as gastrointestinal or extraintestinal and can occur individually or in combination.
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  • Symptomatic celiac disease may comprise typical (classic) and atypical (nonclassic) types.
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    • Typical celiac disease presentation includes gastrointestinal symptoms (such as diarrhea, abdominal pain, bloating, nausea, and vomiting) and loss of appetite, often accompanied by malabsorption, weight loss, or other signs of nutrient or vitamin deficiency.
    • Atypical celiac disease presentation includes minimal gastrointestinal complaints, and may manifest as constipation, iron-deficiency anemia, osteoporosis, dental enamel defects, arthritis, transaminitis, neurologic symptoms, psychiatric disorder symptoms, infertility, and several associated autoimmune diseases.
  • Other descriptive types of celiac disease may include:
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    • Asymptomatic: symptoms may be limited to signs as subtle as chronic fatigue
    • Subclinical: characterized by symptoms and signs below clinical identification thresholds and often recognizable only after introduction of a gluten-free diet
    • Potential: characterized by positive serologic and genetic markers with normal intestinal mucosa and minimal signs of inflammation, such as increases in intraepithelial lymphocytes; patients can manifest with typical and atypical symptoms or be asymptomatic
    • Seronegative: characterized by lack of demonstrable serologic markers along with clinical signs of severe malabsorption and atrophy of intestinal mucosa consistent with celiac disease, with presence of human leukocyte antigen (HLA)-DQ2 or -DQ8 haplotypes
    • Nonresponsive or refractory celiac disease: characterized by persistent symptoms and atrophy of the intestinal villi after ≥ 12 months of a strict gluten-free diet; can lead to complications such as ulcerative jejunoileitis, collagenous sprue, and intestinal lymphoma

Epidemiology

Incidence/Prevalence

  • Celiac disease occurs at any age from early childhood to older ages and adulthood, with 2 peaks of onset.
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    • In early childhood, celiac disease can present shortly after weaning and within the first 2 years of life. Malabsorption with diarrhea, failure to thrive, poor appetite, and abdominal distention after introduction of gluten to the diet are commonly detected. This is often referred to as "classic celiac disease".
    • In the second or third decades of life, irritable bowel syndrome (IBS)-like symptoms with constipation or alternating bowel and/or dyspepsia-like symptoms, such as nausea and vomiting are commonly detected.
  • > 70% of patients at diagnosis are reported to be > 20 years old.
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  • Celiac disease is reported to be more common in female persons than male persons (female-to-male ratio reported range from 1.5:1 to 3:1).
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  • A prevalence of 0.5%-1% is reported in the worldwide general population, except for areas with a low frequency of predisposing genes and low gluten consumption, such as sub-Saharan Africa and Japan.
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  • STUDY SUMMARY
    pooled global prevalence of celiac disease 1.4% based on serologic tests and 0.7% based on biopsy results
    SYSTEMATIC REVIEW: Clin Gastroenterol Hepatol 2018 Jun;16(6):823

  • STUDY SUMMARY
    nearly 1% of Western population estimated to have celiac disease
    SYSTEMATIC REVIEW: Gastroenterology 2005 Apr;128(4 Suppl 1):S57

  • In the United States, an annual incidence of 6.5 per 100,000 population was reported in 2008 (Am J Gastroenterol 2012 Aug;107(8):1248).
    • STUDY SUMMARY
      prevalence of celiac disease in the United States 0.6%-0.8% in 2009-2014
      CROSS-SECTIONAL STUDY: JAMA Intern Med 2016 Nov 1;176(11):1716

  • Incidence and prevalence of celiac disease in the United Kingdom and Europe:
    • STUDY SUMMARY
      incidence of celiac disease increased from 13.1 per 100,000 person-years in 2000-2002 to 29.6 per 100,000 person-years in 2017-2019 in the United Kingdom, with overall incidence higher in female persons
      COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

    • STUDY SUMMARY
      1% prevalence of celiac disease in populations within Europe
      COHORT STUDY: Ann Med 2010 Dec;42(8):587

  • Prevalence in at risk populations:
    • STUDY SUMMARY
      prevalence of celiac disease 7.5% in first-degree relatives of patients with celiac disease
      SYSTEMATIC REVIEW: Am J Gastroenterol 2015 Nov;110(11):1539

    • STUDY SUMMARY
      4.5% prevalence of celiac disease among first-degree relatives of celiac disease patients in the United States
      COHORT STUDY: Arch Intern Med 2003 Feb 10;163(3):286

    • STUDY SUMMARY
      2.25% prevalence of celiac disease among at-risk patients in primary care in the United States and Canada
      CROSS-SECTIONAL STUDY: Am J Gastroenterol 2007 Jul;102(7):1454

Risk Factors

Genetic Risk Factors
  • Genes associated with an increased risk of celiac disease include human leukocyte antigen (HLA) and non-HLA genes.
    • HLA class 2 gene loci haplotypes, encoding antigen-binding DQ alpha/beta heterodimer proteins are strongly associated with a genetic risk for celiac disease.
      • DQ2 (about 90% of patients with celiac disease carry the HLA-DQ2 genotype) is composed of protein encoded by HLA-DQA1 gene allele HLA-DQA1:0501 or HLA-DQA1:0505 bound to protein encoded by HLA-DQB1 gene allele HLA-DQB1:0201 or HLA-DQB1:0202.
      • DQ8 (about 5%-7% of patients with celiac disease carry the HLA-DQ8 genotype) is composed of protein encoded by HLA-DQA1 gene allele HLA-DQA1:0301 or HLA-DQA1:0302 bound to protein encoded by HLA-DQB1 gene allele HLA-DQB1:0302.
      • < 1% of patients have alternative genetic type often incorporating half of the gene pair encoding DQ2, called DQ2.2.
      • HLA-associated molecules contribute at least 40% of heritable risk for celiac disease.
      • PubMed30711202Gastroenterology clinics of North AmericaGastroenterol Clin North Am201903014811-181Reference - Gastroenterol Clin North Am 2019 Mar;48(1):1
    • Other non-HLA gene loci, which are very weakly associated with a genetic risk for celiac disease include:
      • Lymphocyte SH2B adapter protein 3 gene SH2B3, which expresses a protective factor against bacterial infection
      • Long noncoding lnc13 RNA gene, which is involved in regulating expression of other genes involved in adaptive and innate immunity
      • Genes related to mucosal integrity, epithelial function, or metabolism
      • PubMed30711202Gastroenterology clinics of North AmericaGastroenterol Clin North Am201903014811-181Reference - Gastroenterol Clin North Am 2019 Mar;48(1):1
    • HLA-DQ2/8 alone is reported to confer 35%-40% of the genetic risk for celiac disease.
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    • Overall a 2%-5% penetrance of celiac disease is reported in individuals with HLA-DQ2 and/or HLA-DQ8 haplotypes. This indicates other genetic and environmental elements play a role in disease development.
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    • PubMed31274511The American journal of gastroenterologyAm J Gastroenterol20191001114101587-15921587 Review on celiac disease HLA genetics can be found in Am J Gastroenterol 2019 Oct;114(10):1587.
  • A history of certain genetic diseases such as Down syndrome, Williams syndrome, and Turnery syndrome each may increase the risk of celiac disease (
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    , Eur J Endocrinol 2009 Apr;160(4):675).
Family History
  • A family history of celiac disease, specifically in first-degree relatives, may be associated with an increased risk of celiac disease.
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    • Familial recurrence has been reported in 10%-15% of relatives.
    • Up to 20% of first-degree relatives of an individual with celiac disease may be affected.
    • A concordance rate of 75%-80% has been reported among monozygotic twins.
    • STUDY SUMMARY
      maternal celiac disease and diabetes type 1 before pregnancy associated with increased risk of celiac disease in offspring
      COHORT STUDY: Clin Gastroenterol Hepatol 2015 May;13(5):921

Lifestyle/Behavioral
  • Dietary intake consistent with a Western-style diet, including the consumption of calorie-dense foods, foods high in saturated fats, simple carbohydrates, and animal protein, may be associated with a risk of celiac disease (Front Nutr 2022;9:1054089).
  • The association between a Western-style diet and celiac disease is not well understood but may be due to microbiota changes, mucosal inflammation, and increased intestinal permeability (Front Nutr 2022;9:1054089).
  • For details on early-life dietary factors and risk of celiac disease in children, see Risk Factors in Celiac Disease in Children.

Associated Conditions

Dermatologic Conditions
  • Associated skin and mucosal diseases of celiac disease in adults include:
  • STUDY SUMMARY
    celiac disease associated with increased vitiligo and psoriasis in persons in the United Kingdom
    COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

Immunologic Conditions
  • Immunologic conditions associated with celiac disease in adults include:
    • Selective IgA deficiency
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    • Atopy
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    • Common variable immunodeficiency:
      • 4 (20%) of 20 patients with common variable immunodeficiency presenting with clinical manifestations of celiac disease were carriers of HLA DQ2.5 or DQ8 genotype in case series (J Clin Immunol 2013 Jul;33(5):909).
      • 3 (27%) of 11 patients with common variable immunodeficiency had celiac disease proven by a histologic response to gluten free diet, but serologic antibodies provided equivocal diagnosis of celiac disease in case series (Am J Clin Pathol 2012 Aug;138(2):185).
      • 24-year-old female adult with common variable immunodeficiency presenting with transaminitis, chronic diarrhea, and hematemesis attributed to portal hypertension due to liver cirrhosis confirmed via liver biopsy, PubMed29030367BMJ case reportsBMJ Case Rep201710132017was diagnosed with celiac disease by small bowel biopsy and positive serology in case report (BMJ Case Rep 2017 Oct 13;2017:doi:10.1136/bcr-2017-221657).
Musculoskeletal Conditions
  • Musculoskeletal conditions that may be associated with celiac disease in adults include polymyositis and myasthenia gravis.
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  • STUDY SUMMARY
    celiac disease associated with increased myasthenia gravis in persons in the United Kingdom
    COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

Pulmonary Interstitial Diseases
  • Pulmonary interstitial diseases that may be associated with celiac disease in adults include:
    • PubMed30528262European journal of internal medicineEur J Intern Med201903016115-2415Chronic fibrosing alveolitis (Eur J Intern Med 2019 Mar;61:15)
    • IPubMed30528262European journal of internal medicineEur J Intern Med201903016115-2415diopathic pulmonary hemosiderosis (Eur J Intern Med 2019 Mar;61:15)
    • Sarcoidosis (Eur J Intern Med 2019 Mar;61:15)
Rheumatologic Conditions
  • Certain rheumatologic diseases that may be associated with celiac disease in adults include:
  • STUDY SUMMARY
    celiac disease associated with increased Sjogren syndrome, systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and ankylosing spondylitis in persons in the United Kingdom
    COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

Gastrointestinal Conditions
  • Gastrointestinal conditions that may be associated with celiac disease in adults include:
    • Autoimmune atrophic gastritis
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    • Lymphocytic gastritis
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    • Eosinophilic esophagitis
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    • Inflammatory bowel diseases such as ulcerative colitis and Crohn disease (Eur J Intern Med 2019 Mar;61:15)
    • Irritable bowel syndrome
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  • The association between celiac disease and eosinophilic esophagitis in adults remains uncertain, with conflicting evidence reported:
    • STUDY SUMMARY
      celiac disease may be associated with eosinophilic esophagitis in adults
      CROSS-SECTIONAL STUDY: Clin Gastroenterol Hepatol 2015 Aug;13(8):1426

    • PubMed23672638Scandinavian journal of gastroenterologyScand J Gastroenterol20130701487808-14808Eosinophilic esophagitis and gastroesophageal reflux disease were not associated with celiac disease in adults in cohort study of 1,000 randomly selected persons from the general population (Scand J Gastroenterol 2013 Jul;48(7):808).
  • Evidence for an association between inflammatory bowel disease and celiac disease:
    • STUDY SUMMARY
      celiac disease associated with increased risk for development of inflammatory bowel disease
      COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

    • STUDY SUMMARY
      celiac disease associated with microscopic colitis (lymphocytic colitis and collagenous colitis)
      COHORT STUDY: World J Gastroenterol 2009 Jul 7;15(25):3122

  • Evidence for an association between irritable bowel syndrome (IBS) and celiac disease:

      Evidence Synopsis

      There is conflicting data from observational studies for association between celiac disease in adults and IBS. However, a systematic review of data from observational studies reported data for an association may be limited by changing definitions for IBS and varying diagnostic approaches to celiac disease over time. In addition, the small number of cases of confirmed celiac disease reported in a separate observational study may be insufficient to rule out an association.
      • STUDY SUMMARY
        celiac disease may be more common in adults with irritable bowel syndrome than healthy controls
        SYSTEMATIC REVIEW: Am J Gastroenterol 2017 Jan;112(1):65

      • STUDY SUMMARY
        no significant difference in prevalence of celiac disease between adults with irritable bowel syndrome (IBS) and adults without IBS
        CASE-CONTROL STUDY: Eur J Gastroenterol Hepatol 2018 Feb;30(2):149

      • STUDY SUMMARY
        celiac disease associated with prior diagnosis of irritable bowel syndrome
        CASE-CONTROL STUDY: Scand J Gastroenterol 2013 Jul;48(7):801

  • Other gastrointestinal conditions possibly associated with celiac disease include pernicious anemia or esophagitis.
    • STUDY SUMMARY
      celiac disease associated with increased pernicious anemia in persons in the United Kingdom
      COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

    • STUDY SUMMARY
      celiac disease associated with esophagitis
      COHORT STUDY: Gut 2003 Apr;52(4):514

Endocrine Conditions
  • Diabetes mellitus type 1 appears to be associated with celiac disease.
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    • 8.4% prevalence of celiac disease based on antibody screening and biopsy confirmation was reported in 131 patients aged 10-37 years with type 1 diabetes (Diabetes Care 2005 Apr;28(4):806).
    • 7% prevalence of celiac disease based on antibody screening and biopsy confirmation was reported in 158 patients with type 1 diabetes with 45% of patients with confirmed celiac disease presented without gastrointestinal symptoms (Mayo Clin Proc 2005 Nov;80(11):1429).
  • Other endocrine conditions associated with celiac disease in adults include Graves disease and Addison disease.
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  • STUDY SUMMARY
    celiac disease associated with increased adrenal insufficiency, type 1 diabetes, Graves disease, and Hashimoto thyroiditis in persons in the United Kingdom
    COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

Neurological Conditions
  • Neurological diseases associated with celiac disease in adults include:
    • PubMed30528262European journal of internal medicineEur J Intern Med201903016115-2415Cerebral calcifications
    • Myoclonic seizures
    • Leukoencephalopathy
    • Multiple sclerosis
    • References -
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      , Eur J Intern Med 2019 Mar;61:15
  • STUDY SUMMARY
    celiac disease associated with increased risk of epilepsy
    COHORT STUDY: Neurology 2012 May 1;78(18):1401

Kidney Disease
  • IgA nephropathy (Bergers disease) may be associated with celiac disease in adults.
    • STUDY SUMMARY
      IgA nephropathy associated with biopsy-proven celiac disease
      COHORT STUDY: J Clin Gastroenterol 2013 Sep;47(8):678

    • STUDY SUMMARY
      3.6% prevalence of biopsy-proven celiac disease in patients with IgA nephropathy
      CROSS-SECTIONAL STUDY: Am J Gastroenterol 2002 Oct;97(10):2572

Liver Disease
Hematologic Disorders
  • Autoimmune hemolytic anemia has been reported with celiac disease.
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    • Anemia secondary to an immune response is extremely rare and is infrequently reported in celiac disease. Case report of 52-year old female diagnosed with autoimmune hemolytic anemia of an unknown etiology, who was subsequently diagnosed with celiac disease by biopsy and positive celiac serology can be found in (Am J of Gasteroenterology 2013 Oct ;108:pS285).
    • Report of 66% positive serology for celiac disease in cohort of 21 patients with idiopathic autoimmune hemolytic anemia (AIHA) can be found in (Blood 2016 128(22):4807).
Cardiovascular Disorders
  • Dilated cardiomyopathy and celiac disease:
    • PubMed29626026Clinical medicine (London, England)Clin Med (Lond)20180301182177-179177Data from observational studies for an association between dilated cardiomyopathy and celiac disease has been inconsistent, with several cohort studies reporting a moderate increased risk while fewer cohort studies report no association (Clin Med (Lond) 2018 Mar;18(2):177).
      • PubMed23130142Journal of the American Heart AssociationJ Am Heart Assoc2012060113e001594e001594Risk of idiopathic dilated cardiomyopathy, which was confirmed with patient charts and echocardiography data, was reported to be 73% greater among 29,000 patients with biopsy-verified celiac disease in large population-based Swedish cohort study (J Am Heart Assoc 2012 Jun;1(3):e001594).
      • Prevalence of celiac disease (assessed by the presence of serum anti-transglutaminase antibodies) in patients with dilated cardiomyopathies was reported to be similar to that for the Italian general population in cohort study of 350 patients with idiopathic (182 patients) and with ischemic (168 patients) dilated cardiomyopathy (Scand J Clin Lab Invest 2008;68(8):692).
    • The reported prevalence of celiac disease ranges 2.1%-5.8% in patients with idiopathic cardiomyopathy (Scand J Clin Lab Invest 2008;68(8):692).
    • The presence of cardiac-specific auto-antibodies in some patients with dilated cardiomyopathy and in their relatives has suggested an autoimmune pathogenesis, and a common autoimmune mechanism has been hypothesized to account for an association between celiac disease and idiopathic dilated cardiomyopathy (Scand J Clin Lab Invest 2008;68(8):692).
    • PubMed26976850BMJ case reportsBMJ Case Rep201603142016A 57-year-old male with dilated cardiomyopathy (severely dilated left ventricle with an ejection fraction of 15%) and new diagnosis of celiac disease had markedly improved cardiac function, with an ejection fraction reaching 70% after starting a gluten-free diet in case report (BMJ Case Rep 2016 Mar 14;2016:doi:10.1136/bcr-2015-213301).
  • Other cardiovascular conditions associated with celiac disease may include:
    • Ischemic heart disease
    • Atherosclerosis
    • Rhythm disturbances
    • PubMed28932354World journal of cardiologyWorld J Cardiol2017082698652-666652References -
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      , World J Cardiol 2017 Aug 26;9(8):652
  • STUDY SUMMARY
    celiac disease associated with increased vasculitis in persons in the United Kingdom
    COHORT STUDY: Lancet 2023 Jun 3;401(10391):1878

Psychiatric Disorders
  • PubMed31513026Journal of clinical gastroenterologyJ Clin Gastroenterol202001015418-218Anxiety, depression, and eating disorders have been reported in patients with celiac disease, but distinguishing between these specific manifestations of celiac disease and consequences of suffering from a chronic gastrointestinal disorder and following a strict diet may be difficult (J Clin Gastroenterol 2020 Jan;54(1):8).
  • Psychiatric disorders or symptoms reported associated with celiac disease (though important to note that the cause and magnitude of associations remain unclear, due to limited or conflicting information) include:
    • Depression and related mood disorders
    • Anxiety and anxiety disorders such as social phobia and panic disorder, which have been reported to be linked to a gluten response
    • Schizophrenia
    • Anorexia nervosa
    • Attention deficit hyperactivity disorder (ADHD)
    • Autism
    • Sleep disorders, which may also be related to depression, anxiety, and fatigue in patients with celiac disease
    • PubMed27976606Nutrition research reviewsNutr Res Rev2017060130125-3525References - Nutr Res Rev 2017 Jun;30(1):25, Nat Rev Gastroenterol Hepatol 2015 Oct;12(10):561, Psychiatr Q 2012 Mar;83(1):91
  • STUDY SUMMARY
    anxiety, depression, eating disorders, autism, and attention deficit hyperactivity disorder associated with celiac disease
    SYSTEMATIC REVIEW: Nutrients 2020 Jan 4;12(1):142

  • Schizophrenia and celiac disease:
    • PubMed26000156Auto- immunity highlightsAuto Immun Highlights201410165255-6155Individuals with psychiatric disorders such as schizophrenia and mood disorders are reported to have increased rates of autoimmune disease compared to control populations (Auto Immun Highlights 2014 Sep;5(2):55).
      • Underlying mechanisms behind the association of celiac disease and schizophrenia are unknown, though some have suggested they include a combination of:
        • Micronutritional and vitamin deficiencies from malabsorption and malnutrition
        • Activation of chronic immune-mediated processes
        • Alterations intestinal permeability that lead to pathologic bidirectional communication between the gastrointestinal tract and brain
        • Reference - Nutrients 2018 Jul 6;10(7):875
      • STUDY SUMMARY
        2-fold increased risk of schizophrenia among patients with celiac disease
        SYSTEMATIC REVIEW: Eur J Gastroenterol Hepatol 2018 Apr;30(4):442

    • Immunological patterns in patients with schizophrenia have been reported to include both celiac disease (IgA antigliadin [AGA] and anti-transglutaminase [tTG] antibodies) and nonceliac gluten sensitivity (tTG6 antibodies immune responses).
      • STUDY SUMMARY
        increased prevalence of IgA antigliadin and anti-transglutaminase antibodies but not anti-endomysial antibodies, reported in sera of adults with schizophrenia compared to healthy controls
        COHORT STUDY: Schizophr Bull 2011 Jan;37(1):94

Etiology and Pathogenesis

Causes

  • Celiac disease is an autoimmune-mediated inflammatory disorder caused by an immune reaction to gluten/gliadin fragments (gliadin is a glycoprotein component of gluten) that develops in response to unknown environmental factors in adults and children with a genetic predisposition (presence of human leukocyte antigen [HLA]-DQ2 or HLA-DQ8 haplotypes; > 95% of patients have 1 or both haplotypes).
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Pathogenesis

  • Gluten proteins are found in the rubbery, largely proteinaceous mass, which remains when a dough made from wheat flour and water is gently washed to remove most of the starch and soluble material.
    • Prolamins are proteins from cereal grains high in proline and amide nitrogen.
    • Prolamins that can trigger symptoms in patients with celiac disease include:
      • Gliadin from wheat (gluten contains various types of gliadins)
      • Hordein from barley
      • Secalin from rye
    • PubMed31334243Frontiers in nutritionFront Nutr201907056101101Reference - Front Nutr 2019;6:101
  • Dietary gluten ingestion:
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    • Gluten is a mixture of gliadins and glutenins, which are complex proteins, rich in proline and glutamine, and not fully digestible by intestinal enzymes.
    • Final fragments from partial digestion are peptides that can trigger host responses closely resembling those mediated by exposure to gastrointestinal pathogens.
  • Several underlying physiologic events and immune responses occur in the pathogenesis of celiac disease.
    • Gluten translocation from the mucosal lumen to the lamina propria:
      • Undigestible gluten/gliadin fragments in the mucosal lumen bind to chemokine receptor 3 (CXCR3) with subsequent release of zonulin (modulator of intercellular tight junctions).
      • Zonulin triggers rapid, transient intracellular permeability of intestinal epithelial cells, facilitating gluten/gliadin fragment paracellular translocation to the lamina propria.
    • Innate immune response:
      • The presence of gluten/gliadin fragments in the lamina propria in genetically predisposed individuals triggers an innate immune response that damages mucosal cells and releases tissue transglutaminase (tTG).
      • Cytokines, such as interleukin (IL)-15 and interferon alpha, can prime innate immune responses in the intestinal mucosa by polarizing dendritic cells and intraepithelial lymphocyte function.
      • Neutrophil recruitment through IL-8 production or direct neutrophil chemoattractant effect by gliadin fragments causes a loss of tolerance to gluten in genetically susceptible individuals.
      • Once tolerance to gluten is lost, additional gluten/gliadin fragments complexed with secretory IgA translocate through transcellular pathways to the lamina propria.
    • Adaptive immune response:
      • Gluten fragments in the lamina propria are deamidated by released tTG which enhances their immunogenicity.
      • Contact of CD4+ T cells with deamidated gluten fragments through major histocompatibility complex class II human leukocyte antigen (HLA)-DQ2/8-restricted antigens induces T-cell activation, leading to B-cell proliferation.
      • Antibodies against tTG (anti-tTG IgA antibodies) and deamidated gliadin peptides (endomysial IgA antibodies) are secreted.
      • Gliadin-reactive Th1 cell activation leads to proinflammatory cytokine, metalloprotease, and keratinocyte growth factor production, which induces intestinal intraepithelial lymphocyte insult and cell death.
      • Crypt hyperplasia and villous atrophy result from an imbalance of continuous intestinal epithelial cell death and inability of stem cells to compensate.
    • PubMed28810029JAMAJAMA201708153187647-656647Reference - JAMA 2017 Aug 15;318(7):647
  • Genetic predisposition involving HLA-DQ2/DQ8 heterodimer:
    • Variant HLA-DQ2 and -DQ8 receptor haplotypes on antigen presenting T cells bind to highly negatively charged deamidated gluten fragments (JAMA 2017 Aug 15;318(7):647).
    • The contact of CD4+ T cells with deamidated gluten fragments bound to major histocompatibility complex class II HLA-DQ2/8 receptors on antigen presenting cells induces T-cell activation leading to B-cell proliferation (JAMA 2017 Aug 15;318(7):647).
    • 25%-35% of the general population is reported to carry HLA-DQ2 and/or -DQ8 genotypes.
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    • HLA-DQ2/8 haplotypes alone are reported to confer 35%-40% of the genetic risk for celiac disease.
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    • Overall a 2%-5% penetrance of celiac disease is reported in individuals with HLA-DQ2 and/or HLA-DQ8 haplotypes, which indicates other genetic and environmental elements play a role in disease development.
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  • Histologic changes in small intestinal mucosa include:
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    • Partial to complete villous atrophy
    • Crypt hyperplasia, which is seen as crypt lengthening with an increase in the lamina propria
    • An increase in intraepithelial lymphocyte infiltration into the lamina propria
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