ACRONYMS AND DEFINITIONS

ACG - American College of Gastroenterology

DGP - Deamidated gliadin peptide

HLA - Human leukocyte antigen

RCT - Randomized controlled trial

TTG - Tissue transglutaminase

ULN - Uppper limit of normal

PREVALENCE

About 1% of the world's population is affected by celiac disease, and it occurs anywhere wheat, barley, or rye is consumed. Because of its nonspecific and sometimes mild symptoms, celiac disease is often missed, with up to 79% of cases being undiagnosed in screening studies. The frequency of diagnosis is increasing, however, as celiac disease awareness has grown. [2,3]

RISK FACTORS

Female sex

Women are affected 2 - 3 times more than men

First-degree relative with disease

10 - 15% of people with celiac have a first-degree relative with the disease

Type one diabetes

3 - 16% of type one diabetics have celiac disease

HLA-DQ2 and HLA-DQ8 haplotypes

The HLA-DQ2 haplotype (alleles A1*05 and B1*02) is present in 90% of celiac patients, and one allele (A1*05 or B1*02) is present in 5%. The HLA-DQ8 haplotype is found in the remaining 5%. See celiac labs for more.

IgA deficiency

IgA deficiency is present in 2 - 3% of patients with celiac disease, and IgA levels should be checked if IgA antibodies are used for screening. See celiac labs for more.

Timing of gluten introduction into the diet

Observational studies have found that the timing of gluten introduction into the diet is associated with celiac disease, with introduction between 4 - 6 months reducing the risk and introduction before 4 months and after 7 months increasing the risk. Randomized controlled trials examining this effect have had mixed results. (see celiac prevention studies).

Rotavirus

In some observational studies, rotavirus infection in infancy has been associated with an increased risk of celiac disease

Other autoimmune disease

Celiac disease is more prevalent in patients with other autoimmune diseases (e.g. Hashimoto's thyroiditis, Sjögren's, autoimmune liver disease, IgA nephropathy, peripheral neuropathy)

Down's syndrome

Up to 5% of Down's syndrome patients have celiac disease

Turner's syndrome

Up to 3% of Turner's syndrome patients have celiac disease [1,2,3,4,5,6]

PATHOLOGY

Overview

Celiac disease is caused by an abnormal immune response to gluten peptides in the upper small intestine. Gluten is found in wheat, barley, and rye, and when it reaches the small intestine, it breaks down into gliadin. In celiac disease, gliadin is able to pass through the epithelial barrier in the small intestine and reach the underlying lamina propria. The cause of epithelial gliadin permeability is uncertain but may be due to an underlying pathological process (e.g. infection) or alterations in tight intercellular junctions.
Once gliadin reaches the lamina propria, it is deamidated by tissue transglutaminase (TTG). Deamidated gliadin then reacts with HLA-DQ2 or HLA-DQ8 receptors on antigen-presenting cells that stimulate T- and B-cell activation, leading to cytokine release, antibody production, and lymphocyte infiltration. Over time, inflammation causes villous atrophy and crypt hyperplasia in epithelial cells. [3,4]

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Illustration of celiac disease pathology

NATURAL COURSE

Overview

Celiac disease may develop in childhood or adulthood, and its natural course is highly variable. The pathology progresses through the sequence of events listed below, and the interval between each step may be weeks to years, depending on the individual.
The presence of gluten-related antibodies does not always lead to celiac disease. In one study, 49% of high-risk children with tissue transglutaminase antibodies converted to negative antibodies over time despite continued gluten exposure.

Sequence of events in the development of celiac disease

1. Gluten exposure
2. Development of gluten-related antibodies
3. Duodenal villous atrophy, crypt hyperplasia, and lymphocyte infiltration
4. Symptoms of celiac disease [2,9]

SYMPTOMS

Children

Classic symptoms of celiac disease in infants and young children include diarrhea, abdominal distention, and failure to thrive. Advances in serologic screening and heightened awareness have increased disease recognition, and a broader array of symptoms have now been identified. [3]
Presenting symptoms in 263 children (≤ 16 years) diagnosed with celiac disease in New Zealand are shown in the table below

Reference [7]
Celiac disease in children
Presenting symptom	% of patients
Abdominal pain	44%
Diarrhea	33%
Iron-deficiency anemia	32%
Poor weight gain	25%
Bloating	23%
Nausea and vomiting	16%
Asymptomatic (found during screening)	14%
Lethargy	14%
Weight loss	10%
Micronutrient deficiency (iron, folate, zinc, etc.)	10%
Constipation	6%
Poor health/recurrent infections	5%
Short stature	4%
Irritability	4%
Headaches	2%
Puberty delay	1%
Poor sleep	1%

Adults

Classic symptoms of celiac disease in adults include chronic diarrhea, abdominal distention, steatorrhea, postprandial abdominal pain, bloating, and weight loss. [1]
Results from a study that looked at the presenting symptoms in 172 patients (> 16 years) diagnosed with celiac disease in the U.S. are presented in the table below. The average age in the study was 42 years, and the average duration of symptoms before diagnosis was 4 years.

^✝Other includes abdominal pain, constipation, weight loss, neurologic symptoms, dermatitis herpetiformis, macroamylasemia, hypoproteinemia, elevated sedimentation rate, insulin-dependent diabetes mellitus, increased thyroid hormone replacement requirement, and liver disease (elevated serum aminotransferase levels)

Reference [8]
Celiac disease in adults
Presenting symptom	% of patients
Diarrhea	37%
Other^✝	26%
Anemia	13%
Screening (affected family member)	12%
Bone disease	8%
Childhood celiac disease	8%
Malignancy	5%
Incidental diagnosis (found during EGD for other condition)	5%

WHOM TO TEST

The ACG recommends testing the following patients for celiac disease:

Patients with symptoms, signs, or laboratory evidence suggestive of malabsorption (e.g. chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain and bloating) should be tested for celiac disease
Patients with symptoms, signs, or laboratory evidence for which celiac disease is a treatable cause should be considered for testing for celiac disease
Patients with a first-degree family member who has a confirmed diagnosis of celiac disease should be tested if they show possible signs or symptoms or laboratory evidence of celiac disease
Consider testing of asymptomatic relatives with a first-degree family member who has a confirmed diagnosis of celiac disease
Celiac disease should be sought among the explanations for elevated serum aminotransferase levels when no other etiology is found
Patients with Type I diabetes should be tested for celiac disease if there are any digestive symptoms, or signs, or laboratory evidence suggestive of celiac disease [1]

DIAGNOSIS

ACG 2013 recommendations

All testing should be done while patients are consuming a gluten-containing diet
Positive serologic testing should be confirmed with duodenal biopsies

Adults and children > 2 years: the preferred screening test is TTG IgA
Children younger than 2 years: the preferred screening test is a combination of TTG IgA and DGP (IgG and IgA)
High-probability patients: if suspicion for celiac disease is high, total IgA levels should be measured because IgA deficiency is present in 2 - 3% of celiac disease patients. An alternative approach is to include both IgA and IgG-based testing, such as DGP IgG. Intestinal biopsy should be pursued even if serologies are negative.
Patients with low IgA or IgA deficiency: IgG-based testing (DGP IgG and TTP IgG) should be performed
Genotype testing: see genotype testing

Antibodies directed against native gliadin are not recommended for the primary detection of celiac disease
Combining several tests for celiac disease in lieu of TTG IgA alone may marginally increase the sensitivity for celiac disease but reduces specificity and therefore is not recommended in low-risk populations [1]

References [1,2,3,4,5,6]
ANTIBODY TESTS
Tissue transglutaminase IgA (TTG IgA) antibodies Screening TTG IgA antibodies are the preferred screening test in adults and children > 2 years. In children < 2 years, TTG antibodies are less sensitive, and a combination of TTG IgA + DGP (IgA and IgG) is recommended. IgA deficiency is seen in 2 - 3% of celiac disease patients, so if suspicion for celiac disease is high, total IgA levels should be measured Accuracy Sensitivity: > 95% Specificity: > 95% Effects of a gluten-free diet TTG IgA levels will return to normal in patients consuming a gluten-free diet. Weakly positive patients may return to normal within weeks of starting a gluten-free diet. After 6 - 12 months, 80% of patients will have normal levels, and by 5 years, > 90% of patients will be normal. TTG IgA levels may also be used to monitor gluten-free diet compliance. Studies A cohort study found that TTG IgA levels ≥ 10 X ULN in adults were almost 100% specific for celiac disease (confirmed with biopsy) and had a positive predictive value of 95 - 100%. [PMID 33139268]
Tissue transglutaminase IgG (TTG IgG) antibodies Screening TTG IgG antibodies are useful in patients who have suspected IgA deficiency. The sensitivity and specificity of TTG IgG is variable, therefore, it is not as accurate as TTG IgA. Accuracy Sensitivity: widely variable Specificity: 86 - 100% Effects of a gluten-free diet TTG IgG levels will return to normal in patients consuming a gluten-free diet. Weakly positive patients may return to normal within weeks of starting a gluten-free diet. After 6 - 12 months, 80% of patients will have normal levels, and by 5 years, > 90% of patients will be normal.
Deamidated gliadin peptide IgA and IgG antibodies (DGP Abs) Screening The preferred screening test in children < 2 years is a combination of TTG IgA and DGP (IgG and IgA) DGP IgG antibody is useful in patients who have suspected IgA deficiency Accuracy Sensitivity (IgG): > 90% Specificity (IgG): > 90% Effects of a gluten-free diet DPG Ab levels (IgG and IgA) will return to normal in patients consuming a gluten-free diet. Weakly positive patients may return to normal within weeks of starting a gluten-free diet. After 6 - 12 months, 80% of patients will have normal levels, and by 5 years, > 90% of patients will be normal. DGP Ab levels may also be used to monitor gluten-free diet compliance.
Endomysial antibodies (IgA and IgG) Screening The endomysium is connective tissue that lines muscle fibers, and it contains a form of TTG. Antibodies that bind TTG in endomysial tissue are called endomysial antibodies, and they are highly specific for celiac disease. Endomysial antibody testing may be helpful in cases where small bowel biopsies are undesirable (e.g. children with failure to thrive) or when there is concern for a false-positive TTG test. Accuracy Sensitivity: > 90% Specificity: 98%
Other Anti-gliadin antibodies are antibodies to native gliadin (undeamidated). This test is no longer recommended because newer tests are more sensitive. Anti-reticulin antibodies are antibodies to reticulin, a connective tissue. This test is no longer recommended because newer tests are more sensitive.
GENOTYPE
HLA DQ2/DQ8 genotype HLA-DQ2 (alleles A105 and B102) is found in ∼ 95% of patients with celiac disease, and HLA-DQ8 (alleles A103 and B10302) is present in the remaining 5%. Patients who test negative for both HLA-DQ2 and HLA-DQ8 have a less than 1% chance of having celiac disease (NPV > 99%). Positive testing is less useful, as HLA-DQ2 is present in 25 - 30% of the general population. The ACG states that haplotype testing may be useful in the following situations: Equivocal small-bowel histological finding (Marsh I-II) in seronegative patients Evaluation of patients on a gluten-free diet in whom no testing for celiac disease was done before gluten-free diet Patients with discrepant celiac-specific serology and histology Patients with suspicion of refractory celiac disease where the original diagnosis of celiac remains in question Patients with Down's syndrome

Endoscopy

Patients with positive serologic celiac testing should have their diagnosis confirmed with endoscopy. High-probability patients with negative serology should also have endoscopy.

Histopathological findings in celiac disease include the following:

Villous atrophy
Lymphocytic infiltration of the intestinal epithelium
Crypt hyperplasia [1]

DIFFERENTIAL DIAGNOSIS

Reference [1,2,3]
OTHER CONDITIONS WITH CELIAC-LIKE SYMPTOMS
Disease	Comment
Irritable bowel syndrome (IBS)	Many patients with celiac disease are initially diagnosed with IBS
Non-celiac gluten sensitivity	Diagnosis of exclusion Condition where patients have symptoms of celiac disease when they consume gluten, but they do not meet the serologic or histopathologic criteria for celiac disease
Wheat allergy	May be diagnosed with skin prick tests or blood tests
Lactose intolerance	May be diagnosed with dietary challenge/removal or lactose breath hydrogen test
Pancreatic insufficiency	Often difficult to diagnose Pancreatic calcifications may be seen on radiographs

Reference [1,3]
POTENTIAL CAUSES OF DUODENAL VILLOUS ATROPHY
Disease	Comment
Tropical sprue	Tropical sprue is a chronic diarrheal disease of unknown etiology that occurs in tropical regions along the equator
Small bowel bacterial overgrowth	A condition marked by overgrowth of non-native bacteria in the small bowel Typically occurs in the setting of bowel abnormalities (structural, decreased motility, etc.)
Autoimmune enteropathy	Rare disease caused by autoantibodies to enterocytes
Drug-induced enteropathy	Has been associated with olmesartan (Benicar®)
Whipple disease	Syndrome of chronic diarrhea, joint pain, and malabsorption caused by T. whipplei infection
Collagenous sprue	Rare disease marked by excessive subepithelial collagen deposition in the small bowel
Crohn's disease
Eosinophilic enteritis	Disease is marked by eosinophilic infiltration into the stomach and duodenum
Intestinal lymphoma	Intestinal lymphoma may cause villous atrophy Celiac disease increases the risk of enteropathy-associated T-cell lymphoma, but the disease is still very rare among celiac patients (see cancers below)
Intestinal tuberculosis	Although rare, tuberculosis may infect the gastrointestinal tract
Infectious enteritis	e.g. giardia, amebiasis
Graft vs host disease
AIDS enteropathy	Syndrome of chronic diarrhea and wasting in AIDS patients Infectious and neoplastic causes should be ruled out before making diagnosis

TREATMENT

The primary treatment of celiac disease is a gluten-free diet, which leads to symptom resolution after 6 - 12 months in most people
Newly-diagnosed patients may need to be tested for nutritional deficiencies, including iron, folic acid, vitamin D, and vitamin B12
Gluten is found in products that contain wheat, barley, or rye. Links to information from the Celiac Disease Foundation on gluten-containing foods are provided below.

SEQUELAE

Cancers

Patients with celiac disease are at an increased risk of certain cancers; however, the overall risk of these cancers is still very low. A gluten-free diet appears to lower the risk.

Cancers associated with celiac disease include:

Adenocarcinoma of the small intestine
Enteropathy-associated T-cell lymphoma - may present as recurrent celiac symptoms after a period of control on a gluten-free diet; difficult to treat; has poor prognosis
B-cell and T-cell lymphomas
Esophageal cancers [1,2,3]

Osteoporosis

Osteoporosis is more common in patients with celiac disease due to a number of factors, including decreased calcium and vitamin D absorption, secondary hyperparathyroidism, magnesium deficiency, increased inflammatory mediators, and hypogonadism
High-risk patients should have periodic bone mineral density testing
A gluten-free diet has been shown to improve bone mineral density [1,4]

Iron-deficiency anemia

Celiac disease may reduce iron absorption in the duodenum, leading to iron-deficiency anemia, which is a presenting symptom in up to 32% of children and 13% of adults [1]

Infertility

Women and men with celiac disease appear to have a higher risk of infertility. A gluten-free diet appears to lower the risk. [1,4]

Hyposplenism

Celiac disease is the most common cause of hyposplenism, with 33 - 76% of patients having some degree of hyposplenism in studies. A gluten-free diet can help restore spleen function if splenic tissue loss and atrophy have not occurred.
Spleen atrophy is a poor prognostic indicator in patients with severe celiac disease
See care of the hyposplenic patient for more [11]

REFRACTORY DISEASE

Overview

Most patients with celiac disease have symptom resolution after 6 - 12 months of a gluten-free diet. However, up to 30% of patients do not respond, and these individuals should be referred to a dietician to ensure that they are consuming a strict gluten-free diet. Antibody testing (TTG IgA, DGP IgA and IgG) may also be appropriate to monitor compliance.

Consider the following in non-responsive patients:

Nonadherence to a strict gluten-free diet
Inadvertent gluten ingestion
Other food intolerances (lactose and fructose intolerance)
Incorrect diagnosis (see other causes of villous atrophy above)
Refractory disease (see below)

Refractory disease types

Refractory celiac disease is defined as persistent or recurrent symptoms and signs of malabsorption with small-intestinal villous atrophy despite a strict gluten-free diet for more than 12 months and in the absence of other disorders including overt lymphoma
Refractory celiac disease is uncommon, occurring in 1 - 2% of celiac patients
Refractory celiac disease can be divided into two different types

Type 1 refractory celiac disease

In the U.S., Type 1 is more common than Type 2
Lymphocyte phenotype (CD3+CD8+) and infiltration into mucosa is similar to that seen in untreated celiac disease
May be treated with steroids, immunosuppressants, and biologicals

Type 2 refractory celiac disease

CD3-positive intraepithelial T-cells exhibit an abnormal immunophenotype with lack of expression of normal cell surface differentiation markers such as CD8 (CD3+CD8-)
T-cell receptor analyses may reveal oligoclonal T-cell expansion within the small-bowel mucosa
Type 2 disease is less responsive to therapy, but may be treated with steroids, immunosuppressants, biologicals, and bone marrow transplant
Malnutrition may be severe requiring total parenteral nutrition
RIsk for enteropathy-associated T-cell lymphoma is increased
Prognosis is poor with a 5-year survival of 44%

STUDIES

STUDY
Early Gluten vs Standard Diet for the Prevention of Celiac Disease in the General Population, JAMA Pediatrics (2020) [PubMed abstract]

Design: Randomized controlled trial (N=1004 | length = 3 years) in infants from the general population in England and Wales
Treatment: Early introduction of allergenic foods (peanut, sesame, hen's egg, cow's milk, cod fish, and wheat) at 4 months old vs Standard introduction of allergenic foods at 6 months old
Primary outcome: Diagnosis of celiac disease at 3 years old by positive antitransglutaminase type 2 antibodies and evaluation by gastroenterologist
Results:

Primary outcome: Early - 0%, Standard - 1.4% (p=0.02)

Findings: In this analysis of infants in the EAT Study, the introduction of gluten from age 4 months was associated with reduced CD prevalence. These results suggest that early high-dose consumption of gluten should be considered as a strategy to prevent CD in future studies.

STUDY
Gluten vs Placebo at 4 - 6 Months of Age to Prevent Celiac Disease in High-Risk Children, NEJM (2014) [PubMed abstract]

Design: Secondary analysis of a randomized placebo-controlled trial (N=944, length = 3 years) in infants 4 - 6 months of age who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease
Treatment: Gluten 200 mg daily vs Placebo daily for 8 weeks starting at age 4 months. After the intervention, parents were advised to introduce gluten gradually.
Primary outcome: Frequency of biopsy-confirmed celiac disease at 3 years of age
Results:

Primary outcome: Gluten group - 5.9%, Placebo group - 4.5%

Findings: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children.

STUDY
Gluten Introduction at 6 or 12 Months of Age to Prevent Celiac Disease in High-Risk Children, NEJM (2014) [PubMed abstract]

Design: Randomized controlled trial (N=832, length = 5 years) in newborns who had a first-degree relative with celiac disease
Treatment: Introduction of gluten-containing foods (pasta, semolina, and biscuits) at 6 months of age vs 12 months of age. At 12 months of age, all children began to receive a normal diet containing gluten
Primary outcome: Prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age
Results:

Celiac autoimmunity: 6-month group - 21%, 12-month group - 20%
Overt celiac disease: 6-month group - 16%, 12-month group - 16%

Findings: Neither the delayed introduction of gluten nor breastfeeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease.

STUDY
Gluten Intake during the First 5 Years of Life and Incidence of Celiac Disease in Children at Increased Risk, JAMA (2019) [PubMed abstract]

Design: Prospective cohort study (N=6605 | length = 5 years) in children carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease
Exposure: Gluten intake during first 5 years of life
Primary outcome: Celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples
Results:

Primary outcome: Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-gram/day increase in gluten consumption (HR 1.30 95%CI [1.22 - 1.38])

Findings: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.

BIBLIOGRAPHY

1 - PMID 23609613 - ACR 2013 GL
2 - PMID 23252527 - NEJM 2012 review
3 - PMID 17960014 - NEJM 2007 review
4 - PMID 12907013 - Lancet 2003 review
5 - PMID 25271603 - Early Gluten study 1
6 - PMID 25271602 - Early Gluten study 2
7 - PMID 26566488 - child presenting symptoms
8 - PMID 16564784 - adults presenting symptoms
9 - PMID 17573785 - ttg conversion in children
10 - PMID 21474172 - Post-splenectomy and hyposplenic states, Lancet (2011)

CELIAC DISEASE

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