Celiac disease

ACRONYMS AND DEFINITIONS

ACG - American College of Gastroenterology

DGP - Deamidated gliadin peptide

HLA - Human leukocyte antigen

TTG - Tissue transglutaminase

PREVALENCE

Celiac disease is prevalent in about 1% of the worldwide population. Celiac disease may occur anywhere that wheat, barley, or rye is consumed.
Because of its nonspecific and often mild or nonexistent symptoms, celiac disease is generally underdiagnosed. In some screening studies, up to 79% of cases have been undiagnosed.
Increased awareness of the disease over the past several decades has increased the rate of diagnosis [2,3]

RISK FACTORS

Reference [1,2,3,4,5,6]
Risk factor	Comment
Female sex	The prevalence in women is 2 - 3 times higher than that in men
First-degree relative with disease	The disease is prevalent in 10 - 15% of people who have a first-degree relative with the disease
Type 1 diabetes	Celiac disease is present in 3 - 16% of patients with type 1 diabetes
HLA-DQ2 and HLA-DQ8 haplotypes	The HLA-DQ2 haplotype (alleles A105 and B102) is present in 90% of patients with celiac disease One of two HLA-DQ2 alleles (A105 or B102) is present in 5% of patients The HLA-DQ8 haplotype is present in 5% of patients with celiac disease See labs below for more
IgA deficiency	IgA deficiency is present in 2 - 3% of patients with celiac disease IgA deficiency may affect laboratory diagnosis of celiac disease See labs below 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 Some studies have suggested that the introduction of gluten between 4 - 6 months of age may decrease the risk, while introducing gluten before 4 months and after 7 months may increase the risk Recent randomized trials have evaluated this hypothesis and found no effect - see studies for more
Rotavirus	In some observational studies, rotavirus infection in infancy has been associated with an increased risk of celiac disease
Breastfeeding	In some observational studies, the introduction of gluten while breastfeeding has been associated with a lower risk of celiac disease A recent randomized controlled trial did not confirm this finding - see studies for more
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	Celiac disease is present in up to 5% of patients with Down's syndrome
Turner's syndrome	Celiac disease is present in up to 3% of patients with Turner's syndrome

PATHOLOGY

Overview

Celiac disease is caused by an abnormal immune response to gluten peptides in the upper small intestine. Gluten is found is wheat, barley, and rye.
When gluten 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. Epithelial permeability to gliadin may be due to an underlying pathological process such as an infection or alterations in intercellular tight junctions, but this is not certain.
Once gliadin reaches the lamina propria, it is deamidated by tissue transglutaminase (ttg). Deamidated gliadin then reacts with antigen-presenting immune cells of the HLA-DQ2 or HLA-DQ8 subtype.
Antigen-presenting cells stimulate T-cell and B-cell responses that promote cytokine release, antibody production, and lymphocyte infiltration
These inflammatory processes lead to villous atrophy and crypt hyperplasia in epithelial cells [3,4]

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NATURAL COURSE

Overview

The natural course of celiac disease is highly variable
The disease may develop in childhood or adulthood

In general, the following sequence of events occurs:

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

The interval between each step in the sequence above may be weeks to years depending on the individual
Some patients may be positive for gluten-related antibodies and later become negative for antibodies. In one study, 49% of children at genetic risk for celiac disease who were positive for tissue transglutaminase antibodies converted to negative antibodies over time despite continued gluten exposure. [2,9]

SYMPTOMS

Children

The classic symptoms of celiac disease in infants and young children include diarrhea, abdominal distention, and failure to thrive [3]
Heightened awareness and advances in serologic screening have increased recognition of the disease, and now patients diagnosed with celiac disease have a broad array of presenting symptoms
A study in New Zealand looked at the presenting symptoms/signs in 263 children (≤ 16 years) diagnosed with celiac disease between 2000 - 2010. The results are presented in the table below.

Reference [7]
Presenting symptom/sign	% 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

The classic symptoms of celiac disease in adults include chronic diarrhea, abdominal distention, steatorrhea, postprandial abdominal pain, bloating, and weight loss [1]
Heightened awareness and advances in serologic screening have increased recognition of the disease, and now patients diagnosed with celiac disease have a broad array of presenting symptoms
A study in the U.S. looked at the presenting symptoms/signs in 172 patients (> 16 years) diagnosed with celiac disease between 2000 - 2004. The results are presented in the table below.

✝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)

Average age of the patients was 42 years

Average duration of symptoms before celiac disease was diagnosed was 4 years

Reference [8]
Presenting symptom/sign	% 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%

DIAGNOSIS

Laboratories

Serologic testing for celiac disease includes antibody and genotype testing
The preferred screening test in adults is tissue transglutaminase IgA antibodies. In children younger than 2 years old, the preferred screening test is a combination of tissue transglutaminase IgA antibodies and deamidated gliadin peptide antibodies (IgG and IgA).
The table below details the properties of each test

References [1,2,3,4,5,6]
ANTIBODY TESTS
Tissue transglutaminase IgA antibodies (TTG IgA) TTG IgA is the preferred screening test in adults. In children < 2 years old, TTG Abs are less sensitive, therefore a combination of TTG IgA + DGP (IgA and IgG) is the preferred screening method. IgA deficiency is more common in patients with celiac disease (2 - 3%), so if suspicion for celiac disease is high, total IgA levels should also be drawn Sensitivity: > 95% Specificity: > 95% 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. By 5 years, > 90% of patients will have normal levels. TTG IgA levels may also be used to monitor compliance with a gluten-free diet.
Tissue transglutaminase IgG antibodies (TTG IgG) TTG IgG are useful in patients who have suspected IgA deficiency. The sensitivity and specificity of TTG IgG is highly variable, therefore it is not as accurate as TTG IgA. Sensitivity: widely variable Specificity: 86 - 100% 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. By 5 years, > 90% of patients will have normal levels.
Deamidated gliadin peptide IgA and IgG antibodies (DGP Abs) DGP IgG antibody is useful in patients who have suspected IgA deficiency When screening children younger than 2 years of age for celiac disease, TTG IgA + DGP (IgA and IgG) are the recommended screening tests Sensitivity (IgG): > 90% Specificity (IgG): > 90% 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. By 5 years, > 90% of patients will have normal levels. DGP Ab levels may also be used to monitor compliance with a gluten-free diet.
Endomysial IgA antibody Endomysial antibodies are antibodies to the connective tissue inside muscle. TTG IgA antibody is the target antigen for endomysial antibodies. Endomysial IgA antibodies are highly specific (low false-positives) but less sensitive than other tests. The test is also expensive and typically only recommended when there is concern over a possible false-positive TTG Ab test. Endomysial IgG antibody tests are not widely available 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 The HLA-DQ2 haplotype (alleles A105 and B102) is present in 90% of patients with celiac disease, and one of two HLA-DQ2 alleles (A105 or B102) is present in 5% of patients. The HLA-DQ8 haplotype is present in the remaining 5% of patients with celiac disease. This means a person who tests negative for both HLA-DQ2 and HLA-DQ8 is very unlikely to have celiac disease with a negative predictive value of > 99% The HLA-DQ2 haplotype is present in 25 - 30% of the general population, therefore a positive test has little meaning in screening situations 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 who have positive blood tests for celiac disease should have their diagnosis confirmed with endoscopy
During endoscopy, multiple biopsies of the duodenum should be taken [1]

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

WHOM TO SCREEN

The ACG recommends screening 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]

TREATMENT

The primary treatment of celiac disease is to remove gluten from the diet. In most patients, celiac symptoms will resolve after 6 - 12 months of consuming a gluten-free diet.
Gluten is found in products that contain wheat, barley, or rye
In certain situations, newly-diagnosed patients should be tested for nutritional deficiencies including iron, folic acid, vitamin D, and vitamin B12
The Celiac Disease Foundation has an online food guide that can help with dietary choices

SEQUELAE

Cancers

Patients with celiac disease are at an increased risk of certain cancers
While the risk may be increased, the incidence of these cancers in patients with celiac disease is still very low
Consuming a gluten-free diet appears to lower the risk

Adenocarcinoma of the small intestine - rare cancer that is more common in celiac patients
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 - more common in patients with celiac disease
Esophageal cancers - more common in patients with celiac disease [1,2,3]

Osteoporosis

Patients with celiac disease are at an increased risk of osteoporosis
The reason is likely multifactorial and related to decreased calcium and vitamin D absorption, secondary hyperparathyroidism, magnesium deficiency, increased inflammatory mediators, and hypogonadism
Bone mineral density testing should be performed in high-risk patients
A gluten-free diet has been shown to improve bone mineral density in celiac patients [1,4]

Iron-deficiency anemia

Patients with celiac disease are at an increased risk of iron-deficiency anemia
Iron is absorbed in the duodenum, and celiac disease may decrease absorption [1]

Infertility

Patients with celiac disease are at an increased risk of infertility. Both women and men may be affected.
A gluten-free diet appears to improve fertility in affected individuals [1,4]

Hyposplenism

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

REFRACTORY DISEASE

Overview

In most patients, celiac symptoms will resolve after 6 - 12 months of consuming a gluten-free diet
Up to 30% of patients diagnosed with celiac disease may not respond to a gluten-free diet
Non-responsive patients should be referred to a dietician in order to ensure that they are consuming a strict gluten-free diet
In some cases, blood tests (TTG IgA, DGP IgA and IgG) may be needed to assess compliance

In non-responsive patients, the following should be considered:

Nonadherence to 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)

Types of refractory disease

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

Reference [1,3]
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

Introduction of Gluten vs Placebo at 4 - 6 Months of Age to Prevent Celiac Disease in High-Risk Children, NEJM (2014) [PMID 25271603]

DESIGN: Randomized, controlled trial (N=944, length = 3 years)
EXPOSURE: 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.

Gluten Introduction at 6 or 12 Months of Age to Prevent Celiac Disease in High-Risk Children, NEJM (2014) [PMID 25271602]

DESIGN: Randomized, controlled trial (N=832, length = 5 years)
EXPOSURE: 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.

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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Tissue transglutaminase IgA antibodies (TTG IgA)

Tissue transglutaminase IgG antibodies (TTG IgG)

Deamidated gliadin peptide IgA and IgG antibodies (DGP Abs)

Endomysial IgA antibody

Other

HLA DQ2/DQ8 genotype

Type 1 refractory celiac disease

Type 2 refractory celiac disease