Celiac Disease

Celiac Disease

A comprehensive overview

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FOREWORDS

This learning module was created solely for educational purposes for the PULSE Group Project in PATH 3500 at Schulich School of Medicine and Dentistry. This module hopes to provide students with a comprehensive overview of celiac disease, including:

• What it is
• Signs & Symptoms
• Etiology and Histology
• Pathogenesis
• Diagnosis and Treatment

INDEX

Diagnosis

INTRODUCTION

SigNS & SYMPTOMS

Prognosis

Treatments/THERAPIES

Pathogenesis

REFERENCES

Risk factors

What is Celiac disease?

Celiac disease is an autoimmune disease, where the consumption of gluten recurrently results in damage to the small intestine1.

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What is Celiac disease?

Celiac disease is hereditary, meaning that only genetically predisposed individuals acquire the disease through environmental or genetic factors5.

Question

Commonly, individuals with celiac disease are at risk of developing extraintestinal symptoms alongside GI symptoms, such as peripheral neuropathy, headaches, brain fog, epilepsy, etc6.

In all parts of the world, the prevalence of celiac disease ranges from 0.5-1.0% of the population.5 The typical treatment for celiac disease is the strict restriction of gluten in one’s diet1.

Signs & Symptoms

Patients with Celiac Disease are often split into three subcategories of disease that manifest similar signs and symptoms7:

Classical

Non-Classical

Subclinical

Classical Celiac Disease

More common in children of 5 years and younger7. Symptoms include:

• Chronic diarrhea
• Poor appetite
• Weight loss
• Abdominal distension
• Muscle wasting
• Mood changes

An Awesome Title

What is abdominal distension?

Non-Classical Celiac Disease

Most common form of Celiac Disease7. Symptoms include:

• Recurring abdominal pain
• Bloating
• Diarrhea or constipation
• Extraintestinal symptoms
• System symptoms

What is subclinical celiac disease?

Unlike classical and non-classical Celiac Disease, subclinical Celiac Disease patients do not experience any symptoms and must be diagnosed through various tests7.

Pathogenesis I

Celiac disease is an autoimmune disease, where the immune system attacks self-antigens that it normally would not. In celiac disease, this self-antigen is TISSUE TRANSGLUTAMINASE8.

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But how is this autoimmunity triggered?

By environmental factors, such as...

Pathogenesis II

GLIADINS present in gluten cannot be fully digested. In patients with celiac disease, the incompletely-metabolized peptides trigger the immune response and a rapid, transient increase in gut permeability8.

What is gliadin?

α-gliadin binds cytokine receptor 3, triggering ZONULIN release. This causes tight junction disassembly, weakening the intestinal barrier. Eventually, gluten and gliadin can enter the intestinal lamina propria & cause inflammation8.

This process leadsto INNATE and ADAPTIVE immune responses8.

What are zonulins?

Pathogenesis III

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ADAPTIVE IMMUNITY

In the intestinal lamina propria, T cells are activated by gluten antigens, like gliadin. Helper T cells induce further T cell proliferation, cytokine production, and metalloproteases, and growth factors8. Eventually, this induces CRYPTAL HYPERPLASIA and VILLOUS ATROPHY8.

INNATE IMMUNITY

Gliadin interactions with inflammatory receptors drives production of cytokines IL-8, which promotes neutrophil recruitment, and IL-15, which triggers enterocyte proliferation. In this proinflammatoryenvironment, Toll-like receptors recognize gluten α-AMYLASE & TRYPSIN INHIBITORS and activate8.

Cryptal hyperplasia

Villous atrophy

Risk Factors

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Age

Biological sex

Genetic factors

Associated conditions

Diagnosis of Celiac Disease

Testing is often considered in individuals with persistent gastrointestinal symptoms, unexplained iron-deficiency anemia, a family history of celiac disease, or associated autoimmune conditions.

Individuals presenting with symptoms suggestive of celiac disease or those at increased genetic risk are typically evaluated using serologic/blood testing and biopsies of the small intestine to diagnose celiac disease14.

SEROLOGIC TESTING

The first line screening is done by measuring the concentration of tissue transglutaminase IgA (tTG-IgA) because it has high sensitivity and is effective at ruling out the disease when results are negative15.

If the tTG-IgA is weakly positive, doctors test for endomysial antibodies (EMA) because it has a high specificity15.

Some patients might present with IgA deficiency and they do not produce IgA-TTG or IgA-EMA antibodies which could lead to false negative results of the disease. - For this reason, total IgA levels are often measured alongside serologic testing15.

DUODENAL BIOPSY

After a positive tTG-IgA blood test, the next step is a small intestinal biopsy.

Duodenal biopsy findings such as: - increased intraepithelial lymphocytes - crypt hyperplasia, and - villous atrophy confirms the diagnosis of coeliac disease15.

During gastroscopy we can see abnormalities such as loss of folds or scalloping of folds in the descending duodenum15.

GENETIC TESTING

FOR CELIAC DISEASE

For patients who are already on a gluten-free diet and who are unwilling to change their diet, and those who refuse a gastroscopy, HLA genotyping is done for suspected celiac disease15.

HLA-DQ2 and HLA-DQ8 are the genes present in almost all individuals with celiac disease. If these genes are absent in a person, it is very unlikely that they have the disease16.

True/False

PROGNOSIS

The prognosis of celiac disease is generally excellent when the condition is diagnosed early and patients adhere to a strict gluten-free diet17.

Depending on the severity of intestinal damage at the time of diagnosis, the mucosa healing occurs within 6 to 24 months17.

Without the adherence to a gluten free diet, we have increased risk of17:

Current Treatments and Therapies

Currently, the only treatment for celiac disease is to strictly remove gluten from one’s diet/partaking in a strict gluten-free diet4. This would include restricting consumption of: barley, rye, semolina, wheat, bulgur, etc.4 The complete restriction of gluten from one’s diet can be often difficult and costly as not many appetizing gluten free options exist at affordable costs. Consumption of certain nutrients such as, iron, calcium and folate, in individuals partaking in a gluten-free diet tend to be lower than normal1.

True or False?

The Social Aspect of Celiac Disease

A potential area of concern is the social aspect of celiac disease, especially for individuals that are in their teenage years or that are young adults18. It may be difficult for these individuals to adhere to the strict gluten-free diet as there is a prominent fear of cross-contamination and often a lack of gluten-free options in restaurant settings.

Potential Future Therapies and Treatments for Celiac Disease.

• Drugs that reduce the damage to the intestines/reduce the autoimmune response to gluten consumption are currently in the works19!
• Researchers have been working to reduce the gluten content present in wheat with the use of gene editing20!

REFERENCES

Scan the QR code to view the references used!

If IgA deficiency is identified, then IgG based testing should be performed such as: 1 IgG tissue transglutaminase (IgG-tTG) antibody test 2. IgG deamidated gliadin peptide (IgG- DGP) antibody test (16).

What is celiac disease?

Gluten is a protein complex found in many grains, such as wheat, rye, barley, etc. It acts as a binding agent that provides elasticity, structure and “chewiness” to dough3.

For individuals with celiac disease, ingesting gluten may result in damage to the intestine due the immune response it causes. This damage to the intestinal lining over time can result in malabsorption of nutrients4.

Genetic Factors

Twin studies indicate a genetic background. There is a concordance rate for celiac disease of 75-80% in identical twins. That is, if one twin has celiac disease, there is a 75-80% chance the other twin does too8.Specific alleles have been identified. 90-95% of celiac disease patients carry the HLA-DQ2 allele, and 5-15% carry HLA-DQ8. The HLA genes are related to MHC molecules, which play a key role in the immune system9,10.

Abdominal Distension

Abdominal distension is defined as the measurable increase in abdomen girth (i.e. increase in abdomen diameter)7 Abdominal distension is often presented alongside abdominal bloating.7

The Hygiene Hypothesis

In the past several decades, better hygiene has reduced our exposure to microbes, whether beneficial or harmful. At the same time, cases of autoimmunity have increased8. The hygiene hypothesis suggests that decreased early exposure to commensal microbes removes factors that protect against celiac disease8. While there is evidence of an association between gut microbiome composition and celiac, causation has not been confirmed8.

Sex

Like many other autoimmune conditions, celiac disease is more common in females than in males (1.5 : 1)8.

If positive → does not confirm disease (17) -->many people have these genes but never develop it) Most individuals with the HLA-DQ2 and HLA-DQ8 genes tolerate gluten despite their genetic susceptibility

Gut Health

Imbalances in gut microbiome composition and decreased intestinal barrier integrity can both trigger the onset of celiac disease, in combination with other factors such as immune dysregulation8.

Age

Celiac disease most commonly develops during 1 of 2 age groups8:1. Shortly after weaning (up to 2 years of age) 2. Teenage years & 20s

Associated Conditions

• Down syndrome increases the risk of celiac disease by approximately 6-fold11.
• Type I diabetes is associated with celiac disease, as the HLA-DQ2 allele predisposes to both conditions9.
• IgA deficiency is 10-15 times more common in celiac patients than the general population. Often asymptomatic, when IgA presents clinically, it often does so in the form of autoimmunity - hence, celiac disease12.