All You Need To Know About Coeliac Disease

 
Wheat Field

Posted: 25/10/2017

Updated: 23/06/2018

Related article: Gluten-free diet

Gluten-free” has been seen more common nowadays served in restaurants and bakeries such as gluten-free pizza, gluten-free cereal, gluten-free pastries. Gluten is the protein that makes dough elastic and gives bread its chewy texture.

 

Gluten-free is crucial for those who suffer from coeliac disease or also sometimes referred to coeliac sprue. There is an increasing awareness and improved diagnosis of coeliac disease yet many people who suffer from it does not exhibit symptoms and are unaware of it until later in life.

 

Coeliac disease is a lifelong, autoimmune disease that causes chronic inflammation in the small intestine after the ingestion of gluten which is found in all sorts of wheat and grains, including rye and barley (1).

 

So, where is gluten come from? By taking a deeper look at the inside of wheat kernels, the endosperm provides storage for carbohydrates, starch and some vitamins for the seed’s embryo. The type of protein found here is gluten, the main culprit in Coeliac disease.

Gluten intolerance is different from coeliac disease - this is an auto-immune disease caused by a reaction to gluten, which must be avoided for life.

Source: Old Time Remedies, Health, and Wellness (2).

More specifically, the main culprit behind coeliac disease are prolamins, a group of plant storage proteins.

 

The prolamins in wheat are gliadins, secalins in rye, hordeins in barley, zeins in corn and kafirins in sorghum.

 

Prolamins are rich in proline and glutamine, two amino acids that are difficult to digest. In wheat, the remarkably stable 33-amino acid peptide called gliadin resists being broken down by stomach enzymes.

Health Impacts

The problem begins when gluten initiates an immune response that attacks the small intestine. These attacks lead to damage on the villi, small finger-like projections found along the wall of the small intestine. When the villi are injured, nutrients cannot be absorbed properly into the body (4). This can lead to malnourishment, miscarriages, infertility, and even certain cancers (5).

 

Coeliac disease is one of the most common genetic diseases that result from both environmental and genetic factors (6).

Source: Mayo Clinic (3)

Prevalence

 

Prevalence of coeliac disease worldwide (7).

 

The prevalence of coeliac disease has been estimated to approximate 0.5%-1% in different parts of the world (8). It was once assumed to be a rare disease restricted to Europe. However, it is discovered that it is not that uncommon and occurs equally in both children and adults. Females are more prone to this disease with a male to female ratio of 1:2 (9).

 

In the UK, this condition affects approximately 1 in 100 people and only 24% are diagnosed (10). In America, 1 out of every 133 Americans suffers from coeliac disease according to NIDDK (11). Furthermore, 2.5 million Americans are undiagnosed and are at risk for long-term health complications.

The Coeliac Iceberg

 

The coeliac iceberg model represents the various manifestations of coeliac disease.

At the tip of the iceberg, approximately 30% of sufferers present the typical gastrointestinal symptoms (symptomatic) and thereby, these cases are identified in early life.

 

Despite more cases are being identified, many more remain undiagnosed. This could represent 70%-80% of most cases as shown at the submerged part of the iceberg model.

 

This can be further be subdivided into silent and latent cases either showing ambiguous symptoms or no symptoms at all. This group without receiving any dietary treatment may suffer from complications.

Who are at risk?

  • Families who have it

  • Women

  • Individuals with coeliac disease associated disorders

    • Type 1 diabetes

    • Down syndrome

    • Thyroid disease

    • Rheumatoid arthritis

Source: The patient celiac (12).

 

  • Symptomatic: Clinical symptoms present related to abnormal intestinal absorption. Normally occurs after weaning onto foods comprising prolamins.
    Histology shows damage to the intestinal lining (villous atrophy and crypt hyperplasia) and positive blood test results for coeliac disease.

     

  • Silent: No classic clinical symptoms but present manifestations of nutritional deficiency.
    Histology shows damage to the intestinal lining (villous atrophy and crypt hyperplasia) and positive blood test results for coeliac disease.

     

  • Latent: this represents those who are genetically predisposed to develop coeliac disease but have yet to do so.
    There is no present damage to the intestinal lining but blood test results are positive.

Symptoms

 

The classic symptoms of coeliac disease include gastrointestinal-related symptoms such as abdominal pain, abdominal distension (bloating), diarrhoea, steatorrhea, weight loss.

 

With the damaged intestinal walls, severe malabsorption ensues resulting in several nutritional deficiencies and the failure to thrive during the first couple years of life.

 

Furthermore, approximately 50% of sufferers present extraintestinal symptoms such as dermatitis herpetiformis, infertility and neurological problems as listed below.

Dermatitis herpetiformis is a skin condition in which a bumpy skin rash breaks out and occurs up to 15 to 25% of those with coeliac disease. Note that not all coeliac disease patients have dermatitis herpetiformis but all dermatitis herpetiformis patients have coeliac disease (13).  

Nutritional deficiencies

The damaged gastrointestinal mucosa reduces the surface area for absorption and production of digestive enzymes which causes nutritional deficiencies.

Vitamin B12 deficiency also associated with elevated plasma homocysteine

Impaired calcium and fat-soluble vitamin D absorption subsequently leads to rickets, low bone mineral density and osteoporosis

Iron deficiency occurs as the duodenum is primary absorption site for iron and where lesions occur and results in anaemia

Vitamin K deficiency leads to coagulopathy (impaired clotting) and subsequently excessive bleeding

Low serum folate concentrations associated with elevated plasma homocysteine (article here) but not severe enough to cause megaloblastic anaemia

Clinical Features of Coeliac Disease

Extraintestinal manifestations

Arthritis

Aphthous stomatitis

Dermatitis Herpetiformis

Osteoporosis/Osteopenia

Elevations in transaminases

Infertility

Recurrent abortions

Neurologic

Ataxia

Epilepsy

Psychiatric

Anxiety

Depression

Symptoms

Gastrointestinal

diarrhoea

Abdominal pain

Bloating

Constipation

Growth

Short Stature

Delayed puberty

Associated Conditions

Type 1 diabetes

Autoimmune thyroid disease

Down syndrome

Turner syndrome

IgA deficiency

IgA nephropathy

The list of clinical features of Coeliac Disease (14).

 

Pathophysiology

Source: Mucosal Immunology (15).

 

1. When gliadin reaches the small intestine, it is bound to secretory IgA, an antibody that helps protect intestinal epithelial cells (enterocytes) from pathogens. Anything bound to secretory IgA is usually marked for immune cell destruction, but in coeliac disease, this gliadin IgA complex binds to a transferrin receptor (TfR) which normally works to absorb iron.

 

2. This complex is then trancytosed across the enterocyte and into the lamina propria which is a layer in the gut wall.

 

3. An enzyme called tissue transglutaminase (tTG) cuts off an amide group from the protein, a process called deamidation.

 

4. In the lamina propria, as gliadin is deamidated by the enzyme transglutaminase (tTG), it creates potent immuno-stimulatory epitope (the part of an antigen molecule to which an antibody attaches itself) that are presented via HLA-DQ2 or HLA-DQ8 on antigen presenting cells (APC).

 

Human leukocyte antigen (HLA) are Major Histocompatibility Complex (MHC) class II molecules, a set of cell surface proteins vital for the immune system to recognise foreign molecules (antigens) and remove them (16). Researchers have noticed that patients with coeliac disease typically have HLA-DQ2 or HLA-DQ8 gene that is mainly responsible for the disease.

 

5. With these genes, CD4+ T immune cells are activated secreting inflammatory cytokines like interferon-y (IFN-y) and tumour necrosis factor (TNF α), causing epithelial damage (17).

 

6. The T helper cells also stimulate B immune cells to start releasing IgA antibodies against gliadin, the transglutaminase (tTG) enzyme.

 

7. Leaky Gut

  • Transglutaminase (tTG) has many functions with one that is responsible for holding together the microvilli in our gut. Antibodies produced against gliadin can attack transglutaminase (tTG) causing the atrophy and erosion of microvilli in the gut.

 

  • This worsens when gut cells release zonulin, a protein that breaks apart tight junctions holding the intestine together. This reduces absorption and allows the intestinal walls to become permeable aka “leaky”. A leaky gut allows toxins, microbes and antibodies (even the ones produced against gliadin) to escape from your intestines and travel throughout your body via your bloodstream (18).

 

  • More gliadin can cross from the lumen to the lamina propria of the intestine available to deamidated by transglutaminase (tTG).

 

8. Finally, the T helper cells recruit killer CD8+ cells that are drawn to and destroy cells undergoing inflammation (19)

 

Thereafter, it results in mucosal inflammation, and the growth of unfavourable microbiota, worsening the disease (20).

 

In short, patients eat gluten, the immune system is stimulated and epithelial cells are destroyed. It is possible that the destruction of these cells lets more gliadin across the epithelium since they are not held as tightly as they were before.

 

Check out this informative animation here. 

Genetic Factor

 

The genetic risk for coeliac disease is largely related to HLA genotypes.

 

Individuals with human leukocyte antigen (HLA) DQ2 and DQ8 are at much greater risk of developing the disease. These genes have a high tendency of 10% to be inherited in first degree relatives (21).

 

  • 33% MHC Class II proteins including human leukocyte antigen HLA-DQ2 and HLA-DQ8

    • 90% affected express HLA-DQ2 molecules

    • 10% express HLA-DQ8 (22)

  • HLA is one of the main factors but a multitude of genetic factors are responsible.

 

HLA-DQ is a cell surface receptor protein found on antigen presenting cells and its role is to present peptide fragments of antigens to T cells (23).

 

In addition, coeliac disease also carries an increased risk of developing another autoimmune disorder including type 1 diabetes, thyroid disease, in that the majority of risk in these populations is related to HLA genotype (24).

Environmental Factors

 

The amount of gluten and timing of gluten introduction during weaning can also play a role in influencing the intestinal microenvironment (25).

 

If solid foods are introduced before the intestinal immune system reaches a certain level of maturation, it increases the chance of developing intolerance (26). However, the precise cause is still unknown.

Diagnosis

 

Serology testing looks for antibodies in the blood. Elevated levels of certain antibodies indicate an immune reaction to gluten.

  • IgA blood tests for both transglutaminase (tTG) and endomysial transglutaminase (tTG) in more severe cases

  • Tests for IgA or IgG antibodies against gliadin

Genetic testing for human leukocyte antigens (HLA-DQ2 and HLA-DQ8)

 

Endoscopic biopsy is a more invasive way which requires taking a small tissue sample to analyse intestinal cells.

  • The morphological features include increased numbers of intraepithelial lymphocytes (IELs), decreased enterocyte height, villous atrophy, and crypt hyperplasia.

Coeliac Disease: villi are destroyed and flattened out (villous atrophy) and crypts are elongated (crypt hyperplasia) possibly from the immune response or from the remodelling process that occurs during chronic inflammation. The structural change reduces the amount of epithelial surface available for absorption (27).

 

These characteristic changes can be graded by the Marsh score. Diagnosis is based on abnormalities of small intestinal biopsy.

Modified Marsh-Oberhuber classification of histologic findings on coeliac disease

IEL/100 enterocytes: intraepithelial lymphocytes per 100 enterocytes

Source: Stanford Medicine (28).

 

  • Type 0: Normal; coeliac disease highly unlikely

  • Type 1: Seen in patients on a gluten-free diet (suggesting minimal amounts of gluten or gliadin are being ingested); patients with dermatitis herpetiformis; family members of coeliac disease patients, not specific, may be seen in infections.

  • Type 2: Very rare, seen occasionally in dermatitis herpetiformis.

  • Type 3: Spectrum of changes seen in symptomatic coeliac disease.

Dietary Intervention

 

People diagnosed with coeliac disease must follow a strict life-long of a gluten-free diet.

 

Prolamins in wheat (gliadin), barley (hordein), rye (secalin) and so on must be excluded.

 

Avenin found in oats may not be as toxic as it seems as it occurs in much lower concentrations than other prolamins but this remains controversial (29). Oat products may be contaminated with gluten during manufacturing and impose an imminent risk for those sensitive to gluten. However, due to frequent food contamination, the total avoidance of gluten intake is inevitable (30).

 

Hence in August 2011, the FDA has set the limit of < 20 ppm gluten (equivalent to 10 ppm gliadin) in gluten-free foods for safety purposes. For some individuals, the threshold of prolonged gluten ingestion may be lower than 50 mg/day (31). Products between 21 to 100 ppm may be labelled as “very low in gluten”. In addition, component ingredients must not contain gluten.

 

For some people who begin to adhere to a gluten-free diet, there is still an increased chance of refractory disease such as small bowel cancer, presumably as a result of inflammation over time. However, for most people, inflammation ultimately resolves and the small intestine begins to heal once gluten is removed (32).

 

Severe cases may require both adherence to a gluten-free diet and improvement in nutrient replacement therapy to correct nutritional deficiencies.

The British Society of Gastroenterology and Coeliac UK suggests that all patients with coeliac disease should be advised to take 1000 mg of calcium per day using supplements, increasing to 1200 mg in males over 55 and post-menopausal women.

 

However, remember to make sure these vitamins are gluten-free. In addition, injections may be given by doctors if your digestive tract has problems with absorption.

Supplementation:

  • Calcium

  • Folate

  • Iron

  • Vitamin B-12

  • Vitamin D

  • Vitamin K

  • Zinc

Refractory Coeliac Disease (RCD)

After a period of strict gluten-free diet, the presence of malabsorptive symptoms and villous atrophy may still exist. Apparently, 5-30% patients do not respond to a gluten-free diet and others may initially respond but have reoccurrences of symptoms and intestinal damage (33).

 

There are limited studies on the treatment of coeliac disease and many therapeutic interventions are being studied for use now. Drug treatments such as steroids, immunosuppressive drugs, and chemotherapy are used but only tested in small amounts of people (34).

 

Hopefully, in the near future, more effective treatments for RCD will become available and improve the outlook for patients.