Celiac disease is an autoimmune enteropathy that occurs in genetically predisposed individuals after exposure of the intestinal mucosa to gluten in combination with the influence of environmental factors.
It is an immune-mediated disorder caused by genetic, environmental, and immunological factors.
It has a prevalence of ∼1% in most countries worldwide.
Like many autoimmune diseases, celiac disease is more prevalent in women than men at a ratio of 2 or 3:1.
During Celiac disease there are specific serological and histological alterations happening in the body of the individual.
Celiac is a condition of the small intestine which is characterized by:
1) Nutrient malabsorption in the damaged part of the small intestine
2) Characteristic lesions on the intestinal mucosa
3) Rapid clinical and histological improvements of the patient’s health after the removal of gluten from the diet
Patients with celiac disease can present with severe gastrointestinal issues, such as abdominal cramps, indigestion, bloating, diarrhea and constipation, and failure to thrive- the latest being particularly prevalent in children; some may be asymptomatic.
In recent years, there have been significant changes in the diagnosis, pathogenesis, and natural history of this condition , with a rapidly increasing number of diagnoses being identified, even in patients of advanced age.
This is mainly attributed to the greater availability of sensitive and specific screening tests, which allow identification of the risk groups for Celiac disease, and consequently has led to a significant rise in diagnoses worldwide [8, 9, 10, 11].
Nonetheless, Celiac disease still remains a challenging condition despite a steady increase in knowledge of its pathophysiology, diagnosis, management and possible therapeutic solutions.
The symptoms of celiac disease are due to the damage of enterocytes (intestinal cells) in the small intestine.
For Celiac disease to be present, an individual has to have HLA dominant DQ2 or DQ8 genes.
The condition is a result of the immune system reacting adversely to gluten.
Gluten is a general term for alcohol-soluble proteins present in various cereals, including wheat, barley, rye, spelt, and kamut .
The two main proteins in gluten are glutenin and gliadin.
Gliadin is responsible for most of the negative health effects of gluten.
Gliadin enhances zonulin-dependent increased gut paracellular permeability irrespective of disease status, meaning that even healthy people experience a minor and transient disassembly of their interepithelial tight junction complex after gluten ingestion.
This leads to increased uptake of luminal antigens, that can ignite an immune response.
Several theories have suggested that the globalization and widespread promotion of ‘false’ or ‘extreme’ versions of the Mediterranean diet, including the consumption of very high quantities of gluten (up to 20 g/day), has led to an increase in the predominance and incidence of Celiac disease .
In addition, the quality of gluten itself might also play a contributory role.
Indeed, genetic modification of crops and the production of new grain variants due to technological rather than nutritional incentives may have influenced the observed substantial increase in the number of Celiac diagnoses in the last 30 years [10, 11].
However, these hypotheses have not been confirmed and the real cause of the risk in Celiac disease diagnoses remains unclear.
Furthermore, the epidemiological observation that similar ‘epidemics’ are reported for other autoimmune diseases in the Western world  suggests that environmental factors other than gluten ingestion can be at play.
Some of the important proteins involved in Celiac disease are antibodies to tissue transglutaminase (tTG).
There are, however, other pathways said to contribute to the disease.
The glycoprotein gliadin (a component of gluten) has a direct toxic effect on enterocytes through the up-regulation of the cytokine interleukin-15 (IL-15).
Some studies also propose that gastrointestinal infections in early childhood are relevant to the development of celiac disease later in life.
This is not surprising considering the organ affected, but it is also linked to the fact that celiac disease is caused as a result of immune function dysregulation.
Although some symptoms are overt and easy to recognize, others may be subtle or only manifest as long-term complications when Celiac disease remains untreated.
The clinical manifestations of Celiac disease are classical (signs and symptoms of malabsorption including diarrhea, steatorrhea, weight loss, or growth failure), or non-classical and symptomatic (with evident gastrointestinal and/or extra-intestinal symptoms), or completely asymptomatic .
Celiac disease has diverse manifestations and associations, so all physicians need to be aware of its many potential clinical presentations.
The classic manifestation of celiac disease is more common in young children, consisting primarily of gastrointestinal symptoms with malabsorption (chronic diarrhea, abdominal pain, distension, and failure to thrive or weight loss).
Some patients also present with constipation.
In older teenagers and adults, the presentation of celiac disease is often more subtle and can be mistaken for irritable bowel syndrome (IBS).
Some patients lack evident gastrointestinal symptoms and instead present with nutritional deficiencies (most commonly iron deficiency anemia) or extra-intestinal symptoms, while some are symptom-free (asymptomatic).
Celiac disease has many extra-intestinal presentations, including delayed puberty and short stature.
Fatigue and iron deficiency anemia are also common.
Dermatitis herpetiformis, characterized by an often symmetrical, intensely itchy blistering rash, is typically under-recognized.
Frequent oral aphthous ulcers and dental enamel hypoplasia (abnormally thinning of the enamel) can occur, as well as low bone mineral density and osteoporosis.
Celiac hepatitis or celiac mediated liver inflammation develops in as many as 9% of patients evaluated for cryptogenic elevated transaminases (liver enzymes), and can take 6-12 months to resolve when patients are placed on a gluten-free diet (GFD).
Celiac hepatitis usually follows a benign course, but there have been reports that liver failure was reversed with a gluten-free diet (GFD).
Young adults with celiac disease might also be at increased risk of early atherosclerosis .
Additionally, microvascular complications can accelerate in patients who also have type 1 diabetes .
There have been reports of cardiomyopathy and carditis (heart inflammation) in patients with celiac disease, but the evidence for this association is weak.
However, another report found that women with celiac disease did not showcase an overall higher risk of fertility complications than the general population .
Peripheral neuropathy, seizure disorders, cerebellar ataxia, and impaired cognitive function have most often been described in adults with celiac disease, at a lower incidence than in children [22, 23].
Peripheral neuropathy may precede the diagnosis of celiac disease and was reported in 39% of patients, based on responses to a validated questionnaire .
Seizures (sometimes associated with bilateral occipital calcifications), headaches, learning disorders, developmental delays, hypotonia (abnormally decreased muscle tone), and attention deficit hyperactivity disorder (ADHD) are also observed more frequently in children with celiac disease, compared to control groups .
Up to one-third of adult patients were found to have a history of psychiatric disorders, such as depression or personality changes, and less commonly, psychosis .
Little is understood about the mechanisms by which celiac disease might lead to neurological disorders.
Chronic neurologic changes do not seem to disappear on a gluten-free diet (GFD).
However, a patient’s response to a gluten-free diet (GFD) could be more significant if they are diagnosed early—especially patients with gluten-associated ataxia or those who test positive for anti-gliadin antibodies (AGA), with neurologic symptoms or abnormal findings from brain imaging analyses .
It is important to note that many of these patients with neurological symptoms have not met the full diagnostic criteria for celiac disease.
No Symptoms (Asymptomatic Celiac Disease)
A substantial proportion of patients with autoimmunity and enteropathy are asymptomatic, identified only because of genetic risk or celiac-associated diseases.
There is controversy over whether patients without symptoms or signs should be screened and treated for Celiac.
The rationale for proactive testing and treatment is to prevent the deleterious long-term complications of untreated celiac disease.
Conversely, diagnosis and subsequent adherence to a gluten-free diet (GFD) carry substantial economic and psychosocial costs.
More comprehensive and reliable data are required on the feasibility and cost to benefit ratio of screening at-risk, symptomless populations for celiac disease, in order to guide the rational development of screening programs.
Iron deficiency has been reported in up to 50% of newly diagnosed adults, and in itself should be an indication for screening .
Some patients with folate (vitamin B₉) or vitamin B12 deficiency may develop macrocytic anemia, which can be hard to detect in patients with co-existing iron deficiency.
Co-existing Autoimmune and Other Conditions
Autoimmune thyroid disease (i.e., Hashimoto’s Thyroiditis) and type 1 diabetes mellitus are the most common autoimmune diseases that occur with celiac disease.
Celiac disease is present in about 10% of patients with type 1 diabetes.
On the other hand, people with celiac disease have a 240% increase in risk for type 1 diabetes before they are 20 years old .
Celiac disease is observed in about 7% of patients with autoimmune thyroid disorders.
Celiac disease, type 1 diabetes mellitus, and autoimmune thyroid disease are all associated with HLA risk alleles (namely HLA-DQ2 and/or DQ8).
Direct associations with Sjögren syndrome, Addison’s disease, parathyroid disorders, and growth hormone deficiency have also been reported.
Celiac disease also has a higher prevalence among patients with autoimmune hepatitis or primary biliary cirrhosis, with weaker evidence for primary sclerosing cholangitis .
There is only weak data suggesting that a gluten-free diet (GFD) can affect the risk for other autoimmune conditions in patients with celiac disease.
Cancer Risk in Celiac Disease
Mortality risk was highest shortly after diagnosis and in those with active malabsorption and enteropathy, suggesting a possible beneficial effect of a gluten-free diet (GFD) on cancer prevention [40, 41, 42, 43].
Celiac disease was first associated with small intestinal adenocarcinoma, and then with non-Hodgkins lymphoma, and more specifically with small intestinal T-cell lymphoma, also known as enteropathy-associated T-cell lymphoma (EATL).
Risks for other gastrointestinal cancers, including gastric and colon cancer, are not substantially increased in celiac disease, while risk for some cancers, including breast cancer, may actually be lower [44, 45, 46].
Non-Hodgkins lymphoma is the most common celiac-associated form of cancer.
Early studies suggesting that celiac disease patients are at a high risk of non-Hodgkins lymphoma were based on relatively small case series.
The risk of malignancy is highest in the first years after diagnosis and, similar to overall mortality, decreases to normal or near-normal levels within 5 years after diagnosis.
The post-diagnosis decrease in lymphoma risk distinguishes celiac disease from other autoimmune disorders, including rheumatoid arthritis, Sjögren’s syndrome, and Crohn’s disease, for which the risk of lymphoma remains high or increases over time .
Small intestinal adenocarcinomas are rare in the general population (estimated incidence is 1 in 100,000 people), but the risk is increased by more than 1000% in patients with celiac disease [45, 48, 49].
Unlike enteropathy-associated T-cell lymphoma (EATL), small intestinal adenocarcinoma is not associated with refractory celiac disease.
Refractory celiac disease can be defined as persistent or recurrent small intestinal villous atrophy with symptoms of malabsorption, despite ≥12 months of a strict gluten-free diet (GFD), and in the absence of other conditions that cause villous atrophy .
Patients with celiac disease and obscure gastrointestinal bleeding, new or persistent anemia, or obstructive symptoms should have a careful small bowel examination, by computed tomography or magnetic resonance enterography or capsule endoscopy.
As suggested by its name, enteropathy-associated T-cell lymphoma (EATL) was initially described based on its strong association with celiac disease.
More than half of enteropathy-associated T-cell lymphoma (EATL) cases are diagnosed simultaneously with celiac disease.
There are two types of enteropathy-associated T-cell lymphoma (EATL).
Type I EATL is associated with celiac disease and accounts for 80% of cases in the western world.
Its major risk factor is Type 2 refractory celiac disease .
Type II EATL is less well characterized and not associated with celiac disease or the associated HLA haplotypes DQ2 or DQ8.
Although the risk for certain types of cancer is increased in patients with celiac disease, their most frequent causes of morbidity and mortality are the same as those of the general population: cardiovascular disease, breast cancer (in women), prostate cancer (in men), and colon cancers in both sexes.
Thus, there are no celiac-specific cancer screening recommendations.
Diagnosis / Testing
The diagnosis of celiac disease is made using a combination of serological tests (bloodwork), small bowel biopsies, and the patient’s response to a strict gluten-free diet.
Various antibody tests can be used as initial tests in patients with clinically suspected celiac disease.
Due to their low sensitivity and specificity, antigliadin antibodies (AGA) are no longer recommended for initial screening.
Serological tests performed as part of the disease management protocol include those that detect total IgA antibodies and IgA antibodies against tissue transglutaminase (tTG), endomysium (EMA), and gliadin (AGA).
Many people have detectable, but low IgA levels.
For these people, the accuracy of IgA-based serological tests is considered unreliable and unaffected by celiac disease.
In such cases, the IgG assay of deamidated gliadin peptides can be performed in people with IgA deficiency.
Recently, new methods have been developed based on peptides produced through the deamination of gliadin, that incorporate IgA and IgG antibodies (DGP test).
In that way, Celiac patients who have IgA immunodeficiency and cannot produce IgA antibodies against any naturally soluble antigen, tissue transglutaminase, endomysium, and gliadin, can be properly diagnosed.
About 5% of patients with celiac disease have a deficiency of IgA immunoglobulins.
For a complete diagnosis of celiac disease, in addition to the serological screening, endoscopy of the upper digestive tract along with histological examination of multiple biopsies from the duodenum is required.
Upper gastrointestinal endoscopy along with duodenal biopsy are an important part of the diagnostic procedure in patients with suspected celiac disease and are recommended to confirm the diagnosis.
Finally, another sign of Celiac disease is the relief of symptoms when the patient starts adhering to a strict gluten-free diet (GFD).
The outcome of the disease can very good as long as the diagnosis is timely and the treatment is meticulous.
Celiac cases that are not diagnosed or treated properly can create severe malabsorption and malnutrition issues, and even have fatal complications, such as intestinal bleeding or infection.
Monitoring the course of the disease is mainly based on a biopsy of the small intestinal mucosa.
The number of serum autoantibodies decreases with the improvement of histological lesions and can also be used to monitor already diagnosed Celiac patients.
Celiac disease is a lifelong inflammatory condition that affects multiple organ systems, so patients should be monitored routinely.
There are no differences in recommendations for managing symptomatic vs asymptomatic patients.
Based on expert consensus, at the time of the diagnosis, patients should be evaluated for common co-existing autoimmune conditions, such as thyroid and liver diseases, as well as deficiencies in iron, vitamin D, and vitamin B12.
It is also important to consider zinc, folate, and other nutrient deficiencies, based on regional trends and patient symptoms.
There should be a low-threshold to test patients for other autoimmune diseases based on their symptoms or signs.
There is general agreement among guidelines that patients should be examined at least twice in their first year after diagnosis, to monitor symptoms, dietary adherence, nutrition, body mass index, and blood biomarkers [37, 38, 39].
It is also recommended that all people diagnosed with celiac disease should follow a strict gluten-free diet (GFD).
This adherence is best done under the supervision of a specialist, including a dietician.
In general, symptoms improve on a gluten-free diet within days to weeks.
Unresponsive patients require a further review of the diagnosis, but also an assessment of compliance with the diet.
Bloodwork testing can assess compliance.
Even traces of gluten can have adverse effects on patients with celiac disease.
Patients whose blood biomarkers do not improve should be re-evaluated for continued involuntary gluten exposure (cross-contamination).
Other tests include looking at the impact of malabsorption due to Celiac disease.
The following markers can be monitored: full blood count, iron stores, folate, ferritin, levels of vitamin D and other fat-soluble vitamins, and bone mineral density.
Low bone mineral density is one of the more common extraintestinal manifestations of celiac disease, so DXA evaluation is generally recommended in the first year after diagnosis .
Management of patients with Celiac-positive serum tests, but no abnormal findings on their duodenal biopsy is controversial.
There are many situations when the diagnosis is not clear-cut. Some patients can experience relevant symptoms despite no identified changes in their small intestinal biopsy.
On the opposite side, Celiac disease can also be present when serum tests are negative (seronegative celiac disease).
Although the specific antibodies for Celiac disease can be detected in the vast majority of patients, a small number of Celiac patients (around 2–3%) test negative for serological markers.
This case describes the reverse situation when despite typical symptoms being manifested, there is no evidence of the disease in bloodwork, but there is significant villous atrophy of duodenal biopsy.
If you have gluten or even casein by mistake, the side-effects will vary, depending on your physiology and genetics, how much gluten/casein you consumed, your gut integrity status (how permeable it is), how long you have been gluten-free, and other factors.
From individual to individual, reactions to gluten can vary from severe, unpleasant reactions – like headaches, stomach ache, bloating, constipation, diarrhea, brain fog, severe depression – which can develop quickly, to those where the person does not even realize he/she has ingested gluten.
The individuality factor is so strong that even siblings who both suffer from Celiac disease can exhibit completely different symptomatology when they get “glutened”.
However, in all cases and no matter the overt symptoms, gluten ingestion will lead to autoimmune activity and damage – the intestinal villi will get attacked by the immune system – which will aggressively respond to the semi-digested/undigested gluten molecules floating in the digestive tract.
The nasty side effects (and not the damage) of involuntary gluten consumption may be minimized by a product called Gluten Guardian, which has been shown to minimize cross-contamination symptoms in Celiac patients and gluten-intolerant individuals.
It is a formula blend of 6 plant-based proteolytic enzymes that includes Peptidase DPP-IV (an enzyme clinically proven to help break down gluten) — as well as three enzymes that break down starches and sugars into monosaccharides.
It may be used as a precautionary measure (and not a cure) for anyone dealing with gluten/casein sensitivity or intolerance, Celiac disease, autoimmune issues, bloating, indigestion, excessive gas, or constipation.
Currently, the only recommended treatment for celiac disease is a gluten-free diet.
This can make a significant impact on the lives of people affected and can be challenging to maintain.
There is continuous work on possible non-dietary therapies that will enable people with Celiac disease to tolerate gluten.
One of the main areas of focus of this research is immune modulators.
Other approaches, like immunizations or ingesting substances that would change the toxicity of gluten are also being investigated.
However, none have reached a stage of being recommended or approved as a therapy.
The use of corticosteroids benefits only a small minority of patients with celiac disease.
Although there has been a substantial increase in the number of celiac disease diagnoses over the last 30 years, many patients remain undiagnosed .
The flowchart for identifying celiac disease in adults must always include both bloodwork and intestinal biopsy, whereas genetic testing should only be performed in specific cases.
Diagnostic criteria should help physicians in avoiding misdiagnosis and missing cases of the disease (i.e. patients with negative serum tests and classic symptomatology not undergoing biopsy) and preserve people from an unjustified gluten-free diet (GFD).
The treatment for Celiac disease is still primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up.
Slow response to the diet occurs frequently, particularly in people diagnosed in adulthood.
Persistent or recurring symptoms should point to a review of the patient’s original diagnosis, exclude alternative diagnoses, evaluation of the gluten-free diet’s quality (i.e., exclusion of cross-contamination), and bloodwork, as well as histological assessment in order to monitor disease status.
Additionally, evaluation for other disorders that could cause persistent symptoms and complications of celiac disease, such as refractory celiac disease or lymphoma, should also be pursued.
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About George Kelly
George Kelly M.Sc is a Sports Nutritionist, Functional Nutritional Therapy Practitioner (FNTP), and Metabolic Type expert. He is the CEO and lead author of Metabolic Body.
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