Celiac (coeliac) disease
Sprue / gluten-sensitive enteropathy
Celiac’s disease is an immune-mediated disorder in genetically predisposed individuals associated with the ingestion of gluten, a protein present in wheat, rye and barley. Incompletely digested gluten, or more specifically the gliadin protein portion, leads to inflammatory reactions predominantly in the small intestine.
This process may be enhanced by factors increasing the leakiness of the intestinal lining (increased intestinal permeability), such as infections, drugs and surgery. Breastfeeding infants beyond the time of gluten introduction in the diet may reduce the risk of developing celiac’s disease in childhood.
Frequency in population
Approximately 1% of the population has celiac’s disease, as detected by screening methods, most of whom are asymptomatic. The incidence may be even higher in 1st degree (5-22%) and 2nd degree (2-15%) relatives of individuals with manifest celiac’s disease, as well as in patients with diabetes mellitus type 1 (2-8%), autoimmune thyroiditis (2-7%), liver disease (2-9%), Down’s (5%) and Turner’s (6%) syndromes, unexplained infertility (4%), and especially a skin disease known as dermatitis herpetiformis (100%).
Both children and adults are affected by celiac’s disease.
Twenty-five percent of patients with newly diagnosed celiac’s disease are now over 60 years old.
Symptoms and signs of celiac’s disease range from unspecific, such as fatigue, anemia, osteoporosis, malabsorption of vitamins and minerals, dental enamel malformations, skin, thyroid or liver disease, growth retardation in children, possibly infertility or miscarriages, and neurologic symptoms, to classic gastrointestinal, including diarrhea or constipation, bloating / abdominal distension, flatulence, increased intestinal sounds, abdominal pain and cramps, vomiting and weight loss.
Diverse rheumatologic, dermatologic, neurologic, and autoimmune disorders, as well as depression are associated with celiac’s disease and there is an increased incidence of small bowel cancer in inadequately managed disease. Over 35% of patients with subsequently diagnosed celiac’s disease have earlier received a diagnosis of irritable bowel syndrome. Inflammation in the small intestine due to celiac’s disease is a common reason for so-called secondary lactose (milk sugar) and/or fructose intolerance, unexplained iron deficiency or anemia and osteoporosis. Celiac’s disease may be completely asymptomatic.
Testing and diagnosis
Diagnosis is possible using tissue samples (biopsies) from the small intestine taken during upper endoscopy and with blood tests for specific antibodies (anti-transglutaminase: TG2, anti-gliadin: DGP, anti-endomysium: EMA), as well as genetic markers. Initial diagnosis of the tests discussed below must be performed before exclusion of gluten from the diet. Ideally, blood tests and duodenal biopsy results all support the diagnosis.
Screening for celiac’s disease is best performed in blood samples using IgA anti-transglutaminase antibodies.
This test is accurate in about 90% of cases, but there are differences between the different test assays available.
The tests are less exact in milder than in more severe forms of the disease. IgA anti-endomysial antibody testing is an alternative, but considerably more costly and difficult to perform. Total IgA levels should be measured, if they are suspected to be low. Anti-gliadin antibody tests should no longer be used, except the newest generation of deamidated gliadin peptide (α-DGP) antibody tests. Finger prick blood tests are being marketed, but their usefulness remains to be ascertained.
In case of a positive blood antibody test, a conclusive diagnosis should be made from duodenal biopsies. The antibodies can also be used to monitor long term adherence to the diet, as they correlate with the degree of intestinal inflammation due to the disease process.
In case of negative antibody tests and normal total IgA levels, small intestinal biopsy is the conclusive diagnostic step for exclusion of celiac’s disease.
The genetic markers HLA-DQ2.5 and HLA-DQ8 are very strongly associated with celiac’s disease, as about 95% of patients have DQ2.5 and about 5% have DQ8. However, close to 40% of western populations without celiac’s disease also have these markers. Therefore, as almost all celiac’s disease patients have these markers, absence of the markers virtually excludes the diagnosis, but a positive test is not conclusive for celiac’s disease. Consequently, a positive test must be confirmed by small intestinal biopsies. Negative markers virtually exclude the disease, but positive markers also occur in over 40% of unaffected individuals. As the population prevalence is 1% and heritability is ca. 50%, the 40 known non-HLA genes account for 14% of the genetic variance, while the HLA genes account for 40%.
Conclusive proof or exclusion of celiac’s disease is always by duodenal biopsy, except, possibly, in children.
Between 6-22% of celiac’s disease is not accompanied by increased antibodies (see above), making biopsy the most reliable form of diagnosis.
Pathologists look for characteristic changes in the tissue samples, such as a decrease in the height of the hair-like folds (villi) and the troughs (crypts) of the duodenal lining and an increase in specific inflammatory cells in a part of this lining. These changes may be very subtle and difficult to recognize as well as unevenly distributed in the small intestine, which is why multiple (at least four, better six) biopsies deep down in the duodenum are recommended. If these first biopsies are inconclusive, a second set of biopsies taken after exposure to higher concentrations of gluten for several weeks may be required. Follow-up endoscopies with biopsies are recommended, especially in the case of inadequate symptom relief despite dietary adaptation. The large majority of non-response is due to dietary mistakes, although a small percentage of patients do not respond despite meticulous exclusion of gluten. In the latter case, further diagnostic evaluation by a specialist is warranted.
Further diagnostic considerations
A significant reduction of symptoms on a strict gluten-free diet is an important aspect of the diagnostic evaluation. If there is inadequate symptomatic relief, the diagnostic work-up needs to continue. This will include further biopsies, stool tests for parasites, blood tests for infectious diseases including HIV and allergies, breath tests for food intolerances and, possibly, colonoscopy. Capsule endoscopy, where a miniature capsule-sized video camera is swallowed, can reveal celiac’s disease and exclude other disease. A conclusive diagnosis of celiac’s disease is, however, not possible due to the inability to take tissue samples.
Patients with celiac’s disease often have accompanying diseases or deficiencies, (e.g. vitamins and minerals). Specialist follow-up is absolutely necessary.
The microscopic changes seen in celiac’s disease may occasionally resemble those seen in other diseases, such as infections. If there is any uncertainty, such diseases should be excluded using further tests.
It is estimated a substantial proportion of celiac’s disease may remain undiagnosed. Besides symptomatic individuals, other high-risk populations should be screened as well. These include symptomatic relatives of individuals with known celiac’s disease, individuals with iron deficiency anemia, premature or severe osteoporosis, type 1 diabetes mellitus, certain types of skin, liver, nervous system or thyroid disease, as well as specific genetic disorders (e.g. Down’s and Turner’s syndromes). A careful history, including food reactions and family history, is always required.
Treatment is currently via meticulous and life-long dietary exclusion of gluten.
This requires long-term expert dietary advice, support and medical surveillance. Wheat, rye and barley must be excluded from the diet and they occur in hidden form in many processed foods, beverages and medicines. Oats are gluten-free, but can be gluten-contaminated due to processing procedures. They are tolerated by most patients. A wide range of gluten-free foods are now offered in many countries and patient support organizations offer useful support and resources (see links below, also for food lists). The term ‘gluten-free’ actually implies gluten levels below a certain limit, as defined by governments. Some governments subsidize the special dietary needs.
Once the disease is stable and patients manage their diet without any problems, annual follow-ups should be initiated in this multi-organ disease. The physician should check on intact small intestinal absorption (full blood count, ferritin, serum folate, vitamin B12, calcium, alkaline phosphatase), associated autoimmune conditions (thyroid-stimulating hormone and thyroid hormone(s), and serum glucose) and liver disease (aspartate aminotransferase/alanine aminotransferase). Vitamin and mineral supplements are often necessary. Adherence to the gluten-free diet and disease regression should be periodically assessed using blood antibody tests (e.g. anti-transglutaminase or gliadin antibody), or small intestinal biopsies. In the follow-up of celiac’s disease, the main goals are the absence of symptoms and healing of intestinal inflammation. The proportion of patients who are not able to reach full histological healing on the diet varies between 57–76%.
With strict adherence and a good clinical response, many of the potential disease complications can be prevented. However, due to an increased incidence of some cancers and other autoimmune disorders, follow-up at reasonable intervals is recommended. Improvement in symptoms can occur within 2 weeks of beginning the diet and antibodies can revert to normal within 3-12 months. Lactose intolerance often resolves naturally with time.
Inadequate responses to a gluten-free diet are most commonly due to dietary errors, although about between 4-30% of patients have persisting symptoms (‘non-responsive celiac’s disease”) or abnormal villi (refractory celiac’s disease) despite dietary adherence. In these cases further diagnostic workup is required. Non-responsive celiac’s disease exists in two forms based on immune cell characteristics (T-cells) and may respond to steroids or immunosuppressive drugs.
Currently contentious issues include the necessity of a gluten-free diet in asymptomatic individuals testing positive for celiac’s disease, the maximum amount of gluten permitted in foods labeled as ‘gluten-free” and interpretation of cereal or gluten sensitivity without evidence of celiac’s disease. It should be noted not all intolerances to grains constitute celiac’s disease (non-celiac’s gluten sensitivity). In case of suggestive symptoms other cereal allergies and intolerances should also be considered. Such differential diagnoses are wheat allergy and fructan intolerance.
Various novel therapies are undergoing evaluation, including the development of cereals free of the causative proteins by genetic modification, induction of immune tolerance, tight junction modulators and ingestion of supplements digesting the offending dietary proteins.
Links to literature, including support organizations
Medications and Celiac Disease— Tips From a Pharmacist
The Celiac Diet, Series #5PDF Download