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January Newsletter - Research
Coeliac disease (CD) is defined as an intolerance to gluten proteins from wheat, rye and barley affecting genetically susceptible individuals. The estimated prevalence is around 1%, being the most frequent chronic digestive disease in the general population. Both genetic and environmental factors are involved in the onset of this immunological disorder, which causes villous atrophy in the small intestine and malabsorption of nutrients. Catassi & Fasano (2008) give an overview of the disease, focusing on genetics, treatment and future therapies.
Genetics of CD
Human leukocyte antigen (HLA) alleles coding for the proteins HLA-DQ2 and/or HLA-DQ8 are the main genetic risk factors associated with coeliac disease. However, a number of other genetic regions located in different chromosomes are being investigated. Most of them contain immune-related genes which may contribute to the disease. The main candidate genes are summarized in Catassi & Fasano (2008). On the other hand, a review by Cassinotti et al (2009) shows the main features of the HLA genetic system and the close relationship between these genes and different autoimmune diseases, among which coeliac disease is studied in detail.
Pathogenesis of CD
The gluten intolerance is caused by an abnormal activation of the immune system of the gut in response to some gluten-derived peptides, mainly gliadins. This activation involves both the innate and the adaptative immune response, leading to inflammation-based destruction of the mucosa and autoimmunity. Heap & van Heel (2009) show how gliadins activate the innate immune response causing destruction of the gut epithelium, and also the adaptative immune response, where gliadins deamidated by the enzyme tissue transglutaminase (tTG or TG2) are presented in the context of HLA-DQ2 and/or HLA-DQ8 proteins to gliadin-specific T cells, further enhancing citotoxicity in the gut mucosa and producing antibodies against both gliadins and self antigens such as TG2. Sollid (2002) deepens on the inflammatory mechanisms underlying the coeliac pathology.
Diagnosis of CD
The clinical manifestations of coeliac disease vary from gastrointestinal symptoms due to gut damage to a variety of extra-intestinal alterations derived from the lack of nutrients and the presence of autoantibodies. Gastrointestinal symptoms are common when the onset of the disease occurs during the childhood, while most coeliac adults happen to show extra intestinal manifestations or are even asymptomatic. Zisper et al (2003) evidenced this situation studying the symptoms experienced by over a thousand North American adult coeliac patients. Thus, many (70-90%) people suffering from coeliac disease remains undiagnosed, what might increase the risk to develop any of the so-called CD associated diseases, i.e., endocrine and neurologic disorders and intestinal malignancies. Alaedani & Green (2005) review these associated diseases, as well as the clinical manifestations of coeliac disease and the current diagnostic strategy, based on serum antibody detection and small intestinal biopsy. The need of mass screening to detect the undiagnosed cases and prevent such complications is commonly debated. Two recent investigations address this problem both in children (van Koppen et al, 2009) and adults (Marine et al, 2009).
Treatment of CD
The only treatment for coeliac disease is a long-life gluten-free diet, favoring the disappearance of symptoms and allowing the recovery of the intestinal lesions. However, alternative therapies are being investigated, acting on the cereals themselves (reducing toxicity or accelerating gluten degradation) or in the gut, regulating the permeability of the epithelium or modulating the immune function. These strategies are reviewed by Lerner (2009).
Coeliac disease and gut microbiota
Gut microbiota is emerging as a key factor in the onset of coeliac disease. Thus, new research is focusing in the use of certain microorganism strains as probiotics to prevent the disease and even as a treatment. Microorganisms living in the small intestine are believed to be involved in the development of immune-mediated disorders such as autoimmunity and allergy. Indeed, Bernardo et al (2009) found how the degradation pattern of gliadins is different between coeliac and non-coeliac people, leading to a different immune system activation. On the other hand, Collado et al (2009) analyzes the importance of a balanced microbiota for gut health and the use of probiotics to modulate the immune function.
Coeliac disease and lymphocytic duodenosis
Coeliac disease is currently diagnosed when villous atrophy, that is, a Marsh III lesion, is observed in the biopsy. However, many patients showing mild enteropathy, characterized by gut inflammation (Marhs I-II) without villous atrophy, are thought to be at risk of developing villous atrophy in the future, so it is very much debated whether to recommend or not a gluten-free diet in such cases. Kurppa et al (2009) support the treatment when positive antibody levels are found in serum regardless the severity of the intestinal lesion. However, Vande-Voort et al (2009) conclude that most of patients with lymphocytic duodenosis do not fit within the established coeliac group.
CD-MEDICS: designing a new tool for diagnosis
Early diagnosis is the gold standard in coeliac disease. The high number of undiagnosed coeliac people has a negative impact both in their health and in our economy, due to the complications associated to the disease when it is not properly treated with a gluten-free diet. The diagnosis today requires an antibody test and a small intestinal biopsy (Catassi & Fasano, 2008). However, this protocol is not undertaken in many cases because of a lack of suspicion of coeliac disease. CD-MEDICS is a 4-year European Commission funded project aiming at the design of a portable microsystem for coeliac disease point-of-care diagnosis. The new tool is intended to get a quick and cheap and easy-to-perform way to calculate the probability a patient has to be coeliac, making biopsy unnecessary. Only a single serum drop and no more than 20 minutes will be required to get the results saved on the patient's electronic health record. Serologic detection of antibodies and genetic identification of HLA allele variants associated to CD will take place inside the chip. See more at http://www.cdmedics.eu.
Alaedini A, Green PHR (2005) Narrative Review: Celiac Disease: Understanding a Complex Autoimmune Disorder. Ann Intern Med 2005;142:289-298.
Bernardo D, Garrote A, Nadal I, León AJ, Calvo C, Fernández-Salazar L, Blanco-Quirós A, Sanz Y, Arranz E (2009) Is it true that coeliacs do not digest gliadin? Degradation pattern of gliadin in coeliac disease small intestinal mucosa. Gut 58: 886-887.
Cassinotti A, Birindelli S, Clerici M, Trabattoni D, Lazzaroni M, Ardizzone S, Colombo R, Rossi E, Porro GB (2009) HLA and Autoimmune Digestive Disease: A Clinically Oriented Review for Gastroenterologists. Am J Gastroenterol 104: 195-217.
Catassi C, Fasano A (2008) Celiac disease. Curr Opin Gastroenterol 24: 687-691.
Collado MC, Isolauri E, Salminen S, Sanz Y (2009) The Impact of Probiotic on Gut Health. Curr Drug Metab 10: 68-78.
Heap GA, van Heel DA (2009) Genetics and pathogenesis of coeliac disease. Semin Immunol 21: 346-354.
Kurppa K, Collin P, Viljamaa M, Haimila K, Saavalainen P, Partanen J, Laurila K, Huhtala H, Paasikivi K, Maki M, Kaukinen K (2009) Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology 136: 816-823.
Lerner A (2009) New therapeutic strategies for celiac disease. Autoimmunity Reviews, in press
Mariné M, Fernández-Bañares F, Alsina M, Farré C, Cortijo M, Santaolalla R, Salas A, Tomàs M, Abugattas E, Loras C, Ordás I, Viver JM, Esteve M (2009) Impact of mass screening for gluten-sensitive enteropathy in working population. World J Gastroenterol 15: 1331-1338
Sollid LM (2002) Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2: 647-665.
Vande Voort JL, Murray JA Lahr BD, Van Dyke CT, Kroning CM, Moore B, Wu U (2009) Lymphocytic Duodenosis and the Spectrum of Celiac Disease. Am J Gastroenterol 104:142-148.
van Koppen EJ, Schweizer JJ, Csizmadia CGDS, Krom I, Hylkema HB, van Geel AM, Koopman HM, Verloove-Vanhorick SP, Mearin ML (2009) Long term health and quality of life consequences of mass screening for childhood celiac disease: a 10-year follow-up study. Pediatrics123: 582-588
Zisper RD, Patel S, Yahya KZ, Baisch DW, Monarch E (2003) Presentations of Adult Celiac Disease in a Nationwide Patient Support Group. Dig Dis Sci 48: 761-764.
A recent comprehensive paper provides a thorough review of coeliac disease:
REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY
Celiac Disease: From Pathogenesis to Novel Therapies
DETLEF SCHUPPAN, YVONNE JUNKER, and DONATELLA BARISANI
Coeliac disease in the elderly
A recent review paper investigated the epidemiology, clinical presentations, complications, diagnosis and management of coeliac disease amongst the elderly.
Coeliac disease is a common disorder not only in the young but also in the elderly. Recent reports show an increased rate of diagnosis of coeliac disease in adults.
Symptoms of coeliac disease vary from person to person and can range from mild to severe. Gut symptoms are less prominent in elderly people with coeliac disease compared to younger people. Older people with gut symptoms may present with milder symptoms such as abdominal bloating, flatulence and abdominal discomfort, making diagnosis more difficult.
Signs of nutrient deficiencies may be the first and often the only symptom in the elderly. Anaemia is present in 60% to 80% of elderly people with coeliac disease. Elderly people may also present with deficiencies in calcium and vitamin D and some may have developed low bone density.
Coeliac disease can also present through associated disorders and complications.
Dermatitis herpetiformis is recognised as a skin manifestation of coeliac disease. The average age of presentation is in the 40s, with most people affected between 20 and 70 years old.
Coeliac disease is an autoimmune condition and can occur alongside other autoimmune conditions including, Type 1 diabetes, autoimmune thyroid disease and autoimmune liver disease. Type 1 diabetes is more common in children with coeliac disease than adults, although it can occur at any age. Autoimmune thyroid disorders seen in coeliac disease are more common in older people.
Diagnosis of coeliac disease in older people can be difficult due to the subtle clinical symptoms, lack of awareness of coeliac disease in older people, and consideration of more threatening conditions such as malignancy. Awareness of coeliac disease in older people is important to prevent long delays in diagnosis.
Coeliac disease is diagnosed by screening with a blood test for tissue transglutaminase (TTG) antibody and confirmed by endoscopy with a small bowel biopsy. Healing of the intestine may be slower in older people diagnosed with coeliac disease. Close follow up is important to ensure symptoms improve.
Undiagnosed coeliac disease can result in low bone density and increased risk of bone fractures in older people.
Refractory coeliac disease
Refractory coeliac disease (RCD) is a term used to describe coeliac disease that is not responding to a strict gluten-free diet. Other conditions and gluten in the diet should be ruled out before a diagnosis of RCD is made. RCD can occur in about 5% of people with coeliac disease and is most common in older people.
The risk of small bowel cancer, non-Hodgkins and Hodgkin's lymphoma is increased in undiagnosed coeliac disease. The incidence of lymphoma is greater in older people and occurs more commonly in patients diagnosed with coeliac disease between 50 and 80 years of age. A gluten-free diet has been shown to have a protective effect on the risk of malignancy in people with coeliac disease.
Coeliac disease is managed by a strict gluten-free diet. Data suggest compliance to the diet among older people is high. However, older people may find the diet difficult as a life time of dietary habits may be hard to change.
There may also be difficulties due to the cost of gluten-free foods on a more limited budget and accessing gluten-free substitute foods if mobility is limited. Older people in assisted living accommodation may find it difficult accessing suitable foods on a gluten-free diet. Limited vision can make it difficult to check ingredient lists to find suitable products.
Advice should be tailored to the individual and information should be provided to family members and/or relevant staff at assisted living accommodation where appropriate.
A multidisciplinary approach in the management of coeliac disease can help in following the diet and treating associated conditions where additional considerations are necessary. Investigations for anaemia, calcium and vitamin D deficiency, osteoporosis, thyroid and liver disease should be carried out at follow-up appointments.
Rashtak S, Murray JA (2009) Celiac disease in the elderly. Gastroenterology Clinical North American. 38, 433-446
Copper Deficiency in Coeliac Disease
Coeliac disease has been linked with neurological problems, including neuropathy (numbness and tingling in hands and feet) and ataxia (poor muscle co-ordinations). A recent study linked copper deficiency, neuropathy and coeliac disease.
Copper deficiency and neurological disease
Copper deficiency is rare but can result in neurological disease and blood abnormalities, including anaemia with neutropenia (low neutrophil count). Myeloneuropathy is neuropathy that effects the myelin sheath (a white fatty material that surrounds the nerves) and it can occur due to copper deficiency.
Copper deficiency can be precipitated by excessive zinc or iron intake, malabsorption, history of gastric surgery and nephrotic syndrome. In one-third of the 25 reported cases of copper deficiency myelopathy, a cause could not be found.
A case study report looked at the treatment of a woman diagnosed with copper deficiency myeloneuropathy.
This 69 year old patient had a progressively unsteady gait and numbness in her legs and feet. She had a medical history of osteoporosis and unexplained weight loss but did not experience gut symptoms. Blood tests showed she had low serum copper and borderline low zinc levels. Antibody blood tests (tissue transglutaminase antibodies) and duodenal biopsies confirmed a diagnosis of coeliac disease.
When she began on a gluten-free diet, she received given copper supplements. At her three month follow-up, she had less numbness in her legs and feet and had gained weight. She also improved her gait. A repeat neurological examination showed improvements and her serum copper levels improved and antibody levels decreased.
There have only been two other known reported cases of coeliac disease associated with copper deficiency myeloneuropathy. Both these cases, like the above case study, had symptoms of lower limb sensory loss, sensory ataxia (lack of coordination) and an unsteady gait. The role of coeliac disease as a cause of copper deficiency was not emphasised in these cases. Starting the gluten-free diet and copper supplementation resulted in copper levels returning to normal and improvement in neurological symptoms in the above case study.
The cause of neurological problems in coeliac disease is not known. It may be linked to vitamin deficiency due to malabsorption but this has not been proven. Further research is needed to look at the role of copper deficiency in neurological problems seen in coeliac disease.
Goodman PB, Mistry MD et al (2009) Copper deficiency myeloneuropathy due to occult celiac disease. The Neurologist.15, 6: 355-356.
Long term health and quality of life
Untreated coeliac disease is associated with long term health complications including osteoporosis, anaemia, delayed puberty and growth impairment. A prospective 10 year follow-up study investigated whether detection of childhood coeliac disease by mass screening improves long term health status and quality of life.
After mass screening of 12,672 children aged 2-4 years at a child health centre in Holland, 32 children were diagnosed with coeliac disease. The 32 children identified were followed up in a prospective study from 1998-2007. The children were followed up for their general health, coeliac disease related symptoms and health related quality of life.
At the time of diagnosis, 19 of the 32 children started a gluten-free diet and 13 continued their normal gluten-containing diet. After 10 years, 26 of the children were following the gluten-free diet.
At diagnosis 13 of the children had symptoms of diarrhoea, abdominal pain, constipation, chronic fatigue, irritability and mouth ulcers. After following the diet for 1 year, all the children showed improvement in their symptoms. A further 8 of the children developed symptoms after diagnosis as a result of including gluten in their diet. Symptoms cleared after gluten was removed from the diet.
Also, 7 of the children had an improvement of symptoms including failure to thrive and osteoporosis after starting the gluten-free diet. However, these children developed other health problems including constipation. This could be due to factors unrelated to their coeliac disease or due to reduced fibre in the gluten-free diet. The overall health status improved as the other health problems were less severe.
Long term follow up studies are required to assess possible long term consequences in people with untreated coeliac disease with no symptoms.
Quality of Life
Using the DUX-25, the health related quality of life of the children with symptoms was found to be lower than the general Dutch population at diagnosis. However, their quality of life improved significantly after diagnosis.
Screening for coeliac disease
Mass screening resulted in health improvements in 21 of the 32 children in this study.
Van Koppen E, Schweizer J, Csizmadia C, et al (2009) Long-term health and quality of life consequences of mass screening for childhood celiac disease: a 10year follow-up study. Paediatrics 123, e582- e588
Diagnosis of coeliac disease- research into a non-invasive tool
The process for diagnosis of coeliac disease involves a blood test that detects antibodies specific to coeliac disease followed by endoscopy with a biopsy. The National Institute for Health and Clinical excellence (NICE) guideline on the recognition of coeliac disease recommends the use of tissue transglutaminase or endomysial antibody blood tests to help to identify people with the condition as they have high sensitivity and specificity for coeliac disease.
A recent Dutch pilot study looked at a possible non-invasive tool for early diagnosis and follow up of coeliac disease once established on the gluten-free diet.
Non-invasive tool for diagnosis
The plasma/urinary markers, intestinal fatty acid binding protein (I-FABP) and liver fatty acid binding protein (L-FABP) are markers of damage to intestinal epithelial cells and could potentially be used for diagnosis.
A recent study looked at samples of intestinal tissue from various parts of the gut from the stomach to the sigmoid colon. FABP was measured and quantified by Western blot analysis (a technique used to test specific proteins in a tissue) and enzyme linked immunosorbent assay (ELISA). Analysis was also taken on antibodies against I-FABP and L-FABP.
The results found that I-FABP and L-FABP was expressed specifically on mature enterocytes present on the tip of the villi in the small intestine, in particular the jejunum.
Further tests were then carried out to see if serum concentrations of FABP differed between people with and people without coeliac disease.
Serum FABP concentrations were measured by ELISA in 62 healthy volunteers. A further 13 people newly diagnosed with coeliac disease via biopsy had their serum FABP concentrations measured. The mean serum FABP level was found to be higher in people with coeliac disease compared to healthy controls and mean normal serum levels.
The final test was to check if FABP levels returned to normal after starting a gluten-free diet. I-FABP and L-FABP were measured in ten people within one year of starting the diet and levels were found to have decreased significantly. FABP concentrations could be measured to monitor the effect of the gluten-free diet on recovery of the intestinal mucosa of people with coeliac disease.
Further research is underway to assess the use of FABP in the management of people with coeliac disease by looking at the correlation between urinary FABP levels and the level of gut damage. The potential of urinary FABP concentrations as a tool for evaluating the effect of the gluten-free diet is also being researched in children to see if this can be used as a non-invasive tool in follow up.
Derikx, J. P. M. et al (2009) A pilot study on the non-invasive evaluation of intestinal damage in celiac disease using I-FABP and L-FABP. Journal of Clinical Gastroenterology 43,