Research

Refractory coeliac disease

The prevalence of refractory coeliac disease (RCD) is unknown but is thought to be rare, therefore the amount of research is limited. A recent review paper looks at the diagnosis and management of people with RCD.


What is RCD?

RCD is persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet. Symptoms occur for at least 6-12 months in the absence of other causes of non-responsive treated coeliac disease and malignancy.
Symptoms

The most common symptoms of RCD are persistent diarrhoea, steatorrhoea (fat malabsorption), abdominal pain and unintentional weight loss. Vitamin deficiencies, anaemia, fatigue and coexisting autoimmune disorders are also common.


Types of RCD

RCD can be characterised into two types.

* Type 1 RCD is defined by a normal intraepithelial phenotype. It usually improves after treatment with nutrition support, a strict gluten-free diet and alternative pharmacological therapies.
* Type 2 RCD is the presence of abnormal intraepithelial lymphocyte phenotype. It has a poor prognosis and can include complications like ulcerative jejunitis and enteropathy-associated T cell lymphoma.

Diagnosis

Diagnosis of RCD is by exclusion. Diagnosis of RCD is extremely rare before the age of 30 and in most cases is diagnosed after the age of 50.

If symptoms return or persist and villous atrophy remains despite following a gluten-free diet, RCD should be investigated. This research paper provides a useful diagram of the steps that should be taken in the diagnosis of RCD (access full article on www.gut.bmj.com for full details).
Step 1- Initial diagnosis of coeliac disease should be confirmed

* Positive tissue transglutaminase (tTG) or endomysial antibodies (EMA) help to confirm diagnosis of coeliac disease. This is because they are 99% specific when villous atrophy is present. However, most people with developed RCD are likely to have negative tTG and EMA. Positive antibodies were only found in 19-30% of people with RCD despite keeping to a strict gluten-free diet (assessed by a dietitian).
* The research paper highlights other factors to consider when confirming initial diagnosis, for example family history, presence of HLA-DQ2 or HLA-DQ8 and history of response to the diet.

Step 2- Other causes for not responding to the gluten-free diet should be eliminated

* This research paper highlights the causes of villous atrophy that are not due to RCD including gluten contamination, bacterial overgrowth or microscopic colitis.
* Gluten contamination is the most common cause of ongoing villous atrophy and is seen in 36-51% of people not responding to the diet. Persistent positive tTG or EMA are suggestive of gluten contamination.
* Repeat intestinal biopsy may help to find out the cause of ongoing villous atrophy.

Step 3- Underlying malignancy should be investigated.

* The presence of symptoms including fever, unexplained weight loss, anorexia, overt gastrointestinal bleeding and abdominal pain do not occur in people with treated coeliac disease and suggest underlying complications.
* Enteropathy-associated T-cell lymphoma (EATL) is linked to coeliac disease and RCD. EATL is rare in the general population (incidence of 0.10 per 100,000) but may occur in 60-80% of people with type 2 RCD within five years of diagnosis.

Step 4- RCD should be classified into type 1 or type 2 RCD

* This is by the presence or absence of intraepithelial lymphocyte phenotype (see types of RCD above)

Treatment

An accurate diagnosis of RCD as well as confirming the type of RCD is important for treatment.
Dietary and Nutritional Assessment

The gluten-free diet reduces overall morbidity and mortality in coeliac disease. Although the benefit of the diet is unknown in RCD, it is recommended to follow a strict gluten-free diet. The diet could still be useful for managing symptoms.

Nutritional treatment should include correction of trace element deficiencies including zinc and copper. Bone health should also be monitored by assessment of bone density by Dual Energy X-ray Absorptiometry (DEXA) scanning.

Some people may need to be admitted to hospital to monitor adherence to the diet and treat nutritional deficiencies or dehydration. Research on follow up of people with RCD found that 28-60% of people needed total parenteral nutrition due to severe weight loss, malnutrition, multiple nutritional deficiencies, severe hypoproteinaemia and or steatorrhoea.

A small study found that the elemental diet was beneficial for some people with type 1 RCD. Further research is needed in this area.


Alternative Therapies

Steroids are an effective treatment for inducing remission and healing the damage to the gut in most people with type 1 RCD. 75% of people with type 2 RCD will see an improvement in their symptoms with steroid treatment. However, full mucosal recovery is infrequent and progression to EATL is not prevented in those with type 2 RCD. Other immunosuppressive drugs have been used with some benefit in those not responding to steroids.

High dose chemotherapy followed by autologous haematopoietic stem cell transplantation (ASCT) has been explored for type 2 RCD in a pilot study from a single centre. Further research is required to assess the benefits of these treatments.

The role of surgery in RCD is limited to complications. Long term clinical remission on a gluten-free diet alone after complete resection of ulcerative jejunitis has been reported if the ulceration is localised to one part of the intestine.
Conclusion

RCD is very rare. It is important that anyone with ongoing symptoms of coeliac disease is assessed to diagnose or exclude RCD and appropriate treatment is given.

For further information-

Rubio-Tapia A & Murray J (2010) Classification and management of refractory coeliac disease. Gut,59:547-557



 

Oats in the gluten-free diet

Uncontaminated oats are safe for the majority of people with coeliac disease. Here we take a look at the research on including uncontaminated oats in the gluten-free diet, the nutritional benefits of oats and the latest guidance from the British Society of Gastroenterology (BSG) on the introduction of oats into the diet.

Benefits of oats
Oats are a good source of soluble fibre and have been shown to be beneficial in helping to maintain healthy bowel function, contributing in the management of hyperlipidaemia and helping to improve glycaemic control in people with diabetes.

A recent 2010 study by Kemppainen et al looked at the nutrient intake of the diet in people with coeliac disease consuming oats. The introduction of 100g oats to the diet enhanced the intakes of vitamin B1, magnesium, zinc and vitamin B6. A 1997 paper by the same author have shown 50g of oats a day to improve intakes of vitamin B1 and fibre, and 30g of oats a day to improve intakes of magnesium and iron.

The research

Several studies have reported the safety of consuming large amounts of uncontaminated oats in people with newly diagnosed coeliac disease using clinical, serological and histological parameters (Ciclitira P J et al, 2010). Research suggests that uncontaminated oats and oat products are not toxic to the majority of adults and children with coeliac disease (Janatuinen EK et al, 2002; Garsed K and Scott B, 2007; Hogberg L et al, 2004; Haboubi NY et al, 2006). A minority of people could be sensitive to the protein found in oats (called avenins), which is similar to gluten. Although it is possible that a very small number of people with coeliac disease may still be sensitive to uncontaminated oat products (Lundin K et al, 2003; Haboubi N Y et al, 2006), the weight of evidence supports the safety of oats obtained from gluten-free manufacturers (Ciclitira P J et al, 2010).

Guidance on the introduction of oats

As the evidence suggests a small minority of people may become unwell with oats, the BSG advise it may be helpful not to introduce suitable oat products into the gluten-free diet until the patient with coeliac disease has been on a gluten-free diet for the first six to twelve months. In cases where the introduction of oats into the diet appears to result in development of symptoms the BSG advise it may be worth considering a repeat duodenal biopsy to ensure histological remission.

Which oats can be included?

Uncontaminated oat products that are labelled gluten-free and may also be listed in the Food and Drink Directory are the only appropriate sources . These oats will meet the revised 2008 Codex standard and comply with the Regulation EC 41/2009 that requires products that are labeled gluten-free to be less than 20 parts per million (ppm) of gluten.


References

Kemppainen et al (2010) Nutrient intakes during diets including unkilned and large amounts of oats in coeliac disease. European Journal of Clinical Nutrition

Kemppainen T (1997). Oat meal as a component of a gluten-free diet,nutrient intakes, nutritional status and osteopenia in coeliac patients. Kuopio University Publications, Medical Sciences 118.

Ciclitira P J, Dewar D H, McLaughlin S D, Sanders D S. (2010) The management of adults with coeliac disease. British Society of Gastroenterology.

Ciclitira P J, Ellis H J, Lundin K E A. (2005) Gluten-free diet - what is toxic? Best Practice and Research Clinical Gastroenterology. 19 (3): 359 - 371

Janatuinen E K, Kemppainen T A, Julkunen R J K, Kosma V M, Maki M, Heikkinen M, Uusitupa M I J. (2002). No harm from five year ingestion of oats in coeliac disease. GUT. 50: 332 - 335

Garsed K and Scott-Brian B. (2007) Can oats be taken in a gluten-free diet? A systematic review. Scandinavian Journal of Gastroenterology. 42 (2): 171 - 178

Hogberg L, Laurin P, Falth-Magnusson K, Grant C, Grodzinsky E, Jansson G, Ascher H, Browaldh L, Hammersjo J A, Lindberg E, Myrdal U, Stenhammar L. (2004) Oats to children with newly diagnosed coeliac disease: a randomized double blind study. GUT. 53: 649 - 654

Lundin K, Nilsen E, Soctt H, Loberg E, Gjoen A, Bratlie J, Skar V, Mendez E, Lovik A, Kett K. (2003). Oats induced villous atrophy in coeliac disease. GUT. 52: 1649 - 1652

Haboubi N Y, Taylor S and Jones S. (2006). Coeliac disease and oats: a systematic review. Postgraduate Medical Journal 82: 672 - 678

CREST. (2006). Guidelines for the diagnosis and management of coeliac disease in adults.

Pulido O M, Gillespie Z, Zarkadas M, Dubois S, Vavasour E, Rashid M, Switzer C, Godefroy S. (2009). Chapter 6 introduction of oats in the diet of individuals with celiac disease: a systematic review. Advances in Food and Nutrition Research 57: 235 - 85

 

 


 


CELIAC DISEASE SEROLOGY IN PATIENTS WITH DIFFERENT PRETEST PROBABILITIES: IS BIOPSY AVOIDABLE?
Sugai et al (2010) World Journal of Gastroenterology 16: 3144-3152

Aims

This study evaluates the performance of six different serological tests for the diagnosis of celiac disease (CD). The aims were to analyse the efficiency of different assays using each test individually or in pair-combinations, and to design a strategy that might get an accurate diagnosis of CD avoiding biopsy.

Methods

Patients were classified as having either high risk or low risk for CD according to their symptoms. Individuals in the high risk group were suspected to suffer from a small bowel disorder (diarrhea, weight loss, malabsorption, ...), and those included in the low risk group showed unspecific symptoms not related to CD (epigastric pain, regurgitation, ...).

Blood samples were collected and duodenal specimens were obtained and classified according to Marsh's criteria in all subjects. All six tests were based on the CD-specific tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) autoantibodies. Different parameters were calculated, such as specificity, sensitivity and positive and negative predictive values of each assay tried.

Results

Around 40% of patients in the high risk group were found to have celiac disease, showing more severe clinical manifestations and gut damage than those diagnosed in the low risk group, where CD was only detected in 3% of cases.

The serological tests, used individually, were more efficient in the high risk group, where at least one of the six tests tried was positive in all cases of celiac disease. The IgG-DGP test showed the optimal specificity in this group, with a positive predictive value of 100%, and the DGP/tTG Screen test gave the optimal sensitivity and didn´t miss any case of CD. However, the specificity in the low risk group was lower, and also the sensitivity, In fact, 3 patients (17%) with CD in this group had negative results in all serological tests.

The 2-tests combination assays were less sensitive than the individual ones in both groups of patients; however, the positive predictive values were 100% (optimal specificity) in both groups when the two tests in a given pair-combination assay gave positive results.

The use of 2-tests combination assays would reduce the number of cases requiring biopsy for diagnosis of CD: only those patients showing one positive and one negative result would need a biopsy. Thus, around 92% of biopsies could be avoided using the correct combination of two serological tests. The combination of the DGP/tTG Screen test with either the IgA-DGP or IgA-tTG tests is the one showing optimal specificity with a good sensitivity in both groups.

Conclusions

The authors suggest that the use of the appropriate serologic tests, individually or in pair-combinations, could make diagnosis of CD more accurate. They support the use of the new DGP/tTG Screen test as a first serological step, and the combination of the cited test with either the IgA-tTG test or the IgA-DGP test would avoid the need of biopsy in most cases.