Understanding the Patient: Coeliac Disease and Associated Conditions

Coeliac UK’s annual research conference for 2014 was held at the Royal College of Pathologists on March 12th. Alex Gazzola reports on some of the presentations.

Coeliac UK’s chief executive Sarah Sleet welcomed delegates, and introduced the chair, Professor David Sanders of Sheffield’s Royal Hallamshire Hospital, who in turn introduced the talks and speakers.

First up were Dr Joe West, Dr Colin Crooks and Dr Alysha Abdul Sultan of the University of Nottingham, and Dr Fabiana Zingone of the University of Salerno, Italy. Their talk, ‘Coeliac disease and dermatitis herpetiformis in the UK: occurrence and pregnancy outcome’ presented the various results of research undertaken looking at pregnant women both with and without coeliac disease, to determine whether there was an increased risk of adverse outcomes in those with the autoimmune disease. They found this not to be the case. Data and figures remain under embargo, and we hope to bring you a report on CoeliacsMatter later in the year, when results are published.

‘An extended scope practitioner-led clinic and structured group sessions for annual review’ was the title of the talk given by dietitian Joy Whelan, of Western Health and Social Care Trust in Northern Ireland, in which she outlined her experiences of handling the annual reviews of stable, diagnosed coeliac patients under the long-term care of consultant gastroenterologist Dr William Dickey of Altnegalvin Hospital, and who would normally undertake such a review with him.

She found that 55% of the patients she saw reported GI symptoms, especially constipation, and that the main causes were non-compliance with the gluten-free diet. As a dietitian, she felt able to give dietary advice on constipation to solve such common problems, as she did in 53% of cases on her own. She discussed 37% of cases with the consultant (who himself called 11% for an appointment) and with 10% she requested the input of the coeliac patient’s GP, as the symptoms she felt were related to, for instance, thyroid problems.

Around two thirds of those she saw had dietary worries, and these mainly concerned constipation, weight, diet while on holiday, bone health / calcium, and oats in the diet. Whelan felt she could deal with these in just a few minutes. With 69% of those participating claiming they were happy with seeing a dietitian for their annual review, Whelan considered this a success – given the popularity of Dr Dickey! – and felt that the system allows for greater time and cost effectiveness on the NHS, given dietitians are ‘cheaper’ than gastroenterologists.

Three years ago, Whelan added, there was a backlog of 300 patients awaiting annual review, so the team decided to set up pilot 90-minute group sessions of 15 patients (all of whom could request individual appointments if preferred). Whelan designed the plans, which mainly focused on healthy eating, and they were found to be popular and time effective – saving approximately 34 hours of dietetic clinic time annually, allowing other patients to be seen at an earlier opportunity, thus helping waiting list targets.

Professor Marios Hadjivassiliou of Royal Hallamshire Hospital spoke on the Neurology of Gluten Related Diseases. 

Hadjivassiliou pointed out that for every 7 patients diagnosed with coeliac disease presenting to gastroenterology clinics, there are 2 patients diagnosed with coeliac disease presenting to neurology clinics – indicating the not inconsiderable incidence of neurological dysfunction as a manifestation of gluten-related disorders.

His team has drawn data from over 640 patients seen and followed up at the Hospital over the last 17 years. The commonest manifestions were found to be as follows:

* ataxia – disordered balance, co-ordination and/or speech, affecting almost half of patients;
* peripheral neuropathy – damage to the nerves serving the limbs and organs, and outside of the brain and spinal cord – affecting just over a third: these include symmetrical peripheral neuropathy, and sensory ganglionopathy (which purely effects sensory nerves)
* encephalopathy (headaches with cerebral white matter abnormalities)
* myoclonic ataxia (tics, regular jerky movements)

Much less common are:

* myopathy (muscular disorders)
* myelopathy (spinal cord disorders)
* epilepsy
* chorea (unpredictable involuntary movements – very rare).

Gluten ataxia accounts for one in six of all ataxias, and 40% of idiopathic sporadic ataxias. You can achieve some improvement on a GFD after a year, even though brain tissue is damaged. Improvement is achieved even in those without small bowel enteropathy.

Gluten neuropathy include symmetrical, sensory and motor neuropathies with serological markers to gluten. This accounts for 26% of neuropathies, and 34% of all idiopathic neuropathies. Hadjivassiliou’s team’s ten-year study shows evidence of improvements after a strict GFD, and this was irrespective of whether there was underlying enteropathy, again.

Gluten encephalopathy is characterised by intractable headaches / migraine. The key issue here is that the GFD resolves those headaches. The range of abnormalities can vary hugely.

Via video, Hadjivassiliou then showed delegates the condition he described as hyperexcitable brain – characterised by a severe jerky tremble in the body, in addition to ataxia. The patient experiences restless legs and this is extremely disabling. The condition is strongly associated with refractory coeliac disease.

How common are neurological dysfunctions in patients with CD on a GFD? This figure is difficult to ascertain, as it depends on various factors. Who is collecting the data – a neurologist or a gastroenterologist? What is the type of manifestation – and is linked to gluten/coeliac, or a chance association? Strictness of adherence to the GFD may play a factor, and there may be geographical variations. 10-30% appears a good estimate. Of 33 patients referred to Hadjivassiliou by Dr Sanders, based on whether they complained of headaches, balance problems or sensory loss, and who underwent neurological examinations and brain imaging, 50% were shown to have abnormalities, and their cerebellar volume was significantly less than in healthy controls.

Hadjivassiliou’s fresh ‘off the press’ study results concerned how common neurological dysfunction was in newly diagnosed patients. From 100 consecutive patients, 61% had neurological symptoms, 45% had intractable headaches, 26% had balance problems and 14% sensory symptoms. 42% had evidence of neurological dysfunction on clinical examination – 38% of which had evidence of cerebellar dysfunction and 5% had sensory signs.

When imaging was conducted on these patients, 44% had abnormal spectroscopy, and 56% of these had clinical evidence of balance problems. 29% had white matter changes, and 40% of these complained of headaches.

In terms of the differences between patients presenting with neurological versus gastrointestinal symptoms, the former tend to be older (a mean of 61 versus 47). Neurologically affected patients are more severely effected. The GFD has a stabilising effect but they remain disabled, particularly if they have long-standing ataxia.

Adherence to a GFD may be more important for neurologically affected patients than for those with GI-dominant symptoms, and non-adherence may increase the risk of other symptomatic manifestations (such as DH). Unlike in villous atrophy, which is generally reversible, when it comes to the brain, when you lose certain cells there is no way back. The loss of Purkinje cells – key in maintaining balance – in the cerebellum with gluten ataxia is permanent.

Neurological dysfunction appears present in non-coeliac gluten sensitivity. Of the 640 cohort, 41% of patients referred to Hadjivassiliou had CD on biopsy, 37% had positive serology, positive HLA-DQ2/8 typing, but no enteropathy, and 22% had positive serology, but negative HLH-DQ2/8 typing and no enteropathy – the NCGS group.

The distribution of ataxia in the three groups was found to be similar. The distribution of neuropathy seems to be over-represented in the ‘potential coeliac’ (37%) group. Encepolopathy was found to be more common in patients with enteropathy. All three groups respond to the GFD.

A major breakthrough in this work has come in the transglutaminase enzymes and differential typing: TG2 is the autoantigen in CD, TG3 in dermatitis herpetiformis (DH), and TG6 has been found to be the autoantigen in gluten ataxia (GA) – this antigen is gluten dependent and could be important in neurological manifestations as a specific marker for GA, though tests are not yet widely available.

Of the original cohort of patients with gluten ataxia with positive anti-gliadin antibodies, 73% had positive TG6, but more importantly 36% of idiopathic ataxia patients who are negative for gluten-related disease serology were positive to TG6 and respond to the GFD. In the prospective study, 40% of patients with newly diagnosed CD were positive for TG6, and 94% of those with positive TG6 had one or more neurological symptom, abnormal examination or abnormal MRI scan.

The question remaining, summarised Hadjivassiliou, was what determines the target of the autoimmune response and the clinical manifestations in gluten-related disorders, and how can we predict them using the detected presence of antibodies?

Osteoporosis in CD associated with novel autoantibodies was the talk given by Dr Phillip Riches of the University of Edinburgh. Osteoporosis is reduced bone mass and architectural skeletal weakness, and although it is a recognised secondary complication to coeliac disease, it has always been assumed that this is due to malabsorption / deficiency of calcium and vitamin D, rather than an autoimmune-mediated response.  

Riches described the unusual case of a 40-year-old male, whose clavicle was fractured play-wrestling with his young son. Investigations found severe osteoporosis, high bone turnover and undiagnosed coeliac disease – but a GFD failed to improve the bone condition (in fact, it worsened).

Auto-antibodies were subsequently detected in his blood against osteoprotegerin, a protein which protects bone, and when he was given counter-active treatment, his osteoporosis reversed dramatically.

These antibodies represent a potential new tool to investigate risk factors for osteoporosis in coeliac disease. Preliminary results from 100 coeliac patients have identified less than 5% of those with higher levels of the antibody who do have lower Bone Mineral Density. More work needs to be done to see if those antibodies are functional and cohort needs to be extended.

Dr Peter Gillett of Royal Hospital for Sick Children, also in Edinburgh spoke on The Rising Incidence of Coeliac Disease in Scotland’s Paediatric Population.

In a literature review of 20 years, Gillett and colleagues looked at European and North American studies which have generally shown an increase in incidence in the paediatric population, as antibody and diagnostic strategies have become honed, and more targeted screening has been done. Non-classical symptoms have increased, and there has been a general drift upwards in age of diagnosis. Most published papers have suggested a rise in incidence due to lower threshold to test, although some Finnish studies have found a true rise.

With regard to figures in eastern Scotland that Gillett’s team concentrated on, the incidence of paediatric CD increased over six-fold in the 20-year period from 1990 to 2009. The increase can’t be due to genetics – this is stable in the area – and is double other areas of the UK. Could it be better awareness, and a lower threshold to test? In the population at large, could the hygiene hypothesis, antibiotic use, increased antigenicity of wheat, changing infant feeding patterns, or the microbiome be involved?

Dr Adrian Thomas, Consultant Paediatric Gastroenterologist at Royal Manchester Children’s Hospital spoke on the Diagnosis of Coeliac Disease in Children: Monitoring the Implementation of the BSPGHAN Guidelines.

Dr Thomas spoke about the new ProCeDE study, whose primary aims are to investigate the new diagnostic criteria in clinical practice internationally, in particular to investigate prospectively how certain we can be about the diagnosis without biopsy in certain children.

Secondary aims are to evaluate symptoms in relation to the histology and coeliac-specific antibodies, to determine the optimal cut-off point for antibody levels, to determine whether HLA-typing adds diagnostic value in those with positive antibodies, and to determine which of the available antibody tests are most suitable for the initial diagnosis, and for the follow up in children with proven CD. Other aims include to evaluate prospectively whether a diagnostic score would be appropriate, based on symptoms, histology, serology and HLA testing, and to evaluate the intra-observer variability of histology.

Recruitment is almost complete, and the first results will be available later in 2014.

The day closed with the talk Coeliac Disease vs Gluten Sensitivity vs Wheat Intolerance by Dr Imran Aziz.

IBS is common, and self-reported wheat sensitivities are common too. Aziz told delegates of the Italian DBPC Study from 2012 where 920 patients with IBS and not CD undertook a four-week elimination diet (wheat, milk, egg, tomatoes, chocolate), and were blinded to receive capsules either containing wheat or placebo. A third of patients showed sensitivity to wheat and not placebo (gastrointestinal pain, bloating, irregular stool consistency).

An Australian group dug deeper, finding that gluten could cause GI symptoms in the absence of coeliac disease. 39 patients with gluten sensitivity, who did well on the GFD but had no evidence of CD, were given muffins which were gluten-containing or gluten-free, and both were free of FODMAPs. Those on the gluten-containing muffins deteriorated, with worsening symptoms and increased fatigue.

The immune response appears to be different in NCGS. CD is characterised by an innate immune response, followed by an adaptive response. The response in NCGS was described by Aziz as ‘half hearted’. The inability to find biomarkers in NCGS remains. Some reports suggest that 50% of those with NCGS have raised anti-gliadin antibodies, but this is not reliable as a marker.

In summary, Aziz asked, should NCGS be called non-coeliac wheat sensitivity – at least until gluten could be pinpointed as the culprit?

Points raised from the floor appeared to support this. One delegate suggested resistant starch may be to blame, arguing that there is no evidence to support the idea that gluten is responsible. Another queried whether small intestinal bacterial overgrowth could be responsible for some cases.

The area is controversial, summarised Sanders. “Nutritional therapies for gastrointestinal symptoms are back on the market, after a period in the wilderness of two decades,” he closed. “We do not have all the answers and this is all a work in progress.”

First published March 2014

Further Reading

Gluten Freedom by Alessio Fasano
Coeliac Disease: What you need to know by Alex Gazzola
Fast Facts: Coeliac Disease by Geoffrey Holmes and Carlo Catassi

Click here for more articles on the causes of coeliac disease.

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