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What is Gluten Sensitivity? - 03/06/2010
 

Diagnosis of the Condition: There’s More To Do

1.  Notes presented for GPs and other health professionals by consultant neurologists and gastroenterologists at Sheffield Teaching Hospitals Trust come at a time when mass screening or targeted investigations will engage scrutiny and treatment of clinically diagnosed sufferers with likely symptoms.  It calls for augmentation at a time when the NHS is threatened with severe cuts to health services in “broken Britain.”  We have been for some time warning of the hazards the population faces from rash decisions by ill-advised politicians.  Some of our earlier reservations have centered on vitamin D, rickets, bones and new developments in the biochemistry of this “vitamin” and diagnoses of extended significance.  We return to the long-standing matter of wheat intolerance as we observe the now almost-day-by-day reports of the progress of this year’s harvests, home and abroad, and their use as food or feed or biofuel – as well as possible changes in agriculture and nutrition. Yesterday’s farmer growing oats to feed him and his family and to power his “tractor” had a lot more sense than today’s wiseacres fed on Dr Johnson’s observations on such fundamentals.

2.  Celiac disease or gluten-sensitive enteropathy is defined as “a state of immunological responsiveness to ingested gluten (from wheat, barley, or rye) in genetically-susceptible individuals.”  Historically, it has been considered a disease of childhood presenting with diarrhoea, weight loss, and failure to thrive.  More recently, accurate serological tests, the evolution of endoscopy, and large epidemiological studies have revolutionized the current concept of celiac disease: the modern-day celiac patient is diagnosed in their 40s, of normal or increased body mass index (BMI) and has subtle symptoms.”  Now that uncontaminated oats (free from carryover of an earlier batch of other cereals in a mill) are generally available, oats have been removed from the list of cereals likely to cause gluten sensitivity.  VEGA and its Campaign for Real Bread (CAMREB, which covers many cereals and their significance worldwide in sustaining varied nutritional factors) takes a special interest, in particular in the challenges of plant sources of nutrients in populations subsisting meat-and dairy-free in conditions of sparse supplies of proteins derived from animal commodities.  Food technologists can enjoy the range, rice, oats, potatoes, and sugar, which do not contain the suspect prolamines; and some reservations may be lifted when the assessments include breakfast cereals.

Prevalence

3.  Recent studies in the UK assessing the prevalence of celiac disease in the general population, have consistently reported that the affliction affects about 1% of all adults. Similar findings have been described in epidemiological studies screening cohorts of healthy volunteers in Western Europe and North America.  The increasing recognition of celiac disease is attributed to several factors: novel serological assays, advances in endoscopy allowing ease of duodenal biopsy, the realization that some patients do not have gastrointestinal symptoms, and a possible real increase in the prevalence of celiac disease over time.  For every adult patient currently diagnosed it is estimated that there are 8 cases undetected.  In some respects the level of underreporting resembles the notification of incidents of food-borne illness.  Patients and doctors are losing their coyness over discussing biological functions, many of which are obvious and frequently revealed: steatorrhea, for instance, is a marker of disorded absorption, indicated by the passage of smelly, light-colored stools that float on water (fat being less dense water). Such buoyant feces may be described as floaters – before our very eyes, but not the annoying objects that mar vision.  A medical journal once tried to advise on the lingo of the lavatory and the doctor’s surgery and was set the task of defining the singular of the word feces. Greek and Latin scholarship flourished until the richness of the Anglo-Saxon vocabulary was applied: the word is turd.

Clinical Presentation

4.  Adult presentations are now more frequent than pediatric.  The commonest age for presentation is during the 5th decade.  Patients with adult celiac disease rarely present with symptoms of overt malabsorption.  Far more commonly they describe non-specific or subtle gastrointestinal symptoms such as non-specific abdominal pain, irritable-bowel-type symptoms (IBS), or upper gastrointestinal symptoms such as acid reflux.

5.  Any gastrointestinal presentation of celiac disease is now broadly described as the typical or classical form. A substantial proportion of patients have no gastrointestinal symptoms, but instead present with constitutional complaints such as fatigue, “tired all the time,” arthralgia and myalgia.  Alternatively, they have recognized associated conditions such as osteoporosis.  Finally they may present with extraintestinal manifestations such as dermatitis herpetiformis or neurological problems such as ataxia or peripheral neuropathy.  Presentation without gastrointestinal symptoms is now called the atypical or silent form; these patients may initially be overlooked.  Delays in diagnosis are common, with the average duration of symptoms in patients, prior to the diagnosis, ranging from 4.5 to 11 years.  This is partly driven by the persistent misconception that a celiac patient will be underweight owing to malabsorption.  In fact, most are normal BMI or even overweight.

The Celiac Iceberg

6.  The complex, clinical spectrum of celiac disease is often represented as a triangular iceberg, floating apical truncated tip uppermost.  Patients above the waterline present to health services with typical gastrointestinal symptoms such as diarrhoea.  The next “layer” comprises patients with non-gastrointestinal manifestations such as fatigue, osteoporosis, or ataxia.  Below this are patients with latent celiac disease.  These are patients who have had a 
normal biopsy of the small bowel, but subsequently develop biopsy-positive celiac disease.  The reverse has also been reported:  a patient with biopsy-positive disease continues on a normal diet and is later shown to have normal  small bowel biopsies.  However, recently investigators have found that it is  possible (in a very small number of patients) to develop immune intolerance  and no longer have villous atropy, despite being on a normal (i.e. gluten- containing) diet.  This limited observation should not change or influence our  current clinical practice – which is to emphasize the importance of adhering to  a gluten-free diet in patients with known celiac disease.

7.  The term “potential celiac disease” could be interchanged with gluten   sensitivity.  Historically this has been a research observation and defined as

i. Patients with positive EMA, but normal duodenal biopsy

ii. Presence of increased intraepithelial lyphocytes (IELs) on duodenal biopsy (Marsh Grade 1)

iii. Increased density of IELs expressing gamma/delta.  T-cell receptors  (histological markers (HLAs) currently only used in research) (HLA=human leukocyte antigen).

iv. An HLA pattern consistent with celiac disease (HLADQ2 or DQB)

v. A positive rectal gluten challenge – which results in patients with an  increased  presence of ILEs on retal biopsy

8.  Patients with celiac disease may initially be recognized by using sensitive and specific non-invasive serological tests.  The positive predictive value of these serological markers (IgG/IgA antigliadin antibodies), tissue transglutaminase (TTG) and endomysial antibody (EMA) are greater than 90% in selected populations and around 70% in mass screening.  In the presence of a positive antibody, diagnosis of celiac disease should be confirmed by performing a duodenal biopsy.  Histological demonstration of small bowel villous atrophy remains the gold standard for making the diagnosis of celiac disease.

9.  The notes from the Sheffield Teaching Hospital Trust review some studies on patients of various ages whose symptoms establish a diagnosis of gluten sensitivity.  One group of investigators began with these borderline patients on a gluten-free diet instead of with on a gluten change and watching any improvements.

Symptoms and Treatment – The Gold Standard

10.  IBS symptoms affect a quarter of the population. The prevalence of celiac disease in IBS is around 4%.  In one study 102 people with diarrhoea - prominent IBS, 23% had raised IELs and 35% had the HLADQ2 haplotype associated with celiac disease (present in about a quarter of the total population).  The patients with HLADQ2 were significantly likelier to enjoy symptomatic relief from a gluten-free diet.

11.  Symptoms of gluten sensitivity may present outside the gastrointestinal (GI) tract. Skin diseases including dermatitis herpetiformis, alopecia areata, urticaria and psoriasis have all been shown to improve on a gluten-free diet.  In one study 30 patients with psoriasis and positive anti-gliadin antibodies (two had overt celiac disease and the rest had a normal duodenal biopsy) were put on a gluten-free diet.  All had a highly significant improvement in their symptoms, which relapsed in 18/30 upon gluten reintroduction.  Neurological manifestations are increasingly recognized with ataxia and neuropathy being the commonest.  Gluten ataxia accounts for up to 45% of patients with idiopathic sporadic ataxia.  Gluten-free diet can be an effective treatment, even in the absence of enteropathy. Tropical sprue is an intestinal disorder, manifesting as deficiency of vitamin B12 and probably due to bacterial overgrowth.

12.  In one of the largest studies to date 215 patients with axonal neuropathy were screened for the presence of gluten sensitivity.  No cause for the neuropathy could be found in 140 patients.  One in 3 of this group had positive antigliadin antibodies, 80% had the HLA type associated with celiac disease and 9% had overt celiac disease.  Likewise, patients with idiopathic sensorimotor axonal neuropathy and circulating antigliadin antibodies have been shown to improve symptomatically on a gluten-free diet (GFD).  Myopathy is less common than ataxia and peripheral neuropathy in gluten sensitivity, but it too can improve on GFD.  Finally, headache with white matter abnormalities on MR imaging is another neurological manifestation that improves with a strict GFD.

13.  The composite data suggest that “there may be benefit in considering a GFD in selected patients who are gluten-sensitive, but do not have celiac disease.”  In addition, recent work has noted that antibodies to tissue transglutaminase are present in the gut and extraintestinal tissues of people with celiac disease, latent celiac disease, and dermatitis herpetiformis.  “The neurological work done by one of our colleags has suggested that these same antibodies are found in the perivascular space within the brain of patients with gluten ataxia with  or without an enteropathy, but not in ataxia control subjects.”  These tissue- based antibodies may be present, even if there is no demonstrable antibody  circulating in the serum, i.e. the patients would not necessarily be serologically  positive for celiac disease. This may suggest that these antibodies are involved  in the pathogenesis of both celiac disease and gluten sensitivity.

14.  In dermatitis herpetiformis (which is a cutaneous manifestation of gluten-sensitivity enteropathy), these patients have antibodies to tissue transglutaminase deposited in the epidermis autoantibodies against different transglutaminases may be specific to the type of manifestation, i.e. anti-TG2 in enteropathy, anti-TG3 in dermatitis herpetiformis and anti-TG6 in patients with neurological manifestations.  This dermatitis may be passed off as psoriasis.  It can be treated with a sulfore drug called dapsone, which is also used on patients with leprosy.

15.  The Sheffield team conclude that they have “presented data that may suggest a role for defining patients with gluten sensitivity and acknowledging that these individuals are part of a spectrum ranging from an unaffected person (without celiac disease) to a patient with celiac disease. There may be benefit in considering a GFD in these individuals, who may present with both gastrointestinal and non-gastrointestinal manifestations.  It could be argued, for example, that whilst medications prescribed for IBS may have side-effects, a GFD has no risk/side-effect profile and may result in an improvement in symptoms.  Although the authors believe that there is a role for considering gluten sensitivity in clinical practice, “we would also wish to see further supportive data/research in the form of multicentre randomized studies.”

What Happens Elsewhere?

16.  Not surprisingly, experts elsewhere ponder over the best strategies for increasing the number (and proportions) of diagnoses of celiac condition:  mass screening or, more simply, identification of suspected cases (case-finding).  The results apply to populations primarily of European origin (Europe, North America, and parts of South America, Australia, and New Zealand, but also other areas of the world such as North Africa, the Middle East and parts of the Indian sub-continent).  In countries with a higher socio-economic level, the overall prevalence of celiac condition “actually seems to have been increasing in recent decades for reasons that are unclear at present,” states Professor Carlo Catassi, of the Universita’ Polytecnica Della Marche and Center for Celiac Research, University of Maryland School of Medicine in the USA.  Although suspect villous atrophy has been reported in dogs, the celiac condition has not been noted in other non-human animals.  It is surprising – and we at VEGA are looking into this – that pigs, for instance, seem immune, event after feeding with cereal products containing the prolamines.

17.  The expected number of celiacs in Italy, with its resident population of about 60 million people, is approximately 600,000, according to Professor Catassi; in reality, however, he reckons that fewer than 100,000 cases have actually been diagnosed. The situation is similar in other European countries, although there are regional differences connected in part to varying prevalence of celiac condition in the population, but most of all to the differing levels of knowledge of the condition among doctors.

18.  Finland has aimed at high data detection rates of incidence and prevalence of celiac disease by training health personnel, and had advocated serological screening for known celiac risk groups, the purpose being to assess whether this approach has been effective in clinical practice.  The study was based on a 
prospective database of new celiac patients aged 16 years or more, to whom the Social Insurance Institution had paid monthly compensation for the additional cost of maintaining a gluten-free diet since 2002.  Incidence and prevalence rates were calculated until the end of 2006.  The total population  aged 16 years or more was 4.31 million.  In 2004 to 2006 a total of 5020  persons (64% female) receiving a new dietary grant were identified thru the  database.  The mean annual incidence of proven celiac disease was thus 39 per  100,000 (390 per million); altogether, 23,553 persons received the dietary  grant, which gives a nationwide point prevalence of adult celiac disease of  0.55% (0.70% F; 0.38% M).

19.  Reporting the results of their study on Incidence and Prevalence of diagnosed celiac disease in Finland: results of effective case finding in adults, Li Virta et al (Scand J Gastroenterol 2009, 44 (8), 933-938), state that, to the best of their knowledge, these figures are the highest reported: “increased alertness to the condition and active case-finding have made this efficient diagnostics possible.”

Should We Screen for Celiac Disease?

20.  Screening for a number of diseases, coupled with increasing attention to genetics, familial traits, and post-translational influences (ie epigentics, comprehending fetal origins of adult diseases and lifestyles of pregnancy), occupy hot controversy as “the recession” and politicians find cause to reduce the nation’s wellbeing by cuts on spending on both prevention and cure (eg Fasano, BMJ 2009, 339, 3592).  VEGA has been involved in the deliberations – and associated with researchers in the Finnish Karelia project and in studies on plant-derived components in foods – as it tackles the challenges collated in its Green Plan for farming, food, health, and the land, launched, with its Campaign for Real Bread, in 1976.  We overhaul our Portfolio of Eating Plans in for the celiac interest, as well as presenting feasible means of “cutting down on meat and dairy” in prudent nutritional ways.

21.  Celiac condition seems to meet the main requirements for mass screening:

i. It is a socially significant condition, especially in view of its high frequency

ii. It easily evades diagnosis

iii. If it is not recognized, it can cause serious, irreversible complications

iv. There are simple, reliable diagnostic tests (in particular testing for the presence  of class A anti-transglutaminase and anti-endomysium serum antibodies)

v. A decisive cure is available: the gluten-free diet, which is being increasingly easier to adhere to and even to combine with other special diets(eg  vegetarian).  Advisory IT services abound.

22.  Treating clinically silent cases limits the application of mass screening.  In patients with celiac condition presenting with few symptoms the psychological and social commitment that the treatment requires can be difficult to accept, leading to a risk of little adherence to the gluten-free diet. Further, because the condition can develop at any age, even in old age, the frequency of screening would be high and perhaps prompt unnecessary worry in the elderly (the NHS is, understandably, alarmed over the risks of creating a nation of  hypochondriacs: for researchers this risk is accompanied by ignorance and confusion in pathological studies, the level of uptake and the quality of volunteered postmortems being very low in the UK, even though animal welfarists see it as a good means of replacing painful procedures on living animals of other species; and physicians and surgeons suspect revelations of mistakes incurred in efforts at assessing their performance.

Celiac Symptoms using Case-finding as a Strategy

23.  The HLA system (DQ2 and DQ8) is at the moment the only predisposing genotype as an effective means of identification, but its predictive potential is limited; moreover, doctors’ knowledge and continued training, especially among GPs, need frequent updating – with specialists at different ages, eg paediatricians and genatricians and their status in health services, locally, regionally, and nationally. Clinical symptoms to note in case-finding are:

i. Family history of celiac condition
ii. Chronic intestinal problems
iii. Anemia
iv. Osteoporosis
v. Autoimmune diseases
vi. Hepatic function abnormalities steatorrhea
vii. Epilepsy or other neurological problems
viii. Chronic fatigue syndrome
ix. Symptoms of Down’s syndrome, Turner syndrome, and/or Williams syndrome
x. IgA deficiency

24.  The debate will continue as genetic and evolutionary factors play in farm-to-fork policies and movements of population and climate changes affecting people and other species of animals.  Our children’s education and health must concern teaching professionals and the constant challenges remain, viz:

  • Why did the Groundnuts Scheme fail?
  • Why did the Neanderthals abruptly die out?
  • Why were there riots in Britain’s northern cities in the middle of the 19th-century?
  • Why were many officers in the New York police named Murphy or members  of the Murphia?

25.  Don’t let us undervalue the importance of “real” starchy foods. 

 

ABBREVIATIONS

IELs

Intraepithelial Lyphocytes

HLA

Human Leukocyte Antigen

IgG/IgA

Antigliadin Antibodies

TTG

Tissue Transglutaminase

EMA

Endomysial Antibody

IBS

Irritable Bowel Syndrome

GI

Gastrointestinal 

GFD

Gluten Free Diet

MR

Magnetic Resonance

 

 
 
 

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