MANAGEMENT OF NON- COELIAC GLUTEN SENSITIVITY Dr Sue Shepherd - - PowerPoint PPT Presentation

MANAGEMENT OF NON- COELIAC GLUTEN SENSITIVITY

Dr Sue Shepherd

B.App.Sci. (Health Promotion), M. Nut & Diet., PhD.

Advanced Accredited Practising Dietitian

REPRESENTATIONS AND AFFILIATIONS

DISCLOSURE

• Author of Cookbooks for Coeliac Disease and IBS.

– “Irresistibles for the Irritable”, “Two Irresistible for the Irritable”, “Gluten Free Cooking”, “The Gluten Free Kitchen”, “Allergy Free Cooking”, “Food Intolerance Management Plan”, “Gluten and Wheat Free Diabetes”, “Low FODMAP Recipes”, and “The Complete Low FODMAP Diet”.

• Co-author of “Gastrointestinal Nutrition”.

– Resource manual for dietetic management of gastrointestinal conditions.

• Consultant to Gluten Free Food Show in Melbourne, Sydney,

Brisbane, Launceston.

– for coeliac disease, low FODMAP diet.

• Consultant dietitian to food companies for development of

specialty food products.

• Co-ownership of FODMAP Friendly certification trademark.
• Co-director of company producing FODMAP Friendly food

products.

CHARACTERISTICS OF PATIENTS WITH NON-COELIAC GLUTEN SENSITIVITY

• Functional gut symptoms (IBS-like) e.g., abdominal

bloating, excess wind, altered bowel habits, abdominal pain.1,2

• Systemic manifestations e.g. “foggy head”, headache,

fatigue, joint and muscle pain, leg or arm numbness, dermatitis, depression.1,2

• Symptoms improve on gluten withdrawal.
• Symptoms worsen on gluten consumption.
• 1. Ludvigsson et al, Gut 2012. 2. Catassi et al, 2013

CHARACTERISTICS OF PATIENTS WITH NON-COELIAC GLUTEN SENSITIVITY

• No standard diagnostic approach to NCGS.1,2
• Systematic evaluation recommended.
• Exclude CD (either normal duodenal histology on

gluten or absence of HLA DQ2 or DQ8 genotype).

• Exclude wheat allergy; and
• Exclude other inflammatory disorders as appropriate.
• No major complications of untreated NCGS have been
• described. Natural history data lacking.2
• 1. Ludvigsson et al, Gut 2012. 2. Catassi et al, 2013

CHARACTERISTICS OF PATIENTS WITH NON-COELIAC GLUTEN SENSITIVITY

• Non-coeliac

gluten sensitivity has been estimated to affect 0.5-6% of the population.1,2

• In Australia, it is estimated that for every person

with diagnosed coeliac disease, there are twenty others eating gluten-free food.3

• 1. www.massgeneral.org/children/services/celiac-disease/gluten-sensitivity-faq.aspx
• 2. Catassi et al, 2013. 3. Vinning & McMahon. Rural Industries Research &

Development Corp, Aust Govt, 2006.

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST?

1 Ludvigsson et al, Gut 2012.

NON-COELIAC GLUTEN SENSITIVITY – THE LITERATURE

A mixed bag!.....

• Some studies have had inappropriate inclusion criteria e.g.,

patients with increased density IELs. 1

• Increasing risk that patients with latent coeliac disease were included in

study.

• IBS cases may be classified as NCGS.2
• Terminology issues – “wheat sensitivity”, “gluten sensitivity”,

“gluten intolerance”, “non-coeliac gluten sensitivity”, etc.

• Wheat contains many constituents that could play a role in

triggering symptoms – amylase-trypsin inhibitors (new area of interest – release pro-inflammatory cytokines), fructans (FODMAP), proteins (allergy). These need to be controlled for in studies.

• 1. Wahnschaffe et al, 2001. Catassi et al, 2013

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST?

• Carroccio et al conducted a study in 2012 in a cohort
• f 920 patients with IBS.
• Participants

undertook a 4 week gluten free (elimination) diet then double-blinded crossover rechallenge with wheat or placebo capsules.

• 276 participants (30%) had “wheat sensitivity”.
• 206 of these (75%) had multiple food sensitivities.
• Confusion re: terminology.
• Uncertain if it was gluten withdrawal or other factor

that benefited participants.

Carroccio et al 2012

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST?

• Biesiekierski

et al conducted a double blinded, randomised, placebo-controlled rechallenge trial on 34 patients (29-59y, 4 men) with IBS (self-controlled on a GFD)1.

• CD excluded: negative coeliac serology AND either an

HLA DQ2/8 negative or normal duodenal biopsy.

• Patients were given either gluten (1 muffin and 2 slices

bread = 16g gluten) or placebo for 6 weeks. These were also low FODMAP .

• Background diet not controlled.
• 1. Biesiekierski JR, et al 2011

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST?

• The group given gluten demonstrated a significant

deterioration of symptoms compared to placebo (85% vs 40% p=0.0001).

• Symptoms

included abdominal pain, bloating, satisfaction with stool consistency, and tiredness.

• There was no difference between the groups in tests for

intestinal injury (faecal lactoferrin, CRP or sugar test for intestinal permeability) or coeliac serology.

• We were unable to elucidate a mechanism for the

difference between the groups.

Biesiekierski JR, et al 2011

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST?

Recently…

• A double-blind placebo-controlled cross-over

trial in patients with self-reported NCGS has produced contradicting results, raising some doubt about the existence of NCG.

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST?

• Biesiekierski et al. recruited 37 patients with IBS and

self-reported NCGS. 1

• CD excluded: negative coeliac serology AND either

a HLA DQ2/8 negative or normal duodenal biopsy

(identical inclusion/exclusion criteria as the 2011 study).2

• Recruits were provided all meals during the study and

undertook all three treatment arms, in a cross-over study with >2 week washout periods between arms.

• 1. Biesiekierski JR, et al 2013 2. Biesiekierski JR, et al 2011

Hig igh g glu luten en (16g/gl glute ten) n) Low G Glu luten en (2g g glu luten en/ 14g 14g w whey) Control

• l

(0g g glu luten en/ 16g 16g w whey) ≥2 we week wa wash shout ≥ 2 we week wa wash shout 7 days 7 days 7 days ← Low F FODM DMAP Di Diet et → Lo Low FODM DMAP AP Di Diet et 14 days

n=37 – STUDY PART A

Vis isual A l Analogue S e Scale le ( (VAS AS) symptom scores es Biesiekierski JR, et al 2013

Mean + n +/- SEM EM * * * * * = <0.05 from end of low FODMAP run-in to end of treatment arm Biesiekierski JR, et al 2013

CHANGES IN SYMPTOM SEVERITY FROM RUN-IN FOR EACH 7 DAY DIETARY TREATMENT

Mean + n +/- SEM EM * * * * * = <0.05 from end of low FODMAP run-in to end of treatment arm

In all participants, gastrointestinal symptoms significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten-specific effects were observed in only 8% of participants. There were no diet-specific changes in any biomarker (serum

and faecal markers of intestinal inflammation/injury). Biesiekierski JR, et al 2013

CHANGES IN SYMPTOM SEVERITY FROM RUN-IN FOR EACH 7 DAY DIETARY TREATMENT

Glu luten en a arm (16g g glu luten en/ 0g w g whe hey) Whe hey ar arm (0g g glu luten en/ 16g 16g w whey) Control

• l

(0g g glu luten en/ 0g w g whe hey) ≥3 day washout ≥ 3 day day w was ashout ut 3 days 3 days 3 days ← Low F w FOD ODMAP , L , Low F w Food c chemical, D , Dairy F Fre ree D Diet →

• No differences across dietary treatment arms for change in
• verall symptoms (day 3) vs baseline period (PART A).
• Changes in individual symptoms (e.g., bloating, satisfaction with

stool consistency, wind, pain, tiredness, and nausea) were similar across the 3 dietary periods (all p > 0.209).

Biesiekierski JR, et al 2013

n=37 – STUDY PART B

RESULTS

• All participant’s symptoms improved on reduction in

FODMAPs prior to the delivery of treatment arms.

• There was no difference in VAS symptom scores

between gluten, whey and/or placebo arms.

• The study demonstrated a significant placebo effect

as all treatment groups experienced an increase in symptoms during each of the treatment arms.

Biesiekierski JR, et al 2013

DIFFERENCES IN STUDY DESIGN 2011 VS 2013

Fa Factor Prot

• toc
• col
• l i

in 2011 2011 Chang hange i in n 2013 Rational nale Acce ccess to f food

• od

duri ring stu study Regular diet. Only muffins and bread provided. All meals provided – low FODMAP and gluten free To reduce “background noise”. To control for changes in participant’s usual diet including FODMAP intake. Considerati ation n

• f o
• th

ther p puta tati tive triggers f rs for g r gut symp ymptoms Nil Restriction of dairy products and all food chemicals. Ensured that during Part B, the only difference between treatment arms was the nature of the protein intake. Stu tudy d desi sign Parallel Cross-over To reduce influence of confounders and increase power. Durat ation o n of treatm tment nt 6 weeks 1 week – part A 3 days – part B Symptoms peaked at day 3, unlikely longer time frame would capture delayed response to gluten

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST IN PATIENTS WITH FUNCTIONAL GUT SYMPTOMS?

“In these two double-blind, randomised, placebo-controlled, cross-over trials (Part A and B), specific and reproducible induction

• f symptoms with gluten could not be

demonstrated”. Answer: ??

Biesiekierski JR, et al 2013

• These data suggest that NCGS may not be a

discrete entity; or

• NCGS might be confounded by FODMAP

restriction.

• As suggested by this highly selected cohort,

gluten might be not be a specific trigger of functional gut symptoms

• nce

dietary FODMAPs are reduced.

Biesiekierski JR, et al 2013

CONCLUSION

DOES NON-COELIAC GLUTEN SENSITIVITY EXIST IN PATIENTS WITH EXTRA-GASTROINTESTINAL SYMPTOMS?

Randomised Clinical Trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity – an exploratory clinical study. Answer: unfolding

Peters S, et al 2014

CHARACTERISATION OF ADULTS WITH A SELF-DIAGNOSIS OF NON-COELIAC GLUTEN SENSITIVITY

Jessica Biesiekierski, Evan Newnham, Susan Shepherd, Jane Muir and Peter Gibson Nutrition in Clinical Practice, in press 2014

• Non-coeliac gluten sensitivity (NCGS), is a

condition where patients without coeliac disease report gastrointestinal symptoms improve on a gluten-free diet (GFD).

• NCGS is largely a self-reported diagnosis.
• NCGS appears to be very common.
• Aim: To characterise patients who believed they

have NCGS.

BACKGROUND AND AIM

Biesiekierski JR, et al 2014

PARTICIPANTS

• 147 recruits (mean age 43.5yrs, 88% female).
• Believed they had NCGS.
• Completed a questionnaire about symptoms,

diet and coeliac investigation.

Biesiekierski JR, et al 2014

STUDY DESIGN - QUESTIONNAIRE

• 23 questions, three domains:
• Symptoms

ms: e.g.

• ‘Describe your main symptoms if you eat gluten’
• ‘Do you currently feel in control of your

symptoms?’

• Di

Diet: e.g.

• ‘Do you follow a strict gluten free diet?’
• ‘How long have you been following a gluten free

diet?’

• ‘Where did you find out about a gluten free diet?’

Biesiekierski JR, et al 2014

STUDY DESIGN - QUESTIONNAIRE

• Coelia

liac Disease Investig tigatio tion: e.g:

• ‘Have you had blood tests (or “coeliac antibodies”) for

diagnosis of coeliac disease?’

• ‘Have you had the gene test for coeliac disease?’
• ‘Have you had a gastroscopy (endoscopy) for diagnosis
• f coeliac disease?’
• ‘If yes, were you consuming gluten in the lead up to

the gastroscopy?

• How much gluten and for how long before the

gastroscopy were you eating gluten?

• Were you specifically asked to consume gluten in the

lead up to the gastroscopy?’

Biesiekierski JR, et al 2014

RESULTS - PARTICIPANT PRESENTATION

NCG NCGS 28% 28% No Not NCG NCGS 72% 72%

On Only 28% of 28% of p peop

• ple

compl pleting t g the survey fu y fulfilled t d the crit iteria o a of N f NCG CGS.

• Inade

adequat ate excl clusion of

• f coe

coeliac disea ease 6 e 62%.

• Uncon

control

• lled

sym ympt ptoms de despit pite gl gluten r restriction 24% 24%.

• Not fo

follo lowing a g a GFD 2 D 27%.

40 40 of t these pati tients ts we were re enroll lled ed in in the Bie iesiek ekier erski i (P (PART A A/B) B) study describ ibed ed e earlier ier. Biesiekierski JR, et al 2014

RESULTS – COELIAC INVESTIGATIONS

Adequacy of coeliac disease exclusion based

• n source for initiating the GFD.

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Self Alt practrs Dietitians GPs Inadequate exclusion of CD Adequate exclusion of CD

91/ 91/147 ( 7 (62% 62%) did n not have coeliac di disease ade adequ quate tely ex exclud uded ed

Sourc rce of r referra rral n=65 n=30 n=28 n=24 Biesiekierski JR, et al 2014

RESULTS - SYMPTOMS

“Do you currently feel in control of your symptoms”

NO (22%) SOMETIMES (7%) MOSTLY (12%) YES (59%)

Almost 1 1 in in 4 do don’t fe feel in l in control

• f s

f sym ymptoms o

• n G

GFD D – nons nsens ensical t to presum ume e issue i e is NCG CGS

41% 41% h have in incomplet ete e re resoluti tion o

• f

sy sympto toms o s on GFD Biesiekierski JR, et al 2014

• Only 28% self-reporting as NCGS fulfill criteria for its

diagnosis.

• Ensuring criteria fulfilled is essential prior to recruitment for

any studies to be useful.

• Initiation of a GFD without adequate exclusion of

coeliac disease is common.

• Coeliac disease MUST be excluded. Excluding wheat allergy

also useful.

• In 22%, symptoms are poorly controlled despite gluten

avoidance (and 40% have inadequate control).

• Excluding potential for other common dietary triggers

recommended, e.g., FODMAPs.

Biesiekierski JR, et al 2014

SUMMARY OF FINDINGS

NCGS PATIENT DIAGNOSIS FLOWCHART

Ste tep 1 1. Adequate exclusion of CD Ste tep 2 2. . Other dietary triggers excluded ie. FODMAPS Ste tep 3 3. . Controlled symptoms with gluten restriction Ste tep 4 4. . Symptoms induced with gluten rechallenge Ste tep 5 5. . Establish threshold of gluten tolerance

No Non- coeliac ac gl gluten sensitivi ivity

Biesiekierski JR, et al 2014

Ste tep 1: Definitive exclusion of coeliac disease done by either absence of the coeliac-associated HLA-DQ genotype

• r negative coeliac serology and a normal duodenal biopsy
• n
• n a glut

uten-rich ch di

• diet. (Also exclude any other pathological

causes for symptoms where appropriate). Ste tep 2: After testing for coeliac disease, other possible dietary triggers should be investigated, importantly Fermentable Oligo- Di- and Mono-saccharides And Polyols (FODMAPs), by initiating and trialing the low FODMAP diet for 6 weeks. Skilled educator (e.g., nutritionist) is imperative.

NCGS PATIENT MANAGEMENT FLOWCHART

Biesiekierski JR, et al 2014

Ste tep 3: If the patient experiences no or partial symptom improvement to the low FODMAP diet, it is then worth considering gluten. Patients should exclude dietary gluten for 4 weeks and record symptom response. Ste tep 4: Provided there is marked improvement in symptoms with the GFD, blinded challenges (that is, monitored reintroduction of gluten) can be subsequently undertaken.

NCGS PATIENT MANAGEMENT FLOWCHART

Biesiekierski JR, et al 2014

Ste tep 5: Following a positive challenge, the amount of gluten tolerated should be established by systematic re-challenges beginning with small amounts of gluten.

NCGS PATIENT MANAGEMENT FLOWCHART

Biesiekierski JR, et al 2014

PRACTICAL IMPLICATIONS

• Those fulfilling NCGS criteria (~40 in Biesiekierski et al 2013

study), experienced a superior response to reduced FODMAP diet compared with gluten restriction.

• As a cause for functional gut symptoms, IBS is more common

than NCGS (10-20% vs 0.5-6%), therefore the low FODMAP diet should have greater likelihood to offer symptom relief than the gluten free diet.

• Supported by Biesiekierski et al study.
• In the patient who has had coeliac disease excluded and

believes they have NCGS, however still has GI symptoms despite GFD compliance, consider FODMAP intolerance.

Biesiekierski JR, et al 2013

CASE STUDY

• Ms M.N., 37 y.o. female on gluten free diet

(GFD) for 18 months to manage bloating, excessive wind, abdominal pain.

• Self-initiated GFD.
• No previous coeliac disease investigations

(biopsy or gene test).

• Increased frequency of bloating, wind and

altered bowel actions for past 8 months.

• Self-referred to nutritionist.

CASE STUDY

• Diet history confirms MN is on strict GFD with
• nly occasional gluten intake (beer, cornflakes,

rye bread). Diet also has regular intake of high FODMAP foods.

• Dietitian discusses with patient the possibility

symptoms could be due to coeliac disease.

– MN not keen to undergo gluten challenge as reports she feels better without gluten.

• Gluten challenge = 4 slices wheat bread/day for 6 weeks.

CASE STUDY

• MN agreeable to have HLA testing ordered through

GP:

– If DQ2 and/or DQ8 negative, it rules out CD. – If positive, it doe

• es not
• t di

diag agnose CD CD, only indicates MN has the genetic potential to get CD.

• If positive, would recommend gluten challenge followed up

with coeliac serology and referral to gastroenterologist for consideration of small bowel biopsy.

• While waiting for HLA blood tests to be done and

results returned, MN is taught to combine the GFD and the strict low FODMAP diet (phase 1).

EXAMPLES OF HIGH FODMAP FOODS

Exce cess Fruct ctos

• se

Polyols Lac actose Fruc uctans ns

Gal alac acto-

• ligo

gosacchar arides des

Apples, pears, mangoes, nashi fruit, boysenberry, watermelon, cherries, asparagus, Jerusalem artichokes, sugar snap peas, honey, high fructose corn syrup, agave. Apple, apricot, avocado, blackberry, cherry, nashi fruit, peach, pear, plum, prune, watermelon, cauliflower, mushrooms Milk, ice cream, custard, yoghurt, ricotta cheese, cream cheese, cottage cheese. Custard apple, persimmon, nectarine, watermelon, globe artichoke, asparagus, garlic, legumes, lentils, leek, onion, shallot, spring

• nion (white part),

cashew, pistachio, wheat, rye, barley (in large amounts). Legumes, lentils, chickpeas.

EXAMPLES OF LOW FODMAP FOODS

Fr Fruit* Vege getabl ables Ce Cereal als an and d Grai ains Milk P Produ ducts

Oth Other f food

• ods

Banana, kiwifruit, strawberry, blueberry,

• range,

mandarin, lemon, lime, honeydew melon, grapes, pineapple, passionfruit. *Limit serving size. Potato, carrot, spinach, capsicum, eggplant, zucchini, lettuce, tomato, cucumber, turnip, swede, green beans, parsnip, squash Rice, cornflour, quinoa, millet, sorghum, oats, polenta. Lactose free milk, lactose free yoghurt, fermented cheeses (block cheese) e.g., parmesan, cheddar, gouda, edam, brie, camembert, fetta, mozzarella. Small amounts of cream and soft cheeses. Sugar, maple syrup, golden syrup. Small handful

• f nuts and

seeds (all except cashews and pistachios), unprocessed meat, fish, chicken, eggs. Garlic-infused

• live oil.

CASE STUDY

• MN returns to dietitian in 4wks. She reports symptom resolution on combined

GFD and strict low FODMAP diet (Phase 1).

• HLA results returned negative result (no HLA-DQ2 or 8).

– Coeliac disease excluded.

• MN keen to continue low FODMAP diet and willing to reintroduce gluten
• slowly. Instructed to monitor symptoms and continue to restrict all FODMAPs.

– High gluten/low FODMAP foods include oats, some spelt breads, small amounts of wheat, rye, barley.

• MN returns to nutritionist in 4 wks. Reports gluten reintroduced successfully, no

symptoms experienced. Strict low FODMAP diet alone effective for symptom management.

• MN then instructed on Phase 2 of the low FODMAP diet (liberalisation phase)

to ensure no unnecessary over-restriction.

• After 8wks Phase 2, MN very satisfied with symptom control, increased variety

in her diet and increased understanding of her symptom triggers. If ge f gene t test w was as po posit itive, it it do does n not excl clude coe coeliac d

• disease. So, y

So, you

• u ca

can instruct MN t to u unde dergo go gl gluten chall allenge ge w with lo low F FODM DMAP/high gl gluten fo foods:

• Smal

all am amounts o

• f

f wheat

• Some 1

100% s spe pelt br bread ads

• Oats

ats

• As t

these ar are lo low F FODM DMAP , t they y will ll minimise s sym ymptom i insult, whil ilst stil ill pr provid iding g gl gluten load. ad.

FUTURE DIRECTIONS

• There is a need for large multi-centre studies

investigating the role of gluten in NCGS, which account for potential confounding symptom triggers e.g., FODMAPs (and potentially wheat ATIs).

• Such studies may then further define NCGS and

enable researchers to establish:

– True prevalence figures. – Existence of variation in threshold of sensitivity to gluten. – If it is long term condition or temporary/transient.

Catassi et al. 2013