Non celiac gluten sensitivity

Gluten

• Gluten is a composite protein in the endosperm of cereals like wheat, barley and rye• It gives elasticity to dough and helps it to rise.• Two components of gluten – Gliadin and Glutenin

Background

• Earliest description came in 1980s when Holmes described Gluten sensitivity diarrhea without evidence of celiac disease.

• Total number of publications related to this before 1990 were 125 and within last 25 year risen up to around 900.

• Accumulating evidence led to a conclusion that a group of patients existed who were not fitting in definition of celiac disease but responded to gluten restriction

• London 2011 meet - panel of 15 experts was convened – for classification and nomenclature gluten related disorders.

Definition

• Since the term ‘Gluten sensitivity’ was often confused with celiac disease new term non celiac gluten sensitivity(NCGS) was introduced.

• NCGS can be defined as condition where• Symptoms triggered by gluten ingestion• Absence of celiac specific antibodies• Absence of classic celiac specific histology, variable HLA status• Resolution of symptoms on gluten withdrawal from diet.

Nutrients 2013 Sapone

Epidemiology

• Exact prevalence not known - many of the pts. self diagnose them selves(at least in the west) and start gluten free diet

• No population based surveys from India(or Asia) are available, similarly data from west are scarce

• In a survey by University of Maryland 347 patients satisfied the diagnostic criteria of NCGS of 5896 6%.

• In another study 30% of patients with IBS like symptoms based on Rome – II had NCGS

AJG – 2012 Carrocio

• Adults in general more prone than children, M:F – 1:2.5

Spectrum of gluten related disorders

Bakers asthma Wheat dependent exercise induced anaphylaxis

Clinical picture

• Abdominal • Pain – 66 %• Diarrhoea – 33%• Nausea• Wt. loss• Bloating, flatulence

• Behavioural• Decreased attention• Depression -22%• Hyeractivity• Anxiety

• Cutaneous – 40%• Erythema• Eczema

• Dental• Chronic ulcerative stomatis

• General • Headache -35%• Bone and joint pain 11%• Numbness hand and feet – 20%• Chronic tiredness – 33%

• Hematological• Anemia-20%

University of Maryland 2004-2010

Natural history

• Symptoms usually occur soon after gluten ingestion, disappear with withdrawal and relapse following challenge with in hours or few days

• Children GI manifestation – abdominal pain and diarrhea predominate over the extra intestinal manifestation – MC – tiredness

• It is independent of personality traits, level of somatization, anxiety and depressive disorders, a study found no difference in this factors between celiac disease (CD) and NCGS

Brottveit Scan J Gastro 2012

• No major complications of untreated NCGS described unlike CD.

Pathogenesis

• Gluten is not completely digested by enzymes in stomach

• Gliadin – induces apoptosis and alters permeability in in-vivo models

• In contrast to CD where both innate and adaptive immunity play role in the pathogenesis, innate immunity dominates the picture in NCGS

• TLR – key role in innate immunity – upregulated, NCGS>>CD

• Pathogenetically different from CD also w.r.t. epithelial permeability

• NCGS has increased expression of claudin-4 – marker of decreased intestinal permeability

Claudin

• NCGS is marked by decreased intestinal permeability

• Protein other than gluten – might also be responsible for NCGS – CD differences

• Bucci et al – basophils derived from mucosa in pts. with NCGS were not gluten activated – unlike CD

• In vitro study amylase/trypsin inhibitor(ATI) LMW protein in wheat can also cause release of inflammatory cytokines.

• Biesierkirski et al, pts. with NCGS with low FODMAPs diet had reduced symptoms and reintroduction flared the symptoms

IBS and NCGS complex relationship• Meta-analysis - pooled prevalence of IBS type symptoms in patients treated with CD – 38%

• Pooled odds ratio for IBS in CD • 5.6 – non adherent on gluten free diet(GFD)• 2.6 – strict GFD

• Gluten alters the barrier function in patients with HLA DQ2/DQ8 positive patients

• Landmark study proving role of gluten in 34 patients with IBS and self reported NCGS – double blind crossover trial, CD excluded by Bx and HLA

• 19 on gluten diet, 15 on GFD – Gluten group had more pain and bloating compared to GFD group

• But the markers of intestinal inflammation and permeability - lactoferrin was normal in gluten group unlike CD proving role of innate immunity in NCGS.

Biersckierski, AGJ 2011

IBS-NCGS and subsets

• Study by Carroccio et al – 920patients with IBS(Rome II) fulfilling criteria for gluten sensitivity included

• Four week of wheat restriction – double blind wheat challenge – 276 (30%) became asymptomatic on GFD and had recurrence of symptoms of on reintroduction of gluten containing diet(GCD)

• These 276 further were subjected to GFD and re-challenged with cows milk – 70(25%) remained asymptomatic on cows milk.

• Rest 206 classified as – multiple food allergies

• Suggests that 2 distinct group of NCGS patients exist – only wheat and other with multiple food allergy.

Autism – NCGS connection• Autism is chronic behavioral disorder with onset before 3 years of age

• Studies with dietary interventions have shown that patient with gluten free casein free diet may have better outcome in subgroup of patients.Whiteley Nutri Neurosci 2010

• Hypothesis – Opiod peptides formed from the incomplete breakdown of food containing gluten and casein

• Altered intestinal permeability – Leaky gut syndrome – allows these peptides to cross intestinal membrane bloodstream cross BBB affect endogenous opiate system and neurotransmission in the brain.

• Increased intestinal permeability – by lactulose/mannitol ratio test – 37% had abnormal test compared to normal subjects

J pediatric gastr nutri 2010

Lab evaluation

• No specific lab marker yet identified• But a recent study by Volta suggest there is high titer of 1st generation

IgG Antigliadin(AGA) antibody • CD – 81.2%• NCGS – 56.4%• Connective tissue disorders - 9%• Autoimmune liver disease - 21%• Normal – 2-8%

J Clin Gastro 2012

• On other hand IgA AGA is ~7.7% in NCGS• Anti tTG antibody and anti endomysial antibody is are always negative• IgG Deamidated gliadin peptide antibody is consistently absent

absence of role of adaptive immunity.

• HLA DQ2 and DQ8 seen in CD (95%) is seen in 50% of NCGS patients compared with normal population(30%)• Histopathology• Marsh staging

• Sapone et study, 11 NCGS, 12 CD and 7 controls D2 HPE • NCGS - Marsh 0-1• CD – Marsh 3-4

• CD increased number of CD3+ intraepithelial lymphocytes - >50/100 enterocytes compared to controls, NCGS in between the two.

• Number of TLR gamma/delta increased in CD patients >3.4/100 enterocytes, NCGS number similar to controls

• Carrocio et al study, increased intraepithelial eosinophils(>4/100cells) in colonic mucosa of 174/276(63%) of NCGS patients,

• Similarly higher eosinophil count in duodenum than in IBS, presence could be a guide to elimination diet.

Diagnosis

• Primarily diagnosis of exclusion

• Exclusion of CD histology, serology and HLA

• Wheat allergy excluded by serum IgE levels

• Gluten elimination diet at least for 3 weeks(for practical purposes)

• Salreno expert’s criteria – Nutrients – April 2015 - 3rd international Experts meeting on gluten related disorders, Salreno Italy reaching consensus on diagnosis of NCGS

Diagnostic protocol • Aim – assessing clinical response to GFD, measuring the effect of

reintroduction of GCD.

• Clinical evaluation is based on self administered instrument – modified version of gastrointestinal symptom rating scale.

• Step 1 – Definition of response to GFD• After excluding CD and wheat allergy• Baseline normal gluten containing diet of at least 6 weeks• At time 0 GFD started• At least six week of GFD

• Response is a symptomatic decrease of at least 30% base line score

• Precise response definition – Patients who fulfill the response criteria i.e. >30% reduction of one of the 3 main symptoms or at least 1 symptom with no worsening of others, for at least 50% of the observation time.

• The patient identifies 1 to 3 main symptoms that needs to be quantified using numerical rating scale from 1(mild) to 10(severe)

• Step 2 - Gluten challenge suggested dose of at least 8 gram of gluten per day

• Observation period, one week following a one- week washout of strict GFD.

• Repeat the questionnaire on GCD, an increment of at least 30% of symptoms compared with GFD.

• Patients with negative gluten challenge should be investigated for other possibility of IBS – like symptoms, e.g. intolerance to FODMAPS or SIBO

CD vs NCGS

Conclusions and future perspectives

• NCGS is recently rediscovered clinical entity different from CD, for which we have very little certainty and many gaps in knowledge

• Dire need of the day is identification of biomarker

• As of now 7 studies, registered with www.clinicaltrial.gov are in progress to evaluate the serological and mucosal indices.

Unanswered questions

• Should all patients of IBS be investigated for NCGS ?

• Is the threshold sensitivity same for all individuals ?

• What is the prevalence of NCGS ?

• Clarity on the mechanism of NCGS needs to be explored

Thank you