Adverse Food Reactions: From Allergy to Intolerance Barzin Khalili, MD Adjunct Assistant Professor Allergy & Immunology Oregon Health Sciences University Food Allergy • Food allergy prevalence is increasing in US: – 3-4% of adults – 6-8% of children • More people presenting to primary care with symptoms ascribed to food allergy. • More self-diagnosed patients • More misinformed patients due to lay press and inappropriate testing Adverse Food Reactions • Immune – IgA – IgE • Class 1 • Class 2 – Eosinophil – Mixed • Non-immune – – – – – Pharmacologic Gastrointestinal Toxins Sensitivity to Additives Intolerance • Lactose • Gluten Immune Mediated • IgA • IgE – Class 1 – Class 2 • Eosinophil • Mixed Celiac Sprue • IgA mediated condition against gliaden component of gluten found in wheat, rye, and barley. – Prevalence of 1 in 300 in Western Europe, North America and Australia. • 10% prevalence in 1st degree relatives. – IgA antibodies cause an inflammatory reaction that destroys intestinal villi. – Symptoms and complications include abdominal pain, diarrhea, bloating, steatorrhea, weight loss, bleeding (from low vitamin K) fatigue and weakness (from electrolyte losses) anemia, short stature in children, lymphoma and adenocarcinoma. Celiac Sprue - Pathophysiology Celiac - Testing • Small bowel biopsy is gold standard • Serologic testing – Anti-gliadin antibodies – IgA and IgG • Nonspecific -False positive in IBD, and present in healthy people. – Anti-endomysial antibodies – IgA • Correlates with severity of villous atrophy • If partial atrophy could be seronegative, so we check AGA IgA. • Nearly 100% specific but not 100% sensitive (concordance with TTG IgA lacking). – Anti tissue transglutaminase antibodies – IgA • Correlates with severity of villous atrophy • If partial atrophy could be seronegative, so we check AGA IgA. • False positives in presence of cirrhosis, diabetes, heart failure. – Total IgA • Selective IgA deficiency occurs 10-15 times more common in celiac disease • SIgA patients will lack IgA antibodies, hence AGA IgG. Celiac Genetics • HLA DQ2 or DQ8 gene expression necessary but insufficient to develop disease. • Low specificity limits use in diagnosis – Present in 30% of normal population • High sensitivity helpful to rule out disease if negative. • Optimal role in assessment: – Someone already on gluten-free diet – To determine which family members should be screened. Immune Mediated • IgA • IgE – Class 1 – Class 2 • Eosinophil • T cells • Mixed IgE Mediated Food Allergy • Symptoms – – – – – • • • • Skin – urticaria, pruritus GI – nausea, abdominal pain, diarrhea, Respiratory – dyspnea, wheeze, laryngeal edema Cardiovascular – chest pain, hypotension Timing – usually within 1 hour of ingestion Common foods – usuals plus sesame is on the rise Pathophysiology – mast cell degranulation of histamine Testing/diagnosis – – Skin prick tests – Serological IgE (ELISA) • Treatment – avoidance, education, epinephrine autoinjector Prick Skin Testing • Evaluate for IgE mediated food sensitization ELISA Question If aeroallergen Immunotherapy is effective for pollenosis, why are we advocating food avoidance instead of food immunotherapy? Subcutaneous Immunotherapy • Background: Peanut allergy is prevalent and potentially fatal. Currently, preventative treatment consists of avoidance which is difficult. • Methods: Six hypersensitive adult patients underwent peanut rush immunotherapy followed by 1 year of maintenance injections. Six peanut allergic patients served as untreated controls. All patients underwent 3 DBPC oral peanut challenges (before RIT, at 6 weeks, and 1 year). Nelson HS, et al. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 1997;99:744-51. Rush Immunotherapy Schedule Day Time (am) Concentration Dose (ml) 1 8 1:10,000 wt/vol. 0.05 2 3 9 0.10 10 0.20 11 0.40 8 5 0.05 9 0.10 10 0.15 11 0.20 8 0.30 9 0.40 10 0.50 11 4 1:1000 wt/vol. 1:100 wt/vol. 0.07 8 0.10 9 0.15 10 0.20 11 0.30 8 0.40 10 0.50 Oral Peanut Challenge Schedule Dose No. Amt of peanut 1 1 mg 2 5 mg 3 10 mg 4 20 mg 5 50 mg 6 100 mg 7 200 mg 8 500 mg 9 1 gm 10 2 gm 11 4 gm 12 8 gm • Doses delivered at 30 minute intervals until completion or reaction. • One peanut is equivalent to 432 mg Results – Rush Immunotherapy Subject No. Injections to maintenance Cutaneous reactions Cutaneous & Pulmonary Epinephrine Injections Inhaled Bronchodilator 1 63 5 29 39 7 2 30 7 2 3 0 3 36 3 2 3 0 4 23 3 6 5 4 5 35 9 5 7 1 6 21 2 2 2 1 Mean 34.7 4.8 7.7 9.8 2.2 Median 33 4.0 3.5 4.0 1.0 • Repeat Epinephrine treatments were required 8 times. • Systemic Reaction Rate of 23% Results – Maintenance Immunotherapy Subject No. Maintenance Injections Cutaneous reactions Cutaneous & Pulmonary Epinephrine Injections Inhaled Bronchodilator Final Concentration 1 43 0 30 30 11 1:1000 2 43 0 18 7 6 1:100 3 36 0 13 16 11 1:100 4 34 7 7 5 4 1:100 5 32 11 5 18 0 1:1000 6 21 0 3 0 0 1:100 • Two patients were unable to tolerate the dose achieved during RIT. • Median 13.5 reactions to 35 injections; Systemic reaction rate of 39%. Results – Oral Challenges 9000 Threshold Dose (mg) 8000 7000 6000 5000 Baseline 4000 1 Month 12 Months 3000 2000 1000 0 1 2 3 4 Patients 1,4,5 received a reduced maintenance dose. 5 6 Subcutaneous Immunotherapy • Conclusions: – All 6 patients had increased tolerance to peanut at 6 weeks. – There was partial or complete loss of protection at 1 year in those who required dose reductions. • Most sensitive patient went from 16 mg (1/27th) 7888 mg (18.3) 385mg (less than 1 peanut). – Clinical significance unknown – “The high rate of systemic reactions makes this form of treatment with the currently available peanut extract unacceptable.” Oral Tolerance • 1829 – Populations of Native Americans ate poison ivy leaves to prevent contact hypersensitivity to urushiol. • 1911 – Guinea pigs repeatedly fed hen’s egg protein were protected from anaphylaxis when injected with the protein. • 2013 - We are still gaining more insight into mechanisms of oral tolerance. Promoting Oral Food Tolerance Can patients with milk allergy tolerate extensively-heated milk products? Reacted 23% Strict milk avoidance Reacted to regular milk 68% Heated milk OFC Heated milk diet Tolerated Tolerated Regular milk 9% Add milk to diet Nowak-Wegrzyn A, et al. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol. 2008;122:342-7. Promoting Food Tolerance Baseline median 3 month median P value Milk SPT wheal size 8 7 .001 Casein IgG4 mg/L 0.54 1.02 .005 Undetectable casein IgG4 6 0 0.27 • Challenges notion that strict avoidance is necessary to “outgrow a food allergy” • Demonstrates that eating extensively heated milk products is safe and tolerated and may actually promote tolerance. • Strict milk avoidance may not be necessary for the majority of patients with milk allergy. Milk Oral immunotherapy • Issue: The main benefit of oral immunotherapy is to those patients with the most severe reactions. • Problem: Patients with severe food allergies are often excluded from studies examining oral tolerance induction for fear of lifethreatening conditions. • Solution: Conduct the study overseas. Milk Oral immunotherapy • Objective: Is oral immunotherapy safe and effective for children with severe cow milk allergies? • Methods: – Inclusion Criteria • 5-17 years old • Milk specific IgE > 85 kU/L • History of at least 1 severe allergic reaction Reaction Grade Clinical Features 1 Mild Localized cutaneous 2 Mild Generalized cutaneous 3 Mild 1 or 2 plus GI symptoms 4 Moderate Laryngeal edema, mild asthma 5 Severe Marked dyspnea, hypotension Longo G, et al. Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008;121:343-7. Milk Oral immunotherapy • Methods Cont: All patients underwent a DPPCFC. Only those who reacted to 8 ml or less of a 1:9 mix of milk:amino acid formula solution were randomized. – Group A – 30 received milk oral immunotherapy – Group B – 30 maintained a milk-free diet for 1 year – Repeat oral challenge was performed at 1 year. Treatment Group Phase 1 – In hospital Day Dilution Doses 1 1 drop CM in 10 ml water 5 drops -10 ml 2 5 drop CM in 20 ml water 2 – 16 ml 3 1 ml CM in 20 ml water 2 – 12 ml 4 3 ml CM in 20 ml water 3 – 10 ml 5 10 ml CM in 20 ml water 3 – 9 ml 6 10 ml CM in 10ml water 3 – 9 ml 7 Whole milk 2 – 6 ml 8 Whole milk 4 – 10 ml 9 Whole milk 8 – 15 ml 10 Whole milk 13 – 20 ml Phase 2 – At home • Increase by 1 ml every 2 days until 150 ml reached. Milk Oral immunotherapy Group A Unrestrict ed Diet (7) Group B • Positive food challenges in all 30 cases Maximum Tolerance (4) Partial Tolerance (16) Failure (3) Difference between groups is statistically significant (P < 0.001) Symptoms In hospital patients ( total no. of reactions) At home patients (total no. of reactions) Lip/mouth pruritus 30 (355) 14 (85) Perioral urticaria 28 (37) 17 (22) Generalized urticaria 14 (17) 7 (13) Abdominal pain 23 (47) 14 (32) Rhinoconjunctivitis 18 (23) 3 (8) Mild Laryngospasm 14 (15) 3 (5) Mild bronchospasm 12 (28) 8 (19) In hospital patients ( total no. of treatments) At home patients (total no. of treatments) Oral steroids 8 (16) 17 (35) Nebulized epinephrine 18 (22) 6 (9) 4 (4) 1 (1) Administered Treatment IM epinephrine Group B: 6 (20%) children had adverse reactions caused by accidental milk ingestion. Milk Oral immunotherapy • Conclusions: • 90% of patients with severe milk allergy were able to ingest higher amounts (> 5ml) of cow’s milk without reaction. • No patient required IV fluids/epinephrine. • Increasing the threshold required to cause a reaction is so important in highly allergic patients where minute quantities can be lifethreatening. Peanut Oral Immunotherapy • Objective: Investigate the efficacy and immunologic changes associated with OIT. • Hypothesis: Subjects with peanut allergy who undergo OIT would be shifted toward a TH1-type profile. • Methods: Open label study of 39 peanut allergic children undergoing an OIT protocol followed by food challenges. Immunologic parameters were followed. – Those with severe reactions excluded. Jones SM, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009;124:292-300. Peanut Oral Immunotherapy • Results: – 29 subjects completed the peanut dose escalations and peanut challenge. – 27/29 (93%) reached max dose of 3.9 g of peanut protein (equivalent to 16 peanuts). – Only mild symptoms reported. Peanut-specific Immunoglobulins Regulatory T Cells Peanut Oral Immunotherapy • Conclusions: Humoral and cellular responses suggest that OIT induces transition from shortterm desensitization to long-term tolerance. Peanut Oral Immunotherapy • Objective: To investigate effectiveness of OIT in DBPC study. • Methods: Peanut allergic children age 1-16 years received OIT with peanut flour or placebo. Oral food challenge done at 1 year. • Results: – 16/16 treated subjects ingested 5000 mg (20 peanuts) – 9 placebo patients ingested average dose of 280 mg (range 0-1900 mg). • Conclusion: Peanut oral immunotherapy induces desensitization. Varshney P, et al. A randomized controlled study of peanut oral immunotherapy: Clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011;127:654-60. Tolerance vs. Desensitization Immunologic mechanism of oral IT unclear • Desensitization – A change in threshold of ingested food antigen needed to cause allergic symptoms. Continued exposure of antigen is required to maintain effect. • Tolerance – Long lasting immunity shift away from TH2 phenotype and not dependent upon ongoing therapy. Egg Oral Immunotherapy • Objective: Oral IT with egg white powder for treatment of children with egg allergy. • Methods: DBPCRS of 55 kids age 5-11 years with egg allergy who received oral IT (40 children) or placebo (15).Escalation, build-up, and maintenance phases were followed by oral challenge with egg white powder at 10 and 22 months. – If passed OFC at 22 months, then egg avoidance and rechallenge at 24 months to powder and cooked egg to evaluate for tolerance. – If passed OFC at 24 months, then egg back in diet ad lib and evaluated again at 30 and 36 months. Burks AW, et al. Oral immunotherapy for treatment of egg allergy in children. NEJM. 2012;367:233-43. Egg Oral IT Results Egg Oral Immunotherapy • Conclusions: Oral IT can desensitize a significant proportion of children and induce sustained responsiveness in a subset. Burks et al. NEJM 2012 Immune Mediated • IgA • IgE – Class 1 – Class 2 • Eosinophil • Mixed Class 2 Food Allergy • Also called Oral Allergy Syndrome (OAS) • Symptoms usually confined to oral mucosa and include: – – – – soft palate itching Mucosal swelling Itching/tingling of tongue. lips, throat Tongue swelling • 9% of the time can have systemic symptoms – Nausea, vomiting, diarrhea, abdominal pain – Urticaria, angioedema • 1.7% experience anaphylaxis Oral Allergy Syndrome • Due to IgE cross reactivity between a prior aeroallergen sensitization and a plant derived protein found in food. – PR proteins – labile (cooked forms usually OK) • PR-10 is major birch tree pollen that can cross react with similar PR proteins in foods. – Profilins – labile • Involved in celery-mugwort-spice syndrome – Lipid transfer protein – stable to heat and proteolysis • Responsible for anaphylactic episodes Oral Allergy Syndrome Oral Allergy Syndrome • Testing – Skin prick test to actual food has highest sensitivity (70% - 80% depending on food) • PR proteins denatured during commercial processing – Specific IgE blood testing slightly inferior to skin test with fresh food. – Potential role for component resolved diagnostics (CRD). CRD Imagine this: On a miniature scale (a biochip) using specific allergen recombinant epitopes rather than the whole protein. AND Only requires 20ul of serum via capillary blood sampling CRD - How it Can Help • Component resolved diagnosis is valuable in the investigation of food allergy in children in whom it may be difficult to decide whether a sensitization may be caused by genuine allergy or a cross-reactivity. – IgE to peanut protein Ara h8 (birch pollen homologue) indicative of cross reactivity and OAS. – IgE to Ara h2 indicative of true food allergy and high risk for anaphylaxis. Oral Allergy Syndrome • Treatment as with Class 1 food allergy – Avoidance – Education – Injectable epinephrine • Two potential pitfalls: – Improper diagnosis of OAS in patient with anaphylaxis – Potential to dismiss patient with OAS as having no risk of anaphylaxis. • Remember 1.7% experience shock Question • If OAS is initiated by a primary aeroallergen sensitization…is there a role for immunotherapy (IT)? Oral Allergy Syndrome - Treatment • Objective: Does SIT with birch pollen have an effect on OAS induced by apple or hazelnut? • Methods: 27 birch-allergic patients with OAS to apple or hazelnut underwent oral challenge with both foods at baseline. 15/27 were treated with SIT and 12 were not. Bucher X, et al. Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy. 200459:1272-76. Oral Allergy Syndrome - Treatment • Results: 13/15 (87%) in treated group could eat significantly more apple or hazelnut without symptoms after 1 year. Avg tolerated quantity increased from 12.6 to 32.6 g of apple. 1/12 (8%) untreated patients could consume more. (128g = 2/3 of a medium apple) • Conclusion: Although a positive impact – the amount of tolerated food is small. Bucher et al. Allergy 2004. Oral Allergy Syndrome - Treatment • Background: Birch IT does not consistently improve apple OAS symptoms. Can tolerance be achieved orally? • Methods: Open, randomized trial of 27 allergic patients. – 14 consumed increasing amounts of daily apple for 20 weeks, doubling amount Q 2-3 weeks. – 13 untreated • Endpoint: Proportion of patients that were tolerant to 128gm of apple. • Results: 17/27 patients in active group and 0/13 in untreated group achieved desensitization. If apple not eaten daily, symptoms rapidly returned. Thus, tolerance not achieved. Kopac P, et al. Continuous apple consumption induces oral tolerance in birch-pollen-associated apple allergy. Allergy. 2012:67:280-85. Immune Mediated • IgA • IgE – Class 1 – Class 2 • Eosinophil • Mixed Eosinophilic Esophagitis - History • Essentially a new disease • Described as a distinct clinical entity in 1993 – 10 patients with esophageal eosinophilia, unresponsive to acid blockade who improved with an elemental formula. • Prior to that time, symptoms were primarily attributed to uncontrolled reflux. – Anti-reflux measures were ineffective. • Incidence: 10 per 100,000 per year • Prevalence: 43 - 104 per 100,000 Eosinophilic Esophagitis - Presentation • Symptoms tend to vary depending on age; • Infants – Failure to thrive – Irritability – Food refusal • Young children – – – – vomiting Regurgitation Epigastric pain Abdominal Pain • Older children and adults – – – – Dysphagia > 90% Heartburn Chest Pain Food Impaction > 60% • Easy to see why symptoms often attributed to reflux Eosinophilic Esophagitis - Diagnosis Clinical Feature EE GERD Prevalence of atopy Very high Normal Prevalence of food sensitization Very high Normal Sex preference Male None Abdominal pain and vomiting Common Common Food impaction Common Uncommon Eosinophilic Esophagitis - Diagnosis • EE is a histo-clinical diagnosis – Made by endoscopy and biopsy Concentric rings Linear furrows Mucosal laceration Eosinophilic Esophagitis - Diagnosis • Diagnostic criteria based on consensus recommendations: 1. Clinical symptoms of esophageal dysfunction 2. Greater than 15 eosinophils per hpf • • < 10 eosinophils often seen in reflux Unlike other GI tissues, normal esophagus is devoid of eosinophils. 3. No improvement with high-dose PPI or normal pH probe. Eosinophilic Esophagitis - Diagnosis • Average delay between symptom onset and first endoscopy. – Pediatrics 3 years – Adults 4 years • Most adults are diagnosed as a result of emergent presentation with food impaction – 55% of patients presenting to the ECU with impaction have EE. – Anyone with a food impaction should be scoped and biopsied. • Visual inspection alone is unsatisfactory – 1/3 of all cases have a normal appearance – Multiple biopsies are needed to enhance sensitivity due to patchy eosinophil distribution. Eosinophilic Esophagitis Pathophysiology • Link between EE and food allergy: – Complete symptom resolution and normalization of esophageal tissue when infants are placed on an amino acid diet. Eosinophilic Esophagitis – Evaluation • Atopy Patch Test – Evaluate for delayed T cell mediated reaction – Not yet standardized – Aluminum wells are filled with reconstituted dried powders or single-ingredient baby foods. – Applied to upper back – Removed in 48 hours and read at 72 hours. – APT is complementary to SPT • Prick skin testing • Serologic testing – Food specific IgE testing has shown very poor specificity and positive predictive value. Eosinophilic Esophagitis – Role of Food Allergy Most common foods positive in skin tests (66% of patients react to 1 or more foods) Most common foods positive on atopy patch tests • • • • • • • • • • • • • • • • • • • • • • • • • Cow’s milk Egg Peanut Almonds Soy Rice Beans Pea Mustard Beef Carrot Cow’s milk Egg Beef Lamb Veal Chicken Oat Rye Rice Corn Wheat Soy Potato Peas Eosinophilic Esophagitis – Dietary Treatment • Elemental Diet – 98% effective but not palatable, usually requires nasogastric tube for older children, not plausible in adults • Avoidance diet of the usual foods implicated EE – Egg, wheat, soy, cow’s milk, fish, shellfish, peanuts – 75 % of patient had symptom improvement • Avoidance diet based on skin and patch testing results. • NPV 88 – 100% (except for milk) • PPV 74% for milk, egg, and soy. • 75 % of patient had improvement in symptoms and esophageal eosinophilia • These tests do identify causative foods that may contribute to EE. • Despite improvement with avoidance, relapse is common (50%) when diet is liberalized Eosinophilic Esophagitis – Treatment Swallow Fluticasone • 6 weeks of fluticasone 220ug, 4 puffs twice daily for adults does lead to complete symptom resolution BUT……….. • 90% had recurrence in the first year • 70% required repeat therapy within 3 years • 20% required systemic steroids • 28% had subsequent food impactions • 22% underwent repeat dilation • Children's dose range is 440 – 880 ug per day • Risks – esophageal candidiasis, bone loss Eosinophilic Esophagitis – Treatment Swallowed Budesonide • Once daily suspension of budesonide solution with sucralose (nonabsorbable sugar). – Each 0.5 mg respule mixed with 5 packets of Splenda – < 10 years of age receive 1 mg – > 10 years of age receive 2 mg • All 20 patients had improved symptom scores and 16 had significant decrease in eosinophil count • Risks – No effect on AM cortisol levels – No increased risk of oral candidiasis Aceves SS, et al. Oral viscous budesonide: A potential new therapy for eosinophilic esophagitis in children. Am J of Gastroenterology 2007;102:2271-2279. Eosinophilic Esophagitis – Take Home Points • Increasing prevalence – Because family practitioners, pediatricians, internists are often on the front line for chronic illnesses, you must be familiar with the presentation and evaluation. You will see it. • Clinical presentation similar to reflux but does not respond to anti-reflux therapy – High index of suspicion especially in adults with food impaction • Specific IgE blood tests to foods are not helpful. • Relapses are common Immune Mediated • IgA • IgE – Class 1 – Class 2 • Eosinophil • Mixed Mixed Cell mediated Food Allergy • Atopic Dermatitis • Allergic Contact Dermatitis • Heiner Syndrome – Caused by precipitating antibodies (IgG) to cows milk – Results in lower respiratory symptoms associated with: • • • • Pulmonary infiltrates Pulmonary hemosiderosis in severe cases Failure to thrive Anemia – Milk elimination results in improvement within weeks Mixed Cell mediated Food Allergy • Allergic Proctocolitis – Visible specks of blood in stool and lack of systemic symptoms – Generally occurs while breastfeeding and attributed to maternally ingested proteins. – Milk and soy are common offenders • Food Protein induced enterocolitis – Usually presents with emesis, diarrhea, lethargy, and failure to thrive – Heme positive stools – Usual triggers are milk, soy, rice, oats and other cereals. Non-Immune Mediated • • • • • Pharmacologic Gastrointestinal Toxins Sensitivity to Additives Intolerance – Lactose – Gluten Non-Immune Mediated • Pharmacologic – An adverse reaction in which a chemical found in a food or food additive produces a drug-like effect e.g., caffeine causing "the jitters". • Gastrointestinal – Foods that promote peristalsis such as laxative foods (fresh fruit, juices) and sorbitol Non-Immune mediated • • • • • Pharmacologic Gastrointestinal Toxins Sensitivity to Additives Intolerance – Lactose – Gluten Toxin Food Reactions • Food poisoning: an adverse reaction that does not involve the immune system. It can be caused by food that has been contaminated with – – – – Toxins Bacteria Microorganisms Parasites • An example is scombroid fish poisoning, which can mimic anaphylaxis, but is due to excessive histamine in spoilt fish. Non-Immune Mediated • • • • • Pharmacologic Gastrointestinal Toxins Sensitivity to Additives Intolerance – Lactose – Gluten Sulfite Sensitivity • Sulfites in acidic medium can liberate a sulfurous gas that when inhaled can trigger bronchospasm in asthmatic individuals. • Sulfites in foods such as dried fruit can cause sneezing, swelling of the throat, and hives. Anaphalaxis and life threatening reactions are rare. Non-Immune Mediated • • • • • Pharmacologic Gastrointestinal Toxins Sensitivity to Additives Intolerance – Lactose – Gluten Lactose Intolerance • Pathophysiology – Lactose must be hydrolyzed into glucose and galactose in the intestine by lactase found in tips of villi. – Unabsorbed lactose in the colon is fermented by colonic bacteria producing symptoms of LI including • • • • Loose stools/diarrhea (due to increased osmotic load) Bloating/flatulence Abdominal cramping Systemic symptoms reported between 20 – 86% of patients – Headache, myalgias, mouth ulcers, sore throat, arrhythmia » Pathophysiology unknown but maybe due to toxic metabolites such as acetaldehyde produced in colonic fermentation. Lactose Intolerance • When systemic symptoms present consider: – LI – Coincidental – Cow’s milk allergy • Present in 20% of patients with symptoms of LI • Olivier et al. investigated 46 adult patients with LI and persistent symptoms despite lactose elimination who underwent cow’s milk IgE testing – Between 56 – 69% of patients exhibited sensitization to cow’s milk proteins. Lactose Intolerance Diagnosis • Lactose Hydrogen Breath Test • Baseline breath sample • Oral lactose load • Breath samples taken at regular intervals to analyze for hydrogen gas in ppm • Abnormal if rise of 20 ppm or more of hydrogen compared to baseline • Genetic testing may not detect all SNPs. Lactose Intolerance Diagnosis • Lactose Hydrogen Breath Test – Assumption that if all lactose is absorbed, there should be no spillover to colon. – Lactose in colon is metabolized into hydrogen. – Hydrogen gas absorbed into circulation and excreted in lungs. – Small bowel overgrowth can lead to LI due to early exposure of lactose in the small bowel, not because of enzyme deficiency. • Recent antibiotic use can cause false negative results • So breath test identifies malabsorption, not intolerance. Intolerance is clinical diagnosis, so why test at all? Can try elimination diet. Lactose Intolerance • Diagnosis Difficulties – Self report questionnaires show patients commonly associate lactose containing products with abdominal symptoms, even with normal breath tests. • Nocebo effect – symptoms after ingestion of an inert substance when negative expectations exist • Jellema et al found that both lactose malabsorbers and lactose absorbers reported symptoms during lactose hydrogen breath tests. Lactose Intolerance • Dose dependent symptoms due to lactose load and level of lactase remaining – Most people with LI can tolerate 12 gm of lactose (one glass of milk). – More symptoms with doses larger than 18 gm – Quantities over 50 gm elicit symptoms in most patients – Cow’s milk has solid and liquid phases • Liquid phase (whey) retains lactose • Solid phase (casein) as found in cheese has less lactose due to removal of whey Lactose Intolerance • Treatment – Lactase supplements – Lactose free or reduced milk products – Probiotics – uncertain Non-Immune Mediated • • • • • Pharmacologic Gastrointestinal Toxins Sensitivity to Additives Intolerance – Lactose – Gluten Non Celiac Gluten Sensitivity • Mankind exists for 2.5 million years – Wheat introduced roughly 10,000 years ago – Gluten is a relatively new introduction in our diet. • Gluten is a HMW storage protein found in wheat, rye, and barley. • Until recently, gluten only associated with celiac and wheat allergy. If patients presented with gluten induced symptoms and celiac work up and wheat IgE were negative then gluten not regarded as the cause. Non Celiac Gluten Sensitivity “Gluten Intolerance” Purported to cause variety of: GI Symptoms Extraintestinal symptoms Associations with Bloating Abdominal Pain Diarrhea/Constipation Headaches/Migraines Lethargy/Tiredness ADD Autism Bone and joint pain Schizophrenia Non Celiac Gluten Sensitivity • Pathophysiology not understood – normal intestinal permeability and no histological alterations • Maybe intestinal damage but not to point of villous atrophy? • Lacks definitive criteria for diagnosis – Gold standard for diagnosis is 2-3 month elimination followed by blinded oral challenge • Unknowns: – Is minimum amount tolerated? – Can it reverse after period of avoidance? – Long-term complications if gluten consumed? • Thus diagnosis is controversial! NCGS and IBS • Many symptoms of NCGS are similar to IBS. • AGA antibodies present in 12% of public, and 17% of patients with IBS. • Kaukinen et al. – 93 adults with IBS symptoms after eating gluten cereals • In those in whom celiac disease was excluded, 40% had AGA. – Not cause and effect but suggests in susceptible individuals the consumption of gluten results in an immune response that is manifested by production of antigliadin Ab. • Can foods such as gluten cause low level inflammation? • Are elevations in antigliadin antibodies an indication of immune activation? Kaukinen K, et al. Intolerance to cereals is not specific for coeliac disease. Scand J Gastroenterol. 2000. 35:942-946. NCGS • Objective: To determine whether gluten ingestion can induce symptoms in non-celiac individuals and to examine the mechanism. • Methods: – DBPC randomized challenge in 34 patients with IBS in whom celiac disease was excluded and who were asymptomatic on gluten-free diet. – Received gluten or placebo bread daily for 6 weeks – Evaluated symptomatically and with markers of intestinal inflammation • Results: – 68% in gluten group were symptomatic compared to 40% of placebo group. – Antigliadin Ab were not induced – No changes in intestinal inflammation • Conclusion: NCGS may exist but no clues on mechanism were elucidated. Biesiekierski JR, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo controlled trial. Am J Gastroenterol. 2011;106:508-514. Food Intolerance – IgG Testing • Patients are often heavily invested in the idea of a food allergy causing their symptoms. • If IgE testing is negative, disappointed patients seek confirmation elsewhere. • IgG food testing has taken off…but why? – Capacity for IgG4 to release histamine from basophils has not been established. – IgG4 has been shown to increase during the course of allergen immunotherapy and inhibits IgE activity. – IgG4 responses dominate in frequently stung beekeepers. – Induction of cow’s milk tolerance in milk allergic children is associated by increased specific IgG4 antibodies. – Persistent exposure to foods in the gut leads immune system to react with IgG4 response. But it is not pathologic, it is rather a marker of exposure and immunologic tolerance. IgG in IBS • Background: Patients with IBS often feel they have a dietary intolerance. Dairy and wheat are common offenders. • Aim: Assess the therapeutic potential of dietary elimination based on IgG food testing. • Patients: 150 adults with IBS randomized to receive for 3 months either a diet excluding all IgG positive foods or a sham diet excluding the same number of foods but not those to which they had antibodies. • Methods: DBPC study. Primary outcome measure was change in IBS symptom severity. Atkinson W, et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004;53:1459-1464. IgG in IBS • Results: – True diet resulted in 10% greater reduction in symptom scores than sham – Fully compliant patients had a 26% greater reduction – Conclusion: Food elimination based on IgG antibodies may be effective in reducing IBS symptoms. Atkinson et al. Gut 2004. IgG in IBS • Difference in outcomes can be explained by difference in diets. • True diet excluded milk products for 84% and wheat for 49% of patients. • Sham diet excluded them from 1.3% and 8% respectively. • Dairy and wheat are known to be subjective offenders in IBS. So improvement in true diet group reflects avoidance of common offending foods not value of IgG testing. (Main endpoint was a subjective endpoint.) IgG4 testing • 50 young adults with no history or signs of food reactions had specific IgG4 testing to 14 common foods. – 92% had elevated specific IgG4 to at least one food. – Conclusion: The common occurrence of sIgG4 to foods in healthy persons argues against pathogenesis of these antibodies. Kruszewski J, et al. High serum levels of allergen specific IgG-4 for common food allergens in healthy blood donors. Arch Immun Ther Experim. 1994;42:259. IgG Food Testing • Positive results in absence of clinical symptoms. • EAACI position paper concludes IgG4 testing to foods is irrelevant for food allergy or intolerance. Stapel O, et al. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI task force report. Allergy. 2008;63:793-96. Food Allergy vs. Intolerance Food Allergy • Immune system involvement • Reaction affects multiple organs and can be severe • Symptoms usually occur rapidly • Ingestion of small amounts of food can cause severe symptoms. • Avoidance is mainstay of therapy….thus far. Food Intolerance • Immune system not involved. • Generally less severe and limited to GI symptoms. • Symptoms generally come on gradually • Can eat small amounts of the food without symptoms. • Treatment options do exist (lactase enzymes). Food Related Adverse Reaction NonImmunologic Immunologic IgA Celiac Disease IgE Eosinophil Mixed Intolerance Class 1 Eosinophilic Esophagitis FPIES Lactose Class 2 (OAS) Eosinophilic Gastroenteritis Proctocolitis Gluten Atopic Dermatitis Heiner Syndrome Contact Dermatitis Pharmacologic Caffeine Toxin Additive Sensitivity Gastrointestinal Bacteria Sulfite Sorbitol Scombroid MSG Caffeine Parasites Juices Bibliography 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Nelson,HS, et al. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 1997;99:744-51. Vickery BP, et al. Immunotherapy in the treatment of food allergy: focus on oral tolerance. Curr Opin Allergy Clin Immunol. 2009;9:364-370. Nowak-Wegrzyn A, et al. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol. 2008;122:342-7. Longo G, et al. 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