milk intolerance in infants
DESCRIPTION
Milk intolerance in infants. Food intolerance or food allergy ? Intolerance is not immune mediated For cow’s milk = lactose intolerant Lactose intolerance in infants = enteropathy Allergy is immune mediated IgE-mediated - local or systemic Non-IgE-mediated - local or systemic. - PowerPoint PPT PresentationTRANSCRIPT
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Milk intolerance in infants
Food intolerance or food allergy ? Intolerance is not immune mediated
For cow’s milk = lactose intolerant
Lactose intolerance in infants = enteropathy
Allergy is immune mediated IgE-mediated - local or systemic
Non-IgE-mediated - local or systemic
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Lactose intolerance
Normal in most adults in the world Tolerance mutation arose since dairy farming
North Europeans usually tolerant as adults
Lactase downregulated in teens
Always abnormal in infants Very rare - congenital absence (Lapps)
Very common - enteropathy Temporary – following rotavirus etc
Persistent – with mucosal allergic sensitisation
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David Hill et al
Urticaria,anaphylaxis
Mast cells
RespiratoryGI symptoms Eosinophils
Eczema,GI symptoms
T cells
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Types of milk allergy
IgE-mediated – rapid onset Systemic – anaphylaxis response
Localised to gut – secretion, dysmotility
Non-IgE-mediated – slow onset Systemic – Eczema, asthma
Localised to gut – Enteropathy, colitis, eosinophilic GI disorders
Mixed IgE and Non-IgE-mediated
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Detection of IgE-mediated food allergy usually straightforward Usually rapid onset of symptoms
Symptoms are visible and easily related to food
Usually supportive diagnostic tests
Skin prick tests, specific IgE often positive
Open food challenge easy to interpret
Difficulties mainly occur if complex mixture of food antigens ingested
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Contrasting difficulty in non IgE-mediated food allergy
Often delayed onset symptoms
True association missed
Symptoms often chronic
Eczema, loose stools, ± poor weight gain
Motility disturbance - colic, reflux, constipation
Tests often negative
Skin prick tests, specific IgE
Skin patch tests – variable reports Hill et al, J Pediatr 1999
N =14
N = 4
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Cow’s milk sensitive enteropathy
T cells become milk-sensitised
Causes villous shortening, crypt lengthening
Variable antibody response
Epithelial function impaired Lactose malabsorbed
Protein, fat malabsorption less striking
Barrier function ↓ - 2o sensitisations
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Reflux or milk allergy?
The screaming back-arching baby almost always is milk allergic – not simple GOR
Even more likely if the baby has: Eczema, cradle-cap
Colic
Red swollen anus
Nappy rash
Candida
Prolonged viral infections
FH of atopy, autoimmunity (ask about thyroid disease)
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Causes of milk allergy
Impaired oral tolerance mechanisms Loss of previously acquired tolerance
Often pathogens break epithelial barrier eg Cow’s milk allergy after rotavirus
Secondary sensitisation to soya etc
Failure to establish oral tolerance initially Immunological abnormalities
Inadequate innate immune exposures eg breast-milk sensitisation, multiple food allergy
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Oral tolerance
Dependent on the gut floraInnate immune responses to flora are critical
Mediated by regulatory T cells (TREG)
Different mechanisms for low and high doses
High doses – induce anergy of T cells Antigen presented by the epithelium
Low doses – require active TREG generation
Antigen taken up in lymphoid follicles
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Diagnosis of CMSE Depends on clinical recognition
Skin prick test -ve
Specific IgE -ve
Features include: Post prandial distension, acid stools
Weight gain often impaired
May have eczema, colic, dermatographia
Micronutrient deficiencies
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Coeliac diseasECoeliac diseasE
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Sir Samuel Gee The first modern description of coeliac disease
'chronic indigestion met with in persons of all ages, Yet especially apt to affect children between 1 and 5 years old‘Lecture at GOS, 5th October, 1887
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Hongerwinter – the Dutch famine 1944-5
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Dicke WK (1950) Coeliakie. MD Thesis, Utrecht.
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Diagnostic aids
Antibodies Anti-gliadin – moderate sensitivity- not specific
Anti-reticulin – possibly more specific
Anti-endomyseal/ TTG – sensitive and specific
HLA association B8 – first described
DR3 or DR5/7 - Much more predictive
DQ2/DQ8 – actual association
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Coeliac disease
Farrell and Kelly,NEJM 2002
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Limitations of biopsy
Changes may be non-specific. Similar appearances in other diseases
Lesion may be patchy Capsule biopsies are jejunal, endoscopic are not
Possibly less marked in D2 and D3
May even be absent in D2/3.
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IBD in childhood
Rising incidence and change in phenotype
Advances in genetics
Immunological basisInflammation required to establish tolerance
The central role of the gut flora
Pointers from epidemiology IBD and the “Clean-Child” hypothesis
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Dalziel’s report BMJ 1913
Autopsies on 13 patients with intestinal obstruction
Inflamed jejunum, ileum or colon in all
Transmural inflammation seen on histology
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“Crohn’s disease”
Weiner 1914, Moschowitz & Wilensky 1923, 1927, Goldfarb & Suissman 1931
Ginzburg & Oppenheimer(for Berg) 1927,1928
Ginzburg & Oppenheimer with Crohn. May 2, 1932, AGA
Crohn. May 13 1932, AMA
Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: A pathologic and clinical entity.J Am Med Assoc 1932; 99: 1323 – 1328.
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Crohn’s or UC
Crohn’s – Transmural. Focal chronic inflammation. Fibrosis. Granulomas. Anywhere along GI tract. Th1 response.
UC – Largely mucosal. Diffuse acute and chronic inflammation. Essentially confined to colon.
Indeterminate colitis. Definite IBD. Features between UC and Crohn’s. May evolve with time.
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IBD incidence
Highest Scandinavia, Scotland
Increased incidence on migration from low to high-risk countries
Indian subcontinent origin in UK
Ethnic groups Ashkenazi Jews
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IBD susceptibility genes
European twin-birth registries Concordance for CD: MZ 37%, DZ 7%
Concordance for UC: MZ 10%, DZ 3%
Susceptibility loci from genome-scanning IBD1 – chromosome 16. CD. NOD2 gene
IBD2 – chromosome 12q. UC > CD
IBD3 - chromosome 6p. MHC locus
IBD4 – chromosome 14q. CD
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IBD – breakdown of tolerance to the normal gut flora
Enteric bacteria provide continuous immune challenge
Evidence of specific unreactivity to own flora
This is lost in active IBD Flora reactive T cells, antibody
Reaction to normal flora causes experimental IBD
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Paediatric inflammatory bowel disease
Similarities to adult IBD Essential inflammatory processes
Mucosal lesion
Differences to adult IBD Management emphasis
Growth, puberty, psychosocial
Indications for steroids, surgery
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Patterns of Paediatric IBD
“Classical” Crohn’s disease and UC CD now becoming more prevalent
Marked increase in incidence
Ileocaecal involvement most common in CD
Oral (/anal) Crohn’s
Indeterminate colitis
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Aims of management
Minimise impact of disease on:
Linear growth
Psychosocial development
Pubertal development
The family
ie Multidisciplinary specialised therapy
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Diagnosis
Clinical assessmentexclude infectious aetiologies
Upper endoscopy
Colonoscopy (incl. ileoscopy)
+/- Barium follow-through/ MR enteroclysis
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Mucosal healing
MinimalSteroids, Mesalazine, Antibiotics
Slow but definite healingEnteral nutrition, Azathioprine, 6MP
Rapid but definite healingInfliximab, adlimumab
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Mucosal healing in Crohn’s disease
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Mucosal healing in UC
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Mucosal healing
Only 29% of patients with colonic Crohn’s disease heal with corticosteroids
Role of enteral nutrition
Healing with azathioprine
70% heal with Infliximabsingle infusion improved histology / mucosal inflammation
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Current success...
Induction of remission75-85% within 2-4 weeks
Maintenance of remission60-70% relapse at 12 months
30% steroid dependent
but..40-70% in remission on Aza at 12 months
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IBD Therapies
Aminosalicylates
Nutrition
Antibiotics
Corticosteroids
Immunosuppressants
Immunologic
Surgery
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Steroid therapy
Avoid when possible in children
Poor effect on mucosa
Second line agentrelapsing disease
severe exacerbation (i.v. hydrocortisone)
Reducing course 2mg/kg (max 60mg / day)
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Enteral nutrition in paediatric IBD
Highly effective first-line therapyPolymeric formulas more palatable
Reduce pro-inflammatory cytokines
Increase regulatory cytokinesAnimal models suggest alteration of gut flora
Motivation of child and family critical
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Infliximab safety
Short-terminfusion related
Medium terminfectious complications
delayed hypersensitivity
antibody formation
Long-termMalignancy – Hepato-splenic T cell lymphoma
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