milk intolerance in infants

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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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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 Presentation


Page 1: Milk intolerance in infants

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


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


Red swollen anus

Nappy rash


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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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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Page 17: Milk intolerance in infants

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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Page 19: Milk intolerance in infants

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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Page 22: Milk intolerance in infants

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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Page 30: Milk intolerance in infants

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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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








Page 40: Milk intolerance in infants

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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