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

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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


Lactose intolerance

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


Milk intolerance in infants

Eczema,GI symptoms

T cells

RespiratoryGI symptoms

Eosinophils

Urticaria,anaphylaxis

Mast cells

David Hill et al


Types of milk allergy

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


Detection of ige mediated food allergy usually straightforward

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


Contrasting difficulty in non ige mediated food allergy

Contrasting difficulty in non IgE-mediated food allergy

N =14

  • 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

N = 4

Hill et al, J Pediatr 1999


Cow s milk sensitive enteropathy

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


Reflux or milk allergy

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)


Causes of milk allergy

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


Oral tolerance

Oral tolerance

  • Dependent on the gut flora

    • Innate 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


Diagnosis of cmse

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


Milk intolerance in infants

CoeliacdiseasE


Sir samuel gee the first modern description of coeliac disease

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


Hongerwinter the dutch famine 1944 5

Hongerwinter – the Dutch famine 1944-5


Milk intolerance in infants

Dicke WK (1950) Coeliakie. MD Thesis, Utrecht.


Diagnostic aids

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


Coeliac disease

Coeliac disease

Farrell and Kelly,

NEJM 2002


Limitations of biopsy

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.


Ibd in childhood

IBD in childhood

  • Rising incidence and change in phenotype

  • Advances in genetics

  • Immunological basis

    • Inflammation required to establish tolerance

    • The central role of the gut flora

  • Pointers from epidemiology

    • IBD and the “Clean-Child” hypothesis


Dalziel s report bmj 1913

Dalziel’s report BMJ 1913

  • Autopsies on 13 patients with intestinal obstruction

  • Inflamed jejunum, ileum or colon in all

  • Transmural inflammation seen on histology


Crohn s disease

“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.


Crohn s or uc

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.


Ibd incidence

IBD incidence

  • Highest Scandinavia, Scotland

  • Increased incidence on migration from low to high-risk countries

    • Indian subcontinent origin in UK

  • Ethnic groups

    • Ashkenazi Jews


Ibd susceptibility genes

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


Ibd breakdown of tolerance to the normal gut flora

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


Paediatric inflammatory bowel disease

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


Patterns of paediatric ibd

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


Aims of management

Aims of management

  • Minimise impact of disease on:

    • Linear growth

    • Psychosocial development

    • Pubertal development

    • The family

  • ie Multidisciplinary specialised therapy


Diagnosis

Diagnosis

  • Clinical assessment

    • exclude infectious aetiologies

  • Upper endoscopy

  • Colonoscopy (incl. ileoscopy)

  • +/- Barium follow-through/ MR enteroclysis


Mucosal healing

Mucosal healing

  • Minimal

    • Steroids, Mesalazine, Antibiotics

  • Slow but definite healing

    • Enteral nutrition, Azathioprine, 6MP

  • Rapid but definite healing

    • Infliximab, adlimumab


Mucosal healing in crohn s disease

Mucosal healing in Crohn’s disease


Mucosal healing in uc

Mucosal healing in UC


Mucosal healing1

Mucosal healing

  • Only 29% of patients with colonic Crohn’s disease heal with corticosteroids

  • Role of enteral nutrition

  • Healing with azathioprine

  • 70% heal with Infliximab

    • single infusion improved histology / mucosal inflammation


Current success

Current success...

  • Induction of remission

    • 75-85% within 2-4 weeks

  • Maintenance of remission

    • 60-70% relapse at 12 months

    • 30% steroid dependent

    • but..40-70% in remission on Aza at 12 months


Ibd therapies

IBD Therapies

  • Aminosalicylates

  • Nutrition

  • Antibiotics

  • Corticosteroids

  • Immunosuppressants

  • Immunologic

  • Surgery


Steroid therapy

Steroid therapy

  • Avoid when possible in children

  • Poor effect on mucosa

  • Second line agent

    • relapsing disease

    • severe exacerbation (i.v. hydrocortisone)

  • Reducing course 2mg/kg (max 60mg / day)


Enteral nutrition in paediatric ibd

Highly effective first-line therapy

Polymeric formulas more palatable

Reduce pro-inflammatory cytokines

Increase regulatory cytokines

Animal models suggest alteration of gut flora

Motivation of child and family critical

Enteral nutrition in paediatric IBD


Infliximab safety

Infliximab safety

  • Short-term

    • infusion related

  • Medium term

    • infectious complications

    • delayed hypersensitivity

    • antibody formation

  • Long-term

    • Malignancy – Hepato-splenic T cell lymphoma


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