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

  • 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

  • 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


Eczema,GI symptoms

T cells

RespiratoryGI symptoms

Eosinophils

Urticaria,anaphylaxis

Mast cells

David Hill et al


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

  • 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

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

  • 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?

  • 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

  • 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

  • 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

  • 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


CoeliacdiseasE


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


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


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

Farrell and Kelly,

NEJM 2002


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

  • 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

  • Autopsies on 13 patients with intestinal obstruction

  • Inflamed jejunum, ileum or colon in all

  • Transmural inflammation seen on histology


“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 – 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

  • 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

  • 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

  • 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

  • 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

  • “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

  • Minimise impact of disease on:

    • Linear growth

    • Psychosocial development

    • Pubertal development

    • The family

  • ie Multidisciplinary specialised therapy


Diagnosis

  • Clinical assessment

    • exclude infectious aetiologies

  • Upper endoscopy

  • Colonoscopy (incl. ileoscopy)

  • +/- Barium follow-through/ MR enteroclysis


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 UC


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...

  • 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

  • Aminosalicylates

  • Nutrition

  • Antibiotics

  • Corticosteroids

  • Immunosuppressants

  • Immunologic

  • Surgery


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)


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

  • Short-term

    • infusion related

  • Medium term

    • infectious complications

    • delayed hypersensitivity

    • antibody formation

  • Long-term

    • Malignancy – Hepato-splenic T cell lymphoma


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