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
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


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 straightforward

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 straightforward

  • 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? straightforward

  • 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 straightforward

  • 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 straightforward

  • 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 straightforward

  • 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


Coeliac straightforwarddiseasE


Sir samuel gee the first modern description of coeliac disease
Sir Samuel Gee straightforwardThe 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




Diagnostic aids
Diagnostic aids straightforward

  • 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 straightforward

Farrell and Kelly,

NEJM 2002


Limitations of biopsy
Limitations of biopsy straightforward

  • 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 straightforward

  • 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 straightforward

  • 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” straightforward

  • 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 straightforward

  • 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 straightforward

  • 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 straightforward

  • 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 straightforward

  • 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 straightforward

  • 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 straightforward

  • “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 straightforward

  • Minimise impact of disease on:

    • Linear growth

    • Psychosocial development

    • Pubertal development

    • The family

  • ie Multidisciplinary specialised therapy


Diagnosis
Diagnosis straightforward

  • Clinical assessment

    • exclude infectious aetiologies

  • Upper endoscopy

  • Colonoscopy (incl. ileoscopy)

  • +/- Barium follow-through/ MR enteroclysis


Mucosal healing
Mucosal healing straightforward

  • Minimal

    • Steroids, Mesalazine, Antibiotics

  • Slow but definite healing

    • Enteral nutrition, Azathioprine, 6MP

  • Rapid but definite healing

    • Infliximab, adlimumab



Mucosal healing in uc
Mucosal healing in UC straightforward


Mucosal healing1
Mucosal healing straightforward

  • 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... straightforward

  • 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 straightforward

  • Aminosalicylates

  • Nutrition

  • Antibiotics

  • Corticosteroids

  • Immunosuppressants

  • Immunologic

  • Surgery


Steroid therapy
Steroid therapy straightforward

  • 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 straightforward

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 straightforward

  • Short-term

    • infusion related

  • Medium term

    • infectious complications

    • delayed hypersensitivity

    • antibody formation

  • Long-term

    • Malignancy – Hepato-splenic T cell lymphoma


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