Transcript Mucoviscidosis, celiac disease, lactose intolerance, cow milk allergy

Mucoviscidosis, celiac
disease, lactose
intolerance, cow milk
allergy
CF
• A multisystem disease
• Autosomal recessive inheritance
• Cause: mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR)
– chromosome 7
– codes for a c-AMP regulated chloride channel
Epidemiology
• Most common “life-shortening”
recessive genetic disease in Caucasians
– 1:3,500 newborns in the US
– 1 in 10,500 Native Americans
– 1 in 11,500 Hispanics
– 1 in 14,000 to 17,000 African Americans
– 1 in 25,500 Asians
• About 30,000 people affected in
United States
• >10,000,000 people carriers of
mutant CFTR
• 80% cases diagnosed by age 3
• Almost 10% diagnosed ≥18 years
PATHOPHISIOLOGY
• Mucus-helps clear airway of bacteria
• Clearance of mucus depends on
– Ciliary function
– Mucin secretion
– Volume of airway surface liquid (ASL)
• Forms periciliary liquid layer (PCL)
• Dilutes mucus-facilates entrapment of bacteria and
clearance
• Optimal volume of ASL regulated by Na+ absorption
and Cl- secretion
Airway surface liquid low volume and
consequences
• Cilia do not beat well when PCL ( periciliary
liquid layer)volume is depleted
• Mucins are not diluted and cannot be easily
swept up the airway
• Mucus becomes concentrated
• Results in increased adhesion to airway surface
• Promotes chronic infection
CONSEQUENCE
clinical features of
Cystic Fibrosis
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Chronic Sino-Pulmonary Disease
Nutritional deficiency/GI abnormality
Obstructive Azoospermia
Electrolyte abnormality
CF in a first degree relative
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• General
• Respiratory
– clubbing
– Failure to thrive
– asthma
• GI
– Chronic Obstructive Pulmonary Disease
barrel chest
– meconium ileus in neonate
– productive cough, hemoptysis
– foul smelling stools, bloating
– nasal polyps
– rectal prolapse
– pneumothorax/mediastinum
– cor pulmonale, RVH
– impaction/obstruction
• Metabolic
– pancreatitis
– dehydration (low Na, low Cl)
– low albumin, low sodium
– metabolic alkalosis (esp neonate)
– cholelithiasis, cholecystitis
– DM ( diabetus mellitus)
– heart stroke
– cirrhosis, portal
hypertension
• GU
– infertility in males
– neonatal hyperbilirubinemia
– fat soluble vitamin
deficiency
Endobronchial disease
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Hyperinflation
Peribronchial cuffing
Bronchiectasis
Diffuse fibrosis
Atelectasis
Nasal Polyps
• Benign lesions in nasal
airway
• If large enough, can be
associated with significant
nasal obstruction, drainage,
headaches, snoring
• Likely associated with
chronic inflammation
• May need surgical
intervention
• High recurrence rate
Digital Clubbing
• Bulbous swelling at end
of fingers
• Normal angle between
nail and nail bed lost--Schamroth sign
• Can be associated with
pulmonary disease,
cardiac disease,
ulcerative colitis, and
malignancies
Nutritional deficiency
Pancreatic insufficiency
– Mucus plugging of glandular ducts
– Chloride impermeability affects HCO3- secretion and fluid
secretion in pancreatic ducts
• Pancreatic enzymes stay in ducts and are activated
intraductally
– Autolysis of pancreas
– Inflammation, calcification, plugging of ducts, fibrosis
– Malabsorption
• Failure to thrive
• Fat soluble vitamin deficiency
GI disease
• Intestinal abnormality
– Meconium ileus
– Distal intestinal obstruction syndrome (DIOS)
– Rectal prolapse
• Hepatobiliary disease
– Focal biliary cirrhosis
– Multilobular cirrhosis
• Pancreatic endocrine dysfunction
– Cystic fibrosis related diabetes
Cystic fibrosis related liver disease
– Obstructs biliary ductules
• Second leading cause of death in CF
• Prevalence 9-37%
• Spectrum of disease
– increased liver enzymes
– biliary cirrhosis
– portal hypertension
GI tract manifestations (hepatobiliary): Patients may
present with a history of jaundice or gastrointestinal
tract bleeding.
CLINICS
GI tract manifestations (intestinal)
– Neonates: Infants may present with intestinal
obstruction at birth and various surgical findings
(meconium ileus [7-10% of patients with cystic fibrosis],
volvulus, intestinal atresia, perforation, meconium
peritonitis). Less commonly, passage of meconium may
be delayed (>24-48 h after birth) or cholestatic jaundice
may be prolonged.
– Infants and children: Patients present with increased
frequency of stools, which suggests malabsorption (ie,
fat in stools, oil drops in stools), failure to thrive,
intussusception (ileocecal), or rectal prolapse.
• GI tract manifestations (pancreatic)
– Patients with pancreatic insufficiency (PI) have fatsoluble vitamin deficiency and malabsorption of fats,
proteins, and carbohydrates (however, malabsorption
of carbohydrates is not as severe as that of fats and
proteins). Steatorrhea is characterized by frequent,
poorly formed, large, bulky, foul-smelling, greasy stools
that float in water. Cloth diapers, if used, are difficult to
clean.
– Patients present with failure to thrive (despite an
adequate appetite), flatulence or foul-smelling flatus,
recurrent abdominal pain, and abdominal distention.
Alternatively, some patients have anorexia without
obvious steatorrhea. Many infants have symptoms of
gastroesophageal reflux.
– Hepatosplenomegaly (fatty liver and portal
hypertension)
– Rectal prolapse
– Dry skin (vitamin A deficiency)
– Cheilosis (vitamin B complex deficiency)
Respiratory tract manifestations
– Patients present with a chronic or recurrent cough,
which can be dry and hacking at the beginning and
can produce mucoid (early) and purulent (later)
sputum. Prolonged symptoms of bronchiolitis occur
in infants.
– Paroxysmal cough followed by vomiting may occur.
– Recurrent wheezing, recurrent pneumonia, atypical
asthma, pneumothorax, hemoptysis, and digital
clubbing are all complications and may be the initial
manifestation.
– Dyspnea on exertion, history of chest pain, recurrent
sinusitis, nasal polyps, and hemoptysis may occur
• Physical
• Physical signs depend on the degree of involvement of various
organs and the progression of disease.
• Nose
– Rhinitis
– Nasal polyps
• Pulmonary system
– Tachypnea
– Respiratory distress with retractions
– Wheeze or crackles
– Cough (dry or productive of mucoid or purulent sputum)
– Increased anteroposterior diameter of chest
– Clubbing
– Cyanosis
– Hyperresonant chest upon percussion: Crackles are heard
acutely in associated pneumonitis or bronchitis and
chronically with bronchiectasis.
Infection
• Urogenital tract manifestations
– Males are frequently sterile because of the
absence of the vas deferens. Undescended
testicles or hydrocele may be present.
– Fertility is maintained, although possibly
decreased, in females. Secondary sexual
development is often delayed.
– Amenorrhea may occur in patients with severe
nutritional or pulmonary involvement.
• Other systems
– Scoliosis
– Kyphosis
– Swelling of submandibular gland or parotid gland
– Aquagenic wrinkling of the palms (AWP): A recent
study reported an association between AWP and
cystic fibrosis.Among patients with cystic fibrosis,
a greater degree of AWP is observed in patients
who are homozygous for the 508 del F mutation.
Diagnosis
• Elevated serum trypsinogen in neonate
• Gene testing
– 87 mutation panel (92% sensitivity)
– 1300 mutation panel (97 - 99% sensitivity)
• GOLD STANDARD: CHLORIDE SWEAT TEST
– <40 mEq/L--negative
– 40 - 60 mEq/L--equivocal, needs repeat
– >60 mEq/L--positive, needs confirmation
Diagnosis of cystic fibrosis
• One or more clinical features of CF
PLUS
• Two CF mutations
OR
• Two positive quantative pilocarpine
iontophoresis sweat chloride values
OR
• An abnormal nasal transepithelial potential
difference value
Diagnosis---Sweat chloride
• Technique first
described by Gibson
and Cooke in 1950s
– Chemical that stimulates
sweating placed under
electrode pad; saline
under other electrode
pad on arm
– Mild electric current is
passed between
electrodes
– Sweat collected
Prenatal screening
• American College of Obstetricians and
Gynecologists recommended offering patients
option of prenatal screening for CF
– Carrier testing of 23 most common mutations
– Sensitivity of prenatal screening for CF among the
white population <78%
• lower than that for newborn screening
• sensitivity of prenatal testing in racial and ethnic
minority populations is lower
Newborn Screening for CF
• Goal: diagnose early---evidence that early
diagnosis may be associated with better
nutritional outcome and chest radiographic
scores
– Immunoreactive trypsinogen usually first followed
by either sweat or DNA testing
Differential Diagnosis
• False positives
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adrenal insufficiency
nephrogenic DI
hypothyroidism
mucopolysaccharidosis
G6P deficiency
hypoproteinemia
anemia from poor
nutrition
• False negatives
– severe malnutrition with
edema
– too little sweat
– inexperienced tester
Cystic fibrosis---Treatment
Multidisciplinary
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Airway Clearance
Infection
Nutrition
Gastrointestinal
Inflammation
Infertility
Social Issues
Treatment
• For acute respiratory infections:
hospitalization and aminoglycoside,
pulmonary toilet
• baseline pulmonary therapy
– aerosols (bronchodilation)
– chest physical therapy
– aerosolized antibiotics
– systemic steroids or expectorants--not indicated
Treatment: Pulmonary toilet/Airway
clearance
• Chest physiotherapy
– Postural drainage and percussion
– P.E.P (positive expiratory pressure valve, Acapella
valve, Flutter valve
– High frequency chest wall oscillation
• Albuterol
– Bronchodilation
– Increase ciliary efficiency
• Dornase alpha/recombinant DNase
• Hypertonic Saline by nebulization
Treatment: Chronic infection
• Inhaled antibiotics
– Inhaled tobramycin in patients with pseudomonas
• Sputum cultures
• Treatment of pulmonary exacerbation
– Pulmonary exacerbation-change in symptoms and signs
from baseline (cough, sputum production, lung function,
increased crackles on physical exam)
– Requires hospitalization for antibiotics IV, as well as
increased airway clearance
Treatment: Anti-inflammatory agents
• Ibuprofen
–Slower decrease in FEV1 annually
than placebo group; better
weight maintenance
–No difference in frequency of
hospitalization
–Best effect seen in patients less
than 13 years of age
Treatment
• Nutritional therapy
– high fat, high protein diet
– pancreatic enzyme replacements
– vitamin and mineral supplements
• Other
– no support for growth hormone
– pulmonary transplant--must transplant both lungs
simultaneously!
Treatment
• Pancreatic Enzymes
• These agents aid digestion when the pancreas is malfunctioning.
Current pancreatic enzyme preparations are derived from porcine
extracts and contain various proportions of lipase, amylase, and
protease. Usually, the dose of pancreatic enzymes should not
exceed 2000 U/kg/meal of lipase. The novel preparation Thera
CLEC-Total is a highly purified microbiologically-derived enzyme
preparation
• Pancrelipase (Creon, Pancrease, Ultrase, Viokase)
• Enteric-coated pancreatic enzyme microspheres containing
various amounts of lipase, protease, and amylase. Assists in
digestion of protein, starch, and fat. 500-2000 U of lipase/kg/meal
PO; individualize dose to patient; patient's response guides dose;
dose of 1-3 cap per meal is sufficient for most patients
Adjust dose according to stool fat and nitrogen content
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• Tobramycin, inhaled (TOBI)
• Formulated specifically for inhalation. Chronic
intermittent administration in patients with P aeruginosa
infection improves pulmonary function and nutritional
status and reduces symptomatic pulmonary exacerbation
• Aztreonam inhalation (Cayston)
• Monobactam antibiotic. Elicits activity in vitro against
gram-negative aerobic pathogens, including
Pseudomonas aeruginosa. Binds to penicillin-binding
proteins of susceptible bacteria, thereby inhibiting
bacterial cell wall synthesis, resulting in cell death.
Activity is not decreased in the presence of cystic fibrosis
lung secretions.
Indicated to improve respiratory symptoms in patients
with cystic fibrosis infected with P aeruginosa.
• Gentamicin (Garamycin) 3 mg/kg/dose IV q8h
• Tobramycin (Nebcin) 3 mg/kg/dose IV q8h
• Piperacillin (Pipracil) 300 mg/kg/d IV divided
q6h; not to exceed 24 g/d
• Ceftazidime 200 mg/kg/d IV divided q6h; not to
exceed 6 g/d
• Ciprofloxacin (Cipro) 20-30 mg/kg/d PO divided
q8h
• Trimethoprim and sulfamethoxazole (Bactrim,
Septra) 8 mg/kg/d (based on TMP component)
Prognosis of CF
• Overall trend is improved survival
• Female survival worse than male between 2-20
years of age
• 35% of patients are older than 18 years of age
• Median survival 36.8 years compared to 1930s
when life expectancy was about 6 months
CELIAC DISEASE
ESPGHAN 2012 : Guidelines for the Diagnosis in
Children & Adolescents
Definition:
“CD is an immune-mediated systemic disorder
elicited by gluten and related prolamines in
genetically susceptible individuals characterised by
the presence of a variable combination of gluten
dependent clinical manifestations, CD-specific
antibodies, HLA-DQ2 or DQ8 haplotypes and
enteropathy.”
Coeliac Disease
1988
• Uncommon
• Childhood enteropathy
2012
 Common (1%)
 Children & adults
 Strong genetic
predisposition
 Multi-organ disorder
 Specific antibody tests
• Serology : Gliadin/Reticulin
• Genetics : HLA DQ2/8
• Enteropathy : Variable/patchy
→ Tissue Transglutaminase
(TG2)
→ Endomysial (EMA)
The “Celiac Genes”: HLA DQ2 and DQ8
Genetic predisposition
Human leukocyte antigen (HLA) alleles DQA1 /
DQB1 genes encoding DQ2 and / or DQ8
molecules
Found in 95% of people with CD
70% concordance in identical twins
Gene test has 100% predictive value to
verify when an individual does not have
celiac disease.
Epidemiology
 May be most common predetermined condition
in humans
 Found throughout world
 Perceived greater incidence in Europe, 
gluten in diet
 Recent screenings found 0.5% to 1% in
general population (NIH, 2004; Dube, et al,
2005)
1/77 Swedish children (Carlsson, et al,
2001)
1/230 Italian children (Catassi, et al, 1996)
1/100 5 year old children in Denver
(Hoffenberg, et al, 2003)
Ethnic distribution unknown
 Only 3% with CD are diagnosed
Pathophysiology
Celiac disease is a multifactorial, autoimmune disorder
that occurs in genetically susceptible individuals.
Trigger is an environmental agent-gliadin component of
gluten. The enzyme tissue transglutaminase (tTG) has
been discovered to be the autoantigen against which
the abnormal immune response is directed.
What is gliadin? A glycoprotein present in wheat and
other grains such as rye, barley and to some degree,
oats.
What is gluten? A composite of the proteins gliadin and
glutenin which comprise about 80% of the protein
contained in wheat seed.
Normal small
intestine
Normal villi
Small intestine
with scalloping
Small
intestine
with villous
atrophy
Histology of intestinal biopsy in CD
Modified Marsh score
Classic physical presentation
London, year 1938
ESPGHAN 2012 : Who should be tested for CD?
Group 1 : Symptomatic
Group 2 : Asymptomatic
(with ↑ risk of CD)
Diarrhoea/vomiting
Weight loss
Poor growth/delayed puberty
Iron deficiency anaemia
Chronic abdominal pain
Constipation
Recurrent aphthous ulcers
Abnormal liver biochemistry
IDDM ( insulin diab)
Down’s syndrome
Auto-immune thyroid disease
Auto-immune liver disease
Turner’s syndrome
Williams’ syndrome
First degree relatives
SYMPTOMS
• Some may be
asymptomatic
• Diarrhea
• Short Stature
• Iron Deficiency Anemia
• Lactose Intolerance
• Irritability (common in
children)
• Mood Swings (common
in children)
• Abdominal Pain
• Irritable Bowel
• Osteoporosis
• Skin rash-very itchy with
blisters
• A bloated or painful
belly
Uncommon presentation
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Anemia, fatigue
Vitamin deficiencies
Muscle wasting
Osteopenia
Short stature
Recurrent abortions / infertility
Delayed puberty
Dental enamel hypoplasia
Dermatitis Herpetiformis
Aphthous ulcers
• Silent celiac disease
– Children who are asymptomatic but have + serologic
tests and villous atrophy
• Autoimmune response present but no outward symptoms
• Low-intensity symptoms often present (Fasano, 2005)
• Latent celiac disease
– Children who have a  serology but no intestinal
mucosal changes. They may have symptoms or
mucosal changes in the future.
• Refractory celiac disease
– Persistent symptoms despite gluten-free diet
Diagnosis of celiac disease
 Serology
 Serum immunoglobulin A (IgA) endomysial antibodies and IgA
tissue transglutaminase (tTG) antibodies. Sensitivity and
specificity > 95%.
 Testing for gliadin antibodies is no longer recommended because
of the low sensitivity and specificity for celiac disease.
 The tTG antibody test is less costly because it uses an enzymelinked immunosorbent assay; it is the recommended single
serologic test for celiac disease screening in the primary care
setting.
EPSGHAN 2012 : Diagnostic Tools
* adequate gluten intake
(a) CD-specific antibody tests
- IgA TG2 PLUS Total IgA
(IgG TG2 if IgA deficient)
- EMA autoantibody against endomysium
- (DGP) antibody against deamidated gliadin peptide
(b) HLA typing – DQ2/8 negative “excludes”
(c) Histology – variable/patchy (bulb & D2/3)
ESPGHAN 2012 : SYMPTOMATIC
• IgA TG2 and total IgA (IgG abs if sIgA low)
• If TG2 normal – CD unlikely BUT if strong clinical
suspicion → biopsy ± HLA typing
• If TG2 <10 x ULN (upper normal limit )→ biopsy
• If TG2 >10 x ULN AND EMA/HLA positive → NO
biopsy
ESPGHAN 2012 : ASYMPTOMATIC
• Offer HLA testing as first line (DQ2/8 negative = not CD)
• If HLA positive/not available → IgA TG2
• If TG2 > 3 x ULN → biopsy always necessary
• If TG2 < 3 x ULN → EMA
(if +ve → biopsy)
(if –ve retest every
3-6 months)
Treatment of celiac disease
Avoidance of food products that contain gluten proteins.
It is essential that the diagnosis be confirmed before submitting
patients to this therapy.
Key elements to successful treatment include the motivation of the
patient, the attentiveness of the physician to comorbidities that need
to be addressed.
Formal consultation with a trained dietitian is necessary.
The dietitian plays a vital role in helping the patient successfully
adapt to the necessary behavioral changes and may provide much of
the required follow-up.
National celiac disease support organizations can provide patients
invaluable resources for information and support.
Treatment for celiac disease
• Gluten contained in wheat, rye, barley
– Triticale, kamut, spelt, semolina, farina, einkorn, bulgur, and
couscous
– Malt made from barley
• Malt syrup, malt extract, malt flavoring, malt vinegar
• Beer, whiskey
– Food additives
• Soy sauce, carmel color, bouillon, modified food starch
• Mono or diglycerides, emulsifiers, vegetable protein
– Processed foods
• Sausage, luncheon meat, gravies and sauces
• TV dinners, pot pies
Treatment for celiac disease
• Nutritional deficiencies with CD
– B vitamins, iron, and folic acid
• 4% anemia at time of diagnosis
– GF foods not enriched
• Low in B vitamins, calcium, vitamin D, iron, zinc,
magnesium, and fiber
– High incidence of osteopenia in children
– Other food sensitivities and allergies common
• May resolve with treatment of CD
Treatment for celiac disease
Monitor growth and development
Secondary lactose intolerance common until
gluten-free diet > 6 months
Supplemental vitamins
 Iron, folate
 Calcium
 Fat soluble vitamins
Bone density studies
Re-measure tTGA after 6-12 months of treatment
  antibody titer if on GFD
 Antibody levels return to normal within three to 12 months of starting a glutenfree diet.
 Reaffirm need for GFD
Lactose Intolerance
Lactose Intolerance
• Inability to digest significant amounts of
lactose, which is the predominant sugar in
milk
• A result of lactase insufficiency, the enzyme
essential for the conversion of lactose into
glucose and galactose
Etiology of lactose malabsorption
Primary lactose
malabsorption
Secondary lactose
malabsorption
• Racial or ethnic lactose
malabsorption
• Developmental lactase
deficiency
• Congenital lactase
deficiency
• Bacterial
overgrowth/stasis
• Mucosal injury of GIT that
causes villus flattening
Racial or ethnic lactose malabsorption
• Genetically determined reduction of lactase
activity
• Most common form of lactose malabsorption
• The great majority of the world’s population
develop low intestinal lactase during midchildhood (approximately at age 5 yrs)
• This finding is most prominent in Asian and
African populations; rare in Caucasians of
Scandinavian background
• Molecular basis remains unknown
Developmental lactase deficiency
• Low lactase levels as a consequence of
prematurity
• Lactase activity in the fetus increases late in
gestation
• Premature infants born at 28-32 weeks of
gestation have a reduced lactase activity
Congenital lactase deficiency
• Rare autosomal recessive disorder (Finnish
population)
• Characterized by the absence of lactase
activity in the small intestine, with normal
histologic findings
• A gene located on the same chromosome of
the lactase gene, is responsible for CLD
• Affected infants have diarrhea from birth,
hypercalcemia and nephrocalcinosis
Secondary lactose malabsorption
Bacterial overgrowth or stasis syndromes
• Increased fermentation of dietary lactose in
the small bowel, leading to symptoms of
lactose intolerance
• Suspected from clinical history and from a
very early peak of breath hydrogen during
lactose challenge
Secondary lactose malabsorption
Mucosal injury
Villus flattening or damage to the intestinal
epithelium
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Celiac disease
Crohn’s disease
Radiation enteritis, chemotherapy
HIV enteropathy
Whipple’s disease
Prevalence of Lactose Intolerance
• An estimated 30 to 50 million American adults
are lactose intolerant
• 90% of Asian Americans
• 80% of African Americans
• 62-100% of Native Americans
• 53% of Mexican Americans
• 15% of Caucasians
Clinical manifestations
• Abdominal pain – crampy, localized to periumbilical area, or lower
quadrant
• Bloating
• Flatulence
• Diarrhea
• Vomiting
• Stools are usually bulky, frothy and watery
Clinical manifestations
• Meals with higher osmolality and fat content
slow gastric emptying and reduce the severity
of symptoms
• Rapid intestinal motility  rapid movement
of sugar are more symptomatic
• Individuals have variable sensitivity to the
abdominal distention produced when
undigested lactose stimulates an influx of
water into the lumen or to gas production
Diagnosis
Test absorption (lactose absorption test) or
malabsorption (lactose breath hydrogen test)
Lactose tolerance test
• Oral administration of 50 gram lactose
• Blood glucose levels 0, 60 and 120 min
• Increase of blood glucose by less than
20mg/dl + symptoms – diagnostic
• False negative – diabetes, bacterial
overgrowth, delayed gastric emptying
• Sensitivity of 75%, specificity of 96%
Differential diagnosis
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Irritable bowel disease
Inflammatory bowel disease
Cystic fibrosis
Diverticulitis
Celiac sprue
Acute gastroenteritis
Giardiasis
Symptoms of lactose intolerance
• Nausea, cramping, bloating, abdominal pain,
gas, diarrhea
• Symptoms may begin from 15 minutes to
several hours after eating food with lactose
Infants with lactose intolerance
• Breastfeed
• Alternatives to breastfeeding
– Lactose free formula : Lactose free formulas, such
as Lactofree and Similac Lactose free
– Soy formulas are made with soy protein and are
lactose free. Brands include Enfamil ProSobee,
Similac Isomil, and Nestle Good Start Supreme Soy
Special food products
• Lactose-reduced or lactose-free milk and
other dairy foods: NAN, AL 110,
• Add lactase enzyme to fluid milk
– LactaidTM
– CactraseTM
– DairyEaseTM
• Chew or swallow a lactase supplement before
eating lactose rich foods
Alternative Sources of Calcium
• Vegetables: cooked/raw broccoli, turnip and
collard greens, kale, Chinese cabbage
• Fish/Seafood: canned sardines and salmon
with edible bones, raw oysters
• Calcium-fortified orange juice
• Calcium-fortified soymilk
• Tofu processed with calcium salts
• Almonds
COWS’ MILK PROTEIN ALLERGY (CMPA) OR COW MILK
PROTEIN INTOLERANCE( CMPI)

"...an adverse reaction to cows' milk
resulting from an
immunologic hypersensitivity to one or more
milk proteins“1
How many infants are affected?
 Most common food allergy in infancy

Affects an estimated 2-7.5% of UK births1
– 5% would be 38,000 babies/year
(imagine filling the 02 arena twice over)

Generally
resolves
1-3 years of age
1 Hill DJ et al. J Pediatr
1986; 109; by
270-276.
2. Høst A. Ann Allergy Asthma Immunol 2002; 89 (6 Suppl 1): 33-37.
• Cow's milk proteins are most frequently implicated as a
cause of food intolerance during infancy.
• Soybean protein ranks second as an antigen in the first
months of life, particularly in infants with primary cow's
milk intolerance who are placed on a soy formula. From
school age on, egg protein intolerance becomes more
prevalent.
• Several clinical reactions to food proteins have been
reported in children and adults. Only a few of these
have a clear allergic immunoglobulin E (IgE)–mediated
pathogenesis. For this reason, the term "food protein
intolerance" is usually preferred to "food protein
allergy," in order to include all offending specific
reactions to food proteins, no matter the pathogenesis
ALLERGY VS INTOLERANCE
Hypersensitivity
Involving the
immune system
Food allergy
(allergic hypersensitivity)
IgE mediated allergy
Non-IgE mediated allergy
Adapted from Johansson SGO et al. 2004.
Not involving the
immune system
Food intolerance
(non-allergic hypersensitivity)
PATHOPHYSIOLOGY
• Cow's milk contains more than 20 protein fractions : 4 caseins ,S1, S2, S3, S4: 80%
of the milk proteins; 20% of the proteins globular proteins (eg, lactalbumin,
lactoglobulin, bovine serum albumin)
• Casein is often considered poorly immunogenic because of its flexible,
noncompact structure.
• Lactoglobulin is the major allergen in cow's milk protein intolerance.
• Polysensitization to several proteins is observed in about 75% of patients with
allergy to cow's milk protein.
• The proteins recognized by specific IgE are the lactoglobulin and the casein
fraction. However, all milk proteins appear to be potential allergens, even those
that are present in milk in trace amounts (eg, serum bovine albumin,
immunoglobulins, lactoferrin)
• In each allergen, numerous epitopes can be recognized by specific IgE presence.
Cow's milk proteins introduced with maternal diet can be transferred to the
human milk (presence of bovine lactoglobulin throughout human lactation)
• The GI tract is permeable to intact antigens. The antigen uptake is an endocytotic
process that involves intracellular lysosomes.
• Morphologic studies have demonstrated the role of GI
T lymphocytes (ie, intraepithelial lymphocytes) in the
pathogenesis of GI food allergy.
• Protein intolerance is generally believed to remit by
age 5 years, when the infant's mucosal immune system
matures and the child becomes immunologically
tolerant of milk proteins; in most affected children,
symptoms resolve by age 1-2 years. However, cow's
milk protein intolerance may persist or may initially
manifest in older children, demonstrating characteristic
endoscopic and histopathologic features; it
occasionally recurs in adults.
EPIDEMIOLOGY
• Incidence of food allergy in children has been
variously estimated at 0.3-8%, and the
incidence decreases with age.
• Food allergies affect 6-8% of infants younger
than 2 years.
• Denmark : incidence of 2.2%
• the EuroPrevall-INCO project has been
developed to evaluate the prevalence of food
allergies in China, India, and Russia
CLINICS
Body system affected
Symptoms
Oral tract
• Itching and
redness
of mouth and lips
Respiratory tract
• Rhinitis
• Asthma
• Wheezing
Skin
• Urticaria
• Angiodema
• Atopic dermatitis
Gastrointestinal
tract
• Vomiting
• Abdominal pain
• Diarrhoea
CLINICS
• The typical history is that of an infant younger
than 6 months who is fed for a few weeks with
formula and who then develops diarrhea and,
eventually, vomiting. In the case of the
common enterocolitis syndrome, the infant
can become dehydrated and lose weight. In
the rare instance of cow's milk enteropathy,
amalabsorption syndrome develops, with
growth failure and hypoalbuminemia.
• Cow's milk proteins and soy proteins can cause
an uncommon syndrome of chronic diarrhea,
weight loss, and failure to thrive, similar to that
appearing in celiac disease. Vomiting is present in
up to two thirds of patients. Small bowel biopsy
findings reveal an enteropathy of variable
degrees with villous hypotrophy. Total mucosal
atrophy, histologically indistinguishable from
celiac disease, is a frequent finding. Intestinal
protein and blood losses can aggravate the
hypoalbuminemia and anemia that are frequently
observed in this syndrome.
CLINICS
• GI symptoms Oral allergy syndrome: Oral allergy
syndrome is a form of IgE-mediated contact allergy
that is almost exclusively confined to the
oropharynx and is most commonly associated with
the ingestion of various fresh fruits and vegetables.
Symptoms include itching; burning; and
angioedema of the lips, tongue, palate, and throat.
The clinical picture is usually short-lived, but
symptoms may be more prominent after the
ragweed season.
• Eosinophilic esophagitis occurs in children and adults but
rarely occurs in infants and is characterized by chronic
esophagitis, with or without reflux.
• Children younger than 2 years often present with food
refusal, irritability, vomiting, and abdominal pain.
• In older children, dysphagia, anorexia, and early satiety can
help distinguish eosinophilic gastroenteritis
from gastroesophageal reflux
• Eosinophilic gastritis: Eosinophilic gastritis that is responsive
to elimination diets has occasionally been reported.
Symptoms and signs are those usual for gastritis of different
etiologies, such as postprandial vomiting, abdominal pain,
anorexia, early satiety, and failure to thrive. Approximately
half of these patients have atopic features.
• Eosinophilic gastroenteritis: Symptoms include protracted
vomiting and diarrhea. Vomiting generally occurs 1-3 hours
after feeding, and diarrhea occurs 5-8 hours after feeding.
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Blood in the stools
Chronic constipation
Infantile colic
Endoscopic finding of lymphonodular
hyperplasia
• Multiple food protein intolerance of infancy
Dermatologic symptoms
• urticaria, angioedema, rashes, and atopic
eczema.
• atopic dermatitis is one of the most common
symptoms of protein intolerance- 20-40% of
children younger than 1 year with protein
intolerance have atopic dermatitis. Most children
with atopic dermatitis and protein intolerance
develop a complete tolerance in a few years.
• Umbilical and periumbilical disappeares within
the second week on elimination diet, and
reappears within 24 hours after challenge
• Respiratory symptoms: rhinitis and asthma.
General symptoms
• Nonspecific symptoms: oral aphthae, pyloric stenosis,
and bowel edema and obstruction
• The infant with enterocolitis syndrome can be
dehydrated as a consequence of diarrhea, vomiting, or
both. Signs of dehydration include blunted eyes, dry
mucous membranes, and hypoelastic skin.
• Dystrophy, growth failure, edema (hypoalbuminemia),
rickets (vitamin D malabsorption), and hemorrhages
(vitamin K malabsorption)
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Differential Diagnoses
Crohn Disease
Gastroenteritis
Gastroesophageal Reflux
Ulcerative Colitis
Celiac disease
Lactose intolerance
Prolonged post-enteritis syndrome
Autoimmune enteropathy
Common variable immunodeficiency
Food allergy
Infections (Giardia, Helicobacter, Cryptosporidium, viruses)
Food allergy
Drug reactions (NSAIDS, chemotherapy)
Immune system abnormalities (GVHD, autoimmune enteropathy,
other autoimmune diseases)
Laboratory Studies
• Skin test responses to cow's milk or other food proteins and
detection of food-specific immunoglobulin E (IgE) antibodies are
usually positive in children with IgE-mediated food allergy.
• Serum immunoassays: Serum immunoassays to determine foodspecific IgE antibodies are often used to screen for antigen-specific
IgE in the patient's serum. Enzyme-linked immunosorbent assays
(ELISAs) have been replacing methods that use radiation (eg,
radioallergosorbent test [RAST]).
• Fecal leukocyte testing: Fecal eosinophils are a significant clue to
the diagnosis of allergic colitis.
• Atopy patch testing:
• Elimination dietsThe simplest type of elimination diet is elimination
of suspected food antigens from the diet for 2-4 weeks or longer.
An elimination diet for 10-14 days should precede a food challenge
test.
• Total serum IgE is within the reference range or slightly elevated.
• upper GI and lower ( colonoscopy)
endoscopies : hyperemia of the mucosa, rings,
and plaques
• focal erythema and frequent nodularity
• eosinophilic infiltration, most prominent in
the lamina propria, can be observed in the
biopsy specimens
TREATMENT
• The definitive treatment of food protein
intolerance is strict elimination of the offending
food from the diet
• dietary therapy of 3 possible regimens: strict use
of amino acid–based formula, dietary restriction
based on allergy testing, or dietary restriction
based on eliminating the most likely food
antigens. The committee also recommended that
topical steroids should be considered for both
initial and maintenance therapy ( 2011)
• Topical or orally and intranasally inhaled
corticosteroids are used to treat dermatologic or
respiratory symptoms (Triamcinolone topical ,
Hydrocortisone topical )
• Antihistamines and inhaled
bronchodilatators (Beclomethasone)
• Infants with elevated cord serum immunoglobulin E
(IgE) and a positive family history of atopy are at
risk for the development of atopic disease.
• In some infants at high risk, exclusive breastfeeding
with delayed introduction of solid foods until the
infant is aged 6 months may delay or possibly
prevent the onset of food allergy.
• avoidance of allergenic foods by lactating mothers
• he American Academy of Pediatrics (AAP): avoid eggs
until age 2 years and peanuts, tree nuts, and fish until
age 3 years for infants who are at risk of developing
atopic disease.
• The Committee on Nutrition and Section on Allergy and
Immunology of the AAP states that this raises serious
questions about the benefit of delaying the
introduction of solid foods that are thought to be highly
allergic beyond age 4-6 months
• The intestinal microflora interacts with the mucosal
immune system, and, in germ-free mice, does not
develop a normal oral tolerance. The intestinal flora of
children with atopy has been found to differ from that
of controls. These observations suggest that the normal
flora can play a role in the prevention of food allergies.
• A potential role for probiotics can be hypothesized
(Lactobacillus rhamnosus)
MANAGEMENT IN BREAST FED INFANTS
MILD TO MODERATE:
1. CONTINUE BREAST FEEDING BUT ELIMINATION DIET
IN MOTHER 2-4 WEEKS WITH CA SUPPLEMENT AND
NO EGG
2. IF IMPROVEMENT REINTRODUCE CMP AND CHECK
SYMPTOMS –IF YES THEN eHF AFTER BF, SOLIDS
WITHOUT CMP UNTIL 9-12 MONTHS AND ATLEAST FOR
6/12. EGG TO BE ADDED IF NO SYMPTOMS.
SEVERE CMPA:
1. REFER PAEDIATRICS AND IN MEANTIME ELIMINATION
DIET IN MOTHER PLUS CA SUPPLEMENT
Breastfeeding is the gold standard
in infant nutrition to 6 months
Protection
against
Protection
chest
against
infections
diarrhoea and
and
upset
wheezing
stomach
Lower risk
of
Less
smelly diabetes
nappies
Less
eczema
Protectio
n against
ear
infections
Breastmilk content per 100ml1
Better
mental
development
• Historically used for the management of food hypersensitivity
(e.g. lactose intolerance and CMPA)
• However, studies have shown that some 30-50% of infants
given
a soya-based formula for the management of CMPA present
with concomitant soya protein allergy
• Soya-based formulas should not be first choice for the
management of infants with proven cows’ milk sensitivity due
to the potential risk from their high phytoestrogen levels
• Soya-based formulas should only be used in exceptional
circumstances to ensure adequate nutrition, e.g. for vegans or
infants who find alternatives unacceptable
• ESPGHAN are also in agreement and state that "Soya protein
formula should not be used in infants with allergy during the
first 6 months of life”. They also raise concerns over their use
post 6 months and suggest that soya tolerance "should first
be established by clinical challenge”2
Prescribable indications
Product
Indications
Uses
Cows’ milk protein intolerance
± secondary lactose intolerance
Cows’ milk protein
allergy/intolerance
Disaccharide ± whole protein
intolerance, or where amino acids
and peptides are indicated
for use with MCT
Complex multiple food
intolerances and malabsorption
Disaccharide ± whole protein
intolerance
Cows’ milk protein allergy
Cows' milk allergy, multiple food
protein intolerance and other
conditions where
an elemental diet is indicated
Severe cows’ milk allergy
and multiple food intolerances
CONCLUSION
• CONSIDER CMPA EARLY- REMEMBER GOR IS
AS COMMON AND DOES NOT NEED
ELIMINATION DIET
• TREAT EARLY
• AVOID SOY BASED FORMULAE UNTIL ATLEAST
6 MONTHS. AVOID GOAT’S MILK, RICE MILK
(ARSENIC) AS NOT APPROPRIATE CALORIES
AND NUTRITION
• IF IN DOUBT DISCUSS WITH COLLEAGUES