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

• Chronic Sino-Pulmonary Disease• Nutritional deficiency/GI abnormality• Obstructive Azoospermia• Electrolyte abnormality • CF in a first degree relative

.

• General– Failure to thrive

• GI– meconium ileus in neonate– foul smelling stools, bloating– rectal prolapse– impaction/obstruction– pancreatitis– low albumin, low sodium– cholelithiasis, cholecystitis– cirrhosis, portal

hypertension– neonatal hyperbilirubinemia– fat soluble vitamin

deficiency

• Respiratory– clubbing– asthma– Chronic Obstructive Pulmonary Disease

barrel chest– productive cough, hemoptysis– nasal polyps– pneumothorax/mediastinum– cor pulmonale, RVH

• Metabolic– dehydration (low Na, low Cl)– metabolic alkalosis (esp neonate)– DM ( diabetus mellitus)– heart stroke

• GU– infertility in males

Endobronchial disease

• 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 deficiencyPancreatic 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 hypertensionGI 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 fat-

soluble 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

– 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---TreatmentMultidisciplinary

• 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 patientsAdjust dose according to stool fat and nitrogen content

•

• 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 disorderelicited by gluten and related prolamines ingenetically susceptible individuals characterised bythe presence of a variable combination of glutendependent clinical manifestations, CD-specificantibodies, HLA-DQ2 or DQ8 haplotypes andenteropathy.”

Coeliac Disease

1988 2012

• Uncommon Common (1%)

• Childhood enteropathy Children & adults

Strong genetic predisposition

Multi-organ disorder

Specific antibody tests

• Serology : Gliadin/Reticulin → Tissue Transglutaminase (TG2) → Endomysial (EMA)• Genetics : HLA DQ2/8

• Enteropathy : Variable/patchy

The “Celiac Genes”: HLA DQ2 and DQ8

Genetic predispositionHuman leukocyte antigen (HLA) alleles DQA1 /

DQB1 genes encoding DQ2 and / or DQ8 molecules

Found in 95% of people with CD70% 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

PathophysiologyCeliac 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 IDDM ( insulin diab)Weight loss Down’s syndromePoor growth/delayed puberty Auto-immune thyroid diseaseIron deficiency anaemia Auto-immune liver diseaseChronic abdominal pain Turner’s syndromeConstipation Williams’ syndromeRecurrent aphthous ulcers First degree relativesAbnormal liver biochemistry

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

– 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 enzyme-linked immunosorbent assay; it is the recommended single serologic test for celiac disease screening in the primary care setting.

Confirmatory testing, including small bowel biopsy, is advised.

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 diseaseAvoidance 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 diseaseMonitor 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 gluten-

free 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

• Racial or ethnic lactose malabsorption

• Developmental lactase deficiency

• Congenital lactase deficiency

Secondary lactose malabsorption

• 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 mid-childhood (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 injuryVillus flattening or damage to the intestinal

epithelium

• 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

• 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

"...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 by 1-3 years of age

COWS’ MILK PROTEIN ALLERGY (CMPA) OR COW MILK PROTEIN INTOLERANCE( CMPI)

1 Hill DJ et al. J Pediatr 1986; 109; 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

Hypersensitivity

IgE mediated allergy

Non-IgE mediated allergy

Food allergy (allergic hypersensitivity)

Food intolerance (non-allergic hypersensitivity)

Involving the immune system

Not involving the immune system

Adapted from Johansson SGO et al. 2004.

ALLERGY VS INTOLERANCE

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

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

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.

• 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)

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 food-specific 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 EGG2.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

Breastmilk content per 100ml1

Less eczema

Less smelly nappies

Protection against diarrhoea and upset stomach

Lower

risk of diabetes

Protection against chest infections and wheezing

Protection against ear infections

Better mental development

Fat 3.4g

Vits & mins 0.173g

Carbohydrates

6.7g

Prebiotic

OS 1.0g

Other 0.2gProtein

1.2g

• 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

Product Indications Uses

Cows’ milk protein intolerance

± secondary lactose intoleranceCows’ milk proteinallergy/intolerance

Disaccharide ± whole proteinintolerance, or where amino acids

and peptides are indicated for use with MCT

Complex multiple food intolerances and malabsorption

Disaccharide ± whole proteinintolerance

Cows’ milk protein allergy

Cows' milk allergy, multiple food protein intolerance and other

conditions where an elemental diet is indicated

Severe cows’ milk allergyand multiple food intolerances

Prescribable indications

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