CYSTIC FIBROSISA Presentation by: Jayatheeswaran. Vijayakumar

CYSTIC FIBROSIS

“Woe to the child which when kissed on the forehead tastes

salty. He is bewitched and soon will die” – Old Proverb

CYSTIC FIBROSIS Cystic fibrosis is a disease of exocrine gland function that

involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients

Is a lethal autosomal recessive disease

Has an incidence: 1 in 2000-3000; predominantly in Caucasian populations (carrier frequency 1 in 22-28)

Median age at diagnosis of cystic fibrosis is 6-8 months; two thirds of patients are diagnosed by 1 year of age.

CYSTIC FIBROSIS The disease gene CFTR (cystic fibrosis transmembrane

conductance regulator) is a regulated epithelial Cl- channel; influences other ion channels

The age at diagnosis, the clinical presentation, the severity of the symptoms, and the rate of disease progression in the organs involved varies widely.

Clinical manifestations vary with the patient's age at presentation. e.g. : patients diagnosed later in childhood or in adulthood are more likely to have pancreatic sufficiency and often present with chronic cough and sputum production

GENOTYPE & PHENOTYPE RELATIONSHIP Cystic fibrosis (CF) is caused by mutations in the CF

transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells.

This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype-phenotype studies.

The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers).

GENOTYPE & PHENOTYPE RELATIONSHIP Several candidate genes related to innate and

adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2.

The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so-called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF.

PATHOPHYSIOLOGY Chloride channel.

Five domains: 2 membrane spanning

domains (MSD) 2 nucleotide binding

domains (NBD, for ATP hydrolysis)

1 regulatory domain (R).

Functions in lungs, liver,pancreas, digestive tract,reproductive tract & skin.

PATHOPHYSIOLOGY In normal airway cells, there

are two Cl- channels. Onechannel is regulated by cyclicAMP and ATP (CFTR), and theother is activated by Ca2+.

ATP binding and hydrolysis openCFTR, so that Cl- can move downits electrochemical gradient, intothe mucus of the lungs.

Presence of Cl- in the mucusensures its sufficient watercontent, required for mucusremoval by the cilia of the airwaycells

PATHOPHYSIOLOGY In individuals with CF, the defect in

CFTR protein causes decreased secretion of Cl- ions which cause a compensatory influx of Na+ ions to maintain the electro-neutrality of the cell.

Increase in the osmolarity inside the cell causes a water influx from outside the cell. This leads to the dehydration of the mucus membrane.

The now sticky mucus trapsbacteria, is not remove by cilia of the lung epithelium. As the lungs have the perfect environment for bacterial propagation patients with CF typically get lung infections.

CLASSIFICATION Class I: normal level of mRNA

; defective protein production (premature stop codon).

No or little CFTR protein is produced.

Class II: Defective trafficking: the protein does not reach the membrane

Class III: defective regulation (opening/closing) of the CFTR channel

Class IV: defective conduction(Cl- doesn’t pass through the channel)

Class V: reduced synthesisof functional CFTR

CLASSIFICATION The most common CFTR mutant ΔF508, is a

class II defect.

The defective protein retains substantial chloride-channel function in cell-free lipid membranes.

When synthesized by the normal cellular machinery, however, the protein is rapidly recognized as misfolded and is degraded shortly after synthesis , via proteasome degradation pathway at endoplasmic reticulum (ER).

THE MOST COMMON CFTR MUTATION

Around 75% of mutations observed in CF patients result from a deletion of three base pairs in CFTR's nucleotide sequence. This deletion causes loss of the amino acid phenylalanine located at position 508 in the protein; therefore, this mutation is referred to as delta F508 or ΔF508.

CLINICAL PRESENTATION

Manifestations

Respiratory Tract

Urogenital Tract

Gastrointestinal Tract

Atypical

CLINICAL PRESENTATION Nose examination

may reveal the following:

Rhinitis Nasal polyps

Findings related to the pulmonary system may include the following:

Tachypnea Respiratory distress with retractions Wheeze or crackles Cough (dry or productive of mucoid

or purulent sputum) Increased anterior-posterior

diameter of chest Clubbing Cyanosis Hyperresonant sound heard upon

chest percussion (crackles are heard acutely in associated pneumonitis or bronchitis and chronically with bronchiectasis)

CLINICAL PRESENTATION Findings related to

the GI tract include the following: Abdominal distention Hepatosplenomegaly

(fatty liver and portal hypertension)

Rectal prolapse Dry skin

(vitamin A deficiency) Cheilosis (vitamin B

complex deficiency)

Findings related to the Urogenital tract include the following: Hydrocele Undescended testicles Amenorrhea Sterility

In males: due to the absence of the vas deferens

In females: fertility is maintained although it is severely decreased

CLINICAL PRESENTATION Examination of other systems may reveal the

following: Scoliosis Kyphosis Swelling of submandibular gland or parotid gland Aquagenic wrinkling of the palms (AWP)

One 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 ΔF508 mutation.

CLINICAL PRESENTATIONAtypical Manifestations

Clinical variants have been described, such as adult males with bilateral absence of the vas deferens who have little other clinical involvement. Absence of the vas deferens is considered an atypical presentation of cystic fibrosis, and 80% of men with this presentation have at least one CFTR gene mutation. Zielenski et al reported that the most common of these mutations is the IVS8/5T mutation.

Another atypical manifestation of cystic fibrosis is polyuria and polyphagia

in an infant. Despite not having any initial intestinal symptoms, such as diarrhea, an infant in Belgium with failure to thrive was initially treated for diabetes insipidus before being diagnosed with cystic fibrosis. Although a sweat test result may be abnormal in diabetes insipidus, cystic fibrosis must be excluded upon any positive sweat test result.

CLINICAL PRESENTATIONComplications

The following are potential complications of cystic fibrosis:

Nasal polyps Chronic and persistent sinusitis with

complications such as mucopyocele formation

Bronchiectasis Atelectasis Pneumothorax Hemoptysis Hypertrophic pulmonary

osteoarthropathy Allergic bronchopulmonary aspergillosis

(ABPA) Gastroesophageal reflux Pulmonary hypertension End-stage lung disease Cor pulmonale

Pancreatitis Cystic fibrosis–related diabetes mellitus Meconium ileus Distal intestinal obstruction syndrome Rectal prolapse Vitamin deficiency (especially fat-

soluble vitamins) Fatty liver Focal biliary cirrhosis Portal hypertension Liver failure Cholecystitis and Cholelithiasis Rickets Osteoporosis

THE RELATIONSHIP BETWEEN CLINICAL PRESENTATIONS & RESIDUAL CFTR FUNCTION

% of Normal CFTR Function Clinical Presentations< 1 Pancreatic insufficiency and below

< 4.5 Pulmonary infection and below

< 5 Positive sweat test and symptoms below

< 10 Congenital absence of vas deferens10-49 None50-100 None

34% of patients reach adulthood10% live past age of 30Average Life Expectancy• Male : 31• Female: 28

TREATMENT• The major goal in treating CF is to clear the

abnormal and excess secretions, control infections in the lungs and to prevent obstruction in the intestines.

• For patients with advanced stages of the disease, a lung transplant operation may be necessary.

• Although treating the symptoms does not cure the

disease, it can greatly improve the quality of life for most patients.

TREATMENT Modified Diet

Due to pancreatic disorders, children with CF require a modified diet, including vitamin supplements (vitamins A, D, E, and K) and pancreatic enzymes. Maintaining adequate nutrition is essential. The diet calls for a high-caloric content (twice what is considered normal for the child's age), which is typically low in fat and high in protein. Patients or their caregivers should consult with their health care providers to determine the most appropriate diet.