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Inherited monogenic disorder presenting as a

multisystem disease.

Typically presents in childhood 7% of CF patients diagnosed as adults

Most common life limiting recessive trait among whites

Cystic Fibrosis

Prognosis improving

>38% of CF patients are older than 18 13% of CF patients are older than 30

Median survival Males: 32 years Females: 29 years

Cystic Fibrosis

Autosomal recessive Gene located on chromosome 7 Prevalence- varies with ethnic origin

1 in 3000 live births in Caucasians in North America and Northern Europe

1 in 17,000 live births of African Americans 1 in 90,000 live births in Hawaiian Asians

Genetics of CF

Most common mutation

Occurs in 70% of CF chromosomes 3 base pair deletion leading to absence of

phenylalanine at position 508 of the CF transmembrane conductance regulator (CFTR)

Genetics of CF

Difficult to use DNA diagnosis to screen for

heterozygotes

No simple physiologic measurements yet available for heterozygote detection

Genetics of CF

The CFTR protein

Single polypeptide chain, 1480 amino acids Cyclic AMP regulated chloride channel Regulator of other ion channels Found in the plasma membrane of normal

epithelial cells

Genetics of CF

Protein Function and Biochemistry

CFTR controls chloride ion movement in and out of the cell.

F508 mutation leads to improper processing

and intracellular degradation of the CFTR protein

Other mutations in the CF gene produce fully processed CFTR proteins that are either non-functional or partially functional

Genetics of CF

Mutation of CFTR

Epithelial disfunction

Epithelia containing CFTR protein exhibit array of normal functions Volume absorbing (airway, distal intestine) Salt absorbing without volume (sweat ducts) Volume secretory (proximal intestine, pancreas)

Disfunction in CFTR gene leads to different effects on patterns of electrolyte and water transport

Genetics of CF

Lung

Raised trans-epithelial electric potential difference

Absence of cAMP-dependent kinase and PKC-regulated chloride transport

Raised sodium transport and decreased chloride transport

Alternative calcium-regulated chloride channel in airway epithelia which is a potential therapeutic target

Physiology

Normal airway epithelia

CF altered airway epithelia

Lung

High rate of sodium absorption and low rate of chloride secretion reduces salt and water content in mucus, depletes peri-ciliary liquid

Mucus adheres to airway surface, leads to decreased mucus clearing

Physiology

Gastrointestinal

Pancreas Absence of CFTR limits function of chloride-

bicarbonate exchanger to secrete bicarbonate Leads to retention of enzymes in the pancreas,

destruction of pancreatic tissue. Intestine

Decrease in water secretion leads to thickened mucus and dessicated intraluminal contents

Obstruction of small and large intestines

Physiology

Gastrointestinal

Biliary tree Retention of biliary secretion Bile duct proliferation

Sweat Normal volume of sweat Inability to reabsorb NaCl from sweat as it

passes through sweat duct

Physiology

Common presentations Chronic cough Recurrent pulmonary infiltrates Failure to thrive

Manifestations

Respiratory tract

Chronic cough Persistent Viscous, purulent, green sputum Lung function Small airway disease is first functional lung

abnormality Progresses to reversible as well as irreversible

changes in FEV1 Chest x-ray may show hyperinflation, mucus

impaction, bronchial cuffing, bronchiectasis

Manifestations

Gastrointestinal

Meconium ileus equivalent or distal intestinal obstruction syndrome Loss of appetite Emesis (alkalosis) Palpable mass May be confused with appendicitis

Manifestations

Gastrointestinal

Exocrine pancreatic insufficiency Found in >90% of CF patients Protein and fat malabsorption Frequent bulky, foul-smelling stools Vitamin A, D, E, K malabsorption Sparing of pancreatic beta cells

Beta cell function decreases with age

Manifestations

Genitourinary

Late onset puberty Due to chronic lung disease and inadequate

nutrition >95% of male patients with CF have

azospermia due to obliteration of the vas deferens

20% of female patients with CF are infertile >90% of completed pregnancies produce viable

infants

Manifestations

DNA analysis not useful due to large variety of

CF mutations Sweat chloride test >70 mEq/L 1-2% of patients with clinical manifestations of

CF have a normal sweat chloride test Nasal transepithelial potential difference

Diagnosis

Criteria

One of the following Presence of typical clinical features History of CF in a sibling Positive newborn screening test

Plus laboratory evidence for CFTR disfunction Two elevated sweat chloride concentrations on

two separate days Identification of two CF mutations Abnormal nasal potential difference measurement

Diagnosis

Major objectives

Promote clearance of secretions Control lung infection Provide adequate nutrition Prevent intestinal obstruction

Investigation into therapies to restore the processing of misfolded CFTR protein

Treatment

Lung

>95% of CF patients die from complications of lung infection

Breathing exercises Flutter valves Chest percussion Hypertonic saline aerosols

Treatment

Lung

Antibiotics Early intervention, long course, high dose Staphylococcus- Penicillin or cephalosporin Oral cipro for pseudomonas

Rapid emergence of resistance Intermittent treatment (2-3 weeks), not chronic

IV antibiotics for severe infections or infections resistant to orals

Treatment

Lung

Antibiotics Pseudomonas treated with two drugs with

different mechanisms to prevent resistance e.g. cephalosporin + aminoglycoside

Use of aerosolized antibiotics(convert into a fine spray or colloidal suspension in air.)

Increasing mucus clearance N-acetylcysteine not clinically helpful

Treatment

Lung

Inhaled -adrenergic agonists to control airway constriction No evidence of long-term benefit

Oral glucocoticoids for allergic bronchopulmonary aspergillosis

Treatment

Lung

Respiratory failure therapy Vigorous medical management Oxygen supplementation Only effective treatment for respiratory failure is

lung transplantation 2 year survival >60% with lung transplatation

Treatment

Gastrointestinal

Pancreatic enzyme replacement Replacement of fat-soluble vitamins- especially

vitamin E & K Insulin for hyperglycemia Intestinal obstruction

Pancreatic enzymes + osmotically active agents Distal- hypertonic radiocontrast material via

enema

Treatment

Gastrointestinal

End-stage liver disease- transplantation 2 year survival rate >50%

Hepatic and gallbladder complications treated as in patient without CF

Treatment

CF is an inherited monogenic disorder

presenting as a multisystem disease Physiology is related to abnormal ion

transportation across epithelia Respiratory, GI and GU manifestations Treatment is currently preventative and

supportive

Summary