ALOK SINHADepartment of Medicine

Manipal College of Medical SciencesPokhara, Nepal

Cystic fibrosis (CF) is an inherited disease of mucus glands of body causing progressive disability due to multisystem failure Affects mostly Lungs: chronic suppurative lung disease Pancreas:chronic exocrine pancreatic insufficiency liver intestines sinuses reproductive organs

• An abnormal gene causes mucus to becomeThick and sticky • gene is called CFTR Gene(cystic fibrosis transmembrane conductance regulator) This is also known as delta-F508 mutation

• This gene makes a protein-CFTR Protein • It controls movement of salt and water in

and out of the cells in body

The CFTR gene is found on the long (q) arm of human chromosome 7

Basic defect • Defective channel leads to a high concentration

of sodium & chloride in exocrine secretions (normally Chloride > Sodium in sweat but in CF Sodium > Chloride. Their level is half of Serum and K+ is double)

• Leading to thick viscous & difficult-to-clear

secretions in lungs and other orgnas mentioned earlier

• Patients with CF present with multi systemic disease involving several or all of the organs mentioned

Autosomal recessive disorder

INCIDENCEOne of the most common inherited diseases among CaucasiansAbout 1 in every 3,000 babies born in the United States has CF

heterozygotes (carriers) is estimated to be 5%

CF is much less common among:– Africans – Asians – 10 times less

Previously, CF was a childhood disease, it has become an adult pulmonary condition

Currently, one third of the population with this paediatric disease is adult, and patients as old as 60 years are seen

Median survival now 29-31 years

70% of patients, diagnosed prior to 1 year

In 8% of patients, the diagnosis is not established until after the age of 10 years

Diagnosed in an increasing number of adults

Features at the time of presentation

Meconium ileus: 10% of newborns present as intestinal obstruction in the first days of life– meconium ileus equivalent may occur in later life

Recurrent respiratory infections: common presenting feature

Failure to thrive affects about 50% of CF patients in childhood and infancy; as a result of pancreatic insufficiency

Respiratory manifestations

Thick mucus blocks the airways

Leads to bacterial growth, colonization & repeated serious lung infections leading to lung damage

Lungs are infected with – Staph. aureus initially– Pseudomonas aeruginosa by the time

they reach adolescence

There is frequent colonization and persistent infection by these bacteria

Chronic inflammation promotes tissue destruction via the excessive release of elastase by recruited neutrophils

Bronchiectasis with progressive productive cough and green/brown sputum multiple chest infections– initially in the upper lobes then through out

both lungsPneumothorax may occur

Aspergillus fumigatus and allergic broncho pulmonary aspergillosis may occur in some (20%)

Nasal polyposisEventually pulmonary fibrosis may lead to death from –cor pulmonale –ventilatory failure

OTHER SYSTEM INVOLVEMENT

Gastrointestinal manifestations

Pancreatic insufficiency leading to malabsorption and failure to thriveAcute pancreatitisIntrahepatic bile duct obstruction caused by abnormal inspissated bile causes– Liver cirrhosis– Portal hypertension

gynaecomastia and other signs of chronic liver disease eg hepatosplenomegaly

Distal ileus obstruction syndrome - meconium ileus equivalentRectal prolapse - due to bulky stoolsBiliary strictureGallstones, cholecystitisIntussusceptionComplications secondary to fat-soluble vitamin deficiency

Other manifestations

Infertility due to failure of development of the vas deferens - obstructive azoospermia

Affected females are subfertile

Hypertrophic pulmonary osteoarthropathy

Cystic fibrosis arthropathy

Diabetes mellitus - in 10-20% of adult patients – – a result of blockage of the pancreatic ducts due to

abnormal pancreatic secretions and autodigestion of the pancreas

Vasculitis, purpura

Salt loss syndrome - Acute salt depletion and chronic metabolic alkalosis

CLINICAL FEATURES

• Clubbing- constant feature• Features of hyperinflation

• Increased AP diameter of chest • Decreased expansion of lung• Hyperresonant percussion note & obliternation of

hepatic and card. dullness• Vesicular br. Sound with prolonged exp

• Features of bronchiectasis• clubbing & persistent coarse crepts

• Features of malabsorption

Lab investigations

Sweat test:Diagnostic of cystic fibrosis Induced by intra-dermal injection of pilocarpineChloride concentration > than 60 mmol/l Sodium concentration is greater than 70 mmol/l Sodium concentration is greater than chloride concentration in the sweat

Nasal potential difference testing

Individuals with cystic fibrosis have a raised potential difference across the nasal respiratory epithelium; 45 mV in comparison with 15 mV in normal individuals

ABG analysis- Hypoxemia Compensated resp Acidosis

P.F.T. Mixed Obstructive & Restrictive pattern

fecal fat and pancreatic-enzyme secretion tests

Semen analysis – azoospermia

Ultrasound abdomen – for pancreatitis and cirrhosis

Chest radiography

Chest radiographs may be normal in patients with CF who have mild lung disease

Hyperinflation is the earliest change initially reversible with treatment later becomes persistent

flattening of the diaphragm – classic sign caused by mucus plugging of small bronchioles

• as the disease progresses, bilateral, irregular, fine, blotchy shadowing appears in the middle and upper zones

• more advanced disease yields the radiological features of bronchiectasis, with:

thickened bronchial wallscystic shadows with fluid levels

1. Bilateral diffuse Multiple cavities 2. Bronchiectasis 3. Peribronchial fibrosis 4. Prominent hilum 5. Hyperinflated lungs

sputum cultureskin test for aspergillus as 20% develop allergic bronchopulmonary aspergillosisin severe cases arterial blood gas sampling shows chronic hypoxia and hypercapnia

glucose tolerance testmalabsorption screen: fecal fat estimationfull blood count - macrocytosis suggests vitamin B12 or folate deficiencycalcium - low in vitamin D deficiencyalbumin - protein losing enteropathy; for corrected calcium

severe bronchiectasis regular chest physiotherapymore frequently during exacerbationsinfections with Staph. aureus can often be managed with oral antibioticsI.V. treatment needed for PseudomonasNebulised antibiotic therapy with – Colomycin – Tobramycin

is used between exacerbations to suppress chronic Pseudomonas infection

bronchi of many CF patients become colonised with pathogens resistant to most antibiotics

strains of P. aeruginosa, Stenotrophomonas maltophilia require prolonged treatment with unusual combinations of antibiotics

oral macrolides such as azithromycin also reduce exacerbations and improve lung function in patients with Pseudomonas colonisation

coexistent asthma, which is treated with inhaled bronchodilators & corticosteroids

(allergic bronchopulmonary aspergillosis occasionally occurs in CF)

Nebulised recombinant human deoxyribonuclease (DNase)

liquify the CF sputum by breaking up the excess of viscous DNA derived from disintegrated inflammatory cells significant improvement in pulmonary function and a reduction in the number of infective exacerbations in a subgroup of patients treatment is very expensive

non-respiratory manifestations of CF clear link between good nutrition and prognosis Malabsorption is treated with oral vitamins and pancreatic enzyme supplements increased calorie requirements: supplemental feeding including nasogastric or gastrostomy tube feeding if requiredDiabetes often requires insulin therapy

Osteoporosis secondary to malabsorption and chronic ill health should be sought and treated

somatic gene therapy

Manufactured normal CF gene can be deliveredto the respiratory epithelium by inhaled therapyto correct the genetic defect

Future is always hopeful

Humanity will keep on wining