ALOK SINHA Department of Medicine Manipal College of Medical Sciences Pokhara, 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 become

Thick and sticky

• gene is called

CFTR Gene

(

cystic fibrosis transmembrane conductance regulator) This is also known as delta-F508

mutation • • The CFTR gene is found on the long (q) arm of human chromosome 7 This gene makes a protein-CFTR Protein It controls movement of salt and water in and out of the cells in body

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

INCIDENCE

One of the most common inherited diseases

among Caucasians About 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 lungs Pneumothorax may occur

Aspergillus fumigatus and allergic broncho pulmonary aspergillosis may occur in some ( 20%) Nasal polyposis Eventually pulmonary fibrosis may lead to death from – cor pulmonale – ventilatory failure

OTHER SYSTEM INVOLVEMENT

Gastrointestinal manifestations

Pancreatic insufficiency leading to malabsorption and failure to thrive Acute pancreatitis Intrahepatic 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 equivalent Rectal prolapse - due to bulky stools Biliary stricture Gallstones, cholecystitis Intussusception Complications 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 pilocarpine Chloride 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 walls cystic shadows with fluid levels

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

sputum culture skin test for aspergillus as 20% develop allergic bronchopulmonary aspergillosis in severe cases arterial blood gas sampling shows chronic hypoxia and hypercapnia

glucose tolerance test malabsorption screen: fecal fat estimation full blood count - macrocytosis suggests vitamin B12 or folate deficiency calcium - low in vitamin D deficiency albumin - protein losing enteropathy; for corrected calcium

severe bronchiectasis

regular chest physiotherapy more frequently during exacerbations infections with

Staph. aureus

can often be managed with oral antibiotics I.V. treatment needed for

Pseudomonas

Nebulised 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 required Diabetes 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 delivered to the respiratory epithelium by inhaled therapy to correct the genetic defect

Future is always hopeful

Humanity will keep on wining