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Thursday, February 28, 2013

Cystic Fibrosis: Genetics, Pathogenesis, Epidemiology, Signs and Symptoms, Complications, Investigations, Treatment, Prognosis of Cystic Fibrosis


Cystic fibrosis is an autosomal recessive disease due to mutation in the long arm of chromosome number  7 (in the region 7q31.2) which codes for a critical chloride channel known as cystic fibrosis transmembrane conductance regulator (CFTR) protein.

The most common mutation in norther European and American populations is DF508 (deletion, phenylalanine at position 508).

Cystic fibrosis is the most common fatal genetic disease in Caucasians, with a carrier rate of 1 in 22 and an incidence of about 1 in 2000 live births.


Function of cystic fibrosis transmembrane conductance regulator protein

The cystic fibrosis transmembrane conductance regulator protein influences salt and water movement across epithelial cell membranes.

Pathogenesis of Cystic Fibrosis:


Due to mutation in the long arm chromosome number 7
Cystic fibrosis transmembrane conductance regulator protein cannot function properly
This leads to deranged transport of CFTR-affected ions: chloride, sodium, bicarbonate



Leading to increased sodium and chloride content in sweat and increased resorption of sodium and water from the respiratory epithelium
Leading to relative dehydration of the airway epithelium, alteration in the tenacity and viscosity of mucous and ciliary dysfunction (mucostasis)


Less washout of pathogenic organisms and blockage of airway
Chronic infection, recurrent bronchiectasis and other manifestations of cystic fibrosis appear.



The defect in cystic fibrosis transmembrane conductance regulator protein also causes disorders in the gut epithelium, pancreas, liver and reproductive tract.


Clinical features / Signs and Symptoms of Cystic Fibrosis:

1. Recurrent chest infection in childhood
2. Bronchiectasis in childhood which is progressive.
3. In newborn, thick tenacious intestinal secretion cause small bowel obstruction  This is called meconium ileus (an early manifestation of cystic fibrosis). Meconium ileus equivalent syndrome, a form of small intestinal obstruction unique to CF, develops later in life.
4. Impaired growth in children and delayed puberty
5. Sinusitis
6. Nasal Polyp
7. Steatorrhoea and Diabetes Mellitus due to pancreatic dysfunction
8. Males are infertile due to failure of development of vas deferens and epididymis. Infertility can be treated with microsurgical sperm aspiration and in vitro fertilisation. Females are able to conceive but often develop secondary amenorrhoea as the disease progresses.
9. Progressive lung damage may lead to respiratory failure and death.
10. Spontaneous Pneumothorax due to vigorous cough
11. Haemoptysis, Breathlessness
12. Cor Pulmonale
13. Malnourished due to malabsorption and maldigestion. Poor nutrition is associated with increased lung infection.
13. Clubbing is present in patients with advanced disease.



Complications of Cystic fibrosis:

A. Respiratory system:

  • Infective exacerbation of bronchiectasis
  • Spontaneous pneumothorax
  • Haemoptysis
  • Nasal polyps
  • Respiratory failure
  • Cor pulmonale
  • Lobar collapse due to retention of secretions

B. Gastrointestinal system:

  • Malabsorption and steatorrhoea
  • Distal intestinal obstruction syndrome
  • Biliary cirrhosis and portal hypertension
  • Gallstones
  • Gastrointestinal malignancy

C. Others:

  • Diabetes (25% of adults)
  • Delayed puberty
  • Male infertility
  • Stress incontinence due to repeated forced cough
  • Psychosocial problems
  • Osteoporosis
  • Arthropathy
  • Cutaneous vasculitis

Diagnosis of Cystic Fibrosis:

A. Clinical picture: 

1. A family history cystic fibrosis

2. The sign and symptoms of cystic fibrosis. eg bowel obstruction, failure to thrive, steatorrhoea, chest symptoms in a young child.

3. Absent vas deferens and epididymis


B. Investigations:

1. Sweat sodium measurement:
Sweat sodium level measurement is the initial investigation and must be performed in a laboratory regularly undertaking testing. A value of ³ 60 mmol/L is diagnostic. Lower values but above the normal range still require DNA analysis.

3. Blood DNA analysis of the gene defect.

4. Radiology showing features of bronchiectasis.

5. Neonatal screening for cystic fibrosis using immunoreactive trypsin and genetic testing of newborn blood sample.

6. Prenatal screening by amniocentesis in suspected high risk cases.

Treatment of Cystic fibrosis:

A. Treatment of cystic fibrosis lung disease:

This is the same as the treatment of severe bronchiectasis. 

1. General measures: 

a. Patients should perform regular chest physiotherapy / Postural drainage to expel out the retained secretion

b. Patients should stop smoking and receive vaccination with influenza and pneumococcal vaccines.

2. Antibiotics:

Infection with Staphylococcus aureus treated with oral antibiotics.

Infection with Pseudomonas species is treated with intravenous antibiotics. This can be self-administered at home through a subcutaneous vascular port. Chronic Pseudomonas infection is treated with nebulised antibiotics (colomycin or tobramycin)

The airway of many cystic fibrosis patients eventually becomes colonised with organisms which are resistant to most antibiotics. The main culprits are Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia. This requires prolonged treatment with unusual combination of antibiotics.

Some patients also suffer from asthma along with cystic fibrosis. In such cases, inhaled bronchodilators and corticosteroids are used to manage the asthma.

There are three maintenance treatments which causes modest rise in lung function and reduces the frequency the exacerbation in cystic fibrosis patients:
  • Nebulised recombinant human DNase (dornase alfa) 2.5 mg daily for patients who are more than 5 years and with FVC >  40 % predicted
  • Nebulised tobramycin 300 mg 12 hourly, given in alternate months for patients colonised with Pseudomonas aeruginosa
  • Regular oral azithromycin 500 mg three times a week for patients colonized with Pseudomonas aeruginosa.
For patients with severe cystic fibrosis lung disease, home oxygen and non invasive ventilation (NIV) may be necessary to treat respiratory failure.

Lung or heart-lung transplantation can produce dramatic improvements but is limited by donor organ availability.

B. Treatment of non-respiratory manifestations:

1. Improvement of nutrition. 
  • Malabsorption is treated with oral pancreatic enzyme supplements and vitamins. 
  • The increased calorie requirements of cystic fibrosis patients are met by supplemental feeding, including nasogastric or gastrostomy tube feeding if required.
2. Diabetes eventually appears in over 25% of patients and is treated with insulin therapy

3. Osteoporosis secondary to malabsorption, if detected then treated accordingly.

4. Male infertility is treated with microsurgical sperm aspiration and in vitro fertilisation. 

C. Somatic gene therapy:

Manufactured normal Cystic fibrosis gene can be 'packaged' within a viral (replication-deficient adenovirus) or liposome vector and delivered to the respiratory epithelium to correct the genetic defect. Initial trials in the nasal and bronchial epithelium have shown some effect, and further trials of nebulised bronchial delivery are planned. Improved gene transfer efficiency is needed before this will become a practical clinical treatment.

Prognosis of Cystic fibrosis:

Almost all CF patients develop progressive respiratory failure but the prognosis has improved considerably over the years. 

Ninety per cent of children now survive into their teens and the median survival for those born after 1990 is estimated at 40 years. Most patients die due to advanced lung disease. A major problem is sputum infection with Burkholderia cepacia. It is associated with accelerated lung disease and resistance to antibiotics in some strains. Close contact promotes cross-infection, so siblings and fellow sufferers with cystic fibrosis may pass the organism from one to another.

Genetic screening is available for the four most common mutations and this identifies 85–95% of carriers. Screening for the carrier state should be offered to persons or couples with a family history of CF, together with counselling.

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