Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disorder that affects the respiratory tract, exocrine pancreas, intestine, male genital tract, hepatobiliary system, and exocrine sweat glands. It is a progressive condition with symptoms usually appearing in early childhood. Pulmonary disease is the major cause of morbidity and mortality in CF.

Presentation

Clinical features of CF may include but are not limited to the following:

  • Chronic suppurative lung disease
  • Pancreatic exocrine insufficiency, leading to malabsorption
  • Sweat gland salt loss
  • Male infertility (absent or altered vas deferens) and reduced fertility in women
  • Meconium ileus
  • CF-related diabetes
  • CF liver disease

Immunoreactive trypsinogen (IRT) is now measured on a dried blood spot obtained on the Guthrie card at six days of age. Samples with persistently abnormally raised IRT levels will undergo CFTR mutation screening. This was introduced in 2007, and potentially means that clinical presentation of CF later in life will become rarer.

However screening failures do sometimes occur and, for the Jewish and some other ethnic populations, the screen does not include some relevant mutations.

Please click on the titles to open and close the following information sections.

  • CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7.
  • Pathogenic mutations either remove or reduce the function of the CFTR gene that regulates chloride and sodium transport in the epithelial surfaces of the airway, pancreatic and biliary ducts, the gastrointestinal tract, sweat ducts and the vas deferens.
  • There are at least 1500 mutations in the CFTR gene.
  • Different mutations result in different phenotypes.
  • The most common mutation in Caucasians is the delta-F508.

The abnormality in the CFTR explains the pathology of cystic fibrosis.

 

  • High sodium sweat – CFTR does not absorb chloride ions, which remain in the lumen and prevent sodium absorption.
  • Pancreatic insufficiency – defects in ion transport produce relative dehydration of pancreatic secretions, causing their stagnation and obstruction of the pancreatic ducts.
  • Biliary disease – defective ion transfer across the bile duct causes reduced movement of water in the lumen so that bile becomes concentrated causing plugging and local damage.
  • GI disease – low-volume secretions of increased viscosity, changes in fluid movement across both the small and large intestine, and dehydrated biliary and pancreatic secretions cause intraluminal water deficiency.
  • Respiratory disease – major cause of morbidity and mortality in CF. Patients have lower airway inflammation and infection, cause by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa.

 

  • CF is one of the most common inherited diseases in the Caucasian population with a carrier frequency of 1:25 and an estimated prevalence of 1:2,500 newborns.
  • The Ashkenazi Jewish population has a similar carrier frequency of 1 in 25 to 1:29, with a disease incidence of approximately 1:3,000.
  • The disease frequency is lower in many ethnic populations e.g. 1 in 15,000 in African Americans and 1 in 30,000 in Asian populations.
  • Sweat testing is the first line investigation for suspected CF.
  • Sweat testing confirms the diagnosis. Chloride concentration > 60mmol/L with sodium concentration lower than that of chloride.

Gene specific

  • Molecular genetic testing for CF covers a range of the high prevalence CFTR mutations. Different laboratories vary in the number of mutations they test for.
  • Full CFTR gene sequencing may be employed in cases where there is a clinical CF diagnosis but mutations were not identified by standard testing.
  • Testing for 5 mutations (delta F508, W1282X, N1303K, G542X, 3849 + 10 kb CT) has been shown to account for 97% of CF alleles in patients of Ashkenazi Jewish origin..

Respiratory problems

  • Treatment / prevention of pulmonary complications using oral, inhaled, or IV antibiotics, bronchodilators, anti-inflammatory agents and mucolytic agents.
  • Chest physiotherapy.
  • Lung or heart/lung transplantation in selected patients.

Pancreatic insufficiency

  • Oral pancreatic enzyme replacement with meals.
  • Additional fat-soluble vitamins.

Maintaining adequate weight

  • Supplemental feeding to increase calorie intake.

Biliary sludging / obstruction

  • Oral ursodeoxycholic acid.

Diabetes and glucose intolerance

  • Routine glucose levels annually.
  • Some CF patients may need to be commenced on insulin.

CFTR modulation therapy

  • Therapies designed to correct the malfunctioning protein made by the CFTR gene.
  • The medications that have been developed so far are effective only in individuals with specific mutations.

Psychological problems

  • Particularly stressful times include diagnosis, adolescence and end of life.

Family members should be offered genetic counseling and testing if appropriate. Carrier testing and pre-natal testing is available for this condition.

  • Disease progression varies by severity of the CFTR mutations inherited, genetic modifiers and environmental factors.
  • Prognosis has been improving due to earlier diagnosis from screening and better treatment options. The estimated survival for a child born now is 40-50 years.
  • For children exhibiting features of CF, initial referral is usually to a paediatrician. For patient of Ashkenazi Jewish origin it is valuable to note ancestry as this may impact the specific mutations needing investigation.
  • For patients that have received a positive CF diagnosis
    • On-going management of children is under the care of a respiratory paediatrician with expertise in cystic fibrosis in a specialist CF centre, with other specialist input as appropriate.
    • Management of adult CF patients is under the care of a respiratory CF physician in a specialist CF centre, with other specialist input as appropriate.
    • Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.
The Cystic Fibrosis Trust

This is the UK’s only national charity dedicated to all aspects of Cystic Fibrosis (CF). It funds research to treat and cure CF and is dedicated to ensuring appropriate clinical care and support for people with CF. It provides many services including a helpline, publications and welfare grants. This site also contains a forum for patient and carer support and information.
Switchboard: 020 8464 7211
Helplines – Support: 0300 373 1000; Benefits: 0300 373 1010; Welfare: 0300 373 1020

Cystic Fibrosis Foundation (USA)

This American foundation works to provide support for individuals and families affects by cystic fibrosis. It is involved in research and education initiatives and has an information website.

Cystic Fibrosis Worldwide (Global)

This organisation aims to provide education, training, supplies, and resources to all parts of the world affected by CF so as to improve the quality of life of those affected by the disease. It has 52 member countries.

Cystic Fibrosis Voice

This is an online community for those of all ages affected by Cystic Fibrosis.

GeneReviews: http://www.ncbi.nlm.nih.gov/books/NBK1250

OMIM: #219700

Written by: Jnetics
Approved by: Dr Ranjan Suri, Paediatric Respiratory Consultant, Great Ormond Street Hospital for Children NHS Foundation Trust
Last review: 12.07.2018

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