Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, on chromosome 7.¹
CFTR is an ATP-responsive chloride channel that also affects other cellular activities, such as sodium transport across the respiratory epithelium, composition of cell surface glycoprotein and antibacterial defences.

• Prevalence is 1 in 2,500 with calculated carrier frequency of 1 in 25.²
• The only risk factor is a family history of the condition.

The abnormality in CFTR explains the pathology of cystic fibrosis.

• High sodium sweat: Primary secretion of sweat duct is normal, but CFTR does not absorb chloride ions, which remain in the lumen and prevent sodium absorption.
• Pancreatic insufficiency: Production of pancreatic enzymes is normal but defects in ion transport produce relative dehydration of pancreatic secretions causing their stagnation in the pancreatic ducts.
• Biliary disease: Defective ion transfer across 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 small and large intestine, dehydrated biliary and pancreatic secretions cause intra luminal water deficiency.
• Respiratory disease: Dehydration of the airway surfaces reduces mucociliary clearance and favours bacterial colonisation, local bacterial defences are impaired by local salt concentrations and bacterial adherence is increased by changes in cell surface glycoproteins.
  Increased bacterial colonisation and reduced clearance produces inflammatory lung damage due to an exuberant neutrophilic response involving mediators such as IL8 and neutrophil elastase.

• Because normal digestive function is possible with <5% pancreatic function, cystic fibrosis can present at any age.
• Commonest presentation is with respiratory problems usually recurrent LRTI with chronic sputum production.

Presentation varies with age.

Signs

These include:

• Finger clubbing
• Cough with purulent sputum
• Crackles
• Wheezes (mainly in upper lobes)
• FEV1 shows obstruction

• Sweat testing confirms the diagnosis - chloride concentration >60mmol/l with sodium concentration lower than that of chloride
• Sinus x-rays - opacification of the sinuses is present in almost all patients with CF
• CXR
• Lung function testing - spirometry is unreliable before 6 years
• Sputum microbiology - common pathogens include Haemophilus influenzae, Staphylococcus aureus, P. aeruginosa, Burkholderia cepacia, Escherichia coli, and Klebsiella pneumoniae
• Genotyping
• Semen analysis

Most patients' care is co-ordinated by a cystic fibrosis tertiary centre.³ However the links to local care are highly valued. CF patients perceive a satisfactory doctor-patient relationship to be influenced by three factors:⁴

• GPs' understanding of how people live with CF.
• GPs' ability to prescribe certain specialist medications.
• Sensitive management of the cost of health care for adults with CF.

A doctor-patient relationship based on trust and understanding is seen as desirable, but requires that these factors are addressed both by the GP and the patient.

Respiratory problems

Most of the morbidity and mortality associated with cystic fibrosis is caused by respiratory disease where chronic infection and inflammation leading to bronchiectasis, progressive air flow obstruction, cor pulmonale and finally death.
Management aims will alter depending on the stage of disease:

• In the early, pre-infected stages mucus clearance, preventing infection and maintaining good lung function are the main aims.
  • Chest physiotherapy should be given twice daily and this is increased with infective exacerbations. Additional physical exercise also beneficial. The use of a positive expiratory pressure mask during physiotherapy produces a significantly greater improvement in lung function.⁵
  • Avoid cross infection between patients, especially patients sharing physiotherapy.
  • Pre-colonisation Pseudomonas eradication protocols include both topical (nebulised) and systemic (usually oral ciprofloxacin) antibiotics. Eradication is achieved in 80-90%, but there is uncertainty regarding the long term benefit.⁶
• If the patient is chronically infected with e.g. Pseudomonas confirmed by sputum culture, they are in the intermediate stage. The aim should be to suppress the bacterial load and limit the inflammatory response.
  • Antibiotic choice for infective exacerbations will depend on the organism
    (pseudomonas requires nebulised tobramycin or colomycin); new, faster nebuliser devices (such as e-flow and iNeb) are available. There is no consensus advising when treatment should be started.
  • Infection with less common organisms requires specialist microbiological advice.
  • Reduce inflammation with ibuprofen or macrolide antibiotics (azithromycin). Good evidence of short/medium term benefit, but mechanism of action uncertain. Anti-inflammatory properties are thought likely.
  • There is no evidence supporting a role for corticosteroids except in treating allergic bronchopulmonary aspergillosis.³
• In the end stage management focuses on the common complications, which include haemoptysis, pneumothorax and respiratory failure.
  • Bronchial artery embolisation (rarely lobectomy) may be used to prevent bleeding, which may be fatal.
  • Pneumothoraces are drained. Pleurodesis performed if persistent or recurrent, however, this may affect suitability for transplantation in future.
  • Lung or heart and lung transplantation listing should be considered where there is respiratory failure. Due to scarcity of donor organs, ≥ 50% of CF patients on the list never receive a transplant.
  • Non-invasive ventilatory support may help keep patients alive until transplant but intubation and conventional ventilation are not recommended.
  • Where transplant undertaken, 70% survival at 1 year, 50% at 5 years.⁷

Compounds called inbiotics, e.g. tegrins (a porcine polypeptide) have antibacterial properties are being studied in paediatric infections; and Pulmozyme (recombinant DNAase) may help with expectorating thick mucus and is currently being investigated.

Nasal polyps

50% of adults with CF have nasal polyps. Treat with nasal steroids initially, if this fails polypectomy (50% require repeat within 2 years).

Pancreatic insufficiency

This usually presents with neonatal meconium ileus or failure to thrive, steatorrhoea and malnutrition can cause anaemia, vitamin deficiency and sometimes oedema. It can cause rectal prolapse, intussusception, volvulus and obstruction.
Pancreatic insufficiency should be confirmed with stool elastase; presence of unsplit fat globules in stool or 2-3 days stool collection for faecal fat.

Maintaining adequate weight

Patients should be weighed regularly.

• All patients take enteric-coated enzyme preparations before meals with dose adjusted to achieve normal stools. Drugs may be needed to reduce acid secretion, as well as vitamin supplements for vitamins A, D and E.
• High calorie intake (130% normal) is usually required.⁸
  • Comparing actual resting energy expenditure (REE) to predicted REE is an objective indicator of disease severity and progression as well as energy requirements.⁹
  • Research supports the use of high calorie diets in underweight patients, but further work needs to be done on the most efficacious route of delivery.
  • If the patient is unable to maintain weight, current practice is to opt for enteral feeding via gastrostomy.⁸

Distal intestine obstruction syndrome

A loaded colon and constipation are common and normally respond to enzyme supplements, high fluid and fibre intake.

• Patients may need lactulose occasionally.
• Where patients present with chronic intermittent pain or complete obstruction, exclude appendicitis and treat with balanced intestinal lavage solution by nasogastric tube.

Liver disease

Liver disease is seen in up to 30% of patients by adulthood. Liver cell failure usually occurs late, with ominous prognosis. It is fatal in 2% of CF cases.

• Commonly liver function tests are abnormal - but only significant if > 4x limit. Usually seen as hepatosplenomegaly.
• Ursodeoxycholic acid improves bile flow and produces some improvement but does not alter the course of chronic liver disease.

Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension. They should also have relatively good lung function, to support long-term survival.

• The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases.¹⁰

Diabetes and glucose intolerance

This is rare under 10 years age, but affects 14% by age 15 and >65% at age 25 by which time 32% are diabetic.

• Screening is usually performed as part of out-patient clinic care - as HBA1c or random/fasting blood sugar levels.
• Insulin replacement usually required with dose adjusted to match high dietary intake.
• General condition of patient usually improves with diabetic control and long term adverse effects of diabetes rarely seen.

Reproductive health and fertility

Nearly all males with CF have obstructive azoospermia with sexual function that is otherwise normal; there is normal spermatogenesis, but no vas deferens.

• Early counselling should be offered about infertility and sperm count. In vitro fertilisation with aspirated sperm has been used successfully.
• 1 in 50 risk of offspring being affected without screening.

Women are generally of normal fertility, but need genetic counselling. There is an inherent risk to pregnancy with severe lung disease (FEV1 <30% predicted).

Psychological problems

Cystic fibrosis is a huge burden to patients and families. This is because of:

• The life shortening nature of the disease
• The time consuming treatments prescribed
• The ongoing morbidity

Particularly stressful times include diagnosis, adolescence and end of life. Seeking advice and support from clinical psychologists with experience of the disease is recommended.¹¹

• Median survival in 1999 was 30 years.
• Estimated survival for child born now is 40-50 years.²
• Gene therapy is currently undergoing investigation. Research has supported the principle that gene transfer to the airway epithelium is feasible.¹² Further work needs to be undertaken on viral and non-viral vectors.