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Cystic fibrosis

Definition
  • Severely life-shortening genetic disease
  • Results from abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR)
    • Chloride channel found in cells lining the lungs, intestines, pancreatic ducts, sweat glands, and reproductive organs.
  • There are over 1500 known disease-causing mutations that interrupt various stages of CFTR synthesis and function
  • The most common clinical manifestations are:
    • pancreatic dysfunction, resulting in calorie malabsorption
    • lung disease, resulting from a cycle of mucus retention, infection, and inflammation
Risk Factors
  • FHx
  • Carrier status of parents
Differential diagnosis
  • Primary ciliary dyskinesia
    • Ciliary biopsy will demonstrate ultrastructural abnormalities of respiratory cilia.
  • Primary immunodeficiency
    • Measurement of lymphocyte number and function, neutrophil function, and immunoglobulin levels.
  • Asthma
    • Diagnosis is made clinically
    • Some children with CF also present with asthma.
  • Gastro-oesophageal reflux disease (GORD)
    • Modified barium swallow or gastric emptying studies may be useful
    • May also be positive in patients with CF.
  • Chronic aspiration
    • Modified barium swallow or gastric emptying studies may be useful
    • May also be positive in patients with CF.
  • Failure to thrive
    • Sweat test should be negative if CF is not the cause
    • However, severe malnutrition causes a falsely elevated sweat test.
  • Coeliac disease
    • Intestinal biopsies.
  • Protein-losing enteropathy
    • Intestinal biopsies.
Epidemiology
  • There are about 8500 cases in the UK, 30,000 cases in the US and 70,000 worldwide. [4] [5] 
  • The incidence among white people is about 1/3000
  • The incidence is lower among people of African, Hispanic, and Asian descent.
  • It is most common among people of European descent. [6] 
  • One study suggests that the incidence may be decreasing since the institution of newborn screening. [7] 
  • Lung disease is the most common cause of morbidity and mortality.
Aetiology
  • Genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)
    • An anion channel found in the apical membrane of epithelial cells.
  • Patients may be either homozygous or heterozygous with respect to CFTR mutations.
    • Carriers of one CFTR mutation and one normal CFTR allele do not demonstrate disease in most cases.
Clinical features
  • Key Findings
    • Common
      • presence of risk factors
      • positive newborn screen 
      • failure to pass meconium 
      • failure to thrive 
      • voracious appetite 
      • wet-sounding cough 
      • recurrent infection 
      • chronic sinusitis
      • genital abnormalities in males 
    • Uncommon
      • Haemoptysis 
  • Other diagnostic factors
    • Common
      • malabsorptive stool steatorrhoea 
      • wheeze 
      • digital clubbing 
      • gastro-oesophageal reflux 
    • Uncommon
      • increased anteroposterior (AP) diameter of the chest 
      • hx of pancreatitis (uncommon)
      • hx of acute appendicitis (uncommon)
      • enlarged liver or spleen (uncommon)
Pathophysiology
  • Mutations in CFTR result in abnormal salt (chloride and bicarbonate) transport by epithelial cells
    • Results in thick, sticky secretions.
  • In the pancreas, this leads to:
    • blockage of exocrine ducts
    • early activation of pancreatic enzymes
    • eventual autodestruction of the exocrine pancreas
    • Therefore, most patients require supplemental pancreatic enzymes.
  • In the intestine, bulky stools can lead to intestinal blockage.
  • In the respiratory system, the absence of CFTR function results in:
    • hyperabsorption of sodium from the airway surface liquid to the blood
    • depletion of airway surface liquid
    • Leads to:
      • mucus retention
      • chronic infection
      • inflammation
      • eventuate to destruction of lung tissue. [2] 
    • Lung disease is the most common cause of morbidity and mortality.
Investigations
  • Sweat test
    • Generally considered the most conclusive test for diagnosis.
    • Sweat tests may be performed in children of any age.
    • Some children may not produce enough sweat to give accurate results.
      • If this occurs, the child should be retested within a week.
    • A sweat chloride measurement of <40 mmol/L (<40 mEq/L), essentially rules out the diagnosis.
    • A positive sweat test (>60 mM) is consistent with CF and requires immediate referral to a CF centre.
    • For those with a sweat test falling within 40 and 59 mmol/L, further investigations may be required.
  • Immunoreactive trypsinogen (IRT) test (newborn screening)
    • A positive IRT test, defined differently by each laboratory, is not diagnostic.
    • Each positive result should be followed by confirmatory testing.
    • All patients with a positive IRT test should be referred to a CF centre. [10]
  • Genetic testing
    • Most laboratories will perform an initial 'screen' for the most common CFTR mutations.
    • If two common mutations are not found, most laboratories have an option for sequencing more of the CFTR gene
  • Sinus x-ray
    • May show pansinusitis
  • Deep throat swab
    • Presence of respiratory pathogens
Management

a) conservative
  • monitoring
  • chest physiotherapy
    • manual chest physiotherapy
    • high-frequency oscillatory vest device (VEST therapy)
    • flutter valve
    • positive expiratory pressure mask
  • fat-soluble vitamin supplementation
b) medical
  • pancreatic enzyme replacement
    • Enzyme replacements consist of lipase, protease, and amylase
  • H2 antagonist or proton-pump inhibitor
    • Used to provide a more alkaline environment for pancreatic enzyme supplemental therapy, improving enzyme function
    • Also to treat GORD
  • ursodeoxycholic acid
    • If liver disease present
  • inhaled bronchodilator
    • Salbutamol
  • inhaled mucolytic
    • Dornase alfa
  • inhaled tobramycin
    • Used in patients with chronic infection with Pseudomonas aeruginosa
  • anti-inflammatory agent
    • macrolide, NSAID, corticosteroid
  • inhaled corticosteroid
    • Fluticasone
  • oral osmotic agents
    • For meconium ileus
c) surgical
  • Relief of blockage in meconium ileus/partial distal intestinal obstruction
  • Lung transplantation
Prognosis
  • This is a genetic disease for which there is no cure.
  • However, the outlook for patients with this condition has greatly improved.
  • In the past 50 years, the mean age of survival has risen from infancy/school age to almost 38 years old.
  • Many new, beneficial therapies have emerged over the past 5 decades.
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