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
- Protein-losing enteropathy
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
- 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
- Deep throat swab
- Presence of respiratory pathogens
Managementa) 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
- inhaled bronchodilator
- inhaled mucolytic
- inhaled tobramycin
- Used in patients with chronic infection with Pseudomonas aeruginosa
- anti-inflammatory agent
- macrolide, NSAID, corticosteroid
- inhaled corticosteroid
- oral osmotic agents
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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