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.
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.
Sweat test should be negative if CF is not the cause
However, severe malnutrition causes a falsely elevated sweat test.
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.