Cystic Fibrosis (CF)
Dr Peter Greally MD, FRCPI, FRCPCH, DCH
Introduction
Cystic fibrosis (CF) is an autosomal recessive multi-system disorder which primarily
affects secretory epithelia and results in abnormally viscous mucus secretions. It is
the commonest life-shortening genetic disorder in population of European origin. The
principal manifestations are elevated sweat sodium and chloride, chronic suppurative
obstructive lung disease and pancreatic insufficiency.
Pathophysiology
The CF gene is located on the long arm of chromosome 7 and contains 27 exons. It is
relatively large gene consisting of 250 kilobases of genomic DNA. It codes for a
protein which consists of 1480 amino acid residues called cystic fibrosis
tramsmembrane conductace regulator (CFTR) which is an energy dependent chloride
channel located at the apical surface of secretory epithelia. CFTR is present in
epithelia from the respiratory, gastro-intestinal, renal and hepatobiliary tracts, Its
predicted structure consists of two membrane spanning portions, two nucleotide
binding folds (NBF) and a R domain. It is widely believed that the membrane
spanning portions act as a pore and the R domain acts as channel inhibitor, until it is
phosphorylated by protein kinase A and undergoes a conformation change to make
the pore accessible to chloride ions.
When the R domain channel blockade is relieved by phosphorylation, and binding and
hydrolysis of ATP occur at the first NBF, the channel opens. Binding and hydrolysis
of ATP at the second NBF result in channel closure. Dephosphorylation of the R
domain secures the closed state of the channel.
For CFTR to function correctly, the CF gene must first be correctly transcribed,
CFTR must then be translated from mRNA and processed in the endoplasmic
reticulum and then migrate at sufficient concentrations to the apical surface. Finally,
it should lack any conformational changes that interfere with its regulation and
activation. CF is a genetically and clinically heterogeneous condition. At the time of
writing here are in excess of 800 mutations described. There are 5 mechanistic
classes of mutation in CFTR that result in chloride channel dysfunction: 1 = defective
synthesis eg G542X, 11 = defective maturation and trafficking eg ∆F508, 111 =
blocked activation eg G551D, iv = decreased conductance eg R117H and V =
decreased epithelial abundance eg 3489 + 10 kb C> T. The clinical pehnotype is
determined by the degree of residual CFTR function. Mutation classes 1 and 111 are
associated with a more severe phenotype whereas classes IV and V are associated
with milder disease.
The commonest mutation belongs to class II where there is a deletion of a
phenyialanine residue from the first NBF at position 508 form the N-terminal
(∆F508). It is estimated that this mutation is present in approx. 90% of affected
individuals in Ireland (60% homozygotes, 30% compound heterozygotes). ∆F508 is
associated with a maturation defect whereby inadequate glycosylation of CFTR
results in it being trapped in the endoplasmic reticulum and prevents its migration to
the apical membrane. Other relatively common mutations include G551D. G542X
and 621 + G>T.
It must be stressed that the mechanisms of how defective CFTR function produces
lung disease are not fully understood. The simplest and most widely accepted
paradigm for how defective CFTR function leads to lung disease is that intracellular
chloride ions accumulate which disturb the normal electrochemical equilibrium.
There is hyper-absorption of sodium (and water) through apical sodium channels in an
attempt to restore equilibrium, which renders the epithelial surface fluid deficient in
water, which in turn interferes with normal muco-ciliary clearance. The produces
relentless lung infection with initially Staphylococcus aureus and later Pseudomonas
aeruginosa despite a vigorous inflammatory response within the airway. It is now
generally accepted that the inflammatory process produces immuno-pathogenically
mediated lung injury with contributes significantly to lung CF lung disease. There is
progressive loss of lung parenchyme and eventually death occurs due to respiratory
failure.
Life Expectancy and Mortality
Respiratory disease accounts for more than 90% of mortality and is a major
determinant of quality of life in affected individuals. When the disorder was first
systematically characterised by Dorothy Andersen 1938 survival beyond the age of 2
years was rare. Since then, survival has improved considerably. The latest mortality
data form the US CF Foundation registry indicates that median survival is 31 years.
In the UK, it is estimated that median survival for a child born in 1990- is 40 years.
In Denmark, it is claimed that a zero tolerance policy to Pesudomonas infection
results in greater than 80% of their patients surviving to 45 years of age.
Improved survival is mainly due to centralisation of CF patients at clinics run by
experienced physicians, nursing and paramedical staff who are skilled in the care of
CF patients who require regular supervision and annual screening for pulmonary and
extra-pulmonary complications. One-third of all CF patients will be 18 years or over
which means that they are increasingly becoming the responsibility of adultphysicians.
Prevalence, Incidence and Newborn Screening
There is no registry for CF patients in this country. It is estimated that there are 1000
affected individuals and that 1:19 of the Irish population carry a CF allele. The
incidence is 1 per every 2000 live births which translates into 20-25 new cases each
year. Most physicians who care for individuals with CF would advocate the
introduction of newborn screening. It is argued that early diagnosis and treatment
results in better nutrition and delays the decline in pulmonary disease. It may also
confer significant psycho-social benefits because early diagnosis has been shown to
reduce parental anxiety and may well alter subsequent reproductive plans. Most
authorities would recommend screening with a two-tier system combining
immunoreactive trypsinogen and mutation analysis for ∆F508, as part of the Guthrie
heal-prick test in newborns. The method will detect all affected babies and also
carriers of ∆F508. Preliminary data form large state-wide screening programmes in
Wisconsin is encouraging, but there remains considerable debate as to the cost-benefit
of newborn screening for CF.
Clinical Features
The neonatal intestinal obstruction syndrome of meconium ileus is the earliest feature
and accounts for 10-15% of all cases. Between 85-90% of affected individuals have
exocrine pancreatic insufficiency which is manifest by steatorrhoea and failure to
thrive. Individuals who are pancreatic sufficient have better lung function and a better
prognosis. Respiratory manifestations include recurring lower respiratory infection
(often with wheeze), chronic productive cough and nasal polyposis. Digital clubbing,
chest deformity, chronic crackles, growth retardation and pubertal delay may be
observed on examination. Sinus opacification on x-ray is almost universal although
symptomatic sinus disease is only problematic in older patients. Conventional CF
sputum pathogens include Staphylococcus aureus and Pseudomonas aeruginosa. The
acquisition of the latter organism hastens the decline in pulmonary function.
Aspergillus fumigatus may be isolated in as much as 60% of CR sputum samples. A
hypersensitivity reaction called allergic bronchopulmonary aspergilliosis occurs in up
to 10% of cases and requires systemic steroid therapy. Antimicrobial resistance is an
increasing concern with multi-drug resistant strains of mucoid Pseudomonas
aeruginosa, methicillin-resistant Staphylococcus aureus and Burkholderia cepacia
emerging as major therapeutic challenges for those who treat CF patients.
Virtually all males with CF have obstructive azospermia and are infertile. Of
particular interest are those azospermic males with congenital absence of the vas
deferens who are those believed be at the mildest end of the disease spectrum.
Studies suggest that these individuals often carry one or two CF alleles, but have no
evidence of pancreatic or pulmonary disease. Liver disease (20%) and non-insulin
dependent diabetes mellitus (10%) are seen with in older children and young adults.
Complications such as recurrent pneumothorax and massive haemoptysis are features
of the late stages of CF lung disease.
Diagnosis
A sweat test is the “Gold Standard” for the diagnosis of CF. A sweat chloride of
greater than 60mmol/l by quantitative pilocarpine iontophoresis is diagnostic.
Occasionally, cases are seen where there is a strong clinical suspicion of CF but the
sweat test is equivocal or normal. In such cases extended genotype analysis may be
helpful, eg, the exon 19 mutation 3489 + 10kb C>T is associated with normal sweat
concentrations and a milder pulmonary phenotype. Defective chloride conductance
across respiratory epithelia leads to a greater than normal negative potential difference
across the cell membrane. This observation forms the basis for the nasal potential
difference test that is sometimes used in atypical cases with undiagnostic sweat
electrolyte concentrations.
Treatment
The goals of treatment are to optimise nutritional status and to delay the decline in
lung function.. This is best provided by a multidisciplinary team consisting of
physicians with special expertise in CF, nurse-specialists, nutritionists,
physiotherapists, social workers and psychologists. Regular monitoring of pulmonary
function tests and anthropometry is mandatory.
Airway clearance techniques are taught initially to parents and later to the children
themselves as they mature. Aerosolised bronchodilators can relieve bronchospasm
and promote better mucociliary clearance. Aerosolised recombinant human Dnase
cleaves polymeric DNA in sputum and renders it less viscous. Large multicentre
studies of its efficacy suggest that it produces modest improvements in lung function
and a significant reduction in the number of pulmonary exacerbations.
All pancreatic insufficient patients will require pancreatic enzyme and fat soluble
supplementation. An aggressive approach to nutrition with a high calorie and high fat
diet has been shown to be associated with better survival. Individuals may require
120-140% of the normal recommended daily allowance for calories. Caloric
supplementation and where necessary gastrostomy feeding are indicated when
conventional oral intake is poor.
Antistaphylococcal prophylaxis for the fist two years is a strategy commonly
employed. It is not universally accepted because of concerns that such a practice may
promote earlier colonisation with Pseudomonas aeruginosa. The prompt and
aggressive institution of antimicrobial therapy for pulmonary exacerbations is
aggressive institution of antimicrobial therapy for pulmonary exacervatins is generally
agreed. Oral broad spectrum antibiotics are frequently effective for exacerbations
caused by Staphylococcus sureus, Haemophilus influenzae and Pneumococcus.
Intravenus B-lactam or onobactam antibiotics are combined with aminoglycosides for
pulmonary exacerbations with Pseudomonas aeruginosa. Such combinations are
synergistic and produce less antimicrobial resistance than monotherapy. The
treatment of chronic Pseudomonas aeruginosa colonization with daily aerosolised
antibiotics are proven benefit in the short term. More recently it has been
demonstrated that nebulised high dose tobramycin by inhalation for one year is safe,
efficacious and not associated with the development of drug resistance. The
combination of nebulised colistin and oral ciproxin may be effective for initial isolates
of Pseudomonas aeruginosa and may postpone chronic colonization.
In Denmark, patients chronically colonized with Pseudomoas aeruginosa receive
quarterly courses of intravenous antibiotics for two weeks even when asymptomatic.
It is claimed that this aggressive approach is the basis for their very impressive
survival figures. Approaches to the suppression of harmful airway inflammation
included alternate day prenisone which now cannot be recommended because of
steroid related morbidity including glucose intolerance, cataracts and growth
retardation. Ibuprofen at high dose taken for 4 years is well tolerated and has been
shown to delay the decline in pulmonary function. Surprisingly, clinicians have been
slow to include it in CD treatment regimens.
Lung transplantation is the only option for those individuals with end stage respiratory
disease. Unfortunately, there is an enormous shortage of donor organs which means
that most eligible patients die whilst awaiting translation. Recent results indicate 73%
survival at one year, 63% at 2 years and 57% at 3 years post transplantation. Bilateral
lobar transplantation form living related donors is another option and has similar
survival results.
New Horizons
Since the gene for CF was cloned 1989 there has been significant progress in the
development of gene therapy. The best studies vectors are adenoviruses, adenoassociated viruses and liposomes. Several clinical trials are addressing their efficacy
in the nose and/or the airway of affected individuals, but so far results have been
disappointing. Excessive sodium absorption in the airway can inhibited by nebulised
amiloride which has been shown to reduce sputum viscosity but this finding does not
translate into a clinical benefit. Nucleotide triphosphates such ATP and UTP can
stimulate Ca++ dependant chloride channels can partially reverse the epithelial defect.
Endogenous antimicrobial peptides called human B defensins are inhibited by high
salt concentratins and may explain the predilection of the CF airway to infection.
Novel synthetic salt resistant antimicrobial peptides are being developed which may
massively augment any conventional antibiotic effect.
Better understanding of the different classes of CF mutation has led to a variety of
novel therapeutic approaches. Class I mutations which involve premature stop codons
that lead to early termination of CFTR mRNA can be inhibited by low dose
aminoglycosides. Phase one clinical trials with intranasal gentamicin are ongoing in
homozygotes for these mutations. Chemical chaperones are agents that can promote
the trafficking of CFTR to the cell surface. These may be useful in class II mutations.
Phenylbutyrate is one such agent which has shown some promise in pilot studies and
is now in phase 1 clinical trials in ∆F508 homozygotes. Gene therapy is the most
likely approach for Class III and V mutations. It is hoped that, in the medium to
longer term. These and other developments will address the CF defect in a
fundamental way and therefore produce a normal life expectancy of affected
individuals.