Elsevier

The Lancet

Volume 373, Issue 9678, 30 May–5 June 2009, Pages 1891-1904
The Lancet

Seminar
Cystic fibrosis

https://doi.org/10.1016/S0140-6736(09)60327-5Get rights and content

Summary

Cystic fibrosis is the most common lethal genetic disease in white populations. The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Researchers now have a more complete understanding of the molecular–biological defect that underlies cystic fibrosis, which is leading to new approaches to treatment. One of these treatments, hypertonic saline, is already in use, whereas others are in advanced stages of development. We review clinical care for cystic fibrosis and discuss recent advances in the understanding of its pathogenesis, implementation of screening of neonates, and development of therapies aimed at treating the basic defect.

Introduction

The outlook for people diagnosed with cystic fibrosis—the most common lethal genetic disease in the white population—has improved substantially in the past 10–20 years. The US Cystic Fibrosis Foundation's projected life expectancy for patients has increased from 31 years to 37 years over the past decade,1 and a UK model predicting that a child born with cystic fibrosis today will typically live to be 50 years of age or more seems to be realistic.2

Cystic fibrosis is caused by a mutation in a gene that encodes cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is expressed in many epithelial cells and blood cells. Although CFTR functions mainly as a chloride channel, it has many other regulatory roles, including inhibition of sodium transport through the epithelial sodium channel, regulation of the outwardly rectifying chloride channel, regulation of ATP channels, regulation of intracellular vesicle transport, acidification of intracellular organelles, and inhibition of endogenous calcium-activated chloride channels.3, 4, 5, 6, 7 CFTR is also involved in bicarbonate–chloride exchange. A deficiency in bicarbonate secretion leads to poor solubility and aggregation of luminal mucins.8

More than 1500 CFTR mutations have been identified, but only the functional importance of a small number is known. The table shows one classification system for the most common mutations based on their functional alterations. The absence of phenylalanine at position 508 (Phe508del, also known as F508del; see panel 1 for glossary of genetic terms), which is a class II mutation, accounts for about two-thirds of mutated alleles in northern European and North American populations. Although CFTR mutation frequency varies from population to population, worldwide no other single mutation accounts for more than approximately 5% of CFTR mutations.10, 11

Pancreatic insufficiency is closely associated with class I–III mutations; however, variability in genetic background (ie, all other genes in the genome) and environment make genotype–phenotype associations weak, especially with regard to lung disease. Manifestations of cystic fibrosis can be very different between patients, even siblings, with the same CFTR genotype. Polymorphisms in non-CFTR genes might explain this discrepancy. Several studies have shown that polymorphisms in transforming growth factor β1 and mannose-binding lectin-2 genes are associated with more severe lung disease, with evidence of gene–gene interactions.12, 13, 14 Similarly, two or more modifier genes seem to be the major determinants of intestinal obstruction in newborn babies with cystic fibrosis.15 Identification of modifier-gene polymorphisms could lead to more accurate prediction of the course of illness in an individual patient; the gene products could become therapeutic targets.

Cystic fibrosis is most common in populations of northern European descent, among whom the disease occurs in approximately 1 in 3000 births.11 Birth prevalence varies from country to country, and with ethnic background (figure 1). For example, the disease occurs in roughly 1 in 3000 white Americans, 1 in 4000–10 000 Latin Americans, and 1 in 15 000–20 000 African Americans.11 Cystic fibrosis is uncommon in Africa and Asia, with a reported frequency of 1 in 350 000 in Japan.21 In Europe the Phe508del mutation predominates in the northwest, and decreases in frequency towards the southeast; the most common mutation in Israel is Trp1282X.

There are several hypotheses regarding how CFTR dysfunction leads to the phenotypic disease known as cystic fibrosis. Four hypotheses are outlined below; it is possible that aspects of all four contribute to the pathogenesis of the disease.

The low-volume hypothesis postulates that the loss of inhibition of epithelial sodium channels, because of CFTR dysfunction, leads to excess sodium and water reabsorption, resulting in dehydration of airway surface materials.22, 23, 24 Concomitant loss of chloride efflux prevents the epithelium from correcting the low airway surface water volume. The subsequent decrease in periciliary water volume results in a reduction in the lubricating layer between epithelium and mucus, with compression of cilia by mucus causing inhibition of normal ciliary and cough clearance of mucus. According to this hypothesis, mucus on the epithelium forms plaques with hypoxic niches that can harbour bacteria, particularly Pseudomonas aeruginosa.24, 25

The high-salt hypothesis argues that in the absence of functional CFTR, excess sodium and chloride are retained in airway surface liquid.26, 27 The increased concentration of chloride in the periciliary layer disrupts the function of important innate antibiotic molecules (eg, human β-defensin 1), allowing bacteria that are cleared by normal airways to persist in lungs.28

Dysregulation of the host inflammatory response has been postulated as the putative basic defect in cystic fibrosis. Support for this hypothesis lies in the fact that abnormally high concentrations of inflammatory mediators are seen in cystic fibrosis cell cultures and uninfected ex-vivo tissue samples.29, 30, 31, 32 Furthermore, findings from lung lavage studies show that inflammation is present in children as young as 4 weeks of age who are apparently free of infection.33 An increase in proinflammatory molecules such as interleukin 8, interleukin 6, tumour necrosis factor α, and arachidonic acid metabolites has been found in patients with cystic fibrosis.34, 35, 36 Stimulation of the nuclear factor-κB pathway, platelet hyper-reactivity, and abnormalities in neutrophil apoptosis have also been reported.37, 38, 39 At the same time, concentrations of native anti-inflammatory substances such as interleukin 10, lipoxin, and docosahexaenoic acid are reduced,31, 34, 40 leading to an imbalance between proinflammatory and anti-inflammatory mediators that favours unabated inflammation.

Another hypothesis suggests that primary predisposition to infection is a mechanism by which CFTR dysfunction leads to cystic fibrosis. In normal hosts, P aeruginosa binds to functional CFTR and initiates an innate immune response, which is rapid and self-limiting. In patients with cystic fibrosis, an increase in asialo-GM1 in apical cell membranes allows increased binding of P aeruginosa and Staphylococcus aureus to airway epithelium, without initiation of the CFTR-mediated immune response.41, 42 The result is that in cystic fibrosis, the rapid, self-limiting response that eliminates P aeruginosa from the airways is lost at the same time as there is enhanced attachment of bacteria to the epithelial surface.

Section snippets

Diagnosis

The diagnosis of cystic fibrosis should be considered in any child or adult who presents with the signs or symptoms listed in panel 2. Diagnostic algorithms for classic and non-classic cystic fibrosis have been published by the European Union Cystic Fibrosis Diagnostic Working Group and the US Cystic Fibrosis Foundation.43, 44 These guidelines concur that the diagnosis of cystic fibrosis consists of finding specific clinical (phenotypic) characteristics in combination with biochemical or

Newborn screening

Newborn screening is done by the measurement of immunoreactive trypsinogen (IRT) in blood spots taken from newborn infants. A very high IRT concentration suggests pancreatic injury consistent with (but not specific for) cystic fibrosis. This marker is increased even in infants with class IV or V mutations that are associated with pancreatic sufficiency. Infants who have a high IRT concentration on initial testing undergo further assessment via a repeat IRT 1–3 weeks later (IRT/IRT), or by

Clinical manifestations

Cystic fibrosis-related symptoms appear throughout life, with great overlap and variability of symptoms and timing from patient to patient. Figure 2 shows the approximate age of onset of some of the major clinical complications of the disease.

Chronic pulmonary treatment

An aggressive approach to cystic fibrosis care is supported by two epidemiological studies showing that cystic fibrosis centres with high median pulmonary function test results see patients more frequently, obtain more frequent respiratory-tract cultures, and use more oral and intravenous antibiotics than do centres with lower median lung function results.54, 90 In an evidence-based review, the US Cystic Fibrosis Foundation used the US Preventive Services Task Force recommendation grades to

New horizons

The pronounced improvement over the past two decades in life expectancy for patients with cystic fibrosis is largely the result of centralisation of care at cystic fibrosis centres and aggressive treatment of symptoms. Large patient registries have been used to examine treatment outcomes, and to implement quality improvement programmes.54, 57, 90, 143, 144 Recent advances in the understanding of cystic fibrosis pathophysiology have not yet had time to result in substantial improvements in

Conclusions

Cystic fibrosis is a multifaceted disease that requires close attention to pulmonary and nutritional variables. Patients should be seen in centres that have experience of caring for individuals with the disease and that can offer expertise in a broad range of areas. Physicians alone cannot provide adequate care; a team consisting of nurses, nutritionists, respiratory therapists, social workers, and others is necessary to achieve the best outcomes. The goal in 2009 is to preserve lung function

Search strategy and selection criteria

We searched Medline (up to September, 2008), Google Scholar for specific topics, and the Cochrane Library for English language reviews pertinent to cystic fibrosis. Additionally, we used systematic reviews prepared by Karen Robinson at Johns Hopkins University (Baltimore, MD, USA) for the US Cystic Fibrosis Foundation's Pulmonary Care Guidelines Committee for chronic therapy, airway clearance, and exacerbation sections of the Seminar. References from previously published reviews of cystic

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