Diagnosing cystic fibrosis: what are we sweating about?

Over the last few decades, the paradigm has shifted as cystic fibrosis (CF) is no longer a fatal disease of childhood and should be considered a chronic condition where survival into adulthood is expected. Median survival for current newborns is predicted to be at least 50 years and over 55% of patients in the UK are adults. Over these decades, our knowledge of the underlying pathophysiology has grown exponentially, from its original description in 1938 to the identification of the mutated gene (cystic fibrosis transmembrane conductance regulator, CFTR) in 1989. This has driven the development of effective therapies and brought about an increased understanding of the wide spectrum of diseases that result from abnormal CFTR function. During this time, the humble sweat test has remained at the heart of the diagnostic algorithm, with only modest changes from the original pilocarpine iontophoresis technique first described by Gibson and Cooke over half a century ago. Abnormal sweat electrolytes result from dysfunctional or absent CFTR protein in the epithelial cells of sweat glands. CFTR is widely distributed throughout the body and has many functions, such as encoding a cAMP-activated chloride channel and regulating transepithelial ion movementda phenomenon identified by the measurement of potential difference across the nasal mucosa and later used as the basis of the nasal potential difference (NPD) diagnostic test. 6 With the identification of the mutated gene and extensive knowledge of the associated basic defect, why is there still such a debate about the criteria for diagnosis and why do different diagnostic algorithms exist? When is CF atypical or non-classic and why introduce yet more termsd‘CFTR-related disorders’ and ‘CFTR-related metabolic syndrome’? Are these terms helpful or is this just overcomplicating matters? The study by Ooi et al is a valiant attempt at unravelling some of these issues by testing concordance between the two widely used algorithms of the American and European diagnostic guidelines for patients presenting with single-organ manifestations of disease. The traditional approach of ‘CF excluded’, if the sweat chloride is <60 mmol/l (or sodium <70 mmol/l), has been obsolete for many years and borne out by a greater understanding of the continuum of CFTR dysfunction and the tools available to measure it. Patients presenting in late childhood or adulthood initially gained attention in the 1980s as isolated case reports, but we now recognise an important cohort of patients who generally present late due to milder manifestations or single-organ involvement and, importantly, they are often pancreatic sufficient and therefore nutritionally replete. This is an important prognostic indicator as nutritional depletion from malabsorption is one of the strongest predictors of early presentation and more severe disease. When CFTR was first identified, it was thought that disease variability would be explained by different mutations, but the correlation of genotype with phenotype is generally poor, except for a few mutations that correlate with normal pancreatic exocrine function, for example, the R117H mutation. However, the situation is made more complicated by the poor correlation of lung function severity with genotype, as two individuals with the same genotype may have very different lung function. Putative mechanisms to explain this variability include influences from airway infections (eg, chronic infection with Pseudomonas aeruginosa), and nutritional and environmental influences. Single nucleotide polymorphisms outside of CFTR (‘gene modifiers’) are also probably important. For these reasons, it is unhelpful to use the term ‘mild’ CF, as patients presenting late are still susceptible to these factors and are at risk of similar morbidity and rate of decline later in life as patients with a classic CF genotype/phenotype. Given this risk, American guidelines have tried to steer away from subdividing CF into classic/nonclassic (or atypical/typical), whereas European guidelines still recognise these terms in the context of the diagnosis ‘CFTR dysfunction’, which also includes ‘CFTR-related disorders’. 14 The latter term has recently been defined by a joint European and American working group as ‘a clinical entity associated with CFTR dysfunction that does not fulfil the diagnostic criteria for CF’. Despite CF being a monogenetic disease, molecular (genetic) testing is not always definitive, as failure to identify two CFTR mutations does not rule out the diagnosis. Over 1900 mutations have been identified thus far and the number is continuing to rise. First-line genotyping identifies the most common alleles in a given population (usually 29e50 mutations, which account for 85e90% of mutations), and whole CFTR scanning can be performed but this is expensive, time consuming and, with a detection rate of approximately 95%, some patients will still be missed. This is complicated further by a limited understanding of the functional and clinical implications of very rare mutations and the impact of other genetic variations, such as single nucleotide polymorphisms. For this reason, after first-line genotyping, the American guidelines recommend only testing for the 23 mutations recognised as ‘disease-causing’ by the American College of Medical Genetics compared with the European guidelines, which recommend sequencing the whole gene and classifying patients according to the number of CFTR mutations identified. The latter approach will help us to better understand the relationship between phenotype, genotype and CFTR function, but, interestingly, in the study by Ooi et al, extended genotyping failed to improve the diagnostic yield by the American algorithm. An ambitious project is currently under way with the aim of fully categorising all CF mutations to enrich our understanding of the link between genotype and phenotype. Another important difference between the American and European guidelines is the thresholds for sweat chloride concentration. Both recognise that CF is very likely for a sweat chloride value >60 mmol/l, but the equivocal range is wider in the European algorithm (30e60 vs 40e60 mmol/l for patients older than 6 months)drecognition of a small but important cohort with low sweat chloride Department of Cystic Fibrosis, Royal Brompton Hospital, London, UK; National Heart and Lung Institute, Imperial College, London, UK