© 2004 American Thoracic Society
Cystic Fibrosis Patients, Infertile Men, and Their NosesCystic Fibrosis Center, Azienda Ospedaliera Verona Department of Pediatrics University of Verona Verona, Italy Cystic fibrosis (CF) is an inherited disease caused by mutations in a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR), which codes for a protein that acts as a chloride channel in different cell types (1). The ion transport abnormalities due to deficient CFTR function give rise to a multiorgan disease, which, in its full-blown expression, presents with progressively severe respiratory impairment, pancreatic insufficiency, liver disease, and other complications including obstructive azoospermia in men. The spectrum of disease is broad, and mild "atypical" forms affecting just a single organ can be diagnosed in adulthood. One example is obstructive azoospermia caused by congenital bilateral absence of the vas deferens. In the current issue of the Journal (pp. 174–179). Gilljam and coworkers (2) describe patients who present with the same type of infertility as do patients with CF; some patients also had elevated sweat electrolytes and two CF-causing mutations or abnormal nasal potential difference could also be documented. According to the recent consensus statement on diagnosis, these patients should be considered as having CF (3). Making a diagnosis of CF, a severe disease, in patients with congenital bilateral absence of the vas deferens, a supposedly benign condition, prompts a number of questions. How different are such patients from the "classic" form of CF? Will these patients ever develop classic CF complications later in life? What is their long-term prognosis? How should we handle genetic counseling in subjects bearing the CFTR gene mutations, which is usually detected in patients with congenital bilateral absence of the vas deferens? What is the psychological and social impact of a diagnosis of CF in patients who present without CF complications other than male infertility? These questions will probably be answered in the next few years if long-term studies are conducted in large numbers of subjects with congenital bilateral absence of the vas deferens. Meanwhile, a number of considerations are in order. First, there is an increasing awareness that a number of patients with congenital bilateral absence of the vas deferens also display features of mild respiratory disease when carefully examined by clinicians with expertise in CF (4–6). Patients should undergo a thorough evaluation in a CF center that has substantial experience in unusual forms of CF. Second, even in patients who are apparently free of clinical respiratory symptoms, subclinical pulmonary infection and inflammation may occur. This observation is well described in the paper by Gilljam and coworkers (2). Bronchoalveolar lavage samples revealed the presence of pathogens and inflammatory mediators in the lower airways of subjects with congenital bilateral absence of the vas deferens who presented with laboratory evidence of mild CF (2). These findings are similar to observations in infants with CF diagnosed by neonatal screening (babies that will eventually develop classic CF) (7, 8). Can we be confident that patients with congenital bilateral absence of the vas deferens who harbor gram-negative bacteria in their lower airways will maintain a good clinical status for many years?
Third, how can we handle the genotype of these well characterized subjects with congenital bilateral absence of the vas deferens who present with clinical features of mild CF? For most patients with congenital bilateral absence of the vas deferens, including those in the study by Gilljam and coworkers (2), the detection of mutations, such as R117H, which may be associated with a broad phenotype, does not help in characterizing the disease. It should be noted that asymptomatic newborn babies that are compound heterozygotes for What else should we consider in patients with congenital bilateral absence of the vas deferens so as to detect possible clinical or laboratory prognostic factors? Maybe their noses! Measurement of nasal potential difference is the only practical way to assess CFTR function in the airways in vivo. It is used both for diagnosis and for research purposes (10, 11). When measuring nasal potential difference, the nasal mucosa is perfused with different ion channel blockers and activators, so as to identify the typical defect of CF airway (reduced chloride conductance and increased sodium permeability), and possibly correct it by experimental treatments, such as gene therapy. The detection of a residual chloride secretion in the airways of some patients could explain the mild involvement of their respiratory status. Gilljam and coworkers (2) measured nasal potential difference for the purposes of evaluating CFTR function in their patients with congenital bilateral absence of the vas deferens as a diagnostic aid. Some patients had residual partial chloride secretion, so that a partial function of CFTR may be postulated. This observation, however, needs to be further explored because previous studies have yielded conflicting results: reduced chloride secretion in some cases, and no such secretion in others (12, 13). Because it is still an open issue as to whether residual chloride secretion is common or not in congenital bilateral absence of the vas deferens, how should we interpret the data on nasal potential difference? How much change in nasal potential difference in response to chloride stimulation is significant when determining the benign nature of this condition? The interpretation of results of nasal potential difference is still a matter of debate, particularly in studies aimed at correcting the basic defect of CF, as in gene therapy. In these studies the identification of a small response to chloride stimulation after treatment is considered a major success, although different authors provide different interpretations for similar findings (14, 15). The importance of measuring nasal potential difference more extensively in subjects with congenital bilateral absence of the vas deferens carries at least two major implications. One, the relationship between nasal potential difference and phenotype could help us to achieve a better understanding of the broad spectrum of CF and CFTR-related disorders. Two, defining the exact value of measuring nasal potential difference could be particularly useful in designing research protocols. FOOTNOTES Conflict of Interest Statement: U.P. and G.L.P. have no declared conflict of interest. REFERENCES
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F508 (the main severe mutation in CF patients) and R117H are followed on a regular basis in CF clinics to monitor their clinical status properly (