EPIDEMIOLOGY OF CYSTIC FIBROSIS

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1 EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MEDICAL COMPLICATIONS John Paul Clancy, MD* ABSTRACT Cystic fibrosis (CF) is the most common potentially lethal genetic disorder affecting the Caucasian population. It affects an estimated individuals within the United States; an additional 10 million are carriers of diseaseassociated mutations. Caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, CF is manifested by disruption of ion transport within epithelia primarily affecting chloride and sodium transport. As a result, there is dehydration and production of tenacious secretions in many affected organs, primarily the lungs, pancreas, intestines, and hepatobiliary tree. This pathologic process results in infection, inflammation, and obstruction of the airways as well as damage to vital structures within the gastrointestinal tract. In addition, male patients with CF are generally infertile. Due to progressive damage to the respiratory system coupled with chronic malnutrition that results from malabsorption, the mean survival for patients with cystic fibrosis in 2007 is 37 years, although advances in therapy are regularly increasing life expectancy. This article will discuss the genetic foundations and diagnosis of CF as well as significant pathophysiologic issues associated with CF, including male *Professor, Director, and Raymond K. Lyrene Chair in Pediatric Pulmonology, The Children s Hospital of Alabama and University of Alabama at Birmingham, Birmingham, Alabama. Address correspondence to: John Paul Clancy, MD, Professor, Director, and Raymond K. Lyrene Chair in Pediatric Pulmonology, The Children s Hospital of Alabama and University of Alabama at Birmingham, 620 ACC, th Avenue South, Birmingham, AL jpclancy@peds.uab.edu. infertility and the digestive and nutritional abnormalities that affect the majority of patients with CF. A second article in this monograph will focus on the pulmonary complications of cystic fibrosis. (Adv Stud Med. 2007;7(14): ) EPIDEMIOLOGY OF CYSTIC FIBROSIS Cystic fibrosis (CF) is the most common lifethreatening autosomal recessive disorder affecting Caucasians, affecting approximately 1 in 3200 live births in the United States. Its incidence in Hispanic, Asian, and African American populations is 1 in 9000, 1 in , and 1 in individuals, respectively. 1-4 All in all, more than individuals worldwide have CF (approximately 50% of whom are Americans), and it is estimated that 10 million are carriers of the disorder. 5,6 Data from the Cystic Fibrosis Foundation Patient Registry indicate that the mean life expectancy for people with CF today is 36.9 years a dramatic improvement from just 5 decades ago when the disease was first described, and patients were not expected to live past infancy. However, CF is still a significant cause of morbidity and mortality; it is a multisystem disease primarily affecting the respiratory tract, but also causing severe symptomatology in the gastrointestinal tract, reproductive organs, and occasionally the sweat glands. This review will discuss the genetic basis and pathogenesis of CF, its diagnosis, and digestive and other extrapulmonary issues. 432 Vol. 7, No. 14 December 2007

2 GENETIC FOUNDATIONS Defects in a single large gene located on chromosome 7 that encodes for a membrane localized traffic ATPase protein, called the cystic fibrosis transmembrane conductance regulator (CFTR), causes cystic fibrosis (Figure 1). Normally, the CFTR protein carries out transport functions, specifically serving as a regulated chloride channel, which in turn regulates other ion transport pathways, including non-cftr chloride channels, sodium, bicarbonate, ATP, and glutathione, among others The phenotypic expression of CF varies according to the specific mutations present, coupled with modifying genes, environmental factors, and treatment regimens. Although this protein contains 1480 amino acids, the vast majority of mutations involve 3 nucleotides or less that result in either amino acid deletions, substitutions, frameshifts, splice site, or nonsense mutations. 4 To date, more than 1500 mutations have been identified and reported to the CF Genetic Analysis Consortium ( and are divided into 6 classes based on the type and extent of dysfunction they cause. 11 Class I mutations result in defective protein biosynthesis, as demonstrated by premature stop codons in the CFTR gene and mrna transcript, resulting in severely reduced amounts of truncated and dysfunctional CFTR protein. Class II mutations cause misfolding of the protein and accelerated breakdown in the proteosome before it reaches its final destination in the cell. Class III mutations generally affect the nuclear binding domains, resulting in diminished chloride channel activation due to abnormalities in ATP binding and hydrolysis. Class IV mutations do not involve abnormal protein production or location, but rather defective chloride conductance, whereas class V mutations involve reduced amounts of normal CFTR protein. Class VI mutations are characterized by reduced levels of surface CFTR due to abnormal recycling at the cell membrane (Figure 2). 4 Most of the 1500 mutations are extremely rare. The most common mutation involves a 3-base pair deletion that codes for phenylalanine at position 508 of the CFTR protein; hence, this is known as the F508 mutation and accounts for 70% of all cases of CF in Caucasians. 11 Defective epithelial cell ion transport results in a myriad of defects that are thought to result in the complex pathology observed in CF. Additionally, the absence of CFTR influences other gene products, Figure 1. Hypothesized Structure of CFTR Extracellular Membranespanning domain 1 ΔF508 Intracellular Nucleotidebinding domain 1 The protein contains 1480 amino acids and a number of discrete globular and transmembrane domains. Activation of CFTR relies on phosphorylation, particularly through protein kinase A but probably involving other kinases as well. Channel activity is governed by the 2 nucleotide-binding domains, which regulate channel gating. The carboxyl terminal (consisting of threonine, arginine, and leucine [TRL]) of CFTR is anchored through a PDZ-type binding interaction with the cytoskeleton and is kept in close approximation (dashed arrows) to a number of important proteins. These associated proteins influence CFTR functions, including conductance, regulation of other channels, signal transduction, and localization at the apical plasma membrane. Each membrane-spanning domain contains 6 membrane-spanning alpha helixes, portions of which form a chloride-conductance pore. The regulatory domain is a site of protein kinase A phosphorylation. The common F508 mutation occurs on the surface of nucleotide-binding domain 1. CFTR = cystic fibrosis transmembrane conductance regulator. Reprinted with permission from Rowe et al. N Engl J Med. 2005;352: such as proteins that play an important role in the inflammatory response, transport of ions other than chloride, and cell signaling. 12 PATHOGENESIS Regulatory domain (phosphorylation site) Other ion channels Membranespanning domain 2 Signaltransduction proteins Apical plasma membrane Nucleotidebinding domain 2 TRL Cytoskeleton The exocrine glands are primarily affected in CF, including the sweat glands, various digestive glands, and surface epithelial cells and submucosal glands in the lung. Although still not completely understood, it has historically been believed that early infection with bacteria, including Staphylococcus aureus and Haemophilus influenzae, set off a series of events in the airways resulting in chronic infection and inflammation that is later propagated by more opportunistic Johns Hopkins Advanced Studies in Medicine 433

3 Figure 2. Categories of CFTR Mutations increased levels of arachidonic acid and decreased levels of docohexanoic acid in CF-affected tissues. This may also play a role in the pro-inflammatory response seen in patients with CF. These pathophysiologic changes result in a variety of clinical manifestations that are associated with and/or diagnostic of CF. CLINICAL FEATURES AND DIAGNOSIS OF CYSTIC FIBROSIS d. Classes of defects in the CFTR gene include the absence of synthesis (class I); defective protein maturation and premature degradation (class II); disordered regulation, such as diminished ATP binding and hydrolysis (class III); defective chloride conductance or channel grating (class IV); a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V); and accelerated turnover from the cell surface (class VI). CFTR = cystic fibrosis transmembrane conductance regulator. Reprinted with permission from Rowe et al. N Engl J Med. 2005;352: organisms, such as Pseudomonas aeruginosa. More recent data suggest that P aeruginosa may be present in the lower airways of children with CF in advance of these organisms, and that recurrent viral infections may play a role in subsequent chronic lower airway bacterial infection. On the airway surface, there is depletion of airway surface liquid, dehydration of airway secretions, and ineffective mucociliary clearance producing airway obstruction that leads to severe and progressive damage, including bronchiectasis, respiratory failure, and death. Infection triggers an inappropriately robust and persistent inflammatory response, including excessive pulmonary chemotaxis of neutrophils that release signaling and inflammatory small molecules such as interleukin-8, tumor necrosis factorα, and elastase that damage cells and their support structures and thicken secretions. Ultimately, these processes result in mucus plugging of the airways, bronchial dilation, and saccular bronchiectasis. In addition, defects in the CFTR gene produce abnormalities of fatty acid metabolism, which result in The lungs are commonly and severely compromised in CF. Respiratory involvement is manifested by a chronic productive cough, tachypnea and dyspnea, abnormal pulmonary function tests consistent with obstructive lung disease, and changes on chest X ray, including evidence of hyperinflation of the lungs and mucus plugging. As the disease progresses, digital clubbing is often observed along with bronchiectasis, and patients with advanced disease frequently demonstrate signs of chronic debilitation, including weight loss and cachexia. Other structures of the respiratory tract may be adversely affected by CF, including development of nasal polyps and chronic sinusitis in the upper airways. 13,14 Pathognomonic of CF is chronic colonization of the airways by bacteria, especially P aeruginosa, which seems uniquely capable of adapting to the airway environment established as a result of CFTR mutations. The bacteria can grow in a planktonic state, or adapt to the CF lung by growing in a mucoid state (characterized by extracellular alginate production) and/or a biofilm state. Both of these growth states are highly resistant to antibiotics, and are thought to represent forms of growth that cannot be eradicated by current therapies. Pancreatic insufficiency is also present in the majority of patients with CF. Absence of digestive enzymes cause fat and protein malabsorption with a clinical presentation of steatorrhea and sometimes hypoproteinemia and associated edema. Because of this pancreatic dysfunction, infants with CF often are diagnosed with failure to thrive. Patients with CF with pancreatic disease may also suffer from various defects in glucose metabolism. Many patients with exocrine pancreas deficiency have decreased insulin secretion and develop impaired glucose tolerance or diabetes, but some do not develop diabetes because of increased hepatic glucose production and increased peripheral glucose utilization. The mechanisms by which this occurs are not well understood. 15 Glucose regulation is further complicated by the inflammatory phenotype exhibited by patients with CF, which 434 Vol. 7, No. 14 December 2007

4 is postulated to contribute to insulin resistance. Thus, the diabetic picture in CF can be quite mixed, and represents a unique challenge to optimize care. Other digestive disorders commonly found in patients with CF include meconium ileus, which is part of diagnostic presentation in 10% to 20% of newborns with CF. This process results from the lack of lumenal pancreatic enzymes and hydration, causing an inability of the newborn to process/pass fetal meconium. Small bowel obstruction can also be seen in older children and adults, and is termed distal ileal obstructive syndrome (DIOS). 16 Biliary disease is common in CF, but clinical manifestations are seen in only a small percentage of patients. Finally, male infertility, and less commonly, female infertility (generally due to secondary amenorrhea related to nutritional status) are also commonly seen CF. DIAGNOSTIC WORKUP According to the most recent data available from the Cystic Fibrosis Patient Registry, approximately 1000 cases of CF are diagnosed annually, with more than 70% of patients being diagnosed by age 2 years. 6 The majority of patients (43.8%) present with respiratory signs and symptoms, although other early clinical manifestations include failure to thrive (29.3%), steatorrhea (24.4%), and meconium ileus (18.5%). 6 Newborn screening and genetic testing programs currently identify a small percentage of patients (9.1% and 3.9%, respectively), 6 but as these programs become more widespread, they will afford the opportunity to identify affected individuals even before clinical symptoms develop. Currently, however, the diagnosis is often based on clinical findings. The Cystic Fibrosis Foundation (CFF) has developed guidelines for establishing the diagnosis based upon clinical features, including chronic sinopulmonary disease, endobronchial disease, gastrointestinal and/or nutritional abnormalities, obstructive azoospermia, and salt-loss syndromes (Table 1). 4,17,18 In addition to clinical findings and/or family history, the key diagnostic test for CF remains a positive sweat test persistently elevated concentrations of electrolytes (sodium and chloride) in sweat. 17 At times, diagnosis can be elusive or confusing, such as when patients have a negative sweat test associated with clinical symptoms consistent with CF, as well as abnormal CFTR genotyping. 17 It has also been appreciated that there are many patients with atypical disease, many of which present late in childhood or as adults and are generally less severely affected than those diagnosed in the first 1 to 2 years of life. Thus, CFF criteria for diagnosis encompass several possible scenarios, including 1 or more clinical features consistent with CF, a positive newborn screening test, or a first-degree relative with CF. 18 In addition, individuals must meet 1 or more of the fol- Table 1. Clinical Features Consistent with the Diagnosis of Cystic Fibrosis Chronic Sinopulmonary Disease Persistent colonization/infection with pathogens typical of lung disease, including: Staphylococcus aureus Pseudomonas aeruginosa (mucoid and nonmucoid) Nontypable Haemophilus influenzae Burkholderia cepacia Endobronchial disease manifested by: Cough and sputum production Wheeze and air trapping Radiographic abnormalities Evidence of obstrction on PFTs Digital clubbing Chronic sinus disease: Nasal polyps Radiographic changes Gastrointestinal/nutritional abnormalities Intestinal abnormalities: Meconium ileus Exocrine pancreatic insufficiency DIOS Rectal prolapse Recurrent pancreatitis Chronic hepatobiliary disease manifested by clinical and/or laboratory evidence of: Focal biliary cirrhosis Multilobular cirrhosis Failure to thrive (protein-calorie malnutrition) Hypoproteinemia-edema Fat-soluble vitamin deficiencies Obstructive azoospermia in males Salt-loss syndromes Acute salt depletion Chronic metabolic alkalosis CF = cystic fibrosis; DIOS = distal intestinal obstruction syndrome; PFTs = pulmonary function tests. Adapted with permission from Cystic Fibrosis Foundation Clinical Practice Guidelines Available at: Accessed July 24, Reprinted from Gibson et al. Am J Respir Crit Care Med. 2003;168: Johns Hopkins Advanced Studies in Medicine 435

5 lowing criteria: 2 positive sweat tests, 2 CF-causing gene mutations, or an abnormal nasal transepithelial potential difference test (Table 2). 18 SWEAT TESTING Determining the sweat chloride concentration remains the gold standard screening test for CF. The test was developed in the 1950s, and is performed by using electrical or pharmacologic stimulation (pilocarpine iontophoresis) to produce sweat from the sweat glands. The fluid is collected and measured for electrolytes most notably chloride content. Chloride values greater than 60 meq/l confirm the diagnosis given a suggestive clinical picture and/or a positive family history. It is estimated that less than 1 in 1000 patients with CF will have a sweat chloride less than 50 meq/l. False-negative tests can occur in infants due to an inability to collect adequate quantities of sweat, or due to the presence of edema, hypoproteinemia, or use of medications (eg, steroids) that may affect results. 19 To avoid misdiagnosis, it is important to conduct the test in laboratories experienced with the test and perform diagnostic sweat testing according to CFF guidelines. 20 A small number of patients may have a mixed picture, such as respiratory disease but normal pancreatic function, and intermediate values of sweat chloride ranging from 40 to 60 meq/l. Infants with CF diagnosed by newborn screening may also have lower sweat chloride values, some of which are within the high normal range. Other conditions can cause moderately elevated sweat electrolytes, but generally do not resemble CF clinically. 17 Conversely, approximately 1% of patients with rare types of CF may have normal sweat chloride levels. 21 GENETIC TESTING Although it is an important part of the diagnostic workup, genotyping information needs to be combined with additional information (clinical symptoms and functional evidence of CFTR dysfunction) to make the diagnosis of CF. At least 1500 CFTR mutations associated with cystic fibrosis have been described. 11 Since new mutations that cause CF continue to be identified, there are not commercially available tests for all possible disease-causing mutations. Most diagnostic laboratories in the United States screen for 20 to 30 of the most common mutations, and these include approximately 90% of CF-causing chromosomes, particularly in the Caucasian population. Other ethnicities can have a different mutation prevalence, thus combining ethnic information with genetic testing can help to lead to screens that are more appropriate for different populations. 17 However, failure to find 2 abnormal genes does not rule out the disease because in approximately 1% of those with CF no abnormal gene can be found, and in approximately 18% only 1 abnormal gene will be identified. 17 Thus, CF cannot be diagnosed unless there is a characteristic clinical manifestation, functional evidence of CFTR dysfunction, and/or a family history. The combination of 2 CF mutations plus an abnormal concentration of sweat electrolytes is generally accepted as diagnostic. 17 NEWBORN SCREENING Before 8 weeks of age, most infants with CF have elevated serum levels of immunoreactive trypsin. This may be detected from blood specimens subjected to radioimmunoassay or enzyme-linked immunoassay, and is approximately 95% accurate during the neonatal period Although multiple studies support the rationale that early detection of CF and subsequent early intervention will lead to improved outcomes for these children, currently only 37 states in the United States have statewide testing programs planned or in place. 25,26 NASAL POTENTIAL DIFFERENCE MEASUREMENTS Nasal transepithelial potential difference measurements can reveal abnormalities in epithelial sodium and chloride transport present in most patients with CF. However, this is a sophisticated test that must be performed in specialized centers, and results are subject to confounding variables, such as the presence of nasal polyps or upper respiratory tract infections. A comparison is made between the voltage difference measured in Table 2. Criteria for Diagnosis of Cystic Fibrosis One or more clinical features consistent with cystic fibrosis, positive newborn screening test, or first-degree relative with cystic fibrosis PLUS 1 or more of the following: Two positive sweat tests by pilocarpine iontophoresis Two cystic fibrosis-causing gene mutations Abnormal nasal transepithelial potential difference Reprinted with permission from Cystic Fibrosis Foundation Clinical Practice Guidelines Available at: Accessed July 24, Vol. 7, No. 14 December 2007

6 the subcutaneous space (eg, a site in the forearm) and the lining nasal mucosa under the inferior turbinate. The baseline voltage measured (normal mean [±SE], ± 0.9 mv; CF mean [±SE], -53 ± 1.8 mv) is produced by the absorption of sodium across the nasal mucosa a physiologic function that is abnormally elevated in the presence of mutated CFTR. 27 The change in the nasal potential difference value following perfusion with amiloride (that blocks sodium transport), chloride-free solution, and isoproterenol quantifies CFTR-dependent Chloride secretion, and may demonstrate abnormal CFTR function more reliably than the sweat test. 17 ADDITIONAL TESTING Urologic testing that reveals obstructive azoospermia constitutes additional evidence of organ dysfunction, as does evidence of significant sinusitis on sinus imaging. In the gastrointestinal tract, signs and symptoms of malabsorption that responds to treatment with pancreatic enzyme replacement and/or low levels of pancreatic enzyme or bicarbonate production are also strong evidence of CF-related exocrine gland dysfunction. Bronchoalveolar lavage demonstrating a high percentage of neutrophils (up to 90%) and thus excessive inflammation is a common marker of CF in infants; however, this is an invasive and generally unnecessary test for diagnostic screening purposes. Its use may be reserved for atypical presentations. The presence of P aeruginosa in respiratory secretions or serum levels of immunoglobulin G antibodies against this organism even in the presence of negative cultures may also aid in the diagnosis of CF, but current testing is not completely standardized. 17 DIGESTIVE AND NUTRITIONAL ISSUES Although often considered a pulmonary disease, the impaired chloride transport caused by CFTR gene mutations also lead to the production of abnormally thick mucus and other abnormal secretions in the gastrointestinal tract that, in turn, contributes to obstruction and pathology in the intestines, pancreas, and hepatobiliary tree. Patients with CF can suffer from a variety of digestive and nutritional dysfunctions, including meconium ileus and its adult form (ie, DIOS), rectal prolapse, constipation, intussusception, and a high incidence of gastroesophageal reflux disease relative to the general population. However, pancreatic insufficiency is the most common gastrointestinal-related complication, affecting approximately 85% of patients with CF. 28 PANCREATIC INSUFFICIENCY Defects in sodium, chloride, and bicarbonate transport impair water diffusion from the lining epithelia into the mucous layer of the pancreatic duct lumen, producing tenacious epithelial secretions and proteinrich viscous exocrine fluid that blocks the pancreatic ducts. Subsequently, there is insufficient secretion of pancreatic enzymes into the gut and resultant malabsorption of fat, fat-soluble vitamins (A, D, E, and K), protein, and other nutrients. Patients with CF have low or absent levels of pancreatic amylase, lipase, colipase, and phospholipases. They also have decreased amounts of bicarbonate necessary to neutralize the acidic environment of the digestive tract, thus further compromising pancreatic enzyme functioning and proper digestion. 28 This is manifested by clinical symptoms such as steatorrhea (bulky, foul-smelling, oily stools that may float), edema, failure to thrive, vitamin deficiencies, and malnutrition. Pancreatic insufficiency and its associated fat and protein malabsorption is present to varying degrees of severity in patients with CF, and must be monitored closely with adjustment of treatment regimens accordingly. Both direct and indirect tests can be used to diagnose and monitor pancreatic insufficiency. Direct tests are invasive and expensive, although more accurate. The pancreas is stimulated with a secretagogue, such as secretin, and then duodenal fluid is collected and measured for bicarbonate concentration (<80 meq/l is consistent with pancreatic exocrine insufficiency). 29 Indirect tests measure concentrations of pancreatic enzymes in stool, and include measurement of 72-hour fecal fat excretion (>7% stool detection of fat intake is abnormal) or fecal elastase testing (<100 or <200 µg/g stool). Fecal elastase testing is considered by some experts to be the most clinically useful test because it correlates well with indirect testing, requires only a single stool sample, and requires no special storage. 29,30 Treatment of pancreatic insufficiency is primarily pancreatic enzyme replacement, and this is a key component to overall nutritional management for patients with CF who also require fat-soluble vitamin replacement and general caloric supplementation via oral, tube, or parenteral routes as needed. This general malnutrition is brought about by the energy demands of chronic lung infection and inflammation combined with nutrient malabsorption. Although discussion is beyond the scope of this article, it is important to note that damage to the pancreas can result in chronic pan- Johns Hopkins Advanced Studies in Medicine 437

7 creatitis, and that many older patients with CF also develop endocrine pancreatic insufficiency with cystic fibrosis-related diabetes (CFRD) or glucose intolerance. This insulin deficiency complicates nutritional management, and is frequently treated with subcutaneous insulin preparations and/or oral hypoglycemics. HEPATOBILIARY SYSTEM ABNORMALITIES Similar to other secretions produced by patients with CF, bile is thick, tenacious, and capable of obstructing the intrahepatic bile ducts because of dysfunctional CFTR in epithelial cells lining the biliary ductules. The absence of CFTR activity leads to reduced ion and passive water transport with subsequent reduced biliary hydration. If there is extensive plugging of the ductules, patients can develop obstructive cirrhosis, which may also be related to the release of pro-inflammatory substances. They may have steatosis or fatty liver as a result of multiple etiologies beginning with the genetic defect itself and its consequences, including malnutrition and fatty acid deficiency. Patients with CF also may have altered secretion of mucins, which may contribute to cholelithiasis. Gallstones are more common in this population, affecting approximately 12% of patients. 31 The most common hepatobiliary presentations for CF include asymptomatic elevations of liver function tests and hepatomegaly; however, advanced liver disease occurs in 2% to 5% of patients with CF and may result in portal hypertension, nutritional deficiencies, and overt liver failure. 32 Diagnostic testing for CF-related liver disease is similar to that conducted for other forms of hepatic disease, and includes monitoring of liver function enzymes and routine complete blood counts, chemistry profiles, and clotting studies (particularly prothrombin time, which can be reflective of vitamin K deficiency or reduced liver synthetic function). Abdominal ultrasound is also helpful in visualizing the liver. Other tests should be considered based upon clinical signs and symptoms to evaluate possible portal hypertension, esophageal varices, or cholecystitis/cholelithiasis. Treatment for liver disease is focused upon nutrition, such as reversing vitamin deficiencies. In addition, some studies have noted that administration of ursodeoxycholic acid may slow the progression of CF-related liver disease by replacing toxic bile acids with this nontoxic acid and increasing bicarbonate secretion, but its effects have not been confirmed definitively. 32,33 Sclerotherapy may be indicated for treatment of esophageal varices. Liver transplantation is a treatment of last resort for patients with CF with end-stage liver failure; however, severe liver disease only affects 1% to 2% of patients. 32,34 MALE INFERTILITY More than 95% of men with CF are capable of producing sperm, but are infertile due to a CFTR mutationrelated congenital bilateral absence of the vas deferens (CBAVD) that renders them unable to transport sperm appropriately. As a result of this defect, no spermatozoa are present in semen, a condition known as obstructive azoospermia. 35 This condition cannot be corrected surgically; however, individuals with CBAVD can reproduce with the assistance of modern technology via several procedures. These include surgical collection techniques (microsurgical epididymal sperm aspiration, percutaneous epididymal sperm aspiration, and testicular sperm extraction) combined with intracytoplasmic sperm injection to assist in fertilization of the oocyte via in vitro fertilization. 36 Because the prospects of achieving biological fatherhood through these procedures are promising, it is important for men with CF who desire biologic parenthood to understand the increased risk of having children who will also have CF (and will be obligate carriers of CFTR mutations), and that families should undergo extensive genetic counseling. CONCLUSIONS Cystic fibrosis remains a significant cause of morbidity and mortality for individuals of all backgrounds worldwide. However, with identification of the CFTR gene in 1989 and ever advancing insights into the underlying mechanisms of disease in CF, scientists and clinicians have been able to increase the life expectancy of individuals with CF well into adulthood. It is projected that by 2010, most patients living with CF will be older than age 18 years. 37 As a result, other facets of disease (such as hepatobiliary disease and CFRD) are becoming more appreciated, and management of many of these secondary clinical manifestations is becoming more important to survival. In addition, it is now possible for more men with CF to become fathers, highlighting the need for genetic testing and counseling and increasing awareness of the expected outcomes for individuals with CF a clinical picture that continues to improve. 438 Vol. 7, No. 14 December 2007

8 As we continue to search for answers and gain a better understanding of the basic pathophysiology and genetics underlying CF, scientists continue to look for new approaches to treatment based on this pathophysiology, but also based upon correcting the genetic defect and/or the resultant ion transport defects some of which will be discussed in the article that follows. 37 In addition, systematic refinement of current care at CF care center, including newborn screening, early institution of pancreatic enzyme supplementation and other nutritional therapies, aggressive treatment of CF pulmonary pathogens and decline in lung function, management of emerging CF complications such as CFRD and liver disease, and offering advanced surgical techniques such as assisted reproduction coupled with patient and family genetic education remain the best mechanisms for improving the care and quality of life of patients today. REFERENCES 1. Hamosh A, FitzSimmons SC, Macek M Jr, et al. 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