Cystic Fibrosis

After completing this article, readers should be able to:Cystic fibrosis (CF), among the most common of life-shortening genetic diseases, is characterized by chronic, progressive obstructive lung disease along with other systemic manifestations, such as nutrient malabsorption and malnutrition due to pancreatic insufficiency, liver disease and cirrhosis, and CF-related diabetes mellitus (CFRD). Median survival has improved steadily from less than 2 years (1)(2) at the time of the initial description of the disease in 1938 (3) to 41.1 years currently. (4) This improvement in survival largely results from early diagnosis and implementation of therapies to optimize lung health and nutritional status, treat chronic respiratory infection, and improve quality of life. Although there is currently no cure for CF, newer therapies target the basic genetic defect and hold significant promise for continued improvement in overall health and survival. Because the role of the primary care physician is vital to the well-being of children with CF, this review covers the clinical presentation, diagnosis, and current management of CF and some of the common disease-related concerns and complications.On the basis of 2012 statistics from the Cystic Fibrosis Foundation, there are approximately 30,000 affected individuals in North America, with a predicted median survival of 41.1 years, and 49.1% are adults 18 years or older. (4) Approximately 1000 new cases are diagnosed annually; 70% of affected children are diagnosed by age 2 years, largely as a result of newborn screening, which was implemented in all 50 states by 2010. The incidence varies by race and ethnicity and is estimated to be 1:3200 in whites, (5) 1:15,000 in people of African descent, 1:35,000 in people of Asian descent, and 1:9200 to 1:13,500 in Hispanics. (6) Early disease diagnosis, treatment of chronic infection and malnutrition, and other interventions, such as lung transplantation for end-stage lung disease, have had a significant effect on survival during the past 40 years.The disease results from genetic mutations located on chromosome 7q31.2, which codes for a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR), which functions as an apical epithelial chloride channel. To date, more than 1900 mutations have been identified and categorized into 6 distinct classes that reflect abnormalities of CFTR synthesis, structure, and function (7)(8) (Figure 1). Class I mutations result in no functional CFTR protein being produced because of absent or defective protein biosynthesis. Class II mutations lead to protein variants that are improperly processed or transported to the apical cell membrane. For example, the most common and best characterized CFTR mutation, F508del, is a class II mutation. One copy of F508del is present in 70% of the affected population, and 2 copies are present in approximately 50%. Class III mutations affect CFTR activation and hinder chloride movement through channels at the cell surface. For example, G551D is a class III gating mutation targeted by the medication ivacaftor, which improves chloride conductance in individuals with CF with at least one copy of this mutation. Class IV mutations result in defects that produce a normal or diminished amount of CFTR with decreased function at the apical epithelial cell membrane. Class V mutations result from decreased amounts of fully active CFTR. A sixth mutation class is characterized by diminished stability of a fully processed and functional CFTR at the cell surface and often results in the truncation of CFTR toward the carboxyl terminus. (9)The disease results from 2 CFTR mutations; however, they need not be from the same class. The amount of functional CFTR present at the cell surface, which is determined by genotype, partially accounts for the wide spectrum of CF phenotypes and, to some extent, correlates with the degree of organ involvement and disease severity. Class I, II, and III mutations are typically associated with early involvement of respiratory and digestive manifestations (ie, chronic cough, recurrent sinopulmonary infections, and exocrine pancreatic insufficiency). Class IV and V mutations are generally associated with milder or later-onset lung disease and exocrine pancreatic sufficiency.Diminished or absent chloride channel function results in dehydrated, viscid secretions that contribute to organ dysfunction (Figure 2). In the lungs, mucous plugging leads to inflammation, chronic infection, progressive small airways obstruction, and bronchiectasis. In the exocrine pancreas, intestinal tract, and liver, inspissation of viscid secretions leads to pancreatic insufficiency and results in the malabsorption of fat and protein, intestinal obstruction, and cholestasis. Other clinical manifestations include chronic pansinusitis, nasal polyposis, and reduced fertility. In the sweat gland, abnormal chloride channel function results in excessive salt loss in sweat and forms the basis of the gold standard pilocarpine iontophoresis sweat test for CF diagnosis. (10)In 2008, a Cystic Fibrosis Foundation Consensus Panel established diagnostic criteria (11) that include the following: (1) the presence of one or more characteristic phenotypic features of chronic, recurrent sinopulmonary disease, nutritional and gastrointestinal abnormalities, male urogenital abnormalities (eg, absence of vas deferens), and salt depletion syndromes; (2) a family history of CF in a sibling; and (3) a positive newborn screening test result associated with laboratory-demonstrated evidence of CFTR dysfunction, such as elevation of sweat chloride concentration, identification of 2 disease-causing CFTR mutations, or demonstration in vivo of characteristic ion transport abnormalities across the nasal epithelium. Approximately 2% of cases are known as nonclassic, (12)(13) in which the genotype-CFTR functionality-phenotype correlations are less clear-cut and result in wide disease variability, which in turn is exaggerated further by the large number of identified mutations. A more appropriate diagnostic term for these individuals is CFTR-related disorder. Although the diagnosis of these cases can be challenging, the established diagnostic criteria should be used.The gold standard for diagnosis of CF remains the pilocarpine iontophoresis sweat test developed by Gibson and Cooke in 1959, (10) which measures the chloride concentration in sweat that is typically elevated in those with CF. To maintain quality control, testing must be performed by experienced personnel using standardized methods in accredited laboratories. Normal sweat chloride values are age dependent, but a chloride concentration ≥60 mEq/L (60 mmol/L) is indicative of CF in individuals of all ages (Table). Additional sweat testing or genetic testing should be performed to confirm abnormal sweat chloride test results.Genetic analysis is often helpful to confirm diagnosis, particularly for cases that present with indeterminate sweat chloride measurements. The genotypic criteria for diagnosis (11) include identification of 2 disease-causing mutations on distinct chromosomes. CFTR mutations should meet at least one of the following conditions: (1) alteration of the CFTR sequence with the result of affecting protein structure and/or function; (2) introduction of a premature stop codon, such as with an insertion, deletion, or nonsense mutation; (3) alteration of intron splice sites; and (4) creation of a novel amino acid sequence that does not occur in the normal CFTR genes of the affected individual’s ethnic group. Commercial laboratories test for the most common CFTR mutations (often referred to as CF carrier testing), which will identify most individuals with CF. Complete sequencing of the CFTR gene is also available and can be helpful for confirming diagnosis of clinically atypical cases. Information about the clinical features associated with individual CFTR mutations can be found in the CFTR2 database sponsored by the Cystic Fibrosis Foundation (www.cftr2.org).Nasal potential difference measurements can be beneficial in establishing a CF diagnosis, especially in clinically atypical cases. (14)(15)(16) However, this test is not considered to be a standard diagnostic method and is only performed at a limited number of CF centers. Cystic fibrosis is caused by abnormalities in salt transport that result from a defective CFTR protein, which is a chloride channel that regulates the salt content in the fluid that covers the surface of the nasal passages and airways. Transport of ions, such as sodium and chloride, creates an electrical potential difference across the airway lining. This potential difference can be measured by placing an electrode on the lining of the nose. Because individuals with CF do not have normal CFTR function, the epithelial nasal potential difference responds differentially to administration of the various salt solutions to the nasal epithelium.Newborn screening was pioneered in the United States in the 1980s and by 2010 was implemented in all 50 states. (17) The benefits of newborn screening include early diagnosis, slowing of lung disease progression, prevention of malnutrition, and provision of psychosocial and extended medical support, such as genetic counseling, for individuals with CF and their families. Potential risks of newborn screening include increased medical interventions and increased risk for complications (ie, early treatment of bacterial infection, leading to antimicrobial resistance), earlier exposure to pathogenic bacteria, financial considerations given the high costs of therapies, and psychosocial repercussions stemming from false-positive screening results. (18)Newborn screening for CF is performed by measuring the amount of immunoreactive trypsinogen (IRT) in the newborn blood spots typically obtained by heelstick. State laboratories either perform 2 IRT measurements (IRT/IRT) or perform CFTR mutation testing (IRT/DNA) if the IRT level is elevated. Positive screening results indicate that IRT levels remain persistently elevated by the time the neonate is ages 7 to 14 days or that at least one CFTR mutation has been identified. This result will trigger notification of the primary care physician and the infant’s family. At this point, the infant should be referred to an accredited facility for definitive evaluation with a sweat test. A normal sweat chloride result (<30 mEq/L [<30 mmol/L]) means that CF is unlikely. An elevated (≥60 mEq/L [≥60 mmol/L]) sweat chloride measurement confirms the diagnosis, leading to further diagnostic measures (ie, genetic analysis to identify one or both CFTR mutations, depending on the type of newborn screen performed) and clinical assessment at a CF center accredited by the Cystic Fibrosis Foundation. Indeterminate sweat chloride levels (30–59 mEq/L [30–50 mmol/L]) require further genetic analysis and clinical assessment. With the current practices for newborn screening, the possibility exists for identification of a CFTR abnormality at birth that does not immediately produce clinical manifestations, a syndrome known as CFTR-related metabolic syndrome. (19)(20) It is also important to remember that newborn screening for CF can have false-negative results as well, especially in infants with meconium ileus. Therefore, sweat testing should be performed if there is a clinical suspicion of CF regardless of the individual’s age, even if he or she had a normal newborn screen result.The present diagnostic methods take into account the wide clinical spectrum of disease and permit diagnosis of milder cases earlier in life. Early diagnosis has been found to have a profound effect on preventing lung disease progression and optimizing nutrition, which have had significant effects on survival and quality of life.The clinical diagnosis of CF in most individuals not detected by newborn screening is based on a triad of (1) recurrent sinopulmonary infections, (2) steatorrhea, and (3) failure to thrive. Exocrine pancreatic insufficiency is present in 85% of affected individuals. In infancy and early childhood, particular manifestations are strongly suggestive of a CF diagnosis. For example, the prenatal ultrasonographic finding of hyperechoic bowel is suggestive of intestinal obstruction; CF is present in approximately 10% of fetuses with this finding. Delayed meconium passage, meconium plug syndrome, or meconium ileus are present in approximately 15% to 20% of neonates with CF and result from abnormal meconium with a high protein concentration. Meconium ileus results from inspissation in the small intestine, leading to bowel obstruction; is associated with the clinical findings of abdominal distension and dilated bowel loops on imaging studies; and is complicated by intestinal perforation and peritonitis in approximately 50% of cases. Treatment generally involves surgical intervention. Rectal prolapse occurs in 20% of untreated children with CF between ages 6 months and 3 years and results primarily from malabsorption, malnutrition, and the elimination of bulky stools. Other less common clinical presentations in infancy include the following: (1) salt depletion syndrome, which results in a hyponatremic, hypokalemic, and hypochloremic metabolic alkalosis; (2) prolonged neonatal jaundice, resulting from intrahepatic biliary stasis or extrahepatic bile duct obstruction; (3) edema, hypoproteinemia, and acrodermatitis enteropathica, resulting from malabsorption; and (4) hemorrhagic disease of the newborn secondary to vitamin K deficiency.In older children, adolescents, and adults, clinical findings suggestive of a CF diagnosis include both respiratory and gastrointestinal presentations. Chronic and recurrent infections of the sinuses and respiratory tract, poorly controlled or refractory asthma, and the findings of nasal polyposis, bronchiectasis, and digital clubbing are typical of respiratory involvement. Alternatively, individuals in this age group may also present at diagnosis with gastrointestinal features, such as poor weight gain and growth, steatorrhea, rectal prolapse, intestinal obstruction, chronic constipation, or liver disease. Pancreatitis can be seen in individuals with pancreatic sufficient CF. These clinical presentations will become less common because most children diagnosed as having CF are now identified by newborn fibrosis results in inspissation of mucous secretions in the leading to chronic obstruction, infection, and that lead to and (Figure lung disease chronic respiratory such as and The of the treatment of respiratory disease on optimizing lung function and preventing disease progression and other The overall of treatment of CF gastrointestinal disease are to optimize nutritional and and weight For both and gastrointestinal manifestations, treatment is and generally at the time of diagnosis. In the United individuals with CF require at a care center accredited by the Cystic Fibrosis Foundation, which and treatment of CF lung disease the of chronic airways infection, particularly with bacterial such as airway of and the of In the Cystic Fibrosis developed that based on a review of the and assessment of the available evidence based on an established These in to review the evidence on therapies to maintain lung health and newer of chronic airways infection of respiratory secretions for bacterial and (Figure Other atypical and can have a significant effect on CF lung disease. 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The role of CFTR is to and movement chloride bile The by which abnormal CFTR leads to liver disease in CF is The result of liver disease in CF is the of biliary leading to biliary that may to affected individuals and associated The of and of CF such that liver disease is the leading of in CF, for of overall CF of the of the history of CF liver disease a of between and is to the of liver disease in the CF most common clinical of is the finding of affected individuals are with to and of liver disease even the of Because and are not available to screen for biliary and dysfunction, the early diagnosis of on clinical and the of and imaging to for the of The gold standard of diagnosis remains presence of should be considered with at least 2 of the following: (1) abnormal findings and/or (2) abnormalities of liver function test results the of normal on at least 3 during a (3) ultrasonographic evidence of abnormal liver or and (4) of by Treatment with acid is the diagnosis of is screening of individuals with liver disease is and should include assessment of liver function, evaluation as clinically and evaluation by a for other and associated with liver disease as and for for other such as liver chloride channel function leads to secretions that obstructive to the exocrine and results in and of cell which in turn an is more common in individuals with pancreatic insufficiency and has been associated with a early diagnosis and may this in has been associated with decreased and lung in these clinical may be due to such as and occur in as in other forms of and are associated with the presence of is with the of the incidence of approximately in individuals older than years and approximately 10% in individuals older than to the 2010 screening using the test is for those with CF are older than of is not an screening because overall is the treatment of for are not treatment remains on and not in this The of is not however, of that are high in content and in nutritional is to survival is for individuals affected with CF. Treatment include early diagnosis, screening, and treatment of the disease and associated manifestations toward optimizing function and nutritional interventions, the therapies, have had a profound effect on the overall health and well-being for individuals with CF. among primary care and the and family are to health and quality of life.