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CYSTIC FIBROSIS: INTRODUCTION

Cystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease. The first signs and symptomstypically occur in childhood, but about 5% of patients in the United States are diagnosed as adults. Due to improvementsin therapy, >46% of patients are now adults ( 18 years old) and 16.4% are past the age of 30. The median survival is>37.4 years for patients with CF; thus, CF is no longer only a pediatric disease, and internists must be prepared torecognize and treat its many complications. CF is characterized by chronic bacterial infection of the airways that leads tobronchiectasis and bronchiolectasis, exocrine pancreatic insufficiency and intestinal dysfunction, abnormal sweat glandfunction, and urogenital dysfunction.

PATHOGENESIS

Genetic ConsiderationsCF is an autosomal recessive disease resulting from mutations in the CFTR gene located on chromosome 7. Themutations in the CFTR gene fall into five major classes, as depicted in Fig. 259-1. Classes I–III mutations are considered"severe," as indexed by pancreatic insufficiency and high sweat NaCl values (see below). Class IV and V mutations canbe "mild," i.e., associated with pancreatic sufficiency and intermediate/normal sweat NaCl values.

Figure 259-1

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Schema describing classes of genetic mutations in CFTR gene and effects on CFTR protein/function. Notethe F508 mutation is a class II mutation and, like class I mutations, would be predicted to produce no mature CFTRprotein in the apical membrane. CFTR, cystic fibrosis transmembrane conductance regulator.

The prevalence of CF varies with the ethnic origin of a population. CF is detected in approximately 1 in 3000 live births inthe Caucasian population of North America and northern Europe, 1 in 17,000 live births of African Americans, and 1 in90,000 live births of the Asian population of Hawaii. The most common mutation in the CFTR gene (~70% of CFchromosomes) is a 3-bp deletion (a class II mutation) that results in an absence of phenylalanine at amino acid position508 ( F508) of the CF gene protein product, known as cystic fibrosis transmembrane conductance regulator (CFTR).The large number (>1500) of relatively uncommon (<2% each) mutations identified in the CFTR gene makes genetictesting challenging.

CFTR ProteinThe CFTR protein is a single polypeptide chain, containing 1480 amino acids, that functions both as a cyclic AMP

–regulated Cl– channel and a regulator of other ion channels. The fully processed form of CFTR localizes to the plasmamembrane in normal epithelia. Biochemical studies indicate that the F508 mutation leads to improper maturation andintracellular degradation of the mutant CFTR protein. Thus, absence of CFTR in the plasma membrane is central to themolecular pathophysiology of the F508 mutation and other classes I–II mutations. Classes III–IV mutations produceCFTR proteins that are fully processed but are nonfunctional or only partially functional in the plasma membrane. Class Vmutations include splicing mutations that produce small amounts of functional CFTR.

Epithelial Dysfunction

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The epithelia affected by CF exhibit different functions in their native state, i.e., some are volume-absorbing (airways anddistal intestinal epithelia), and some are salt- but not volume-absorbing (sweat duct), whereas others are volume-secretory (proximal intestine and pancreas). Given this diversity of native activities, it is not surprising that CF producesorgan-specific effects on electrolyte and water transport. However, the unifying concept is that all affected tissues expressabnormal ion transport function.

Organ-Specific PathophysiologyLUNGThe diagnostic biophysical hallmark of CF airway epithelia is the raised transepithelial electric potential difference (PD),which reflects both the rate of active ion transport and epithelial resistance to ion flow. CF airway epithelia exhibit

abnormalities in both active Cl– secretion and Na+ absorption (Fig. 259-2). The Cl– secretory defect reflects the

absence of cyclic AMP–dependent kinase and protein kinase C–regulated Cl– transport mediated by CFTR itself. An

important observation is that there is also a molecularly distinct Ca2+-activated Cl– channel (CaCC, TMEM16a)

expressed in the apical membrane. This channel can substitute for CFTR with regard to Cl– secretion and is a potential

therapeutic target. The abnormal Na+ transport reflects a second function of CFTR, its function as a tonic inhibitor of the

epithelial Na+ channel. The molecular mechanisms mediating this action of CFTR remain unknown.

Figure 259-2

Comparison of ion transport properties of normal (top) and CF (bottom) airway epithelia. The vectors describeroutes and magnitudes of Na+ and Cl– transport that is accompanied by osmotically driven water flow. The normal basalpattern for ion transport is absorption of Na+ from the lumen via an amiloride-sensitive epithelial Na+ channel (ENaC)composed of , , and ENaC subunits. This process is accelerated in CF. The capacity to initiate cyclic AMP–mediatedCl– secretion is diminished in CF airway epithelia due to abnormal maturation/dysfunction of the CFTR Cl– channel.The accelerated Na+ absorption in CF reflects the absence of CFTR inhibitory effects on Na+ channels. A Ca 2+-activated Cl– channel, likely a product of the TMEM16a gene, is expressed in normal and CF apical membranes andcan be activated by extracellular ATP. Horizontal arrows depict velocity of mucociliary clearance ( m/sec).

Mucus clearance is the primary innate airways defense mechanism against infection by inhaled bacteria. Normal airways

vary the rates of active Na+ absorption and Cl– secretion to adjust the volume of liquid (water), i.e., "hydration," on airwaysurfaces for efficient mucus clearance. The central hypothesis of CF airways pathophysiology is that the faulty regulation

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of Na+ absorption and inability to secrete Cl– via CFTR reduce the volume of liquid on airway surfaces; i.e., they are"dehydrated." Dehydration of both the mucus and the periciliary liquid layers produces adhesion of mucus to the airwaysurface, which leads to a failure to clear mucus from the airways both by ciliary and cough-dependent mechanisms. Theabsence of a strict correspondence between gene-mutation class and severity of lung disease suggests important rolesfor modifier genes and gene-environmental interactions.

The infection that characterizes CF airways involves the mucus layer rather than epithelial or airway wall invasion. Thepredisposition of CF airways to chronic infection by Staphylococcus aureus and Pseudomonas aeruginosa is consistentwith failure to clear mucus. Recently, it has been demonstrated that the O2 tension is very low in CF mucus, andadaptations to hypoxemia are important determinants of the physiology of bacteria in the CF lung. Indeed, both mucusstasis and mucus hypoxemia contribute to (1) the propensity for Pseudomonas to grow in biofilm colonies within CFairway mucus and (2) the presence of strict anaerobes in CF lungs.

GASTROINTESTINAL TRACT

The gastrointestinal effects of CF are diverse. In the exocrine pancreas, the absence of the CFTR Cl– channel in the

apical membrane of pancreatic ductal epithelia limits the function of an apical membrane Cl–-HCO3– exchanger to

secrete bicarbonate and Na+ (by a passive process) into the duct. The failure to secrete Na+ HCO3– and water leads to

retention of enzymes in the pancreas and destruction of virtually all pancreatic tissue. Because of the lack of Cl– andwater secretion, the CF intestinal epithelium fails to flush secreted mucins and other macromolecules from intestinalcrypts. The diminished CFTR-mediated liquid secretion may be exacerbated by excessive absorption of liquid, reflecting

abnormalities of CFTR-mediated regulation of Na+ absorption (both mediated by Na+ channels and possibly other Na+

transporters, e.g., Na+-H+ exchangers). Both dysfunctions lead to dehydrated intraluminal contents and intestinal

obstruction. In the hepatobiliary system, defective hepatic ductal salt (Cl–) and water secretion causes thickened biliarysecretions, focal biliary cirrhosis, and bile-duct proliferation in approximately 25–30% of patients with CF. The inability ofthe CF gallbladder epithelium to secrete salt and water can lead to both chronic cholecystitis and cholelithiasis.

SWEAT GLANDCF patients secrete nearly normal volumes of sweat in the sweat acinus, but are not able to absorb NaCl from the sweat

duct due to the inability to absorb Cl– via CFTR across ductal epithelial cells. This sweat gland dysfunction is typically

measured by measuring Cl– concentrations in sweat collected after iontophoresis of cholinergic agonists.

CLINICAL FEATURES

Most patients with CF present with signs and symptoms of the disease in childhood. Approximately 20% of patientspresent within the first 24 h of life with gastrointestinal obstruction, termed meconium ileus. Other common presentationswithin the first year or two of life include respiratory tract symptoms, most prominently cough and/or recurrent pulmonaryinfiltrates, and failure to thrive. A significant proportion of patients (~5%), however, are diagnosed after age 18.

Respiratory TractUpper respiratory tract disease is almost universal in patients with CF. Chronic sinusitis is common in childhood, and theincidence of nasal polyps, which often requires treatment with topical steroids and/or surgery, approaches 25%.

In the lower respiratory tract, the first symptom of CF is cough. With time, the cough becomes persistent and producesviscous, purulent, often greenish-colored sputum. There are protracted periods of clinical stability interrupted by"pulmonary exacerbations," often triggered by viral infections, and defined by increased cough, weight loss, low-gradefever, increased sputum volume, and decrements in pulmonary function. Over the course of years, the exacerbationfrequency increases and the recovery of lost lung function becomes incomplete, leading to respiratory failure.

CF patients exhibit a characteristic sputum microbiology. Haemophilus influenzae and S. aureus are often the firstorganisms recovered from lung secretions in newly diagnosed CF patients. P. aeruginosa, often mucoid and antibiotic-resistant, is typically cultured from lower respiratory tract secretions thereafter. Burkholderia cepacia is also recoveredfrom CF sputum and is pathogenic. Patient-to-patient spread of certain strains of these organisms mandates strictinfection control in the hospital. Other gram-negative rods recovered from CF sputum include Alcaligenes xylosoxidans,B. gladioli; and, occasionally, Proteus, Escherichia coli, and Klebsiella. Up to 50% of CF patients have Aspergillusfumigatus in their sputum, and up to 10% of these patients exhibit the syndrome of allergic bronchopulmonaryaspergillosis. Mycobacterium tuberculosis is rare in patients with CF. However, 10–20% of adult patients with CF havesputum cultures positive for nontuberculous mycobacteria, and in some patients, these microorganisms are associatedwith disease.

The first lung-function abnormalities in CF children, increased ratios of residual volume to total lung capacity, suggestthat small-airways disease is the first functional lung abnormality in CF. As disease progresses, both reversible and

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irreversible changes in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) develop. The reversiblecomponent reflects the accumulation of intraluminal secretions and/or airway reactivity, which occurs in 40–60% ofpatients with CF. The irreversible component reflects chronic destruction of the airway wall and bronchiolitis.

The earliest chest x-ray change in CF lungs is hyperinflation, reflecting small-airways obstruction. Later, signs of luminalmucus impaction, bronchial cuffing, and finally bronchiectasis, e.g., ring shadows, are noted. For reasons that remainspeculative, the right upper lobe displays the earliest and most severe changes.

CF pulmonary disease is associated with many intermittent complications. Pneumothorax is common (>10% of patients).The production of small amounts of blood in sputum is common in CF patients with advanced pulmonary disease.Massive hemoptysis is life-threatening. With advanced lung disease, clubbing of digits appears in virtually all patients withCF. As late events, respiratory failure and cor pulmonale are prominent features of CF.

Gastrointestinal TractMeconium ileus in infants presents with abdominal distention, failure to pass stool, and emesis. The abdominal flat platecan be diagnostic, with small intestinal air-fluid levels, a granular appearance representing meconium, and a small colon.In children and young adults, a syndrome termed distal intestinal obstruction syndrome (DIOS) occurs, which presentswith right lower quadrant pain, loss of appetite, occasionally emesis, and often a palpable mass. DIOS can be confusedwith appendicitis, whose frequency is not increased in CF patients.

Exocrine pancreatic insufficiency occurs in >90% of patients with CF. Insufficient pancreatic enzyme secretion yieldsprotein and fat malabsorption, with frequent, bulky, foul-smelling stools. Signs and symptoms of malabsorption of fat-soluble vitamins, including vitamins E and K, are also noted. Pancreatic beta cells are spared early, but functiondecreases with age. This effect, plus inflammation-induced insulin resistance, causes hyperglycemia and a requirementfor insulin in >29% of older patients with CF (>35 years).

Genitourinary SystemLate onset of puberty is common in both males and females with CF. More than 95% of male patients with CF areazoospermic, reflecting obliteration of the vas deferens due to defective liquid secretion. Some 20% of CF women areinfertile due to effects of chronic lung disease on the menstrual cycle and thick, tenacious cervical mucus that blockssperm migration. Most pregnancies produce viable infants, and CF women breast-feed infants normally.

DIAGNOSIS

The diagnosis of CF rests on the combination of clinical criteria and abnormal CFTR function as documented by sweat

tests, nasal PD measurements, and CFTR mutation analysis. Elevated sweat Cl– values are nearly pathognomonic for

CF. The sweat concentration values for Cl– (and Na+) vary with age, but, typically, a Cl– concentration of >70 meq/L inadults discriminates between CF and other lung diseases. DNA analysis of the most common mutations identify CF

mutations in >90% of affected patients. The nasal PD measurement can document CFTR dysfunction if the sweat Cl– testis normal or borderline and two CF mutations are not identified. DNA analysis is performed routinely in patients with CF,because pancreatic genotype-phenotype relationships have been identified and mutation class–specific treatments arebeing developed.

Between 1 and 2% of patients with the clinical syndrome of CF have normal sweat Cl– values. In most of these patients,the nasal transepithelial PD is raised into the diagnostic range for CF, and sweat acini do not secrete in response toinjected -adrenergic agonists. A single mutation of the CFTR gene, 3849 + 10 kb C T, is associated with most CF

patients with normal sweat Cl– values.

Treatment: Cystic FibrosisThe major objectives of therapy for CF are to promote clearance of secretions and control infection in the lung, provideadequate nutrition, and prevent intestinal obstruction. Ultimately, therapies that restore the processing of misfoldedmutant CFTR or gene therapy may be the treatments of choice.

LUNG DISEASEMore than 95% of CF patients die of complications from lung infection. Theoretically, promoting clearance of adherentmucus should both treat and prevent progression of CF lung disease, whereas antibiotics principally reduce the bacterialburden in the CF lung.

The time-honored techniques for clearing pulmonary secretions are exercise, flutter valves, and chest percussion.Regular use of these maneuvers is effective in preserving lung function. Inhaled hypertonic saline (7%) hasdemonstrated efficacy in restoring mucus clearance and pulmonary function in short-term studies and in reducing acuteexacerbations in a long-term (one-year) study. Hypertonic saline is safe but produces bronchoconstriction in somepatients, which can be prevented with coadministered bronchodilators. Inhaled hypertonic saline is becoming a standard

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of care for all CF patients.

Pharmacologic agents for increasing mucus clearance are in use and in development. An important adjunct to secretionclearance can be recombinant human DNAse, which degrades DNA in CF sputum, increases airflow during short-termadministration, and increases the time between pulmonary exacerbations. Most patients receive a therapeutic trial ofDNAse for several months to test for efficacy. Clinical trials of experimental drugs aimed at restoring salt and watercontent of secretions are under way, but these drugs are not yet available for clinical use.

Antibiotics are used to treat lung infection, and their selection is guided by sputum culture results. However, becauseroutine hospital microbiologic cultures are performed under conditions that do not mimic conditions in the CF lung, (e.g.,hypoxemia) clinical efficacy often does not correlate with sensitivity testing. Because of increased total-body clearanceand volume of distribution of antibiotics in CF patients, the required doses are higher for patients with CF.

Early intervention with antibiotics in infants with infection may eradicate P. aeruginosa for extended periods. In olderpatients with established infection, suppression of bacterial growth is the therapeutic goal. Azithromycin (250 mg/d or 500mg three times weekly) is often used chronically, although it is unclear whether its actions are antimicrobial or anti-inflammatory. Inhaled aminoglycosides, (e.g., tobramycin 300 mg bid) are also used. "Mild exacerbations," as defined byincreased cough and mucus production, are treated with additional oral antibiotics. Oral agents used to treatStaphylococcus include a semisynthetic penicillin or a cephalosporin. Oral ciprofloxacin may reduce pseudomonalbacterial counts and control symptoms, but its clinical utility is limited by emergence of resistant organisms. Accordingly, itis often used with an inhaled antibiotic, either tobramycin or colistin (75 mg bid). More severe exacerbations requireintravenous antibiotics. Intravenous therapy is given both in hospital and outpatient settings. Usually, two drugs withdifferent mechanisms of action (e.g., a cephalosporin and an aminoglycoside) are used to treat P. aeruginosa to minimizeemergence of resistant organisms. Drug dosage should be monitored so that levels for gentamicin or tobramycin peak atranges of ~10 g/mL and exhibit troughs of <2 g/mL. Antibiotics directed at Staphylococcus and/or H. influenzae areadded, depending on culture results.

Inhaled -adrenergic agonists can be useful to control airways constriction, but long-term benefit has not been shown.Oral glucocorticoids may reduce airway inflammation, but their long-term use is limited by adverse side effects; however,they may be useful for treating allergic bronchopulmonary aspergillosis.

The chronic damage to airway walls reflects in part the destructive activities of proteolytic enzymes generated, in part, byinflammatory cells. Specific antiprotease therapies are not available. However, a subset of adolescents with CF maybenefit from long-term, high-dose nonsteroidal (ibuprofen) therapy.

Pulmonary complications often require acute interventions. Atelectasis requires treatment with inhaled hypertonic saline,chest physiotherapy, and antibiotics. Pneumothoraxes involving 10% of the lung can be observed, but chest tubes arerequired to expand a collapsed, diseased lung. Small-volume hemoptysis typically requires treatment of lung infectionand assessment of coagulation and vitamin K status. For massive hemoptysis, bronchial artery embolization should beperformed. The most ominous complications of CF are respiratory failure and cor pulmonale. The most effectiveconventional therapy for these conditions is vigorous medical management of the lung disease and O2 supplementation.Ultimately, the only effective treatment for respiratory failure in CF is lung transplantation (Chap. 266). The 2-yearsurvival for lung transplantation exceeds 60%, and transplant-patient deaths result principally from obliterativebronchiolitis.

GASTROINTESTINAL DISEASEMaintenance of adequate nutrition is critical for the health of the CF patient. Most (>90%) CF patients require pancreaticenzyme replacement. Capsules generally contain between 4000 and 20,000 units of lipase. The dose of enzymes(typically no more than 2500 units/kg per meal, to avoid risk of fibrosing colonopathy) is adjusted on the basis of weight,abdominal symptomatology, and stool character. Replacement of fat-soluble vitamins, particularly vitamins E and K, isusually required. Hyperglycemia most often becomes manifest in the adult and typically requires insulin treatment.

For treatment of acute distal intestinal obstruction, megalodiatrizoate or other hypertonic radiocontrast materialsdelivered by enema to the terminal ileum are used. For control of symptoms, adjustment of pancreatic enzymes andsolutions containing osmotically active agents, (e.g., propyleneglycol) is recommended. Persistent symptoms mayindicate a gastrointestinal malignancy, which is increased in incidence in patients with CF.

Cholestatic liver disease occurs in about 8% of CF patients. Treatment with urodeoxycholic acid is often initiated, but hasnot been shown to influence the course of hepatic disease. End-stage liver disease occurs in about 5% of CF patientsand is treated by transplantation.

OTHER ORGAN COMPLICATIONSDehydration due to heat-induced salt loss occurs more readily in CF patients. CF patients also have an increasedincidence of osteoarthropathy, renal stones, and osteoporosis, particularly following transplant.

PSYCHOSOCIAL FACTORS

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CF imposes a tremendous burden on patients, and depression is common. Health insurance, career options, familyplanning, and life expectancy become major issues. Thus, assisting patients with the psychosocial adjustments requiredby CF is critical.

FURTHER READINGS

Boucher RC: Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Ann Rev Med 58:157, 2007[PMID:17217330] [Full Text]

Boyle MP: Cystic fibrosis: Year in review. Curr Opin Pulm Med 16:583, 2010[PMID: 20829695] [Full Text]

Davies JC et al: Cystic fibrosis. Br Med J 335:1255, 2007[PMID: 18079549] [Full Text]

Davis PB: Cystic fibrosis since 1938. Am J Respir Crit Care Med 173:475, 2006[PMID: 16126935] [Full Text]

Elizur A et al: Airway inflammation in cystic fibrosis. Chest 133:489, 2008[PMID: 18252915] [Full Text]

Elkins MR et al: A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med354:229, 2006[PMID: 16421364] [Full Text]

Ferkol T et al: Cystic fibrosis pulmonary exacerbations. J Pediatr 148:259, 2006[PMID: 16492439] [Full Text]

Flume PA, Stenbit A: Making the diagnosis of cystic fibrosis. Am J Med Sci 335:51, 2008[PMID: 18195584] [Full Text]

Guggino WB, Stanton BA: New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat Rev Mol Cell Biol7:426, 2006[PMID: 16723978] [Full Text]

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