Chapter 259.

Cystic Fibrosis

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CYSTIC FIBROSIS: INTRODUCTION

Cystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease. The first signs and symptoms typically occur in childhood, but about 5% of patients in the United States are diagnosed as adults. Due to improvements in 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 to recognize and treat its many complications. CF is characterized by chronic bacterial infection of the airways that leads to bronchiectasis and bronchiolectasis, exocrine pancreatic insufficiency and intestinal dysfunction, abnormal sweat gland function, and urogenital dysfunction.

PATHOGENESIS Genetic Considerations

CF is an autosomal recessive disease resulting from mutations in the CFTR gene located on chromosome 7. The mutations in the CFTR gene fall into five major classes, as depicted in Fig. 259-1. Classes IIII mutations are considered "severe," as indexed by pancreatic insufficiency and high sweat NaCl values (see below). Class IV and V mutations can be "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. Note the F508 mutation is a class II mutation and, like class I mutations, would be predicted to produce no mature CFTR protein 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 in the Caucasian population of North America and northern Europe, 1 in 17,000 live births of African Americans, and 1 in 90,000 live births of the Asian population of Hawaii. The most common mutation in the CFTR gene (~70% of CF chromosomes) is a 3-bp deletion (a class II mutation) that results in an absence of phenylalanine at amino acid position 508 ( 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 genetic testing challenging.

CFTR Protein
The 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 plasma membrane in normal epithelia. Biochemical studies indicate that the F508 mutation leads to improper maturation and intracellular degradation of the mutant CFTR protein. Thus, absence of CFTR in the plasma membrane is central to the molecular pathophysiology of the F508 mutation and other classes III mutations. Classes IIIIV mutations produce CFTR proteins that are fully processed but are nonfunctional or only partially functional in the plasma membrane. Class V mutations 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 and distal intestinal epithelia), and some are salt- but not volume-absorbing (sweat duct), whereas others are volumesecretory (proximal intestine and pancreas). Given this diversity of native activities, it is not surprising that CF produces organ-specific effects on electrolyte and water transport. However, the unifying concept is that all affected tissues express abnormal ion transport function.

Organ-Specific Pathophysiology LUNG

The 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 AMPdependent kinase and protein kinase Cregulated 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 describe routes and magnitudes of Na+ and Cl transport that is accompanied by osmotically driven water flow. The normal basal pattern 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 AMPmediated Cl 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 and can 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 airway surfaces 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 airway surface, which leads to a failure to clear mucus from the airways both by ciliary and cough-dependent mechanisms. The absence of a strict correspondence between gene-mutation class and severity of lung disease suggests important roles for modifier genes and gene-environmental interactions. The infection that characterizes CF airways involves the mucus layer rather than epithelial or airway wall invasion. The predisposition of CF airways to chronic infection by Staphylococcus aureus and Pseudomonas aeruginosa is consistent with failure to clear mucus. Recently, it has been demonstrated that the O2 tension is very low in CF mucus, and adaptations to hypoxemia are important determinants of the physiology of bacteria in the CF lung. Indeed, both mucus stasis and mucus hypoxemia contribute to (1) the propensity for Pseudomonas to grow in biofilm colonies within CF airway 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 and water secretion, the CF intestinal epithelium fails to flush secreted mucins and other macromolecules from intestinal crypts. 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 biliary secretions, focal biliary cirrhosis, and bile-duct proliferation in approximately 2530% of patients with CF. The inability of the CF gallbladder epithelium to secrete salt and water can lead to both chronic cholecystitis and cholelithiasis.

SWEAT GLAND
CF 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 patients present within the first 24 h of life with gastrointestinal obstruction, termed meconium ileus. Other common presentations within the first year or two of life include respiratory tract symptoms, most prominently cough and/or recurrent pulmonary infiltrates, and failure to thrive. A significant proportion of patients (~5%), however, are diagnosed after age 18.

Respiratory Tract
Upper respiratory tract disease is almost universal in patients with CF. Chronic sinusitis is common in childhood, and the incidence 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 produces viscous, 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-grade fever, increased sputum volume, and decrements in pulmonary function. Over the course of years, the exacerbation frequency 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 first organisms recovered from lung secretions in newly diagnosed CF patients. P. aeruginosa, often mucoid and antibioticresistant, is typically cultured from lower respiratory tract secretions thereafter. Burkholderia cepacia is also recovered from CF sputum and is pathogenic. Patient-to-patient spread of certain strains of these organisms mandates strict infection 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 Aspergillus fumigatus in their sputum, and up to 10% of these patients exhibit the syndrome of allergic bronchopulmonary aspergillosis. Mycobacterium tuberculosis is rare in patients with CF. However, 1020% of adult patients with CF have sputum cultures positive for nontuberculous mycobacteria, and in some patients, these microorganisms are associated with disease. The first lung-function abnormalities in CF children, increased ratios of residual volume to total lung capacity, suggest that 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 reversible component reflects the accumulation of intraluminal secretions and/or airway reactivity, which occurs in 4060% of patients 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 luminal mucus impaction, bronchial cuffing, and finally bronchiectasis, e.g., ring shadows, are noted. For reasons that remain speculative, 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 with CF. As late events, respiratory failure and cor pulmonale are prominent features of CF.

Gastrointestinal Tract
Meconium ileus in infants presents with abdominal distention, failure to pass stool, and emesis. The abdominal flat plate can 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 presents with right lower quadrant pain, loss of appetite, occasionally emesis, and often a palpable mass. DIOS can be confused with appendicitis, whose frequency is not increased in CF patients. Exocrine pancreatic insufficiency occurs in >90% of patients with CF. Insufficient pancreatic enzyme secretion yields protein and fat malabsorption, with frequent, bulky, foul-smelling stools. Signs and symptoms of malabsorption of fatsoluble vitamins, including vitamins E and K, are also noted. Pancreatic beta cells are spared early, but function decreases with age. This effect, plus inflammation-induced insulin resistance, causes hyperglycemia and a requirement for insulin in >29% of older patients with CF (>35 years).

Genitourinary System
Late onset of puberty is common in both males and females with CF. More than 95% of male patients with CF are azoospermic, reflecting obliteration of the vas deferens due to defective liquid secretion. Some 20% of CF women are infertile due to effects of chronic lung disease on the menstrual cycle and thick, tenacious cervical mucus that blocks sperm 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 in adults 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 test is 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 classspecific treatments are being 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 to injected -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 Fibrosis

The major objectives of therapy for CF are to promote clearance of secretions and control infection in the lung, provide adequate nutrition, and prevent intestinal obstruction. Ultimately, therapies that restore the processing of misfolded mutant CFTR or gene therapy may be the treatments of choice.

LUNG DISEASE
More than 95% of CF patients die of complications from lung infection. Theoretically, promoting clearance of adherent mucus should both treat and prevent progression of CF lung disease, whereas antibiotics principally reduce the bacterial burden 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%) has demonstrated efficacy in restoring mucus clearance and pulmonary function in short-term studies and in reducing acute exacerbations in a long-term (one-year) study. Hypertonic saline is safe but produces bronchoconstriction in some patients, 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 secretion clearance can be recombinant human DNAse, which degrades DNA in CF sputum, increases airflow during short-term administration, and increases the time between pulmonary exacerbations. Most patients receive a therapeutic trial of DNAse for several months to test for efficacy. Clinical trials of experimental drugs aimed at restoring salt and water content 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, because routine 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 clearance and 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 older patients with established infection, suppression of bacterial growth is the therapeutic goal. Azithromycin (250 mg/d or 500 mg three times weekly) is often used chronically, although it is unclear whether its actions are antimicrobial or antiinflammatory. Inhaled aminoglycosides, (e.g., tobramycin 300 mg bid) are also used. "Mild exacerbations," as defined by increased cough and mucus production, are treated with additional oral antibiotics. Oral agents used to treat Staphylococcus include a semisynthetic penicillin or a cephalosporin. Oral ciprofloxacin may reduce pseudomonal bacterial counts and control symptoms, but its clinical utility is limited by emergence of resistant organisms. Accordingly, it is often used with an inhaled antibiotic, either tobramycin or colistin (75 mg bid). More severe exacerbations require intravenous antibiotics. Intravenous therapy is given both in hospital and outpatient settings. Usually, two drugs with different mechanisms of action (e.g., a cephalosporin and an aminoglycoside) are used to treat P. aeruginosa to minimize emergence of resistant organisms. Drug dosage should be monitored so that levels for gentamicin or tobramycin peak at ranges of ~10 g/mL and exhibit troughs of <2 g/mL. Antibiotics directed at Staphylococcus and/or H. influenzae are added, 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, by inflammatory cells. Specific antiprotease therapies are not available. However, a subset of adolescents with CF may benefit 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 are required to expand a collapsed, diseased lung. Small-volume hemoptysis typically requires treatment of lung infection and assessment of coagulation and vitamin K status. For massive hemoptysis, bronchial artery embolization should be performed. The most ominous complications of CF are respiratory failure and cor pulmonale. The most effective conventional 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-year survival for lung transplantation exceeds 60%, and transplant-patient deaths result principally from obliterative bronchiolitis.

GASTROINTESTINAL DISEASE
Maintenance of adequate nutrition is critical for the health of the CF patient. Most (>90%) CF patients require pancreatic enzyme 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, is usually 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 materials delivered by enema to the terminal ileum are used. For control of symptoms, adjustment of pancreatic enzymes and solutions containing osmotically active agents, (e.g., propyleneglycol) is recommended. Persistent symptoms may indicate 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 has not been shown to influence the course of hepatic disease. End-stage liver disease occurs in about 5% of CF patients and is treated by transplantation.

OTHER ORGAN COMPLICATIONS

Dehydration due to heat-induced salt loss occurs more readily in CF patients. CF patients also have an increased incidence 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, family planning, and life expectancy become major issues. Thus, assisting patients with the psychosocial adjustments required by 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 Med 354:229, 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 Biol 7:426, 2006[PMID: 16723978] [Full Text]

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