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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 I–III 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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Chapter 259. Note the F508 mutation is a class II mutation and. and 1 in 90. The large number (>1500) of relatively uncommon (<2% each) mutations identified in the CFTR gene makes genetic testing challenging.000 live births of the Asian population of Hawaii. like class I mutations. absence of CFTR in the plasma membrane is central to the molecular pathophysiology of the F508 mutation and other classes I–II mutations. Classes III–IV mutations produce CFTR proteins that are fully processed but are nonfunctional or only partially functional in the plasma membrane. would be predicted to produce no mature CFTR protein in the apical membrane. Cystic Fibrosis Schema describing classes of genetic mutations in CFTR gene and effects on CFTR protein/function. 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. cystic fibrosis transmembrane conductance regulator. The prevalence of CF varies with the ethnic origin of a population. Class V mutations include splicing mutations that produce small amounts of functional CFTR. 1 in 17.000 live births of African Americans. Thus. that functions both as a cyclic AMP –regulated Cl– channel and a regulator of other ion channels. Epithelial Dysfunction 4371 / 7122 . known as cystic fibrosis transmembrane conductance regulator (CFTR). CF is detected in approximately 1 in 3000 live births in the Caucasian population of North America and northern Europe. Biochemical studies indicate that the F508 mutation leads to improper maturation and intracellular degradation of the mutant CFTR protein. containing 1480 amino acids. CFTR Protein The CFTR protein is a single polypeptide chain. The fully processed form of CFTR localizes to the plasma membrane in normal epithelia. CFTR.

TMEM16a) expressed in the apical membrane. . The Cl– secretory defect reflects the absence of cyclic AMP–dependent kinase and protein kinase C–regulated Cl– transport mediated by CFTR itself.. A Ca 2+activated Cl– channel. The abnormal Na+ transport reflects a second function of CFTR. This process is accelerated in CF. Organ-Specific Pathophysiology LUNG The diagnostic biophysical hallmark of CF airway epithelia is the raised transepithelial electric potential difference (PD). "hydration. which reflects both the rate of active ion transport and epithelial resistance to ion flow. Normal airways vary the rates of active Na+ absorption and Cl– secretion to adjust the volume of liquid (water).Chapter 259.e. The central hypothesis of CF airways pathophysiology is that the faulty regulation 4372 / 7122 . i. is expressed in normal and CF apical membranes and can be activated by extracellular ATP. This channel can substitute for CFTR with regard to Cl– secretion and is a potential therapeutic target." on airway surfaces for efficient mucus clearance. Horizontal arrows depict velocity of mucociliary clearance ( m/sec).e.. The accelerated Na+ absorption in CF reflects the absence of CFTR inhibitory effects on Na+ channels. and some are salt. some are volume-absorbing (airways and distal intestinal epithelia). its function as a tonic inhibitor of the epithelial Na+ channel. The molecular mechanisms mediating this action of CFTR remain unknown. i. Given this diversity of native activities. However. The capacity to initiate cyclic AMP–mediated Cl– secretion is diminished in CF airway epithelia due to abnormal maturation/dysfunction of the CFTR Cl– channel. the unifying concept is that all affected tissues express abnormal ion transport function. whereas others are volumesecretory (proximal intestine and pancreas). and ENaC subunits. The normal basal pattern for ion transport is absorption of Na+ from the lumen via an amiloride-sensitive epithelial Na+ channel (ENaC) composed of . 259-2). likely a product of the TMEM16a gene. The vectors describe routes and magnitudes of Na+ and Cl– transport that is accompanied by osmotically driven water flow. Cystic Fibrosis The epithelia affected by CF exhibit different functions in their native state. Figure 259-2 Comparison of ion transport properties of normal (top) and CF (bottom) airway epithelia. CF airway epithelia exhibit abnormalities in both active Cl– secretion and Na+ absorption (Fig. An important observation is that there is also a molecularly distinct Ca2+-activated Cl– channel (CaCC. Mucus clearance is the primary innate airways defense mechanism against infection by inhaled bacteria. it is not surprising that CF produces organ-specific effects on electrolyte and water transport.but not volume-absorbing (sweat duct).

As disease progresses. the CF intestinal epithelium fails to flush secreted mucins and other macromolecules from intestinal crypts.Chapter 259. SWEAT GLAND CF patients secrete nearly normal volumes of sweat in the sweat acinus. There are protracted periods of clinical stability interrupted by "pulmonary exacerbations. it has been demonstrated that the O2 tension is very low in CF mucus. are diagnosed after age 18. P. gladioli . Up to 50% of CF patients have Aspergillus fumigatus in their sputum. The diminished CFTR-mediated liquid secretion may be exacerbated by excessive absorption of liquid. In the exocrine pancreas. reflecting abnormalities of CFTR-mediated regulation of Na+ absorption (both mediated by Na+ channels and possibly other Na+ transporters. aureus are often the first organisms recovered from lung secretions in newly diagnosed CF patients. often greenish-colored sputum. leading to respiratory failure. suggest that small-airways disease is the first functional lung abnormality in CF. In the hepatobiliary system.g. and the incidence of nasal polyps. these microorganisms are associated with disease. and adaptations to hypoxemia are important determinants of the physiology of bacteria in the CF lung. low-grade fever. 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 first lung-function abnormalities in CF children. and in some patients. both reversible and 4373 / 7122 . CF patients exhibit a characteristic sputum microbiology. The infection that characterizes CF airways involves the mucus layer rather than epithelial or airway wall invasion. Na+-H+ exchangers). Escherichia coli . is typically cultured from lower respiratory tract secretions thereafter. the first symptom of CF is cough. 10–20% of adult patients with CF have sputum cultures positive for nontuberculous mycobacteria. i. However. This sweat gland dysfunction is typically measured by measuring Cl– concentrations in sweat collected after iontophoresis of cholinergic agonists. Respiratory Tract Upper respiratory tract disease is almost universal in patients with CF. 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. In the lower respiratory tract. CLINICAL FEATURES Most patients with CF present with signs and symptoms of the disease in childhood. most prominently cough and/or recurrent pulmonary infiltrates. Proteus. increased ratios of residual volume to total lung capacity. Approximately 20% of patients present within the first 24 h of life with gastrointestinal obstruction. e. The predisposition of CF airways to chronic infection by Staphylococcus aureus and Pseudomonas aeruginosa is consistent with failure to clear mucus. 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. Burkholderia cepacia is also recovered from CF sputum and is pathogenic.. The inability of the CF gallbladder epithelium to secrete salt and water can lead to both chronic cholecystitis and cholelithiasis. however. A significant proportion of patients (~5%). and failure to thrive. B. Other common presentations within the first year or two of life include respiratory tract symptoms. Other gram-negative rods recovered from CF sputum include Alcaligenes xylosoxidans. purulent. Both dysfunctions lead to dehydrated intraluminal contents and intestinal obstruction. weight loss. GASTROINTESTINAL TRACT The gastrointestinal effects of CF are diverse. The failure to secrete Na+ HCO3– and water leads to retention of enzymes in the pancreas and destruction of virtually all pancreatic tissue. Haemophilus influenzae and S. which often requires treatment with topical steroids and/or surgery." often triggered by viral infections. Chronic sinusitis is common in childhood. Recently. but are not able to absorb NaCl from the sweat duct due to the inability to absorb Cl– via CFTR across ductal epithelial cells. which leads to a failure to clear mucus from the airways both by ciliary and cough-dependent mechanisms. termed meconium ileus. Indeed. and Klebsiella. increased sputum volume. and defined by increased cough. often mucoid and antibioticresistant. aeruginosa. Over the course of years." Dehydration of both the mucus and the periciliary liquid layers produces adhesion of mucus to the airway surface. Mycobacterium tuberculosis is rare in patients with CF. Cystic Fibrosis of Na+ absorption and inability to secrete Cl– via CFTR reduce the volume of liquid on airway surfaces. focal biliary cirrhosis. With time. Because of the lack of Cl– and water secretion. the cough becomes persistent and produces viscous. approaches 25%. and up to 10% of these patients exhibit the syndrome of allergic bronchopulmonary aspergillosis. and.e. the exacerbation frequency increases and the recovery of lost lung function becomes incomplete. and bile-duct proliferation in approximately 25–30% of patients with CF.. and decrements in pulmonary function. occasionally. Patient-to-patient spread of certain strains of these organisms mandates strict infection control in the hospital. defective hepatic ductal salt (Cl–) and water secretion causes thickened biliary secretions. they are "dehydrated.

3849 + 10 kb C T. Between 1 and 2% of patients with the clinical syndrome of CF have normal sweat Cl– values. the right upper lobe displays the earliest and most severe changes. causes hyperglycemia and a requirement for insulin in >29% of older patients with CF (>35 years). plus inflammation-induced insulin resistance. Pancreatic beta cells are spared early. Regular use of these maneuvers is effective in preserving lung function. and chest percussion. The reversible component reflects the accumulation of intraluminal secretions and/or airway reactivity. which can be prevented with coadministered bronchodilators. In children and young adults. which occurs in 40–60% of patients with CF. Theoretically. respiratory failure and cor pulmonale are prominent features of CF. For reasons that remain speculative. foul-smelling stools. DIOS can be confused with appendicitis. with small intestinal air-fluid levels. The irreversible component reflects chronic destruction of the airway wall and bronchiolitis. reflecting small-airways obstruction. a granular appearance representing meconium. Massive hemoptysis is life-threatening.g.Chapter 259. clubbing of digits appears in virtually all patients with CF. More than 95% of male patients with CF are azoospermic. DNA analysis of the most common mutations identify CF mutations in >90% of affected patients. e. and sweat acini do not secrete in response to injected -adrenergic agonists. whereas antibiotics principally reduce the bacterial burden in the CF lung. The abdominal flat plate can be diagnostic. bronchial cuffing. bulky. signs of luminal mucus impaction. This effect. Gastrointestinal Tract Meconium ileus in infants presents with abdominal distention. Most pregnancies produce viable infants. a Cl– concentration of >70 meq/L in adults discriminates between CF and other lung diseases. failure to pass stool. flutter valves. Later. CF pulmonary disease is associated with many intermittent complications. Hypertonic saline is safe but produces bronchoconstriction in some patients. ring shadows. occasionally emesis. Signs and symptoms of malabsorption of fatsoluble vitamins. nasal PD measurements. a syndrome termed distal intestinal obstruction syndrome (DIOS) occurs. Ultimately. and often a palpable mass. The sweat concentration values for Cl– (and Na+) vary with age. whose frequency is not increased in CF patients. typically. and finally bronchiectasis. Inhaled hypertonic saline is becoming a standard 4374 / 7122 . tenacious cervical mucus that blocks sperm migration. and emesis. therapies that restore the processing of misfolded mutant CFTR or gene therapy may be the treatments of choice. Cystic Fibrosis irreversible changes in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) develop. with frequent. As late events. A single mutation of the CFTR gene. Insufficient pancreatic enzyme secretion yields protein and fat malabsorption. are also noted. including vitamins E and K. The earliest chest x-ray change in CF lungs is hyperinflation. DIAGNOSIS The diagnosis of CF rests on the combination of clinical criteria and abnormal CFTR function as documented by sweat tests. With advanced lung disease. DNA analysis is performed routinely in patients with CF. the nasal transepithelial PD is raised into the diagnostic range for CF. but function decreases with age. Elevated sweat Cl– values are nearly pathognomonic for CF. which presents with right lower quadrant pain. The time-honored techniques for clearing pulmonary secretions are exercise. and CFTR mutation analysis. loss of appetite. and prevent intestinal obstruction. promoting clearance of adherent mucus should both treat and prevent progression of CF lung disease. The production of small amounts of blood in sputum is common in CF patients with advanced pulmonary disease. Exocrine pancreatic insufficiency occurs in >90% of patients with CF. 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. LUNG DISEASE More than 95% of CF patients die of complications from lung infection. provide adequate nutrition. and CF women breast-feed infants normally. and a small colon. Genitourinary System Late onset of puberty is common in both males and females with CF. The nasal PD measurement can document CFTR dysfunction if the sweat Cl– test is normal or borderline and two CF mutations are not identified. because pancreatic genotype-phenotype relationships have been identified and mutation class–specific treatments are being developed. but.. is associated with most CF patients with normal sweat Cl– values. In most of these patients. are noted. reflecting obliteration of the vas deferens due to defective liquid secretion. Treatment: Cystic Fibrosis The major objectives of therapy for CF are to promote clearance of secretions and control infection in the lung. Pneumothorax is common (>10% of patients). Some 20% of CF women are infertile due to effects of chronic lung disease on the menstrual cycle and thick.

Treatment with urodeoxycholic acid is often initiated. chest physiotherapy. Clinical trials of experimental drugs aimed at restoring salt and water content of secretions are under way. Cystic Fibrosis of care for all CF patients. CF patients also have an increased incidence of osteoarthropathy." as defined by increased cough and mucus production. Hyperglycemia most often becomes manifest in the adult and typically requires insulin treatment. particularly following transplant. The chronic damage to airway walls reflects in part the destructive activities of proteolytic enzymes generated. but their long-term use is limited by adverse side effects. Inhaled aminoglycosides. An important adjunct to secretion clearance can be recombinant human DNAse. Oral agents used to treat Staphylococcus include a semisynthetic penicillin or a cephalosporin. hypoxemia) clinical efficacy often does not correlate with sensitivity testing. particularly vitamins E and K. Replacement of fat-soluble vitamins. the only effective treatment for respiratory failure in CF is lung transplantation (Chap. "Mild exacerbations. OTHER ORGAN COMPLICATIONS Dehydration due to heat-induced salt loss occurs more readily in CF patients. because routine hospital microbiologic cultures are performed under conditions that do not mimic conditions in the CF lung. Intravenous therapy is given both in hospital and outpatient settings. Ultimately. End-stage liver disease occurs in about 5% of CF patients and is treated by transplantation. Oral ciprofloxacin may reduce pseudomonal bacterial counts and control symptoms. aeruginosa for extended periods. it is often used with an inhaled antibiotic.g. is usually required.. Pneumothoraxes involving 10% of the lung can be observed. Oral glucocorticoids may reduce airway inflammation. The 2-year survival for lung transplantation exceeds 60%. renal stones. but these drugs are not yet available for clinical use. For control of symptoms.. Early intervention with antibiotics in infants with infection may eradicate P. however. although it is unclear whether its actions are antimicrobial or antiinflammatory. a cephalosporin and an aminoglycoside) are used to treat P. a subset of adolescents with CF may benefit from long-term. bronchial artery embolization should be performed. and osteoporosis. PSYCHOSOCIAL FACTORS 4375 / 7122 . propyleneglycol) is recommended. by inflammatory cells. Cholestatic liver disease occurs in about 8% of CF patients. Most patients receive a therapeutic trial of DNAse for several months to test for efficacy. but its clinical utility is limited by emergence of resistant organisms. either tobramycin or colistin (75 mg bid).g. The dose of enzymes (typically no more than 2500 units/kg per meal. but has not been shown to influence the course of hepatic disease. For massive hemoptysis. However. Pharmacologic agents for increasing mucus clearance are in use and in development.g. which is increased in incidence in patients with CF. and transplant-patient deaths result principally from obliterative bronchiolitis. Most (>90%) CF patients require pancreatic enzyme replacement. Antibiotics directed at Staphylococcus and/or H. to avoid risk of fibrosing colonopathy) is adjusted on the basis of weight. they may be useful for treating allergic bronchopulmonary aspergillosis. (e. Persistent symptoms may indicate a gastrointestinal malignancy. Inhaled -adrenergic agonists can be useful to control airways constriction. are treated with additional oral antibiotics. abdominal symptomatology. Because of increased total-body clearance and volume of distribution of antibiotics in CF patients. but long-term benefit has not been shown.Chapter 259.000 units of lipase. two drugs with different mechanisms of action (e. and increases the time between pulmonary exacerbations. Capsules generally contain between 4000 and 20. adjustment of pancreatic enzymes and solutions containing osmotically active agents. but chest tubes are required to expand a collapsed. 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. Atelectasis requires treatment with inhaled hypertonic saline. Usually. tobramycin 300 mg bid) are also used. influenzae are added. 266). aeruginosa to minimize emergence of resistant organisms. which degrades DNA in CF sputum. suppression of bacterial growth is the therapeutic goal. high-dose nonsteroidal (ibuprofen) therapy. diseased lung.g. and antibiotics. GASTROINTESTINAL DISEASE Maintenance of adequate nutrition is critical for the health of the CF patient. the required doses are higher for patients with CF. Antibiotics are used to treat lung infection. Azithromycin (250 mg/d or 500 mg three times weekly) is often used chronically. Accordingly. However. and their selection is guided by sputum culture results. Pulmonary complications often require acute interventions. (e.. The most effective conventional therapy for these conditions is vigorous medical management of the lung disease and O2 supplementation. depending on culture results. megalodiatrizoate or other hypertonic radiocontrast materials delivered by enema to the terminal ileum are used. in part. In older patients with established infection. Small-volume hemoptysis typically requires treatment of lung infection and assessment of coagulation and vitamin K status. More severe exacerbations require intravenous antibiotics. increases airflow during short-term administration.. The most ominous complications of CF are respiratory failure and cor pulmonale. and stool character. (e. For treatment of acute distal intestinal obstruction. Specific antiprotease therapies are not available.

Br Med J 335:1255. 2006[PMID: 16723978] [Full Text] Copyright © The McGraw-Hill Companies. and life expectancy become major issues. Chest 133:489. 2010[PMID: 20829695] [Full Text] Davies JC et al: Cystic fibrosis. 2006[PMID: 16126935] [Full Text] Elizur A et al: Airway inflammation in cystic fibrosis. assisting patients with the psychosocial adjustments required by CF is critical. Curr Opin Pulm Med 16:583.Chapter 259. 2008[PMID: 18195584] [Full Text] Guggino WB. career options. Am J Respir Crit Care Med 173:475. 2006[PMID: 16492439] [Full Text] Flume PA. Nat Rev Mol Cell Biol 7:426. Thus. family planning. Stanton BA: New insights into cystic fibrosis: molecular switches that regulate CFTR. J Pediatr 148:259. Ann Rev Med 58:157. 4376 / 7122 . 2007[PMID: 17217330] [Full Text] Boyle MP: Cystic fibrosis: Year in review. 2007[PMID: 18079549] [Full Text] Davis PB: Cystic fibrosis since 1938. and depression is common. All rights reserved. FURTHER READINGS Boucher RC: Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. 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. Cystic Fibrosis CF imposes a tremendous burden on patients. Health insurance. 2006[PMID: 16421364] [Full Text] Ferkol T et al: Cystic fibrosis pulmonary exacerbations. Stenbit A: Making the diagnosis of cystic fibrosis. Am J Med Sci 335:51.