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INTRODUCTION Cystic fibrosis (CF) is a multisystem disorder affecting children and, increasingly, adults. 1 CF is characterized chiefly by chronic airways obstruction and infection and by exocrine pancreatic insufficiency with its effects on gas- trointestinal function, nutrition, growth, and maturation. This condition is the most common life-threatening genetic trait in the white population. 2 Numerous mutations of a single gene are responsible for the CF s
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  INTRODUCTION Cystic fibrosis (CF) is a multisystem disorder affecting children and, increasingly, adults. 1 CF is characterizedchiefly by chronic airways obstruction and infection and by exocrine pancreatic insufficiency with its effects on gas-trointestinal function, nutrition, growth, and maturation.This condition is the most common life-threatening genetictrait in the white population. 2 Numerous mutations of asingle gene are responsible for the CF syndrome and for variations in its severity. The gene encodes a membraneprotein called the cystic fibrosis transmembrane regulator(CFTR). CFTR functions in many tissues as a kinase-regulated Cl - channel. In some tissues, CFTR also regulatesthe activity of other ion channels. Typically, mutations inCFTR affect both of these functions.Cystic fibrosis is an important medical problem for anumber of reasons. It is the major source of severe chroniclung disease in children and has become an important causeof morbidity and mortality from chronic lung disease in young adults. CF is responsible for most cases of exocrinepancreatic insufficiency in childhood and early adulthoodand for many cases of nasal polyposis, pansinusitis, rectalprolapse, nonketotic insulin-dependent hyperglycemia, andbiliary cirrhosis in these age groups. Therefore, CF entersinto the differential diagnosis of many pediatric and youngadult patients. Finally, research advances have introducedthe challenge of designing pharmacologic and gene trans-fer therapies to combat the broad range of manifestationsand complications.Central to CF diagnosis and care is a carefully integratedand closely monitored network of approximately 115 refer-ral centers in the United States sponsored by the CysticFibrosis Foundation. The Foundation also supports asmaller number of multidisciplinary research centers aimedat elucidating the molecular pathophysiology and improv-ing the quality of life for patients with CF. Similar care and research centers are found in Canada and in many European countries. HISTORICAL PERSPECTIVES Cystic fibrosis was first described as a distinct clinical entity in the late 1930s. However, numerous references to infantsand children with meconium ileus and characteristic pan-creatic and lung diseases are sprinkled throughout the lit-erature from as early as 1650. Of interest are references inEuropean folklore to the association of salty skin and early demise. 3 Dorothy Andersen, a pathologist at Babies Hospi-tal in New York City, is usually credited with the first com-prehensive description of CF in 1938. 4 She coined the term cystic fibrosis of the pancreas. In 1945, Farber suggested thatCF is a disease of exocrine glands, characterized largely by failure to clear their mucous secretory product. 5 He intro-duced the term mucoviscidosis,  which was used for a numberof years. Chronic infection of the lungs was recognized early as a major contributing factor, and antibiotics were first usedfor the treatment of CF in the 1940s. At the same time, an autosomal-recessive inheritance pattern for CF was 38 IntroductionHistorical PerspectivesEpidemiologyGenetic BasisPathology Lung PathologyOther Respiratory Tract PathologyNonrespiratory Pathologic Features Pathophysiology Cystic Fibrosis Transmembrane Regulator Protein:Structure, Metabolism, and FunctionAbnormal Airway Mucosal Salt and Water TransportActive Ion Transport Properties of Airway EpitheliaMucin Macromolecule Secretion in the Cystic FibrosisAirwayPathophysiology of Infection Clinical Manifestations Lower Respiratory Tract DiseaseUpper Respiratory Tract DiseaseComplications of Respiratory Tract DiseaseGastrointestinal ManifestationsPancreatic DiseaseHepatobiliary DiseaseGenitourinary Tract AbnormalitiesSweat Gland Dysfunction DiagnosisTreatment Ambulatory CareHospital Therapy Course of the Disease and PrognosisSummary1217 Cystic Fibrosis Richard C. Boucher, M.D. , Michael R. Knowles, M.D. ,  James R. Yankaskas, M.D.  1218Section J ãOBSTRUCTIVE DISEASES suggested by Andersen and Hodges. 6 In 1953, di Sant’Ag-nese and colleagues investigated salt depletion in children with CF during a summertime heat wave and concludedthat excessive loss of salt occurred via sweat. 7 Subsequently,they documented that sodium and chloride levels in sweatare elevated in virtually all ( > 98%) persons with CF. Thisobservation led to a description by Gibson and Cooke of the pilocarpine iontophoresis method for sweat testing, 8 amethod that remains the diagnostic standard to this day. By the late 1950s, CF was reported occasionally in older chil-dren and young adults. Soon thereafter, comprehensive andaggressive approaches to the care of patients were institutedin many treatment centers, and these approaches have beencredited with the survival into adulthood of a steadily increasing number of patients with CF. In the past 40 years,a markedly refined description of the CF syndrome and themany related complications has emerged.Several recent observations have resulted in partial under-standing of CF pathogenesis at a molecular level. In theearly 1980s, epithelial physiologists described abnormalitiesof both sodium and chloride transport by CF respiratory epithelia 9 and the chloride impermeability of sweat glandducts in patients with CF. 10 These observations focusedattention on a pathogenetic role for abnormal electrolyteand water movement across CF epithelia. From 1985 to1987, geneticists, using restriction fragment length poly-morphism analysis, located the CFTR gene on the long armof chromosome 7. 11–14 Shortly thereafter, the CFTR gene was isolated, cloned, and sequenced, 15 and the major muta-tion of this gene was characterized. 16 Transfer of a wild-type(normal) gene into CF cells corrected the chloride trans-port defect. 17,18 The product of the CF gene, the CFTR, was studied and found to be both a Cl - channel 19–21 and aregulator of other channels. 22,23 Studies of the metabolismof CFTR suggested that mutations could lead to abnormalfolding and mislocation of the protein. 24–26 Knockout of theCFTR gene in transgenic mice has provided an animalmodel that possesses several physiologic and clinical simi-larities to human CF. 27–30 These observations provided adetailed understanding of CFTR structure and function andhave laid the groundwork for development of more specifictherapeutic interventions, including gene therapy. EPIDEMIOLOGY Cystic fibrosis is recognized in approximately 1:2500 31 and1:17,000 32 live births in white and black populations,respectively, in the United States. The range of reportedincidence figures worldwide varies from 1:569 33 in a confined Ohio Amish population to 1:90,000 in an Asianpopulation of Hawaii. 34 Generally, mutations of the CF gene are most prevalentin northern and central Europeans and in persons whoderive from these areas. An intermediate incidence is likely although less well documented in non-European whites. CFis considered rare in American Indians, Asian populations,and black natives of Africa. It has been suggested that therelatively low frequency in populations living in tropical andsemitropical geographic locations is related to adverse con-sequences in the past from excessive salt loss in heterozy-gotes as well as homozygotes for the CF gene. In whitepopulations, 2% to 5% are carriers of a CF gene mutation.These people have no clinical stigmas of CF. Although anumber of chemical or physiologic alterations have beendescribed in heterozygotes, these alterations can be identi-fied only on a statistical basis. GENETIC BASIS Cystic fibrosis is an autosomal-recessive trait resulting frommutations at a single gene locus on the long arm of chro-mosome 7. 2,31 This locus spans approximately 250kB of DNA, contains at least 27 exons, and codes for a largeprotein that has several transmembrane domains, two cyto-plasmic nucleotide (ATP) binding folds, and numerousphosphorylation sites containing a cytoplasmic regulatory (R) domain (Fig. 38.1). The primary and secondary struc-ture of the protein product of the CF gene resembles othermembrane proteins that act as pumps [e.g., the ATP-binding cassette (ABC) transporters]. 15 The predominant CFTR  mutation is a 3-bp deletion thateliminates the phenylalanine of CFTR at position 508, theso-called D F508 mutation. 16 This deletion has been detectedin 66% of more than 20,000 CF patient chromosomes analyzed worldwide, 2,31,35 but its prevalence varies consider-ably from population to population (Table 38.1). Ingeneral, D F508 is more prevalent in northern Europeanthan southern European or in Middle Eastern popula-tions. 31 More than 1000 other mutations of the CF genehave been reported but all at a relatively low frequency. The occurrence of known mutations accounts for only 90%of all CF gene abnormalities. 31 CFTR  mutations includeother deletions, missense mutations, nonsense mutations,frameshift mutations, and introduction of new splice sites. 31 Correlations between genotype and phenotype are begin-ning to emerge. For example, homozygosity for the D F508mutation almost always confers exocrine pancreatic insuffi-ciency. 32  A severe phenotype, including meconium ileus andliver disease, is strongly associated with the presence of two“severe” (i.e., pancreatic exocrine insufficiency) alleles. 36–38  A region on human chromosome 19q13 has recently beenidentified as a modifier locus for meconium ileus. 39 Con-flicting data exist on whether D F508 homozygosity versusother severe alleles is associated with a more severe form of  Table 38.1 Frequency of the D F508 Mutation Cystic Fibrosis PopulationChromosomes (%) North American Caucasians76North American Hispanics46United Kingdom74Spain49Italy43Ashkenazi Jews30 From Leinna WK, Feldman GL, Kerem B, et al: Mutation analysis forheterozygote detection and the prenatal diagnosis of cystic fibrosis. N Engl J Med 322:291–296, 1990.  chronic lung disease. 33 On the other hand, “mild” muta-tions with some residual CFTR function and preservationof pancreatic exocrine function have been identified that areassociated with normal concentrations of sweat chloride,exocrine pancreatic sufficiency, or both. 40,41 Moreover, vari-able phenotypes with “mono-organ” disease are also emerg-ing; for example, idiopathic pancreatitis and congenitalbilateral absence of the vas deferens are associated withmutations in the CFTR  gene. 42–44 In summary, it is now clear that CF is indeed a syndrome caused by many combi-nations of mutations at a single gene locus, each of whichmay confer a slightly different phenotype. 45 The ultimatephenotype of each person with CF is undoubtedly also influ-enced by genetic background (i.e., “modifier genes” 46 ) as well as postnatal environmental factors.Deoxyribonucleic acid (DNA) analysis can now be usedto confirm the diagnosis, make prenatal diagnoses, andscreen for carrier status in selected cases. For example,probes for 28 of the most common CF mutations in NorthCarolina provided definitive diagnostic information in fewerthan 90% of persons with CF. Screening for CF carriersusing the D F508 probe identifies only 50% to 60% of couples at risk of having a CF child. 47 The high frequency of CF gene mutations in many pop-ulations has been ascribed to an unknown heterozygoteadvantage. Some evidence suggests a reproductive advan-tage for the carrier state. 48,49 Others have postulated thatreduced capacity to generate a secretory diarrhea inresponse to cholera infection because of diminished intes-tinal chloride transport may have provided a historical survival advantage to heterozygotes. 50–52 PATHOLOGY Soon after the srcinal description of the CF syndrome,Farber pointed out the prominent accumulation of mucusin the respiratory and gastrointestinal tracts. 5 Subsequently,mucus stasis has been described in numerous sites, includ-ing the conducting airways of the lung, 53 paranasal sinuses,mucus-secreting salivary glands, apocrine sweat glands,small intestine, appendix, pancreas, biliary system, uterinecervix, and wolffian duct structures. However, the eccrinesweat gland, which figures prominently in the pathophysi-ology of CF, is morphologically normal at all ages. Patho-logic changes in the lung, which is the primary site of organdysfunction, also reflect chronic infection. LUNG PATHOLOGY It is clear that disease of the conducting airways in CF isacquired postnatally. The airways of children with CF whohave died within the first days of life display only subtleabnormalities. The earliest macroscopic pathologic lesion is reported to be mucus obstruction of bronchioles. 53 However, the numbers and distribution of mucus-produc-ing goblet cells and the numbers and size of submucosalglands appear to be within normal ranges at birth. A carefulmorphometric analysis of CF airways early in life demon-strated dilation of submucosal gland acinar and ductallumens before reaction to chronic infection would beexpected. 54 This finding suggests that either hypersecretionor, more likely, failure to clear secretions at an early ageaccounts for mucus accumulation in bronchial regions, 121938 ãCystic Fibrosis R domainOutsideNH 2 NBD 1 D F508 MutationChargedside chainsProtein kinase CProtein kinase ANBD 2 CO 2 HN-linkedcarbohydrateCalculated net charge on the CFTR isindicated by color intensity. The darkestpurple is +12 and the darkest gray is –6. NBD = Nucleotide Binding DomainATP bindingdomains 0 +6 +12–6 Figure 38.1 Proposed structure for the cystic fibrosis transmembrane regulator (CFTR) protein. Two repeat segments each consist of six transmembrane spans followed by a nucleotide-binding fold (NBF). The segments are joined by a highly charged region thatcontains multiple phosphorylation sites, the R domain. Much of the CFTR is intracytoplasmic. Glycosylation occurs on an extracellularloop of the second motif.  1220Section J ãOBSTRUCTIVE DISEASES  whereas the mucus retention in bronchioles presumably reflects the failure to clear mucus secreted by surface secre-tory (goblet) cells. Failure to clear secretions from theairway lumens likely initiates infection. With the progression of lung disease, evidence for bron-chiolitis and bronchitis becomes more prominent, the submucosal glands hypertrophy, and goblet cells not only become more numerous but also propagate into the bron-chioles. Small airways may be completely obstructed by secretions (Fig. 38.2). 55 Bronchiolectasis and thenbronchiectasis are consequences of persistent obstruc-tion–infection cycles. Bronchiectasis had been thought tomanifest in the second decade of life but now is beingdetected earlier in life with increased use of computedtomography (CT) scans. Pneumonia, when present, gener-ally assumes a peribronchial pattern.Detailed pathologic descriptions of lung disease are basedon examination of lungs at autopsy or lung transplant, andthey reflect advanced changes. 56–59 Bronchiectatic cystsoccupy as much as 50% of the cross-sectional area of thelate-stage CF lung. 60 In general, bronchiectasis is moresevere in upper lobes than in lower lobes. In addition todilation of the small airways, bronchioles may be stenoticor even obliterated. The extent of obliterative bronchiolitisappears to be directly correlated with age at death. 57  Autop-sied lungs also show extensive overinflation of air spaces.Small amounts of destructive emphysema are seen in many patients, especially those who have lived for two to threedecades. 57  Absence of more extensive alveolar wall destruc-tion can be explained by the confinement of chronic infec-tion to conducting airways. Several patterns of interstitialpneumonia have also been described in autopsied lungs,including usual interstitial pneumonitis, interstitial pneu-monitis with organizing pneumonia, and diffuse alveolardamage. 61 Fibrosis is extensive in peribronchiolar and peri-bronchial regions and may contribute to the restrictive lungfunction pattern that is superimposed on obstruction inend-stage lung disease. 62 Subpleural cysts often occur on themediastinal surfaces of the upper lobes and are thought tobe related to the frequent occurrence of pneumothorax inpatients with advanced lung disease. 63 The bronchial arteries become large and tortuous, 64 contributing to apropensity for hemoptysis in ectatic airways. The pulmonary arteries display varying degrees of change reflecting pul-monary hypertension. OTHER RESPIRATORY TRACT PATHOLOGY Hypertrophy and hyperplasia of secretory elements, mucusaccumulation, and chronic inflammatory changes are alsofeatures of the paranasal sinuses and the nasal passages. A common feature of nasal pathology is inflammatory edemaof the mucosa with subsequent pedunculation and forma-tion of polyps. 65 NONRESPIRATORY PATHOLOGIC FEATURES Most of the nonpulmonary pathology in CF occurs in thegastrointestinal tract and related organs. Striking changesare seen in the exocrine pancreas. 66 Obstruction of ducts by inspissated secretions is an early feature, followed by dila-tion of secretory ducts and acini and flattening of the epithe-lium. Loss of acinar cells is widespread, and areas of destruction are replaced by fibrous tissue and fat. Intra-luminal calcifications may occur and may be recognizedroentgenographically. Small cysts are common and gener-ally represent dilated ducts. Inflammatory changes are notprominent. The islets of Langerhans are spared until laterperiods of life. Changes in the islets include disruption by fibrous tissue bands that may provide a barrier betweenhormone-secreting cells and the vascular spaces. 67 Patho-logic changes in the pancreas are used occasionally to makea postmortem diagnosis in atypical or missed cases of CF.The pancreas is abnormal in almost all patients with CFand is virtually destroyed in approximately 90% of CFpatients studied at autopsy. Liver changes are not as fre-quent or consistent. 68 In 25% or more of all autopsies,islands of relatively normal parenchymal cells are divided by fibrotic bands, creating a distinctive multilobular appear-ance. Microscopically, this focal biliary cirrhosis is A B Figure 38.2 A, Hypertrophied submucosal gland in the trachea of an 18-year-old woman with cystic fibrosis is shown. Mucus-containing acini are distended. The gland occupies almost the entire thickness of the tracheal wall. B, Large and small bronchioles inthe lungs of a 21-year-old man with cystic fibrosis. These airways are completely obstructed with secretions and display chronicinflammation of the walls and surrounding tissues. Peribronchiolar fibrosis also can be demonstrated with appropriate stains. Airspace enlargement is prominent ( right  ), but more normal-appearing peripheral lung architecture is present ( left  ). ( A, B: Hematoxylinand eosin stain; ¥ 42.)


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