Version July 2025
INTRODUCTION —
Cystic fibrosis (CF) is a multisystem disease affecting the lungs, digestive system, sweat glands, and reproductive tract. The primary abnormality is in transport of chloride and sodium across secretory epithelia, resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestines, and reproductive system [1,2]. Although the disease is systemic, progressive lung disease continues to be the major cause of morbidity and mortality for most patients. Over a highly variable time course ranging from months to decades after birth, individuals eventually develop chronic infection of the respiratory tract with a characteristic array of bacterial flora, leading to progressive respiratory insufficiency and eventual respiratory failure [3].
The genetics and pathogenesis of CF are discussed here. CF-associated lung disease is discussed in the following topic reviews:
●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)
●(See "Cystic fibrosis: Overview of the treatment of lung disease".)
●(See "Cystic fibrosis: Treatment with CFTR modulators".)
●(See "Cystic fibrosis: Management of pulmonary exacerbations".)
●(See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)
●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)
●(See "Cystic fibrosis: Management of advanced lung disease".)
The diagnosis of CF and its manifestations in other organ systems are also discussed separately:
●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)
●(See "Cystic fibrosis-related diabetes mellitus".)
●(See "Cystic fibrosis: Overview of gastrointestinal disease".)
●(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)
●(See "Cystic fibrosis: Nutritional issues".)
●(See "Cystic fibrosis: Hepatobiliary disease".)
GENETICS
CFTR protein — The cystic fibrosis transmembrane conductance regulator (CFTR) protein belongs to the ABC (ATP-binding cassette) family of proteins, a large group of related proteins that share transmembrane transport functions. ABC proteins include bacterial transporters for amino acids and other nutrients, surfactant transport proteins, and the mammalian multidrug-resistant protein (or P-glycoprotein).
The CFTR protein functions as a regulated chloride channel, which, in addition to transporting chloride, also appears to transport bicarbonate and glutathione. It also regulates the activity of other chloride and sodium (epithelial sodium) channels at the cell surface [4-7]. The genomic exons, protein, and a model of protein domains are shown in the figure (figure 1). The mature 1480 amino acid protein has two groups of six membrane-spanning regions (consisting of 12 hydrophobic segments), two intracellular nucleotide-binding folds (NBFs), and a highly charged "R domain" containing multiple phosphorylation sites. Activation of the chloride channel requires phosphokinase A-mediated phosphorylation of the R domain and the continuous presence of ATP in the NBFs [8,9].
CFTR gene — CF is caused by pathogenic variants in CFTR, a large (250 kilobase) gene on the long arm (q) of chromosome 7 [10-15]. Clinical disease generally requires biallelic pathogenic variants in the CFTR gene (homozygous or compound heterozygous), but individuals with a single pathogenic variant (carrier status) occasionally develop disease limited to one organ system, known as CFTR-related disorder. (See 'CFTR-related disorder' below.)
CFTR pathogenic variants — The phenotypic expression of disease varies widely, primarily as a function of the specific pathogenic variant(s) present [16-21].
The CFTR2 database lists more than 2000 different variants (mutations) in the CFTR gene, not all of which cause disease. Several nomenclature systems can be used to describe these variants, including one based on the deoxyribonucleic acid (DNA) sequence change, amino acid change, or the more commonly used colloquial nomenclature, which we use below [22,23].
The most common pathogenic variant is F508del (also noted as delta F508, delF508, p.Phe508del, or c.1521_1523delCTT), which describes the deletion of three DNA bases coding for the 508th amino acid residue, phenylalanine (F). Approximately 90 percent of people with CF are heterozygous for the F508del variant, and 50 percent are homozygous [24].
Certain disease variants are found at higher frequency in some ethnic groups because of apparent founder effects. As an example, five pathogenic variants account for an estimated 97 percent of CF alleles in the Ashkenazi Jewish population [25].
A subset of the most frequent CFTR disease variants is used for initial screening since the majority of individual mutations are very rare (table 1) [26]. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Molecular diagnosis'.)
DISEASE PATHOGENESIS —
The pathogenesis of the organ dysfunction seen in CF has been studied in humans and CFTR-knockout mice but remains incompletely understood [27,28].
Abnormal secretions — It appears that the physical and chemical abnormalities of CF airway secretions result in chronic infection with phenotypically unique bacteria, particularly Pseudomonas species. Pathogenic variants in TNF and other genes may increase susceptibility to Pseudomonas aeruginosa infection and contribute to pulmonary disease. (See 'Pulmonary disease' below.)
CFTR malfunction in the respiratory epithelium is associated with a variety of changes in electrolyte and water transport. The mechanisms involved and ultimate electrolyte composition of airway surface fluid in CF airways is a subject of ongoing research [5-7,29-32]. The net result of these changes is an alteration in the rheology of airway secretions, which become thick and difficult to clear [33]. An associated finding is an increased concentration of chloride in sweat secretions, which constitutes one of the methods of diagnosis of CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
Gastrointestinal effects — Thickened secretions caused by CFTR dysfunction cause the gastrointestinal complications of CF. Impaired flow of bile and pancreatic secretions cause maldigestion and malabsorption, as well as progressive liver and pancreatic disease, leading to CF-related diabetes (CFRD). (See "Cystic fibrosis-related diabetes mellitus".)
Because of thickened intestinal secretions and maldigestion, individuals with CF are prone to intestinal obstruction (distal intestinal obstruction syndrome or intussusception) and to rectal prolapse. (See "Cystic fibrosis: Overview of gastrointestinal disease".)
Chronic lung infection — The chronic airway obstruction caused by viscous secretions is followed by progressive chronic infection (colonization) with pathogenic bacteria, including Haemophilus influenzae, Staphylococcus aureus, and eventually P. aeruginosa and/or B. cepacia complex bacteria. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Progression of pulmonary disease'.)
Once infection is established, neutrophils are unable to control the bacteria, even though there is massive infiltration of these inflammatory cells into the lung tissue [34]. Recruited neutrophils subsequently release elastase, which overwhelms the antiproteases of the lung and contributes to tissue destruction in a process known as "prolonged endobronchial protease activity" [35]. In addition, large amounts of DNA and cytosol matrix proteins are released by degranulating neutrophils, contributing to the increased viscosity of the airway mucus [36].
Inflammation has been noted prior to the development of bacterial colonization and may be triggered by viral infections [37]. In turn, chronic infection appears to be the major stimulus for an exuberant but ultimately ineffective inflammatory response that subsequently results in bronchiectasis [38,39]. The inflammatory response itself appears to contribute to the progression of pulmonary dysfunction; this mechanism is the basis for the use of some antiinflammatory agents in treating CF lung disease [40,41].
Individuals with CF are particularly prone to chronic infection with P. aeruginosa, due in part to increased oxygen utilization by epithelial cells, which results in an abnormally decreased oxygen tension within the hyperviscous mucous layer (figure 2) [42]. This local hypoxia induces the characteristic phenotypic changes in P. aeruginosa (and some other gram-negative bacteria), including production of the exopolysaccharide alginate and loss of motility. This phenotype is consistent with the development of bacterial macrocolonies (or "biofilms") within the hypoxic regions of the airway mucus layer. Once this occurs, eradication of the organism is almost impossible and the rate of decline in lung function increases [43,44]. (See "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection", section on 'Persistence of the organism in the airways'.)
Bacterial infection in the CF airway results in increased intranuclear translocation of the nuclear transcription factor NF kappa B and subsequent immunoactivation [45-47]. This process does not occur in the presence of abnormal CFTR or in CFTR-knockout mice [47], which may partially explain the inability of people with CF to control these infections.
Disease-modifier genes appear to further affect the predisposition to P. aeruginosa infection, as described above. (See 'Genetic modifiers' below and "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection".)
IMPLICATIONS FOR DISEASE MANIFESTATIONS AND TREATMENT —
Pathogenic variants in the CFTR gene have been divided into five different classes as depicted in the figures (figure 3 and figure 4) [2,48-51].
In general, variants in classes I to III cause more severe disease than those in classes IV and V [19,50]. However, the clinical implications of a specific combination of variants also depend on the influence of genetic modifiers and other elements of the protein network that mediate CFTR folding, trafficking, and function; this network is sometimes termed the CFTR "functional landscape" [52]. Genotype-phenotype correlations are weak for pulmonary disease in CF and somewhat stronger for the pancreatic insufficiency phenotype. (See 'Genetic modifiers' below.)
In most cases, the specific disease variants should not be used to make assumptions about the severity of disease in an individual patient. Knowledge of the variants may be useful to guide initial therapy, but clinical decisions should be guided by observable parameters of growth, lung function, and nutritional status. Some therapies are directed at specific classes of CFTR variants. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Drug selection'.)
In general, class IV and class V variants are associated with adequate pancreatic function (pancreatic sufficiency phenotype), even when paired with a more severe class I to III variant. However, these individuals are susceptible to pancreatitis. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Genotype associations' and "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)
Class I mutations: No protein produced — Class I variants, in which no protein is produced, are usually nonsense, frameshift, or splice-site mutations, or large insertions or deletions, leading to premature termination of the messenger ribonucleic acid (mRNA) and complete absence of CFTR protein. Examples include G542X, W1282X, R553X, 621+G>T, and 1717-1G>A [50,53]. This type of mutation is present in approximately 20 percent of patients with CF (figure 4). In some genetically homogenous populations, the percentage may be much higher [54].
Class II mutations: Abnormal protein processing — Class II variants cause abnormal post-translational processing of the CFTR protein, which prevents the protein from trafficking to the correct cellular location (figure 4). This category includes the F508del (c.1521_1523delCTT) mutation. Approximately 50 percent of individuals with CF are homozygous for F508del, and 90 percent are compound heterozygous for F508del plus a different CFTR variant [50]. N1303Lys (N1303K) and A455E are also class II mutations; the latter is associated with relatively mild lung disease and pancreatic sufficiency.
Newly developed modulators of CFTR (eg, the triple drug combination elexacaftor-tezacaftor-ivacaftor) function in part by causing the cell to send the abnormally processed CFTR protein to the cell surface, where it may have some degree of function. Widespread use of these medications since 2020 has led to dramatic improvements in overall health for many patients and related improvements in survival (figure 5). (See "Cystic fibrosis: Treatment with CFTR modulators".)
Class III mutations: Abnormal channel regulation — Class III variants, also known as gating mutations, lead to diminished channel activity in response to ATP. Many involve alterations of the NBF regions, NBO1 and NBO2, which may retain varying degrees of sensitivity to nucleotide binding (figure 3).
Other CFTR mutations, mapped to the R domain, may also fall into this category. G551D is the most common class III mutation in White populations [50].
Ivacaftor, a modulator of CFTR function, improves CFTR function in patients with gating abnormalities by allowing constitutive (unmodulated) opening of the CFTR channel; these and other mutations that are responsive to ivacaftor are included in the table (table 2). (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Ivacaftor monotherapy'.)
Class IV mutations: Decreased channel conductance — With class IV mutations, the CFTR protein is produced and correctly localized to the cell surface. However, although chloride currents are generated in response to cAMP stimulation, the rate of ion flow and the duration of channel opening are reduced when compared with normal CFTR function.
R117H is the most common class IV variant in White populations [50].
Class V and VI mutations: Reduced amounts of functional CFTR protein — This class of variant is not included in some schemes. It includes variants that alter the stability of mRNA and others that alter the stability of the mature CFTR protein (the latter is sometimes classified separately into a class VI) [55,56]. The mutation A455E has been classified as class II [53] or class V [19,57,58].
GENETIC MODIFIERS —
The inconsistent association between CF genotypes and phenotypes points to a role for gene modifiers. These genetic variations are not directly related to the CFTR gene but affect the severity or clinical manifestations of disease.
Research into a variety of candidate genes is ongoing. These candidate genes may interact with CFTR function in different domains:
●Inflammatory response (TGFB1; interleukins IL8, IL1B, and IL10; TNF; and others)
●Infectious response (MBL2, toll-like receptors, CD14, and others)
●Tissue damage and repair
●Pharmacogenetic response (eg, beta adrenergic receptor ADRB2)
●Ion transport
●Cytoskeletal interaction [59]
Pulmonary disease — Many studies are in early stages, but there is good evidence that the following genes act as modifiers in CF and that approximately 20 percent of patients with classic CF carry genetic variants in one or both of these genes that exacerbate pulmonary disease [60].
●Transforming growth factor-beta (TGF-beta) – TGF-beta, encoded by the TGFB1 gene is a potent suppressor of T cell activation and can decrease T cell proliferation and cytokine production. In a study of 808 patients who were homozygous for F508del, pathogenic variants in TGFB1 were associated with more severe CF lung disease [61]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Role of cytokines in negative feedback' and "The adaptive cellular immune response: T cells and cytokines", section on 'Treg'.)
●MBL2 – Mannose-binding lectin (MBL), encoded by the MBL2 gene, is an important component of the complement system, and deficiencies increase the risk for pyogenic infections. In individuals with CF, pathogenic variants in MBL2 are associated with reduced lung function, increased risk for chronic P. aeruginosa and Burkholderia cepacia complex infections, and early death [62].
In young patients with CF and pancreatic insufficiency, lower MBL protein levels were associated with a steeper rate of decline in lung function and earlier age at first infection with P. aeruginosa [60]. These effects were exaggerated in individuals who also carried a pathogenic variant in TGFB1. (See "Overview and clinical assessment of the complement system", section on 'Lectin pathway activation'.)
●TNF – Tumor necrosis factor (TNF)-alpha, encoded by the TNF gene, is important in response to certain infections. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokines'.)
Variants in the TNF gene may increase susceptibility to P. aeruginosa infection and contribute to the clinical manifestations of CF [63].
Cystic fibrosis-related diabetes — CF-related diabetes (CFRD) has multifactorial causes leading to reduced number of beta cells, reduced islet cell density, and diminished beta cell function. CFRD is more likely to occur in those with severe CFTR pathogenic variants, but there is a wide variety of risk even among patients with the same disease-causing CFTR variants, implicating the potential contribution of modifying genes to its development [64].
Many candidates are under evaluation; among them are:
●SLC26A9 – SLC26A9 encodes an epithelial chloride and bicarbonate channel protein that interacts with CFTR and may alter the function of both channels. Some variants seem to confer increased function of the defective CFTR channel, while others may further reduce its function.
●Genes known to be associated with type 2 diabetes (T2D) – Genome-wide association studies have identified a number of variants in genes that are known to be associated with the development of T2D but not with type 1 diabetes (T1D). These include TCF7L2, which may affect beta cell mass and proinsulin processing, variants of the CDKN2A/CDKN2B locus, and PTMA. It appears that development of CFRD correlates strongly with the genetic risk for T2D and only weakly with known risk factors for T1D [65].
Meconium ileus — Approximately 15 percent of CF patients present with meconium ileus (MI). In a study comparing the incidence of MI in related individuals, groups of monozygous twins, dizygous twins, and siblings were compared. Concordance of MI was greatest among the monozygous twins, indicating that genetic factors played a significant role in its occurrence. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus'.)
Genomic regions that may contain relevant modifier genes have been identified on chromosomes 4, 8, and 11. There are areas on chromosomes 20 and 21 that may confer some protection from MI. Interestingly, distal ileal obstructive syndrome, which is known to occur more frequently in individuals who have had MI, does not appear to be significantly impacted by modifier genes and is more likely related to environmental factors [66].
INCOMPLETE PHENOTYPES
CFTR-related disorder — A CF transmembrane conductance regulator (CFTR)-related disorder is defined as clinical disease limited to only one organ system associated with some evidence of CFTR dysfunction that does not meet full genetic or functional criteria for a CF diagnosis. In general, this diagnosis only applies to individuals who are heterozygous for a CFTR variant; if they have biallelic pathogenic variants, they should be classified as having CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CFTR-related disorder'.)
Clinical manifestations may include isolated obstructive azoospermia, chronic rhinosinusitis, chronic pancreatitis, or pulmonary disease in adulthood [67,68]. The pathogenetic mechanisms responsible for clinical disease without two CFTR gene mutations is unclear, but other genetic or environmental factors likely contribute to the risk in some cases.
CFTR-related metabolic syndrome — CFTR-related metabolic syndrome is a term that describes infants and children with an equivocal diagnosis following newborn screening for CF and is found in 3 to 4 percent of infants with a positive newborn screen (table 3). The term "CF screen positive, inconclusive diagnosis" is equivalent and is used in Europe. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CRMS/CFSPID'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)
SUMMARY
●Genetic basis of cystic fibrosis (CF)
•CF is caused by biallelic pathogenic variants the CFTR gene on chromosome 7; CFTR encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a regulated chloride channel, that transports chloride, bicarbonate, and glutathione. (See 'CFTR gene' above and 'CFTR protein' above.)
•The phenotypic expression of disease varies widely as a function of the specific pathogenic variants present and the presence of gene modifiers. (See 'CFTR pathogenic variants' above.)
●Disease pathogenesis
•CFTR malfunction is associated with low water content in secretions from the respiratory, pancreatic, and biliary epithelium, which causes the secretions to be viscous and difficult to clear. (See 'Abnormal secretions' above.)
•In the gastrointestinal tract, the abnormal bile and pancreatic secretions cause maldigestion and malabsorption, progressive liver and pancreatic disease, rectal prolapse, and intestinal obstruction (distal intestinal obstruction syndrome or intussusception). (See 'Gastrointestinal effects' above.)
•In the lung, the abnormal secretions cause chronic airway obstruction and reduce bactericidal killing, leading to progressive pulmonary colonization with pathogenic bacteria and formation of bacterial biofilms. Chronic infection causes an inflammatory response and tissue destruction, causing bronchiectasis. Infection with Pseudomonas aeruginosa occurs due to abnormally decreased oxygen tension within the hyperviscous mucous layer. (See 'Chronic lung infection' above.)
●CFTR mutation classes – Five different classes of CFTR variants have been defined, as depicted in the figures (figure 3 and figure 4). In general, mutations in classes I to III cause more severe disease than those in classes IV and V. However, the clinical implications of a specific combination of mutations are often unclear and specific mutations should not be used to make assumptions about the severity of disease in an individual patient. (See 'CFTR pathogenic variants' above.)
●Common CFTR mutations
•A subset of the most common CFTR disease variants is recommended for initial testing (table 1). (See 'CFTR pathogenic variants' above.)
•The most common pathogenic variant is F508del (also noted as delta F508 or c.1521_1523delCTT), referring to deletion of three DNA bases coding for the 508th amino acid residue, phenylalanine. Approximately 50 percent of individuals with CF are homozygous for F508del, and 90 percent are compound heterozygous for F508del plus a different CFTR variant. (See 'Class II mutations: Abnormal protein processing' above.)
●Gene modifiers – Genetic modifiers are gene variants distinct from CFTR that affect the severity or clinical manifestations of CF. Genes that encode transforming growth factor-beta (TGFB1), mannose-binding lectin (MBL2), and tumor necrosis factor alpha (TNF) are important genetic modifiers in CF that may exacerbate pulmonary disease. (See 'Genetic modifiers' above.)
●Incomplete phenotypes – CFTR-related disorder (CFRD) refers to limited manifestations in individuals who are heterozygous for a CFTR pathogenic variant. CFTR-related metabolic syndrome refers to infants and children with an equivocal diagnosis following newborn screening for CF. (See 'Incomplete phenotypes' above.)
