Clinical Description
Cystic fibrosis (CF) affects the epithelia in several organs resulting in a complex, multisystem disease primarily involving the respiratory, gastrointestinal, genitourinary, and endocrine systems and the sweat glands.
Table 2.
Cystic Fibrosis: Frequency of Select Features
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Feature | % of Persons w/Feature 1 | Comments |
---|
Lung disease
| 100% | |
Chronic sinus disease
| ~38% | |
Pancreatic insufficiency
| ~85% | |
Pancreatitis
| ~1% | More common in persons w/PS CFTR variants |
Liver disease
| ~6%-8% | |
Diabetes
| 18% | |
Depression &/or anxiety
| ~15% | |
CF = cystic fibrosis; PS = pancreatic sufficient
- 1.
Respiratory
Pulmonary. Lung disease is the major cause of morbidity and mortality in people with CF. Without adequate ion transport out of the respiratory epithelium via the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, the airway surface layer is not well hydrated. The resulting thickened airway surface layer attracts bacteria; subsequent white blood cell reaction leads to bronchiectasis (an abnormal dilatation of the airways). Bronchiectasis may be detected in infants as early as age ten weeks [Sly et al 2013]. Allergic bronchopulmonary aspergillosis, caused by a hypersensitivity reaction to Aspergillus fumigatus, is monitored by testing of serum IgE. Additional complications from airway damage include hemoptysis and pneumothorax. Progression to severe lung disease occurs in many people with CF, in whom lung transplantation is a treatment option.
Infections. Specific to CF, gram-negative bacteria infections (e.g., Pseudomonas aeruginosa) are especially common. People with CF can also have infections from Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, Hemophilus influenzae, and other bacteria in their airways. Bacterial infections accelerate CF lung disease. When the bacterial load is elevated, pulmonary exacerbations occur, characterized by increased cough and sputum production, decreased lung function, and worsening overall clinical outcomes [Zemanick & Hoffman 2016]. Pulmonary exacerbations contribute to the decline in lung function over time [Waters et al 2012]. Transmission of bacteria between people with CF has been documented; thus, contact precautions should be used when treating all people with CF [Saiman et al 2014].
Otolaryngology. Many people with CF have nasal and sinus complications. Anatomic differences in individuals with CF (e.g., sinus hypoplasia, medial bowing of the lateral nasal wall, lower fovea ethmoidalis) and thickened nasal secretions lead to chronic rhinosinusitis and diffuse pansinusitis, both of which can affect quality of life. Additionally, nasal polyps can lead to nasal obstruction. Hearing loss is more common in individuals with CF as a result of medication side effects (e.g., intravenous aminoglycosides) and is not directly related to disease pathophysiology.
Pancreatic
Exocrine pancreatic insufficiency. Inspissated secretions within the pancreatic ducts block passage of the pancreatic enzymes into the intestines, where they aid in nutrient digestion. Instead, the enzymes autodigest the pancreas, with ultimate interstitial fibrosis leading to pancreatic insufficiency (PI). As a result of inadequate absorption of protein and fat, the clinical manifestations of PI are steatorrhea, excessive gassiness, malnutrition, poor weight gain, and growth deficiency [Sathe & Freeman 2016].
Pancreatitis. Pancreatitis is more likely to occur in individuals with milder CFTR pathogenic variants classified as pancreatic sufficient (PS; 10.3%) versus individuals with pancreatic insufficient (PI; 0.5%) CFTR variants (see Genotype-Phenotype Correlations) [Sathe & Freeman 2016]. Pancreatitis can be a presenting feature of CF in both children and adults.
Gastrointestinal
Bowel manifestations. People with CF can have decreased stomach and bowel transit time, which can contribute to bowel blockage. In the newborn period, inspissated meconium may cause ileus, which often requires surgical intervention. After the newborn period, inspissated stool leads to primarily left-sided stool retention and constipation. Progression to intestinal obstruction syndrome may require significant laxative treatment or surgical intervention [Sathe & Freeman 2016]. Inspissated secretions may also lead to appendiceal obstruction, intussusception, and rectal prolapse. Celiac disease and inflammatory bowel disease have increased prevalence in individuals with CF; the incidence of gastrointestinal cancers is also elevated (23-fold increased lifetime risk) [Sathe & Freeman 2016, Hadjiliadis et al 2018].
Gastroesophageal reflux disease (GERD). People with CF have an increased incidence of GERD compared to those without CF. However, despite approximately 50% of children with CF having evidence of reflux on pH impedance evaluation, close to two thirds had no symptoms [Sathe & Freeman 2016].
Liver disease. CF-associated liver disease includes a wide range of hepatobiliary complications, from transient elevations in liver function tests to focal biliary cirrhosis. In those that develop cirrhotic liver disease, complications include esophageal and gastric varices with or without associated gastrointestinal bleeding, splenomegaly, hypersplenism, encephalopathy, and ascites; liver transplantation is needed in some individuals [Sathe & Freeman 2016]. Liver disease, both cirrhotic and noncirrhotic, occurs in 3.1% and 3.6%, respectively, and is the cause of mortality in 3.2% of individuals with CF [Cystic Fibrosis Foundation Patient Registry 2020].
Endocrine
Diabetes. Cystic fibrosis-related diabetes (CFRD) increases in prevalence with age; approximately 20% of adolescents and 50% of adults have CFRD [Moran et al 2009, Moran et al 2014]. CFRD is distinct from type 1 and type 2 diabetes. Glucose metabolism in CFRD is impaired due to a loss of islet cells leading to absence of insulin and glucagon; fluctuating insulin resistance secondary to inflammation; need for high caloric intake; gut abnormalities; altered intestinal motility; and liver disease [Moran et al 2014, Moran et al 2018].
Additional endocrine-related complications in individuals with CF include delayed puberty and delayed linear growth with reduced adult height [Blackman & Tangpricha 2016].
Musculoskeletal
Osteopenia and osteoporosis develop in individuals with CF as a result of multiple contributing factors (e.g., nutritional deficiencies, inflammation, altered sex steroids) [Blackman & Tangpricha 2016].
Clubbing is apparent when the finger- and toenail beds become convex, leading to a "club"-shaped distal digit. Hypertrophic osteoarthropathy characterized by a combination of clubbing, increased periosteal reaction of tubular bones, arthralgia, and synovial effusions also occurs as a result of CF-related pulmonary disease.
Additional musculoskeletal manifestations include arthritis and thoracic postural defects (e.g., thoracic kyphosis, scoliosis) [Botton et al 2003].
Genitourinary
Fertility is altered in both men and women with CF.
Men with CF often have congenital bilateral absence of the vas deferens (CBAVD) [Yu et al 2012]. This congenital hypoplasia or aplasia usually occurs bilaterally but may occur unilaterally. When the vas deferens are absent, atrophic, or fibrotic, men will have obstructive severe oligospermia or azoospermia. CFTR has also been shown to play a role in spermatogenesis; reduced CFTR expression in men with CBAVD undergoing sperm retrieval has been associated with low sperm count and concentration, decreased motility, decreased bicarbonate sensitivity, and lower fertilization rates. However, most men with CF are infertile but not sterile because testicular development and spermatogenesis can be normal [Shteinberg et al 2021]. Based on this pathophysiology, men with CF are often still able to have biological children through assisted reproductive technology.
Women with CF are typically fertile. However, abnormal, pH imbalanced, and thickened cervical mucus contribute to reduced fertility and infertility in some women with CF [Shteinberg et al 2019, Jain et al 2022]. Women with severe illness, malnutrition, and reduced body mass index may be anovulatory [Shteinberg et al 2021]. Until recent years, pregnancy rates in people with CF had remained relatively stable. With the introduction of highly effective CFTR modulator therapy, the rate of pregnancies has increased; more than 600 pregnancies were reported in women with CF (ages 14 to 45 years) in 2020 and 2021, which was more than twice the pregnancies reported in 2019 [Cystic Fibrosis Foundation Patient Registry 2020, Cystic Fibrosis Foundation Patient Registry 2021].
Salt Loss Syndrome
People with CF are at increased risk for excessive sodium chloride loss across various epithelial surfaces. This is particularly true during infancy and during episodes of sweating, vomiting, or diarrhea. Infants are at increased risk during the transition from human milk or infant formulas to baby food because of the lack of added salt in commercially available baby foods. Because of increased salt losses, people with CF are at increased risk for developing hyponatremic, hypochloremic dehydration. Chronically depleted levels of total body sodium can lead to chronic metabolic alkalosis. Children, adolescents, and adults must monitor dietary salt intake particularly in hot and humid climates and during periods of increased sweating (e.g., physical exercise, illness).
Mental Health
Anxiety and depression are increasingly recognized as major complications of CF. Elevated levels of anxiety have been reported in as high as 22% of the adolescent population and 32% of the adult population, while depression has been reported in as high as 10% of the adolescent population and 19% of the adult population. These rates of increased depression and anxiety are two to three times higher than community samples [Quittner et al 2014].
Palliative care in CF focuses on reducing physical and emotional symptoms and improving quality of life [Kavalieratos et al 2021]. Palliative care occurs alongside usual treatments and is individualized according to the unique goals, hopes, and values of each person [Dellon et al 2018]. One specific area that palliative care can aid in improving the quality of life for people with CF is related to pain, since 60%-89% of children and adults in various studies have reported pain [Masson et al 2017].
Genotype-Phenotype Correlations
The Clinical and Functional Translation of CFTR website provides genotype-phenotype information for CFTR pathogenic variants including sweat chloride, lung function, pancreatic status, and pseudomonas infection rates.
The strongest genotype-phenotype correlations have been identified in the context of pancreatic function. The most common CFTR pathogenic variants have been classified as pancreatic sufficient (PS) or pancreatic insufficient (PI). Individuals who are PS usually have one or two PS alleles, indicating that PS alleles are dominant with respect to pancreatic phenotype [Rueda-Nieto et al 2022].
Beyond pancreatic function, genotype does not consistently predict phenotype. Pulmonary disease severity varies widely among individuals with identical genotypes (see Molecular Genetics, Genetic Modifiers).
CFTR pathogenic variants associated with protein trafficking, channel gating, and channel conductance have approved targeted therapies. See Table 5 and Jia & Taylor-Cousar [2023].