CYSTIC FIBROSIS
Cystic fibrosis (CF) is
the most common autosomal recessive life-shortening disease among whites but
also affects all races. There are approximately 30,000 individuals in the
United States with diagnosed CF. Progress in the understanding of the
underlying genetic defect and pathophysiology and the impact of this knowledge
on CF care have been rapid over the past 20 years, resulting in remarkable
improvements in quality of life and survival. These gains have converted CF
from a respiratory and digestive disease of young children to a complex,
multisystem disorder extending into adulthood.
GENETICS
CF is caused by mutations in the CF transmembrane
conductance regulator (CFTR), a 230-kb gene on chromosome 7 encoding a chloride
channel expressed in epithelial cells in the sweat duct, airway, pancreatic
duct, intestine, biliary tree, and vas deferens. More than 1000 mutations in
CFTR have been described, although far fewer have been clearly identified as
causing disease. These mutations can be grouped into six classes based on their
function (Plate 4-45). The level of functional CFTR is important in determining
the manifestations of CF, and the broad spectrum of disease related to CFTR
dysfunction is increasingly being recognized (Plate 4-45). Attempts to predict
the severity of lung disease, the major cause of morbidity and mortality in CF,
from the CFTR genotype have been unsuccessful. It is likely that environmental
factors and modifier genes play important roles in determining the phenotype of
patients with CF.
DIAGNOSIS
Updated guidelines for the diagnosis of CF have
recently been published. Although symptoms suggestive of CF include poor weight
gain, steatorrhea, rectal prolapse, chronic cough, and recurrent sinusitis, CF
is increasingly diagnosed via prenatal or newborn screening. Until the advent
of widespread newborn screening for CF, suspicion for CF arose only from the appearance of symptoms or a family history of the
disease. But by 2010, newborn screening for CF will be universal throughout the
United States, and most individuals will enter the diagnostic algorithm because
of a positive newborn screen result. The primary test for establishing the
diagnosis of CF remains the sweat chloride test, which is performed by the
pilocarpine iontophoresis method. The identification of two CF disease-causing mutations can also establish the
diagnosis.
CLINICAL MANIFESTATIONS
Manifestations of CF may include chronic sinusitis,
recurrent nasal polyposis, progressive obstructive pulmonary disease, exocrine
pancreatic insufficiency, biliary disease, CF-related diabetes, and male infertility. Given the
chronic, complex, multisystem nature of the illness, patients with CF should be
followed in a specialized CF center, such as those accredited in the United
States by the Cystic Fibrosis Foundation.
PULMONARY DISEASE
Lung disease is the primary cause of morbidity and
mortality in people with CF. It is characterized by a vicious cycle of
endobronchial bacterial infection and a vigorous host neutrophilic inflammatory
response, resulting in progressive structural damage (bronchiectasis) and
obstructive lung disease (see Plate 4-46). The airways of CF patients become
infected with a distinctive spectrum of bacterial pathogens, generally acquired
in an age-dependent fashion. Common pathogens at an early age include Staphylococcus
aureus and Haemophilus influenzae. Later, infection with Pseudomonas
aeruginosa becomes increasingly prevalent. At first, P. aeruginosa infection
is intermittent and non-mucoid, but it eventually becomes chronic and mucoid in
phenotype. Acquisition of P. aeruginosa, particularly mucoid strains, is
associated with more rapid clinical deterioration.
Respiratory treatments vary by age and disease
severity; guidelines have recently been published. These treatments, although
dramatically improving pulmonary outcomes over the past 2 decades, also represent
the greatest challenge to patients and families. The inhaled therapies and
airway clearance can take more than 1 hour each day and can cause financial
hardships. Chronic treatments may include airway clearance techniques;
mucolytics such as inhaled rhDNase and hypertonic saline; and in patients
chronically infected with P. aeruginosa, oral macrolides and
alternate-month inhaled antibiotics.
Individuals with CF intermittently experience episodes
of increased cough, increased sputum production, and decline in lung function,
often in conjunction with anorexia and fatigue, termed a pulmonary
exacerbation. Milder exacerbations are typically treated with oral or
inhaled antibiotics coupled with increased airway clearance. Severe
exacerbations or those that fail to resolve with outpatient therapy require
treatment with intravenous antibiotics, generally in the inpatient setting. In an effort to slow or avoid the decline in lung
function associated with chronic Pseudomonas infection, first acquisition
of Pseudomonas spp. is treated with an eradication protocol, which may
include oral, inhaled, or intravenous antibiotics, often in combination.
Complications include hemoptysis and pneumothoraces.
Bilateral lung transplantation is an option for some CF patients with end-stage
lung disease.
GASTROINTESTINAL DISEASE
Approximately 20% of infants with CF present acute
intestinal obstruction caused by meconium ileus in the neonatal period.
Exocrine pancreatic insufficiency occurs in approximately 90% of individuals
affected with CF. Patients with two severe CFTR mutations (class 1, 2, or 3)
present with pancreatic insufficiency, and those with one or more mild mutations (class 4 or 5) may be pancreatic sufficient. Pancreatic
insufficiency places CF patients at risk for fat malabsorption, suboptimal
nutrition, and inadequate circulating levels of fat-soluble vitamins. CF
patients with pancreatic insufficiency are treated with a high-fat, high-calorie
diet and pancreatic enzyme replacement therapy in the form of capsules taken with
each meal. Patients with pancreatic sufficiency are at increased risk of acute
or chronic pancreatitis.
Some level of liver disease is common in CF patients,
with the prevalence increasing with advancing age. Abnormalities may include
elevated transaminases, hepatosteatosis, or biliary tract disease.
Cholelithiasis is also common. A small number of patients develop frank biliary
cirrhosis with portal hypertension. Management of CF liver disease often
includes ursodeoxycholic acid.
ENDOCRINE DISEASE
The prevalence of CF-related diabetes also increases
with advancing age. The prevalence is 9% at ages 5 to 9 years, increasing to
43% for age older than 30 years. CF-related diabetes is a risk factor for more
accelerated decline in lung function and higher mortality. There- fore, routine
screening is recommended. Treatment generally involves maintenance of a
high-fat, high-calorie diet plus insulin therapy.
Osteopenia is also an increasingly recognized com-
plication of CF. The cause is likely related to poor nutritional status,
malabsorption of vitamins K and D, delayed pubertal maturation, steroid
exposure, inactivity, and chronic pulmonary inflammation. Routine screening is
recommended, and prevention via aggressive nutritional interventions,
fat-soluble vitamins, and maximization of pulmonary health is critical.
FERTILITY
At least 98% of men with CF are infertile because of
absence or atresia of the vas deferens and absent or dilated seminal vesicles.
Men with CF can become fathers with artificial insemination procedures. Female
reproduction is normal, and an increasing number of women with CF are becoming
mothers.
PROGNOSIS
Survival of patients with CF has made continuous,
sustained improvements over the past 50 years, with median survival in the
United States improving from 8 years in 1969 to more than 37 years today (see
Plate 4-47). Female survival has been lower than male, but this “gender gap”
appears to be closing. Potential contributors to improved survival include CF center care, aggressive
nutritional support, and the introduction of new pulmonary therapies. Major
quality improvement initiatives, the widespread uptake of newborn screening,
and new therapies aimed at restoring CFTR function and combating chronic
inflammation are sure to result in continued improvement in quality of life and survival for individuals with CF.
