Cystic Fibrosis

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Cystic Fibrosis

Chapter Objectives

After reading this chapter, you will be able to:

• List the anatomic alterations of the lungs associated with cystic fibrosis.

• Describe the causes and classifications of cystic fibrosis.

• List the cardiopulmonary clinical manifestations associated with cystic fibrosis.

• Describe the general management of cystic fibrosis.

• Describe the clinical strategies and rationales of the SOAPs presented in the case study.

• Define key terms and complete self-assessment questions at the end of the chapter and on Evolve.

Key Terms

Anatomic Alterations of the Lungs*

Although the lungs of patients with cystic fibrosis appear normal at birth, abnormal structural changes develop quickly. Initially, the patient has bronchial gland hypertrophy and metaplasia of goblet cells, which secrete large amounts of thick, tenacious mucus. Because the mucus is particularly tenacious, impairment of the normal mucociliary clearing mechanism ensues, and many small bronchi and bronchioles become partially or totally obstructed (mucous plugging). Partial obstruction leads to overdistention of the alveoli, and complete obstruction leads to patchy areas of atelectasis. The anatomic alterations of the lungs associated with cystic fibrosis may result in both restrictive and obstructive lung characteristics, but excessive bronchial secretions, bronchial obstruction, and hyperinflation of the lungs are the predominant features of cystic fibrosis in the advanced stages.

The abundance of stagnant mucus in the tracheobronchial tree also serves as an excellent culture medium for bacteria, particularly Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa. Some gram-negative bacteria are also commonly associated with cystic fibrosis, such as Stenotrophomonas maltophilia, Burkholderia cepacia, Burkholderia pickettii, and Burkholderia gladioli. The infection stimulates additional mucous production and further compromises the mucociliary transport system. This condition may lead to secondary bronchial smooth muscle constriction. Finally, as the disease progresses, the patient may develop signs and symptoms of recurrent pneumonia, chronic bronchitis, bronchiectasis, and lung abscesses (Figure 14-1).

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FIGURE 14-1 Cystic fibrosis. AT, Atelectasis; HALV, hyperinflation of alveoli; MA, mucous accumulation; MP, mucous plug; PO, partial obstruction of the airways.

The major pathologic or structural changes associated with cystic fibrosis are as follows:

Etiology and Epidemiology

Cystic fibrosis is the most common inherited disorder in childhood. Cystic fibrosis is an autosomal recessive gene disorder caused by mutations in a pair of genes located on chromosome 7. Under normal conditions, every cell in the body (except the sex cells) has 46 chromosomes—23 pairs (one half inherited from father and the other half from mother). Over 1000 different mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) have been described. One genetic defect linked to cystic fibrosis involves the absence of three base pairs in codon 508 (ΔF508) that codes for phenylalanine on chromosome 7 (band q31). Because of the loss of these three base pairs, the CFTR gene becomes dysfunctional. This is the most common genetic mutation associated with cystic fibrosis and accounts for 70% to 75% of the cystic fibrosis patients tested.

The abnormal expression of the CFTR results in abnormal transport of sodium and chloride across many types of epithelial surfaces, including those lining the bronchial airways, intestines, pancreas, liver ducts, sweat glands, and vas deferens. As a result, thick, viscous mucus accumulates in the lungs, and mucus blocks the passageways of the pancreas, preventing enzymes from the pancreas from reaching the intestines. This condition inhibits the digestion of protein and fat, which in turn leads to deficiencies of vitamins A, D, E, and K. In addition, diarrhea, malnutrition, and weight loss are also common. Some infants with cystic fibrosis develop a blockage of the intestine shortly after birth—a condition called meconium ileus. Most men with cystic fibrosis are infertile as a result of a missing or an underdeveloped vas deferens. Infertility is not common in women with cystic fibrosis.

How the Cystic Fibrosis Gene Is Inherited

Because cystic fibrosis is a recessive gene disorder, the child must inherit two copies of the defective cystic fibrosis gene—one from each parent (cystic fibrosis carriers)—to have the disease. Even though the carrier of the cystic fibrosis gene may be identified through genetic testing, the carrier (heterozygote) does not demonstrate evidence of the disease. However, if both parents carry the cystic fibrosis gene, the possibility of their children having cystic fibrosis (regardless of gender) follows the standard Mendelian pattern: there is a 25% chance that each child will have cystic fibrosis, a 25% chance that each child will be completely normal (and not carry the gene), and a 50% chance that each child will be a carrier. Thus, when both patients have the cystic fibrosis gene, there is a one in four chance that the child will have cystic fibrosis (Figure 14-2). It is estimated that more than 10 million Americans are unknowing, symptomless carriers of the mutant cystic fibrosis gene.

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FIGURE 14-2 Standard Mendelian pattern of inheritance of cystic fibrosis.

According to the Cystic Fibrosis Foundation, cystic fibrosis affects about 30,000 children and adults in the United States. About 1000 new cases of cystic fibrosis are diagnosed each year in the United States (70,000 worldwide). More than 70% of the patients are diagnosed by age 2. More than 40% of the cystic fibrosis patient population is age 18 or older.* Other researchers state that whites are most often affected (1 in 2500 to 3500). Cystic fibrosis is less common in Hispanics (1 in 9500) and African-Americans (1 in 17,000). Cystic fibrosis is rarely seen in Asians (1 in 31,000). The predicted median life expectancy is 37 years. Death usually is caused by pulmonary complications.

Screening and Diagnosis

The diagnosis of cystic fibrosis is based on clinical manifestations associated with cystic fibrosis, family history of cystic fibrosis, and laboratory findings. Box 14-1 provides common clinical indicators that justify evaluation for cystic fibrosis.

Box 14-1   Clinical Indicators Justifying the Initial Evaluation for Cystic Fibrosis

Pulmonary

The diagnosis of cystic fibrosis is based on results of one or more of the laboratory tests discussed in the following sections.

Sweat Test

The sweat test (sometimes called the sweat chlorine test) is the gold standard diagnostic test for cystic fibrosis. The sweat test is a reliable test for the identification of approximately 98% of patients with cystic fibrosis. This test measures the amount of sodium and chloride in the patient’s sweat. During the procedure a small amount of a colorless, odorless sweat-producing chemical called pilocarpine is applied to the patient’s arm or leg—usually the forearm. An electrode is attached to the chemically prepared area, and a mild electric current is applied to stimulate sweat production (Figure 14-3). To collect the sweat, the area is covered with a gauze pad or filter paper and wrapped in plastic. After about 30 minutes the plastic is removed, and the sweat collected in the pad or paper is sent to the laboratory for analysis. The test is usually done twice.

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FIGURE 14-3 Sweat test. During the procedure a small amount of a colorless, odorless sweat-producing chemical called pilocarpine is applied to the patient’s arm or leg—usually the forearm. An electrode is attached to the chemically prepared area, and a mild electric current is applied to stimulate sweat production. Used with permission Wescor, Inc—an ELITech Group Company. Used with permission Wescor, Inc—ELITech Group Company.

Although the sweat glands of patients with cystic fibrosis are microscopically normal, the glands secrete up to four times the normal amount of sodium and chloride. The actual volume of sweat, however, is no greater than that produced by a normal individual. In children, a sweat chloride concentration greater than 60 mEq/L is considered to be a diagnostic sign of the disease. In adults, a sweat chloride concentration greater than 80 mEq/L usually is required to confirm the diagnosis. The sweat chloride level in the patient with cystic fibrosis may be up to five times greater than normal.

Immunoreactive Trypsinogen Test

An immunoreactive trypsinogen test (IRT) (also called trypsin-like immunoreactivity, serum trypsinogen, and serum trypsin) may be ordered as an initial test for (1) babies who are not creating enough sweat to perform a sweat test, or (2) infants with meconium ileus (no stools in the first 24 to 48 hours of life). The test may be particularly useful for small or malnourished infants in whom the sweat chloride test cannot be performed successfully. An IRT is also ordered for children and adults with signs and symptoms associated with cystic fibrosis and pancreatic dysfunction, such as persistent diarrhea; foul-smelling, bulky, greasy stools; malnutrition; and vitamin deficiency. During this procedure, a blood sample is analyzed twice for a specific protein called trypsinogen. Patients with cystic fibrosis have elevated blood levels of IRT. Two positive test results indicate cystic fibrosis, abnormal pancreatic enzyme production, pancreatitis, or pancreatic cancer. Elevated levels need to be followed with further testing, such as a cystic fibrosis gene mutation test.

Nasal Potential Difference

The impaired transport of sodium (Na+) and chloride (Cl−) across the epithelial cells lining the airways of the cystic fibrosis patient can be measured. As the Na+ and Cl− ions move across the epithelial cell membrane they general what is called an electrical potential difference—the amount of energy required to move an electrical charge from one point to another. In the nasal passages this electrical potential difference is called the nasal potential difference (NPD). The NPD can be measured with a surface electrode over the nasal epithelial cells lining the inferior turbinate. An increased (i.e., more negative) nasal potential difference strongly suggests cystic fibrosis. The NPD is recommended for patients with clinical features of cystic fibrosis who have borderline or normal sweat test values and nondiagnostic cystic fibrosis genotyping.

Genetic Testing

With a sample of the patient’s blood, a genetic test (also called a genotype test, gene mutation test, or mutation analysis) can be performed to analyze deoxyribonucleic acid (DNA) for the presence of CFTR gene mutations. From over 1000 different CFTR gene mutations, the most common gene alteration in cystic fibrosis is ΔF508. Although genetic testing for cystic fibrosis is considered a valuable diagnostic tool, it does have its limitations. For example, some individuals have CFTR mutations but demonstrate no typical clinical manifestations of cystic fibrosis. In addition, some patients may have CFTR mutations, but the mutations cannot be identified with our current gene analysis methods. It is estimated that genetic testing can confirm cystic fibrosis in about 80% to 85% of the patients tested. As a general rule, genetic testing is performed in patients who have negative sweat test results but still demonstrate a variety of clinical manifestations associated with cystic fibrosis (see following section).

Prenatal Testing

In women who are pregnant and who wish to make informed reproductive decisions, prenatal diagnosis may be performed by chorionic villus biopsy in the first trimester or by amniocentesis in the second or third trimester. Such testing is usually carried out in a family that has previously had a child with cystic fibrosis.

image OVERVIEW of the Cardiopulmonary Clinical Manifestations Associated with Cystic Fibrosis

The following clinical manifestations result from the pathophysiologic mechanisms caused (or activated) by Atelectasis (see Figure 9-8), Bronchospasm (see Figure 9-11), and Excessive Bronchial Secretions (see Figure 9-12)—the major anatomic alterations of the lungs associated with cystic fibrosis (CF) (see Figure 14-1).

CLINICAL DATA OBTAINED AT THE PATIENT’S BEDSIDE

The Physical Examination

Spontaneous Pneumothorax

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