eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Cystic Fibrosis

Author: Girish D Sharma, MD, Associate Professor, Department of Pediatrics, Rush University Medical Center, Rush Children's Hospital; Director of Pediatric Pulmonary Section and Rush Cystic Fibrosis Center
Contributor Information and Disclosures

Updated: Nov 19, 2009

Introduction

Background

Cystic fibrosis (CF) is the most common lethal inherited disease in white persons.¹ Cystic fibrosis is an autosomal recessive disorder, and most carriers of the gene are asymptomatic. Cystic fibrosis is a disease of exocrine gland function that involves multiple organ systems and chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients. Pulmonary involvement occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

Pathophysiology

Cystic fibrosis is caused by defects in the gene for cystic fibrosis transmembrane conductance regulator (CFTR), which encodes for a protein that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. Resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which results in infection and inflammation. These abnormalities result in viscid secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.

Lung

Most fatalities associated with cystic fibrosis result from progressive lung disease. For individuals with cystic fibrosis, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation (except possibly for the presence of dilated submucosal gland ducts in the airways). Shortly after birth, many patients with cystic fibrosis acquire a lung infection, which incites an inflammatory response. Infection becomes established with a distinctive bacterial flora. A repeating cycle of infection and neutrophilic inflammation develops.

Cleavage of complement receptors CR1 and C3bi and immunoglobulin G (IgG) by neutrophil elastase (NE) results in failure of opsonophagocytosis, leading to bacterial persistence. NE also causes production of the neutrophil chemoattractant interleukin (IL)–8 from epithelial cells and elastin degradation and acts as secretogogue, thereby contributing to persistence of inflammation and infection, structural damage, impaired gas exchange, and, ultimately, end-stage lung disease and early death. One study reported that exposure to secondhand smoke adversely affects both cross-sectional and longitudinal measures of lung function in individuals with cystic fibrosis.² Variations in CFTR and a cystic fibrosis–modifier gene (TGFβ1) amplify the negative effects of secondhand smoke exposure.

Intestine

Defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life. In addition, other pathologic disorders complicate the simple relationship between the apical chloride and water secretion and the disease. The pancreatic insufficiency (PI) decreases the absorption of intestinal contents. Mechanical problems associated with inflammation, scarring, and strictures may predispose the patient to sludging of intestinal contents, leading to intestinal obstruction by fecal impaction or to intussusception. Adhesions may form, leading to complete obstruction. A complete obstruction may require resection, leading to loss of absorptive epithelium of the distal ileum.

Pancreas

As a part of normal digestion, stomach acid is neutralized by pancreatic bicarbonate, leading to the optimal pH for pancreatic enzyme action. Reduced bicarbonate secretion in response to secretin stimulation has been demonstrated in patients with cystic fibrosis with both PI and pancreatic sufficiency (PS). Reduced bicarbonate secretion affects the digestion so that neither endogenous nor exogenous pancreatic enzymes can work at their optimal pH.

Other factors, such as reduction of water content of secretions, precipitation of proteins, and plugging of ductules and acini, prevent the pancreatic enzymes from reaching the gut. Autodigestion of the pancreas occasionally leads to pancreatitis. Most patients with cystic fibrosis (90-95%) have pancreatic enzyme insufficiency and present with digestive symptoms and/or failure to thrive early in life. However, onset of PI varies and may occur in patients older than 6 months.

Some patients never develop PI. Patients with PI typically present with poor weight gain in association with frequent stools that are malodorous, greasy, and associated with flatulence and colicky pain after feeding. The combination of increased energy intake demand at baseline, the added energy intake demand of chronic disease, difficulty sustaining energy uptake because of malabsorption, and anorexia associated with ongoing lung inflammation leads to poor weight gain. PI predisposes patients to poor absorption of fat-soluble vitamins A, D, E, and K. Symptomatic deficiency of any of these vitamins can occur before diagnosis or as a later complication of the disease.

Liver

Absence of functional CFTR in epithelial cells lining the biliary ductules leads to reduced secretion of chloride and reduction in passive transport of water and chloride, resulting in increased viscosity of bile. The biliary ductules may be plugged with secretions. If this process is extensive, obstructive cirrhosis complicated by esophageal varices, splenomegaly, and hypersplenism may occur. Secondary involvement of the liver may also occur because of involvement of other organs; for example, malnutrition may be associated with hepatic steatosis, and right heart failure caused by chronic hypoxia may result in passive congestion of the liver.

Gallstones are more prevalent in patients with cystic fibrosis than in age-matched control subjects. As many as 15% of young adults with cystic fibrosis have gallstones, irrespective of the status of the pancreatic function. Abnormal mucin in the gallbladder and malabsorption of bile acids in a patient with PI result in a higher frequency of gallstones.

Frequency

United States

Cystic fibrosis is the most common lethal disease inherited by the white population. Cystic fibrosis is inherited as an autosomal recessive trait. In the United States white population of Northern European origin, prevalence is 1 case per 3,200 population. In blacks, prevalence is 1 case per 15,000 population. In Hispanics, prevalence is 1 case per 9,200 population. In Asian Americans, prevalence is 1 case per 31,000 population.

International

Prevalence ranges from 1 case per 620 in a confined population with Dutch ancestry to 1 case per 90,000 in Asians.

Mortality/Morbidity

Currently, the median age of survival is 36.9 years; the median age of survival is significantly higher in males than in females. Pulmonary involvement is progressive. Beginning as bronchitis, bronchiolitis, and then bronchiectasis, pulmonary involvement leads to cor pulmonale and end-stage lung disease. Hemoptysis and pneumothorax are complications.

Sweat abnormalities may result in heat stroke and salt depletion, especially in infants. Mucocele and mucopyocele associated with chronic sinusitis and nasal polyps can cause erosion of the sinus wall, resulting in CNS complications from the space-occupying effect of mucopyocele or from associated complications.³ Portal hypertension occasionally causes death through esophageal varices.

The clinical presentation, age at diagnosis, severity of symptoms, and rate of disease progression in the organs involved widely vary. GI tract complications result from pancreatic involvement (leading to insufficient pancreatic enzymes), pancreatic tissue damage (leading to diabetes mellitus in 8-12% of patients >25 y), and excessive administration of exogenous pancreatic enzymes (resulting in fibrosing colonopathy).

Intestinal complications range from meconium ileus with associated complications during the neonatal period (12% of neonates with cystic fibrosis) to distal intestinal obstruction syndrome, rectal prolapse, peptic ulcer, and gastroesophageal reflux. Liver involvement may result in a fatty liver (30-60% of patients), focal biliary cirrhosis, multinodular biliary cirrhosis, and associated portal hypertension.

The prevalence of cholecystitis and gallstones is higher in patients with cystic fibrosis than in other individuals. Delayed puberty and reduced fertility are other complications; most males are azoospermic because of agenesis of the vas deferens. Female fertility is probably only mildly impaired, and many successful pregnancies have been reported in women with cystic fibrosis.

Race

Distribution of CFTR mutations varies according to the background of patients; for example, 508delF is the most common mutation found in the white population of Northern European origin. Variability in clinical features between people of different races with same genotype has not been reported. Clinical manifestations are similar in black and white populations, except that a poorer nutritional status is observed in black patients. Black patients with cystic fibrosis are younger at diagnosis and have poorer nutritional status and pulmonary function than white patients with cystic fibrosis. Whether this is genetic or due to socioeconomic factors is unclear; low socioeconomic status is associated with significantly worse pulmonary outcomes in patients with cystic fibrosis.

Sex

Male patients with cystic fibrosis appear to be less affected than female patients with cystic fibrosis. Females have greater deterioration of pulmonary function with increasing age and younger mean age at death. Although the idea has been suggested that the increase in hormone secretion related to menarche may interfere with the defense mechanisms of the immune system, thereby promoting progressive pulmonary involvement, the immune system in patients with cystic fibrosis is fundamentally intact.

Age

Clinical manifestations vary with the patient's age at presentation; for example, neonates may present with meconium ileus or, rarely, with other features such as anasarca. In patients younger than 1 year, patients can present with wheezing, coughing, and/or recurring respiratory infections and pneumonia. GI tract presentation in early infancy may be in the form of steatorrhea, failure to thrive, or both. Patients diagnosed later in childhood or in adulthood have PS more frequently and often present with chronic cough and sputum production.

Clinical

History

A correlation is emerging between the specific mutation and the patient's clinical condition. Based on current knowledge of the association between genotype and phenotype, the clinical characteristics of patients with cystic fibrosis (CF) are divided into severe, milder than severe, and variable phenotypes.

• GI tract manifestations (intestinal)
  • Neonates: Infants may present with intestinal obstruction at birth and various surgical findings (eg, meconium ileus [7-10% of patients with cystic fibrosis], volvulus, intestinal atresia, perforation, meconium peritonitis). Less commonly, passage of meconium may be delayed (>24-48 h after birth) or cholestatic jaundice may be prolonged.
  • Infants and children: Patients present with increased frequency of stools, which suggests malabsorption (ie, fat in stools, oil drops in stools), failure to thrive, intussusception (ileocecal), or rectal prolapse.
• GI tract manifestations (pancreatic)
  • Patients with pancreatic insufficiency (PI) have fat-soluble vitamin deficiency and malabsorption of fats, proteins, and carbohydrates (however, malabsorption of carbohydrates is not as severe as that of fats and proteins). Steatorrhea is characterized by frequent, poorly formed, large, bulky, foul-smelling, greasy stools that float in water. Cloth diapers, if used, are difficult to clean.
  • Patients present with failure to thrive (despite an adequate appetite), flatulence or foul-smelling flatus, recurrent abdominal pain, and abdominal distention. Alternatively, some patients have anorexia without obvious steatorrhea. Many infants have symptoms of gastroesophageal reflux.
• GI tract manifestations (hepatobiliary): Patients may present with a history of jaundice or gastrointestinal tract bleeding.
• Respiratory tract manifestations
  • Patients present with a chronic or recurrent cough, which can be dry and hacking at the beginning and can produce mucoid (early) and purulent (later) sputum. Prolonged symptoms of bronchiolitis occur in infants.
  • Paroxysmal cough followed by vomiting may occur.
  • Recurrent wheezing, recurrent pneumonia, atypical asthma, pneumothorax, hemoptysis, and digital clubbing are all complications and may be the initial manifestation.
  • Dyspnea on exertion, history of chest pain, recurrent sinusitis, nasal polyps, and hemoptysis may occur.
• Urogenital tract manifestations
  • Males are frequently sterile because of the absence of the vas deferens. Undescended testicles or hydrocele may be present.
  • Fertility is maintained, although possibly decreased, in females. Secondary sexual development is often delayed.
  • Amenorrhea may occur in patients with severe nutritional or pulmonary involvement.

Physical

Physical signs depend on the degree of involvement of various organs and the progression of disease.

• Nose
  • Rhinitis
  • Nasal polyps
• Pulmonary system
  • Tachypnea
  • Respiratory distress with retractions
  • Wheeze or crackles
  • Cough (dry or productive of mucoid or purulent sputum)
  • Increased anteroposterior diameter of chest
  • Clubbing
  • Cyanosis
  • Hyperresonant chest upon percussion: Crackles are heard acutely in associated pneumonitis or bronchitis and chronically with bronchiectasis.
• GI tract
  • Abdominal distention
  • Hepatosplenomegaly (fatty liver and portal hypertension)
  • Rectal prolapse
  • Dry skin (vitamin A deficiency)
  • Cheilosis (vitamin B complex deficiency)
• Other systems
  • Scoliosis
  • Kyphosis
  • Swelling of submandibular gland or parotid gland
  • Aquagenic wrinkling of the palms (AWP): A recent study reported an association between AWP and cystic fibrosis.⁴ Among patients with cystic fibrosis, a greater degree of AWP is observed in patients who are homozygous for the 508delF mutation.

Causes

• Cystic fibrosis is an autosomal recessive disease caused by defects in the CFTR gene, which encodes for a protein that functions as a chloride channel and is regulated by cAMP. CFTR mutations result in abnormalities of cyclic adenosine monophosphate (cAMP)-regulated chloride transport across epithelial cells on the mucosal surfaces. Thus far, 1604 CFTR mutations have been identified.⁵
• The failure of chloride conductance by epithelial cells and associated water transport abnormalities result in viscid secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.

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