Which non-pulmonary manifestation of cystic fibrosis is commonly seen in this patient population

Practice Essentials

Cystic fibrosis (CF) is a disease of exocrine gland function that involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients. Pulmonary involvement (see the image below) occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

Signs and symptoms

Median age at diagnosis is 6-8 months; however, age at diagnosis varies widely. Clinical manifestations vary with the patient’s age at presentation.

Gastrointestinal (GI) symptoms may include the following:

• Meconium ileus

• Abdominal distention

• Intestinal obstruction

• Increased frequency of stools

• Failure to thrive (despite adequate appetite)

• Flatulence or foul-smelling flatus, steatorrhea

• Recurrent abdominal pain

• Jaundice

• GI bleeding

Respiratory symptoms may include the following:

• Cough

• Recurrent wheezing

• Recurrent pneumonia

• Atypical asthma

• Dyspnea on exertion

• Chest pain

Genitourinary symptoms may include the following:

• Undescended testicles or hydrocele

• Delayed secondary sexual development

• Amenorrhea

Physical signs depend on the degree of involvement of various organs and the progression of disease, as follows:

• 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 chest diameter, clubbing, cyanosis, hyperresonant chest on percussion

• GI tract – Abdominal distention, hepatosplenomegaly, rectal prolapse, dry skin, cheilosis

See Clinical Presentation for more detail.

Diagnosis

Requirements for a CF diagnosis include either positive genetic testing or positive sweat chloride test findings and 1 of the following:

• Typical chronic obstructive pulmonary disease (COPD)

• Documented exocrine pancreatic insufficiency

• Positive family history (usually an affected sibling)

Parameters for the sweat chloride test are as follows:

• The reference value is less than 40 mmol/L

• A value higher than 60 mmol/L of chloride is consistent with CF

• A value of 40-60 mmol/L is considered borderline, and the test must be repeated

• In babies aged 3 months or younger, a value of 30-60 mEq/L is considered borderline and requires retesting [1]

Imaging studies that may be helpful include the following:

• Radiography (chest, sinus, abdomen)

• CT of the chest (not yet advised as a routine modality in CF)

• Ultrasonography

• Contrast barium enema

Additional tests that may be warranted are as follows:

• Genotyping

• Nasal potential difference measurement

• Pulmonary function testing

• Bronchoalveolar lavage

• Sputum microbiology

• Immunoreactive trypsinogen

See Workup for more detail.

Management

The primary goals of CF treatment include the following:

• Maintaining lung function as near to normal as possible by controlling respiratory infection and clearing airways of mucus

• Administering nutritional therapy (ie, enzyme supplements, multivitamin and mineral supplements) to maintain adequate growth

• Managing complications

Mild acute pulmonary exacerbations of CF can be treated successfully at home with the following measures:

• Increasing the frequency of airway clearance

• Inhaled bronchodilator treatment

• Chest physical therapy and postural drainage

• Increasing the dose of the mucolytic agent dornase alfa

• Use of oral antibiotics (eg, fluoroquinolones)

Medications used to treat CF may include the following:

• Pancreatic enzyme supplements

• Multivitamins (including fat-soluble vitamins)

• Mucolytics

• Nebulized, inhaled, oral, or intravenous antibiotics

• Bronchodilators

• Anti-inflammatory agents

• Agents to treat associated conditions or complications (eg, insulin, bisphosphonates)

• Agents devised to reverse abnormalities in chloride transport (eg, ivacaftor [2] )

• Inhaled hypertonic saline

Surgical therapy may be required for the treatment of the following respiratory complications:

• Respiratory – Pneumothorax, massive recurrent or persistent hemoptysis, nasal polyps, persistent and chronic sinusitis

• GI – Meconium ileus, intussusception, gastrostomy tube placement for supplemental feeding, rectal prolapse

Lung transplantation is indicated for the treatment of end-stage lung disease. [3]

See Treatment and Medication for more detail.

Background

Cystic fibrosis (CF) is the most common lethal inherited disease in white persons. [4] 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 but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients (see Clinical). Pulmonary involvement occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

The diagnosis of cystic fibrosis is based on typical pulmonary manifestations, GI tract manifestations, a family history, and positive sweat chloride test results (see Workup). Newborn screening for cystic fibrosis is universally offered in the United States. As a result of the complex and multisystemic involvement of cystic fibrosis and the need for care by specialists, treatment and follow-up care at specialty centers with multidisciplinary care teams (ie, cystic fibrosis centers) is recommended (see Treatment).

Pathophysiology

Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) 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.

Six classes of defects resulting from CFTR mutations have been described and are as follows [5] :

• Complete absence of CFTR protein synthesis

• Defective protein maturation and early degradation (caused by the most common mutation, ΔF508)

• Disordered regulation (diminished ATP binding and hydrolysis)

• Defective chloride conductance or channel gating

• Diminished transcription due to promoter or splicing abnormality

• Accelerated channel turnover from the cell surface

CFTR mutations have poor penetrance. This means that the genotype does not predict the pattern or severity of disease.

Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. Secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues have increased viscosity, which makes them difficult to clear.

Most patients with cystic fibrosis have severe chronic lung disease and exocrine pancreatic insufficiency. Additional manifestations include the following:

• Nasal polyposis

• Pansinusitis

• Rectal prolapse

• Chronic diarrhea

• Pancreatitis

• Cholelithiasis

• Cirrhosis or other forms of hepatic dysfunction

Sinus disease

The exact mechanism by which malfunctioning CFTR causes sinus disease is not completely understood. Chloride ions cannot be excreted, sodium is excessively absorbed, and water passively follows. This desiccates the mucosal surface and alters the viscosity of the normal mucus blanket, which alone can lead to obstruction of sinus ostia. [6]

Additional abnormalities exist in these patients, including ciliary dysfunction, increased inflammatory mediators, and increased colonization with Pseudomonas aeruginosa, all of which further impair normal sinus clearance and aeration. [7] Chronic sinus infection and inflammation are the net result.

Lung disease

Most deaths associated with cystic fibrosis result from progressive and end-stage lung disease. In 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 persons 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. [8] Variations in CFTR and a cystic fibrosis–modifier gene (TGFβ1) amplify the negative effects of secondhand smoke exposure.

Intestinal disease

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 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.

Meconium ileus

The meconium of fetuses with cystic fibrosis and meconium ileus has increased viscosity and decreased water content compared with those of healthy controls. The developmental sequence of mucin secretion in the fetal intestine is not fully understood, although the CFTR ion channel defect possibly leads to dehydration of intraluminal contents.

Meconium in patients with meconium ileus also has higher protein and lower carbohydrate concentration than that in control populations. Albumin is the major protein in the meconium of infants with meconium ileus, and is present in concentrations 5-10 times higher than normal. [9] In addition, there is a significant increase in the liver's production of intraluminal glutamyltranspeptidase (GGTP) and 5'-nucleotidase, which enters the meconium and promotes meconium ileus.

The addition of albumin to normal meconium makes it viscid; the addition of pancreatic protease liquefies the viscid mass. This led to the belief that pancreatic insufficiency played a central role in the pathogenesis of meconium ileus, although pancreatic insufficiency is not the sole cause of abnormal meconium in meconium ileus. In 1988, however, Lands et al reported 2 infants with cystic fibrosis and meconium ileus, aged 9 and 11 months, who displayed no clinical evidence of pancreatic insufficiency. [10]

In the murine model of cystic fibrosis, developed in 1992, newborn mice had severe intestinal obstruction at birth with minimal pulmonary or pancreatic involvement. These animal studies support the concept that meconium ileus may occur in patients with sufficient pancreatic activity. The lack of concordance between meconium ileus and severity of pancreatic disease suggests that intraluminal intestinal factors contribute to meconium ileus development.

Abnormal intestinal motility may also contribute to meconium ileus development. Some patients with cystic fibrosis have prolonged small intestinal transit times. Diseases other than cystic fibrosis in which there is abnormal gut motility (eg, Hirschsprung disease, chronic intestinal pseudo-obstruction) have been associated with meconium ileus–like disease, suggesting that decreased peristalsis may allow increased resorption of water, thus favoring meconium ileus development.

Pancreatic disease

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 pancreatic insufficiency and sufficiency. Reduced bicarbonate secretion affects the digestion so that neither endogenous nor exogenous pancreatic enzymes can work at their optimal pH.

Other factors, such as reduced 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. Onset of pancreatic insufficiency varies, however, and may occur in patients older than 6 months. Some patients never develop pancreatic insufficiency.

Patients with pancreatic insufficiency 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.

Pancreatic insufficiency 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 disease

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 their pancreatic function. Abnormal mucin in the gallbladder and malabsorption of bile acids in a patient with PI result in a higher frequency of gallstones.

Urogenital disease

Congenital absence of vas deferens may result in male infertility. Undescended testicles or hydroceles may be present in boys. Fertility is possibly decreased in females. Amenorrhea may occur in females with severe nutritional or pulmonary involvement.

Etiology

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 also regulates the flow of other ions across the apical surface of epithelial cells. In 1989, the CF locus was localized through linkage analysis to the long arm of human chromosome 7, band q31. [11]

Thus far, 1893 CFTR mutations have been identified. [12] Half of affected individuals of northern European descent are homozygous for the ΔF508 mutation, which is the deletion of a single phenylalanine residue at amino acid 508 of the CFTR gene (a class II defect). Another 25%-30% have one copy of ΔF508 plus another mutation. [13]

Certain alleles cluster with increased frequency in specific populations. For example, W1282X is common in Ashkenazi Jews, and A455E is common both in Dutch people and in individuals from northern Quebec. Δ1152H is the third most prevalent allele in Ashkenazi and other ethnic Jewish groups. The prevalence of Δ1152 mutation in Jewish populations comprises 5.2% of all CFTR mutations.

CFTR mutations result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. 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.

Genotype-phenotype correlation demonstrates that ΔF508 homozygosity nearly always confers a pancreatic exocrine insufficiency. Individuals with 1 or 2 copies of missense mutations (eg, R117H) tend to be pancreatic sufficient and have milder disease.

The incidence of meconium ileus is higher in patients who are homozygous for ΔF508 or who have ΔF508 plus G542X. Conversely, not all patients with these genotypes have meconium ileus, so other non -CFTR factors must be involved in meconium ileus pathogenesis.

The incomplete correlation of genotype with phenotype suggests either an environmental component of organ dysfunction or modifying genes that are only recently being characterized. [14] The role of modifier genes is supported by the fact that neonates with cystic fibrosis who have intestinal obstruction most commonly have abnormalities in 2 or more CFTR modifier genes. In contrast, older children develop obstruction mostly as a result of environmental factors, such as introduction of pancreatic enzymes causing a stricture. [15, 16]

Studies in murine CF models have shown an increase in mast cells and neutrophils as part of the immune response. For example, the KITL gene plays a vital role in the differentiation of mast cells, as demonstrated by a decreased expression of MCPT2. Another focus includes the proteins selectin and intercellular adhesion molecule–1 (ICAM-1), which facilitate neutrophil extravasation. Neutrophils and mast cells release proteases, prostaglandins, and histamine, influencing mucus production.

A research model found in CFTR- knockout gene mice highlighted the importance of MCLCA3 expression in goblet cells. This gene influences mucus production, among other activities, and its expression was noted to be diminished in these mice. Correction of this deficiency increased survival and decreased intestinal disease. In humans, this finding may translate to applications such as correcting modifier genes (eg, HCLCA1) in order to improve outcomes in patients with CF. [17]

Additional genetic modifiers include a 129/Sv allelic contribution in mice that yields a milder inflammatory response in CF and is potentially linked to chromosomes 1, 9, and 10. The regulation of these genes and processes helps explain the range of phenotypic variability in similar genetic mutations.

Epidemiology

Cystic fibrosis is an autosomal-recessive disease. Its estimated heterozygote frequency in white people is up to 1 in 20. Each offspring of 2 heterozygote parents has a 25% chance of developing cystic fibrosis.

Cystic fibrosis is the most common lethal hereditary disease in the white population. In the United States, the prevalence is as follows:

• Whites of northern European origin - 1 case per 3,200-3,500 population

• Hispanics - 1 case per 9,200-9,500 population

• African Americans - 1 case per 15,000-17,000 population

• Asian Americans - 1 case per 31,000 population

The worldwide incidence varies from 1 per 377 live births in parts of England to 1 per 90,000 Asian live births in Hawaii. The higher frequency in Asian American or African American populations compared with native Asians or Africans reflects white admixture. [18]

Race demographics

The distribution of CFTR mutations varies according to the background of patients; for example, ΔF508 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 demographics

Compared with males, females with cystic fibrosis have greater deterioration of pulmonary function with increasing age and younger mean age at death. [19] Although it has been suggested that the increase in hormone secretion with puberty in females 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.

Prognosis

Worldwide, the median survival age in patients with cystic fibrosis varies from country to country; it is highest in the United States. [20] Median survival age is 36.9 years, but progress in medical and surgical treatment options have improved the prognosis over the last few decades. An individual with cystic fibrosis born in the United States today is expected to survive longer than 40 years. [21] The median survival age is higher in males than in females.

With current treatment strategies, 80% of patients should reach adulthood. Nevertheless, cystic fibrosis remains a life-limiting disease, and a cure for the disease remains elusive.

The clinical presentation, age at diagnosis, severity of symptoms, and rate of disease progression in the organs involved widely vary. 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. [22]

GI tract complications include pancreatic involvement. Pancreatic tissue damage leads to diabetes mellitus in 8-12% of patients older than 25 years. Excessive administration of exogenous pancreatic enzymes can result 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. Portal hypertension occasionally causes death through esophageal varices. 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.

Severity of pulmonary disease determines prognosis and ultimate outcome. Pulmonary involvement is progressive: beginning as bronchitis, bronchiolitis, and then bronchiectasis, pulmonary involvement leads to cor pulmonale and end-stage lung disease. Cause of death is generally respiratory failure and cor pulmonale.

A review of 6750 deaths due to cystic fibrosis in England and Wales from 1959-2008 reported that female sex and low socioeconomic status are associated with poorer outcomes than male sex and high socioeconomic status. [23]

A study of 1517 patients with cystic fibrosis who were registered with the UK Cystic Fibrosis Registry showed that lower muscle mass, shorter stature, and a low body mass index are associated with increased mortality. [24]

In a prospective observational study of 3142 patients from the Cystic Fibrosis Foundation Registry, weight for age percentile at 4 years of age was associated with improved clinical outcomes including lung function, fewer complications of cystic fibrosis and better survival through the age of 18. [25]

Patient Education

Provide counseling at the time of initial diagnosis, including information regarding inheritance and risk for recurrence in subsequent pregnancies, and instruct patients and parents regarding appropriate airway clearance technique and the need for chest physical therapy. Also, instruct patients and parents regarding the use of various drug delivery devices, such as valved holding chambers, and nebulizers, and the methods for modifying the pancreatic enzyme dosage.

Discuss when to contact cystic fibrosis center personnel (eg, for acute pulmonary exacerbation or complications) with patients and parents, and be prepared to counsel families regarding the impact of the diagnosis on the emotional life of parents, siblings, and members of the extended family.

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Author

Girish D Sharma, MD, FCCP, FAAP Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush Children's Hospital, Rush University Medical Center

Girish D Sharma, MD, FCCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Charles Callahan, DO Professor, Chief, Department of Pediatrics and Pediatric Pulmonology, Tripler Army Medical Center

Charles Callahan, DO is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American College of Osteopathic Pediatricians, American Thoracic Society, Association of Military Surgeons of the US, Christian Medical and Dental Associations

Disclosure: Nothing to disclose.

Chief Editor

Kenan Haver, MD Associate Professor of Pediatrics, Harvard Medical School; Director of Asthma Program, Director of Flexible Bronchoscopy Program, Director of Pulmonary Division Asthma Program, Co-Director of Primary Ciliary Dyskinesia, Co-Leader of Empyema Standardized Clinical Assessment and Management Plans (SCAMP), Boston Children’s Hospital

Kenan Haver, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society

Disclosure: Author for: UptoDate.

Additional Contributors

Susanna A McColley, MD Professor of Pediatrics, Northwestern University, The Feinberg School of Medicine; Director of Cystic Fibrosis Center, Head, Division of Pulmonary Medicine, Children's Memorial Medical Center of Chicago

Susanna A McColley, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Sleep Disorders Association, American Thoracic Society

Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from Genentech for consulting; Partner received consulting fee from Boston Scientific for consulting; Received honoraria from Gilead for speaking and teaching; Received consulting fee from Caremark for consulting; Received honoraria from Vertex Pharmaceuticals for speaking and teaching.

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