Cystic Fibrosis

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Cystic fibrosis

Autosomal recessive disease affecting upper & lower airway, lungs, exocrine pancreas, small & large intestines, hepatobiliary system, salivary & sweat glands, and the vas deferens

Most common fatal autosomal recessive disease among Caucasian populations

Occurs in 1 in 3000 Caucasians, 1:9200 Hispanics, 1:10,900 Native Americans, 1:15,000 African Americans, and 1:30,000 Asian Americans

Affected gene:  Cystic fibrosis transmembrane regulator (CFTR), chromosome 7

 

Transmembrane chloride channel

Regulates other ion channels, including ENaC, K channels, gap junction channels, and other cellular processes

Most common cystic fibrosis mutation:  DF508; results in abnormal folding, processing, and trafficking of CFTR protein

CFTR function is tissue-specific à impact of mutations is also tissue-specific

Defect in NaCl reabsorption in sweat glands à hypertonic sweat

Reduction in secretion of mucus in respiratory tract

Reduction in exocrine pancreatic secretions

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http://discovermagazine.com/2013/september/14-doorway-to-a-cure

 

Classic CF

At least one phenotypic characteristic and elevated sweat chloride concentration (>60 mmol/L)

One established CF-causing mutation on each copy of the CF transmembrane regulator (CFTR) gene

Severity of disease varies; patients may or may not have pancreatic insufficiency

 

Non-classic CF

Presence of clinical disease in at least one organ system and normal (<30 mmol/L) or borderline (30-60 mmol/L) sweat chloride

1 disease causing mutation on each copy of the CFTR gene, or CFTR dysfunction detected by nasal potential difference measurements

Most patients have exocrine pancreatic insufficiency and milder lung disease

Notes:

Family history of CF can be helpful in establishing diagnosis

Other causes of elevated sweat chloride levels include adrenal insufficiency, hypothyroidism, malnutrition, mucopolysaccharidoses, glycogen storage diseases, familial hypoparathyroidism, lab errors

 

Clinical features:

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Respiratory tract involvement

  • Persistent, productive cough
  • Hyperinflated lung fields on CXR
  • PFTs consistent with obstructive disease
  • Chronic bronchitis +/- bronchiectasis as disease progresses
  • Increased cough, dyspnea, increased sputum production, malaise, anorexia, weight loss, clubbing
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    https://en.wikipedia.org/wiki/Cystic_fibrosis

Colonization of airways with pathogenic bacteria

  • Staphylococcus aureus
  • Haemophilus influenzae
  • Pseudomonas aeruginosa

Sinus disease

Pancreatic disease

  • Exocrine pancreatic insufficiency – usually present from birth
  • Insufficient lipase causing steatorrhea and protein malabsorption
  • Infants & children commonly present with failure to thrive
  • Less commonly, infants present w/ variable hypoproteinemia, electrolyte loss, and anemia due to nutrient deficiencies
  • Fat-soluble vitamin deficiencies:  A, D, E, K
  • Patients may also develop dysfunction of the endocrine pancreas à glucose intolerance, CF-related diabetes

Meconium ileus 

  • Presenting problem in 10-20% of newborns with CF; pathognomonic of CF.  "Soap bubble" appearance on xray

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Meconium illeus - www.adhb.govt.nz

 

Meconium peritonitis secondary to perforation

Small bowel obstruction in older children and adults – distal intestinal obstruction syndrome (DIOS)

  • Presents in 15% of adult patients with CF and in pts with severe CFTR genotypes and advanced lung disease
  • Can be controlled medically
  • Surgical intervention for severe obstruction à may be complicated by recurrent symptoms due to adhesions

Biliary disease

  • Inpissated bile, cholestasis à jaundice, focal biliary cirrhosis
  • Elevations in alk phos
  • Lobular hepatomegaly
  • Commonly see asymptomatic liver disease on autopsy
  • In a minority of patients, liver disease is progressive with periportal fibrosis, cirrhosis, symptomatic portal hypertension, variceal bleeding
  • CF is the 3rd leading cause of liver transplantation in late childhood

Infertility Affects more than 95% of men with CF

  • Defects in sperm transport, 
  • Incompletely developed Wolffian structure 
  • Absent vas deferens
  • Fertility w/ epididymal sperm aspiration, intracytoplasmic sperm injection

20% of women with CF Secondary amenorrhea due to malnutrition

  • Production of abnormally tenacious cervical mucus
  • Pregnancy outcomes for patients with CF are generally favorable if pre-pregnancy FEV1 exceeds 50-60% of predicted value

Skeletal disorders

  • Reduced bone mineral content – 20% less than age/gender-matched controls
  • Reduced rate of bone accretion and accelerated bone loss
  • Hypertrophic osteoarthropathy – abnormal proliferation of skin and osseous tissue at distal ends of extremities
  • Radiographically confirmed periosteal new bone formation
  • Similar to pathogenesis of clubbing
  • CF-associated arthropathy in 2-9% of patients:  brief episodes of pain and swelling of joints, occasionally w/ painful nodular skin lesions and purpura

Venous thrombosis

  • CF is a risk factor for recurrence of DVTs
  • Also associated with Burkholderia cepacia colonization and presence of a central venous catheter

 

Treatment of cystic fibrosis

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https://www.cff.org/Living-with-CF/Treatments-and-Therapies/

 

Respiratory

  • Mobilization of chest secretions
  • Chest physiotherapy
  • Inhaled bronchodilators
  • Mucolytics – N-acetylcysteine, dornase alfa (Pulmozyme)
  • Cystic Fibrosis Foundation recommendations for maintaining lung health
  • Beta2 agonist (albuterol) – bronchodilator; improves respiratory function
  • Hypertonic saline – reduces airway edema; reduces CF exacerbations in children >6 years old
  • Dornase alfa – clears respiratory secretions; may reduce CF exacerbations
  • Ibuprofen – reduces inflammatory airway response; may slow progression of disease
  • Antibiotics (tobramycin, azithromycin) – treatment of chronic infections; may reduce CF-related hospitalizations; also used in treatment of pulmonary exacerbations
  • Oral corticosteroids may slow progression of CF lung disease, may impair growth

 

For patients with pancreatic insufficiency:

  • Fat-soluble vitamin supplementation (vitamins A, D, E, and K)
  • Oral pancreatic enzyme replacements
  • Nutrition recommendations
  • Balanced high-calorie high-protein diet
  • Oral supplements, enteral feeds w/ gastrostomy to increase caloric intake

Routine vaccinations, including annual influenza vaccine

Regular monitoring:  pulmonary function tests, CXRs, bone density, glucose, and respiratory cultures for P. aeruginosa

 

Prognosis

Pulmonary disease accounts for most morbidity and mortality

Median survival 37.4 years in United States

92% of children born with CF in the US from 1990 to 1994 were alive at age 19

Predicted median survival >50 years for children born with CF in 21st century

Factors associated with poor prognosis:

  • BMI < 19
  • Long-term O2 use
  • Nebulized antibiotics
  • MRSA, P. aeruginosa Liverpool strain infections in respiratory tract

 

References

  1. Rowe S.M. et al. Mechanisms of Disease: Cystic Fibrosis. NEJM 2005
  2. Montgomery G.S. and Howenstine M. Cystic Fibrosis. Peds in Review 2009
  3. O’Sullivan B.P. and Freedman S.D. Cystic Fibrosis. Lancet 2009
  4. Ratjen F.A. Cystic Fibrosis: Pathogenesis and Future Treatment Strategies. Respiratory Care 2009
  5. Tuchman L.K. Cystic Fibrosis and Transition to Adult Medical Care. Pediatrics 2010
  6. Davis P.B. Therapy for Cystic Fibrosis — The End of the Beginning? NEJM 2011