Cystic Fibrosis

From Anvita Health Wiki

Contents 1 Epidemiology 2 Pathology 3 Genetics 4 Clinical-manifestations 5 Laboratory 6 Diagnostic-procedures 7 Radiology 8 Differential-diagnosis 9 Management 10 More General Terms 11 Additional Terms 12 Internet Database 13 References

Epidemiology

• Caucasians:

• 1 in 2000-3500 live births
• 1 in 20 (3-5%) are heterozygous carriers
• the most common lethal genetic disease in Caucasians

• Blacks: 1 in 17,000 live births
• Asians: 1 in 90,000 live births
• no sex predominance
• 10% of cases diagnosed in patients > 10 years of age

Pathology

• clinical manifestations reflect alterations in exocrine secretions such that mucus becomes excessively thick & tenacious
• impaired mucociliary clearance
• bacterial colonization of airways
• lysis of neutrophils releases DNA & actin filaments further reducing mucociliary clearance
• the DNA in purulent sputum forms a viscous gel that that increases viscosity of sputum [9]
• chronic inflammation leads to bronchiectasis, obstructive lung disease, pulmonary fibrosis & cor pumonale
• all exocrine glands, except sweat glands are adversely affected; sweat becomes salty
• 10% of patients & carriers develop hyper-responsive airways & asthma
• 10% of patients develop bronchopulmonary aspergillosis
• azoospermia is due to congenital absence of a vas deferens

• congenital bilateral absence of the vas deferens may represent a mild form of cystic fibrosis
• majority of men with cystic fibrosis lack the vas deferens

Genetics

• autosomal recessive, with asymptomatic heterozygous carriers
• mutations in the cystic fibrosis transmembrane regulator ( CFTR) gene, which encodes an epithelial chloride channel
• about 70% of patients carry the same mutation, a deletion of phenylalanine 508 in one of the two CFTR ATP-binding domains

• this mutation results in a temperature-sensitive defect in protein processing (not in aberrant regulation by ATP)
• at 27 C, the mutant form of CFTR forms functionally active chloride channels, but at 37 C, it gets stuck in the maturation pathway & fails to reach plasma membrane, thus giving rise to a very severe disease state in which epithelial chloride channels are absent

• about 400 different mutations are known
• other implicated genes

• PLCZ1

Clinical-manifestations

• pulmonary (97% of adult CF patients)

• accounts for most of the morbidity & mortality
• chronic & progressive with acute exacerbations
• almost always begins in the upper lobes
• hyperinflation, bronchiectasis & microabscesses occur secondary to mucous plugging
• chest may be hyperresonant to percussion
• purulent sputum
• atelectasis
• persistent respiratory tract infections with

• Pseudomonasa aeruginosa
• Burkholderia cepacia

• hemoptysis (60-71% of adult CF patients)
• pneumothorax (16% of adult CF patients)

• extrapulmonary manifestations include:

• upper respiratory tract (48% of adult CF patients)

• sinusitis
• nasal polyps

• intestinal:

• constipation
• volvulus
• intussusception
• fecal impactation
• rectal prolapse
• steatorrhea

• pancreatic:

• malabsorption (95%), but seldom symptomatic
• malnutrition
• pancreatitis
• diabetes mellitus

• hepatobiliary:

• fatty liver
• cholelithiasis
• biliary cirrhosis
• portal hypertension

• genitourinary

• infertility & sterility: azoospermia (95% of males)

• may rarely present in adulthood with isolated azoospermia as the only symptom

• epididymitis

• skeletal

• hypertrophic osteoarthropathy
• retardation of growth
• retardation of bone maturation
• demineralization of bone
• clubbing

Laboratory

• sweat chloride using pilocarpine iontophoresis is the gold standard for diagnosis of CF

• > 80 meq/L is abnormal in adults; > 60 meq/L in children
• abnormal results on at least 2 tests is necessary for diagnosis

• sputum culture & sensitivity: Common organisms include:

• Pseudomonas aeruginosa

• dominant organism
• impossible to eradicate

• Pseudomonas cepacia (Burkholderia cepacia)

• associated with rapid deterioration in lung function

• Staphylococcus aureus
• Haemophilus influenza

• genotyping ( PCR/ southern blot)
• sperm analysis

• azoospermia
• absence of fructose from the seminal vesicles

• newborn screening may be of benefit [7]

Diagnostic-procedures

• Pulmonary function tests:

• obstructive pattern with evidence of air trapping & bronchial hyper-reactivity in some patients
• later in the course of the disease, hypoxemia & hypercapnia

Radiology

• chest X-ray

• hyperinflation
• bronchiectasis & hilar adenopathy
• microabscesses
• increased interstitial reticular marking
• upper lobes are generally more involved than the lower lobes

• abdominal imaging: dilated loops of small intestine

Differential-diagnosis

• (in adults)
• clinical features of cystic fibrosis
• positive family history
• sweat chloride > 80 meq/L
• pancreatic insufficiency

Management

• goals of therapy:

• control infections

• exacerbations of pulmonary infections may present subacutely
• treat any change in pulmonary function as infection
• most patients are chronically infected with Pseudomonas aeruginosa
• maintenance aerosolized tobramycin for control of chronic pulmonary infection [5]
• maintenance azithromycin may be useful [6]

• provide bronchopulmonary hygiene

• antibiotics:

• 3rd generation cephalosporin + aminoglycoside
• empiric coverage for Pseudomonas aeruginosa
• because of increased clearance & volume of distribution, larger than usual doses of antibiotics may be needed
• direct aerosolized tobramycin NOT useful for infectious exacerbations

• chest physiotherapy & postural drainage
• adequate hydration
• immunization against influenza
• treat reactive airway disease ( asthma)

• bronchodilators
• glucocorticoids (controversial)

• recombinant human deoxyribonuclease I ( rhDNAse)

• FDA-approved
• decreases viscoelasticity of sputum
• dornase alpha ( Pulmozyme) 2.5 mg/day inhaled via jet nebulizer

• adverse reactions:

• pharyngitis, laryngitis, rash, chest pain, conjunctivitis

• rhDNAse therapy associated with decreased mortality [9]

• oral ivacaftor 150 mg PO every 12 hours improves pulmonary function in patients with CFTR mutation G551D [10]
• aerosolized hypertonic saline (7%) may be useful [8]
• oxygen therapy
• bilateral lung transplantation - 3 year survival is 50-55%
• liver transplantation for advanced liver disease [5]
• gene therapy not yet successful
• preventive medicine

• Pneumovax
• annual flu vaccine

• prognosis:

• mean age of survival is about 25-30 years; median survival has improved to 33.5 years [7]
• poor prognostic indicators:

• female sex
• residence in a northern climate
• pneumothorax
• hemoptysis
• recurrent bacterial infections
• infection with Pseudomonas cepacia
• systemic complications

More General Terms

• pancreatic disease
• lung disease
• inborn error of metabolism

Additional Terms

• chloride (Cl-) & sodium (Na+) in sweat
• PCR/southern blot for cystic fibrosis

Internet Database

OMIM: 219700

References

1. Mendelian Inheritance in Man (1990) MIM#219700
2. Miller Nature 362:106 1993
3. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 245-47
4. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 744-46
   - Medical Knowledge Self Assessment Program (MKSAP) 11, 14, American College of Physicians, Philadelphia 1998, 2006
5. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1038
6. Journal Watch 22(23):175, 2002 Equi A et al, Lancet 360:978, 2002
7. Sims EJ, McCormick J, Mehta G, Mehta A; UK CF Database Steering Committee. Newborn screening for cystic fibrosis is associated with reduced treatment intensity. J Pediatr. 2005 Sep;147(3):306-11. PMID: [1]
   - Schechter MS, Margolis P. Improving subspecialty healthcare: lessons from cystic fibrosis. J Pediatr. 2005 Sep;147(3):295-301. No abstract available. PMID: [2]
8. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006 Jan 19;354(3):229-40. PMID: [3]
   - Ratjen F. Restoring airway surface liquid in cystic fibrosis. N Engl J Med. 2006 Jan 19;354(3):291-3. No abstract available. PMID: [4]
9. George PM et al. Improved survival at low lung function in cystic fibrosis: Cohort study from 1990 to 2007. BMJ 2011 Feb 28; 342:d1008 PMID: [5]
10. Ramsey BW et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011 Nov 3; 365:1663. PMID: [6]
    - Davis PB. Therapy for cystic fibrosis - The end of the beginning? N Engl J Med 2011 Nov 3; 365:1734. PMID: [7]
11. NIDDK: Cystic Fibrosis Research Directions [8]
    - Cystic Fibrosis: NIH Institute and Center Resources [9]
12. National Guideline Clearinghouse
    - Cystic fibrosis prenatal screening in genetic counseling practice: recommendations of the National Society of Genetic Counselors. ngc-guideline: [10]
    - Best evidence statement (BESt). Airway clearance technique with patients with cystic fibrosis. Cincinnati Children's Hospital Medical Center ngc-guideline: [11]
    - Best evidence statement (BESt). Infection control in cystic fibrosis (CF). Cincinnati Children's Hospital Medical Center ngc-guideline: [12]

cystic fibrosis (CF, mucoviscidosis)