Cystic Fibrosis

Cystic Fibrosis Esmeralda E. Morales, MD August 28, 2006

Objectives
Know the clinical features of cystic fibrosis.
Know how CF is inherited.
Be familiar with criteria to diagnose CF.
Become aware of the myriad of treatments used in CF.

What is cystic fibrosis (CF)?
A multisystem disease
Autosomal recessive inheritance
Cause: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)
chromosome 7
codes for a c-AMP regulated chloride channel
Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.

Diagnosis of cystic fibrosis
One or more clinical features of CF
PLUS
Two CF mutations
OR
Two positive quantative pilocarpine iontophoresis sweat chloride values
OR
An abnormal nasal transepithelial potential difference value
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

Clinical features of Cystic Fibrosis
Chronic Sino-Pulmonary Disease
Nutritional deficiency/GI abnormality
Obstructive Azoospermia
Electrolyte abnormality
CF in a first degree relative
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997 .

Welsh, MJ and Smith, AE. Cystic Fibrosis. Scientific American . 273 (6): 52, 1995.

Burden of CF
Most common “life-shortening” recessive genetic disease in Caucasians
1:3,500 newborns in the US
1 in 10,500 Native Americans
1 in 11,500 Hispanics
1 in 14,000 to 17,000 African Americans
1 in 25,500 Asians
http://www.cff.org

Burden of CF (continued)
About 30,000 people affected in United States
>10,000,000 people carriers of mutant CFTR
80% cases diagnosed by age 3
Almost 10% diagnosed ≥18 years
http://www.cff.org

CF Survival
Overall trend is improved survival
Female survival worse than male between 2-20 years of age 1
35% of patients are older than 18 years of age 2
Median survival 36.8 years 3 compared to 1930s when life expectancy was about 6 months 2
1.Goss, CH and Rosenfeld, M. Update on cystic fibrosis epidemiology. Current Opinion in Pulmonary Medicine. 10:510-514; 2004. 2. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005. 3.www.cff.org/news/general_news

Autosomal recessive inheritance in CF
Let C = normal CFTR
Let c = mutant CFTR
If mom and dad are both carriers then:
With mom and dad carriers, then:
50% chance of having child who is a carrier
25% chance of child being affected
25% of child with no mutant copies of CFTR
CC C c C c cc C c C c

Cystic fibrosis transmembrane conductance regulator (CFTR) gene
The CFTR gene is located on the long arm of chromosome 7.
There are 1522 mutations in CFTR listed on the CFTR mutation database ( http://www.genet.sickkids.on.ca/cftr/ )
The most common mutation is Δ F508---70% CF alleles in caucasians. 1
http://www.ornl.gov/sci/techresources/ Human_Genome/posters/chromosome/cftr.shtml 1. Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

Cell membrane diagram From: http://library.thinkquest.org/C004535/cell_membranes.html

CFTR Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

Types of mutations in CFTR
Class I
Defective protein production
Class II
Defects in processing
Δ F508
Class III
CFTR reaches cell surface but regulation is defective (channel not activated)
Class IV
CFTR in membrane with defective conduction
Class V
Decreased synthesis of CFTR
http://www.cysticfibrosismedicine.com/ htmldocs/CFText/genetics.htm

CFTR and Airway Surface Liquid Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

Airway surface liquid low volume hypothesis
Mucus---helps clear airway of bacteria
Clearance of mucus depends on
Ciliary function
Mucin secretion
Volume of airway surface liquid (ASL)
Forms periciliary liquid layer
Dilutes mucus---facilates entrapment of bacteria and clearance
Optimal volume of ASL regulated by Na+ absorption and Cl- secretion
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

Airway surface liquid low volume hypothesis and CFTR
Normal CFTR inhibits a sodium channel (ENaC)
Mutant CFTR----ENaC not inhibited
Sodium absorption is increased
Water follows sodium
ASL volume decreases
Normal CFTR will cause Cl- ions to be secreted if the ASL fluid is low
Mutant CFTR Cl- ions not secreted

Airway surface liquid low volume hypothesis and consequences
Cilia do not beat well when PCL volume is depleted
Mucins are not diluted and cannot be easily swept up the airway
Mucus becomes concentrated
Results in increased adhesion to airway surface
Promotes chronic infection

CF Clinical Signs

Chronic Sino-Pulmonary Disease
Chronic infection with CF pathogens
Endobronchial disease
Cough/sputum production
Air obstruction---wheezing; evidence of obstruction on PFTs
Chest x-ray anomalies
Digital Clubbing
Sinus disease
Nasal Polyps
CT or x-ray findings of sinus disease

Infection Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

CF Infections--- Pseudomonas aeruginosa
80% CF patients eventually infected with pseudomonas
Association between acquiring pseudomonas and clinical status deterioration
Form biofilms
Relatively large genome
Pseudomonae collected from sputa of CF patients have been noted to have larger genomes than lab strains
Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

Pseudomonas genome http://www.pseudomonas.com/

Burkholderia cepacia complex
B. cepacia syndrome: fevers, rapidly progressive necrotizing pneumonia, death
Chronic cepacia infection—decreased lung function and increased mortality
Several closely related species termed genomovars 1
III has been associated with more severe disease
Holmes, A, Govan, J, and Goldstein, R. Agricultural Use of Burkholderia (Pseudomonas) cepacia: A Threat to Human Health? Emerging Infectious Diseases. 4(2):221-227; 1998 1. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

Endobronchial disease
Hyperinflation
Peribronchial cuffing
Bronchiectasis
Diffuse fibrosis
Atelectasis
From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

Nasal Polyps
Benign lesions in nasal airway
If large enough, can be associated with significant nasal obstruction, drainage, headaches, snoring
Likely associated with chronic inflammation
May need surgical intervention
High recurrence rate
From: http://www.emedicine.com/ ped/topic1550.htm

Digital Clubbing
Bulbous swelling at end of fingers
Normal angle between nail and nail bed lost---Schamroth sign
Can be associated with pulmonary disease, cardiac disease, ulcerative colitis, and malignancies
From: Fawcett et al., 2004

Nutritional deficiency
Pancreatic insufficiency
Autopsy of malnourished infants--1938--- “cystic fibrosis of the pancreas”---mucus plugging of glandular ducts 1
Chloride impermeability affects HCO3- secretion and fluid secretion in pancreatic ducts 2
Pancreatic enzymes stay in ducts and are activated intraductally
Autolysis of pancreas
Inflammation, calcification, plugging of ducts, fibrosis
Malabsorption
Failure to thrive
Fat soluble vitamin deficiency
Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
Doi: 10.1164/rccm.200505-840OE; 2005.
2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999.

GI disease
Intestinal abnormality
Meconium ileus
Distal intestinal obstruction syndrome (DIOS)
Rectal prolapse
Hepatobiliary disease
Focal biliary cirrhosis
Multilobular cirrhosis
Pancreatic endocrine dysfunction
Cystic fibrosis related diabetes

Cystic fibrosis related liver disease
Focal inspissation of bile
Obstructs biliary ductules
Second leading cause of death in CF 1
Prevalence 9-37% 1
Spectrum of disease
increased liver enzymes
biliary cirrhosis
portal hypertension
1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF. European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.

Cystic fibrosis related diabetes mellitus
Screening
Oral glucose tolerance test (OGTT)
Every two years in patients 10-16 years
Any patient with random plasma glucose >180
Fasting>=140 mg/dl
initiate insulin treatment
Fasting<140 and OGTT at 2 hrs>200 mg/dl
Home glucose monitoring; consider insulin
Fasting <140 and 2 hour 140-200
Impaired glucose tolerance
OGTT annually
Fasting and 2 hour <140
Normal glucose tolerance

Infertility
Men
Abnormal embryologic development of the epididymal duct and vas deferens---may be incomplete of absent 1
Congential bilateral absence of the vas deferens—97-98% of men with CF 1
1. Lewis-Jones et al, Cystic fibrosis in infertility: screening before assisted reproduction: Opinion. Human Reproduction 15(11): 2415-2417.

Infertility
Women
Lower fertility rate than non-CF women
Viscid mucoid cervical secretions of low volume in women with CF 1
Pregnancy and CF:
Goss et al, 2003---no significant difference in survival in women who became pregnant with CF compared to women who did not become pregnant (after adjusting for disease severity) 2
1.Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999 2.Goss, CH, Rubenfeld, GD, Otto, K and Aitken, ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest 124(4):1460-68; 2003.

Electrolyte abnormality---history
Dr. Paul di Sant’ Agnese
1949 NYC heat wave----noted CF infants to have a higher rate of heat prostration than non-CF
Showed that sodium and chloride concentration in CF patients’ sweat was 5 times higher than in non-CF 1
Became basis for sweat chloride test
Davis, P. Cystic Fibrosis Since 1938. American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 475-482, (2006)

Electrolyte abnormality
Clinically---hypochloremic metabolic alkalosis
CFTR on luminal side of sweat duct
Chloride goes in from lumen via CFTR and out to blood by other transporters
Sodium goes in via ENaC
Defective CFTR---Na and Cl- movement and reabsoprtion into lumen impeded
Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv Physiol Educ. 29 (79-82); 2005

CF: Diagnostic Methods

Diagnosis---Sweat chloride
Technique first described by Gibson and Cooke in 1950s
Chemical that stimulates sweating placed under electrode pad; saline under other electrode pad on arm
Mild electric current is passed between electrodes
Sweat collected
http://www.nucleusinc.com Illustration copyright 2003 Nucleus Communications, Inc.

Sweat chloride
Positive Sweat chloride: 60-165 meq/L
Borderine sweat chloride: 40-60 meq/L
Normal sweat chloride: 0-40
False positives:
Hypothyroidism
Addison disease
Ectodermal dysplasia
Glycogen storage disease
Edema
Malnutrition
Lab error (evaporation or contamination of sample)
False negatives:
Edema
Malnutrition
Some CF mutations
Sample diluted
Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005.

Genetic testing
Mutation analysis available
Varies from screening for most common mutations to sequencing entire CFTR gene

Prenatal screening
American College of Obstetricians and Gynecologists recommended offering patients option of prenatal screening for CF
Carrier testing of 23 most common mutations
Sensitivity of prenatal screening for CF among the white population < 78% 1
lower than that for newborn screening
sensitivity of prenatal testing in racial and ethnic minority populations is lower 1
1. Grosse et al. Newborn Screening for Cystic Fibrosis. MMWR.53 (RR13):1-36; 2004.

Newborn Screening for CF
Goal: diagnose early---evidence that early diagnosis may be associated with better nutritional outcome and chest radiographic scores 1
Several different protocols in different states
Immunoreactive trypsinogen usually first followed by either sweat or DNA testing
Mérelle ME, Nagelkerke AF, Lees CM, Dezateux C. Newborn screening for
cystic fibrosis. Cochrane Database of Systematic Reviews. Issue3; 2005.

Cystic fibrosis---Treatment Multidisciplinary
Airway Clearance
Infection
Nutrition
Gastrointestinal
Inflammation
Infertility
Social Issues

Treatment: Pulmonary toilet/Airway clearance
Chest physiotherapy
Postural drainage and percussion
P.E.P valve, Acapella valve, Flutter valve
High frequency chest wall oscillation
Albuterol
Bronchodilation
Increase ciliary efficiency
Dornase alpha/recombinant DNase
Hypertonic Saline by nebulization

Treatment: Chronic infection
Inhaled antibiotics
Inhaled tobramycin in patients with pseudomonas
Sputum cultures
Treatment of pulmonary exacerbation
Pulmonary exacerbation---change in symptoms and signs from baseline (cough, sputum production, lung function, increased crackles on physical exam)
Requires hospitalization for antibiotics IV, as well as increased airway clearance

Treatment: Anti-inflammatory agents
Ibuprofen
Konstan et al., 2003
85 patients 5-39 years of age with mild lung disease randomized to placebo or high dose ibuprofen over 4 years
Ibuprofen group:
Slower decrease in FEV1 annually than placebo group; better weight maintenance
No difference in frequency of hospitalization
Best effect seen in patients less than 13 years of age
Konstan et al., Effect of High Dose Ibuprofen in Patients with Cystic Fibrosis. NEJM. 332:848-54; 2003.

Treatment: Azithromycin
Saiman et al., 2003 double blind placebo controlled trial of azithromycin
185 patients randomized to receive 3 times weekly azithromycin or placebo
Improvements in lung function, weight, and number of pulmonary exacerbations (decreased courses of antibiotics and days in hospital)
Saiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.

Treatment: Nutrition
Follow nutrition parameters closely
Pancreatic enzymes
Vitamin supplementation
Other nutritional supplementation
Tube feedings
High calorie supplemental shakes, formulas

Nutrition parameters
Percent ideal body weight (IBW%)
90-110%: Normal
85-89%: Underweight
80-84%: Mild malnutrition
75-79%: Moderate malnutrition
<75%: Severe malnutrition
Height as a percentage of 50 th percentile height for age (height/50 th percentile height for age )X100.
95-100% normal
90-94%: mildly stunted
85-89%: moderately stunted
<85%: severely stunted

Treatment: Pancreatic enzymes
Initiate if have malabsorption history
Fecal fat
Fecal elastase
May need H2 blocker or PPI to activate enteric coated enzyme
Fibrosing colonopathy
Strictures in the colon associated with high dose enzyme use (enzyme gets to colon and causes damage leading to scarring/stricture)

Treatment: Cystic fibrosis related liver disease
Ursodiol
Increased bile flow
Decrease toxicity of bile acids
Sclerotherapy, portosystemic shunts
Liver transplantation---only curative treatment for portal hypertension

Treatment: Infertility
Microsurgical epididymal sperm aspiration coupled plus in vitro technology
Percutaneous epididymal sperm aspiration
Testicular sperm extraction
Maternal genetic testing
McCallum, TJ et al., Fertility in men with cystic fibrosis. Chest 118:1059-1062; 2000.

Psychosocial issues
Quality of life
Frequent hospitalizations
Time spent on therapies
Morbidity from disease
Restrictions secondary to disease
Adherence to therapies
Family planning
End of life issues

“ It is, in fact, nothing short of a miracle that the modern methods of instruction have not entirely strangled the holy curiosity of inquiry.” ----Albert Einstein

Cystic Fibrosis

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Cystic Fibrosis

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Cystic Fibrosis Presentation Transcript

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