Transcript Cystic Fibrosis More than just mucus

Cystic Fibrosis
Esmeralda E. Morales, MD
August 28, 2006
Objectives
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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)?
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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
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Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.
Diagnosis of cystic fibrosis
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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
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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
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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
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Overall trend is improved survival
Female survival worse than male between 2-20
years of age1
35% of patients are older than 18 years of age2
Median survival 36.8 years3 compared to 1930s
when life expectancy was about 6 months2
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:
C
c
C
CC
Cc
c
Cc
cc
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With mom and dad
carriers, then:
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50% chance of having
child who is a carrier
25% chance of child
being affected
25% of child with no
mutant copies of CFTR
Cystic fibrosis transmembrane
conductance regulator (CFTR) gene
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http://www.ornl.gov/sci/techresources/
Human_Genome/posters/chromosome/cftr.shtml
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.o
n.ca/cftr/)
The most common mutation
is Δ F508---70% CF alleles in
caucasians.1
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
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Class I
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Defective protein production
Class II
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Defects in processing
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Class III
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http://www.cysticfibrosismedicine.com/
htmldocs/CFText/genetics.htm
CFTR reaches cell surface but
regulation is defective (channel
not activated)
Class IV
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ΔF508
CFTR in membrane with
defective conduction
Class V
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Decreased synthesis of CFTR
CFTR and Airway Surface Liquid
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung
disease.
Airway surface liquid low volume
hypothesis
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Mucus---helps clear airway of bacteria
Clearance of mucus depends on
Ciliary function
 Mucin secretion
 Volume of airway surface liquid (ASL)
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Forms periciliary liquid layer
 Dilutes mucus---facilates entrapment of bacteria and
clearance
 Optimal volume of ASL regulated by Na+ absorption
and Cl- secretion
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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
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Normal CFTR inhibits a sodium channel
(ENaC)
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Mutant CFTR----ENaC not inhibited
Sodium absorption is increased
 Water follows sodium
 ASL volume decreases
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Normal CFTR will cause Cl- ions to be secreted
if the ASL fluid is low
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Mutant CFTR Cl- ions not secreted
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 consequences
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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
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Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.
Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
CF Clinical Signs
Chronic Sino-Pulmonary Disease
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Chronic infection with CF pathogens
Endobronchial disease
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Cough/sputum production
Air obstruction---wheezing; evidence of obstruction on PFTs
Chest x-ray anomalies
Digital Clubbing
Sinus disease
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Nasal Polyps
CT or x-ray findings of sinus disease
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
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
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80% CF patients eventually infected with pseudomonas
Association between acquiring pseudomonas and
clinical status deterioration
Form biofilms
Relatively large genome
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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
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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
B. cepacia syndrome: fevers,
rapidly progressive
necrotizing pneumonia, death
Chronic cepacia infection—
decreased lung function and
increased mortality
Several closely related species
termed genomovars1
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III has been associated with
more severe disease
1. Gibson, RL, Burns, JL, and Ramsey, BW.
AJRCCM 168 (918-951); 2003.
Endobronchial disease
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From:
http://www.meddean.luc.edu/lumen/med
ed/elective/pulmonary/cf/cf_f.htm
Hyperinflation
Peribronchial cuffing
Bronchiectasis
Diffuse fibrosis
Atelectasis
Nasal Polyps
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From: http://www.emedicine.com/
ped/topic1550.htm
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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
Digital Clubbing
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From: Fawcett et al., 2004
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
Nutritional deficiency
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Pancreatic insufficiency
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Autopsy of malnourished infants--1938--- “cystic fibrosis of
the pancreas”---mucus plugging of glandular ducts1
Chloride impermeability affects HCO3- secretion and fluid
secretion in pancreatic ducts2
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Pancreatic enzymes stay in ducts and are activated intraductally
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Autolysis of pancreas
Inflammation, calcification, plugging of ducts, fibrosis
Malabsorption
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Failure to thrive
Fat soluble vitamin deficiency
1. 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
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Intestinal abnormality
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Hepatobiliary disease
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Meconium ileus
Distal intestinal obstruction syndrome (DIOS)
Rectal prolapse
Focal biliary cirrhosis
Multilobular cirrhosis
Pancreatic endocrine dysfunction
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Cystic fibrosis related diabetes
Cystic fibrosis related liver disease
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Focal inspissation of bile
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Obstructs biliary ductules
Second leading cause of death in CF1
Prevalence 9-37%1
Spectrum of disease
increased liver enzymes
 biliary cirrhosis
 portal hypertension
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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
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Screening
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Oral glucose tolerance test (OGTT)
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Fasting>=140 mg/dl
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initiate insulin treatment
Fasting<140 and OGTT at 2 hrs>200 mg/dl
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Home glucose monitoring; consider insulin
Fasting <140 and 2 hour 140-200
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Impaired glucose tolerance
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Every two years in patients 10-16 years
Any patient with random plasma glucose >180
OGTT annually
Fasting and 2 hour <140
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Normal glucose tolerance
Infertility
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Men
Abnormal embryologic development of the
epididymal duct and vas deferens---may be
incomplete of absent1
 Congential bilateral absence of the vas deferens—
97-98% of men with CF 1
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1. Lewis-Jones et al, Cystic fibrosis in infertility: screening before assisted reproduction: Opinion. Human Reproduction
15(11): 2415-2417.
Infertility
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Women
Lower fertility rate than non-CF women
 Viscid mucoid cervical secretions of low volume in
women with CF 1
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Pregnancy and CF:
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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
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Dr. Paul di Sant’ Agnese
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1949 NYC heat wave----noted CF infants to have a
higher rate of heat prostration than non-CF
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Showed that sodium and chloride concentration in CF
patients’ sweat was 5 times higher than in non-CF1
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Became basis for sweat chloride test
1. Davis, P. Cystic Fibrosis Since 1938. American Journal of Respiratory and Critical
Care Medicine Vol 173. pp. 475-482, (2006)
Electrolyte abnormality
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Clinically---hypochloremic metabolic alkalosis
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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
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Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport.
Adv Physiol Educ. 29 (79-82); 2005
CF: Diagnostic Methods
Diagnosis---Sweat chloride
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Technique first described
by Gibson and Cooke in
1950s
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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
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Positive Sweat chloride: 60-165
meq/L
Borderine sweat chloride: 4060 meq/L
Normal sweat chloride: 0-40
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False positives:
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Hypothyroidism
Addison disease
Ectodermal dysplasia
Glycogen storage disease
Edema
Malnutrition
Lab error (evaporation or
contamination of sample)
False negatives:
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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
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Mutation analysis available
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Varies from screening for most common mutations
to sequencing entire CFTR gene
Prenatal screening
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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
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lower than that for newborn screening
 sensitivity of prenatal testing in racial and ethnic minority
populations is lower1
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1. Grosse et al. Newborn Screening for Cystic Fibrosis. MMWR.53 (RR13):1-36; 2004.
Newborn Screening for CF
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Goal: diagnose early---evidence that early
diagnosis may be associated with better
nutritional outcome and chest radiographic
scores1
Several different protocols in different states
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Immunoreactive trypsinogen usually first followed
by either sweat or DNA testing
1. Mérelle ME, Nagelkerke AF, Lees CM, Dezateux C. Newborn screening for
cystic fibrosis. Cochrane Database of Systematic Reviews. Issue3; 2005.
Cystic fibrosis---Treatment
Multidisciplinary
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Airway Clearance
Infection
Nutrition
Gastrointestinal
Inflammation
Infertility
Social Issues
Treatment: Pulmonary toilet/Airway
clearance
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Chest physiotherapy
Postural drainage and percussion
 P.E.P valve, Acapella valve, Flutter valve
 High frequency chest wall oscillation
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Albuterol
Bronchodilation
 Increase ciliary efficiency
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Dornase alpha/recombinant DNase
Hypertonic Saline by nebulization
Treatment: Chronic infection
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Inhaled antibiotics
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Inhaled tobramycin in patients with pseudomonas
Sputum cultures
Treatment of pulmonary exacerbation
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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
Cystic Fibrosis Foundation. Clinical Practice Guidelines for
Cystic fibrosis.1997.
Treatment: Anti-inflammatory
agents
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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
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Ibuprofen group:
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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
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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)
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Saiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with
Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.
Treatment: Nutrition
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Follow nutrition parameters closely
Pancreatic enzymes
Vitamin supplementation
Other nutritional supplementation
Tube feedings
 High calorie supplemental shakes, formulas
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Nutrition parameters
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Percent ideal body weight (IBW%)
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90-110%: Normal
85-89%: Underweight
80-84%: Mild malnutrition
75-79%: Moderate malnutrition
<75%: Severe malnutrition
Height as a percentage of 50th percentile height for age
(height/50th percentile height for age )X100.
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95-100% normal
90-94%: mildly stunted
85-89%: moderately stunted
<85%: severely stunted
Treatment: Pancreatic enzymes
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Initiate if have malabsorption history
Fecal fat
 Fecal elastase
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May need H2 blocker or PPI to activate enteric
coated enzyme
Fibrosing colonopathy
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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
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Ursodiol
Increased bile flow
 Decrease toxicity of bile acids
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Sclerotherapy, portosystemic shunts
Liver transplantation---only curative treatment
for portal hypertension
Treatment: Infertility
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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
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Quality of life
Frequent hospitalizations
 Time spent on therapies
 Morbidity from disease
 Restrictions secondary to disease
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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