2. If your baby tastes of
salt,he is not long for this
world
3. INTRODUCTION
Cystic fibrosis is a multisytem genetic disease
that affects children and young adults
Most common monogenetic disease in
Caucasian populations
Caused by mutation in CF transmembrane
conductance regulator(CFTR) protein,an anion
channel expressed on the epithelial surface
CF is typified by the presence of chronic upper
and lower respiratory tract infection leading to
bronchiectasis and end-stage lung disease
Manifestations in pancreas,git,skin and male
reproductive tract also prominent
4. WHY
UNDERSTANDING
OF CF IS
IMPORTANT?
Most common cause of chronic respiratory
failure in children and young adults
Most common reason for pancreatic
exocrine dysfunction in children and young
adults
Major cause of bronchiectasis and
pansinusitis in this age group
Advances in CF research provided a roadmap
for understanding pathophysiology and
treatment for other severe airway diseases
5. HISTORICAL
PERSPECTIVE
1938-Anderson described CF as a distinct
clinical entity-CYSTIC FIBROSIS OF THE
EXOCRINE PANCREAS
1945-Farber described condition as
GENERALISED MUCOVISCIDOSIS
1948-di Sant’Agnese demonstrated elevated
sodium and chloride levels in sweat of CF
patients
1989-discovery of CFTR gene and protein
Gibson and Cooke-developed pilocarpine
method of sweat chloride testing
6. EPIDEMIOLOGY
1 in 2500 to 3000 live births in US
1 in 6000 in Hispanics
1 in 10,000 in African Americans
1 in 90,000 in Asian populations
In white population,1 in 25 caucasians are
carriers for gene mutation,resulting in carrier
rate of 2% to 5%
CFTR mutation offers protection against cholera
toxin
7. GENETIC
BASIS
Autosomal recessive pattern of inheritance
CFTR gene mutation
CF gene-long arm of chromosome 7
-230kb of DNA,27 exons
CFTR protein-integral membrane glycoprotein,1480
AA
Most common mutation(66%)-three base deletion in exon 10
that causes a deletion of PHENYLALANINE from position 508 of
CFTR glycoprotein
More than 1900 CF mutations
21. • Earliest pathologic lesion found in distal bronchioles
• In neonates with CF-demonstration of mucus obstructing
submucosal gland ducts in airways
• Common pathogens isolated from sputum cultures
-Staph aureus MOST COMMON
-Pseudomonas aeruginosa
-E-coli
-H.influenza
-MDRO-Strenotrophomonas maltophilia
-Achromobacter xylosoxidans
-Burkholderia cepacia complex
-Aspergillus and NTM
22. • Central Bronchiectasis in CF-neutrophil dominated lower airway
inflammation
• BAL-increased neutrophils and various cytokines,especially IL-8
even in infants whose BALF is sterile
• Increased secretions increased cough and sputum
exacerbation of pulmonary disease RR & chest retraction
• Diffuse coarse inspiratory crackles
23. • CXR-worsening hyperinflation
-peribronchial thickening
-nodular/cystic densities
• PFT-residual volume increases
-FVC & FEV1 decreases
-FEF(25%-75%) decreases
• Treatment-antibiotics & chest physiotherapy
-reduces number & virulence of
organisms
• Complications
bronchiectasis/atelectasis
irreversible decrease in pulmonary function
24.
25.
26.
27.
28. GASTROINTESTINAL
TRACT- PANCREAS
Pancreatic ducts become
progressively obstructed by
thick,viscous secretions from
exocrine portion of organ
Pancreatic enzymes trapped within
ducts lead to autodestruction of
pancreas
Cycle of destruction & obliteration
of ducts leads to cystic dilatation of
ducts and fibrosis of body of
pancreas which further causes
obliteration of islets of Langerhans
and consequently diabetes.
30. CFTR is localized to the apical surface of the
bile duct epithelium and not in the
hepatocytes.
Primary mechanism appears to be
obstruction of small intrahepatic bile ducts by
abnormally viscid secretions, leading to
accumulation of toxic bile acids, depletion of
hepatic antioxidants, and subsequent liver
injury
Elevated liver enzymes in 40% to 50% of
patients with CF
Focal biliary cirrhosis, multilobular cirrhosis,
and portal hypertension are also seen
31. INSPISSATED
BILE
SYNDROME
Some newborn infants with
CF develop the inspissated
bile syndrome, characterized
by prolonged obstructive
jaundice starting at 2 to 8
weeks of age
Jaundice often clears without
therapy
33. INTESTINE
Most striking pathologic
change in the intestines is
hyperplasia of the mucus
glands and goblet cells.
Biochemical abnormalities in
intestinal mucins may
contribute to malabsorption of
specific nutrients and bile
acids.
Much of the malabsorption in
CF can be corrected by
administration of pancreatic
enzyme replacement therapy
(PERT).
34. The fecal impaction, in turn, occasionally causes
volvulus or intussusception of the bowel
The slowing,combined with maldigestion of food
substances, sometimes causes fecal impaction in the
terminal ileum and ileocecal area, a condition
referred to as meconium ileus equivalent or distal
intestinal obstruction syndrome.
However, the abnormal mucins may lead to slowing
of intestinal transit time
35.
36.
37. ENDOCRINE
INSUFFICIENCIES
: CYSTIC
FIBROSIS
RELATED
DIABETES
According to data from University of
Minnesota where annual cystic fibrosis–
related diabetes (CFRD) screening is
recommended for all patients ≥6 years
CFRD affects 2% of children, 19% of
adolescents, and 40% to 50% of adults
CFRD has been associated with
decreased survival,worse pulmonary
function, and lower BMI
38. Microvascular complications,
such as retinopathy,
nephropathy,and neuropathy
also occur in CFRD but may be
limited to those individuals with
fasting hyperglycemia (FH).
Insulin treatment of adults with
CFRD without FH improves BMI
39. OSTEOPOROSIS/
VITAMIN D
DEFICIENCY
Low bone mineral density occurs in
as many as 85% of adults with CF
Osteoporosis due to pancreatic
insufficiency and malnutrition and
poor growth, CFRD, deficiencies in
vitamin D, vitamin K, and calcium
levels, elevated inflammatory
cytokines, pubertal delay, diabetes,
and exposure to glucocorticoids
40. Bone histology in clinically
stable CF adults is significant
for decreased cancellous
bone volume and decreased
connectivity
increased risk of vertebral
and rib fractures
increased risk of kyphosis
42. MALES
Vas deferens is either atretic or absent at
birth.
Viscous secretions may contribute to
obstruction in utero, followed by failure of
development of the vas
deferens.
Spermatogenesis and testicular
development are otherwise normal.
Because of either partial or complete
obstruction of the vas
deferens,approximately 98% of males with
CF are aspermic
43. SWEAT GLANDS
• No distinctive histologic changes.
• Micropuncture experiments have shown that the precursor solution
secreted by the sweat glands is isotonic to plasma, both in CF
patients and in normal subjects
• In normal persons, as the sweat flows along the duct of the gland,
sodium and chloride are reabsorbed, so that by the time the opening
at the skin surface is reached, sweat is hypotonic to plasma with
respect to both sodium and chloride concentrations.
44. • In CF, the relative impermeability to chloride ions is thought to be
responsible for the elevated chloride and sodium concentrations
which are the basis for the diagnostic test, the quantitative
pilocarpine iontophoresis sweat test, and are also responsible for the
characteristic increase in potential differences across isolated,
perfused sweat glands from CF patients
47. DIAGNOSIS
Most prominent clinical features
are chronic pulmonary disease and
pancreatic insufficiency.
If the clinical picture and/or the
family history support the
diagnosis, and if two sweat tests
using the quantitative pilocarpine
iontophoresis method are clearly
positive, the diagnosis of CF can be
made with assurance.
48. DIAGNOSIS
Identification of two
pathologic mutations, in
addition to the
characteristic clinical
picture, is accepted as a
criterion for the diagnosis.
Most consistent feature of
CF is an abnormally high
concentration of sodium
and chloride in sweat.
49. PILOCARPINE
IONTOPHORESIS
TEST
Based on iontophoresis of
pilocarpine, followed by
quantitative determination of
the concentration of chloride
in an adequate, measured
volume of sweat
Children- chloride of less than
40 mEq/L –NORMAL and
between 40 and 60 mEq/L –
BORDERLINE ELEVATED
50. Average of values for sodium
and chloride concentrations
is about 20 mEq/L for normal
subjects and 95 mEq/L for
those with CF.
Sweat chloride values above
30 mEq/L may be diagnostic
in the first few months of life.
52. NASAL POTENTIAL DIFFERENCE
MEASUREMENT
• This test is helpful when sweat chloride tests and/or genetic tests are
inconclusive
• As Na+ and Cl- ions move across the membranes of the cells lining
airway,an electrical potential difference is generated
• In nasal passage it is called nasal potential difference
• In CF,failure of secretion of Cl- and Na+ ions into the lumen causes
more negative charge in the lumen and more positive charge
intracellularly resulting in abnormal nasal potential difference
53. CLINICAL
EVALUATION-
PULMONARY
ASSESSMENT
CHEST XRAY
Initial stages, mild hyperinflation
and minimal peribronchial
thickening,peribronchial
thickening, which is often most
prominent in the upper lobes
Advanced stages,ring shadows,
cystic lesions, and nodular
densities,areas of bronchiectasis
and atelectasis,enlarged central
pulmonary artery
60. SPUTUM
CULTURE
Acquisition of mucoid Pseudomonas
predicts more rapid progression of CF lung
disease
Methicillin-resistant S. aureus is associated
with a decline in pulmonary function and
worse survival
B. cepacia complex organisms may be
aggressive with rapid deterioration of
clinical status
Presence of mucoid-positive organisms
appears to be protective
Nontuberculous mycobacteria prevalence
7% to 24% Mycobacterium avium complex
and Mycobacterium abscessus
61. PANCREATIC
FUNCTION
90% of patients have pancreatic
insufficiency.
Infants with pancreatic insufficiency
due to CF can present with failure to
thrive and loose or frequent stool
Diagnosis of pancreatic insufficiency
can be made by measuring fecal
elastase (FE)-1 levels
Assessment of the degree of
malabsorption-determination of the
coefficient of fat malabsorption.
62. The FE-1 test is performed on a
random single stool sample.
Coefficient of fat absorption is
performed by collecting stools for
72 hours while the patient is
ingesting a high-fat diet
(documented on a 3-day diet
record) and analyzing the stool fat
content.
63. A malabsorption coefficient
of greater than 7% is usually
considered abnormal.
Patients with CF usually have
a malabsorption coefficient
around 20% to 30%.
Pancreatic stimulation tests
are the most accurate
measurement
64.
65. CFRD
Annual CFRD screening with an oral glucose tolerance
test (OGTT) starting by age 10 is recommended.
Normal glucose tolerance (NGT) = PG1 <200 mg/dL and
PG2<140 mg/dL
Indeterminate = PG1 ≥200 mg/dL but PG2 <140 mg/dL
Impaired glucose tolerance (IGT) = PG2 ≥140 and <200
mg/dL
CFRD = PG2 ≥200 mg/dL
Without FH = PG0 <126 mg/dL
With FH = PG0 ≥126 mg/dL
67. LIVER
FUNCTION
Evaluation of liver function (transaminases,
bilirubin, gamma glutamyl transferase
[GGT]) is an important part of the evaluation
of CF.
Prothrombin time is sometimes prolonged,
owing to a combination of malabsorption
and decreased synthesis of clotting factors
by the liver.
Fatty liver, cirrhosis, splenomegaly, varices,
and reversal of portal blood flow can be
seen on ultrasound
Bleeding esophageal varices from advanced
cirrhosis
70. A high clinical suspicion for CF
because mutation analyses will be
used to determine eligibility for
mutation-specific protein-correcting
therapies.
For example, therapy for CF patients
with the G551D mutation with the
CFTR potentiator ivacaftor® results in
astonishing improvements in
respiratory tract symptoms,weight
gain, and shift from positive to
borderline sweat chloride values.
76. Pulmozyme,inhaled once daily over 96
weeks, maintained pulmonary function
and decreased the relative risk of
respiratory tract exacerbations in young
CF patients with normal FEV1 (≥85%).
Patients with CF, age 6 years and older,
inhaled 7% hypertonic saline twice daily
following a bronchodilator for 48 weeks;
results revealed only a modest
improvement in FEV1, but a significant
reduction in the number of pulmonary
exacerbations and days lost from school
or work
78. CFTR POTENTIATORS AND CORRECTORS : IVACAFTOR
CORRECTED THE
PHYSIOLOGIC IMPACT OF A
CFTR MUTATION, G551D.
ADMINISTERED ORALLY, 150
MG TWICE PER DAY FOR 48
WEEKS
INCREASES FEV1 DECREASES RISK OF
PULMONARY
EXACERBATIONS
IMPROVED CF QUALITY OF
LIFE (CFQL)
DECREASES SWEAT
CHLORIDE VALUES BY 48
MMOL/L
ASSOCIATED WITH AN
AVERAGE 2.7-KG WEIGHT
GAIN
79. LIVER
UDCA 10 to 20
mg/kg/d as a
choleretic agent to
improve bile flow
Liver transplantation
in patients with CF
who have end-stage
liver disease.
80. NUTRITIONAL
SUPPORT
High-calorie balanced diet
Calorie boosters (vegetable oils, butter, and cheese)
are recommended followed by the use of high-
calorie supplements (shakes)
Mainstay in managing pancreatic insufficiency of CF
is PERT which consists of enteric coated capsules
containing amylases, proteases, and lipases
Vitamin D supplementation
Supplemental salt is needed by patients to prevent
salt depletion
81. CFRD
MANAGEMENT
Combinations of basal
(long-acting) and bolus
(rapid-acting) insulins are
used in the treatment of
CFRD with FH.
In the absence of FH,
premeal rapid-acting
insulin is the main
treatment approach.
84. Psychosocial issues: The
patient who gives up
hope is liable to undergo
rapid deterioration
Reproductive issues:
Microsurgical epididymal
sperm aspiration (MESA),
coupled with in vitro
fertilization
85. REFERENCES
Murray & Nadel’s Textbook Of Respiratory
Medicine,sixth Edition
Fishman’s Pulmonary Diseases and
Disorders,Fifth Edition
Journal of Cystic Fibrosis, Vol. 18, Issue 4
BMJ. 2007 Dec 15; 335(7632): 1255–1259
86.
87.
88. THANK YOU
“65 roses, cystic fibrosis,
made her so tired she had
to stay in bed
65 roses cystic fibrosis i
wish she had roses instead
65 roses cystic fibrosis i
wish that she could come
out to play
life one supposes is no bed
of roses
I wish she had roses
instead”
WOLVERINES, AUSTRALIAN
BAND
