Outline of Key Learning Areas related to PBL Case
Relevant Symptoms (incl. relevant negatives)
Lesley R is 11 years old, presents with sore throat and cough 1 week ago
Other Significant History
Lesley was diagnosed at birth with cystic fibrosis
Older sister died from CF
Taking vitamins and enzymes to help digest food
persistent infections: Thrush, UTI
Examination and Signs
Lesley was very short of breathe, and bracing self to increase use of accessory muscles to breathe
Provisional Diagnosis
Cystic Fibrosis
Differential Diagnoses
Cause of cough:
Exogenous irritants;allergies;asthma;acid reflux;chronic infection;bronchiocarcinoma
Risk Factors and Aetiology
Cystic fibrosis is an autosomal recessive disease caused by defects in the CFTR gene, which encodes for a protein that functions as a chloride channel, and
also regulates the flow of other ions across the apical surface of epithelial cells. The CF locus was localized through linkage analysis to the long arm of
human chromosome 7, band q3. Multiple CFTR mutations have been identified, the most common a ΔF508 mutation which exists particularly in northern
European descent. This mutation is manifests with the deletion of a single phenylalanine residue at amino acid 508 of the CFTR gene (a class II defect).
Thus the main risk factor for an unborn child is whether the parents are carriers or suffers of cystic fibrosis. Having one parent with cystic fibrosis means
there is a 100% Risk of CF carriers per pregnancy. If someone with CF marries a carrier then there is a 50% Risk of CF per pregnancy
Key Basic Science Learning Issues (incl. diagrams, mechanisms,
concept maps if desired)
1) Anatomy
-respiratory tract
3) Microbiology
Appendix 2,3
4) Pathophysiology
Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for
a protein transmembrane conductance regulator (CFTR) that functions as a
chloride channel and is regulated by cyclic adenosine monophosphate
(cAMP). Mutations in the CFTR gene result in abnormalities of cAMPregulated chloride transport across epithelial cells on mucosal surfaces.
CLASSES OF CF GENE MUTATIONS
CFTR
production
-all other associated tubes that have this CFTR channel
2) Physiology/Biochemistry
CFTR
functionality
Examples
Severity
CLASS Complete
lack of
I
CFTR.
Truncated
mRNA due
to stop
mutations.
Nil. No Cltransporters at
the apical cell
membrane
G542X
CLASS CFTR fails
to mature,
II
thus
degraded by
proteases in
ER
Nil. No Cltransporters at
the apical cell
membrane
ΔF508
CLASS Correctly
processed
III
CFTR but
defective
regulation
due to
abnormal
protein
Cl- transporters
are present but
poor
opening/closing
regulation.
G551D (3% Less severe than
of CF)
ΔF508
? most severe?
(X
represents
stop codon)
(70% of CF
individuals)
Clinicall
most
severe form of
CF
Ion Channels
Ion channels span the lipid bi-layer and allow small ions to pass through.
Each channel is made up of a protein and is specific for each ion.
Channels can be gated to allow or prevent the transport of ions.
Primary Active Transport
Primary active transport involves phosphorylating ATP, which releases
energy, to pump ions in or out of a cell (often against a concentration
gradient). When the ATP phosphorylates it causes a conformational
change in the transport protein which is what allows ions to be pushed
against a concentration gradient.
Secondary Active Transport
When ions are transported using primary active transport they can create a
concentrations gradient. This gradient is a form of potential energy, this
energy can be used as molecules diffuse back into the cell along the
concentration gradient. As they diffuse back into the cell with the help of
a carrier protein it is able to drag other ions of molecules along with it.
The Na+/K+/2Cl symporter carries 1x Na, 1x K, 2x Cl ions into the cell.
Na has a higher concentration outside of the cell and as it diffuses back
into the cell it drags K and Cl with it.
1. Draw diagrams of epithelial cells indicating the mechanisms of ion
transport in simple sodium absorbing and chloride secreting epithelia
SODIUM ABSORBING EPITHELIA
Lumen Side
substitution.
CLASS Mature
CFTR,
IV
pr
ein
normally
activated.
Cl- movement
diminished.
R117H (2%
of CF)
Mild phenotype
CLASS Mature
CFTR at
V
apical
epithelial
surface,
normal,
decreased
abundance.
Defect in intron
splicing or
promoter->
decreased
amount of full
length mRNAs.
(Very rare
these
mutations
make up
<1% of CF)
Mild phenotype.
May go
unnoticed.
CFTR mutations have poor penetrance. This means that the genotype does not
predict the pattern or severity of disease.
Defective CFTR results in decreased secretion of chloride and increased
reabsorption of sodium and water across epithelial cells. The resultant reduced
height of epithelial lining fluid and decreased hydration of mucus results in
mucus that is stickier to bacteria, which promotes infection and inflammation.
Secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other
exocrine tissues have increased viscosity, which makes them difficult to clear.
Small Intestines (Meconium Ileus)
 Plugging of the small intestine with meconium. It consists of mucous, cell
debris and bile and is passed from the newborn just after birth
 In cystic fibrosis, the mucous is abnormally viscous and the meconium may
be hard to pass, or it may obstruct the small intestine.
 Without surgical treatment the small intestine may rupture.
Lung
 Stagnation of the defensive mucocillary action, due to the dense immobile
viscoid mucous
 Inability of the cilia to remove the stagnant mucous increases the risk of
pulmonary infection
 The combination of obstruction (thick mucous) and the infection causes
dilatation of the airways
 Thick bronchial secretions block the small airways, which become
inflamed.
 As the disease progresses, the bronchial walls thicken, the airways fill with
infected secretions, areas of the lung collapse and contract, and lymph
nodes enlarge  Lung damage and secondary lung disease of
bronchiectasis
Basolateral Side
In this situation active transport is used to pump in K+ and pump out Na+
on the basolateral side  Greater [Na+] in the lumen compared to the
inside of the cell. Because of the concentration gradient Na+ diffuses
from the lumen into the cell.
CHLORIDE EXCRETING CELL
Lumen side
Pancreas
 Bile ducts that carry enzymes become blocked due to obstruction of
viscous pancreatic secretions.
 Obstruction causes back pressure atrophy in the vessel and results in
damage to the exocrine portion of the pancreas.
 This upstream atrophy causes inflammation which is eventually replaced
with fibro-fatty tissue  Destruction of Tissue
 Obstruction of the bile ducts due to thick mucoid viscous may cause
upstream hepatic cirrhosis.
 Hence, supplementary enzymes are taken with meals to aid digestion.
Liver
 Thick secretions block the bile ducts.
 Obstruction may also occur in the gallbladder.
Reproductive Organs
 Are affected by cystic fibrosis in various ways, often resulting in infertility,
eg. Excessively thick mucus in vagina; Blokages or malformation of Vas
Deferens
Basolateral side
In this situation K+ is pumped into the cell and Na+ is pumped out of the
cell using active transport on the basolateral side of the cell. But a the
process of secondary active transport Na+ diffuses back into the cell
dragging K+ and Cl- back with it  Increased concentration of Clinside the cell. The excess Cl- then diffuses through chloride channel on
the lumen side of the cell.
Where CL is excreted into the lumen Na+ is also dragged into the lumen to
help balance the charge difference, this creates a higher salt concentration in
the lumen. This creates osmotic pressure and water is dragged across the
membrane into the lumen.
Investigations and Results
1) Blood tests
Other possible investigations
1) Blood tests
blood from heel and sweat test - Screening at birth
2) Imaging
2) Imaging
Chest radiographs may be normal in patients with cystic fibrosis who
have mild lung disease. Hyperinflation is the earliest discernible change,
which is initially reversible with treatment but which later becomes
persistent.
3) Other
-Prenatal, Neonatal, and Postnatal Testing
- Chloride in sweat test: must be performed at least twice in each patient,
preferably several weeks apart. The sweat chloride reference value is less
than 40 mmol/L. A value of more than 60 mmol/L of chloride in the
sweat is consistent with a diagnosis of cystic fibrosis.
Management Plan
Problem
Goal/desired outcome
3) Other
Method (incl. patient actions)
Resources/health professional s
risk of CF in children
Manage
Gene defect
gene therapy – targeting problems
rather than just treating symptoms
CF symptoms



Maintaining lung function
as near to normal as
possible by controlling
respiratory infection and
clearing airways of mucus
Administering nutritional
therapy (ie, enzyme
supplements, multivitamin
and mineral supplements)
to maintain adequate
growth
Managing complications
-identify partner genetic status
(carrier/non carrier)
-seek counselling for all options and
understanding of probabilites
gene therapy aimed at up regulating
expression via infection with virus
containing genetic material that codes
for this CFTR gene
 Increasing the frequency of
airway clearance
 Inhaled bronchodilator
treatment
 Chest physical therapy and
postural drainage
 Increasing the dose of the
mucolytic agent dornase alfa
(Pulmozyme)
 Use of oral antibiotics (eg, oral
fluoroquinolones)
 A high-energy and high-fat
diet, in addition to
supplemental vitamins
(especially fat soluble) and
minerals, is recommended to
compensate for malabsorption
and the increased energy
demand of chronic
inflammation.
involved
clinic counsellor
Gp, physiotherapists
Medications
Mode of action
Side effects
Vitamins & Enzymes
Supplementing for malabsorption
+ supplementing digestive
enzymes that should come from
pancreatic juices
Steroid for Mx of airway
inflammation- glucocorticoid
none
Prednisone
Any specific monitoring
required?
high blood glucose levels; insomnia,
euphoria
Bronchodilators; mucolytic agents;
antibiotics
Other Psychosocial/ethical/legal/patient-centred considerations
-ethical and personal issues in chronic and fatal illness - QOL
PPH/PPD implications
-screening/testing for genetic abnormalities
- Prenatal, Neonatal, and Postnatal Testing
-genetic modelling
Resources used/discovered
-Weekly LO’s
-BMJ
Appendix 1:
EXPLAIN THE CONCEPT UNDERLYING THE HARDY-WEINBERG LAW

The Hardy-Weinberg Law is a mathematical concept that can predict how gene frequencies will be inherited from generation to generation, given a
specific set of assumptions


It states that in a large, randomly breeding population, allele frequencies will REMAIN THE SAME from generation to generation, assuming that
there is no mutation, gene migration, genetic selection or genetic drift
This principle is important because it gives biologists a standard from which to measure changes in allele frequency in a population
The mathematical formula used to calculate the Hardy-Weinberg law is:
p2 + 2pq + q2 = 1  where p (dominant) and q (recessive) are the frequency of alleles in a set population
and
p + q = 1 (ie: the sum of both alleles must equal 100%)
Derivation of p’s and q’s !!!
Paternal Gametes
Maternal Gametes
A (p)
a (q)
A (p)
AA (p x p = p2)
Aa (pq)
a (q)
Aa (pq)
aa (q x q = q2)
Genotype
AA
Aa
Aa
Frequency
p2
2pq
q2
Phenotype
Homozygous normal
Heterozygous normal (carrier)
Homozygous abnormal
CALCULATE CARRIER FREQUENCY FROM DISEASE INCIDENCE FOR RECESSIVE GENES, USING THE HARDY-WEINBERG EQUATION
An example:
The current incidence of cystic fibrosis in Caucasians is 1 in 2500. (Let presence of cystic fibrosis = aa)
Thus aa = q2 =
q=
q=
p+q=1
p+
=1
p=1–
p=
Using the Hardy-Weinberg Equation:
2pq = heterozygous normal carrier
=2x
x
=
≈ 0.04 =
= current ratio of carrier amongst Caucasians
p = homozygous dominant allele = AA = 0.9996
2pq = heterozygous allele (carrier) = Aa = 2 x 0.9996 x 0.0004 ≈ 0.0008 ≈
q = homozygous recessive allele = aa = 0.0004 =
Appendix 2:
Common Upper Respiratory Tract Infections
Infection
Agent
Clinical Features
> 70% viral – rhinovirus,
coronavirus
Resp synctial virus (RSV)
Rapid onset. Sneezing, sore
throat, watery nasal discharge,
cough
Pharyngitis/tonsillitis
As above + haemolytic
streptococci, EBV
More severe sore throat, hoarse
or loss of voice, painful cough
Acute Laryngotracheobronchitis
Parainfluenza viruses, influenza
virus, RSV
Sudden attack of cough with
stridor and breathlessness. Can
lead to cyanosis and asphyxia in
small children
Sinusitis
Strep. Pneumoniae,
Haemophilus influenza
Fever, Unilateral pain over
sinuses, purulent nasal
discharge
Acute Coryza
(Common Cold)
Epiglottitis
Haemophilus Influenzae
Mostly affect young children.
Fever, sore throat, progressing
to stridor and dysphagia
Acute otitis media (middle ear
infection via Eustachian tube)
Strep. Pneumoniae,
Haemophilus influenza,
Moraxella catarrhalis but can
also be viral
Fever, ear pain, and associated
symptoms such as runny nose
and cough
Appendix 3:
Common Lower Respiratory Tract Infections
Infection
Agent
Clinical Features
Bronchiolitis (mainly affects
babies and little children)
RSV, parainfluenza virus,
adenovirus
Cough, runny nose, dyspnoea
Acute Bronchitis
Rhinovirus, adenovirus,
influenza virus, RSV
Often follows common cold.
Initially dry, painful cough. Then
chest tightness, wheeze and
breathlessness. May have fever
Whooping cough
Bordetella pertussis
Features of the common cold but
also persistent cough and sticky
mucous develops in RT making
breathing difficult
Chronic bronchitis exacerbation
Strep. Pneumoniae,
Haemophilus influenza,
Moraxella catarrhalis
When breathing suddenly
becomes more difficult for a
person with chronic bronchitis
(due to narrowing or airway and
secretion of large amounts of
mucous)
Acute typical pneumonia
Strep. Pneumoniae,
Haemophilus influenza,
Moraxella catarrhalis, Staph.
Aureus, Legionella + many
others
Fever, shivering, vomiting,
breathlessness, cough (at start
short, painful + dry but later
accompanied by sputum), chest
pain
Atypical pneumonia
Mycoplasma pneumoniae,
Chlamydia pneumoniaeS
Symptoms much milder than
acute typical pneumonia