FLASHPATH

HAZEM ALI
CYSTIC FIBROSIS
HAZEM ALI
CLINICAL
Autosomal recessive disorder of ion transport that affects fluid
secretion in exocrine glands and in the epithelial lining of the
respiratory, gastrointestinal, and reproductive tracts.

Common disease in Caucasian

1 in 2500 live births have disease
1 in 20 are carriers

Much lower incidence in other ethnic groups

Usually manifests in Children and Adolescents

CLINICAL
Clinical picture: Note that the severity of clinical picture phenotype
depends on the type of the mutation
Respiratory: (See Later)
Recurrent infections
COPD Bronchiectasis

GIT, Liver & Pancreas:

Pancreatic insufficiency Steatorrhea, malnutrition
Hepatobiliary disease and cirrhosis
Meconium ileus

Genitourinary:
Congenital bilateral absence of the vas deferens Infertility
CLINICAL
Common associated respiratory infections:
Allergic bronchopulmonary aspergillosis
Pseudomonas aeruginosa
Hemophilus influenza
Mycobacteria (atypical)
Staphylococcus aureus

Two unique organisms for cystic fibrosis:

Burkholderia cepacia
Both are aggressive
Stenotrophomonus maltophilia Both are treated withtrimethoprim-
sulfamethoxazole
CLINICAL
Treatment:
Antibiotics for respiratory infections

Postural drainage and chest physiotherapy for airway clearance

Lung transplant for end-stage lung disease

Pancreatic enzyme replacement therapy and supplemental feedings

Remember Fibrosing Colonopathy
Colonic strictures due to submucosal fibrosis seen in children with CF
receiving high-strength pancreatic supplements

Oral ursodiol for biliary buildup/obstruction

Assisted reproductive technologies for infertility

PATHOPHYSIOLOGY
CFTR:
Cystic Fibrosis Transmembrane conductance
Regulator
Gene location: chromosome 7 (at 7q31)
Function:
Regulate epithelial Chloride channel
Also regulate other ion channels
E.g., Sodium, Potassium, and Bicarbonate ions

Components: Five domains

Two trans-membrane domains
Two cytoplasmic nucleotide-binding domains (NBDs)
One regulatory (R) domain
Activation:
Agonists (e.g., acetylcholine) Increase cAMP Activates protein kinase A
Phosphorylating the CFTR at the R domain (using ATP bound to NBDs) CFTR Activation
PATHOPHYSIOLOGY
CFTR function is Tissue-specific (differ from site to another)
Sweat gland ducts:
Normal CFTR increases the reabsorption of Chloride ion and augments the
reabsorption of Sodium ions via regulation of epithelial Na channel = ENaC
Mutated CFTR decreases the reabsorption of Sodium chloride
Hypertonic Salty sweat
PATHOPHYSIOLOGY
Lung / GIT / Pancreas:
Normal CFTR increases the secretion of Chloride ion and reduces the
reabsorption of Sodium ions via regulation of epithelial Na channel = ENaC
Mutated CFTR decreases the secretion of Chloride ion and augments the
reabsorption of Sodium ion (with passive Water reabsorption)
Hyperconcentrated dehydrated viscid secretions
PATHOPHYSIOLOGY
As regards the Bicarbonate ion:

Normal CFTR increases the concentration of Bicarbonate ion into the

lumen via regulation of anion exchangers = SLC26
Normal Alkaline secretion

Mutated CFTR decreases the concentration of Bicarbonate ion into

the lumen
Acidic secretion increased mucin precipitation and plugging,
increase bacterial activity
GROSS
Nose:
Nasal polyps
Single or Multiple polypoid masses
Soft and edematous

Lung:
Bronchiectasis
Enlarged, dilated bronchi
Diameter of the bronchus should exceed the diameter of the accompanying bronchial artery
Dilated bronchi are extending to pleural surface
Filled with yellow-green mucopurulent secretions
GROSS
Pancreas:
Cystic changes 2ry to ductal obstruction
Multiple, small cysts (1-3 mm in diameter)
Filled with thick, tenacious secretions

Hepatobiliary:
Bile duct obstruction
Enlarged, dilated bile ducts
filled with thick, tenacious secretions
End-stage: Cirrhosis
 Stains blue with Alcian blue/PAS
MICROSCOPY

Glands contain acid mucin

Glands contain neutral

Stains purple red with

Inflammatory polyps
Nose:

Polyps in CF

AB/PAS
mucin
Nasal polyps
Covering:
Respiratory epithelium pseudostratified columnar ciliated
Inflammatory/allergic polyps

Delicate basement membrane (not thickened)

Core:
Loose, Edematous
DD from

Large cystic mucous glands, with inspissated secretion in their lumina

Contain acid mucin (not neutral mucin)
Mixed inflammatory cells
May contain some eosinophils (not extensive)
Chronic cases fibrotic cores
MICROSCOPY
Lung:
Bronchiectasis
Wall:
Ectatic, dilated airways
Chronic inflammatory cells and fibrosis
Mucosa:
Ulceration
Squamous metaplasia

Follicular bronchiolitis
Lymphoid hyperplasia with germinal centers

Pneumonia
Acute or Organizing
Features of causative organisms (if any)
MICROSCOPY
Pancreas:
Cystic changes
Ectatic, dilated ducts filled with eosinophilic material
Obstruction-related changes:
Exocrine acinar atrophy
Replacement of atrophic lobules by interstitial fibrosis
Scattered islets of Langerhans could be seen

Grading:
Grade I: accumulation of secretion
Grade II: exocrine atrophy
Grade III: atrophy with lipomatosis
Grade IV: fibrosis with total obliteration of the
exocrine glands and ducts with scattered islets
MICROSCOPY
Hepatobiliary:
Ductular reaction 2ry to Bile duct obstruction
Portal tracts expansion by inflammation and increased numbers of bile
ductules
Bile ductules are dilated and contain plugs of a light eosinophilic material

Portal fibrosis, bridging fibrosis and cirrhosis

SPECIAL STUDIES
Laboratory tests:
Elevated sweat chloride (>60 mEql/L)
Remember that sweat glands are morphologically unaffected.

Abnormal nasal trans-epithelial potential difference

Useful in cases with low sweat chloride
Milder CFTR mutations

Azoospermia on semen analysis

Obstructive type (due to structural abnormalities of the vas
deferens)
SPECIAL STUDIES
Molecular studies: CFTR gene mutation
More than 1800 mutations, classified into Six groups:
Clas Defect Result
s
Defective protein synthesis No CFTR protein synthesis from
I
the start
Defective protein folding and CFTR protein is synthesized, but it is
II glycosylation degraded before reached the cell
(in Golgi/endoplasmic reticulum) surface
Defective ATP binding CFTR protein reaches the cell surface
III (to NBDs) in normal amount, but it is
Nonfunctioning
Defective chloride ion CFTR protein reaches the cell surface
IV transport/conductance in normal amount, but with
(through transmembrane domains) reduced function
Defective introns splicing CFTR protein reaches the cell surface
V
(within the gene) in reduced amount
SPECIAL STUDIES
Class I, II, and III Total loss of function (Severe clinical picture
phenotype)
I.e., Bronchiectasis, pancreatic insufficiency, male infertility, hepatic cirrhosis
Examples
F508 deletion
Class II Defective protein folding
The most common mutation in Caucasian
W1282X nonsense mutation
Class I Defective protein synthesis
The most common mutation in Ashkenazi Jews

Class IV, V, and VI Reduced function (Milder clinical picture

phenotype)
I.e., Congenital bilateral absence of vas deference and infertility
Example R117H missense mutation (in trans with 5T allele)
Class V Defective chloride ion transport/conductance
5T allele modifies Poly-T tract in intron 8 and reduces its splicing efficacy
SPECIAL STUDIES
Remember that cystic fibrosis is an autosomal
recessive disease
Mutation of one allele carrier
Mutation of both alleles disease

Also the type of mutation plays a role in the overall

phenotype
If two severe mutations (e.g. class I, II, III) severe clinical
picture
If one severe + one mild mutation (e.g. class IV, V, VI)
less severe
If two mild mutations very mild
DIFFERENTIAL DIAGNOSIS
Lung:
Other congenital / cystic lung diseases
Congenital:
Bronchogenic cysts
Congenital pulmonary cysts
Congenital pulmonary airway malformation
Congenital lobar emphysema
Pulmonary sequestration
Acquired:
Emphysema
Healed abscess
Honeycombing
DIFFERENTIAL DIAGNOSIS

Also:

O t h e r c a u s e s o f p a n c r e a t i c i n s u ffi c i e n c y, c h r o n i c
pancreatitis

Other causes of bile ductular reaction, cirrhosis

Other causes of nasal polyps

DIFFERENTIAL DIAGNOSIS
Primary cilia dyskinesis:
Immotile cilia, Kartagener syndrome, Young syndrome,
secondary cilia dyskinesis

Ultrastructural abnormalities affect virtually all cilia and

are characterized by:
Loss of dynein arms
Absence of radial spokes
Transposition or absence of microtubules
Compound or disorientated cilia
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HAZEM ALI