This document provides information on cystic fibrosis including its clinical presentation, pathophysiology, gross and microscopic findings, and differential diagnosis. Key points: - Cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR gene resulting in defective ion transport in exocrine glands. - Clinical manifestations include recurrent respiratory infections, pancreatic insufficiency, liver disease, and male infertility. Severity depends on mutation type. - Pathophysiology involves defective CFTR chloride channel function leading to dehydrated secretions in the lungs, pancreas and other organs. - Gross findings include bronchiectasis, pancreatic cysts and cirrhosis. Microscopy shows features of infection

1. FLASHPATH
H A Z E M A L I

2. CYSTIC FIBROSIS
H A Z E M A L I

3. 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

4. CLINICAL
Clinical picture:
• Respiratory:
– 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”
Note that the severity of clinical picture “phenotype”
depends on the type of the mutation
(See Later)

5. CLINICAL
Common associated respiratory infections:
• Allergic bronchopulmonary aspergillosis
• Pseudomonas aeruginosa
• Hemophilus influenza
• Mycobacteria (atypical)
• Staphylococcus aureus
Two unique organisms for cystic fibrosis:
• Burkholderia cepacia
• Stenotrophomonus maltophilia
• Both are aggressive
• Both are treated with trimethoprim-sulfamethoxazole

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. MICROSCOPY
• Nose:
– Nasal polyps
• Covering:
– Respiratory epithelium “pseudostratified columnar ciliated”
– Delicate basement membrane (not thickened)
• Core:
– Loose, Edematous
– 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
PolypsinCF
Glandscontainacidmucin
StainsbluewithAlcianblue/PAS
DDfrom
Inflammatory/allergicpolyps
Inflammatorypolyps
Glandscontainneutralmucin
StainspurpleredwithAB/PAS

14. 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)

15. 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

16. 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

17. 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)

18. SPECIAL STUDIES
Molecular studies: CFTR gene mutation
More than 1800 mutations, classified into Six groups:
Class Defect Result
I Defective protein synthesis No CFTR protein synthesis from the start
II
Defective protein folding and glycosylation
(in Golgi/endoplasmic reticulum)
CFTR protein is synthesized, but it is
degraded before reached the cell surface
III
Defective ATP binding
(to NBDs)
CFTR protein reaches the cell surface in
normal amount, but it is Nonfunctioning
IV
Defective chloride ion transport/conductance
(through transmembrane domains)
CFTR protein reaches the cell surface in
normal amount, but with reduced
function
V
Defective introns’ splicing
(within the gene)
CFTR protein reaches the cell surface in
reduced amount
VI
Defective regulatory role on other ion
channels
(e.g., Na, K, HCO3)
CFTR protein reaches the cell surface in
normal amount, but with altered function

19. 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 
• ΔF508 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

20. 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

21. DIFFERENTIAL DIAGNOSIS
L u n g :
“ O t h e r c o n g e n i t a l / c y s t i c l u n g d i s e a s e s ”
• Congenital:
– Bronchogenic cysts
– Congenital pulmonary cysts
– Congenital pulmonary airway malformation
– Congenital lobar emphysema
– Pulmonary sequestration
• Acquired:
– Emphysema
– Healed abscess
– Honeycombing

22. DIFFERENTIAL DIAGNOSIS
Also:
“ O t h er c a u ses of p a n creat ic i n s u ffi cien cy, c h ron i c p a n creat itis “
“ O t h er c a u ses of b i l e d u c t u lar re acti on , c i r r h osi s “
“ O t h er c a u ses of n a sal p o l yps ”

23. 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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