Cystic Fibrosis

CF an autosomal recessive disorder. Approximately 50% will survive to the age of 25. In 1989, the CF gene was found to be located on the long arm of chromosome 7, The CF protein is called the cystic fibrosis transmembrane regulatory protein (CFTR). The most common mutation is the three-base deletion removing a phenylalanine residue at position 508 of CFTR, called the F508 mutation. The basic defect is due to a defect in chloride permeability, which can result in the accumulation of mucus and can lead to stasis and obstruction. Both the upper and lower airways can be involved, and they can lead to frequent bronchial infections predominated early by Staphylococcus aureus and Hemophilus influenzae and in late disease by Pseudomonas aeruginosa. The diagnosis is usually made by the sweat test performed by quantitative pilocarpine iontophoresis. CF diagnosis is confirmed by an elevated sweat chloride concentration greater than 60 mEq/L.

Pseudomonas aeruginosa REF: Mayo Clinic Internal Medicine Board Review 9th edition Page 845, Infectious diseases of the respiratory tract by Michael E. Ellis Page 511

“Pseudomonas aeruginosa is a ubiquitous organism commonly isolated from patients with cystic fibrosis and bronchiectasis”

Endocrine REF: Harrison’s Internal Medicine, Chapter 253, Davidson’s internal medicine 20^th edition page-685

FEATURES OF CYSTIC FIBROSIS:

• A- Autosomal recessive
• B- Bronchiectasis
• C- Chloride channel block/Ciliary dysfunction
• D- Diabetes mellitus
• E- Exocrine pancreatic failure (> 90% of patients with CF)
• F- Fat malabsorption (steatorrhoea)
• G- Gall stone/Gene mutation on chromosome 7
• H- Hepatic cirrhosis/Hemoptysis
• I- Intestinal obstruction/Infertility

Pseudomonas aerugenosa (non mucoid) [Ref^. Nelson Pediatrics 18/e p 1209, 1210]

• The incidence of pseudomonas aeruginosa infections in cystic has not diminished. Pseudomonas aeruginosa in the most common cause of respiratory failure in cystic _.fibrosis patients.
• Acquisition of pseudomonas infection begins early in childhood the initial acquisition of P.aeruginosa in the CF lung is with nonmucoid strains and occurs early in life. Over time there is transition to mucoid strain.
• Hemophilus influenza. Staphycoccus Aureus and pseudomonas aeruginosa are the most prevalent early pathogen in patients with cystic fibrosis.

–     Most patients have colonization with at least 1 of these bacteria by 1 years of age.

–     Early infection with Pseudomonas aeruginosa can be transient and approximately half clears, spontaneously. – However, by their teenage years most of the cystic fibrosis patients have colonization with Pseudomonas aeruginosa.

• Although most patients are initially infested with nonmucoid Pseudomonas aeruginosa, it later transition to a mucoid state.

–     in a recent study of patients with cystic _.fibrosis identified by neonatal screening, acquisition of nonmucoid and mucoid pseudomonas aeruginosa occurs at a median age of 1.0 and 3.0 years.

–     Early acquisition of mucoid was associated with a 4 _.fold greater decrease in cumulative survival.

• Mucoid pseudomonas is much more difficult to treat and eradicate because it lives in a defensive mode of growth called “biofilm”.

– Infant and children experience transient pseudomonas aeruginosa infection within 1 year although they have no symptom.

–     The infection eventually becomes chronic with nonmucoid pseudomonas aeruginosa. This happens by teenage years.

Initial infection with

• Staphylococcus Aureus
• Pseudomonas Aeruginosa (non mucoid strain)
• H influenza

By teenage years

• Almost all patients are colonized by Pseudomonas
• The colonization is with nonmucoid Pseudomonas

Later on

• Non mucoid strain transitions to mucoid strain

Burkholderia cepacia

• Infection with others less common organism has become a problem of increasing importance in the care of patients with CF. Burkholderia cepacia complex a unique family of gram negative bacteria, also can be a cause of rapid decline in lung.function.
• Two Burkholderia species B.mutivorans and B cenocepacia are of particular concern. Infection with these can lead to “cepacia syndrome” a rapidly progressive course characterized by : – Fever, uncontrolled bronchopneumonia weight loss and often death.

Pseudomonas aeuroginosa is the most common organism causing chronic lung disease in patients with cystic fibrosis.

In young children with cystic fibrosis, Staphylococcus aureus and Hemophilus influenzae are the most common pathogens. The prevelance of Pseudomonas aeruginosa increases with increasing age.

The CFTR protein is a single polypeptide chain, containing 1480 amino acids. It functions as a cyclic AMP–regulated Cl– channel and as a regulator of sodium channels.

The fully processed form of CFTR is found in the plasma membrane of normal epithelial cells.

In cystic fibrosis, F508 mutation leads to improper maturation and intracellular degradation of the mutant CFTR protein.

The CFTR protein consists of two similar halves, each containing six transmembrane regions and a nucleotide (ATP)-binding fold (NBF).

The two halves of the molecule are joined by a regulatory domain. F508 is located in NBF1.

Normally, CFTR is synthesized on bound polyribosomes and is then exported to the plasma membrane, where it functions.

Many mutations affect the folding of the protein and cause a marked reduction of its function.

Ref: Current Medical Diagnosis and Treatment, 2012, Chapter 9 ; Harrison’s Internal Medicine, 18th Edition, Chapter 259 ; Harper’s Illustrated Biochemistry, 29th Edition, Chapter 57

P. aeruginosa is the most common cause of gram-negative bacteremia in neutropenic patients and it is the most common contributing factor to respiratory failure in cystic fibrosis and is responsible for the majority of deaths among them. P. aeruginosa infection in burns is no longer a major problem.

For reasons that still are not understood, the most common bacterial organisms infecting the lungs of children with cystic fibrosis are Staphylococcus aureus and Pseudomonas aeruginosa. This has not changed much in the past two decades despite major changes in our antibiotic usuage. Pseudomonas is particularly difficult to eradicate despite sensitivity in vitro to a variety of antibiotics.

The earliest chest x-ray finding in CF lungs is hyperinflation, reflecting small-airways obstruction. Later, signs of luminal mucus impaction, bronchial cuffing, and finally bronchiectasis, e.g., ring shadows, are noticed.

Cystic fibrosis is associated with hypochloremic metabolic alkalosis not metabolic acidosis. It can also cause respiratory acidosis. Important causes of chronic respiratory acidosis in children are chronic lung disease, cystic fibrosis, extensive bronchiectasis and neuromuscular defects.

The most common inherited disorder of cholangiocyte injury is cystic fibrosis.

C i.e. Cystic fibrosis

Ans. is ‘b’ i.e., Cystic fibrosis; ‘c’ i.e., Congenital hepatic fibrosis

A heterogenous group of lesions causing altered architechture of intrahepatic billiary tree. They are :

           Von Meyenburg complexes                      Congenital hepatic fibrosis

           Polycystic liver disease                            Caroli disease

o Alagille syndrome is absence of portal tract, bile duct peculiar facies, vertebral anomalies and CVS defects.

o In cystic fibrosis — bile canaliculi are plugged by mucinous material when longstanding, can cause biliary cirrhosis. It cause ductular proliferation and portal inflammation.

Ans. is `b’ i.e., Increased

CYSTIC FIBROSIS

o Cystic fibrosis is an inherited disease of the mucus and sweat glands.

o Cystic fibrosis follows on autosomal recessive transmission.

o There is a defect in ion transport of epithelial cells that affects fluid secretion in

i)      Exocrine glands (pancreas)

ii)     Epithelial lining of respiratory, gastrointestinal and reproductive tract.

Pathophvsiologv

o In normal duct epithelia, chloride is transported by plasma membrane channels (chloride channels)

o The primary defect in cystic fibrosis results from abnormal function of an epithelial chloride channel protein

encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q 31.2.

o Protein encoded by CFTR is a chloride channel through which chloride passes –> In cystic fibrosis activity of chloride channel is decreased.

o Along with chloride channel, CFTR can regulate other channel also, for example epithelial sodium channels (ENaC). ENaC is inhibited by normally functioning CFTR; hence, in cystic fibrosis, ENaC activity increases, markedly augmenting sodium uptake across the apical membrane (especially in respiratory and gastrointestinal system).

Clinical features of CF

o Functions of CFTR are tissue specific, i.e. its functions signify whether the epithelium is secretory (secrete CI- into lumen) or absorptive (reabsorb Cl- from lumen).

o Therefore clinical features are tissue specific:

Respiratory tract

o Respiratory epithelium is secretory, i.e. there is active secretion of CI-.

o CFTR mutation in cystic fibrosis results in loss or reduction of chloride secretion in lumen.

o Active luminal sodium absorption is also increased (due to loss of inhibition of ENaC activity)

o Both these decreased Cl- secretion and increased Na’ absorption from lumen) lead to increased passive water

reabsorption (As you all know diffusion of water occurs from high osmolar to low osmolar concentration area). o This results in accumulation of dehydraded hyperconcentrated viscid secretion in respiratory lumen and defective

mucociliary clearance –> obstruction and recurrent respiratory tract infection; and bronchiectasis.

Intestine

o Similar to respiratory epithelium, intestinal epithelium is secretory and in CF there is defective Cl- secretion and

enhanced Na’ absorption from lumen –> Increased passive reabsorption of water from lumen.

o This results in accumulation of dehydrated desciated intraluminal contents —> obstruction of small and large

intestine.

Pancreas

o The absence of CFTR Cl- channel in the apical membrane of pancreatic ductal epithelium limits the function of an

apical membrane Cl- -HCH0₃ exchanger to secrete bicarbonate and Na’ (by a passive process) into the duct. o The failure to secrete bicarbonate and Na⁺ leads to retention of enzyme in the pancreas and ultimately destruction

of all pancreatic tissues due to pancreatitis.

Hepatobiliary system

o Similar to respiratory and intestinal epithelium, defective biliar Cl- and water secretion causes thickened biliary secretions —^p biliary cirrhosis, cholecystitis, cholelithiasis.

Sweat glands

o In contrast to respiratory and intestinal epithelium, sweat gland duct epithelium is absorptive, i.e. function of normal CFTR in the sweat gland ducts is to reabsorb Cl- ions and Na⁺ from lumen.

o Therefore, in the sweat ducts, loss of CFTR function leads to decreased reabsorption of NaC1 —> Hypertonic sweat with increased Na⁺ and Cl- in sweat.

Ans. is ‘c’ i.e., Associated with 7p chromosome

Ans. is d i.e., Renal failure

o Thick viscid plugs of mucus may also be found in the small intestine of infants. Sometimes these cause small-bowel obstruction, known as meconium ileus.

o Chronic sinopulmonary disease manifested by : Persistent colonization/infection with typical cystic fibrosis

pathogens, including Staphylococcus aureus, non typeable Hemophilus influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, Burkholderia cepacia; Chronic cough and sputum production, nasal polyps.

o Azoospermia and infertility are found in 95% of the males who survive to adulthood; congenital bilateral absence of the vas deferens is a frequent finding in these patients.

Ans. is ‘c’ i.e., Chramosome 7

The primary defect in cystic fibrosis results from abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (cfTR) gene on chromosome band 7q3 1.2.

Ans. is ‘a’ i.e., Meconium ileus

Cystic fibrosis

o Cystic fibrosis (mucoviscidosis) is a hereditary disease affecting the exocrine (mucus) glands of the lungs, liver, pancrease and intestines, causing progressive disability due to multisystem failure.

o It has an autosomal recessive pattern of inharitance.

Pathogenesis

o The basic defect in CF is mutation in the cystic fibrosis transmembrane regulator (CFTR) gene that regulates chloride conductance channel in outer membrane of exocrine glands.

Clinical manifestations

1) Lungs and sinus disease

• Sinusitis                 
• Bronchiactasis               
• Lower respiratory tract infection
• Nasal polyps        
• Chronic lung disease     
• Pulmonary hypertension can cause heart failure
• Allergic bronchopulmonary aspergillosis

2) GIT, Liver and pancrease

• Meconium ileus
• Rectal prolapse
• Malabsorption               
• Pancreatitis
• Constipation      
• Intussusception
• Meconium peritonitis
• Bile duct obstruction and biliary cirrhosis

3) Endocrine and growth

• Diabetes                                
• Osteoporosis                   
• Poor growth

4) Infertility

• In men due to absence of vas deference       
• In women due to thick cervical mucus.

Ans is ‘b’ i.e., Abnormality in CFTR which leads to defective calcium transport

Cystic fibrosis is an autosomal recessive disorder of ion transport in epithelial cells that affect fluid secretion in exocrine glands and the epithelial lining of the respiratory, gastrointestinal and reproductive tracts.

• Cystic fibrosis occurs due to mutation in the CFTR gene.
• CFTR was initially recognized as chloride conductance channel but it is now recognized that CFTR can regulate multiple ion channels and cellular processes. These include :

o Chloride channels

Potassium channels

Gap junction channels

Bicarbonate ions

Ans. is ‘a’ i.e., Lung normal at birth; ‘b’ i.e., Abnormal sweat chloride tests

o Cystic fibrosis (C.F.) is an autosomal recessive disease, where all the exocrine glands in the body especially those in the respiratory & G.I.T. system are involved & produce abnormal visid mucous. The gene is located on the chromosome-7.

o Most patients with CF present in childhood. Approx 18% of patients present within the first 24 hr of life with Gastrointestinal obstruction, termed Meconium ileus.

o Other systems dysfunctions are not present at birth, they may manifest within the first year or two of life including respiratory tract system.

The diagnosis is confirmed by demonstration of a high sweat chloride (>60 mEq/L) on repeated measurements. Pathophysiology of high sweat chloride

o Cystic fibrosis patients secrete nearly normal volumes of sweat in the sweat acinus.

o However, CF patients are not able to absorb NaC1 from sweat as it moves through the sweat duct due to the inability to absorb Cl- across the ductal epithelial cells.

o This dysfunction in the sweat gland is typically measured by collecting sweat after iontophoresing a cholinergic agonist into the forearm.

Ans is ‘a’ i.e., Pseudomonas aerugenosa (non mucoid)

o The most common and important pathogen in cystic fibrosis is Pseudomonas aeruginosa,which causes infections that, once established, are impossible to eradicate.

o Acquisition of Pseudomonas infection begins early in childhood. The initial acquisition of P. aeruginosa in the CF lung is with nonmucoid strains and occurs early in life. Over time there is transition to mucoid strain, and with age mucoid strain becomes predominant with age.

o Non-mucoid P. aeruginosa can be eradicated with aggressive anti-pseudomonal antibiotic theraphy. Mucoid strain cannot be eradicated by current antibiotics and therefore predicts shortened survival.

Ans. is ‘a’ i.e., Cystic Fibrosis

o Recurrent chest infection in a child with evidence of exocrine pancreatic insufficiency (bulky, foul smelling stool) suggest a diagnosis of cystic fibrosis.

Ans. is ‘c’ i.e., 0

o Cystic fibrosis is an autosomal recessive disorder.

o If husband and wife are clinically normal and the child has developed the disease that means both husband & wife are carrier.

o 25% will be affected and 75% will be phenotypically normal.

o If one child is already affected, the chance for the disease in the second offspring is zero.

Answer is C (Defect in chloride channel leading to water reabsorption):

Thick exocrine secretions in Cystic Fibrosis result from a defect in CFTR Protein which acts as a chloride channel (defect in chloride channel is the primary abnormality).

Cystic Fibrosis CF is characterized by a defect in Cystic Fibrosis Transmembrane Regulator (CFTR) gene found on chromosome 7. The CFTR gene codes for the cell membrane transporter protein (CFTR Protein) that normally forms chloride channels in the plasma membrane. Defect in CFTR Protein results in a decrease in chloride permeability across the membrane of epithelial cells of exocrine glands. Since chloride transport across membranes is closely linked to Sodium transport, the defect in chloride channels, leads to an influx of salt and water into the cells resulting in dehydration of the extracellular fluid compartment, an increased chloride concentration in sweat (The basis of diagnostic sweat test) and thickening of exocrine secretions. Virtually all of the clinical manifestations of the disease can be attributed to the thick, tenacious secretions that accumulate in the ducts of exocrine glands

Answer is B (Demonstrate an abnormal nasal potential difference)

Nasal Potential Difference is a sensitive test of electrolyte transport (CFTR function) that can be used to support or refute a diagnosis of cystic fibrosis when sweat chloride levels are normal or border line and two CF mutations cannot be demonstrated by DNA testing.

Diagnostic criteria for cystic fibrosis

The patient in question has typical clinical features of cystic fibrosis; however the sweat chloride levels are border line (between 40-60meq/1) on two separate occasions. To establish the diagnosis of cystic_. fibrosis, another laboratory evidence demonstrating CFTR dysfunction is therefore required.

This can be achieved by demonstration of abnormal CF mutation by DNA analysis or by demonstrating an abnormal  nasal potential difference.

The diagnostic criteria for cystic fibrosis requires demonstration of at least two CF mutations and hence demonstration of an abnormal F508 mutation alone is not sufficient to establish the diagnosis of CF

An abnormal CFTR nasal potential difference is an established laboratory evidence of CFTR dysfunction and is accepted as a diagnostic criterion to establish the diagnosis of cystic fibrosis.

Answer is D (Endocrine):

Cystic fibrosis is typically charachterized by Exocrine Pancreatic insufficiency. Endocrine Pancreatic insufficiency is not seen as a tyical manifestation of cystic fibrosis.

Charachteristic Classical Manifestations of Cystic Fibrosis (Typical System Involvement)

Respiratory system (Sinopulmonary disease)

• Pulmonary infection
• Persistant colonization/infection with typical cystic fibrosis pathogens, including Staphylococcus aureus, nontypeable, Hemophilus influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, Burkholderia cepase
• Chronic obstructive Pulmonary Disease
• Bronchiectasis is typical
• Airway obstruction manifested by wheezing and air trapping
• Chronic cough & sputum production
• Digital clubbing
• Persistent chest radiograph abnormalities (eg. Bronchiectasis, atelectasis, infiltrates, hyperinflation)
• Nasal Polyps radiographic or computed tomographic abnormalities of paranasal sinuses

Gastrointestinal System (Intestinal; Hepatobiliary; Pancreatic)

Intestinal meconium ileus, distal intestinal obstruction syndrome, rectal prolapse.

Pancreatic

Pancreatic exocrine deficiency

Hepatobiliary

Hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis, or multilobular cirrhosis

Nutritional

Failure to thrive (protein-calorie malnutrition), hypoproteinemia, edema, complications secondary to fat-soluble vitamin deficiency

Genitourinary System

(Male Infertility)  Male urogenital abnormalites resulting in obstructive azoospermia are typical

Metabolic Abnormalities are typically charachterized by salt depletion syndrome, (Hyponatremia, Hypocholeremia and Hypokalemic Metabolic Alkalosis)

Answer is A (Pseudomonas Aeroginosa):

The most common cause of Pulmonary infections in cystic fibrosis is Pseudomonas aeroginosa

The most common pathogen in CF is Pseudomonas Aeroginosa followed by Staphylococcus’ – `Pseudomonsa:Getntnu & Molecular Biology’ (Harizon Scientific Press)2008/160

Pulmonary Infection in Cystic Fibrosis

• The most common cause of Pulmonary infection in cystic fibrosis in children is staphylococcus aureusQ
• The most common cause of Pulmonary infection in cytic fibrosis in adolescents and adults is Pseudomonas Aeroginosa.
• The two most common cause of pulmonary infection in cystic fibrosis are staphylococcus aureus and Pseudomonas Aeroginosa.

Overall (all age groups) Pseudomonas Aeroginosa is marginally more common than staphylococcus aureus as a cause of pulmonary infection in cystic fibrosis.

• The most common organism causing chronic lung disease in patients with cystic fibrosis is pseudomonas aeroginosa

Answer is A (Staphylococcus Aureus):

Staphylococcus Aureus (Methicillin sensitive) are the most common pathogen isolated in sputum of children with cystic fibrosis during the first decade.

The most prevalent pathogen to cause pulmonary infection in cystic fibrous during childhood is staphylococcus aureus. Pseudomonas aeroginosa becomes the most common organism in adolescents and adults. Hemophilus influenza is also seen in early life (2-5 years) and its frequency decreases with age. Bukholderia capacia is also infrequent but its incidence increase with age. Stenotrophomonos is an infrequent organism seen at any age. – USMLE Step III: Review/Q1 Case 7

The most common cause of pneumonia in a patient with cystic_, fibroses is Pseudomonas aeroginosa, but initial infection is most often due to staphylococcus aureus’- Microbiology: Pearls of Wisdom’ by Booth (Jones & Barlett) 2000/203

Bronchial Ademoma and Bronchial Cysts

Ans. b and c

Ans. B i.e. Ultimately lead to bronchogenic carcinoma

Cystic fibrosis:

• Autosomal recessive,
• Results due to mutation in a gene on chromosome 7,
• Predisposes to chronic infection by staph. aureus and pseudomonas,
• Cavitation is oftenly seen with staphylococcal infections

Ans. is ‘b’ i.e., 7q

Cystic fibrosis

Cystic fibrosis is an inherited disease of the mucus and sweat glands.

Cystic fibrosis follows on autosomal recessive transmission.

There is a defect in ion transport of epithelial cells that affects fluid secretion in

i)      Exocrine glands (pancreas)

ii)     Epithelial lining of respiratory, gastrointestinal and reproductive tract.

Ans. is’b’ i.e., Cystic fibrosis

The distribution ()I^. bronchiectasis mar be important diagnostically

A central                                                            →        Perihilar allergic bronchopulmonary aspergillosis. 

Predominant upper lobe o Middle and lower lobe    →       Cystic fibrosis or one of its variants. Distribution is consistent with PCD

Lower lobe involvement is   →  Middle lobe and lingular segment of the LUL involvement is characteristic of non tuberculous mycobacteria (NTM). Idiopathic bronchiectasis

 Cystic fibrosis

Disease shown: Central bronchiectasis

Demonstration of central bronchiectasis (CB) with normal peripheral bronchi is an essential requirement for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). Although the results of bronchography remain the gold standard for demonstration of central bronchiectasis they are not always diagnostic.

Ans. a. It formed a biofilm on bronchial walls

Ans. is ‘c’ i.e., Sweat gland

Most CF patients have 3 distinct abnormal characteristics.

• The ducts of the mucus-secreting glands are obstructed due to an increase in viscosity of these secretions leading to glandular dilatation and destruction.
• CF patients are prone to chronic bacterial colonization and infections.
• The sweat glands are not obstructed in CF patients because in serous glands such as sweat glands there are abnormal concentrations of inorganic ions, rather than glandular obstruction with thick mucus.
• The quantitative pilocarpine iontophoresis sweat test is a uniformly accepted method for diagnosing CF. The sweat gland ducts must be patent for this test.
• Obstruction of airways leads to bronchiectasis and atelectasis; pancreatic duct obstruction leads to pancreatitis and malabsorption; and plugging of bile ducts leads to obstructive jaundice.

Ans. is ‘b’ i.e., 50%

Ans. is ‘b’ i.e., Increased

CYSTIC FIBROSIS

• Cystic fibrosis is an inherited disease of the mucus and sweat glands. 
• Cystic fibrosis follows on autosomal recessive transmission.
• There is a defect in ion transport of epithelial cells that affects fluid secretion in

1. Exocrine glands (pancreas)
2. Epithelial lining of respiratory, gastrointestinal and reproductive tract.

Pathophysiologv

• In normal duct epithelia, chloride is transported by plasma membrane channels (chloride channels)
• The primary defect in cystic fibrosis results from abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q 31.2.
• Protein encoded by CFTR is a chloride channel through which chloride passes In cystic fibrosis activity of chloride channel is decreased.
• Along with chloride channel, CFTR can regulate other channel also, for example epithelial sodium channels (ENaC). ENaC is inhibited by normally functioning CFTR; hence, in cystic fibrosis, ENaC activity increases, markedly augmenting sodium uptake across the apical membrane (especially in respiratory and gastrointestinal system).
• Normal CFTR gene product  Defective (mutated) Crl R gene product in cystic fibrosis

Induce Cl- conductance through itself (chloride channel)              Reduced or lost Cl conductance

Inhibits Na⁺ conductance through            Augmented sodium uptake across apical membrane ENaC

Clinical features of CF

• Functions of CFTR are tissue specific, i.e. its functions signify whether the epithelium is secretory (secrete Cl- into lumen) or absorptive (reabsorb Cl- from lumen).
• Therefore clinical features are tissue specific:

Respiratory tract

• Respiratory epithelium is secretory, i.e. there is active secretion of C1-.
• CFTR mutation in cystic fibrosis results in loss or reduction of chloride secretion in lumen.
• Active luminal sodium absorption is also increased (due to loss of inhibition of ENaC activity)
• Both these decreased Cl secretion and increased Na⁺ absorption from lumen) lead to increased passive water reabsorption (As you all know diffusion of water occurs from high osmolar to low osmolar concentration area). 
• This results in accumulation of dehydraded hyperconcentrated viscid secretion in respiratory lumen and defective mucociliary clearance obstruction and recurrent respiratory tract infection; and bronchiectasis. ¹.Intestine
• Similar to respiratory epithelium, intestinal epithelium is secretory and in CF there is defective Cl- secretion andenhanced Na⁺ absorption from lumen → Increased passive reabsorption of water from lumen.
• This results in accumulation of dehydrated desciated intraluminal contents obstruction of small and largeintestine.

Pancreas

• The absence of CFTR Cl channel in the apical membrane of pancreatic ductal epithelium limits the function of an apical membrane Ct -HCHD₃ exchanger to secrete bicarbonate and Na⁺ (by a passive process) into the duct.
• The failure to secrete bicarbonate and Na⁺ leads to retention of enzyme in the pancreas and ultimately destruction of all pancreatic tissues due to pancreatitis.

Hepatobiliary system

• Similar to respiratory and intestinal epithelium, defective biliar Cl- and water secretion causes thickened biliary secretions→biliary cirrhosis, cholecystitis, cholelithiasis.

Sweat glands

• In contrast to respiratory and intestinal epithelium, sweat gland duct epithelium is absorptive, i.e. function of normal CFTR in the sweat gland ducts is to reabsorb Cl- ions and Na’ from lumen.
• Therefore, in the sweat ducts, loss of CFTR function leads to decreased reabsorption of NaC1→ Hypertonic sweat with increased Na⁺ and Ct in sweat.

Ans:B.)Cystic Fibrosis

Autosomal Recessive inheritance pattern is shown in the image.

Determine if the pedigree chart shows an autosomal or X linked disease.

• If most of the males in the pedigree are affected, then the disorder is X-linked
•  If it is a 50/50 ratio between men and women the disorder is autosomal.

Determine whether the disorder is dominant or recessive.

•  If the disorder is dominant, one of the parents must have the disorder.
•  If the disorder is recessive, neither parent has to have the disorder because they can be heterozygous.

AUTOSOMAL RECESSIVE INHERITANCE PATTERN

• In autosomal recessive inheritance, two copies of a disease allele are required for an individual to be susceptible to expressing the phenotype.

• Typically, the parents of an affected individual are not affected but are gene carriers.

• With each pregnancy of carrier parents:

  • There is a one in four (25%) chance the offspring will inherit two copies of the disease allele and will therefore have the phenotype.

  • There is a one in two (50%) chance the offspring will inherit one copy of the disease allele and will be a carrier.

  • There is a one in four (25%) chance the offspring will inherit no copies of the disease allele and will not express the phenotype or be a carrier. This individual would not be at risk for passing the disorder on to his/her offspring.

• As with autosomal dominant inheritance, the proportion of affected males should be equal to the proportion of affected females in a given population.

• Autosomal recessive diseases are observed more frequently in consanguineous relationships (relationships in which the couple is related by blood, such as first cousins) because the individuals are descendants of the same ancestors and are, therefore, more likely to carry the same gene mutations.

ORGAN-BASED AUTOSOMAL RECESSIVE DISEASES
• Albinism
• α1 -Antitrypsin deficiency
• Ataxia-telangiectasia
• Autosomal recessive polycystic kidney disease
• Bernard-Soulier syndrome
• Bloom syndrome
• Chédiak-Higashi syndrome
• Crigler-Najjar syndrome type I
• Cystic fibrosis
• Dubin-Johnson syndrome
• Ehlers-Danlos syndrome (certain forms)
• Familial Mediterranean fever
• Fanconi anemia
• Friedreich ataxia
• Glanzmann thrombasthenia
• Hemochromatosis
• Kartagener syndrome
• Pseudohypoparathyroidism
• Rotor syndrome
• Severe combined immune deficiency
• Sickle cell anemia
• Thalassemia
• Wilson disease
• Xeroderma pigmentosum