Cystic Fibrosis

Cystic fibrosis (CF) is the commonest lethal autosomal recessive disorder in Caucasians, caused by mutations in the CFTR gene that cripple chloride transport across epithelia, producing thick, viscid secretions in the lung, pancreas, gut, liver and reproductive tract. It is a favourite NEET PG topic because the genetics, the sweat chloride cut-off, meconium ileus and the new CFTR-modulator drugs are all tightly testable, single-best-answer facts.

Definition and basic genetics

CF is a multisystem exocrinopathy resulting from loss of function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a cyclic-AMP–regulated chloride channel of the ATP-binding cassette (ABC) transporter family.

• Gene locus: long arm of chromosome 7 (7q31.2).
• Inheritance: autosomal recessive.
• Protein: CFTR, an apical membrane chloride (and bicarbonate) channel; also regulates the epithelial sodium channel (ENaC).
• Commonest mutation: ΔF508 (F508del) — an in-frame deletion of three base pairs removing phenylalanine at codon 508. Accounts for ~70% of CF alleles worldwide; it is a Class II (processing/trafficking) defect.

High-yield: CFTR is on chromosome 7, the gene defect is autosomal recessive, and the single most common mutation is ΔF508. Memorise these three as a unit — they are repeatedly examined.

Mutation classes (drives modulator therapy)

CFTR mutations are grouped by the mechanism of dysfunction; this classification now directly determines which drug works.

Class	Defect	Example	CFTR at membrane	Therapeutic strategy
I	Defective protein synthesis (premature stop codon)	G542X, W1282X	Absent	Read-through agents (ataluren – experimental)
II	Defective processing/trafficking	ΔF508	Reduced/absent	Correctors (lumacaftor, tezacaftor, elexacaftor)
III	Defective gating ("on" channel won't open)	G551D	Present but shut	Potentiator (ivacaftor)
IV	Defective conductance	R117H	Present, low flow	Potentiator
V	Reduced quantity (splicing)	3849+10kb C→T	Reduced	Correctors ± potentiator
VI	Reduced stability at surface	rare	Unstable	Stabilisers

High-yield: G551D is the classic gating (Class III) mutation that responds to the potentiator ivacaftor. ΔF508 is a Class II trafficking defect requiring a corrector.

Pathophysiology

The unifying lesion is defective chloride and bicarbonate secretion with excessive sodium and water reabsorption at affected epithelia.

Mechanism flow: CFTR loss → ↓ luminal Cl⁻ secretion + ↑ ENaC-driven Na⁺ absorption → water drawn out of the airway surface liquid → dehydrated, thick mucus → impaired mucociliary clearance → mucus plugging, chronic infection and neutrophilic inflammation → bronchiectasis and progressive lung destruction.

Tissue-specific consequences:

• Airways: depleted periciliary fluid layer; thick mucus; chronic infection with characteristic organisms; neutrophil-derived DNA and elastase amplify obstruction and tissue damage.
• Sweat gland: the duct cannot reabsorb chloride (here CFTR normally reabsorbs Cl⁻ from sweat), so sweat becomes salty — the basis of the diagnostic test. This is the one site where the defect causes high luminal salt rather than thick secretions.
• Pancreas: inspissated secretions block ducts → autodigestion → exocrine pancreatic insufficiency; later CF-related diabetes from islet loss.
• Gut: thick meconium → meconium ileus; later distal intestinal obstruction syndrome (DIOS).
• Hepatobiliary: bile plugging → focal biliary cirrhosis.
• Reproductive: in males, congenital bilateral absence of the vas deferens (CBAVD) → obstructive azoospermia and infertility.

High-yield: In the sweat gland, CFTR normally reabsorbs chloride; its loss leaves chloride (and sodium) in sweat → hypertonic, salty sweat. Hence sweat chloride is the cornerstone diagnostic test.

Clinical features by system

CF is a "great masquerader" of paediatric chronic disease. Presentation varies with age.

Respiratory (dominant cause of morbidity and mortality):

• Chronic productive cough, recurrent "pneumonias", wheeze.
• Bronchiectasis, especially upper lobes.
• Nasal polyps and pansinusitis in a child — strongly suggests CF.
• Digital clubbing.
• Progressive obstructive then mixed lung disease, cor pulmonale.

Characteristic airway pathogens (age-dependent):

• Infancy/early childhood: Staphylococcus aureus and Haemophilus influenzae.
• Older child/adult: Pseudomonas aeruginosa — its mucoid strains are a hallmark and a poor prognostic marker.
• Burkholderia cepacia complex — feared because it causes rapid decline ("cepacia syndrome") and is a contraindication/risk for transplant.

High-yield: Chronic infection sequence is Staph aureus → Haemophilus → Pseudomonas aeruginosa (mucoid) → Burkholderia cepacia. Mucoid Pseudomonas and B. cepacia both signal worse prognosis.

Gastrointestinal and nutritional:

• Meconium ileus in neonates (failure to pass meconium in first 24–48 h, bilious vomiting, abdominal distension) — pathognomonic enough that any neonate with meconium ileus is CF until proven otherwise.
• Steatorrhoea, bulky greasy foul stools, failure to thrive despite good appetite.
• Fat-soluble vitamin (A, D, E, K) deficiency from fat malabsorption.
• Rectal prolapse in toddlers.
• DIOS (distal intestinal obstruction syndrome) — the older-child/adult equivalent of meconium ileus.
• CF-related liver disease, cholelithiasis.

Endocrine/metabolic:

• CF-related diabetes mellitus (CFRD) — adolescents/adults; a major comorbidity.
• Salt-loss syndrome / pseudo-Bartter — hyponatraemic, hypochloraemic metabolic alkalosis with hypokalaemia, especially in hot climates (very relevant to Indian summers) or with vomiting.

Reproductive: male infertility (CBAVD/azoospermia); reduced fertility in females from thick cervical mucus.

High-yield: A baby that "tastes salty" on kissing, a child with nasal polyps + steatorrhoea + failure to thrive, or an azoospermic man with CBAVD are all classic CF vignette triggers.

Diagnosis and investigation of choice

Diagnosis requires clinical features or a positive newborn screen PLUS evidence of CFTR dysfunction.

Sweat chloride test — the investigation of choice

The pilocarpine iontophoresis sweat chloride test is the gold-standard confirmatory test.

Sweat chloride (mEq/L)	Interpretation
< 30 (≤ 29)	CF unlikely (normal)
30 – 59	Intermediate / indeterminate — repeat, do genetics
≥ 60	Diagnostic of CF

High-yield: Sweat chloride ≥ 60 mEq/L confirms CF; < 30 mEq/L essentially excludes it; 30–59 is the borderline zone needing genetic testing. The classic exam cut-off is > 60 mEq/L.

Diagnostic approach (stepwise):

1. Newborn screening: raised immunoreactive trypsinogen (IRT) on heel-prick blood spot →
2. If positive, confirm with sweat chloride ± CFTR mutation panel →
3. Sweat chloride ≥ 60 → diagnosis confirmed; if intermediate →
4. CFTR genotyping (two disease-causing mutations) or nasal potential difference measurement clinches the diagnosis.

Supportive/ancillary tests:

• Faecal elastase — low, indicating exocrine pancreatic insufficiency.
• HRCT chest — bronchiectasis, mucus plugging, tree-in-bud.
• Sputum culture — Pseudomonas, Staph, Burkholderia.
• Nasal potential difference — abnormally elevated (more negative) baseline; useful when sweat test equivocal.

High-yield: IRT is the newborn screening test; sweat chloride is the confirmatory test; genotyping/NPD resolve indeterminate cases.

Management

CF care is multidisciplinary and lifelong, combining airway clearance, infection control, nutrition, and — the major recent advance — CFTR modulators that treat the underlying defect.

Airway and pulmonary

• Airway clearance — chest physiotherapy, postural drainage, oscillatory PEP devices.
• Mucolytics: dornase alfa (recombinant human DNase) cleaves neutrophil-derived extracellular DNA, reducing sputum viscosity. Hypertonic saline (7%) rehydrates airway surface liquid.
• Bronchodilators for reversible obstruction.
• Antibiotics:
  • Acute exacerbation — guided by culture; anti-pseudomonal cover often two agents (e.g. an antipseudomonal beta-lactam + aminoglycoside).
  • Chronic Pseudomonas — inhaled tobramycin or inhaled colistin/aztreonam; eradication protocols at first isolation.
  • Azithromycin chronically for its anti-inflammatory/immunomodulatory effect (not merely antibacterial).
• Lung transplantation for end-stage disease.

CFTR modulators (treat the molecular defect — high yield)

Drug	Class	Action	Mutations targeted
Ivacaftor	Potentiator	Holds the channel open (improves gating)	G551D and other gating (Class III); also R117H
Lumacaftor	Corrector	Improves folding/trafficking of CFTR to surface	ΔF508 (with ivacaftor → "Orkambi")
Tezacaftor	Corrector	Improves trafficking	ΔF508 (with ivacaftor → "Symdeko")
Elexacaftor	Corrector	Second-site corrector	ΔF508

• Triple therapy — elexacaftor/tezacaftor/ivacaftor (Trikafta/Kaftrio) — is the landmark advance, effective in patients with at least one ΔF508 allele (the majority), producing large gains in FEV₁ and reductions in sweat chloride.

High-yield: Remember the pairing — Ivacaftor = potentiator (opens the gate, for G551D); lumacaftor/tezacaftor/elexacaftor = correctors (fix trafficking, for ΔF508). The triple combo elexacaftor–tezacaftor–ivacaftor is the current game-changer.

Mnemonic — "iVA-cafTor opens, the rest correct": iVAcafTor = potenTiator (gating); the other -caftor drugs are correctors.

Nutrition and GI

• Pancreatic enzyme replacement therapy (PERT) — lipase/protease/amylase with every meal and snack to correct steatorrhoea and growth failure.
• High-calorie, high-fat diet (paradoxically encouraged) with fat-soluble vitamin (A, D, E, K) supplementation.
• Salt supplementation, especially in hot weather, to prevent salt-loss syndrome.
• Meconium ileus: Gastrografin (water-soluble contrast) enema can be both diagnostic and therapeutic for uncomplicated cases; surgery if complicated (perforation, atresia, volvulus).
• DIOS: oral osmotic laxatives / polyethylene glycol, Gastrografin; rarely surgery.

High-yield: PERT + fat-soluble vitamins + high-calorie diet is the nutritional triad. A Gastrografin enema relieves uncomplicated meconium ileus.

Complications

• Respiratory: bronchiectasis, recurrent pneumonia, pneumothorax, massive haemoptysis, allergic bronchopulmonary aspergillosis (ABPA), respiratory failure, cor pulmonale.
• GI/hepatic: meconium ileus, DIOS, rectal prolapse, focal biliary cirrhosis → portal hypertension, gallstones, pancreatitis.
• Endocrine: CF-related diabetes, osteopenia/osteoporosis (vitamin D deficiency + chronic disease).
• Metabolic: hypochloraemic, hypokalaemic metabolic alkalosis (pseudo-Bartter / salt loss).
• Reproductive: male infertility (CBAVD).
• Growth: failure to thrive, delayed puberty.
• Digital clubbing and hypertrophic osteoarthropathy.

High-yield: New or worsening wheeze with a rising IgE and central bronchiectasis in a CF patient → think ABPA (aspergillus hypersensitivity). Cor pulmonale and respiratory failure are the eventual causes of death.

Key differentials

CF must be separated from other causes of chronic suppurative lung disease, malabsorption and neonatal obstruction.

Condition	Discriminating features vs CF
Primary ciliary dyskinesia (Kartagener)	Situs inversus + bronchiectasis + sinusitis; normal sweat chloride; immotile cilia on EM
Shwachman–Diamond syndrome	Pancreatic insufficiency + neutropenia/marrow failure + skeletal dysplasia; normal sweat test
Immunodeficiency (e.g. CVID, HIV)	Recurrent infections but no salty sweat, no pancreatic exocrine failure
Asthma/recurrent viral wheeze	No failure to thrive, no steatorrhoea, normal sweat chloride
Coeliac disease	Malabsorption but no chronic lung disease; anti-tTG positive, villous atrophy
Hirschsprung disease	Neonatal obstruction but rectal biopsy shows absent ganglion cells; normal sweat test

High-yield: Situs inversus + bronchiectasis + chronic sinusitis = Kartagener (PCD), not CF — sweat chloride is normal. Pancreatic insufficiency + neutropenia = Shwachman–Diamond, not CF.

Recently asked / exam angle

• Gene and chromosome: CFTR on chromosome 7; ΔF508 the commonest mutation — direct one-liners.
• Sweat chloride cut-off of > 60 mEq/L as diagnostic; IRT as the newborn screening test.
• Drug–mutation matching: ivacaftor ↔ G551D (gating); correctors ↔ ΔF508 (trafficking) — increasingly common as modulators enter syllabi.
• Meconium ileus as the neonatal presentation; Gastrografin enema management.
• Mucoid Pseudomonas aeruginosa as the characteristic chronic pathogen; Burkholderia cepacia as a transplant contraindication/poor prognostic sign.
• Mechanism of dornase alfa (breaks down neutrophil DNA in sputum).
• CBAVD / obstructive azoospermia in an infertility-clinic vignette pointing to CF.
• Pseudo-Bartter (hypochloraemic metabolic alkalosis) as an electrolyte-pattern question.
• Fat-soluble vitamin (ADEK) deficiency and need for PERT.

Rapid revision

1. CF = autosomal recessive; CFTR gene on chromosome 7; commonest mutation ΔF508 (Class II trafficking defect).
2. G551D is the gating (Class III) mutation treated by the potentiator ivacaftor.
3. Sweat chloride ≥ 60 mEq/L is diagnostic; < 30 excludes; 30–59 is indeterminate (do genetics).
4. IRT (immunoreactive trypsinogen) is the newborn screening test; sweat chloride is confirmatory.
5. In the sweat gland CFTR normally reabsorbs chloride → its loss gives salty sweat.
6. Airway pathogen sequence: Staph aureus → H. influenzae → mucoid Pseudomonas → Burkholderia cepacia.
7. Meconium ileus in a neonate = CF until proven otherwise; treat uncomplicated cases with Gastrografin enema.
8. DIOS is the older-age equivalent of meconium ileus; managed with osmotic laxatives/Gastrografin.
9. Dornase alfa cleaves neutrophil DNA; hypertonic saline rehydrates airway mucus.
10. Nutrition: PERT + high-calorie/high-fat diet + ADEK vitamins + salt supplementation.
11. Elexacaftor–tezacaftor–ivacaftor (Trikafta/Kaftrio) = highly effective triple modulator for ΔF508 patients.
12. Mimics: Kartagener (PCD) — situs inversus, normal sweat test; Shwachman–Diamond — pancreatic insufficiency + neutropenia; male CF → CBAVD/azoospermia.