• Cystic fibrosis (CF) is an inherited disorder of epithelial ion transport affecting:
  • exocrine glands
  • respiratory tract
  • gastrointestinal tract
  • reproductive tract
• Defective ion transport produces thick, viscid secretions.
• These secretions block:
  • airways → recurrent/chronic pulmonary infections
  • pancreatic ducts → pancreatic insufficiency
• A characteristic biochemical finding is high sodium chloride in sweat, even though sweat glands remain structurally normal.
• Clinical features vary widely because of:
  • different CFTR mutations
  • effects of modifier genes
• CF is transmitted as an autosomal recessive disorder.
• In the United States:
  • incidence is about 1 in 2500 live births
  • carrier frequency among individuals of European descent is about 1 in 20
• Even heterozygous carriers may have increased susceptibility to pulmonary and pancreatic disease compared with the general population.

Pathogenesis

• The basic defect is reduced production or abnormal function of CFTR.
• CFTR is an epithelial chloride and bicarbonate channel.
• CFTR mutations make epithelial membranes relatively impermeable to chloride ions (Fig. 4.7).
• The effect differs by tissue.
• In sweat ducts:
  • normal CFTR → reabsorbs chloride and supports sodium reabsorption through ENaC
  • defective CFTR → ↓ NaCl reabsorption
  • result → salty, hypertonic sweat
• In respiratory and intestinal epithelium:
  • normal CFTR → secretes chloride into the lumen
  • defective CFTR → ↓ chloride secretion
  • loss of CFTR inhibition on ENaC → ↑ sodium absorption
  • water follows sodium back into cells
  • result → dehydrated surface fluid
• In the lungs:
  • dehydrated surface fluid → impaired mucociliary clearance
  • mucus becomes thick and concentrated
  • → airway obstruction + recurrent pulmonary infections
• Thick secretions can also obstruct:
  • pancreatic ducts → pancreatic insufficiency
  • vas deferens → male infertility
• In the exocrine pancreas, CFTR also regulates bicarbonate secretion.
• Defective CFTR → ↓ bicarbonate → more acidic pancreatic secretions.
• Acidic secretions cause:
  • mucin precipitation
  • ↓ activity of digestive enzymes such as trypsin
• Both worsen pancreatic insufficiency.
• More than 2000 disease-causing CFTR mutations have been identified.
• Mutations may:
  • reduce delivery of CFTR to the cell surface
  • impair CFTR function
• Severe mutations → little or no CFTR function.
• Mild mutations → some residual CFTR function.
• The most common mutation is ΔF508:
  • deletion of 3 nucleotides
  • loss of phenylalanine at position 508
  • CFTR misfolds → degraded inside the cell
  • small amount reaching the surface is also dysfunctional
  • found in about 70% of patients worldwide
• Disease severity is also influenced by modifier genes, including:
  • MBL2
  • TGF-β1
• These may modify how well the lungs tolerate severe infections.

KEY CONCEPT

• CF = autosomal recessive CFTR defect → abnormal chloride/bicarbonate transport.
• Sweat gland → ↓ NaCl reabsorption → salty sweat.
• Lung/intestine → ↑ Na⁺ and water absorption + ↓ Cl⁻ secretion → dehydrated mucus → thick secretions.
• Main consequences:
  recurrent lung infections + pancreatic insufficiency + male infertility.
• ΔF508 = most common CFTR mutation.

CONCEPTUAL EXAMPLES

• Sweat duct cannot reabsorb salt properly → salty sweat.
• Airway surface loses water → mucus becomes thick → poor mucociliary clearance + infection.
• Pancreatic duct becomes blocked by thick secretion → pancreatic insufficiency.
• Vas deferens obstruction → male infertility.

FIG. 4.7 — CYSTIC FIBROSIS: SWEAT DUCT vs AIRWAY

🧠 Simplest idea

The same CFTR defect gives 2 different effects:

Sweat duct → salt cannot be reabsorbed → SALTY SWEAT
Airway → salt + water are pulled into cells → mucus loses water → THICK, DEHYDRATED MUCUS

🔵 LEFT = NORMAL

1️⃣ TOP LEFT — Normal SWEAT DUCT

🎨 Color key

• 🟢 Green dots = Cl⁻ (chloride)
• 🟠 Orange dots = Na⁺ (sodium)
• 🔴 Red channel = CFTR
• 🟧 Orange channel = ENaC
• 🩷 Cells = sweat duct epithelial cells

Arrow-by-arrow

🔴 CFTR takes Cl⁻ from sweat lumen → into cell

Green downward arrow:

Cl⁻ in sweat
⬇️ through CFTR
Cl⁻ reabsorbed

CFTR also helps ENaC absorb Na⁺

Green + sign means:

Normal CFTR → promotes Na⁺ absorption through ENaC

🟠 Na⁺:
Sweat lumen → ENaC → cell

Result

NaCl is removed from sweat

➡️ Final sweat contains less salt.

🧠 Memory

Normal sweat duct = REABSORB SALT

🔴 TOP RIGHT — CYSTIC FIBROSIS in SWEAT DUCT

Dotted red CFTR + ❌ = mutated/nonfunctional CFTR

What happens?

↓ Cl⁻ reabsorption
+
↓ Na⁺ reabsorption

So Na⁺ and Cl⁻ remain in the sweat lumen.

⬆️

Hypertonic / very salty sweat

⭐ This is the classic basis of the sweat chloride test.

Fast memory

CF sweat = cannot TAKE salt back → salt stays in sweat

🔵 BOTTOM LEFT — Normal AIRWAY

Here CFTR behaves differently.

🔴 CFTR secretes Cl⁻ toward airway lumen

Green upward arrow:

Cl⁻ → out into airway surface fluid

This helps keep water at the airway surface.

CFTR also inhibits ENaC

🔴 minus sign between CFTR and ENaC:

CFTR ┤ ENaC

So less Na⁺ is absorbed into airway cells.

Therefore:

Less Na⁺ taken in
+
Cl⁻ secreted out
+
H₂O stays in airway lumen

⬇️

🟢 Normal mucus

= thin and hydrated

⬇️

Normal mucociliary function

Cilia can easily move mucus and trapped microbes out.

🧠 Memory

Normal airway CFTR keeps WATER with mucus.

🔴 BOTTOM RIGHT — CYSTIC FIBROSIS in AIRWAY

Mutated CFTR ❌ causes two major problems.

1️⃣ ↓ Cl⁻ secretion

CFTR cannot properly move chloride into airway lumen.

So:

↓ Cl⁻ in lumen

2️⃣ ENaC loses CFTR inhibition

Normally CFTR restrains ENaC.

But in CF:

CFTR defective → ENaC activity ↑

🟠 Na⁺ moves:

Airway lumen → epithelial cell

Water follows sodium:

Na⁺ inward → H₂O inward

⬇️

Airway surface loses water🟢 Thick yellow-green layer = DEHYDRATED MUCUS

Because water has been removed:

Mucus becomes thick + sticky

⬇️

Defective mucociliary clearance

Cilia cannot move the thick mucus properly.

⬇️

Mucus plugging + trapped bacteria → recurrent lung infections

⭐ MOST IMPORTANT CONTRAST

Sweat duct	Airway
CFTR normally reabsorbs Cl⁻	CFTR normally secretes Cl⁻
Helps Na⁺ reabsorption	Inhibits ENaC
CF → NaCl stays in sweat	CF → Na⁺ + water absorbed into cells
Salty sweat	Dry, thick mucus

🧠 Fastest exam recall

SWEAT

Broken CFTR → ↓ Cl⁻ & Na⁺ reabsorption → ↑ sweat chloride → SALTY SWEAT

AIRWAY

Broken CFTR → ↓ Cl⁻ secretion + ↑ ENaC Na⁺ absorption → water follows Na⁺ → DEHYDRATED THICK MUCUS

🔥 One-line memory

CF = “Salt stays OUT in sweat, but water leaves mucus in airway.

MORPHOLOGY

• Patients with cystic fibrosis (CF) can show many different manifestations (Fig. 4.8).
• Pancreatic abnormalities occur in about 85%–90% of patients.
• In mild disease:
  • thick mucus accumulates in small pancreatic ducts
  • exocrine glands may become mildly dilated
• In more advanced disease:
  • pancreatic ducts become completely plugged
  • → exocrine gland atrophy
  • → progressive fibrosis (Fig. 4.9)
• Loss of pancreatic exocrine secretion → poor fat absorption → may cause vitamin A deficiency.
• Vitamin A deficiency may promote squamous metaplasia of pancreatic duct epithelium → may worsen injury from thick mucus.
• In infants, thick mucus may plug the small intestine → small-bowel obstruction called meconium ileus.
• Pulmonary disease is the most serious complication of CF (Fig. 4.10).
• Lung changes result from:
  • airway obstruction by thick mucus from submucosal glands
  • superimposed infections
• Bronchioles become distended with thick mucus, with:
  • hyperplasia
  • hypertrophy
    of mucus-secreting cells.
• Recurrent infections → severe chronic bronchitis + bronchiectasis.
• Lung abscesses are also common.
• Common pulmonary pathogens include:
  • Staphylococcus aureus
  • Pseudomonas aeruginosa
  • nontuberculous mycobacteria
• Burkholderia cepacia complex is particularly serious and may cause rapidly severe “cepacia syndrome.”
• In the liver:
  • bile canaliculi become plugged with mucin
  • ductular proliferation and portal inflammation occur
  • hepatic steatosis (fatty liver) is common
• With time → cirrhosis → diffuse hepatic nodularity.
• Severe liver disease occurs in less than 10% of patients.
• In males:
  • about 95% of those surviving to adulthood have azoospermia and infertility
  • CF may cause atrophy of the vas deferens during development
  • → bilateral absence of the vas deferens
• In some males, absent vas deferens may be the only clue to a CFTR mutation.

KEY CONCEPT

• Pancreas → mucus plugging → atrophy + fibrosis → exocrine insufficiency.
• Intestine → thick mucus → meconium ileus.
• Lungs → thick mucus + recurrent infection → bronchiectasis, bronchitis, abscesses.
• Liver → mucin plugging → fatty liver → possible cirrhosis.
• Male reproductive tract → absent vas deferens → azoospermia and infertility.

CONCEPTUAL EXAMPLES

• Pancreatic duct plugged by mucus → enzymes cannot reach intestine → fat malabsorption.
• Infant small bowel blocked by thick mucus → meconium ileus.
• Bronchioles blocked by mucus + bacteria → repeated infection → bronchiectasis.
• Vas deferens absent → sperm cannot enter semen → male infertility.

Clinical Features

• Cystic fibrosis (CF) has highly variable clinical manifestations (Fig. 4.8).
• About 5%–10% of patients present at birth or soon after with meconium ileus.
• Exocrine pancreatic insufficiency occurs in about 85%–90% of patients and is usually associated with two severe CFTR mutations, such as ΔF508/ΔF508.
• About 10%–15% have enough pancreatic function to avoid enzyme replacement:
  • one severe + one mild mutation, or
  • two mild mutations
  • → pancreas-sufficient phenotype.
• Pancreatic insufficiency → poor digestion and absorption of fat and protein → increased loss in stool.
• Malabsorption usually appears during the first year of life:
  • large, foul-smelling stools
  • abdominal distention
  • poor weight gain
• Poor fat absorption → deficiency of fat-soluble vitamins:
  • vitamin A
  • vitamin D
  • vitamin K
• Severe protein malnutrition → hypoproteinemia → generalized edema.
• Persistent diarrhea may cause rectal prolapse in up to 10% of children.
• Patients with the pancreas-sufficient phenotype usually have fewer gastrointestinal problems and show good growth and development.
• Endocrine pancreatic failure (diabetes) is much less common and usually appears late in the disease.
• The major cause of death is cardiorespiratory disease, accounting for about 80% of deaths.
• Important pulmonary complications include:
  • chronic cough
  • persistent lung infections
  • obstructive pulmonary disease
  • cor pulmonale
• By age 18 years, about 80% of patients with severe CF harbor Pseudomonas aeruginosa.
• Some also harbor Burkholderia cepacia.
• Excessive antibiotic prophylaxis has contributed to the emergence of antibiotic-resistant Pseudomonas strains.
• Significant liver disease usually develops later, after pulmonary and pancreatic disease.
• With longer survival, liver disease has become the third most common cause of death, after cardiopulmonary and transplant-related complications.
• CF can also present in less typical forms.
• Some patients with recurrent childhood pancreatitis previously labeled idiopathic are now known to have biallelic CFTR variants different from classic CF mutations.
• CF carriers were once considered completely asymptomatic, but they may have an increased lifetime risk of:
  • chronic lung disease, especially bronchiectasis
  • recurrent sinonasal polyps
• Diagnosis is usually supported by:
  • persistently elevated sweat electrolytes
  • characteristic sinopulmonary and gastrointestinal findings
  • family history
• A classic clue is that the infant’s skin “tastes salty.”
• CFTR gene sequencing is the gold standard for diagnosis.
• Management has improved through:
  • stronger antimicrobial therapy
  • pancreatic enzyme replacement
  • bilateral lung transplantation
• These advances have increased median life expectancy to about 40 years, changing CF from mainly a fatal childhood disease into a chronic adult disease.
• New drugs can improve:
  • CFTR folding
  • CFTR movement to the cell membrane
  • CFTR function
• The long-term effect of these newer molecular treatments on survival was still uncertain in the source text.

KEY CONCEPT

• Severe CFTR mutations → pancreatic insufficiency + severe multisystem disease.
• Milder mutations → pancreas may remain functional.
• Major clinical problems:
  malabsorption + recurrent pulmonary infection + progressive cardiorespiratory disease.
• Most deaths are due to cardiopulmonary complications.
• Diagnosis → high sweat electrolytes + clinical features + CFTR sequencing.

CONCEPTUAL EXAMPLES

• Pancreatic ducts blocked → digestive enzymes do not reach intestine → fat/protein malabsorption → foul stools + poor growth.
• Poor fat absorption → A, D, K vitamin deficiency.
• Thick airway mucus → repeated infection → chronic lung disease → cor pulmonale.
• Severe CFTR mutation on both alleles → pancreatic insufficiency more likely; milder mutations → pancreas-sufficient phenotype.

Diseases Caused by Mutations in Genes Encoding Enzymes

Phenylketonuria (PKU)

• Phenylketonuria (PKU) is caused by mutations producing severe deficiency of phenylalanine hydroxylase (PAH).
• PAH deficiency → ↑ phenylalanine in blood = hyperphenylalaninemia.
• PKU is an autosomal recessive disorder.
• Classic PKU affects about 1 in 10,000 live-born infants of European descent.
• Infants are usually normal at birth.
• Within weeks:
  ↑ plasma phenylalanine → impaired brain development.
• By about 6 months, severe intellectual disability may become evident if untreated.
• Untreated children may also develop:
  • seizures
  • other neurologic abnormalities
  • light skin and hair
  • eczema
• Early restriction of dietary phenylalanine can prevent hyperphenylalaninemia and severe neurologic damage.
• Therefore, newborns are routinely screened for PKU soon after birth.
• Dietary treatment is recommended for life.
• Maternal PKU:
  • A woman with PKU may appear healthy after stopping treatment but still have very high phenylalanine levels.
  • Phenylalanine or its metabolites cross the placenta → damage the developing fetus.
  • Children may develop:
    • severe intellectual disability
    • microcephaly
    • congenital heart disease
  • This occurs even though the infants themselves may only be heterozygous carriers.

Pathogenesis

• The basic biochemical defect is inability to convert:

Phenylalanine → Tyrosine

• Normally, PAH converts excess dietary phenylalanine into tyrosine (Fig. 4.11).
• In PKU:
  ↓ PAH → phenylalanine cannot be converted efficiently → ↑ phenylalanine.
• Excess phenylalanine is diverted into alternative shunt pathways.
• These produce abnormal metabolites that are excreted in:
  • urine
  • sweat
• These metabolites produce the characteristic musty or mousy odor.
• Excess phenylalanine or its metabolites contribute to brain injury.
• Tyrosine is also reduced.
• Because tyrosine is a precursor of melanin:
  ↓ tyrosine → ↓ melanin → lighter skin and hair.
• About 1000 different PAH mutant alleles have been identified.
• Severe PAH deficiency → classic PKU.
• Partial PAH activity → milder disease or benign hyperphenylalaninemia.
• Serum phenylalanine measurement is used to distinguish these conditions.
• In classic PKU, phenylalanine is typically about 5 times normal.
• After biochemical diagnosis, the specific mutation can be identified → allows carrier testing in family members.
• Phenylalanine ammonia lyase (PAL) therapy has been studied to reduce phenylalanine by converting it into ammonia and other metabolites.

KEY CONCEPT

• PKU = autosomal recessive PAH deficiency → phenylalanine cannot become tyrosine → hyperphenylalaninemia.
• Main consequences:
  brain injury + musty odor + reduced pigmentation.
• Early dietary phenylalanine restriction prevents severe neurologic damage.
• Maternal PKU → high maternal phenylalanine damages the fetus.

CONCEPTUAL EXAMPLES

• PAH absent → phenylalanine builds up → brain development is impaired.
• Phenylalanine enters shunt pathways → abnormal metabolites → musty odor.
• ↓ Tyrosine → ↓ melanin → light skin and hair.
• Early newborn diagnosis + low-phenylalanine diet → major complications can be prevented.