Cystic Fibrosis

 

How to Use These Notes

• School and first-year students: read Level 1 and the revision summary.
• Undergraduate biology, nursing, pharmacy and medical students: read Levels 1 and 2, then attempt the practice questions.
• Postgraduate and advanced learners: focus on Level 3 (molecular classes, modulators, microbiology, emerging therapies).

LEVEL 1: BASICS

1.1 What is Cystic Fibrosis?

Cystic Fibrosis (CF) is a life-limiting genetic disease passed on through the family. It mainly affects the lungs and digestive system however also affects the sweat glands, liver, pancreas, intestine and reproductive tract. The disease is caused due to faulty genes which cause thick sticky mucus to be produced by the body.

This name was given as when doctors looked at autopsies they found fluid filled cysts and fibrosis (scarring) to the pancreas.

A one-liner: Cystic Fibrosis is an autosomal recessive disorder which results from mutation in the CFTR gene causing impaired chloride and bicarbonate transport in epithelial cells resulting in increased mucus production in several organs.

1.2 Key Facts at a Glance

Feature	Detail
Type of disease	Genetic, multisystem
Inheritance	Autosomal recessive
Gene	CFTR (Cystic Fibrosis Transmembrane conductance Regulator)
Chromosome	7 (long arm, 7q31.2)
Most common mutation	F508del (also written ΔF508)
Main organs affected	Lungs, pancreas, intestines, liver, sweat glands, reproductive tract
Typical sweat test	High sweat chloride (60 mmol/L or more)
Most common cause of death	Respiratory failure from chronic lung infection
Treatment today	Airway clearance, antibiotics, nutrition, CFTR modulators, transplant in end-stage disease

1.3 Who Gets CF?

• •    CF is most common in people of Northern European ancestry (about 1 in 2,500 to 3,500 births in this group).
• •  It is less common, but not absent, in people of African, Asian, Hispanic and Middle Eastern ancestry. It is often under-recognised in these groups, which can delay diagnosis.
• •  Around 1 in 25 to 1 in 30 people of European descent are carriers (they carry one faulty copy and are healthy).
• •   Worldwide, there are roughly 100,000 or more people living with CF.
• •  Males and females are affected equally.

1.4 A Short History

•       1938: Dorothy Andersen describes "cystic fibrosis of the pancreas" as a distinct disease.

•       1940s to 1950s: Doctors notice that children with CF have unusually salty sweat. In 1953, Paul di Sant'Agnese links salt loss in heat waves to CF.

•       1959: Gibson and Cooke develop the pilocarpine iontophoresis sweat test, still the diagnostic gold standard.

•       1989: The CFTR gene is identified by Tsui, Collins, Riordan and colleagues.

•       2012 onward: First CFTR modulator, ivacaftor, approved, the first drugs to treat the underlying cause rather than only the symptoms.

•       2019 onward: Triple therapy (elexacaftor/tezacaftor/ivacaftor) transforms outcomes for most patients.

1.5 The Normal Role of Mucus

Healthy mucus is a thin, watery gel that:

• 1. Traps dust, microbes and pollutants in the airways.
• 2. Is swept upward by tiny hairs called cilia (the mucociliary escalator) and swallowed or coughed out.
• 3. Lubricates the digestive tract and ducts.

In CF, mucus becomes thick and dehydrated, so cilia cannot move it. It blocks tubes (airways, pancreatic ducts, bile ducts, intestines) and becomes a breeding ground for bacteria.

1.6 Common Symptoms (Simple List)

Lungs and breathing

• •       Persistent cough with thick mucus

• •   Wheezing, breathlessness

• •   Frequent chest infections, pneumonia

Digestion and growth

•     Poor weight gain and growth despite a good appetite

•  Greasy, bulky, foul-smelling stools (steatorrhoea)

•  Abdominal pain and bloating

Other

   •  Very salty-tasting skin

• Nasal polyps, sinus problems

• Clubbing of fingers (rounded fingertips)

• Infertility in most males

LEVEL 2: INTERMEDIATE

       2.1 Genetics and Inheritance

The CFTR gene

• •   Located on chromosome 7q31.2, about 190 kilobases long with 27 exons.
• •   Encodes a protein of 1,480 amino acids, the CFTR protein, which acts as an ion channel on the apical (lumen-facing) surface of epithelial cells.
• •   More than 2,000 mutations have been described, though not all cause disease. Roughly 700 or more are confirmed disease-causing.

Autosomal recessive inheritance

A person must inherit two faulty copies (one from each parent). Parents are usually healthy carriers.           

                     CARRIER PARENT 1 (Nn)   x   CARRIER PARENT 2 (Nn)

                                          Parent 2 gametes
                                               N         n
                                         +---------+---------+
            Parent 1          N   |   NN    |   Nn    |
            gametes               +---------+---------+
                                     n   |   Nn    |   nn    |
                                          +---------+---------+

   N = normal CFTR allele      n = CF-causing allele

   NN (25%)  = unaffected, not a carrier
   Nn (50%)  = unaffected carrier
   nn (25%)  = has cystic fibrosis 

Every pregnancy of two carrier parents carries:

• •       25% chance of a child with CF
• •       50% chance of a carrier child
• •       25% chance of a child who is neither

Important genetic terms

• •   Genotype: the actual mutations a person carries (for example F508del/F508del).

• •   Phenotype: the observable disease picture. Genotype only partly predicts phenotype.

• •   Homozygous: same mutation on both copies. Compound heterozygous: two different mutations.

• •   Carrier: one mutation, no disease.

The F508del mutation

F508del is a deletion of three nucleotides that removes the amino acid phenylalanine at position 508. The protein misfolds, is recognised by the cell's quality-control machinery, and is destroyed before reaching the cell surface. About 85% of people with CF in Europe and North America carry at least one F508del allele, and roughly half are homozygous.

2.2 Normal CFTR Function

CFTR is a member of the ABC transporter family (ATP-binding cassette). Its structure includes:

• •  Two membrane-spanning domains (MSD1, MSD2) forming the channel pore

• •  Two nucleotide-binding domains (NBD1, NBD2) that bind ATP

• •  One regulatory (R) domain that is phosphorylated by protein kinase A (PKA)

1.   Channel gating cycle:

1.  Hormonal signal raises cAMP, which activates PKA.

2. PKA phosphorylates the R domain.

3. ATP binds to NBD1 and NBD2, which dimerise.

4. The pore opens and chloride (Cl-) and bicarbonate (HCO3-) pass through.

5. ATP hydrolysis resets the channel. 

CFTR also regulates other channels. It normally inhibits ENaC (epithelial sodium channel). When CFTR is absent, ENaC becomes overactive and absorbs too much sodium, and water follows.

  2.3 Pathophysiology: From Gene to Disease

   CFTR gene mutation (both alleles)
                          |
                          v
   Defective or absent CFTR protein at cell surface
                          |
                          v
   Reduced Cl- and HCO3- secretion  +  Overactive ENaC (excess Na+ absorption)
                          |
                          v
   Less water in the airway surface liquid (dehydration)
                          |
                          v
   Thick, sticky, acidic mucus  +  Collapsed periciliary layer
                          |
                          v
   Cilia cannot beat -> mucociliary clearance fails
                          |
                          v
   Mucus plugging + bacterial colonisation
                          |
                          v
   Chronic infection <-> chronic inflammation (neutrophils, elastase)
                          |
                          v
   Bronchiectasis -> progressive lung damage -> respiratory failure                                          

The airway surface in health and in CF

                    HEALTHY AIRWAY                                   CF AIRWAY

    ~~~~~ mucus layer (thin) ~~~~~              ####### thick mucus plug #######
   ----- watery periciliary layer ----                     ---- shrunken periciliary layer ---
   |||||||| cilia beat freely |||||||                                xxxxxx cilia flattened xxxxxxx
   [ epithelial cells, CFTR working ]                    [ epithelial cells, CFTR absent ]
   Cl- out -> water follows -> hydrated              Cl- trapped, Na+ in -> dehydrated

Why salty sweat?

In the sweat duct, CFTR normally reabsorbs chloride (and sodium follows) back into the body. In CF, this reabsorption fails, so salt stays in the sweat. Thus sweat chloride is high, which is the basis of the diagnostic sweat test. This is the opposite problem to the airway, where chloride secretion is lost.

2.4 Clinical Features by Organ System

Respiratory system (the major cause of illness and death)

• •  Chronic productive cough, wheeze, exertional breathlessness
• •  Recurrent infections and acute pulmonary exacerbations (periods of worsening symptoms and lung function)
• • Bronchiectasis (permanent widening of airways)
• • Haemoptysis (coughing blood), often from bronchial artery enlargement
• • Pneumothorax (collapsed lung)
• • Chronic sinusitis and nasal polyps
• • Digital clubbing
• •  Late disease: respiratory failure and cor pulmonale (right heart failure from lung disease)

Gastrointestinal and pancreatic

• •       Meconium ileus in newborns (about 15% of babies with CF): thick first stool obstructs the small bowel. Presents with abdominal distension and failure to pass meconium in the first 24 to 48 hours.
• •       Exocrine pancreatic insufficiency (about 85% of patients): ducts blocked, digestive enzymes cannot reach the gut, causing malabsorption of fat and fat-soluble vitamins (A, D, E, K) and poor growth.
• •       Distal intestinal obstruction syndrome (DIOS) in older patients: blockage of the terminal ileum and caecum.
• •       Rectal prolapse in children (from bulky stools and straining).
• •       Gastro-oesophageal reflux disease.
• •       Pancreatitis in pancreatic-sufficient patients.

Hepatobiliary

• •       Thick bile leads to focal biliary cirrhosis and CF-related liver disease (CFLD), which can progress to portal hypertension and varices.
• •       Gallstones and gallbladder abnormalities.

Endocrine

• •       CF-related diabetes (CFRD): caused mainly by insulin deficiency from pancreatic damage. It is neither classic type 1 nor type 2. Screening is done yearly with an oral glucose tolerance test from about age 10.
• •       Poor bone health: osteopenia and osteoporosis from vitamin D and K deficiency, inflammation and low body weight.

Reproductive

•Males: about 98% are infertile due to congenital bilateral absence of the vas deferens (CBAVD). Sperm production is normal, so assisted reproduction using surgically retrieved sperm is possible.

• Females: fertility is reduced because of thick cervical mucus and poor nutritional status, but many can conceive, especially with good lung function.

Other

• Salt-loss syndrome: hyponatraemic hypochloraemic dehydration, heat exhaustion, metabolic alkalosis in hot weather.

• Hypertrophic osteoarthropathy and arthropathy.

• Kidney stones (oxalate) and vitamin K-related bleeding.

2.5 Diagnosis

Diagnosis combines clinical features, newborn screening, sweat testing and genetics.

Newborn screening

•  Heel-prick blood spot measuring immunoreactive trypsinogen (IRT), a pancreatic enzyme precursor that leaks into blood when the pancreas is damaged.

• If IRT is raised, a second test follows (repeat IRT or DNA panel for common mutations).

• A positive screen is not a diagnosis; it leads to a sweat test.

Sweat chloride test (gold standard)

Performed by pilocarpine iontophoresis: a small electric current drives pilocarpine into the skin to stimulate sweating, and sweat is collected and analysed for chloride.

Sweat chloride (mmol/L)	Interpretation
60 or more	CF is diagnosed (if consistent clinical picture)
30 to 59	Intermediate: further testing needed
Below 30	CF unlikely

(For infants under 6 months, an intermediate range of 30 to 59 mmol/L is used; below 30 makes CF unlikely.)

Genetic testing

• Targeted panels for common mutations, then full gene sequencing and deletion/duplication analysis when needed.

• Used to confirm the diagnosis, guide modulator eligibility, and offer cascade testing to relatives.

Other supportive tests

• Faecal elastase-1: low in pancreatic insufficiency (below 200 micrograms/g stool). 

•  Nasal potential difference or intestinal current measurement: assess CFTR function when sweat and genetics are unclear.

•  Chest X-ray/CT: bronchiectasis, hyperinflation, mucus plugging.

•  Sputum cultures: to identify organisms.

•  Spirometry: measures lung function (see below).

Diagnostic summary flow

         New born screen (IRT)  OR  Symptoms  OR  Family history
                                             |
                                            v
                 SWEAT CHLORIDE TEST
                              /             |              \
                       >= 60       30 - 59       < 30
                             |              |               |
                            v              v              v
                    CF likely      Genetic testing +     CF unlikely
               (confirm with     other function       (consider other
                 genetics)         tests                      diagnoses)

2.6 Monitoring Lung Function

• FEV1 (forced expiratory volume in 1 second) is the key measure, expressed as percent predicted for age, sex, height and ethnicity.

• FVC (forced vital capacity) and the FEV1/FVC ratio show an obstructive pattern in early disease and a mixed pattern later.

• A falling FEV1 over time indicates progression or an exacerbation.

• Newer tools: Lung Clearance Index (LCI) from multiple-breath washout, which detects early small-airway disease in young children.

2.7 Day-to-Day Management

Care is delivered by a multidisciplinary CF team: doctors, specialist nurses, physiotherapists, dietitians, pharmacists, psychologists, social workers and diabetes specialists.

1. Airway clearance

•Chest physiotherapy: postural drainage, percussion, active cycle of breathing technique (ACBT), autogenic drainage.
•Devices: positive expiratory pressure (PEP) masks, oscillating PEP devices (Flutter, Acapella), high-frequency chest wall oscillation vests. 
•Exercise: strongly recommended and has both airway-clearing and general health benefits.

2. Mucus-thinning drugs

• Dornase alfa (recombinant human DNase): breaks down DNA released from    dead neutrophils that makes mucus viscous. 
• Hypertonic saline (3% to 7%) nebulised: draws water into the airway surface     liquid. 
• Mannitol dry powder: another osmotic agent.

3. Antibiotics and infection control

• Oral, inhaled and intravenous antibiotics, chosen using sputum culture and       sensitivity. 
•  Inhaled antibiotics (tobramycin, aztreonam, colistin) for chronic            Pseudomonas infection.

• Azithromycin long-term for its anti-inflammatory benefits. 
• Eradication therapy when Pseudomonas is first isolated. 
• Infection control: patients with CF avoid close contact with each other (cross-infection risk), and hospital segregation policies apply.  

• Vaccinations: routine plus influenza, pneumococcal and COVID-19.

4. Nutrition

• High-calorie, high-fat diet (often 120% to 150% of normal energy intake). 
• Pancreatic enzyme replacement therapy (PERT): capsules taken with every meal and snack containing fat. 
• Fat-soluble vitamin supplements (A, D, E, K) and salt supplements in hot weather or with heavy sweating.  

• Overnight tube feeding in some patients with poor weight gain.

5. Treating complications

• CFRD: insulin therapy.
• DIOS: laxatives, osmotic agents, rehydration.
• Liver disease: ursodeoxycholic acid, monitoring for portal hypertension.
• Bone disease: vitamin D, calcium, weight-bearing exercise, sometimes bisphosphonates.
• Haemoptysis: tranexamic acid, bronchial artery embolisation for major bleeds.
• Allergic bronchopulmonary aspergillosis (ABPA): corticosteroids and antifungals.             

LEVEL 3: ADVANCED

3.1 CFTR Mutation Classes

Mutations are grouped by how they damage CFTR. This classification guides therapy choice.      

CFTR GENE --> mRNA --> PROTEIN --> FOLDING --> CELL SURFACE --> FUNCTION

   Class I   : [ X ]  No protein made (nonsense, frameshift)
   Class II  : ...... Protein misfolded, destroyed (F508del)
   Class III : ...... Protein at surface but channel will not open (G551D)
   Class IV  : ...... Channel opens but conducts poorly (R117H, R334W)
   Class V   : ...... Reduced amount of normal protein (splicing variants)
   Class VI  : ...... Unstable protein, rapid turnover at the surface

Class	Defect	Example	Severity	Treatment approach
I	No protein synthesis	G542X, W1282X	Severe	Read-through agents (experimental), gene/mRNA therapy
II	Trafficking and processing defect	F508del	Severe	Correctors (lumacaftor, tezacaftor, elexacaftor)
III	Gating defect	G551D	Severe	Potentiators (ivacaftor)
IV	Conductance defect	R117H	Milder	Potentiators
V	Reduced quantity	A455E, splicing variants	Milder	Potentiators plus correctors, splicing modulators
VI	Reduced stability	Rescued F508del	Variable	Stabilisers (experimental)

Notes:

• Classes I to III usually cause severe disease with pancreatic insufficiency.
• Classes IV and V usually keep some residual function and are often associated with pancreatic sufficiency and milder lung disease. 
• Many alleles have more than one defect (F508del is mainly Class II but also has gating and stability defects).

3.2 Genotype-Phenotype Relationship and Modifiers

• Pancreatic status correlates well with genotype; lung disease correlates only loosely.
• Even identical F508del homozygotes can differ greatly in outcome.
• Modifier genes influence severity. Examples: TGFB1, EDNRA, MBL2, SLC26A9, and genes affecting the airway epithelium and inflammation. 
• Environmental factors matter: air pollution, smoke exposure, socioeconomic status, adherence, access to care and early infection history. 
• CFTR-related disorders (CFTR-RD): people with CFTR mutations may have only one organ affected, such as isolated congenital absence of the vas deferens, idiopathic pancreatitis or disseminated bronchiectasis, without meeting full CF criteria. A related category in new born screening is CRMS/CFSPID (CFTR-related metabolic syndrome or CF screen-positive, inconclusive diagnosis), where babies have a positive screen and equivocal tests, and require long-term follow-up.

3.3 CFTR Modulator Therapy

Modulators are small molecules that correct or potentiate the faulty protein. They represent the biggest advance in CF care.   

 F508del CFTR made in cell
        |
   CORRECTORS (lumacaftor, tezacaftor, elexacaftor)
        |  help protein fold and reach the cell surface
        v
   CFTR protein at surface (but gates poorly)
        |
   POTENTIATOR (ivacaftor)
        |  holds channel open longer
        v
   Chloride and bicarbonate flow restored (partially)

Drug (examples)	Class	Used for
Ivacaftor (Kalydeco)	Potentiator	Gating mutations such as G551D and many residual-function mutations
Lumacaftor/ivacaftor (Orkambi)	Corrector + potentiator	F508del homozygous
Tezacaftor/ivacaftor (Symdeko or Symkevi)	Corrector + potentiator	F508del homozygous and some residual-function genotypes
Elexacaftor/tezacaftor/ivacaftor (Trikafta or Kaftrio)	Two correctors + potentiator	At least one F508del allele and many other eligible variants
Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek)	Newer once-daily triple combination	Broadly eligible genotypes; approved in several countries

Clinical impact

• Large improvements in FEV1 (about 10 to 14 percentage points with triple therapy), fewer exacerbations, weight gain, and lower sweat chloride. 

• Dramatic reductions in hospitalisations and transplant referrals.  

• Projected life expectancy now extends well beyond 50 years for those starting therapy early, and children diagnosed today may have a near-normal outlook.

Practical issues

•  Drug interactions: metabolised by CYP3A4. Strong inducers (rifampicin, carbamazepine, St John's wort) reduce levels. Inhibitors (azole antifungals, clarithromycin, grapefruit) raise levels, so doses may need adjustment.

• Monitoring: liver function tests (risk of raised transaminases), eye checks in children (cataract risk), mood and sleep changes in some patients.

• Cost and access: these drugs are very expensive, creating global inequity. Many people, especially in low- and middle-income countries, still lack access.

• Not everyone is eligible: people with Class I mutations and some rare variants currently have no approved modulator.

• Gaps remain: infection and inflammation may persist, and modulators do not reverse established bronchiectasis. Lifelong airway clearance, nutrition and surveillance still matter for many patients.

3.4 Microbiology of CF Lung Disease

The CF airway is colonised in a predictable sequence:  

  Infancy / early childhood                       Adolescence / adulthood
   --------------------------                               ---------------------------------------
   Staphylococcus aureus    ---->  Pseudomonas aeruginosa (chronic, mucoid)
   Haemophilus influenzae               Burkholderia cepacia complex
                                                            Stenotrophomonas, Achromobacter
                                                            MRSA, Aspergillus, NTM (M. abscessus)

• Pseudomonas aeruginosa: the key pathogen. Forms biofilms and switches to a mucoid phenotype (alginate overproduction), making it extremely hard to eradicate. Chronic infection is linked to faster decline in lung function.
• Burkholderia cepacia complex: associated with rapid deterioration, so-called cepacia syndrome (fulminant pneumonia with septicaemia), and is highly transmissible and often multi-resistant. It may be a contraindication to transplant in some centres.
• Staphylococcus aureus: includes MRSA; common early. 

• Non-tuberculous mycobacteria (NTM): especially Mycobacterium abscessus; require prolonged multi-drug treatment.
• Aspergillus fumigatus: can cause ABPA, an allergic reaction in the airways. 
• Inflammation: neutrophils release neutrophil elastase, DNA and oxidants, which damage the airway wall and prolong the cycle of infection and inflammation. The CF airway is inflamed even in infants before overt infection.

3.5 Pulmonary Exacerbations and Advanced Respiratory Complications

An exacerbation is an acute worsening, often defined by increased cough, sputum, breathlessness, weight loss, fatigue and a fall in FEV1 of 10% or more.

•  Management principles:

• Intensify airway clearance and nutrition.
• Give antibiotics guided by previous sputum cultures, often two anti-pseudomonal agents intravenously for about 14 days, sometimes at home.
• Monitor kidney function and drug levels when using aminoglycosides. 
• Reassess lung function after treatment; incomplete recovery predicts long-term decline.

•   Advanced complications:

•   Respiratory failure: type 2 (hypercapnic) failure may need non-invasive ventilation (NIV) as a bridge to transplant or for comfort.
• Pneumothorax: manage with chest drain; recurrent cases may need pleurodesis (discuss early with the transplant team, since pleurodesis can complicate later surgery).
• Massive haemoptysis: bronchial artery embolisation. 

• Pulmonary hypertension and cor pulmonale: supplemental oxygen and treatment of the underlying lung disease.

3.6 Lung Transplantation

• Considered when FEV1 falls below about 30% predicted, with rapid decline, frequent hospitalisation, worsening nutrition, or respiratory failure.
• Usually bilateral lung transplant (the infection is in both lungs and native lungs act as a reservoir).
• Outcomes: median survival after transplant is around 9 to 10 years and improving.
• Challenges: chronic rejection (bronchiolitis obliterans syndrome), immunosuppression complications, infection, CFRD and kidney disease.
• Since modulators became widespread, transplant numbers have fallen sharply.

3.7 Nutrition and Metabolic Details

• Pancreatic enzyme dosing: typically started at 500 to 1,000 lipase units per kg per meal (lower for snacks), generally not exceeding 2,500 lipase units/kg/meal or 10,000 units/kg/day, because very high doses are linked to fibrosing colonopathy. 
• Fat-soluble vitamins: monitor serum levels yearly. 
• Salt: infants need sodium chloride supplementation. 
• CFRD: screen annually with a 2-hour OGTT; HbA1c is unreliable in CF. Insulin is standard, and the diet is not calorie-restricted because weight maintenance is a priority. 
• Bone health: DEXA scans from adolescence or adulthood. 
• BMI targets: commonly BMI of at least 22 for women and 23 for men; children aim for the 50th percentile for weight-for-age and height.

3.8 Special Situations

Pregnancy and CF

• Many women with CF now have successful pregnancies, particularly with good baseline lung function (FEV1 above about 60% predicted) and nutrition. 
• Requires specialist pre-conception counselling, medication review and close monitoring for CFRD, nutrition and lung function. 
• Partner carrier testing is recommended to assess risk to the baby.

Male fertility

• Men can father children through microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction combined with ICSI.

Carrier screening and prenatal options

• Carrier screening is offered to couples planning a pregnancy in many countries.

• Prenatal options include chorionic villus sampling or amniocentesis, and pre-implantation genetic testing (PGT) with IVF.

Heat, travel and sports

• Risk of salt depletion: increase fluids and salt. 

• Continue airway clearance during travel; carry medications and a treatment summary.

Mental health and quality of life

• Anxiety and depression are common in patients and caregivers. Screening and psychological support are part of routine CF care. 
• Treatment burden (hours of daily therapy) affects adherence, particularly in adolescence.

3.9 Emerging and Future Therapies

• Gene therapy: delivering a working CFTR gene to airway cells using viral vectors (AAV, lentivirus) or non-viral nanoparticles. Challenges include immune responses, reaching airway stem cells and durability.
• mRNA therapy: inhaled lipid nanoparticles delivering CFTR mRNA are in clinical trials.
• Gene editing: CRISPR-based correction and base editing in airway stem cells are being explored in laboratory models.
• Read-through agents and nonsense-mediated decay inhibitors: help ribosomes bypass premature stop codons (Class I).
• Alternative ion channel activators: for example targeting TMEM16A or SLC26A9, to restore chloride transport independent of CFTR.
• ENaC inhibitors: to reduce sodium hyperabsorption.
• Anti-inflammatory therapies, new antibiotics and phage therapy for resistant infections.
• Early modulator therapy for infants, aiming to prevent damage before it starts. 
• Equity: global efforts to increase access to modulators in low- and middle-income countries.

3.10 Prognosis and Outcomes

• In the 1960s, children with CF rarely survived childhood. 
• By 2020, median predicted survival in many high-income countries exceeded 50 years. 
• With early modulator therapy, projections suggest much longer survival for infants born today. 
• In many registries more than half of people with CF are now adults, creating new needs: adult care, fertility, ageing, colorectal cancer screening (higher risk), kidney disease and mental health. 

REVISION TOOLS

Quick Summary (Cheat Sheet)

1.What: autosomal recessive multisystem disease from CFTR mutations (chromosome 7). 
2.Defect: loss of chloride and bicarbonate transport, plus excess sodium absorption, giving thick dehydrated secretions. 
3.Commonest mutation: F508del (Class II). 
4.Organs: lungs (cause of most deaths), pancreas, gut, liver, sweat glands, vas deferens. 
5.Diagnosis: newborn screening (IRT), sweat chloride 60 mmol/L or more, genetic testing. 
6.Pathogens: S. aureus early, P. aeruginosa later, B. cepacia (dangerous), NTM, Aspergillus. 
7.Treatment: airway clearance, mucolytics, antibiotics, PERT and nutrition, modulators, transplant. 
8.Modulators: potentiators open the channel; correctors help the protein reach the surface. 
9.Complications: CFRD, DIOS, liver disease, bone disease, haemoptysis, pneumothorax. 

10.Inheritance risk: two carriers have a 25% chance of an affected child in each pregnancy.

Mnemonics

"CF PANCREAS" (features)

• Chronic cough 
• Failure to thrive 
• Pancreatic insufficiency 
• Azoospermia (CBAVD) 
• Nasal polyps 
• Clubbing 
• Rectal prolapse 
• Electrolytes: high sweat chloride 
• Aspergillus/ABPA 
• Salty skin

Mutation classes I to VI: 

None made, Misfolded, Gate stuck, Conducts poorly, Quantity low, Short-lived.

Sweat test cut-offs: "60 is CF, 30 is a maybe, below 30 is no."

Common Exam Questions

Question	Key answer
Why salty sweat but sticky airway mucus?	Sweat duct cannot reabsorb Cl- (CFTR needed); airway cannot secrete Cl- (CFTR needed) and has excess Na+ uptake
Which drug helps G551D?	Ivacaftor (potentiator)
Which drugs help F508del?	Correctors plus potentiator (elexacaftor/tezacaftor/ivacaftor)
Why are pancreatic enzymes given with meals?	To digest fat, protein and starch; they replace what blocked ducts cannot deliver
Why is HbA1c unreliable in CF?	Red cell turnover and inflammation affect it; use OGTT
Why are most men infertile?	Congenital bilateral absence of the vas deferens
Why is CF autosomal recessive?	Two defective alleles are needed; carriers are healthy

Practice Questions

Short answer

1.      Define cystic fibrosis and name the gene involved.  

2.      Explain how a CFTR defect leads to thick airway mucus.

3.      List four gastrointestinal manifestations of CF.

4.      Describe the sweat test and its interpretation.

5.      Compare corrector and potentiator drugs, giving one example of each.

Multiple choice (correct answer in bold)

1.      The most common CF mutation is: a) G551D  b) F508del  c) W1282X  d) R117H

2.      A sweat chloride of 72 mmol/L in an infant with poor weight gain suggests: a) Normal  b) Intermediate result  c) CF likely  d) Coeliac disease

3.      Which organism is classically associated with chronic infection in adult CF? a) Streptococcus pyogenes  b) Pseudomonas aeruginosa  c) Neisseria meningitidis  d) Klebsiella oxytoca

4.      Ivacaftor primarily acts as a: a) Corrector  b) Mucolytic  c) Potentiator  d) ENaC inhibitor

5.      Meconium ileus in a newborn is strongly associated with: a) Hirschsprung disease only  b) Cystic fibrosis  c) Coeliac disease  d) Pyloric stenosis

       Essay / advanced

1.Discuss the classification of CFTR mutations and how it informs modulator therapy. 
2.Explain the pathophysiology of CF lung disease, including the role of infection and inflammation. 
3.Critically evaluate the impact of CFTR modulators on CF care and the remaining challenges.

Glossary

•       Airway surface liquid (ASL): thin fluid layer lining airways, essential for ciliary beating.

•       Biofilm: a community of bacteria embedded in a protective matrix.

•       Bronchiectasis: irreversible widening and scarring of airways.

•       CFTR: cystic fibrosis transmembrane conductance regulator.

•       CBAVD: congenital bilateral absence of the vas deferens.

•       DIOS: distal intestinal obstruction syndrome.

•       ENaC: epithelial sodium channel.

•       FEV1: forced expiratory volume in one second.

•       IRT: immunoreactive trypsinogen.

•       Meconium ileus: newborn bowel obstruction from thick meconium.

•       PERT: pancreatic enzyme replacement therapy.

•       Steatorrhoea: fatty, pale, offensive stools.