Description
- AR multisystem exocrinopathy - defective CFTR chloride/bicarbonate channel -> viscous secretions obstructing every exocrine duct
- Now an adult disease - median survival has crossed into the 5th decade and CFTR modulators are changing it again
Organ involvement
- Respiratory - bronchiectasis, chronic infection, obstructive defect, nasal polyps, chronic sinusitis, haemoptysis, pneumothorax, ABPA
- Pancreas - exocrine insufficiency ~85% (steatorrhoea, fat-soluble vitamin deficiency, failure to thrive); CF-related diabetes; recurrent pancreatitis in pancreatic-sufficient genotypes
- GI - meconium ileus (neonate), distal intestinal obstruction syndrome (DIOS) in adults, GORD, constipation, rectal prolapse
- Liver - focal biliary cirrhosis -> multilobular cirrhosis with portal hypertension in ~5-10%, cholelithiasis
- Reproductive - congenital bilateral absence of the vas deferens in ~98% of men (obstructive azoospermia); reduced fertility in women (thick cervical mucus)
- Other - salt-loss/pseudo-Bartter syndrome in heat, CF bone disease, arthropathy, digital clubbing, amyloidosis
Epidemiology
- Commonest lethal AR disease in people of European ancestry - ~1:2,500 births in Australia; carrier ~1:25
- ~3,500 Australians live with CF; >60% are now adults
- F508del present on ~70% of Australian CF alleles; ~50% of patients are F508del homozygous
Aetiopathogenesis
- CFTR, chromosome 7q31, an ATP-gated cAMP-regulated Cl- and HCO3- channel at the apical membrane
- Loss -> dec Cl-/HCO3- secretion + inc ENaC-mediated Na+ absorption -> dehydrated, acidic, viscous airway surface liquid -> impaired mucociliary clearance -> infection/inflammation cycle
- In sweat duct the defect is reabsorptive -> high sweat chloride**
Mutation classes - determine which modulator works
| Class | Defect | Example | Phenotype |
|---|---|---|---|
| I | No protein (nonsense/frameshift) | G542X, W1282X | Severe; modulators do not work |
| II | Misfolding, degraded | F508del | Severe; needs corrector + potentiator |
| III | Gating failure at the membrane | G551D | Severe; potentiator (ivacaftor) alone works |
| IV | Reduced conductance | R117H | Milder, often pancreatic-sufficient |
| V | Reduced quantity | 3849+10kbC>T | Milder |
| VI | Unstable at membrane | Milder |
- Classes I-III = pancreatic insufficient, severe; IV-VI = residual function, milder, later diagnosis
- CFTR-related disorders (not full CF): isolated CBAVD, idiopathic recurrent pancreatitis, disseminated bronchiectasis, chronic rhinosinusitis
Diagnosis
A. Newborn screening (Australia - all states)
- IRT on the Guthrie card -> if raised, CFTR mutation panel -> sweat test to confirm
B. Sweat chloride (pilocarpine iontophoresis) - still the diagnostic standard
| Sweat Cl- (mmol/L) | |
|---|---|
| >=60 | Diagnostic of CF |
| 30-59 | Intermediate - repeat, genotype, functional testing |
| <30 | CF unlikely (but does not exclude in adults with residual-function mutations) |
- False positives: malnutrition, hypothyroidism, adrenal insufficiency, eczema, anorexia nervosa
C. Genotype
- Extended CFTR panel then full sequencing; two disease-causing variants in trans confirms the diagnosis
- *Genotype is now essential for treatment, not only diagnosis* - it determines modulator eligibility
D. Consider CF in an adult with
- *Bronchiectasis with Pseudomonas or Staphylococcus aureus, upper-lobe predominant*
- Obstructive azoospermia / male infertility
- Idiopathic recurrent pancreatitis
- Nasal polyps + chronic sinusitis, unexplained pancreatic insufficiency, hypochloraemic metabolic alkalosis with heat exposure
- Adult diagnosis often has a milder genotype, normal or intermediate sweat chloride, and pancreatic sufficiency
Annual review investigations
- Spirometry (FEV1 is the key prognostic variable), sputum culture (including NTM and fungal), CXR/HRCT
- OGTT annually from age 10 - CF-related diabetes is usually asymptomatic and HbA1c is insensitive
- LFTs + liver ultrasound, DEXA, fat-soluble vitamins A/D/E/K, faecal elastase
Management
MDT specialist CF centre care; strict infection-control segregation between patients.
A. CFTR modulators - the change in the disease
- Elexacaftor/tezacaftor/ivacaftor (Trikafta) - for >=1 F508del or other responsive mutation
- Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) - first once-daily triple combination; PBS-listed from 1 Feb 2026, age >=6 with >=1 responsive mutation
- Ivacaftor alone for gating (class III) mutations, e.g. G551D
- Effects: inc FEV1 ~10-14 points, marked dec exacerbations, inc weight, dec sweat chloride
- Monitor LFTs (hepatotoxicity), cataracts, drug interactions (CYP3A - rifampicin and azoles matter); depression/anxiety and mental-health change reported
- >95% of Australians with CF now have access to a modulator - class I nonsense mutations remain the unmet need
B. Airways
- Airway clearance daily (PEP, ACBT, exercise) - non-negotiable
- Nebulised hypertonic saline 6-7% +/- dornase alfa
- *Chronic Pseudomonas: inhaled tobramycin or colistin* (usually month-on/month-off)
- Azithromycin 3x/week - anti-inflammatory (exclude NTM first)
- Bronchodilator before clearance; treat ABPA (steroids +/- itraconazole)
C. Infection
- *First isolation of Pseudomonas -> aggressive eradication* (inhaled tobramycin +/- oral ciprofloxacin)
- Exacerbation: 2 weeks IV, two antipseudomonal agents from different classes (e.g. piperacillin-tazobactam or ceftazidime + tobramycin)
- Higher doses and shorter dosing intervals - CF patients have inc clearance and inc volume of distribution
- **Burkholderia cepacia complex - transmissible, accelerates decline, may contraindicate transplant; strict segregation**
- Rising incidence of NTM (M. abscessus) - screen annually
D. Nutrition and GI
- Pancreatic enzyme replacement with every meal and snack, titrated to stool and growth
- High-energy, high-fat, high-salt diet; supplement vitamins A, D, E, K
- DIOS: oral/NG gastrografin or polyethylene glycol; not surgery - distinguish from true obstruction
- CF-related diabetes -> insulin (not oral agents; do not restrict calories)
- Ursodeoxycholic acid for CF liver disease (benefit uncertain); portal hypertension managed conventionally
E. Other
- Bone: DEXA, vitamin D, bisphosphonate if osteoporotic
- Haemoptysis: tranexamic acid, stop NSAIDs/nebulised irritants, bronchial artery embolisation if massive
- Pneumothorax: drain; pleurodesis complicates future transplant - discuss with the transplant unit
- Lung transplantation - refer when FEV1 <30% predicted, rapid decline, massive haemoptysis, recurrent ICU admissions, or pulmonary hypertension
- Fertility: ICSI with surgical sperm retrieval for men; women can conceive - preconception genotyping of the partner
- Vaccination, salt supplementation in hot weather, mental health screening, transition planning
Associations
- Bronchiectasis, chronic rhinosinusitis and nasal polyps
- Allergic bronchopulmonary aspergillosis (~10%)
- Non-tuberculous mycobacterial infection
- CF-related diabetes (~50% by age 30) - intermediate phenotype between type 1 and type 2
- CF liver disease, cholelithiasis, cholestasis
- Osteoporosis and CF arthropathy; digital clubbing and hypertrophic osteoarthropathy
- Male infertility (CBAVD), delayed puberty
- Distal intestinal obstruction syndrome, rectal prolapse, GORD
- Increased risk of GI malignancy (colorectal in particular) - colonoscopy screening from age 40, or 30 post-transplant
- Pseudo-Bartter syndrome (hypochloraemic hypokalaemic metabolic alkalosis)
- Depression and anxiety - screen annually
Natural history & complications
- Progressive obstructive lung disease punctuated by exacerbations; each exacerbation leaves a lower FEV1 baseline
- Respiratory failure causes >80% of deaths
- Median predicted survival now >50 yr and rising with modulators - the historical "median survival 40" figure is already out of date
- *FEV1, exacerbation frequency, nutritional status (BMI) and Burkholderia colonisation are the main prognostic markers*
- Microbiological succession with age: **S. aureus and H. influenzae in childhood -> chronic Pseudomonas aeruginosa in adolescence/adulthood* -> Burkholderia, Stenotrophomonas, NTM, Aspergillus*
- Post-transplant ~60% 5-year survival; CF-specific issues (sinus disease, GI, diabetes) persist
- The adult CF population is shifting from a decline-and-transplant trajectory to a chronic disease with a near-normal lifespan - surveillance for diabetes, bone disease and GI cancer matters more each year
7 of 7 sections written · drafted 2026-09-12