What are the key points to know about cystic fibrosis for the MRCP (Membership of the Royal College of Physicians) Part 1 UK exam?

Cystic Fibrosis: MRCP Part 1 Flashcard

Genetics & Pathophysiology

Cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR gene on chromosome 7, encoding a chloride channel protein that regulates ion transport across epithelial cells. 1, 2

• F508del (ΔF508) is the most common mutation, accounting for 30-88% of CF chromosomes worldwide depending on ethnicity 3
• Over 1,950 CFTR mutations have been identified, classified by their functional consequences on the CFTR protein 4, 5
• The protein defect leads to impaired mucus hydration and clearance across multiple organ systems 1

Diagnostic Criteria

Diagnosis requires BOTH clinical features of CF AND evidence of CFTR dysfunction (sweat chloride ≥60 mmol/L or two CF-causing mutations). 6

Sweat Chloride Testing (Gold Standard):

• ≥60 mmol/L = diagnostic for CF (with clinical features, positive family history, or positive newborn screen) 6
• 30-59 mmol/L = intermediate/ambiguous - requires repeat testing and further evaluation 6
• <30 mmol/L = CF unlikely (but consider if clinical features strongly suggest CF) 3
• Must be performed bilaterally in newborns >2 kg, ≥36 weeks corrected gestational age, ideally after 10 days of age 6
• Analysis must occur within hours of collection for accuracy 6

Genetic Testing:

• Identification of two CF-causing mutations confirms diagnosis regardless of sweat test results 6
• Extended CFTR gene sequencing (including intronic regions) recommended when initial panel identifies <2 variants 3
• Parental testing ("phasing") determines if variants are in cis (same chromosome = carrier) or trans (different chromosomes = CF) 3

Clinical Manifestations

Respiratory:

• Chronic pulmonary infection and inflammation with progressive lung disease 1
• Bronchiectasis develops due to chronic infection and inflammation 3
• Pseudomonas aeruginosa colonization is common and clinically significant 3

Gastrointestinal:

• 85% have pancreatic exocrine insufficiency beginning in infancy 3
• Meconium ileus in neonates 3
• Failure to thrive, steatorrhea, fat-soluble vitamin deficiencies 1

Hepatobiliary:

• CF-related liver disease occurs in 20-40% of patients, ranging from hepatic steatosis to multilobular cirrhosis with portal hypertension 3
• Can progress to liver failure requiring transplantation 3

Endocrine:

• Cystic fibrosis-related diabetes (CFRD) affects 20% of adolescents and 40-50% of adults 3
• Insulin insufficiency is the primary defect, worsened by infection and inflammation 3
• Annual OGTT screening recommended (A1C ≥6.5% also diagnostic but less sensitive for screening) 3

Reproductive:

• Male infertility due to congenital bilateral absence of vas deferens (CBAVD) in >95% of males 3

Newborn Screening

• Initial test measures immunoreactive trypsinogen (IRT), which is elevated but NOT diagnostic 6
• IRT can be elevated due to prematurity, stressful delivery, or CF carrier status 6
• All positive screens require confirmatory sweat chloride testing - diagnosis cannot be made on screening alone 6
• Algorithms vary: IRT/repeat IRT or IRT/DNA mutation analysis 6

Ethnic Considerations

• Ashkenazi Jewish population: Common mutations include W1282X, F508del, G542X, N1303K, 3849+10kbC→T 3
• African-American population: Specific mutations include 3120+1G→A, A559T, G330X, 2307insA 3
• Carrier frequency: 1/25 in Caucasians and Ashkenazi Jews 3

Monitoring & Complications

• Annual follow-up minimum for confirmed CF patients 3
• Screen for CFRD annually with OGTT, especially after age 10 years 3
• Monitor for hepatobiliary disease with clinical assessment and imaging 3
• Assess for allergic bronchopulmonary aspergillosis (ABPA) with total IgE and Aspergillus-specific IgE 3

Key Exam Pitfalls

• Do not diagnose CF based on newborn screening alone - sweat test is mandatory 6
• Intermediate sweat chloride values (30-59 mmol/L) do not rule out CF - these patients need repeat testing and genetic analysis 6
• A1C is insensitive for CFRD screening - OGTT is preferred 3
• Remember CF is a multisystem disease - look beyond respiratory symptoms for pancreatic, hepatic, and endocrine involvement 1