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Cystic fibrosis

Cystic fibrosis ( CF ) is an autosomal recessive , monogenetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR ) Nature reviews 2015

most common lethal inherited disease in the white population monogenic , autosomal recessive due to absence of CFTR it is thought to affect about 1 in 2500 live births usually diagnosed in the first few months of life ○ universal newborn bloodspot screening ( NBS ) in the UK since 2007 This involves taking blood from the newborns heel on day 5 to check for 6 inherited metabolic conditions ○ NBS was started in the US since 2004 ○ milder phenotypes may be diagnosed in later life This means that people born before the screening programs were introduced may have the condition but have not been diagnosed. It has been reported that 935 adults in 2016 with CF had been diagnosed at age 16 or after new data has shown that the incidence may be lower than previously thought ie between 1/3000 and 1 / 6000 it is estimated that 1 in 25-30 Caucasians are carriers of a pathogenic mutation of the CFTR gene median age at diagnosis is 2 months ( BMJ ) seen less commonly in other ethnicities but CF should not be excluded in patients with suggestive clinical findings solely based on patients ethnicity

CF happens due to loss of the function of the CF transmembrane 

conductance regulator protein caused by mutations in the CFTR gene CFTR is found in various tissues ( respiratory epithelia , submucosal glands , exocrine pancreas , liver , sweat ducts and the reproductive tract ) regulates and participate in the transport of chloride ions across epithelial cell surfaces ie abnormal salt and water transport leading to end-organ damage CFTR gene mutation disrupts chloride secretion , sodium reabsorption and water transport -lead to mucus hyper concentration and decreased mucociliary clearance ( thicker mucus secretions on epithelial linings and more viscous secretions from exocrine tissues ) More than 1500 mutations have been reported and the most common disease causing CFTR mutation worldwide is ΔF508 CF is a multisystem disorder- affects lungs , pancreas , liver and intestine ○ affects the lungs causing chronic suppurative lung disease ○ exocrine pancreatic insufficiency which affects gastrointestinal function and causes restricted growth and maturation Some patients with CF may have abnormal results – but they may not meet the full diagnostic criteria for CF- terms as CF Transmembrane Conductance Regulator Metabolic Syndrome ( CRMS ) in the US and CF Screened Positive Inconclusive Diagnosis ( CFSPID ) have been introduced

Diagnosis-positive test result for e,g from universal screening – followed by sweat and gene tests , clinical manifestations – further supported by sweat or gene test results , clinical manifestations alone -in people with normal sweat or gene tests ( rare )

When to suspect -family h/o CF congenital intestinal atresia meconium ileus symptoms and signs suggest distal intestinal obstruction syndrome faltering growth undernutrition recurrent and chronic presentations suggestive of pulmonary disease ○ recurrent lower respiratory tract infections ○ imaging /clinical evidence of lung disease ( particularly bronchiectasis ) ○ persistent CXR changes ○ chronic wet productive cough chronic sinus disease obstructive azoospermia ( in young people / adults ) acute or chronic pancreatitis malabsorption rectal prolapse ( in children ) pseudo- Bartter syndrome.

positive or equivocal sweat test result assessment suggests that they have CF but their test results are normal gene testing reveals 1 or more CF mutations ( more than 1500 CF mutations have been identified )

The most common newborn screening method involves measuring the levels of immunoreactive trypsinogen ( a pancreatic enzyme precursor in blood spots ) it has high sensitivity but low specificity Sweat test ( NaCl ) levels of ≥ 60 mmol / L is diagnostic of CF Genetic analysis may be needed in some cases where the clinical suspicion is high and the sweat test is in the normal range.

Lung disease -mucous plugging in bronchioles leads to obstructive lung disease it is known that chronic colonisation of the lower airways by bacterial pathogens is the leading cause of morbidity and mortality in CF patients CFTR dysfunction leads to a vicious cycle of infection , inflammation and tissue damage due to obstruction of the airways by thick , sticky mucus FEV1 remains the most commonly tracked measure of lung disease early interventions to treat infections and monitoring response remains a vital component of the CF patients care NICE guideline provides detailed guidance on monitoring strategies and treatment recommendations for specific infections ( and for mucolytic agents and use of airway clearing techniques ) problems encountered in CF patients include chronic bronchitis , abnormal pulmonary function tests , bronchiectasis , atypical asthma , allergic bronchopulmonary aspergillosis and colonization with pseudomonas aeruginosa milder infections can be treated in primary care ( always consider obtaining respiratory secretions sample for microbial investigations ) 

Pancreas -affects both exocrine and endocrine functions but exocrine pancreatic insufficiency is more marked in about 85 % of cases the pancreatic exocrine ducts are blocked enough to cause maldigestion and intestinal malabsorption thickened secretions block / obstruct pancreatic ductules malabsorption -particularly fat soluble vitamins ADEK is frequently seen autodigestion of pancreas can cause pancreatitis endocrine pancreatic failure can mimic type 1 diabetes

Nutrition-malnutrition is commonly seen and contributes to mortality exocrine and endocrine dysfunction in association with high basal metabolic requirements exposes patients to high risk of malnourishment failure to thrive- can be seen even in 1st few weeks of life NICE guideline provides recommendations on detection , monitoring and management of nutritional problems

Liver -severe liver disease is an important cause of mortality in CF initial problems manifest as biochemical derangements in liver enzymes with structural problems developing later biliary duct obstruction can lead to periportal inflammation and fibrosis obstructive cirrhosis , post-hepatic hyperbilirubinemia , increased hepatic portal vein pressure causing esophageal varices , splenomegaly and hypersplenism may be see gallbladder disease including gall stone

Intestine -manifests in children with meconium ileus at birth and intestinal obstruction in later about 15 % of infants with CF present with meconium ileus at birth distal intestinal obstruction syndrome rectal prolapse in children.

Reproductive tract- 90 % of the males suffer with congenital b/l absence of the vas deferens CBAVD ) females -reduced fertility due to thickened cervical mucus.

Sinus -chronic rhinosinusitis , chronic post-nasal drip , nasal polyposis , panopacification of the paranasal sinuses.

MSK-kyphoscoliosis , osteopenia/ osteoporosis and arthropathy

salty sweat , digital clubbing and cyanosis

Management -multidisciplinary team -specialist centres ensure vaccination as per guidance treatment of flare ups / exacerbations -treatment of airway infections are critical and antibiotics play a critical role in CF management prescribe promptly , duration of treatment may be longer than 1 week ( seek advise as needed from specialist teams ) Primary care is responsible for prescribing much of the routine therapy recommended by the specialist CF centres Prescribing for longer than 1 month may be expected beware of complications as listed below.

Complications -being underweight meconium ileus ( can affect 1 in 7 newborns ) fat soluble vitamin deficiencies ( including A,D, E, K ) distal intestinal obstruction syndrome ○ suspect in those who present with acute onset of peri-umbilical or RLQ abdominal pain with any – palpable mass in RLQ – faecal loading in ELQ on plain abdominal XR particularly if associated with small intestinal air-fluid levels ○ clinical picture indicates partial or complete obstruction muscle pains and arthralgia male infertility ( almost all males are infertile due to obstructive azoospermia ) reduced female fertility upper airway complications ( including nasal polyps and sinusitis ) chronic liver disease urinary stress incontinence CF related diabetes reduced BMD ( including osteoporosis ) the following less common complications may also be seen CF related arthritis delayed puberty ( in severe cases ) renal calculi

prognosis has improved considerably over the last decades in the UK the estimated median survival age is 48 for males and 44 for females prognosis has improved due to a combination of factors ○ early diagnosis ( screening programs ) ○ specialist centres ○ better understanding ○ improved treatments including aggressive nutritional support , enhanced mucociliary clearance and mucus drainage , prompt antimicrobial treatment and timely treatment of pulmonary exacerbations ○ infection control ○ rapid identification and treatment of CF related complications

Patient Information

Cystic Fibrosis Foundation US-based charity founded in 1955 an important patient information resource on CF https://www.cff.org/intro-cf/about-cystic-fibrosis

CF Trust UK based charity https://www.cysticfibrosis.org.uk/what-is-cystic-fibrosis

Quick printable leaflet 20 facts about CF from American Thoracic Society https://www.thoracic.org/patients/patient-resources/resources/cystic-fibrosis-facts.pdf

British Lung Foundation on CF excellent explanation https://www.blf.org.uk/support-for-you/cystic-fibrosis

European Lung Org providing information about CF in multiple languages https://europeanlung.org/en/information-hub/lung-conditions/cystic-fibrosis/

Dealing with exacerbations from Cystic Firosis. com https://cystic-fibrosis.com/treatment/exacerbation

Vaccination in CF patients – valuable information from Cystic Fibrosis database https://www.cfdb.eu/en/topics/detail/code/142

References

  1. Yu E, Sharma S. Cystic Fibrosis. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493206/
  2. Naehrig, Susanne et al. “Cystic Fibrosis.” Deutsches Arzteblatt international vol. 114,33-34 (2017): 564-574. doi:10.3238/arztebl.2017.0564
  3. Brown, Sheena D. PhD, MSCR; White, Rachel MMSc, PA-C; Tobin, Phil DHSc, PA-C Keep them breathing, Journal of the American Academy of Physician Assistants: May 2017 – Volume 30 – Issue 5 – p 23-27 doi: 10.1097/01.JAA.0000515540.36581.92
  4. Ratjen, F., Bell, S., Rowe, S. et al. Cystic fibrosis. Nat Rev Dis Primers 1, 15010 (2015). https://doi.org/10.1038/nrdp.2015.10 ( Abstract )
  5. Villanueva GMarceniuk GMurphy M SWalshaw MCosulich RDiagnosis and management of cystic fibrosis: summary of NICE guidance doi:10.1136/bmj.j4574
  6. Overview | Cystic fibrosis: diagnosis and management | Guidance | NICE
  7. Cystic fibrosis – The Lancet ( Abstract )
  8. Sanders, Don B, and Aliza K Fink. “Background and Epidemiology.” Pediatric clinics of North America vol. 63,4 (2016): 567-84. doi:10.1016/j.pcl.2016.04.001
  9. *Cystic Fibrosis Trust Standards of care.pdf

 

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