Pathophysiology
Cystic fibrosis is caused by a mutation in the gene encoding which structure? What is the normal function of this structure?
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) transporter.
An ATP-binding cassette transporter involved in chloride and bicarbonate secretion.
Name three clinical features of cystic fibrosis.
Persistant productive cough.
Shortness of breath on exertion (SOBOE).
Salty sweat.
Wheezing.
Frequent respiratory infections.
Tiredness, lethargy.
Failure to thrive.
Poor appetite.
Steatorrhea.
Flatulance and bloating
Abdominal pain
What mode of inheritance does Cystic Fibrosis follow.
Autosomal recessive.
Name three non-pharmacological treatments used to manage/treat cystic fibrosis.
Breathing support (oxygen therapy, pulmonary rehabilitation, ventilator support, ECMO), manual chest physical therapy, therapy vests, transplantation (lung, liver), sinus surgery, bowel surgery, gene therapy.
What is duty of care?
A registered medical practitioner has an obligation to adhere to a standard of reasonable care to patients in the confines of a patient-doctor relationship. Duty of care is both an ethical and a legal concept.
What second messenger is responsible for regulating CFTR chloride secretion?
cyclic AMP (cAMP).
What term refers to damage to the respiratory passages leading to an inability to effectively clear the airways.
Bronchiectasis.
Explain the hypothesis for the prevalence of the cystic fibrosis gene.
Heterozygote advantage - carriers are less susceptible to cholera like infectious diseases which involve massive chloride loss via intestinal and pulmonary secretions.
What is the mechanism of action of Ivacaftor. What form of Cystic Fibrosis is it most useful in managing.
Binds to CFTR channels in the membrane to induce non-conventional gating. Increases chloride secretion and reduces excessive sodium and water reabsorption.
Requires the protein to be present in the membrane so most effective for class III.
How do you assess capacity related to medical or dental treatment?
An individual must be able to understand, retain, weigh up and communicate the information and consequences of their decision.
Explain the mechanism by which defects in the CFTR channel cause thickened mucous.
Decreased secretion of chloride retains negative charge inside the cell. To maintain electrical neutrality, sodium is pumped into the cell via ENaC (epithelial sodium channels). This increases the osmolarity of the cell, causing movement of water into the cell. This manifests as thickened mucous secretions.
What are some extrarespiratory complications of cystic fibrosis?
Pancreatic insufficiency.
Biliary cirrhosis.
Portal hypertension and liver cirrhosis.
Distal intestinal obstruction.
Malabsorption.
Infertility.
Osteoporosis and osteopaenia.
Hyponatraemic dehydration.
What is the physiological basis of the sweat test for diagnosing cystic fibrosis.
Increased chloride retention leads to sodium and water absorption into the cell. This creates a more highly concentrated sweat product than normal which can be detected by the sweat test.
What is triple therapy in the context of cystic fibrosis.
Three pharmacological drugs: Ivacaftor, Elexacaftor and Tezacaftor.
Elexacaftor and tezecaftor bind to faulty CFTR to assist in proper protein folding and shuttling to the membrane. Ivacaftor then increases Cl secretion.
Explain the concept of the therapeutic alliance.
A collaborative relationship that exists between the medical professional and the patient with the aim of treatment of therapy. Is built on a backbone of mutual knowledge, trust, loyalty and regard.
Why are individuals with cystic fibrosis more prone to respiratory infections?
Thickened mucous creates an inflammatory environment which results in neutrophil infiltration. Chronic inflammatory conditions damage the respiratory passages, damaging epithelial integrity and cilia, making the airways prone to infection. Infectious microorganisms become trapped in the thick mucous. Mucocilliary clearance is ineffective, so pathogens can more easily enter the respiratory tract and cause disease.
An individual with cystic fibrosis is experiencing fatigue, weight loss, polyphagia, polydypsia and polyuria. Explain why individuals with cystic fibrosis are prone to experiencing these symptoms.
Blockage of pancreatic ducts causes inflammation and fibrosis of the pancreatic tissue. Leads to insulin deficiency and CF-related diabetes. Treatment differs in that a high caloric diet to maintain body weight is recommended as well as supplementation of vitamin and mineral deficits.
Class II cystic fibrosis is most commonly associated with which mutation?
∆F508.
Why is pancreatic enzyme replacement therapy often used in the management of cystic fibrosis.
Obstruction of exocrine ducts in the pancreas by mucus causes pancreatic insufficiency. Specifically, decreased lipase and protease exocrine secretions into the duodenum which can result in malabsorption and failure to thrive if not managed by pancreatic enzyme replacement therapy.
Define patient autonomy.
The right of the competent patient, acting of their own free will, to make informed decisions as to their own medical care.
What are the classes of cystic fibrosis? How do they differ?
Class I: no CFTR synthesis (truncated mRNA). Severe disease.
Class II: no maturation of CFTR (degradation by proteases in ER). Severe disease.
Class III: processed protein is inserted into the membrane but cannot conduct ions. Severe disease.
Class IV: mature protein is normally activated but chloride conductance is diminished. Milder disease.
Class V: decreased functional CFTR abundance. Milder disease.
Class VI: decreased protein stability. Variable disease severity.
Explain why individuals with cystic fibrosis are prone to bleeding and bone fractures.
Vitamin K is a fat soluble vitamin which is vital in the clotting cascade and in formation of bones. Pancreatic insufficiency and biliary obstruction as a result of cystic fibrosis leads to malabsorption, particularly of fat soluble vitamins which require pancreatic lipase and bile salts to be broken down and absorbed properly. As a result this can lead to vitamin K deficiency, increasing the risk of bleeding and bone fractures.
What is the three required pieces of evidence for CFTR diagnosis.
1. Elevated sweat chloride on two occasions.
2. Two disease causing CFTR mutations.
3. Abnormal nasal potential difference.
Explain the molecular basis of gene therapy for cystic fibrosis.
Cells are removed from a patient.
A virus is altered such that it carries an insertion of a functional CFTR gene. Possible viral vectors include retrovirus and adenovirus.
The altered virus is mixed with the patient cells.
Patient cells become transgenic.
The cells are injected back into the patient, introducing functional copies of the defective gene.
What are the requirements of consent and refusal of medical treatment.
In order to be valid, consent and the decision to refuse treatment must be given freely and voluntarily, by a person with capacity, after a weighing up of information, associated risks, benefits and alternatives and must be specific to the treatment which has been recommended.