Theme 3: Lecture 17 - Primary and secondary dyslipidaemias Flashcards
According to the Framingham heart study, what are the major CVD risk factors
- High blood pressure
- High blood cholesterol
- Smoking
- Obesity
- Diabetes
- Physical inactivity
Name 3 studies that investigate the risk factors for CVD
- Framingham heart study
- Cholesterol treatment trialists
- Copenhagen city heart study
What was the aim of the cholesterol treatment trialists study
conducting periodic meta-analyses of large-scale (≥1000 participants), long-term (≥2 years treatment duaration) unconfounded, randomized controlled trials of lipid intervention therapies
What were the findings of the cholesterol treatment trialists
- Reduction of LDL cholesterol using statin therapy substantially reduces the risk of major vascular events (major coronary events, strokes or the need for coronary revascularization) and vascular mortality
- Further reductions in LDL cholesterol with more intensive statin therapy produce further reductions in the incidence of major vascular events
Modifiable risk factors for CVD
- Smoking
- Obesity
- Sedimentary lifestyle
- Diabetes
- High cholesterol
- Hypertension
- Excess alcohol intake
Un-modifiable risk factors for CVD
- Age > 50
- Gender
- Genetic factors
- Pre-existing CVD
Name 2 risk calculator tools
- QRISK3
- NICE guidelines
What does a QRISK3 over 10 mean
- 10% risk of CVD event over the next ten years
- Primary prevention with lipid lowering therapy (such as statins) should be considered
Why treat lipid disorders which are often asymptomatic
- To reduce the atherosclerotic process and the incidence of clinical vascular disease.
- To prevent pancreatitis which is associated with grossly increased serum triglyceride (>10mmol/L, usually >20mmol/L).
Describe LDLRs
- LDLR is a cell-surface receptor (encoded by LDLR gene) that recognizes ApoB-100 (apolipoproteinB-100) which is embedded in the phospholipid outer layer of LDL particles.
- Present on most cells but the majority on the liver.
- LDLR on hepatocytes binds to LDL particles and remove them from the circulation. The LDLR then return to the cell surface to repeat this process.
What is the first line treatment for hypercholesterolaemia
Statins
Describe Ezetimibe
- Is a potent and selective inhibitor of absorption of cholesterol in the small bowel.
- The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter
What is the membrane transporter that Ezetimibe inhibits
Niemann-Pick C1-Like 1 (NPC1L1)
Describe PCSK9 inhibitors
PCSK9 functions as a binding protein; it is expressed primarily in hepatocytes and after secretion binds to the LDLR and promotes their degradation. By blocking PCSK9, these drugs result in increased availability of LDLR to remove LDLC from the circulation.
What are the 3 main patterns of lipid profiles in lipoprotein abnormality
- Hypercholesterolaemia
- Mixed hyperlipidaemia
- Hypertriglyceridaemia
Describe the pattern of lipoprotein abnormality in hypercholesterolaemia
Raised TC (total cholesterol) and LDLC (LDL cholesterol)
Describe the pattern of lipoprotein abnormality in mixed hyperlipidaemia
Raised TC and LDLC with raised TG, often low HDLC
When is hypercholesterolaemia seen
typically seen in familial hypercholesterolaemia (FH)
When is mixed hyperlipidaemia seen
This pattern is often seen in patients with glucose intolerance and diabetes and arises from the increased production and reduced breakdown of triglyceride-rich lipoproteins
Describe hypertriglyceridaemia
Pure hypertriglyceridaemia is less common, may be familial and (unlike most other dyslipidaemias), tending to cause harm through acute pancreatitis.
What should TC (total cholesterol) be in a healthy adult
<5, ideal <4
What should TG be in a healthy adult
<1.7
What should HDLC (HDL cholesterol) be in a healthy adult
> 1
What should LDLC (LDL cholesterol) be in a healthy adult
<3, ideal <2
What should non HDL cholesterol be in a healthy adult
<2.8, or <2.5 if on statins
What is lipoprotein (a)
A macromolecular complex, similar to LDL but contains Apolipoprotein (a) as well as Apolipoprotein B
What does elevated lipoprotein(a) cause
it has been suggested that there is an association between elevated Lp(a) concentrations and myocardial infarction, stroke, and aortic valve stenosis
When would you consider measuring Lipoprotein(a)
- Intermediate or high risk of CVD(≥3% over 10 years of fatal CVD and or >10% over 10 years of fatal and non-fatal CVD)
- Subjects with premature CVD
- FH cases
- Fhx of premature CVD or raised LP(a)
- Recurrent CVD despite on statin treatment
Treatments for raised lipoprotein (a)
- Lipid apheresis
- PCSK9 inhibitors
- Antisense therapy (Small molecules directly binds to apo(a) mRNA in the nucleus of hepatocytes) - can reduce LP(a) levels by up to 90%.
What is lipid apheresis
LDL apheresis is a nonsurgical therapy that removes low-density lipoprotein (LDL) cholesterol from a patient’s blood. During LDL apheresis, the plasma portion of the blood, which contains cholesterol, is separated and run through a machine that removes the LDL
Describe Familial Hypercholesterolaemia
- Common (1:200-250 ) genetic disordercharacterised by increased Serum LDL-Cholesterol and earlyCVD.
- Autosomal dominant
- Mutations in theLDLRgene that encodes theLDLR protein which reduces its function.
- In a few cases (~ 3%) with the same clinical phenotype; it is either a mutation in ApoB which is the part of LDL that binds with the receptor, or a gain of function mutation in LDL receptor degradation (PCSK9).
Clinical presentation of FH
- Tendon xanthoma
- Corneal arcus
- Deposits of cholesterol derived from LDL resulting in bumps on the skin
What is tendon xanthoma
cholesterol deposits in tendons. They appear as slowly enlarging papules or subcutaneous nodules attached to tendons, ligaments, fascia and periosteum
What is corneal arcus
a deposit of cholesterol, phospholipids, and triglycerides in an “arc” on either the top or bottom side of the iris
Treatment for FH
- Low Saturated Fat Diet and exercise
- Statins
- Possible addition of cholesterol absorption inhibitor (ezetimibe)
- Rarely resins/surgery/LDL apheresis
- Anti–PCSK9
- Involve patient self help group, offer DNA testing and get the family tested.
