Primary and secondary dyslipidaemias Flashcards
What 3 things is cardiovascular risk associated with?
Smoking, Hypertension and Hypercholesterolaemia
When risk factors co-exist the effect is often exponential
What are the modifiable risk factors for having a heart attack or stroke?
What are the un-modifiable risk factors for having a heart attack or stroke?
What is QRISK 3?
- QRISK3 takes into account many of the traditional risk factors (eg, age, sex, cholesterol-high density lipoprotein ratio, blood pressure, diabetes and smoking status)
- Plus additional risk factors, such as ethnicity, deprivation score, blood pressure treatment, family history of CVD, renal failure, body mass index, migraine, Rheumatoid arthritis, atypical antipsychotics, severe mental illness, SLE, steroids
What does a QRISK3 score over 10 indicate?
A QRISK3 over 10 (10% risk of CVD event over the next ten years) indicates that primary prevention with lipid lowering therapy (such as statins) should be considered
What is the NICE lipid modification guideline?
-Measure a full lipid profile:
total cholesterol (TC), high density lipoprotein cholesterol(HDL), non-HDL-cholesterol , and triglyceride(TG) before starting lipid modification therapy
-Exclude possible common secondary causes of dyslipidaemia (such as excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease, and nephrotic syndrome) before referring for specialist review
•A fasting sample is not needed
What is the primary prevention in the NICE lipid modification guideline 2016?
What is the secondary prevention in the NICE lipid modification guideline 2016?
Why treat lipid disorders?
- 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).
What is LDLR?
LDLR is a cell-surface receptor(encoded by LDLR gene) that recognizes ApoB-100 (apolipoprotein B-100) which is embedded in the phospholipid outer layer of LDL particles.
Where is LDLR found?
Present on most cells but the majority on the liver.
What do LDLR on hepatocytes do?
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 are statins?
HMGCoA reductase Inhibitor
What is ezetimibe?
Is a potent and selective inhibitor of absorption of cholesterol in the small bowel.
How does ezetemibe work?
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 (Niemann-Pick C1-Like 1 -NPC1L1)
•Ezetimibe at 10 mg/day has been shown to induce an about _________% reduction in LDLC and ________% reduction in TG.
20%
8%
What do PCSK9 inhibitors do?
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.
How are PCSK9 inhibitors administered?
Administered bimonthly subcutaneous injections
What are PCSK9 inhibitors?
Monoclonal antibodies to PCSK9
What observation led to the delevlopment of PCSK9 inhibitors?
Developed after the observation that naturally occurring loss-of-function polymorphisms resulting in PCSK9 under expression led to lower LDLC levels.
What 3 patterns do lipid profiles tend to form?
- Hypercholesterolaemia (raised TC and LDLC)
- Mixed hyperlipidaemia (raised TC and LDLC with raised TG, often low HDLC)
- Hypertriglyceridaemia
Where is the hypercholesterolaemia pattern usually seen?
Such a pattern is typically seen in familial hypercholesterolaemia (FH) where total cholesterol levels may range between 7 and 20 mmol/L (average 9 mmol/L) in heterozygotes but are even higher in the rare homozygotes (15–30 mmol/L).
Where is the mixed hyperlipidaemia pattern normally 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.
Where is hypertriglyceridaemia usually seen?
Pure hypertriglyceridaemia is less common, may be familial and (unlike most other dyslipidaemias), tending to cause harm through acute pancreatitis.
What is lipoprotein A?
Human Lipoprotein (a) or Lp(a) is a macromolecular complex in plasma.
LDL-like +ApoB+ Apo(a)
Where is lipoprotein A made?
•Lipoprotein made by the liver.
What is high levels of lipoprotein A assocatiated with?
Several observational studies, including meta-analyses and genetic studies have suggested an association between elevated Lp(a) concentrations and myocardial infarction, stroke, and aortic valve stenosis (genome-wide association studies).
What is Apo(a)
- is a glycoprotein, similar to plasminogen 300-800kDa
- Physiological function unclear
- Pathological function: atherosclerosis and thrombosis formation
In which patients would you measure lipoprotein A levels?
- 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
What are the treatments for lowering lipoprotein A?
- Lifestyle changes-controlled trials show marginal effects so far or lacking evidence
- Approved and investigational drugs are present that lower Lp(a)
- 3 effective therapies on continued trial:
- Lipid apheresis - 80-90% reduction in major cardiovascular event rates
- PCSK9i - reduce levels by 25%. ARR higher when Lp(a)>500mg/L, ?Mechanism
- 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 Familial Hypercholesterolaemia(FH)?
Common (1:200-250 ) genetic disorder characterised by increased Serum LDL-Cholesterol and early CVD.
Autosomal dominant
What mutation causes Familial Hypercholesterolaemia(FH)?
Mutations in the LDLR gene that encodes the LDLR 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)
What is the typical age range for first cardiovascular event in Familial Hypercholesterolaemia(FH)?
What are the clinical presentations of Familial Hypercholesterolaemia(FH)?
- Tendon xanthoma
- Corneal arcus
- Deposits of cholesterol on skin
What is the 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.
