Primary and secondary dyslipidaemias

Question 1

What 3 things is cardiovascular risk associated with?

Answer 1

Smoking, Hypertension and Hypercholesterolaemia

When risk factors co-exist the effect is often exponential

Question 2

What are the modifiable risk factors for having a heart attack or stroke?

Answer 2

Question 3

What are the un-modifiable risk factors for having a heart attack or stroke?

Answer 3

Question 4

What is QRISK 3?

Answer 4

• 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

Question 5

What does a QRISK3 score over 10 indicate?

Answer 5

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

Question 6

What is the NICE lipid modification guideline?

Answer 6

-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

Question 8

What is the primary prevention in the NICE lipid modification guideline 2016?

Answer 8

Question 9

What is the secondary prevention in the NICE lipid modification guideline 2016?

Answer 9

Question 10

Why treat lipid disorders?

Answer 10

• 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).

Question 11

What is LDLR?

Answer 11

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.

Question 12

Where is LDLR found?

Answer 12

Present on most cells but the majority on the liver.

Question 13

What do LDLR on hepatocytes do?

Answer 13

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.

Question 14

What are statins?

Answer 14

HMGCoA reductase Inhibitor

Question 15

What is ezetimibe?

Answer 15

Is a potent and selective inhibitor of absorption of cholesterol in the small bowel.

Question 16

How does ezetemibe work?

Answer 16

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)

Question 17

•Ezetimibe at 10 mg/day has been shown to induce an about _________% reduction in LDLC and ________% reduction in TG.

Answer 17

20%

8%

Question 18

What do PCSK9 inhibitors do?

Answer 18

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.

Question 20

How are PCSK9 inhibitors administered?

Answer 20

Administered bimonthly subcutaneous injections

Question 21

What are PCSK9 inhibitors?

Answer 21

Monoclonal antibodies to PCSK9

Question 22

What observation led to the delevlopment of PCSK9 inhibitors?

Answer 22

Developed after the observation that naturally occurring loss-of-function polymorphisms resulting in PCSK9 under expression led to lower LDLC levels.

Question 23

What 3 patterns do lipid profiles tend to form?

Answer 23

• Hypercholesterolaemia (raised TC and LDLC)
• Mixed hyperlipidaemia (raised TC and LDLC with raised TG, often low HDLC)
• Hypertriglyceridaemia

Question 24

Where is the hypercholesterolaemia pattern usually seen?

Answer 24

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).

Question 25

Where is the mixed hyperlipidaemia pattern normally seen?

Answer 25

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.

Question 26

Where is hypertriglyceridaemia usually seen?

Answer 26

Pure hypertriglyceridaemia is less common, may be familial and (unlike most other dyslipidaemias), tending to cause harm through acute pancreatitis.

Question 27

What is lipoprotein A?

Answer 27

Human Lipoprotein (a) or Lp(a) is a macromolecular complex in plasma.

LDL-like +ApoB+ Apo(a)

Question 28

Where is lipoprotein A made?

Answer 28

•Lipoprotein made by the liver.

Question 29

What is high levels of lipoprotein A assocatiated with?

Answer 29

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).

Question 30

What is Apo(a)

Answer 30

• is a glycoprotein, similar to plasminogen 300-800kDa
• Physiological function unclear
• Pathological function: atherosclerosis and thrombosis formation

Question 31

In which patients would you measure lipoprotein A levels?

Answer 31

• 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

Question 32

What are the treatments for lowering lipoprotein A?

Answer 32

• 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%.

Question 33

What is Familial Hypercholesterolaemia(FH)?

Answer 33

Common (1:200-250 ) genetic disorder characterised by increased Serum LDL-Cholesterol and early CVD.

Autosomal dominant

Question 34

What mutation causes Familial Hypercholesterolaemia(FH)?

Answer 34

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)

Question 35

What is the typical age range for first cardiovascular event in Familial Hypercholesterolaemia(FH)?

Question 36

What are the clinical presentations of Familial Hypercholesterolaemia(FH)?

Answer 36

• Tendon xanthoma
• Corneal arcus
• Deposits of cholesterol on skin

Question 37

What is the treatment for FH?

Answer 37

• 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.