Hyperlipidaemia

Question 1

Question 2

Describe briefly the exogenous and endogenous pathways for lipid metabolism [5]

Answer 2

Exogenous:
- Dietary lipids broken down by pancreatic lipase into FFA monoacylglycerol

• Broken down by bile into micelles and taken up by enterocytes where they form triglycerides
• In enterocytes, triglycerides and cholesterol are packaged into chylomicrons
• Apo-B-48 is core molecule of chylomicron
• Chylomicrons are absorbed through lymphatic system and delivered by systemic circulation via lymphatic duct

Question 3

Apolipoprotein [] on the chylomicron that is able to bind to LDL receptors and be uptake by hepatocytes.

A
B
C
D
E

Answer 3

Apolipoprotein [] on the chylomicron that is able to bind to LDL receptors and be uptake by hepatocytes.

A
B
C
D
E

Question 4

Describe briefly the endogenous and endogenous pathways for lipid metabolism [5]

Answer 4

• In the liver, cholesterol may be synthesised de novo by the conversion of acetyl coenzyme A into mevalonate and then cholesterol by the action of HMG-CoA reductase
• Cholesterol and triglycerides are formed into very-low-density lipoproteins (VLDL).
• VLDLs are broken down by lipases in circulation into intermediate density lipoproteins; these are metabolised by liver or converted to LDLs
• The majority of LDLs are cleared from the circulation by LDL receptors found on hepatocytes. The remainder is **cleared by peripheral tissue. **

Question 5

very-low-density lipoproteins (VLDL) have which core structural protein? [1]

Answer 5

Apo B-100

Question 6

State three signs that indicate hyperlipidaemia [3]

Answer 6

Corneal arcus: white or grey opaque ring in the corneal margin

Tendon xanthoma: hard, non-tender nodular enlargement of tendons. Common on knuckles and achilles

Xanthelasma: yellow plaques on the upper eyelids

Question 7

What are the arrows pointing to? [1]

Answer 7

Tendon xanthoma

Question 8

What is the name for this sign of hyperlipidaemia? [1]

Answer 8

Corneal arcus

Question 9

What initial investigations would you use for hyperlipidaemia? [5]

Answer 9

• Non-fasting full lipid profile
• HbA1c
• Assess for secondary causes of hyperlipidaemia (e.g. alcohol, smoking, CKD)
• Assess risk for anti-lipid therapy (includes baseline renal, thyroid, and liver profiles +/- CK if unexplained muscle pain)
• Determine any contraindications/drug interactions
• If non-fasting TG > 4.5 mmol/L arrange a fasting sample

Question 10

In which cases should you suspect familial hypercholesterolaemia? [2]

Answer 10

• Total cholesterol > 7.5 mmol/L, AND/OR
• Personal or family history (first-degree relative) of premature coronary artery disease (a cardiovascular event < 60 years)

Question 11

A specialist referral to a lipid clinic should be made regardless of family history if:

Clinical diagnosis of [], OR
Total cholesterol > [] mmol/L, AND/OR
LDL cholesterol > [] mmol/L, AND/OR
Non-HDL cholesterol > [] mmol/L OR
Fasting triglycerides > [] mmol/L

Answer 11

Clinical diagnosis of FH, OR
Total cholesterol > 9.0 mmol/L, AND/OR
LDL cholesterol > 6.5 mmol/L, AND/OR
Non-HDL cholesterol > 7.5 mmol/L OR
Fasting triglycerides > 10 mmol/L

Question 12

Statins inhibit which enzyme? [1]

What is the MoA? [2]

Answer 12

Statins inhibit HMG-CoA reductase

It converts HMG-CoA into mevalonic acid, which is a cholesterol precursor.

The reduction in hepatic cholesterol production leads to upregulation of hepatic LDL receptors that reduce circulating levels of LDL in the blood.

Question 13

When should patients take statins? [1]
Why? [1]

Answer 13

at night as HMG Co-A reductase is most active at night

Question 14

hether a statin is high-intensity depends on the type and dose. For example, [] 20 mg PO once daily is a high-intensity treatment, whereas [] 10 mg PO once daily is a low-intensity treatment.

Answer 14

hether a statin is high-intensity depends on the type and dose. For example, atorvastatin 20 mg PO once daily is a high-intensity treatment, whereas simvastatin 10 mg PO once daily is a low-intensity treatment.

Question 15

Which drug class are commonly used alongside statins to reduce serum lipid levels (if statins have not work by themselves) [1]

Name an example

Answer 15

Fibrates are commonly used in combination with statins where there has been an inadequate fall in serum lipids.
- E.g. ezetimibe

Question 16

Describe the MoA of fibrates [5]

Answer 16

• Reduce triglyceride synthesis in the liver
• Increase removal of LDL particles
• Induce lipoprotein lipase gene transcription
• Stimulate cellular fatty acid uptake
• Increase HDL production by inducing apo-AI and apo-AII gene transcription

Question 17

What is the MoA of Bempedoic acid? [1]

What is the drug class? [1]

Answer 17

adenosine triphosphate citrate lyase (ACL) inhibitor. It works by inhibiting the synthesis of cholesterol in the liver, which lowers LDL-C.

Question 18

What type of drug are the following? [1]

Alirocumab: monoclonal antibody
Evolocumab: monoclonal antibody
Inclisiran: small interfering mRNA

Answer 18

PCSK9 inhibitors

Question 19

Name three PCSK9 inhibitors that can reduce lipid levels [3]

Answer 19

Alirocumab: monoclonal antibody
Evolocumab: monoclonal antibody
Inclisiran: small interfering mRNA

Question 20

Describe the MoA of PCSK9 inhibitors

Question 21

What are the indications for statins use? [4]

Answer 21

Ages ≤84 and QRISK ≥10% over the next ten years (if ≥85 years consider comorbidities, frailty, life expectancy)

Type 2 diabetes mellitus and QRISK ≥10% over the next ten years

Type 1 diabetes mellitus and additional risk (Age > 40, diabetes > 10 years, other CVD risk factors, established nephropathy): Can be considered in all patients with Type 1 diabetes mellitus

Patients with CKD (eGFR < 60 mL/min/1.73m2 and/or albuminuria)

Question 22

Following initiation of a statin, patients should have a full lipid profile repeated at 3 months. The aim is to achieve a reduction in non-HDL cholesterol by > []% from baseline (targets are higher in familial hyperlipidaemia).

Answer 22

Following initiation of a statin, patients should have a full lipid profile repeated at 3 months. The aim is to achieve a reduction in non-HDL cholesterol by > 40% from baseline (targets are higher in familial hyperlipidaemia).

Question 23

What is the first line treatment (and dose) for hyperlipidaemia [1]

Answer 23

If lifestyle factors are ineffective or inappropriate then statin therapy with atorvastatin 20 mg PO once at night should be advised (this is a high-intensity statin regimen).

Question 24

State three complications of statin use [3]

Answer 24

Myopathy
Liver impairment
? Intracerebral haemorrhage

Question 25

FH is one of the most common autosomal dominant genetic disorders. A mutation may be identified in one of which three keys genes? [3]

Answer 25

Low-density lipoprotein receptor (LDLR) gene: also referred to as the ApoB/E receptor - most common

Proprotein convertase subtilisin kexin 9 (PCSK9) gene

Apolipoprotein B gene

Question 26

Describe the treatment regime for FH [6]

Answer 26

• High-intensity statin therapy
• Ezetimibe: alone in those unable to have statins or in combination
• PCSK9 inhibitors (e.g. alirocumab)

A variety of additional options are usually restricted to patients with homozygous FH and include:

• Evinacumab (new therapy for homozygous FH)
• Lomitapide (inhibits microsomal triglyceride transfer protein)
• Other therapies (e.g. aphesis, liver transplantation)