Hyperlipidaemia

Notes

Overview

Hyperlipidaemia is an umbrella term which encompasses genetic and acquired disorders that raise lipid levels within the blood. Hyperlipidaemia does not independently cause clinical symptoms, rather can lead to other disorders that can manifest in possible life-threatening presentations. Most notably, hyperlipidaemia causes atherosclerosis which may lead to cardiovascular, cerebrovascular, and peripheral vascular disease.¹

Objectively, hyperlipidaemia can be defined as the following levels being in the 90^th percentile or greater in comparison to the general population:

Low density lipoproteins (LDL)
Total cholesterol
Triglycerides

Or if the high-density lipoproteins (HDL) levels are less than the 10^th percentile in comparison to the general population.

Definition

Hyperlipidaemia: elevated levels of lipids in the blood, including cholesterol and/or triglycerides. Increases cardiovascular risk. (In Australia total cholesterol > 5.5 mmol/L or triglycerides > 2.0 mmol/L.)
Hypertriglyceridaemia: Triglyceride levels in the blood are raised, due to genetic, metabolic, or lifestyle factors. It increases the risk of pancreatitis and may contribute to cardiovascular disease. (In Australia fasting triglycerides > 2.0mmol/L.)
Hypercholesterolaemia: elevated level of cholesterol in the blood, typically referring to high low-density lipoprotein (LDL) cholesterol, which is a major risk factor for atherosclerotic cardiovascular disease. (In Australia, total cholesterol > 5.5 mmol/L or LDL-C > 3.5 mmol/L.)
Lipoproteins: spherical particle made up of lipids (fats) and proteins (apolipoproteins) that transports cholesterol, triglycerides, and other fats through the bloodstream.

Physiology

Triglycerides

Triglycerides are the main form of stored energy in the body. They consist of three fatty acids attached to a glycerol backbone. Triglycerides are packaged into chylomicrons (from the intestine) and VLDL (from the liver) for transport through the blood. They are broken down by lipoprotein lipase at tissues to release fatty acids for energy use or storage.

Cholesterol

Cholesterol is a key structural component of cell membranes, providing fluidity and stability. It is also the precursor for steroid hormones, vitamin D, and bile acids. Cholesterol in the blood comes from dietary intake and hepatic synthesis. It is transported mainly in LDL (delivers cholesterol to tissues) and HDL (returns excess cholesterol to the liver for excretion).

Lipid Metabolism

After a meal, chylomicrons carry dietary triglycerides and cholesterol through the lymphatics into the bloodstream. The liver produces VLDL to export triglycerides. LDL arises from VLDL remnants and delivers cholesterol to tissues. HDL collects excess cholesterol for return to the liver (reverse cholesterol transport).

Classifications

Primary (genetic) hyperlipidaemia
Inherited disorders of lipid metabolism (e.g. familial hypercholesterolaemia, familial combined hyperlipidaemia)

Primary Hyperlipidaemia will be covered in more detail separately

Secondary hyperlipidaemia
Due to other conditions or risk factors, including:
– Diabetes mellitus
– Hypothyroidism
– Nephrotic syndrome
– Excess alcohol intake
– Obesity
– Certain medications (e.g. corticosteroids, antiretrovirals)

Think

Familial hyperlipidaemia presents early with high LDL-C (>5 mmol/L), premature cardiovascular disease, tendon xanthomas, corneal arcus in young patients, or a strong family history.

Aetiology and Risk Factors

Aetiology

Primary (genetic hyperlipidaemia)
Secondary hyperlipidaemia

Risk factors

Obesity
Consumption of high fatty foods
Family history of high cholesterol or premature cardiovascular disease
Lack of physical activity
Smoking (lowers HDL, promotes atherogenesis)
Age: as you age, the risk of high cholesterol goes up

Pathophysiology

Increased levels of lipids in the blood make a person at increased risk for atherosclerosis. Atherosclerosis develops through the continuous growth of lipid lesions within the arterial wall (intimal layer) which results in chronic inflammation. The development of atherosclerosis is like so:

LDL uptake and oxidisation

High circulating LDL increased entry of LDL into intima accumulation of LDL
LDL oxidised taken up by receptors results in foam cell formation modification of LDL induces endothelial dysfunction

Endothelial dysfunction

Numerous factors can induce endothelial dysfunction including:

LDL, smoking, diabetes, hypertension
Results in deficiencies in nitrous oxide (NO) and prostacyclin and increase in cell adhesion molecules (CAMs)

Adhesion of lymphocytes and monocytes

The above step increases the adhesion of monocytes and lymphocytes
Monocytes then mature into macrophages

Foam cell formation fatty streak formation

Macrophages phagocytose modified lipids foam cells fatty streak lesions

Fatty streak early fibroatheroma formation

After foam cell formation, smooth muscle cells (SMCs) migrate into the tunica intima from tunica media under control of PDGF, IGF, T-helper cells and lymphocytes in the area form fibrous plaque

Late fibroatheroma formation

Overtime, more lipids accumulate plaque enlarges may partially/completely occlude the vessel lumen
Late plaques have low SMCs, high lipids and macrophages thin fibrous cap, large plaque

Complications of hyperlipidaemia

As a result of plaque formation and growth, blood flow to tissues decreases resulting in hypoperfusion to various tissues including the heart, peripheries, and brain.
Plaque rupture: if plaques have thin fibrous caps, or external factors such as high blood pressure are involved, plaques can rupture and clot, causing a sudden occlusion leading to life-threatening conditions such as:
- myocardial infarction
- stroke
- acute limb ischemia.

Clinical Manifestations

Hyperlipidaemia

Xanthoma (Tendon xanthomas suggest familial hypercholesterolaemia)
Xanthelasma
Corneal arcus (grey-white ring at the corneal margin, especially if <50 years old)
Eruptive xanthomas (small yellow papules on extensor surfaces, buttocks — often seen with very high triglycerides)
Lipemia retinalis (creamy appearance of retinal vessels with markedly raised triglycerides)
high blood pressure: hyperlipidaemia can contribute to the development of hypertension

Diagnosis

Management of hyperlipidaemia is determined through the cardiovascular risk calculator, taking into consideration investigations as well as pertinent points of their lifestyle and demographic⁹.

This calculator can be found here: https://www.cvdcheck.org.au/calculator

Desirable parameters in Australia

Total cholesterol: 3.9 – 5.5 mmol/L
HDL: 0.9 – 2.1 mmol/L
LDL: 1.7 – 3.5 mmol/L
Triglycerides: 0.5 – 1.7 mmol/L

Remember

Non-fasting samples can falsely elevate triglycerides.

Remember

Elevated triglycerides >10 mmol/L → risk of pancreatitis.

Remember

Exclude secondary causes before starting long-term lipid therapy: Check TSH, fasting glucose/HbA1c, liver function, renal function, and urine ACR (albumin:creatinine ratio).

Treatment

Lifestyle improvements

exercise
dietary changes: reduced intake of saturated fats and cholesterol
smoking cessation

Medications

Statins (first-line) lower sLDL-C by 25–55%, depending on type and dose:
- Low intensity: simvastatin 5–10 mg, pravastatin 10–20 mg
- Moderate intensity: atorvastatin 10–20 mg, rosuvastatin 5–10 mg
- High intensity (>50% reduction): atorvastatin 40–80 mg, rosuvastatin 20–40 mg
Ezetimibe
Bile acid binding resins
PCSK9 inhibitors

Side note

Other medications that may be suggested to lower lipid levels: Fibrates, Niacin, Omega-3 fatty acid supplement.

Side note

Combination therapy (statin + ezetimibe ± PCSK9 inhibitor) may lower LDL-C by >80%.

Target

LDL-C <2 mmol/L for primary prevention
LDL-C <1.8 mmol/L for secondary prevention

Complications and Prognosis

Hypertension
Recurrent pancreatitis
Cardiac complication
- ^·Stable angina
- ^·Acute coronary syndrome
Neurologic complication
- ^·Syncope
- ^·TIA/Stroke
Peripheral arterial disease
- · acute limb ischemia
- · Intermittent claudication
- ^·Subclavian steal syndrome

References

Hill MF, Bordoni B. Hyperlipidemia.. Treasure Island (FL): StatPearls Publishing; 2023.
Centers for Disease Control and Prevention. Risk Factors for High Cholesterol [Internet}. United States of America: US Department of Health and Human Services; 2024 [cited 2025 July 6]. Available from: https://www.cdc.gov/cholesterol/risk-factors/index.html
Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, Benito-Vicente A, Martín C. Pathophysiology of atherosclerosis. Int J Mol Sci. 2022;23(6):3346. doi: 10.3390/ijms23063346.
American Heart Association. Ischemic heart disease and silent ischemia. About Heart Attacks. December 11, 2024. Accessed July 4, 2025. https://www.heart.org/en/health-topics/heart-attack/about-heart-attacks/silent-ischemia-and-ischemic-heart-disease
Lee RHC, Lee MHH, Wu CYC, Couto E Silva A, Possoit HE, Hsieh TH, Minagar A, Lin HW. Cerebral ischemia and neuroregeneration. Neural Regen Res. 2018;13(3):373-385. doi: 10.4103/1673-5374.228711.
Cassar K. Intermittent claudication. BMJ. 2006;333(7576):1002-5. doi: 10.1136/bmj.39001
Foundation to Advance Vascular Cures. Warning signs of CLTI. Chronic Limb-threatening Ischemia. Accessed July 4, 2025. https://www.vascularcures.org/chronic-limb-threatening-ischemia
Emergency Care Institute. Acute limb ischemia. Agency of Clinical Innovation. 2024. Accessed July 3, 2025. https://aci.health.nsw.gov.au/networks/eci/clinical/tools/acute-limb-ischaemia
Stocks N, Allan J, Mansfield PR. Management of hyperlipidaemia. Australian Family Physician. 2005;34(6): 447-452.
eTG complete [Internet]. Melbourne (AU): Therapeutic Guidelines Ltd; 2025. Lipid Modification [updated 2017 Feb; cited 2025 Jul 6]. Available from: https://app-tg-org-au.ap1.proxy.openathens.net/viewTopic?etgAccess=true&guidelinePage=Cardiovascular&topicfile=lipid-modification&guidelinename=Cardiovascular&sectionId=toc_d1e263#toc_d1e256