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.

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)

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

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

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

1. Hill MF, Bordoni B. Hyperlipidemia.. Treasure Island (FL): StatPearls Publishing; 2023.
2. 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
3. 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.
4. 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
5. 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. 
6. Cassar K. Intermittent claudication. BMJ. 2006;333(7576):1002-5. doi: 10.1136/bmj.39001
7. 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
8. 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
9. Stocks N, Allan J, Mansfield PR. Management of hyperlipidaemia. Australian Family Physician. 2005;34(6): 447-452.
10. 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