In patients with Familial Hypercholesterolemia (FH), the liver is unable to effectively process and breakdown low-density lipoprotein cholesterol (LDL-C) in a controlled manner. As a result, LDL-C remains elevated in the plasma for extended periods. This prolonged exposure increases the likelihood of LDL cholesterol particles to undergo a process known as oxidation. These excess oxidized LDL particles eventually accumulate in the innermost layers of arteries known as arterial intima. This subsequently trigger the formation of cholesterol-laden "foam cells," which are the hallmark of atherosclerotic plaque. The accumulation of these plaques in the arterial walls significantly raises the risk of clinical manifestations such as atherosclerotic cardiovascular disease (ACD), myocardial infarction (MI), and sudden death. Early intervention and management of elevated cholesterol levels are crucial in preventing the progression of atherosclerosis and reducing these life-threatening risks.

Primary Diagnostic Criteria for Familial Hypercholesterolemia (FH) in Adults:

• Elevated LDL Cholesterol Due to a strong personal history and/or family history of high cholesterol.
• Premature Cardiovascular Disease (CVD)
• Tendon Xanthoma and/or Corneal arcus Occurrence before the age of 45 in the individual or their first-degree relatives.

Before diagnosing familial hypercholesterolemia (FH), it is essential to exclude other secondary causes of hypercholesterolemia. The following table, adapted from ‘Integrated Guidane for Enhancing the Care of Patients with FH in Australia (2021), outlines the lifestyle factors, clinical conditions, and medications that may contribute to increased plasma LDL-C deposition.

LDL-C levels

Patients should undergo a complete fasting cholesterol profile blood test on two separate occasions to confirm elevated LDL cholesterol (LDL-C) levels. These tests should be conducted during periods of stable health, as they should not be performed during episodes of illness. Familial hypercholesterolemia (FH) should be considered in adults who have a total cholesterol level of 7.5 mmol/L or higher, or an LDL-C level of 5.0 mmol/L or higher, particularly when there is a personal or family history of premature cardiovascular disease (CVD).

Tendon xanthoma

Fatty deposit that accumulates at the heels and knuckles. Slow-growing, subcutaneous nodules that typically appear on the tendons over the knuckles or Achilles tendon. These lesions are caused by cholesterol buildup under the skin, but the skin colour remains normal. They are more commonly seen in HoFH are hardly seen in children with HeFH.

Xanthelasma palpebrarum

Also known as xanthelasma palpebrum, fatty deposit on the eyelids. Soft, yellow or yellow-orange macules, papules or plaques that develop around the inner corner of the upper eyelid, often symmetrically affecting both the upper and lower eyelids however not always. This condition is caused by excess cholesterol accumulation and can take several months to appear.

Corneal arcus

Also known as arcus senilis, fatty deposit that forms in the cornea of the eye. It is a condition where cholesterol deposits accumulate in the cornea, the clear front part of the eye. This results in a distinctive arc-shaped, opaque white or grey ring around the iris, the coloured part of the eye. It often appears on both eyes however sometimes it may only affect one eye.