Lipid Disorders

Lipid disorders are a broad group of conditions characterised by abnormal circulating lipid and lipoprotein concentrations. They include:

• elevated low density lipoprotein cholesterol (the most extensively studied and clinically significant abnormality, given its well established, causal relationship with atherosclerotic cardiovascular disease)
• elevated triglycerides (relevant to cardiovascular risk and, at very high levels, to acute pancreatitis risk)
• reduced high density lipoprotein cholesterol
• specific inherited lipid disorders (most notably familial hypercholesterolaemia, which carries substantially elevated cardiovascular risk and needs specific recognition and intensive management)

The overarching approach centres on accurate cardiovascular risk assessment, incorporating lipid levels alongside other established risk factors. This guides targeted lipid lowering treatment, given the well established relationship between lipid lowering therapy and reduced cardiovascular event risk in appropriately selected patients.

Classification and pathophysiology

• Elevated low density lipoprotein cholesterol most commonly reflects genetic predisposition combined with lifestyle factors (diet, physical activity, body weight).
• Low density lipoprotein particles deposit within the arterial wall and drive the atherosclerotic process underlying coronary artery disease, stroke and peripheral arterial disease. Extensive epidemiological and interventional trial evidence now firmly establishes the causal relationship.
• Familial hypercholesterolaemia is an autosomal dominant condition, most commonly caused by mutations affecting the low density lipoprotein receptor. It produces markedly elevated low density lipoprotein cholesterol from birth, with substantially elevated lifetime cardiovascular risk.
• The less common homozygous form causes very early onset, aggressive atherosclerotic disease.
• Familial hypercholesterolaemia needs specific recognition and cascade family screening, given the implications for early, intensive treatment in confirmed cases and affected relatives.
• Elevated triglycerides reflect a combination of genetic factors, obesity, insulin resistance and type two diabetes, excess alcohol intake, and certain medications.
• Very significantly elevated triglyceride levels (generally above 10 mmol per litre) carry a specific, additional risk of acute pancreatitis. This is distinct from the more general cardiovascular risk association of moderate triglyceride elevation.
• Always consider secondary causes of dyslipidaemia, and address them where identified: hypothyroidism, nephrotic syndrome, chronic kidney disease, certain medications (including corticosteroids and certain antiretroviral agents), and excess alcohol intake.
• This is relevant to both accurate diagnosis and targeted management.

• The great majority of lipid disorders are entirely asymptomatic. They are identified through routine or targeted biochemical screening, reflecting the silent, though clinically highly significant, nature of dyslipidaemia as a cardiovascular risk factor.
• Specific, though uncommon, clinical signs may be present in more severe or longstanding dyslipidaemia.
• Xanthelasma: yellowish cholesterol deposits around the eyelids. It is relatively non specific and also occurs in individuals with normal lipid levels.
• Tendon xanthomata: particularly characteristic of familial hypercholesterolaemia, typically affecting the Achilles tendon and extensor tendons of the hands.
• Corneal arcus: a greyish white ring at the corneal periphery. It is more common and less specific as an incidental finding in older individuals, but more strongly suggests an underlying lipid disorder in a younger patient.
• Very significantly elevated triglycerides can produce eruptive xanthomata (small, yellowish papules, typically over the buttocks and extensor surfaces).
• At the most extreme levels, lipaemia retinalis occurs (a pale, creamy appearance to the retinal vessels on fundoscopic examination). Very high triglycerides also carry the important risk of acute pancreatitis.
• Premature cardiovascular disease (at an unusually young age) in the patient or in first degree relatives should prompt consideration of an inherited lipid disorder, particularly familial hypercholesterolaemia. This has significant implications for the patient and potentially affected family members.

• A fasting or non fasting lipid profile provides the essential initial biochemical assessment. It measures total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglycerides.
• Most contemporary guidelines increasingly accept non fasting sampling as adequate for routine cardiovascular risk assessment, which simplifies testing. Fasting sampling remains preferred where significant hypertriglyceridaemia is a concern, because triglyceride quantification is more reliable in the fasting state.
• Formal cardiovascular risk assessment uses a validated risk calculation tool. It incorporates the lipid profile alongside other established risk factors: age, sex, blood pressure, smoking status, diabetes status and, in some tools, family history and specific biomarkers.
• This provides the framework for determining the intensity of lipid lowering treatment. Treatment decisions are generally guided by overall cardiovascular risk rather than lipid levels in isolation.
• The exceptions are very high low density lipoprotein cholesterol (particularly suggestive of familial hypercholesterolaemia) and very high triglycerides (carrying specific pancreatitis risk). Both warrant treatment based on the absolute lipid level, independent of the calculated cardiovascular risk score.
• Screen for familial hypercholesterolaemia, using established clinical diagnostic criteria and, where appropriate, genetic testing. The criteria incorporate the degree of low density lipoprotein cholesterol elevation, tendon xanthomata, and personal or family history of premature cardiovascular disease.
• Consider screening in any patient with markedly elevated low density lipoprotein cholesterol (generally above 5 mmol per litre in an adult) or a suggestive personal or family history. This has significant implications for cascade family screening and early, intensive treatment in confirmed cases.
• Screen for and address secondary causes of dyslipidaemia as a routine component of evaluation: thyroid function testing, renal function and urinalysis for proteinuria, assessment of alcohol intake, and medication review.

• Lifestyle modification is an important foundation of management across the spectrum of lipid disorders. It is an initial approach for lower risk patients and an essential adjunct to pharmacological treatment where indicated.
• It includes dietary modification (reducing saturated fat intake, increasing dietary fibre and, for triglyceride management, reducing alcohol intake), regular physical activity, weight management where relevant, and smoking cessation.
• Statin therapy (HMG CoA reductase inhibitors) is first line pharmacological treatment for elevated low density lipoprotein cholesterol. Statins reduce hepatic cholesterol synthesis and upregulate low density lipoprotein receptor expression, thereby reducing circulating low density lipoprotein cholesterol.
• Select the agent and intensity (moderate versus high intensity dosing) according to the calculated cardiovascular risk category and the treatment target. Atorvastatin and rosuvastatin are commonly used, higher potency agents for patients needing more intensive lowering.
• Ezetimibe, a cholesterol absorption inhibitor, is added to statin therapy where low density lipoprotein cholesterol targets are not achieved with statin monotherapy. It can also be used as an alternative in genuine statin intolerance. It has a complementary mechanism of action and generally favourable tolerability.
• PCSK9 inhibitors (evolocumab or alirocumab, given as subcutaneous injection) are a further option for persistently elevated low density lipoprotein cholesterol despite maximally tolerated statin and ezetimibe therapy.
• They are particularly relevant for familial hypercholesterolaemia or established, high risk atherosclerotic cardiovascular disease. They give substantial low density lipoprotein cholesterol reduction and associated cardiovascular event risk reduction in appropriately selected, high risk patients.
• Manage significant hypertriglyceridaemia (particularly at levels carrying pancreatitis risk) with dietary fat restriction, strict alcohol avoidance, and optimised glycaemic control in patients with coexisting diabetes.
• Where indicated, add specific pharmacological treatment: fibrates or, for very high risk patients, omega three fatty acid preparations. The absolute triglyceride level and associated pancreatitis risk guide treatment intensity and urgency.
• Familial hypercholesterolaemia requires intensive lipid lowering treatment, given the substantially elevated lifetime cardiovascular risk. This is generally high intensity statin therapy, frequently combined with ezetimibe and, where targets are not achieved, a PCSK9 inhibitor.
• Cascade screening of first degree relatives is essential. Use the identified genetic mutation where available, or lipid profile testing where genetic testing is not performed or has not identified a causative mutation despite a clinically convincing diagnosis.
• Cascade screening supports early identification and treatment in affected relatives, ideally from childhood in confirmed cases, given evidence that early treatment reduces lifetime cardiovascular risk in this high risk population.
• Monitor lipid profile and liver function after treatment initiation and dose adjustment, given the recognised, though generally uncommon, risk of statin related hepatotoxicity.
• Manage all relevant modifiable cardiovascular risk factors fully, not lipids in isolation. This underpins effective long term management of this common and clinically highly significant group of conditions.