Lipid Profile

The lipid profile measures total cholesterol, HDL cholesterol (HDL-C) and triglycerides, and gives LDL cholesterol (LDL-C) and non-HDL cholesterol by calculation, or LDL-C by direct assay. It is used to estimate cardiovascular risk, to detect inherited and secondary dyslipidaemia, to identify risk of pancreatitis from severe hypertriglyceridaemia, and to monitor treatment. Cholesterol and triglycerides are measured by enzymatic methods, and HDL-C and direct LDL-C by homogeneous assays.

Lipid abnormalities are among the most common findings in adult screening. Familial hypercholesterolaemia (heterozygous) affects about 1 in 250 people and is underdiagnosed. A non-fasting sample is acceptable for routine screening and risk assessment.

Indications. Cardiovascular risk assessment in adults, premature atherosclerotic disease, family history of early vascular disease or high cholesterol, xanthomata or corneal arcus at a young age, diabetes, hypertension, chronic kidney disease, HIV, obesity, hypothyroidism, pancreatitis, and monitoring of lipid lowering drugs. Screening of children with a family history of dyslipidaemia or early vascular disease, and universal screening once in childhood in some services.

Specimen. Serum or lithium heparin plasma. Fasting is not needed for routine assessment, since triglycerides rise by only about 0.3 mmol/L (27 mg/dL) after usual meals. A fasting sample (9 to 12 hours) is requested when non-fasting triglycerides are over 5 mmol/L (about 440 mg/dL), when LDL-C is calculated at high triglyceride levels, in suspected primary hypertriglyceridaemia, and in monitoring of severe hypertriglyceridaemia. Conversion: cholesterol mg/dL equals mmol/L multiplied by 38.7, and triglyceride mg/dL equals mmol/L multiplied by 88.5.

Adult ranges are given. Targets depend on individual cardiovascular risk, and local ranges take precedence.

Total cholesterol. Cholesterol carried by all lipoproteins. Range: desirable under 5.2 mmol/L (200 mg/dL), borderline 5.2 to 6.1 mmol/L (200 to 239 mg/dL), high 6.2 mmol/L (240 mg/dL) or more. Raised: polygenic and familial hypercholesterolaemia, hypothyroidism, nephrotic syndrome, cholestasis, pregnancy, obesity, high intake of saturated fat, anorexia nervosa, and drugs (corticosteroids, ciclosporin, thiazides, protease inhibitors, retinoids).

Lowered: hyperthyroidism, malnutrition, malabsorption, advanced liver disease, chronic infection or inflammation, malignancy, abetalipoproteinaemia, familial hypobetalipoproteinaemia, and lipid lowering drugs.

It is less informative than its components, since a high value from HDL-C is not harmful and a normal value can hide a high LDL-C. The ratio of total cholesterol to HDL-C over 5 indicates raised risk.

LDL cholesterol (LDL-C). Cholesterol in LDL particles, the main atherogenic fraction. The usual calculation (Friedewald) is total cholesterol minus HDL-C minus triglycerides divided by 2.2 in mmol/L (or by 5 in mg/dL). It is invalid when triglycerides exceed 4.5 mmol/L (400 mg/dL) and unreliable at low LDL-C (under 1.8 mmol/L, 70 mg/dL) or triglycerides over 2.0 mmol/L (about 180 mg/dL).

Newer equations (Martin-Hopkins, Sampson) extend accuracy, and one is valid up to triglycerides of 9.0 mmol/L (800 mg/dL). Direct assays are used when the calculation is unreliable. Range: optimal under 2.6 mmol/L (100 mg/dL), borderline 3.4 to 4.0 mmol/L (130 to 159 mg/dL), high 4.1 to 4.8 mmol/L (160 to 189 mg/dL), very high 4.9 mmol/L (190 mg/dL) or more. Raised: the causes of a raised total cholesterol.

Lowered: statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, inclisiran, hyperthyroidism, malnutrition, liver disease, acute illness, and genetic hypobetalipoproteinaemia.

Treatment targets are risk based. For people with established atherosclerotic disease, usual targets are under 1.4 mmol/L (55 mg/dL) in many services, and under 1.8 mmol/L (70 mg/dL) in others. For primary prevention, targets are under 2.6 to 3.0 mmol/L (100 to 116 mg/dL), depending on risk.

An untreated LDL-C of 4.9 mmol/L (190 mg/dL) or more in an adult, or 4.0 mmol/L (155 mg/dL) or more in a child, suggests familial hypercholesterolaemia once secondary causes are excluded. Lipoprotein(a) cholesterol is included in LDL-C and can overstate it by up to about 0.3 times the lipoprotein(a) mass in mg/dL.

HDL cholesterol (HDL-C). Cholesterol in HDL particles, involved in reverse cholesterol transport.

Range: low under 1.0 mmol/L (40 mg/dL) in men and under 1.3 mmol/L (50 mg/dL) in women, over 1.6 mmol/L (60 mg/dL) is usually protective.

Raised: genetic (CETP deficiency), alcohol, oestrogen, exercise, fibrates, primary biliary cholangitis, hyperthyroidism.

Lowered: obesity, insulin resistance, diabetes, smoking, inactivity, hypertriglyceridaemia, inflammation, genetic disorders (Tangier disease, LCAT deficiency, apolipoprotein A-I variants), anabolic steroids, progestins and beta blockers.

HDL-C is an inverse risk marker, and drugs that raise it have not reduced events, so it is not a treatment target. Very high values (over 2.6 mmol/L, 100 mg/dL) are not protective and are associated with higher mortality in some cohorts.

Triglycerides. Mostly carried by chylomicrons and VLDL. Range (fasting): normal under 1.7 mmol/L (150 mg/dL), borderline 1.7 to 2.2 mmol/L (150 to 199 mg/dL), high 2.3 to 5.5 mmol/L (200 to 499 mg/dL), very high 5.6 mmol/L (500 mg/dL) or more.

Raised:

• obesity
• insulin resistance and type 2 diabetes
• excess alcohol
• high refined carbohydrate intake
• hypothyroidism
• nephrotic syndrome
• chronic kidney disease
• pregnancy (third trimester)
• familial hypertriglyceridaemia
• familial combined hyperlipidaemia
• familial dysbetalipoproteinaemia
• drugs (oral oestrogens, tamoxifen, thiazides, beta blockers, corticosteroids, retinoids, protease inhibitors, atypical antipsychotics, sirolimus, ciclosporin, propofol, bile acid sequestrants)

Lowered:

• hyperthyroidism
• malnutrition
• malabsorption
• fibrates
• omega-3 fatty acids
• abetalipoproteinaemia

Values of 10 mmol/L (885 mg/dL) or more carry a risk of acute pancreatitis, rising steeply over 20 mmol/L (about 1770 mg/dL). Triglycerides vary by 20 to 25% from day to day, so a single value is interpreted with care. Severe primary chylomicronaemia arises from defects of lipoprotein lipase, APOC2, APOA5, GPIHBP1 or LMF1, and polygenic factors with a secondary trigger.

Non-HDL cholesterol. Total cholesterol minus HDL-C, representing all apolipoprotein B-containing particles. Targets are about 0.8 mmol/L (30 mg/dL) over the LDL-C target: under 3.4 mmol/L (130 mg/dL) for lower risk, under 2.6 mmol/L (100 mg/dL) for high risk, and under 2.2 mmol/L (85 mg/dL) for very high risk. It does not need fasting and remains valid at high triglycerides, and it is better than LDL-C when triglycerides are raised.

Isolated high LDL-C. Polygenic hypercholesterolaemia, familial hypercholesterolaemia (LDLR, APOB or PCSK9 variants, with tendon xanthomata, corneal arcus and premature disease), hypothyroidism, nephrotic syndrome, cholestasis, high-saturated-fat diet, drugs.

High triglycerides with low HDL-C. Metabolic syndrome and insulin resistance, type 2 diabetes, obesity, alcohol, chronic kidney disease. Apolipoprotein B is often raised, with small dense LDL particles despite normal LDL-C.

Combined high cholesterol and triglycerides. Familial combined hyperlipidaemia, hypothyroidism, nephrotic syndrome, diabetes, cholestasis.

Familial dysbetalipoproteinaemia. Cholesterol and triglycerides raised to a similar degree (both often 6 to 12 mmol/L), palmar xanthomata and tubero eruptive xanthomata, and apolipoprotein E2/E2 genotype with a second metabolic trigger. Non-HDL-C is high with a low apolipoprotein B relative to total cholesterol.

Severe hypertriglyceridaemia with milky plasma. Chylomicronaemia with risk of pancreatitis, eruptive xanthomata and lipaemia retinalis.

Very low LDL-C and cholesterol. Abetalipoproteinaemia and hypobetalipoproteinaemia (fat malabsorption, neuropathy, acanthocytes), hyperthyroidism, malnutrition, liver failure, and intensive therapy.

Secondary causes to exclude first. TSH, glucose or HbA1c, liver and renal function, urine protein, alcohol intake, drug history and pregnancy. Treating a secondary cause often normalises the lipids.

Critical values and findings needing immediate action.

• Triglycerides over 10 mmol/L (885 mg/dL) with abdominal pain or vomiting: lipase and urgent assessment for acute pancreatitis.
• Triglycerides over 20 mmol/L (about 1770 mg/dL), eruptive xanthomata, or lipaemia retinalis.
• LDL-C over 13 mmol/L (500 mg/dL), or tendon xanthomata in childhood, suggesting homozygous familial hypercholesterolaemia and needing urgent specialist referral.
• Any acute coronary or cerebral event in a person with severe untreated dyslipidaemia.

Interferences and pitfalls.

• Lipids fall during acute illness, sepsis, surgery and after myocardial infarction. A sample within 24 hours of an infarction is reliable, and later values are depressed for about 2 to 3 months.
• Within person variation is about 5 to 6% for total cholesterol, 7 to 9% for LDL-C and HDL-C, and 20 to 25% for triglycerides, so two samples are averaged when a decision depends on the value.
• Prolonged venous stasis, standing then lying posture, and recent weight change alter results.
• The calculated LDL-C is unreliable at high triglycerides and at very low LDL-C.
• Lipaemic samples interfere with other assays, and very high triglycerides distort sodium by volume displacement with some methods.
• Tangier disease and other genetic disorders give an HDL-C near zero.
• Raised lipoprotein(a) can make LDL-C appear resistant to treatment.

Special groups.

• Children: universal screening once between 9 and 11 years in some services, and earlier with a family history. An LDL-C of 3.4 mmol/L (130 mg/dL) or more is high, and 4.0 mmol/L (155 mg/dL) or more suggests familial hypercholesterolaemia.
• Pregnancy: total cholesterol rises by about 25 to 50% and triglycerides by 2 to 3 times in late pregnancy, so lipid testing is delayed until about 6 weeks after delivery and the end of lactation unless severe.
• Older adults: risk based thresholds apply, and low cholesterol can reflect illness or frailty.
• Chronic kidney disease and dialysis: high triglycerides and low HDL-C are typical.
• HIV: protease inhibitors and some other antiretrovirals raise triglycerides and LDL-C.
• South Asian populations carry higher risk at the same lipid levels, and risk calculators may underestimate it.

Follow up tests. Apolipoprotein B, lipoprotein(a), TSH, HbA1c, urea and electrolytes, liver function tests, urine albumin-to-creatinine ratio, creatine kinase when muscle symptoms occur on statins, genetic testing for LDLR, APOB, PCSK9, LPL, APOC2, APOA5, cascade testing of first degree relatives, carotid ultrasound, coronary calcium score.