Lipoprotein(a)

Lipoprotein(a) is an LDL-like particle in which apolipoprotein(a) is linked to apolipoprotein B-100. It contributes to atherosclerosis through its cholesterol content and oxidised phospholipids, and to thrombosis because apolipoprotein(a) resembles plasminogen. Concentration is determined more than 90% by variants in the LPA gene, mainly the number of kringle IV type 2 repeats. Small isoforms give high levels. Levels are stable from early childhood, so a single measurement in a lifetime usually defines the risk.

A raised concentration is an independent, causal risk factor for myocardial infarction, ischaemic stroke, peripheral artery disease and calcific aortic valve stenosis. It is not corrected by diet, exercise or statins. About 1 in 5 people have a concentration of 125 nmol/L (about 50 mg/dL) or more. Median levels are higher in people of African and South Asian ancestry.

Indications.

• Measure once in adults for risk assessment, and in all with premature atherosclerotic disease, familial hypercholesterolaemia, a family history of early vascular disease or high lipoprotein(a), recurrent events despite treated LDL-C, borderline risk in whom the result would change decisions, and calcific aortic valve stenosis.
• Selected children with stroke, a family history of high lipoprotein(a), or familial hypercholesterolaemia.
• Repeated only when a condition that alters it appears (kidney or thyroid disease, change in hormone status), or after specific lowering therapy.

Specimen. Serum or plasma, non-fasting. Samples are stable for several days at 2 to 8 °C, and for long periods when frozen at minus 70 °C.

Units. Results are best reported in nmol/L with an isoform insensitive, calibrated assay, since this measures particle number. Results in mg/dL reflect mass and depend on isoform size. No exact conversion exists, and about 2.0 to 2.5 nmol/L corresponds to 1 mg/dL.

Categories.

• Under 75 nmol/L (about 30 mg/dL): low or no added risk.
• 75 to 124 nmol/L (about 30 to 49 mg/dL): intermediate.
• 125 nmol/L (about 50 mg/dL) or more: raised, and counted as a risk enhancing factor.
• 430 nmol/L (about 180 to 200 mg/dL) or more: very high, with lifetime risk comparable to heterozygous familial hypercholesterolaemia.

Risk rises continuously with concentration, and there is no sharp threshold. A value over the risk enhancing limit leads to earlier and more intensive control of LDL-C, blood pressure, glucose and smoking, and to cascade testing of first degree relatives, who each carry a 50% chance of inheriting a high level.

Treatment effects. Statins do not lower it and can raise it modestly. PCSK9 inhibitors lower it by about 20 to 30%. Niacin lowers it by about 20 to 30% but is no longer used for this. Lipoprotein apheresis lowers it by about 60 to 70% for each session, and is used in selected patients with progressive disease despite controlled LDL-C. Agents that target apolipoprotein(a) production are under evaluation in outcome studies.

Causes of raised levels. Inherited LPA variants (dominant effect), chronic kidney disease and nephrotic syndrome, hypothyroidism, menopause, and modest rises in pregnancy and in the acute phase response.

Causes of lowered levels. Severe liver disease, hyperthyroidism, oral oestrogen and hormone replacement (by about 20 to 25%), growth hormone therapy, and PCSK9 inhibitors.

Critical findings needing immediate action. There is no emergency value. A very high level in a patient under 50 years with a first vascular event, or a high level in a patient with aortic stenosis or recurrent events, needs a specialist risk review and family screening.

Pitfalls.

• Assays differ in antibody design and sensitivity to isoform size, so results from different methods are not interchangeable. Use an assay traceable to a common calibrator and reported in nmol/L.
• A lipoprotein(a) value in mg/dL cannot be converted exactly.
• The cholesterol in lipoprotein(a) (about 30 to 45% of its mass) is included in LDL-C, so a high lipoprotein(a) can make a patient appear resistant to LDL-C lowering, and true LDL-C is lower than reported.
• Levels vary little between samples in healthy people, but they change with kidney disease, thyroid disease and hormone therapy.
• Raised lipoprotein(a) does not alter acute management, and it is not a marker of disease activity.

Special groups.

• Children: levels reach adult values early in life. Testing is useful in the family of a person with early events.
• Pregnancy: levels rise modestly, so testing is deferred until after delivery where possible.
• Ancestry: the same concentration may carry different risk in different groups, and risk is strongest in European and South Asian cohorts. Median levels are higher in people of African ancestry.
• Chronic kidney disease: levels are higher and interpretation is less certain.
• Older adults: a high value remains informative for stenosis and event risk.

Follow up tests. Lipid profile with non-HDL-C, apolipoprotein B, TSH, HbA1c, urea and electrolytes, urine albumin-to-creatinine ratio, liver function tests, LPA genotyping where available, cascade testing of relatives, coronary calcium score, carotid ultrasound, echocardiography for aortic valve disease.