Lipoprotein X - Pathophysiology, diagnosis, and management

Lipoprotein X (LpX) was first discovered in the 1960s in patients with severe cholestatic diseases as an abnormal lipoprotein that is distinct from other lipoproteins because it is not produced through regulated pathways, contains albumin as the primary protein, and is rich in free cholesterol (FC) and phospholipids. Over the next few decades, its biochemical properties and composition were characterized.

Elevated blood levels of LpX are now also known to occur in various other conditions, such as lecithin cholesterol acyltransferase (LCAT) deficiency, graft versus host disease, and after lipid infusions for nutritional support. LpX cannot be measured by conventional testing with a standard lipid panel. The cholesterol content of LpX is included in total cholesterol (TC) and misreported as elevated low-density lipoprotein cholesterol (LDL-C) - this is due to similar densities of LpX and LDL on ultracentrifugation. Typically, the elevations are severe in magnitude, to the extent that the standard lipid panel can look similar to a patient with homozygous familial hypercholesterolemia.

When LpX is clinically suspected, laboratory testing with measurements of apolipoprotein B, nuclear magnetic resonance (NMR) spectroscopy, lipoprotein gel electrophoresis, or measurement of FC is required to distinguish elevated levels of LpX from other forms of hypercholesterolemia, such as familial hypercholesterolemia. Being an uncommon disorder with an estimated prevalence of 0.02% to 0.09%, if LpX is not considered in the differential diagnosis, the presence of falsely reported levels of elevated LDL-C and low levels of high-density lipoprotein cholesterol (HDL-C) may mimic an atherogenic phenotype, leading to treatment with lipid-lowering therapy.

Rather than atherosclerosis, patients with increased blood LpX levels are at risk of other complications, including hyperviscosity syndrome and xanthomatosis. The usual lipid-lowering drugs do not effectively lower elevated LpX levels; thus, treatment is primarily directed at the underlying disease, with plasma exchange being reserved for hyperviscosity syndrome. This review discusses the biology, pathogenesis, clinical features, diagnosis, and management of elevated LpX levels.