Lipoprotein X: clinical implications

Abstract

In this issue of the journal, Stepien et al. describe a case of serum lipoprotein X (Lp-X) in a patient with cholestasis and severe hyperlipidaemia. This abnormal lipoprotein is rich in phospholipid and unesterified cholesterol. The main protein component is albumin within the core and apolipoprotein C upon the surface. Unlike low-density lipoprotein (LDL), Lp-X does not contain apolipoprotein B nor is it removed by the LDL receptor, but Lp-X is cleared by the reticuloendothelial system and the kidneys. Lp-X is about 50 nm in diameter and its major component bile acid is lithocholic. Early studies reported the presence of Lp-X in the serum of patients with cholestasis. The failure of Lp-X to exert feedback inhibition on cholesterol synthesis may contribute to the mechanism of hypercholesterolaemia in obstructive jaundice. However, the presence of serum Lp-X does not facilitate the distinction between intrahepatic and extrahepatic cholestasis. Bile lipoprotein is a precursor of Lp-X and in cholestasis this refluxes into the plasma pool and binds to albumin to form Lp-X. Serum Lp-X usually disappears soon after the cholestasis is relieved. The ratio of plasma bile salts to albumin is important for the integrity of Lp-X and it is catabolized by the action of phospholipase which helps convert lecithin into lysolecithin. In graft versus host disease involving the liver and with cholestasis plasma Lp-X can result in severe hypercholesterolaemia, xanthelasma and cholesteroloma. Lp-X can also be found in cholestasis of pregnancy and primary biliary cirrhosis (PBC). The case presented by Stepien et al. confirms these earlier observations of raised serum Lp-X in cholestasis. Increased serum cholesterol concentrations occur in PBC and this is largely due to the presence of Lp-X, although it is debatable whether this confers increased cardiovascular risk. Indeed, Lp-X may not be atherogenic and data suggest it may have antioxidant LDL activity. Additionally, Lp-X is not significantly taken up by macrophages but is taken up by hepatocytes. Sometimes severe and prolonged cholestasis can result in very high serum Lp-X concentrations resulting in severe hypercholesterolaemia and tendon xanthomata. Complete regression of these xanthomata has been described by treatment with apheresis, which the authors stated should be considered possible first-choice treatment for patients with massive Lp-X accumulation due to cholestasis. Statin therapy may be ineffective in lowering Lp-X. Lecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for cholesterol esterification in plasma. Lp-X is found in LCAT deficiency which is characterized by low concentrations of high-density lipoprotein (HDL) as well as anaemia, corneal opacities, proteinuria and chronic kidney disease. The Lp-X found in LCAT deficiency may contribute to the renal disease observed in this condition by stimulating monocyte renal infiltration. Proteoglycans have an important role in regulating the uptake of Lp-X into kidney mesangial cells and this mechanism is independent of the scavenger receptor. Guerin et al. reported that in LCAT deficiency the presence of Lp-X is correlated with a progressive change in renal function. In addition to cholestasis and LCAT deficiency, Lp-X may also be found in the plasma after intravenous infusion of Intralipid emulsion such as occurs with total parenteral nutrition. Intralipid administration can elicit an increase in serum total cholesterol (mainly unesterified), phospholipid and LDL. The Lp-X associated with Intralipid infusion seems to occur when phospholipid clearance is exceeded, resulting in phospholipid accumulation with unesterified cholesterol. Pseudohyponatraemia has also been described in some patients with severe hypercholesterolaemia secondary to raised Lp-X. Thus the presence of Lp-X should be considered in pseudohyponatraemia associated with cholestasis. Sivakumar et al. described not only pseudohyponatraemia, but also pseudohypokalaemia and pseudohypochloridaemia in the presence of high concentrations of Lp-X. Various researchers have also found assay bias for serum LDL-cholesterol in the presence of Lp-X. This is an important practical point when it comes to interpreting LDL cholesterol results in severely cholestatic serum samples. Lp-X possesses strong aggregatory properties and can bind to alkaline phosphatase (ALP) producing a Lp-X-ALP complex. This complex may be found in cholestasis; typically that evoked by hepatic malignancy. The Lp-X-ALP complex is also associated with the presence of high-molecular mass ALP and the liver isoenzyme of ALP. Brocklehurst et al. described a stationary band of ALP using starch gel electrophoresis of serum samples from patients with biliary obstruction which was thought to be due to ALP binding to Lp-X. The strong aggregating ability of Lp-X may be important as it can bind and remove free cholesterol from the circulation. There are various assays available for measuring serum Lp-X. Agarose gel electrophoresis utilizes the cathodal