Discussion
GVHD of the liver is one of the known complications of allogeneic HSCT characterized by elevation of hepatic enzymes, cholestasis, severe hypercholesterolemia and hypertriglyceridemia (in excess of 1,000 mg/dL). In contrast to hypercholesterolemia contributed by medications such as cyclosporine (5, 6), sirolimus (7, 8), mycophenolate and glucocorticoids (9) which are usually below 7.8 mmol/L (300 mg/dL) and medicated by LDL-C, hypercholesterolemia caused by GVHD of liver is mediated by cholestasis. In general, there are 2 sources of cholesterol in the body - dietary cholesterol absorption from the intestine and de novo synthesis of cholesterol, which mainly takes place in the liver. Liver is the primary site of cholesterol biosynthesis and storage and is also the principal site of sterol elimination by converting cholesterol to bile acids and removing free cholesterol as neutral sterols via biliary excretion (10, 11). In patients with cholestasis related to liver GVHD, the impaired bile flow in cholestasis results in accumulation of cholesterol and bile salts, and hence elevated LDL-C. On the other hand, Lp-X is another major cause of hyperlipidaemia in cholestasis, during which bile constituents are refluxed from the bile ducts or hepatocytes into the blood stream. Lp-X particles are formed when bile lipoprotein enters the blood stream and incorporates triglycerides, ApoC and esterified cholesterol. Unlike LDL-C, Lp-X does not contain apolipoprotein B, which is the most important ligand to the hepatic LDL-C receptor. Therefore, Lp-X could not internalized into the hepatocyte (10, 11) . As Lp-X hypercholesterolemia is not due to overproduction by hepatocytes, usage of statin drugs to downregulate cholesterol synthesis is not effective (4). Indeed, since LP-X does not contain apolipoprotein B, which is the major component of LDL and one of the most important factors in the pathogenesis of atherosclerotic plaques. Therefore, it is not atherogenic (12). However, Lp-X could be associated with hyperviscosity syndrome (13) and that plasma exchange or apheresis might be indicated (14). Both of our cases reported here did not have complications of hypercholesterolemia include exanthemata, retinal thromboembolism and pulmonary cholesteroloma. They were also not associated with hyperviscosity syndrome requiring plasma exchange or apheresis.
As reported in literature, hypercholesterolemia secondary to intra-hepatic cholestasis caused by liver GVHD can appear at any time between 2 months to 2 years post-HSCT. The condition could be easily diagnosed by demonstrating discordance between calculated and directly measured LDL-C levels, as well as lipoprotein electrophoresis. With the resolution of cholestasis, Lp-X would also resolve with no specific treatment.