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.