Scintigraphic evaluation of Tc‐99m‐low‐density lipoprotein (LDL) distribution in patients with Gaucher disease

Abstract

Gaucher disease (GD) is frequently associated with reduced plasma levels of low density lipoproteins, presumably due to increased catabolism of LDL. The purpose of this study was to determine the distribution of Tc‐99m LDL (Tc‐LDL) in Gaucher patients, and compare the findings to bone marrow distribution. Four patients with non‐neuropathic Gaucher disease (type 1) underwent baseline whole body imaging at 4 and 24 h after injection of dialyzed autologous LDL labeled with 10–20 mCi Tc‐99m‐pertechnetate. Three of the four patients were treated with macrophage‐targeted alglucerase (Ceredase). The LDL studies were compared to concurrent bone marrow scans performed with 10 mCi Tc‐99m sulfur colloid (Tc‐SC). Follow‐up Tc‐LDL and Tc‐SC scans were obtained 12–14 months later. Tc‐LDL activity was abnormally increased in the spleen and long bones of the upper and lower extremities. Liver activity was also increased. Prominent blood pool activity 4 h after injection mostly cleared on the 24‐hour images. The distribution of Tc‐SC was congruent with Tc‐LDL activity. All patients had mild‐to‐moderate hepatomegaly and peripheral bone marrow expansion. One patient had been previously splenectomized and the remaining three had moderate‐to‐severe splenomegaly. Two of the three treated patients showed regression of peripheral bone marrow activity with therapy, along with a comparable decrease in Tc‐LDL uptake. Our study with Tc‐LDL and Tc‐SC suggests that in patients with Gaucher disease native LDL is taken up by the reticuloendothelial system (RES) of the spleen and bone marrow in addition to increased uptake by the liver. This abnormal uptake (presumably by macrophages of the RES) may account for accelerated LDL catabolism and reduced plasma levels of LDL. Serial LDL studies can be performed, allowing for longitudinal follow‐up after drug or enzyme therapies.

Evaluation of high density lipoprotein as a circulating biomarker of Gaucher disease activity

“…Taken together with the increased level of apo E, available data suggest a central role of the pathological glucosylceramide-laden macrophages in aberrant lipoprotein metabolism in GD. Consistent with this notion, imaging for sites of lipoprotein uptake in vivo in GD revealed increased uptake of LDL primarily in the spleen and bone marrow, sites of major accumulation of glucosylceramide-laden macrophages in GD (Lorberboym et al 1997). However, the site(s) of increased HDL uptake in vivo in GD is not known.…”

“…Both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) appear to be enriched in glucosylceramide (Clarke 1981). Associated with this altered lipoprotein composition, there is profound hypolipidemia due to decreased number of lipoprotein particles, attributed to increased rates of catabolism (Ginsberg et al 1984; Le et al 1988; De Fost et al 2009; Lorberboym et al 1997). Moreover, cell types other than macrophages are involved in the development of GD, underscoring the necessity to develop a “biomarker basket” to monitor diverse aspects of GD beyond the macrophage system (Mistry et al 2010)…”

High incidence of cholesterol gallstone disease in type 1 Gaucher disease: characterizing the biliary phenotype of type 1 Gaucher disease

“…Reduction of HDL cholesterol appears to be the key abnormality. Whereas there is evidence that hypercatabolism of LDL in GD may occur via the macrophage system, such evidence is lacking for HDL (Le et al 1988; Lorberboym et al 1997; Ginsberg et al 1984). Turnover studies of radio-labeled HDL in GD1 showed an increased fractional catabolic rate of apoA1, which may reflect increased reverse cholesterol transport to result in enhanced biliary cholesterol secretion (Le et al 1988; Thornton et al 1981).…”

“…It was suggested that increased lipoprotein catabolism was mediated via the activated macrophage system. However, the question of whether lipid flux through the hepatocyte is also abnormal has not been investigated (Le et al 1988; Lorberboym et al 1997; Ginsberg et al 1984). Finally, recent data suggest impaired insulin signaling in GD1 due to enrichment of lipid rafts harboring insulin receptors, with GM3 arising from accumulation of its precursor, GlcCer (Langeveld and Aerts 2009; Langeveld et al 2008).…”