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To the Editor:

In rats with secondary biliary cirrhosis 4 weeks after double ligatures and resection of the common bile duct, Dr. Thabut and colleagues1 revealed that a pretreatment of reconstituted high-density lipoprotein (rHDL) at a dose of 80 mg/kg increased the ability of circulating high-density lipoprotein (HDL) particles to bind to lipopolysaccharide (LPS) following intravenous administration of 0.17 mg/kg of LPS derived from Escherichia coli, and they demonstrated that at 4 hours after intravenous administration of LPS at a dose of 0.5 mg/kg, rHDL pretreatment attenuated increases in both plasma and hepatic tissue tumor necrosis factor α activities, reduced hepatic expression of inducible nitric oxide synthase, and significantly decreased the mortality due to endotoxemia. Furthermore, the authors added a new finding that rHDL could restore hepatic endothelial nitric oxide synthase activity, leading to improvements in intrahepatic microvascular and extrahepatic portal circulation in endotoxemic cirrhotic rats. The authors concluded that the administration of rHDL should be considered a useful strategy for the treatment of cirrhosis-associated complications such as endotoxemia and portal hypertension.

I would like to commend the authors for completing such an excellent but difficult study. I would like to address some questions. First, why did the authors administer a different dose of LPS (0.17 mg/kg) in the first study to evaluate the effects of rHDL on LPS neutralization? In the following studies, a dose of 0.5 mg/kg was repeatedly used. In the first experiment, mean baseline serum HDL levels in cirrhotic rats were 0.25 g/L, and the levels rose to 0.47 g/L after decapitation following the completion of the experiment in rats without rHDL treatment. It is well known that serum levels of HDL, which is a negative acute-phase protein, decrease with time during an inflammatory process. Second, I would like to know why serum HDL levels increased during the invasive experiment under anesthesia. We have previously reported the suppressive effects of apolipoprotein A-I, which is the core for LPS neutralization by HDL, on the release of tumor necrosis factor α in noncirrhotic rats.2 Apolipoprotein A-I was intraperitoneally injected 1 hour after 1 mg/kg of LPS challenge. Third, I would like to ask the authors why rHDL was administered before LPS challenge. The authors mention that a dose of rHDL was determined according to the previous findings after LPS exposure in mouse and rabbit models. The LPSs are a heterogeneous group of molecules with interspecies differences in the length and position of the acyl chains in the lipid A. It is suggested that the effective neutralization of LPS by human lipoproteins depends on the type of LPS. The inactivation of LPS derived from Neisseria meningitis by HDL was less efficient than that of E. coli–derived LPS, and the neutralization of E. coli–derived LPS in human mononuclear cells was dependent on the preincubation times of lipoprotein with LPS.3 I think that a study using different doses of HDL can validate the usefulness of rHDL treatment.

In primary biliary cirrhosis, most patients have high serum total cholesterol levels due to a reduction in biliary lipid secretion.4 In such patients, the safety of rHDL administration should be a concern because much higher elevations in serum total cholesterol resulting from rHDL supply may cause cardiovascular events. It is suggested that a total cholesterol level greater than 250 mg/dL may increase the risk for the development of cardiovascular events among patients with primary biliary cirrhosis.5

References

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  • 1
    Thabut D, Tazi KA, Bonnefont-Rousselot D, Aller M, Farges O, Guimont MC, et al. High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats. HEPATOLOGY 2007; 46: 18931906.
  • 2
    Imai T, Fujita T, Yamazaki Y. Beneficial effects of apolipoprotein A-I on endotoxemia. Surg Today 2003; 33: 684687.
  • 3
    Sprong T, Netea MG, van der Ley P, Verver-Jansen TJG, Jacobs LEH, Stalenhoef A, et al. Human lipoproteins have divergent neutralizing effects on E. coli LPS, N. meningitis LPS, and complete Gram-negative bacteria. J Lipid Res 2004; 45: 742749.
  • 4
    Nikkila K, Hockerstedt K, Miettinen TA. High cholesterol and low campesterol-to-sitosterol ratio in serum of patients with primary biliary cirrhosis before liver transplantation. HEPATOLOGY 1991; 13: 663669.
  • 5
    Longo M, Crosignani A, Battezzati PM, Giussani CS, Invemizzi P, Zuin M, et al. Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut 2002; 51: 265269.

Tetsuji Fujita M.D.*, * Department of Surgery Jikei University School of Medicine Tokyo, Japan.