Abstract. Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Since neovascularization plays an important role in hepatocarcinogenesis and IR, an angiostatic therapy may be considered as one of the promising approaches for chemoprevention against HCC. The aim of the current study was to examine the combination effect of a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I), both reportedly possess anti-angiogenic and IR-improving activities, on the cumulative recurrence after curative therapy. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered after the curative therapy for HCC, and several indices were analyzed. A 48-month followup revealed that the combination treatment with BCAA and ACE-I markedly inhibited the cumulative recurrence of HCC under IR conditions, whereas neither single treatment exerted a significant inhibition. The soluble form of the vascular endothelial growth factor (VEGF; a central angiogenic factor) receptor-2 (sVEGFR2) was significantly decreased only three months after the treatment without recurrence. We also observed that IR, determined by the homeostasis model assessment (HOMA-IR), was significantly improved by this regimen, indicating that an inhibitory effect was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. In conclusion, since both BCAA and ACE-I are widely used in clinical practice with safety, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC recurrence in the future. Moreover, sVEGFR2 may become a useful clinical predictive marker of this combination treatment.
Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimer (UL-VWFM) and the formation of platelet thrombi. It remains controversial whether or not plasma ADAMTS13:AC decreases in patients with liver cirrhosis (LC), and its relationship to clinical features has not been fully investigated. We measured ADAMTS13:AC and its related parameters in plasma in 33 patients with chronic hepatitis (CH) and in 109 patients with LC. ADAMTS13:AC decreased with increasing severity of liver disease (controls means 100%, CH 87%, Child A-LC 79%, Child B-LC 63%, and Child C-LC 31%), and showed severe deficiency (<3% of controls) in five end-stage LC. Activities measured by act-ELISA strongly correlated with those determined by the VWFM assay and ADAMTS13 antigen. Multivariate analysis showed Child-Pugh score and spleen volume independent factors contributing to ADAMTS13:AC. VWFM patterns were normal in 53% of cases, degraded in 31%, and unusually large in 16%. Patients with unusually large VWFM had the lowest ADAMTS13:AC as well as the highest Child-Pugh score, serum creatinine and blood ammonia levels. Plasma inhibitor against ADAMTS13 detected in 83% of patients with severe to moderate ADAMTS13:AC deficiency mostly showed marginal zone between 0.5 and 1.0 BU/ml. The IgG-type autoantibodies specific to plasma derived-ADAMTS13 was detected by Western blot in only five end-stage LC with severe ADAMTS13:AC deficiency. In conclusion, both plasma ADAMTS13 activity and antigen levels decreased with increasing severity of cirrhosis. An imbalance between the decreased ADAMTS13:AC and its increased substrate may reflect the predisposing state for platelet thrombi formation in patients with advanced LC.
Decreased ADAMTS13 activity and increased VWF:Ag could be induced not only by pro-inflammatory cytokinemia, but also by its inhibitor, both of which may be closely related to enhanced endotoxemia in patients with AH and SAH.
ADAMTS13:AC concomitantly decreases as the functional liver capacity decreases. This activity may be a useful prognostic marker that is equal or superior to the CTP score and the MELD score to predict not only the short-term prognosis but also the long-term survival of the cirrhotic patients.
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