Differential evaluation of hepatocyte apoptosis and necrosis in acute liver injury.
OBJECTIVE
The significance of cytokelatin-18 fragment cleaved by caspase-3 (CK-18-fr) and high mobility group box-1 (HMGB-1) were evaluated experimentally and clinically for the differential evaluation of hepatocyte apoptosis and necrosis in patients with acute hepatic injury (AHI).


METHODS
In this study, typical apoptosis and necrosis were induced in HepG2 cells by staurosporin (STS) and hydrogen peroxide, respectively. Intracellular generation of CK-18-fr and extracellular leakage of CK-18-fr and HMGB-1 were determined. In the clinical study, serum CK-18-fr and HMGB-1 levels in 84 patients with AHI of varied severity and etiology were measured and compared with conventional liver tests.


RESULTS
In the experimental study, CK-18-fr was rapidly increased after STS stimulation, and peaked after 6 h inside the cells but increased in the medium 12 h after stimulation, while hydrogen peroxide stimulation caused no increase either in- or outside the cells. Extracellular HMGB-1 levels markedly increased after hydrogen peroxide stimulation, but did not change after STS stimulation. In the clinical study, serum CK-18-fr increased in correlation with serum aminotransferase, but not other liver tests or markers of disease severity of AHI,. Serum HMGB-1 levels mildly increased without any correlation to liver test or disease severity. Serum HMGB-1 levels in patients with circulation disturbance was significantly higher than that in patients with other etiologies.


CONCLUSIONS
The simultaneous determination of the serum CK-18-fr and HMGB-1 may be useful in the differential diagnosis of hetocellular death in AHI, which is primarily due to apoptosis except in patients with circulation disturbance.
Onodera
Mio
M
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, 020-8505, Japan. Email: ytakikaw@iwate-med.ac.jp.
Takikawa
Yasuhiro
Y
Kakisaka
Keisuke
K
Wang
Ting
T
Horiuchi
Saburo
S