Background: Extensive hepatectomy is inevitable to some patients with serious liver diseases in order to obtain cure. However, excessive surgical removal of liver tissue can lead to post-hepatectomy liver failure. Therefore, a marker to predict whether the remaining liver is capable to regenerate, or is prone to develop liver failure is an immediate need. Activins are members of the TGF-b superfamily, which are an autocrine inhibitory growth factor of hepatocytes. We have shown that follistatin, an activin binding protein, blocks the anti-proliferative effect of endogenous activin, and thereby stimulate hepatocyte growth (Endocrinology 1999; 140: 3125-3132). This was also the case in normal adult rat liver, which was demonstrated to increase in size by adenovirus-mediated overexpression of follistatin (Hepatology 32: (4), Pt.2 Suppl; 321A). Moreover, serums of patients with liver disease were shown to have elevated follistatin levels.
Method: Male Wistar rats (180-200g) were used for rat study, and human samples were obtained from patients who admitted Yokohama City University Hospital with their consent. Serum follistatin was measured by ELISA assay.
Results: We have developed a novel technique by which we can perform a 90% hepatectomy (90%Hx) in rats that results in 100% survival for more than 2 weeks. This model is an excellent tool to study differences between survival case (90%Hx) and mortal liver failure case (95%Hx) after extensive hepatectomy. Total and direct bilirubin levels were elevated after both 90%Hx and 95%Hx. In contrast to the 90%Hx, in which their levels of bilirubin decreased dramatically in 48 hours, the levels remained significantly elevated in the 95%Hx rats. There were no significant difference between 90%Hx and 95%Hx in AST, ALT, Albumin, and ALP levels. However, serum free follistatin levels remained significantly elevated only in the 95%Hx group 24 hours after surgery, in contrast to the 30, 70, and 90%Hx groups. Therefore, serum free follistatin levels represents a novel early detection marker for liver failure. Furthermore, we found that in clinical samples of two patients who suffered severe liver failure following hepatectomies had elevation of their serum follistatin levels, when compared with patients who were discharged without any unusual event after either hepatectomy or extensive gastrectomy.
Conclusion: Our results suggest that serum follistatin level can be used as an early predictor for post-hepatectomy liver failure.