Assessment of Morpho-Functional State of the Liver in Selecting Treatment Strategy for Patients with Mechanical Jaundice

The dissertation is devoted to the assessment of the morpho-functional state of the liver in patients with mechanical jaundice of various etiologies and the justification of optimal timing for surgical treatment. The research aims to advance methods for assessing liver dysfunction using the MELD index (Model for End-Stage Liver Disease), as well as to investigate the mechanisms of hepatocyte death in obstructive cholestasis. A quantitative analysis of hepatocyte death and dynamics of biochemical parameters of blood and bile was conducted both in an experimental model of mechanical jaundice in rats and in clinical material. Data were obtained on the prognostic significance of the MELD index for determining the degree of surgical risk, and an algorithm for treatment strategy was developed to select optimal timing for surgical intervention after minimally invasive decompression of the biliary tract.

Relevance of the Problem

In the 1960s-1970s, postoperative mortality in the treatment of patients with mechanical jaundice of various etiologies reached 45-50% [Galperin E. I. et al., 1978]. The main cause of death in these patients was hepatocerebral insufficiency. In the last decade, it has been possible to achieve a reduction in postoperative mortality among these patients to 1.5-14.3% [Borisov A. E. et al., 1997; Mumladze R. B. et al., 2005; Hotineanu V. et al., 2005; Bhati S. S. et al., 2007]. This is due to the advancement of diagnostic and treatment methods. In particular, the implementation of minimally invasive technologies has made it possible to perform treatment of patients with mechanical jaundice in two stages. At the first stage, percutaneous drainage under ultrasonographic control or endoscopic stenting of the biliary tract is performed. After resolution of biliary hypertension and restoration of liver functional state, radical or palliative surgical intervention is carried out.

At the same time, the overall number of complications in the treatment of patients with mechanical jaundice remains high and amounts to 10.8-50.4% [Borisov A. E. et al., 1997; Mumladze R. B. et al., 2004; Sewnath M. E. et al., 2001; Tomazic A., Pleskovic A., 2006].

One of the main causes of unsatisfactory results of two-stage treatment of patients with mechanical jaundice is the duration of preoperative drainage. It has been established that during prolonged periods of biliary tract decompression, bacterial contamination of bile occurs, immune disturbances develop, and in cases of malignant jaundice, tumor progression takes place [Roughneen R. T. et al., 1987; Jiang W. G., Puntis M. C., 1997; Aly E. A. H., Johnson C. D., 2001; Mok K. T. et al., 2001; Matsumoto Y. et al., 2002].

Therefore, in recent years surgeons have sought to shorten the duration of preoperative biliary drainage [Kubyshkin V. A., Vishnevsky V. A., 2003; Putov N. V. et al., 2005]. The most important problem in this regard is the assessment of surgical risk and prediction of the development of postoperative liver dysfunction.

Widely used "functional tests", including the determination of such biochemical blood parameters as alanine and aspartate aminotransferases, alkaline phosphatase, total bilirubin and its fractions, prothrombin time, and albumin, when used in isolation, do not allow proper characterization of liver functional state, let alone prediction of its changes [Rodionov V. V. et al., 1991; Lisenko V. M., Anikina E. V., 2000; Zimmermann N., Reichen J., 1998]. Therefore, a large number of scoring systems have been proposed that combine various laboratory tests with the aim of improving the diagnosis and prediction of liver dysfunction in surgery [Machulin E. G., 2000; Fedorov V. D. et al., 2000; Vishnevsky V. A. et al., 2003; Tarasenko S. V. et al., 2005; Pugh R. N. H. et al., 1973; Hamilton M., 1977; Malinchoc M. et al., 2000; Han X. S. et al., 2003; Pitiakoudis M. et al., 2004; Nagashima I. et al., 2005].

Thus, the development of a method that allows characterization of the morpho-functional state of the liver and determination of the timing of surgical treatment of patients with mechanical jaundice is an exceptionally relevant problem.

It has been established that the main morphological substrate of liver insufficiency is hepatocyte damage [Nazarenko G. I., Kishkun A. A., 2002]. Two types of cell death are known: necrosis and apoptosis [Lushnikov E. F., Abrosimov A. Yu., 2001]. It has been shown that in the pathogenesis of many liver diseases, along with hepatocyte necrosis, their apoptosis plays a significant role [Aruin L. I., 1998; Patel T., 2000; Ghavami S. et al., 2005]. Most studies devoted to the investigation of mechanisms of hepatocyte death in obstructive cholestasis have been performed using cell cultures or experimental animals. At the same time, it has been established that bile acids play a leading role in the pathogenesis of liver cell death [Danchenko E. O., 2001; Fricker G. et al., 1989; Schmucker D. L. et al., 1990]. At the same time, works devoted to the quantitative assessment of hepatocyte death in obstructive cholestasis in experiments and in clinical practice have not been encountered in the available literature. Nor have changes in biochemical parameters of blood and bile been established that would allow assessment of the intensity of liver cell death processes in mechanical jaundice.

Thus, the study of mechanisms of hepatocyte death and assessment of the role of cell death in the pathogenesis of liver insufficiency is also a relevant problem.