Gc-globulin in liver disease.

This doctoral thesis is based on seven previously published papers and reports on the role of the actin-scavenger Gc-globulin in acute and chronic liver diseases. Gc-globulin is synthesized in the liver and is a multifunctional protein; however, its main physiologic function is presumably actin binding and actin scavenging. Actin is a major cellular protein released during cell necrosis that may cause fatal formation of actin-containing thrombi in the circulation if the actin scavenging capacity of Gc-globulin is exceeded. In my studies, I found serum Gc-globulin levels to be reduced in liver disease, most so in patients with acute liver failure (ALF). In patients admitted with acetaminophen (paracetamol) overdose, Gc-globulin concentrations were lower in patients with hepatic encephalopathy than in those without and the levels nadired at approximately 60-72 hours after acetaminophen ingestion, corresponding with the peak in aminotransferese levels (and thus, hepatic necrosis). In patients with ALF, admission Gc-globulin was significantly lower in 47 nonsurvivors than in 30 survivors, 26% and 46% of normal, respectively (P<0.001). The predictive value of outcome using a Gc-globulin cutoff level of 100 mg/L equaled that of the internationally accepted King's College Hospital criteria. The prognostic value of Gc-globulin was confirmed in a separate study including 106 patients from the United States with nonacetaminophen-induced ALF now using an automated nephelometric assay whereas the prognostic value seemed less obvious for acetaminophen-induced ALF. Multiple organ failure (MOF) is a frequent complication of ALF. In ALF patients with deep coma (hepatic encephalopathy grade III or IV) Gc-globulin levels correlated inversely with the number of failing organs. Levels were lower in patients who later developed MOF than in those who did not. Surprisingly, kinetic studies in patients with ALF and acute on chronic liver disease showed Gc-globulin production to be 7-fold increased in these conditions. Despite this increase Gc-globulin levels were severely reduced and the reduction must therefore be due to a highly increased consumption of Gc-globulin - probably because of hepatocyte necrosis and removal from the circulation of Gc-globulin:actin complexes or because of its role in immune-related functions. Patients with chronic liver disease had reduced Gc-globulin levels, but the reduction was less pronounced than in ALF. After liver transplantation, Gc-globulin concentrations normalized within two weeks, in contrast to the continuous decrease in albumin levels suggesting a very different regulation of these two phylogenetically related proteins. It remains to be studied if lack of Gc-globulin contributes to the pathogenesis of patients with ALF or chronic liver disease. Future studies should focus on the potential value of Gc-globulin substitution in these patients.