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.