Original Articles Significance of Serum Human Hepatocyte Growth Factor Levels in Patients with Hepatic Failure TOMOAKITOMIYA, SUMIKO NAGOSHI AND mNJI FUJIWAFLA First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113 Japan
fulminant hepatic failure in relation to grades of hepatic coma (4). Similar factors with high homology in the amino acid sequence derived from other sources (hepatocyte growth factor; HGF) (5-8) have also been shown to be increased in the blood of animals given carbon tetrachloride (9-11)or after partial hepatedomy (11-13). Thus it is proposed that the increase of these factors in serum is associated with liver regeneration. Patients with fulminant hepatic failure not only have severe inflammation and necrosis of the liver resulting in hepatocellular dysfunction but also frequently have multiple organ failure including renal failure. Serum hHGF levels might be altered depending on these situations because HGF is shown to be synthesized in various kinds of cells and organs such as Kupffer cells (14,151,leukocytes (16) and the kidney (10, 17) and be able to act on cells other than hepatocytes (18). In addition, patients with hepatic failure receive various therapies, including artificial liver support systems, especially when hepatic coma progresses, which might affect clearance of proteins such as hHGF from the circulation. In this paper, we studied serum changes of hHGF in patients with liver disease of various types and renal failure to explain the mechanism of the increase of serum hHGF levels in patients with fulminant hepatic failure and to clarify the clinical significance of its measurement,
Serum human hepatocyte growth factor levels were measured using a newly developed enzyme-linked immunosorbent assay kit in patients with liver diseases. Serum human hepatocyte growth factor levels were increased in correlation with derangements of prothrombin time, total bilirubin and other parameters reflecting hepatocellular dysfunction in 112 patients with chronic liver disease. The levels were positively correlated with serum AST and ALT levels in 59 of these patients whose prothrombin times were within the normal range. Abnormally increased serum human hepatocyte growth factor levels were found in 100% of the determinations in 16 patients with fulminant hepatic failure and in 80% of the determinations in 16 patients with chronic hepatic failure. The levels greater than 1 ng/ml, however, were found in 94% of determinations in the former group, but only in 16% of the determinations in the latter group. This difference was seen irrespective of prothrombin time or hepatic coma grades. In patients with fulminant hepatic failure serum human hepatocyte growth factor levels were increased immediately after plasma exchange using heparin as the anticoagulant in 71% of the determinations. This increase disappeared 12 hr after discontinuation of plasma exchange. In 17 of 39 patients with chronic renal failure who had no liver disease, serum human hepatocyte growth factor levels were abnormally increased before hemodialysis using heparin, and the levels were elevated immediately after hemodialysis in all the patients. The increase of serum human hepatocyte growth factor levels in hepatic failure may be the result of hepatocellular dysfunction and necrosis. Renal failure and extracorpored circulation may also increase serum human hepatocyte growth factor levels. The determination of the levels may be useful to differentiate fulminant and chronic types of hepatic failure. (HEPATOLOGY 1992;15: 1-4.)
PATIENTS AND METHODS patients. Sixteen patients with fulminant hepatic failure,
112 patients with chronic liver disease and 39 patients with chronic renal failure were studied. The criterion of fulminant hepatic failure was hepatic coma of grade I1 or more developing less than 8 wk after onset of symptoms of presumed acute hepatitis, with prothrombin time less than 40% of normal. Eight men andeight women with fulminant hepatic failure, average age 49 yr, were studied The cause was presumed to be hepatitis A in patient, 'HBV in patients and non-A, n0n-B hepatitis virus in 10 patients. Plasma exchange was performed using a membrane plasma separator with heparin in 12 patients and nafamostat mesylate in 4 patients as an antico&ulant in addition to the standard Drocedures for hepatic-failure. Seventy-five men and 37 women with chronic liver disease, average age 54 yr, were studied. The cause was presumed to be HBV in 2o patients, non-A*non-B hepatitis vlms In80 patients and alcohol consumption in l2patients. All these patients had neither HCC evaluated by abdominal ultrasonography or computed tomography nor renal disease
Human hepatowe growth factor (hHGF) is a beterodimer protein of 76 to 92 kD with four kringles in the (l, 2), which can stimulate DNA rat hepatocfies in primary (3)- Serum levels Of hHGF were reported to be increased in Patients with
Received February 4, 1991; accepted August 14,1991. Address reprint requests to: Kenji Fujiwara, M.D., First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. 3111133278
3
2
TOMIYA, NAGOSHI AND FUJIWARA TABLE1. Correlationsof serum hHGF levels with liver function tests in patients with chronic liver disease Parameters
Prothrombin timeb Serum albumin Serum cholinesterase Serum total bilirubin Serum conjugated biliruibin Serum total bile acid Serum AST In normal PT" In prolonged PT Serum ALT In normal PT In prolonged PT
Correlation coefficient"
p Value
- 0.62 - 0.60 -0.56 0.49 0.50 0.45 0.37 0.46 0.04 0.07 0.27 - 0.23
fulminant hepatic failure in relation to grades of hepatic coma (4). Similar factors with high homology in the amino acid sequence derived from other sources (hepatocyte growth factor; HGF) (5-8) have also been shown to be increased in the blood of animals given carbon tetrachloride (9-11)or after partial hepatedomy (11-13). Thus it is proposed that the increase of these factors in serum is associated with liver regeneration. Patients with fulminant hepatic failure not only have severe inflammation and necrosis of the liver resulting in hepatocellular dysfunction but also frequently have multiple organ failure including renal failure. Serum hHGF levels might be altered depending on these situations because HGF is shown to be synthesized in various kinds of cells and organs such as Kupffer cells (14,151,leukocytes (16) and the kidney (10, 17) and be able to act on cells other than hepatocytes (18). In addition, patients with hepatic failure receive various therapies, including artificial liver support systems, especially when hepatic coma progresses, which might affect clearance of proteins such as hHGF from the circulation. In this paper, we studied serum changes of hHGF in patients with liver disease of various types and renal failure to explain the mechanism of the increase of serum hHGF levels in patients with fulminant hepatic failure and to clarify the clinical significance of its measurement,
Serum human hepatocyte growth factor levels were measured using a newly developed enzyme-linked immunosorbent assay kit in patients with liver diseases. Serum human hepatocyte growth factor levels were increased in correlation with derangements of prothrombin time, total bilirubin and other parameters reflecting hepatocellular dysfunction in 112 patients with chronic liver disease. The levels were positively correlated with serum AST and ALT levels in 59 of these patients whose prothrombin times were within the normal range. Abnormally increased serum human hepatocyte growth factor levels were found in 100% of the determinations in 16 patients with fulminant hepatic failure and in 80% of the determinations in 16 patients with chronic hepatic failure. The levels greater than 1 ng/ml, however, were found in 94% of determinations in the former group, but only in 16% of the determinations in the latter group. This difference was seen irrespective of prothrombin time or hepatic coma grades. In patients with fulminant hepatic failure serum human hepatocyte growth factor levels were increased immediately after plasma exchange using heparin as the anticoagulant in 71% of the determinations. This increase disappeared 12 hr after discontinuation of plasma exchange. In 17 of 39 patients with chronic renal failure who had no liver disease, serum human hepatocyte growth factor levels were abnormally increased before hemodialysis using heparin, and the levels were elevated immediately after hemodialysis in all the patients. The increase of serum human hepatocyte growth factor levels in hepatic failure may be the result of hepatocellular dysfunction and necrosis. Renal failure and extracorpored circulation may also increase serum human hepatocyte growth factor levels. The determination of the levels may be useful to differentiate fulminant and chronic types of hepatic failure. (HEPATOLOGY 1992;15: 1-4.)
PATIENTS AND METHODS patients. Sixteen patients with fulminant hepatic failure,
112 patients with chronic liver disease and 39 patients with chronic renal failure were studied. The criterion of fulminant hepatic failure was hepatic coma of grade I1 or more developing less than 8 wk after onset of symptoms of presumed acute hepatitis, with prothrombin time less than 40% of normal. Eight men andeight women with fulminant hepatic failure, average age 49 yr, were studied The cause was presumed to be hepatitis A in patient, 'HBV in patients and non-A, n0n-B hepatitis virus in 10 patients. Plasma exchange was performed using a membrane plasma separator with heparin in 12 patients and nafamostat mesylate in 4 patients as an antico&ulant in addition to the standard Drocedures for hepatic-failure. Seventy-five men and 37 women with chronic liver disease, average age 54 yr, were studied. The cause was presumed to be HBV in 2o patients, non-A*non-B hepatitis vlms In80 patients and alcohol consumption in l2patients. All these patients had neither HCC evaluated by abdominal ultrasonography or computed tomography nor renal disease
Human hepatowe growth factor (hHGF) is a beterodimer protein of 76 to 92 kD with four kringles in the (l, 2), which can stimulate DNA rat hepatocfies in primary (3)- Serum levels Of hHGF were reported to be increased in Patients with
Received February 4, 1991; accepted August 14,1991. Address reprint requests to: Kenji Fujiwara, M.D., First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. 3111133278
3
2
TOMIYA, NAGOSHI AND FUJIWARA TABLE1. Correlationsof serum hHGF levels with liver function tests in patients with chronic liver disease Parameters
Prothrombin timeb Serum albumin Serum cholinesterase Serum total bilirubin Serum conjugated biliruibin Serum total bile acid Serum AST In normal PT" In prolonged PT Serum ALT In normal PT In prolonged PT
Correlation coefficient"
p Value
- 0.62 - 0.60 -0.56 0.49 0.50 0.45 0.37 0.46 0.04 0.07 0.27 - 0.23
