Portal serum human hepatocyte growth factor levels after partial hepatectomy.

BACKGROUND/AIMS: We investigated whether or not hepatocyte growth factor increases in portal serum via an endocrine mode after partial hepatectomy in humans. METHODOLOGY: Portal blood was sampled through a catheter inserted through the umbilical vein to the portal trunk during surgery in 17 patients. Serum human hepatocyte growth factor levels were determined by enzyme-linked immunosorbent assay. RESULTS: Human hepatocyte growth factor levels were higher in portal than in peripheral serum throughout the study. Portal and peripheral serum human hepatocyte growth factor levels without complications increased rapidly and reached a maximum level 1 day after partial hepatectomy. The maximal level of portal and peripheral serum human hepatocyte growth factor was 1.20 and 1.00 ng/ml, respectively. In the case of hepatic failure after partial hepatectomy, portal and peripheral serum human hepatocyte growth factor levels markedly increased and reached 9.31 ng/ml and 6.78 ng/ml 2 days before death, respectively. CONCLUSIONS: These results suggest that hepatocyte growth factor increases in portal serum via an endocrine mode after partial hepatectomy in humans. Furthermore, measurement of the portal and peripheral serum human hepatocyte growth factor levels may be useful for the clinical evaluation of patients with post-operative hepatic failure.     

Obesity is associated with increased levels of circulating hepatocyte growth factor

OBJECTIVES: This study evaluated whether obesity in humans was associated with an increase in circulating hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels. BACKGROUND: Obesity acts as a cardiovascular risk factor by mechanisms that are not fully understood. Adipose tissue is able to secrete multiple cytokines and growth factors ex vivo. We hypothesized that the increased presence of adipose tissue in obese subjects results in systemic elevations of the mitogenic factors HGF and VEGF. METHODS: Blood samples were obtained from lean (n = 21) and obese (n = 44) volunteers. Serum HGF and VEGF levels were assessed by enzyme-linked immunoadsorbent assay. Insulin and fasting glucose levels were measured to evaluate insulin sensitivity. Conditioned medium of adipose cells was assayed for HGF secretion. RESULTS: Serum HGF levels in obese subjects were more than three-fold higher than those of lean subjects (2,462 +/- 184 pg/ml vs. 765 +/- 48 pg/ml, p < 0.0001). The VEGF levels were not significantly elevated in obese subjects (135 +/- 31 pg/ml vs. 128 +/- 37 pg/ml). The HGF concentrations, but not VEGF concentrations, were significantly correlated with body mass index (BMI) (p < 0.0001, r = 0.74). The observed increases in HGF concentrations of obese subjects were not secondary to insulin resistance or hypertension. Freshly isolated human adipose cells secreted HGF. CONCLUSIONS: Our results indicate that obesity is associated with a marked increase in circulating HGF levels, which correlate linearly with BMI. Because vascular growth factors have been associated with the pathogenesis of atherosclerosis, the possible role of such humoral factors as a link between obesity and cardiovascular disease is very intriguing.     

Significance of serum human hepatocyte growth factor levels in patients with hepatic failure.

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.(ABSTRACT TRUNCATED AT 250 WORDS)     

Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis

OBJECTIVE: To determine whether elevated levels of the angiogenic cytokine vascular endothelial growth factor (VEGF), detected on presentation to an early arthritis clinic, are associated with the development of chronic and erosive arthritis. METHODS: Concentrations of VEGF and its soluble receptor, soluble fms-like tyrosine kinase 1 (sFlt-1), were measured by enzyme-linked immunosorbent assay in serum samples from patients with early (<2 years from onset) arthritic symptoms in the peripheral joints, namely early rheumatoid arthritis (RA), self-limiting arthritis (viral, reactive, and idiopathic inflammatory arthritis), or psoriatic arthritis. In addition, measurements were made in random samples from patients with longstanding (>3 years from symptom onset) RA treated with disease-modifying antirheumatic drugs, from patients with osteoarthritis (OA), and from patients with polyarthralgia without arthritis, as well as from nonarthritic controls. RESULTS: Serum VEGF levels at presentation were elevated in patients with inflammatory arthritis (RA, psoriatic, and self-limiting arthritis) as well as in patients with OA, in comparison with nonarthritic controls. Moreover, serum VEGF concentrations were significantly higher in patients with early RA than in patients with self-limiting arthritis. Serum VEGF levels at presentation in patients with early RA correlated significantly with the development of radiographic damage after 1 year. Improvement in the clinical symptoms of RA was associated with a reduction in serum VEGF levels. Serum sFlt-1 levels were raised in patients with early and longstanding RA and in those with self-limiting arthritis, and correlated positively with the serum VEGF concentrations in patients with inflammatory arthritis. CONCLUSION: These findings implicate the proangiogenic cytokine VEGF in the persistence of inflammatory arthritis, and support the hypothesis that expansion of the synovial vasculature is important for the development of joint destruction in RA.     

Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia

Hepatocyte growth factor (HGF) is a protein produced by mesenchymal cells in many organs, which can stimulate epithelial growth. An enhanced production and concentration of HGF is observed after injuries. The lung is one of the major sources of HGF. By cooling exhaled air, a condensate is formed containing molecules from bronchi and alveoli. In order to investigate HGF-concentration and time course in pneumonia, paired serum and exhaled breath condensate was collected from 10 patients with pneumonia, 10 patients with non-respiratory infections and 11 healthy controls. The concentration of HGF was measured by an immunoassay kit. In the acute phase HGF-levels in breath condensate and serum were significantly higher in the patients with pneumonia compared to the control groups. Similar concentrations in breath condensate were seen in healthy controls and in patients with non-respiratory infections. In the patients with pneumonia a decrease in serum HGF was seen already after 4-7 days while HGF values in breath condensate remained elevated even after 4-6 weeks. These results might imply local product on of HGF in the lungs and a long repair and healing process after pneumonia.     

Serum hepatocyte growth factor levels are increased in patients with congestive heart failure

BACKGROUND: Hepatocyte growth factor (HGF) is a potent endothelial cell-specific mitogen. We investigated the clinical importance of HGF in congestive heart failure (CHF). METHODS AND RESULTS: Thirty-five patients with acute exacerbation of CHF and 7 control subjects were examined. Serum and peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood on days 1, 7, and 14 after admission. PBMCs were cultured at a density of 1 x 10(7) cells/mL for 24 hours. HGF levels in serum and the PBMC culture medium and serum interleukin 6 (IL-6) levels were measured by enzyme-linked immunosorbent assay. Serum HGF levels in patients with CHF were markedly increased at admission compared with those in control subjects and gradually returned to control levels during hospitalization. HGF levels in the PBMC culture medium were also significantly increased in CHF patients compared with control subjects. There was a positive correlation between HGF levels in serum or those in the PBMC culture medium and serum IL-6 levels. HGF levels in serum and the culture medium were not notably different between CHF patients regularly treated with and without angiotensin-converting enzyme inhibitors. CONCLUSIONS: HGF levels in serum are increased in patients with acute exacerbation of CHF.     

Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is a common hepatic malignancy worldwide. Its nature of rapid growth results in a grave prognosis. Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, responsible for their proliferation. The aim of the present study was to investigate the prognostic roles of serum HGF in untreated HCC patients.Methods Fifty-five patients with inoperable HCC were studied. The diagnosis of HCC was based on either liver histopathology or imaging evidence of a liver mass, together with elevated serum alpha-fetoprotein. Serum HGF levels of the patients, at the time of diagnosis, were compared to those of 28 healthy controls. All patients received only palliative treatments and were followed up until they died. Comparison of survival curves between patients with a serum HGF level of 1.0ng/ml or more and those with lower serum HGF was performed, using the log-rank test. Data values are expressed as means and SD.Results Fifty-one men and four women with inoperable HCC were recruited. The mean age was 54.15 ± 15.34 years. The serum HGF levels in the inoperable HCC patients were significantly higher than those in the controls (0.58 ± 0.43 vs 0.14 ± 0.04ng/ml; P < 0.001). The patients mean survival time was 5.28 ± 6.73 months (range, 0.1–33 months). Serum HGF levels exhibited a negative correlation with the survival time (P = 0.032). In addition, HCC patients with serum HGF levels of 1.0ng/ml or more had a shorter survival time than the other HCC patients (P = 0.0025).Conclusions Patients with inoperable HCC had higher levels of serum HGF than the healthy controls, and serum HGF was negatively correlated with the survival time. Serum HGF levels of 1.0ng/ml or more in HCC patients are suggestive of a grave prognosis, indicating that HGF plays important and active roles in the disease progression. The detailed mechanisms need to be further investigated.     

Low circulating insulin-like growth factor-1 levels are associated with high serum uric acid in nondiabetic adult subjects

Background and aimsLow insulin-like growth factor-1 (IGF-1) levels and high uric acid concentrations are associated with cardio-metabolic disorders. Acute IGF-1 infusion decreases uric acid concentration in healthy individuals. In this study, we aimed to examine the relationship between IGF-1 and uric acid levels.Methods and results1430 adult non diabetic subjects were stratified into quartiles according to their circulating IGF-1 values. Significant differences in uric acid concentration, measured by the URICASE/POD method were observed between low (quartile 1), intermediate (quartile 2 and 3), and high (quartile 4) IGF-1 levels groups after adjusting for age, gender, and body mass index (P = 0.02). These differences remained significant after adjustment for blood pressure, total cholesterol, high density lipoprotein, triglycerides, fasting and 2 h post-load glucose levels, HOMA-IR index (P = 0.005), liver enzymes (P = 0.03), glucose tolerance status (P = 0.02), growth hormone levels (GH) (P = 0.05), anti-hypertensive treatments (P = 0.04) or diuretics use (P = 0.04)). To clarify the molecular links between IGF-1 and uric acid, we performed an in vitro study, incubating human hepatoma cells with uric acid for 24 or 48 h in the presence of GH and observed a 21% and 26% decrease, respectively, in GH-stimulated IGF-1 mRNA expression (P = 0.02 and P = 0.012, respectively). This effect appears to be mediated by uric acid ability to down regulate GH intracellular signaling; in fact we observed a significant decrease of GH activated JAK2 and Stat5 phosphorylation.ConclusionsThese data demonstrate an inverse relationship between IGF-1 and uric acid levels in adults and suggest that uric acid might affect hepatic IGF-1 synthesis.     

Peritoneal fluid contains high concentration of hepatocyte growth factor and vascular endothelial growth factor after resection for hepatocellular carcinoma

BACKGROUND/AIMS: Surges in blood growth factor levels is a typical response to surgical stress. However, growth factor profiles in peritoneal fluid after hepatectomy for hepatocellular carcinoma (HCC) have not been clarified. We evaluated hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in blood and peritoneal fluid preoperatively and postoperatively. METHODOLOGY: Serial blood and peritoneal fluid samples were collected from 47 patients who underwent curative hepatectomy for primary HCC at a university hospital. Blood samples were collected postoperative days 0, 1, 3, 5, and 7; peritoneal fluid was collected at the same time except day 0. VEGF and HGF concentrations were determined, and correlations between concentrations and clinical parameters of HCC were analyzed. RESULTS: HGF surges appeared postoperatively in blood and peritoneal fluid; concentrations paralleled each other. There was no postoperative surge of VEGF in blood, but peritoneal fluid VEGF concentration was remarkably high after hepatectomy. Both HGF and VEGF levels in blood and peritoneal fluid correlated with some clinical parameters. The difference in HGF and VEGF patterns in blood and peritoneal fluid imply that the origins of these two growth factors differ. CONCLUSIONS: Post-hepatectomy, VEGF and HGF levels surged in peritoneal fluid, whereas only HGF surged in blood, suggesting independent origins for the two growth factors. Both VEGF and HGF concentrations correlated with some clinical parameters.     

High serum hepatocyte growth factor levels in the acute stage of community-acquired infectious diseases

Acute serum levels of hepatocyte growth factor (HGF) were studied in 6 clinical groups with (i) gastroenteritis, (ii) skin and soft tissue infection, (iii) urinary tract infection, (iv) septicemia, (v) influenza, and (vi) chronic hepatitis C in comparison with a normal control group using an enzyme-linked immunosorbent assay method. We found that serum HGF levels were significantly higher in patients with acute infectious diseases (p < 0.0001) compared to patients with chronic viral hepatitis and healthy controls. Serum HGF and CRP levels were correlated significantly (r=0.65, p < 10(-7)). We conclude that serum HGF levels are elevated in patients with acute infectious diseases.     

Serum endothelin-1 and hepatocyte growth factor levels in patients with obstructive jaundice.

BACKGROUND/AIMS: Endothelin-1, a potent vasoconstrictive peptide, is known to modulate changes in local circulation. Additionally, hepatocyte growth factor, a potent mitogen for hepatocytes, is increased in various liver diseases. The present study examined changes in serum endothelin-1 and hepatocyte growth factor levels in patients with obstructive jaundice before and after percutaneous transhepatic cholangio drainage. METHODOLOGY: Endothelin-1 and hepatocyte growth factor levels were measured by enzyme-linked immunosorbent assay using sera from 16 patients with obstructive jaundice before and after percutaneous transhepatic cholangio drainage. RESULTS: Serum endothelin-1 levels decreased rapidly in the good bilirubin decrease group after biliary drainage. Endothelin-1 levels decreased 1 week after drainage but then increased gradually in the worse bilirubin decrease group. Serum hepatocyte growth factor levels decreased gradually after biliary drainage, and were higher in the worse bilirubin decrease group than in the good bilirubin decrease group throughout the study. CONCLUSIONS: These results suggest that endothelin-1 may be associated with the microcirculatory disturbance in obstructive jaundice and prolonged cholestasis. Measurement of hepatocyte growth factor levels in patients with obstructive jaundice before percutaneous transhepatic cholangio drainage may be an early clinical predictor of the subsequent rate of decrease of the serum bilirubin concentration.     

Hepatocellular carcinoma associated with hemophagocytic syndrome.

Hepatocellular carcinoma may manifest various paraneoplastic syndromes. There are some reports describing hematological change due to hepatocellular carcinoma. However, there have been no reports on hepatocellular carcinoma accompanied by hemophagocytic syndrome. We report here for the first time a 51-year-old man with a liver tumor and pancytopenia. Since the patient had showed a strong hemorrhagic diathesis because of thrombocytopenia, we treated him with blood transfusion, but there was no response. Thereafter, we administered the anticancer agents thinking that the hematological change was due to the liver tumor. Though a slight curative effect was obtained, we had to discontinue the treatment because the patient complained of severe side effects. Finally, the patient died of acute cholangitis. Although we could not determine the cause of the pancytopenia before he died, autopsy findings indicated that hemophagocytic syndrome had occurred. Hemophagocytic syndrome related to a solid tumor very rarely occurs. However, when malignant tumor is accompanied by pancytopenia, hemophagocytic syndrome should be considered.     

关于高血压患者血清HGF、sICAM-1水平的研究（英文）

目的：探讨高血压患者血清肝细胞生长因子（HGF）,可溶性细胞间黏附分子-1（sICAM-1）水平的变化及其意义。方法：选择59例高血压患者,其中高血压1级组20例,高血压2级组19例,高血压3级组20例,并选择30例健康体检者作为正常对照组。用酶联免疫双抗体夹心法检测各组血清HGF和sICAM-1浓度,并进行比较。结果：与正常对照组相比,高血压患者血清HGF[（641.65±142.90）pg/ml比（998.15±241.38）pg/ml]、sI-CAM-1[（161.70±32.36）ng/ml比（327.17±31.28）ng/ml]水平明显升高（P〈0.01）,血压越高,其变化越显著（P〈0.01）,HGF浓度与sICAM-1浓度呈正相关（r=0.317,P〈0.01）。结论：HGF与sICAM-1可能参与了高血压的发病过程,而且HGF在高血压内皮细胞损伤的修复中可能具有重要作用。     

Serum hepatocyte growth factor levels in hepatectomized and nonhepatectomized surgical patients.

Serum hepatocyte growth factor levels were measured in hepatectomized and nonhepatectomized surgical patients. The levels were significantly increased and reached a maximum within 7 days after surgery in both groups, returning to preoperative levels 28 days after partial hepatectomy and 7 days after other operations. Multiple regression analysis showed that such maximal hepatocyte growth factor levels were significantly related to having liver cirrhosis and postoperative maximal serum total bilirubin and alanine aminotransferase levels and peripheral white blood cell counts in the hepatectomized group and to postoperative maximal peripheral white blood cell counts and serum C-reactive protein levels in the nonhepatectomized group. However, the levels showed no relation to the resected liver volume and increment of the remaining liver volume 28 days after partial hepatectomy. It is concluded that serum hepatocyte growth factor levels were increased after partial hepatectomy in association with hepatocellular dysfunction and necrosis and systemic inflammation. It is unlikely that the increase was related to liver regeneration.     

Human hepatocyte growth factor levels in patients undergoing thoracic operations.

Human hepatocyte growth factor (hHGF) is the most potent mitogen identified for alveolar type II cells, and may have other important functions in the repair of the alveolar epithelium and compensatory lung growth. A study was conducted to evaluate the changes of serum hHGF levels in patients who underwent thoracic surgical procedures. The patients comprised 17 males and 14 females with a mean age of 47.1+/-13.5 yrs, who underwent either lung resection (LR group) or nonlung resection (nonLR group) thoracic procedures. The changes of hHGF levels were analysed in the pre- and post-operative periods in both groups. The pre-operative hHGF levels did not differ between the LR and the nonLR groups, which were 333.2+/-72.9 pg x mL(-1) and 343.6+/-125.3 pg x mL(-1), respectively. The hHGF levels in the LR group significantly increased up to 433.6+/-128.1 pg x mL(-1) and 430.8+/-128.2 pg x mL(-1) in post-operative days 1 and 3, respectively. However, the same levels in the nonLR group appeared as 333.2+/-77.0 pg x mL(-1) and 311.9+/-73.0 pg x mL(-1), respectively. In conclusion, the increases of serum human hepatocyte growth factor levels following pulmonary resection may imply the important role of human hepatocyte growth factor in lung regeneration or compensatory lung growth in humans.     

Prognostic value of serum hepatocyte growth factor in patients with acute coronary syndromes.

The present study examined whether or not hepatocyte growth factor (HGF), an endothelium-specific growth factor that stimulates regeneration of the endothelium, is increased or has a prognostic significance in patients with acute coronary syndromes. HGF was measured in 106 patients with coronary artery disease (20 stable effort angina, 12 unstable angina without adverse events, 24 unstable angina with adverse events and 50 acute myocardial infarction) on admission and 21 normal volunteers. The measurements in all patients were recorded before administration of heparin, and in acute myocardial infarction patients they were recorded from days 2 to 6 after heparin discontinuation on day 1. HGF levels (ng/ml) were 0.30+/-0.06 for the controls, 0.31+/-0.08 for stable effort angina patients, 0.31+/-0.08 for unstable angina patients without adverse events, 0.40+/-0.20 for unstable angina patients with adverse events and in acute myocardial infarction patients they were 0.45+/-0.18 on day 0, 0.57+/-0.45 on day 2, 0.50+/-0.35 on day 3, 0.48+/-0.32 on day 4, 0.44+/-0.20 on day 5, and 0.38+/-0.14 on day 6. HGF plays a crucial role in the restoration of injured endothelial cells and is a predictor of adverse events in patients with acute coronary syndromes.     

Hepatocellular carcinoma and cholangiocarcinoma: an update

Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide and is rising in incidence. Ultrasound is the preferred modality for screening high-risk patients for HCC because it detects clinically significant nodules, widespread availability and lower cost. HCC does not require a biopsy for diagnosis if specific imaging criteria are fulfilled. Transarterial chemoembolization (TACE) is the most common modality used to treat HCC followed by ablation. Cholangiocarcinoma (CCA) is increasing in incidence and the second most common primary malignancy of the liver. There is no effective screening strategy for CCA although magnetic resonance imaging and carbohydrate antigen 19-9 (CA 19-9) are commonly used without proven benefit. Therapy for CCA is challenging and resection, when possible, is the mainstay of therapy. Gemcitabine in combination with cisplatin or biologics may offer a modest survival benefit. Liver transplantation for CCA is associated with reasonable survival in select cases. Molecular diagnostics offer the potential to develop personalized approaches in the management of HCC and CCA.     

Felty''s syndrome associated with high levels of IgA rheumatoid factor.

A 64-year-old woman with rheumatoid arthritis developed Felty's syndrome. Her serum contained large amounts of IgA rheumatoid factor (RF) but insignificant levels of IgM-RF and IgG-RF. It is postulated that the high levels of IgA-RF may have contributed to the neutropenia.