Liver regeneration and the effect of exogenous putrescine on regenerative activity after partial hepatectomy in cirrhotic rats.

There are conflicting data regarding the ability of the liver to regenerate after partial hepatectomy in animals and humans with cirrhosis. The purpose of this study was to document liver regeneration after partial hepatectomy in a carbon tetrachloride rat model of cirrhosis and to determine whether exogenous putrescine, a polyamine that has been reported to stimulate liver regeneration in animal models of acute liver failure, enhances regenerative activity in cirrhosis. Liver fibrosis and cirrhosis were produced by weekly intragastric gavage with carbon tetrachloride in 130 adult male rats. Vehicle-gavaged rats (n = 12) served as healthy controls. At surgery and at 4 and 8 hr after 70% hepatectomy, rats received normal saline solution or 1 or 10 mg/kg putrescine by intraperitoneal injection. Another group (n = 32) of carbon tetrachloride-treated rats was given putrescine (100 mg/kg) or normal saline solution twice daily for 10 days before partial hepatectomy and at 0, 4 and 8 hr after partial hepatectomy. Liver regeneration was documented 24 and 48 hr after partial hepatectomy on the basis of restitution of liver mass, ornithine decarboxylase activity and [3H]thymidine incorporation into liver DNA. Automated image analysis of the resected liver specimens separated carbon tetrachloride-treated rats into two subgroups: those with bridging fibrosis (fibrotic group) and those with micronodular cirrhosis (cirrhotic group). Restitution of liver mass and ornithine decarboxylase activity at 24 and 48 hr after partial hepatectomy were similar to carbon tetrachloride-treated rats (both fibrotic and cirrhotic) and vehicle-treated healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats

BACKGROUND AND AIM: The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle-related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats. METHODS: We performed 70% partial hepatectomy in both control and porcine serum-induced fibrotic rats, and 45% partial hepatectomy in thioacetamide-induced cirrhotic rats because of the high mortality associated with 70% partial hepatectomy. Liver regeneration was monitored by proliferating cell nuclear antigen labeling index and the expression of G1 regulatory cell cycle-related proteins was determined by immunoblot analysis. RESULTS: Compared with controls, hepatocyte DNA synthesis, and induction of cyclin D1 and p21(CIP1) proteins were delayed but not suppressed in porcine serum-induced fibrotic rats and markedly inhibited in thioacetamide-induced cirrhotic rats. p27(KIP1) protein levels were unaffected by partial hepatectomy and did not differ among all three groups. CONCLUSION: Two distinct rat models of liver fibrosis and cirrhosis showed markedly different proliferative responses after partial hepatectomy. The delay or failure of cyclin D1 induction, but not the increase of p21(CIP1) or p27(KIP1) might be responsible for their impaired liver regeneration.     

Expressions of molecules associated with hepatocyte growth factor activation after hepatectomy in liver cirrhosis

BACKGROUND/AIMS: The activation pathway of hepatocyte growth factor (HGF), including HGF activator (HGFA) and HGFA inhibitor-1, 2 (HAI-1, 2), has recently been clarified. The present study examined mRNA expressions of HGF, HGFA and HAI-1 following partial hepatectomy in normal and cirrhotic rats. METHODOLOGY: Liver cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine. Two weeks after, the cirrhotic and normal rats underwent 70% hepatectomy and the liver regeneration rate, DNA synthesis of hepatocytes, plasma HGF level, and mRNA expressions of HGF, HGFA, and HAI-1 in the liver, spleen, and lung were examined at different times. RESULTS: Liver regeneration in the cirrhotic rats was deteriorated with a later peak of hepatocellular DNA synthesis. Hepatic HGF mRNA and splenic HAI-1 mRNA were upregulated and liver HGFA mRNA was downregulated in the cirrhotic rats. CONCLUSIONS: Insufficient HGF activation both by a reduced expression of hepatic HGFA and an increased expression of splenic HAI-1 may be one of the reasons for the impaired liver regeneration in cirrhosis.     

Tumor progression in hepatocellular carcinoma: relationship with tumor stroma and parenchymal disease

BACKGROUND: Encapsulation in hepatocellular carcinoma is associated with decreased invasiveness and improved survival in several series. Although active fibrogenesis by myofibroblasts has been demonstrated in the capsule, it is unclear if the capsule results from a general increase in peritumoral fibrosis, or an inherently less invasive tumor phenotype. The relationship between collagen deposition within tumor stroma, presence of cirrhosis and invasiveness also needs clarification. METHODS: We performed immunohistochemistry for collagens I, III, IV and VI on sections of encapsulated and non-encapsulated hepatocellular carcinoma, arising in cirrhotic and non-cirrhotic livers. Staining was graded semi-quantitatively in tumor stromal elements and adjacent parenchymal sinusoids. The relationship of this staining with encapsulation, cirrhosis, and vascular invasion was analyzed. RESULTS: Formation of a discrete capsular layer was associated with reduced vascular invasion, but not with a pervasive increase in peritumoral fibrosis. Increased collagen I content of tumor stroma and adjacent parenchymal sinusoids was associated with non-encapsulated tumors and vascular invasion. The presence of cirrhosis had little effect on capsule composition. CONCLUSIONS: Encapsulation of hepatocellular carcinoma reflects reduced invasiveness, rather than increased peritumoral collagen synthesis, which may instead enhance invasion. Increased intratumoral collagen I protein is also associated with increased tumor invasiveness. Pre-existing cirrhosis has little effect on tumor progression, possibly because the characteristics of cirrhosis are overwhelmed by tumor-induced changes in the adjacent parenchyma.     

Heparin accelerates liver regeneration following portal branch ligation in normal and cirrhotic rats with increased plasma hepatocyte growth factor levels

BACKGROUND/AIMS: Heparin is widely used as a general anticoagulant, and has been recently reported to elevate plasma hepatocyte growth factor (HGF) levels by releasing HGF sequestrated in the extracellular matrix. Therefore, we investigated the effects of heparin administration on liver regeneration following portal branch ligation (PBL) in normal and cirrhotic rats. METHODS: Dimethylnitrosamine-induced cirrhotic rats and control rats underwent portal ligation of the left lateral and median branches, followed by intraperitoneal heparin injections, every 12 h. To examine the feasibility of an extensive hepatectomy in the cirrhotic livers, cirrhotic rats with or without heparin treatment underwent resection of occluded lobes at 72 h after the PBL. RESULTS: Heparin injections significantly augmented liver regeneration after PBL in both normal and cirrhotic rats, following an increase in hepatocellular DNA synthesis at 24 h after the PBL. The plasma HGF concentrations were elevated by heparin treatment in both groups. In addition, heparin administration dramatically improved the survival rate after an extensive hepatectomy in the cirrhotic rats. CONCLUSIONS: Heparin treatment significantly accelerated liver regeneration following the PBL, with an increase in the plasma HGF levels in both normal and cirrhotic rats. Heparin administration may make an extensive hepatectomy clinically feasible even for cirrhotic livers.     

Role of angiotensin‐1 receptor blockade in cirrhotic liver resection

Background: The regeneration capacity of cirrhotic livers might be affected by angiotensin‐1 (AT1) receptors located on hepatic stellate cells (HSC). The effect of AT1 receptor blockade on microcirculation, fibrosis and liver regeneration was investigated. Materials and methods: In 112 Lewis rats, cirrhosis was induced by repetitive intraperitoneal injections of CCl₄. Six hours, 3, 7 and 14 days after partial hepatectomy or sham operation, rats were sacrificed for analysis. Animals were treated with either vehicle or 5 mg/kg body weight losartan pre‐operatively and once daily after surgery by gavage. Microcirculation and portal vein flow were investigated at 6 h. The degree of cirrhosis was assessed by Azan Heidenhein staining, activation of HSC by desmin staining, apoptosis by ssDNA detection and liver regeneration by Ki‐67 staining. Changes in expression of various genes important for liver regeneration and fibrosis were analysed at 6 h and 3 days. Haemodynamic parameters and liver enzymes were monitored. Results: Losartan treatment increased sinusoidal diameter, sinusoidal blood flow and portal vein flow after partial hepatectomy (P<0.05), but not after sham operation. AT1 receptor blockade resulted in increased apoptosis early after resection. HSC activation was reduced and after 7 days, a significantly lower degree of cirrhosis in resected animals was observed. Losartan increased the proliferation of hepatocytes at late time‐points and of non‐parenchymal cells early after partial hepatectomy (P<0.05). Tumour necrosis factor (TNF)‐α was significantly upregulated at 6 h and stem cell growth factor (SCF) was downregulated at 3 days (P<0.05). Conclusion: Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.     

Activated protein C prevents multiple organ injury following extensive hepatectomy in cirrhotic rats

BACKGROUND/AIMS: Extended hepatectomy for cirrhotic liver in patients with hepatocellular carcinoma often triggers posthepatectomy liver failure. It has been shown that the microcirculatory disturbance caused by microthrombus formation and sinusoidal endothelial cellular injury is one of the causes of post-hepatectomy liver dysfunction. We therefore investigated the effect of activated protein C (APC), a potent antithrombotic serine protease with anti-inflammatory effects, on posthepatectomy liver dysfunction and multiple organ injury in cirrhotic rats. METHODS/RESULTS: Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received lipopolysaccharide (200 microg/kg) 48 h later to prepare a lethal posthepatectomy acute liver failure model. APC (1500 U/kg), given intravenously 15 min before and 1 h after endotoxin challenge, attenuated liver dysfunction and decreased serum tumor necrosis factor-alpha concentration. APC significantly improved the survival rate of rats at 12 h after endotoxin challenge. Histological examination revealed that APC treatment inhibited not only intrasinusoidal fibrin deposition and massive hepatocellular necrosis but also pulmonary injury and glomerular fibrin deposition. Immunohistochemically, expression of intercellular adhesion molecule-1 on sinusoidal cells and renal glomeruli was decreased in the APC-treated animals. CONCLUSIONS: APC administration prevented acute liver dysfunction and attenuated multiple organ injury following extended hepatectomy in cirrhotic rats, possibly via anticoagulant and anti-inflammatory effects.     

Decompensated hepatitis B virus-related cirrhosis successfully treated with lamivudine allowing surgery for hepatocellular carcinoma

A 39-year-old man was diagnosed with hepatitis B virus-related cirrhosis, and because of hepatic exacerbations with icterus and ascites, he had been repeatedly hospitalized. He was treated with lamivudine. Several months later, his ascites disappeared and his liver function was improved from class C to A according to the Child-Pugh classification. Two years later, one small hepatocellular carcinoma was detected, and he underwent a successful hepatectomy. From this case, we consider lamivudine to be useful for improving hepatic function in decompensated liver cirrhosis type B and lamivudine might enable surgical resection of hepatocellular carcinoma.     

Serum markers of liver fibrosis and histologic severity of fibrosis in resected liver

BACKGROUND/AIMS: Serum concentrations of the 7S fragment of type IV collagen (7S collagen), amino-terminal propeptide of type III procollagen (PIIIP), and hyaluronic acid (HA) have been reported to serve as serologic markers of liver fibrosis in hepatitis and cirrhosis. We investigated whether these fibrosis markers reliably reflect histologic changes in the livers of patients with hepatocellular carcinoma. METHODOLOGY: Subjects included 165 patients undergoing liver resection for hepatocellular carcinoma. Most were seropositive for chronic hepatitis B or C. Histopathologic changes in liver tissue resected with the tumor were scored according to Knodell's histologic activity index. Serum was sampled for assays shortly before surgery. RESULTS: Significant correlations were found between hepatitis activity score and 7S collagen, PIIIP, and HA. Concentrations of 7S collagen differed significantly between activity grades, but differences were not significant for PIIIP or HA. Significant correlations were found between fibrosis staging score and all these three markers. When patients were divided according to activity grade, 7S collagen showed stronger correlation with fibrosis staging score than did PIIIP or HA. CONCLUSIONS: The 7S collagen fragment correlated more strongly than PIIIP or HA with stage and activity grade in patients with hepatocellular carcinoma. However, overlapping of results between histologically defined groups appeared to limit clinical diagnostic usefulness of all markers in individual patients.     

Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats

Hepatic fibrosis is associated with activation of hepatic stellate cells (HSC), the major source of the extracellular matrix (ECM) proteins. The predominant ECM protein synthesized by the HSC is collagen type I. We evaluated the effect of halofuginone-an inhibitor of collagen synthesis-on thioacetamide (TAA)-induced liver fibrosis in rats. In the control rats the HSC did not express smooth muscle actin, collagen type I gene, or tissue inhibitor of metalloproteinases-2 (TIMP-2), suggesting that they were in their quiescent state. When treated with TAA, the livers displayed large fibrous septa, which were populated by smooth muscle actin-positive cells expressing high levels of the collagen alpha1(I) gene and containing high levels of TIMP-2, all of which are characteristic of advanced fibrosis. Halofuginone given orally before fibrosis induction prevented the activation of most of the stellate cells and the remaining cells expressed low levels of collagen alpha1(I) gene, resulting in low levels of collagen. The level of TIMP-2 was almost the same as in the control livers. When given to rats with established fibrosis, halofuginone caused almost complete resolution of the fibrotic condition. The levels of collagen, collagen alpha1(I) gene expression, TIMP-2 content, and smooth muscle actin-positive cells were as in the control rats. Halofuginone inhibited the proliferation of other cell types of the fibrotic liver in vivo and inhibited collagen production and collagen alpha1(I) gene expression in the SV40-immortalized rat HSC-T6 cells in vitro. These results suggest that halofuginone may become an effective and novel mode of therapy in the treatment of liver fibrosis.     

Cholangiocarcinoma arising in Von Meyenburg complex associated with hepatocellular carcinoma in genetic haemochromatosis

A 61-year-old man had a liver resection for a bilobar mass thought to be, by imaging techniques, an hepatocellular carcinoma. He had been treated for the last 12 years by venesections for genetic haemochromatosis complicated by well-compensated cirrhosis. At surgery, prothrombin time and platelet count were normal, as was alpha-fetoprotein. On the resected specimen, the non-tumoral liver was not cirrhotic; septal fibrosis was present as well as mild iron overload and numerous Von Meyenburg complexes. The bilobar tumour was composed of two different parts: one was a cholangiocarcinoma arising from Von Meyenburg complexes, the other was a moderately differentiated hepatocellular carcinoma with a partially invaded capsule. The two tumours, in close proximity, did not communicate. This observation raises three questions: the relative risk of primary liver cancer including both hepatocellular carcinoma and cholangiocarcinoma in haemochromatosis without cirrhosis; the development of cholangiocarcinoma from Von Meyenburg complexes; the reversibility of cirrhosis in treated patients.     

Cardiotrophin‐1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation

Background/Aim: Hepatic resection is not applicable to a certain proportion of hepatocellular carcinoma patients owing to an insufficient liver function reserve. The present study was designed to investigate the effects of cardiotrophin‐1 (CT‐1) on improving the function of CCl₄‐induced cirrhotic liver remnant after major hepatectomy. Methods: CT‐1 was administered to rats after hepatectomy according to different protocols. Results: A double‐dose CT‐1 protocol improved liver function, enlarged the volume of liver remnant, upregulated the expression of von Willebrand factor and increased the number of BrdU⁺ or Ki‐67⁺ hepatocytes. Administration of CT‐1 enhanced the expression of nuclear factor‐κB (P65), vascular endothelial growth factor (VEGF), CyclinD1 and p42/44 in the liver remnant. However, the effects of CT‐1 were blocked by a VEGF receptor blocker, PTK787. Although the expression of gp130, a receptor of CT‐1, was downregulated in the diseased hepatocytes isolated from the cirrhotic liver, CT‐1 could still stimulate the cell proliferation. CT‐1 administration enhanced the expression of P65 and VEGF in the diseased hepatocytes, but the augmented P65 and VEGF expression was blocked by PTK787 administration. Conclusion: Short‐term administration of CT‐1 could improve the function of cirrhotic liver remnant and stimulate liver regeneration through promotion of angiogenesis and cell proliferation.     

Effects of recombinant human growth hormone on remnant liver after hepatectomy in hepatocellular carcinoma with cirrhosis

AIM: To explore the effects of recombinant human growth hormone (rhGH) on the remnant liver after hepatectomy in hepatocellular carcinoma with liver cirrhosis. METHODS: Twenty-four patients with hepatocellular carcinoma who underwent hepatectomy were randomly divided into 2 groups: parenteral nutrition (PN) group (n=12) and rhGH+PN group (n=12). Liver function, blood glucose, AFP, serum prealbumin and transferrin were detected before operation, at post-operative d 1 and d 6. Albumin (ALB) mRNA in liver biopsy specimens was detected by RT-PCR at post-operative d 6. Liver Ki67 immunohistochemical staining was studied. RESULTS: On post-operative d 6, compared with PN group, the levels of blood glucose, serum prealbumin, transferrin, the expression of hepatic ALB mRNA and liver Ki67 labeling index were higher in rhGH+PN group. CONCLUSION: rhGH can improve protein synthesis and liver regeneration after hepatectomy in hepatocellular carcinoma with liver cirrhosis.     

Effect of granulocyte-macrophage colony-stimulating factor on hepatic regeneration after 70% hepatectomy in normal and cirrhotic rats

BackgroundPost-hepatectomy liver insufficiency is one of the most serious postoperative problems and its prevention is important after major hepatic resection, especially in the cirrhotic liver. Some growth factors and cytokines appear to play important roles in liver regeneration. In the present study we have investigated the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hepatic regeneration after 70% partial hepatectomy (PH) in cirrhotic and non-cirrhotic rats.MethodsA rat model of liver cirrhosis was prepared using thioacetamide (TAA) (a dose of 20 mg/100 g body w, intra-peritoneally) on three days a week for 12 weeks. Adult male rats were divided into four groups:Group 1 (n=10) no cirrhosis and no GM-CSF; Group 2 (n=10) no cirrhosis and GM-CSF; Group 3 (n=10) cirrhosis and no GM-CSF; and Group 4 (n=10) cirrhosis and GM-CSF. All the rats underwent a 70% hepatectomy, and GM-CSF was administrated immediately after operation in Groups 2 and 4. On postoperative days 2 and 7, fresh samples from the remnant liver were obtained to evaluate its regenerative capacity.The liver regenerative process was estimated by DNA synthesis, using flow cytometry.ResultsProliferation index (PI) of hepatocytes at 48 h was higher in Group 4 rats than Group 3 rats (p<0.05). On postoperative day 7, PI was elevated in Group 3 rats compared with Group 4 rats, but this difference was not statistically significant. In non-cirrhotic rats given GM-CSF, PI was increased compared with Group 1 rats at day 2 (p<0.05), but not at day 7.ConclusionsThe findings suggest that the proliferative capacity of liver cells is impaired and delayed after 70% PH in cirrhotic rat liver. GM-CSF administration might enhance the liver PI in both normal and TAA-induced cirrhotic rats.     

Hepatic resection for hepatocellular carcinoma existing with liver cirrhosis

BACKGROUND/AIMS: Hepatocellular carcinoma is usually complicated with liver cirrhosis, which makes its treatment difficult. Also a high rate of recurrence exists after surgical resection. However, how the prognosis after surgical treatment is affected by the severity of coexisting cirrhosis has not been clarified. METHODOLOGY: We compared the postoperative longterm courses of hepatocellular carcinoma patients with cirrhosis according to the liver function. All 112 hepatocellular carcinoma patients in this study underwent curative hepatic resection, and were classified into three groups according to the severity of liver dysfunction. The ICG R15' (indocyanine green retention test) normal: < 10%) was used in this study. Patients whose ICG R15' was less than 20% were classified as group I of 62, patients equal to 20% or between 20% and 30% as group II of 24, and patients equal to and more than 30% as group III of 26. RESULTS: In this series, 76 of 112 patients had recurrence (68%). A second hepatic resection was performed in six cases of group I and one case in group II. Fifty-eight of 76 recurrent cases (76%) were treated with transcatheter arterial chemoembolization. A total of eleven cases had no transcatheter arterial chemoembolization in the three groups: 3 cases in group I, 5 cases in group II, and 3 cases in group III; The three cases of group III had no treatment because of extremely poor liver dysfunction, whilst the 8 patients without transcatheter arterial chemoembolization in groups I and II had hepatocellular carcinoma itself and other diseases. The 1-, 3-, and 5-year survival rates after recurrence were 92%, 48%, and 14%, respectively, in group I; 83%, 37%, 12%, respectively, in group II; and 66%, 30%, 0%, respectively, in group III. The prognosis was significantly worse according to the degree of liver dysfunction (p = 0.0206). CONCLUSIONS: The prognosis of hepatocellular carcinoma with liver cirrhosis is affected not only by hepatocellular carcinoma itself, but also by the severity of the coexisting cirrhosis. Moreover, the cirrhotic liver can decline due to surgery. Surgical resection of this disease should be performed after careful patient selection and using a less invasive technique.     

Impaired activities of cyclic adenosine monophosphate-responsive element binding protein, protein kinase A and calcium-independent phospholipase A2 are involved in deteriorated regeneration of cirrhotic liver after partial hepatectomy in rats

Aims: This study is to elucidate whether cyclic adenosine monophosphate (cAMP)-mediated signal is involved in lower regenerative potential of cirrhotic liver. Methods: Hepatic cAMP concentration, activities of protein kinase A (PKA), c-AMP responsive element binding protein (CREB) and Ca(2+) -independent phospholipase A(2) (iPLA2) and regeneration rate were compared between rats with thioacetamide-induced cirrhotic and normal livers after two-third hepatectomy. Results: The liver regeneration estimated by the rates of [(3) H]-thymidine incorporation and staining of proliferating cell nuclear antigen was significantly lower in the cirrhotic group. CREB, PKA and iPLA2 activities, assessed by western blots and electromobility shift assay, were significantly impaired after hepatectomy in the cirrhosis group. PKA and iPLA2 silencing by siRNA transfection significantly inhibited CREB activity and cell growth in transformed hepatocytes in vitro. Conclusions: CREB dysfunction, mediated by PKA and iPLA2 suppression, may be involved in the deteriorated liver regeneration in the cirrhotic rats.     

Hepatic resection for hepatocellular carcinoma in diameter of > or = 10 cm

BACKGROUND/AIMS: Definitive efficacy of hepatic resection for hepatocellular carcinoma larger than or equal to 10 cm in diameter remains to be resolved. METHODOLOGY: The surgical outcomes in 33 consecutive patients with hepatocellular carcinoma in diameter of > or = 10 cm who underwent hepatic resection were retrospectively clarified. Postresection prognostic factors were evaluated by univariate and multivariate analysis using Cox's proportional hazards model. RESULTS: The overall incidence of postoperative complications was 39%, and 5 patients among them had hospital deaths (15%) including 2 (6%) operative deaths. The 3-year, 5-year, and 9-year overall survival rates after hepatic resection were 32%, 27%, and 17%, respectively. Univariate analysis revealed that liver cirrhosis and stage IV-A (pTNM staging) were significant factors of poor overall survival. By Cox's proportional hazards model, liver cirrhosis was an independently unfavorable prognostic factor of long-term survival. Hospital mortality rate in patients with cirrhosis was 31%. The 5-year overall survival rate in patients with cirrhosis (7%) was significantly shorter than that in patients without cirrhosis (43%) (P = 0.006). In addition, the 5-year overall survival rate in patients with stage IV-A (11%) was significantly shorter than that in patients with stage II and III (48%) (P = 0.024). The incidence of stage IV-A in patients with cirrhosis (77%) was significantly higher than those without cirrhosis (35%) (P = 0.032). CONCLUSIONS: Hepatic resection for hepatocellular carcinoma in diameter of > or = 10 cm was effective for patients without liver cirrhosis and with stage II or III. Appropriate selection of the candidates for partial hepatectomy based on the above prognostic factors may play an important role in the improvement of high mortality rate and poor long-term survival for such patients. Prospective randomized trials are needed to define the role of hepatic resection for cirrhotic patients with large HCC.     

Serum matrix metalloproteinase-3 (stromelysin-1) concentration in patients with chronic liver disease.

BACKGROUND/AIMS: Matrix metalloproteinase (MMP)-3 plays an important role in extracellular matrix degradation, because of its broad substrate specificity and its activation of other proMMPs. Our aims in the present study were to determine whether the measurement of serum MMP-3 is clinically useful for assessing ongoing liver fibrolysis in patients with chronic liver disease. METHODS: We measured the serum MMP-3 concentrations with a sandwich enzyme immunoassay in 58 patients with chronic hepatitis, 22 patients with liver cirrhosis, 45 patients with hepatocellular carcinoma and 124 healthy individuals. The liver MMP-3 content was also measured in autopsied livers. RESULTS: Among the healthy controls, the serum levels of MMP-3 were about 2-fold higher in the males than in the females. In this study, the serum MMP-3 results of mainly the male group were analyzed because of the large number of male subjects. Compared to the control level, the mean serum MMP-3 concentration was 55% lower in chronic hepatitis, 53% lower in liver cirrhosis and 46% lower in hepatocellular carcinoma. There was no significant difference in the serum MMP-3 levels among the chronic hepatitis, liver cirrhosis and hepatocellular carcinoma groups. The serum MMP-3 levels were not related to the histological degree of necroinflammation or of liver fibrosis in the patients with chronic hepatitis. No significant difference in serum MMP-3 levels was observed among three Child's subgroups in the group of cirrhotic patients. In the group of patients with hepatocellular carcinoma, the serum MMP-3 levels were not related to the severity of liver function, the HCC tumor size, or the histological differentiation. The serum MMP-3 level was not correlated with serum markers for connective tissue turnover, i.e. procollagen type III peptide, 7S fragment of type IV collagen, hyaluronan and tissue inhibitor of metalloproteinase-1 in the patients with chronic liver disease or hepatocellular carcinoma. CONCLUSIONS: The measurement of serum MMP-3 is of little use for assessing fibrolysis in chronically diseased livers.