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PubMed1982

Effect of doxorubicin on liver regeneration and host survival after two-thirds hepatectomy in rats.

The effects of doxorubicin (Adriamycin) on regenerating liver were studied after two-thirds hepatectomy in rats. In Group I, standard two-thirds hepatectomy was performed. Doxorubicin in a dose of 2 mg/kg (Group II) and 6 mg/kg (Group III) was given intravenously immediately after the same hepatectomy. In Group IV, 6 mg/kg doxorubicin was given after sham operation. Animal survival, body weight restoration, wet weight and mitotic activity of remnant livers, and serum albumin concentrations were examined 1-14 days after operation. The survival rates were 95.5% in Group I, 76.8% in Group II, 10.3% in Group III, and 96.7% in Group IV. Although there were no differences in the residual liver weights among the hepatectomized groups, treatment with doxorubicin induced substantial, dose-dependent suppression and delay of liver cell division. Serum albumin levels dropped considerably in hepatectomized, doxorubicin-treated rats. Light microscopy showed degenerative changes with a single cell necrosis of hepatocytes in Group III. Death among rats hepatectomized and treated with doxorubicin was considered to be mainly due to the failure of residual livers since albumin synthesis was impaired and no marked changes were seen in vital organs other than the liver. For patients with hepatoma, the present results may indicate that the administration of adjuvant chemotherapy with doxorubicin, when necessary immediately after hepatectomy, should be performed with great care. In the absence of such necessity, doxorubicin should be withheld until life-sustaining liver regeneration has taken place.

Animals↗
PubMed1990

Extended hepatectomy for hepatocellular carcinoma.

The results of extended hepatectomy in 25 patients with hepatocellular carcinoma performed over a 16 year period have been reviewed, analysed and compared with those of 144 patients who underwent lesser liver resection. Five left and 20 right extended hepatectomies were performed for tumours ranging from 3 to 20 cm in diameter. Seventeen (68 per cent) of the patients had non-cirrhotic livers. The major postoperative complications were: haemorrhage in five cases, major bile duct injury in three, subphrenic abscess in two, liver failure in one and wound dehiscence in one. The 30-day (operative) mortality rate was 12 per cent and the median survival duration, including operative mortality, was 9.7 (range 0.2-32.1) months. The survival rate was 46 per cent at 1 year, 33 per cent at 2 years and 22 per cent at 3 years. The morbidity, mortality and survival data of extended hepatectomy were comparable with the results of lesser hepatic resections for hepatocellular carcinoma. We conclude that extended hepatectomy is a worthwhile operation for large hepatocellular carcinomas and a viable alternative to liver transplantation.

Adult↗
PubMed1994

Results of major hepatectomy for large primary liver cancer in patients with cirrhosis.

Major hepatectomy is associated with a high operative risk in patients with cirrhosis. Between June 1983 and December 1991, 33 cirrhotic patients, 31 with good liver function, underwent major liver resection for a large hepatic primary cancer. The hospital mortality rate was 3 per cent; the only death resulted from liver failure after extended right hepatectomy. None of the patients had variceal bleeding during the postoperative period. Survival rates at 1, 2 and 3 years were 66, 43 and 37 per cent respectively. Recurrence was the most common reason for late death. These results suggest that the operative risk of major hepatectomy in cirrhotic patients with a large tumour and good liver function is comparable to that of minor liver resection. Late survival is also similar to that of patients with a small tumour. Cirrhotic patients with hepatic carcinoma and good liver function are suitable for major hepatectomy.

Adult↗
PubMed1995

Tumour growth stimulation after partial hepatectomy can be reduced by treatment with tumour necrosis factor alpha.

This study investigated whether partial hepatectomy enhances the growth of experimental liver metastases of colonic carcinoma in rats and whether treatment with recombinant human tumour necrosis factor (TNF) alpha can reduce this increased growth. Resection of 35 or 70 per cent of the liver was performed in inbred WAG rats, with sham-operated controls (five to eight animals per group). Immediately after surgery 5 x 10(5) CC531 colonic tumour cells were injected into the portal vein. After 28 days the animals were killed and the number of liver metastases counted. A 35 per cent hepatectomy induced a significant increase in the median number of liver metastases (28 versus 3 in controls), whereas a 70 per cent resection provoked excessive growth, consistently leading to more than 100 liver metastases and a significantly increased wet liver weight in all animals. TNF-alpha was given intravenously to rats following 70 per cent hepatectomy or sham operation in a dose of 160 micrograms/kg three times per week. This had only a marginal effect on tumour development in sham-operated rats but was very effective following partial hepatectomy (median 45 liver metastases). These observations confirm previous findings that surgical metastasectomy may act as a 'double-edged sword' by provoking outgrowth of dormant tumour cells and suggest that adjuvant treatment with TNF-alpha may be of benefit in patients undergoing resection of metastases.

Animals↗
PubMed1996

Hepatic bile acid synthesis and DNA synthetic rate after partial hepatectomy.

The relationship between hepatic DNA synthetic rate and activity of cholesterol 7 alpha-hydroxylase, the rate limiting enzyme for bile acid synthesis, was examined in regenerating liver after partial hepatectomy or sham operation in rats. Hepatic cholesterol 7 alpha-hydroxylase activity was significantly (P < 0.001) suppressed on days 1 and 2, returned to the control level on day 3, and was significantly raised on day 7 after hepatectomy. The rate of DNA synthesis was significantly (P < 0.001) activated during the first 3 days after hepatectomy and returned to the control level on day 7. Enzyme activities regulating hepatic bile acid synthesis and DNA synthesis change inversely during liver regeneration after hepatectomy.

Animals↗
PubMed2003

Autologous blood storage before hepatectomy for hepatocellular carcinoma with underlying liver disease.

BACKGROUND: Preoperative autologous blood donation has been suggested for patients with liver disease who are to undergo liver resection. The aim of this retrospective study was to clarify the risk factors for increased blood loss and the need for blood transfusion during hepatectomy for hepatocellular carcinoma (HCC). METHODS: From January 1996 to December 2000, 206 consecutive patients, 98.5 per cent of whom had underlying liver disease, underwent elective hepatectomy for HCC. RESULTS: Major hepatectomy was performed in 34 patients (16.5 per cent) and minor hepatectomy in 172 patients (83.5 per cent). The mean blood loss was 410 (median 260) ml. Eleven (5.3 per cent) of the 206 patients received blood transfusion during or after the operation. Operation time (P = 0.004) and central venous pressure (CVP) (P = 0.041) were independently correlated with blood loss of more than 1000 ml. Only preoperative haemoglobin level (P = 0.001) was independently correlated with the need for blood transfusion. CONCLUSION: In patients with underlying liver disease, maintaining CVP at a level below 5 cm H2O during parenchymal transection to reduce blood loss is more important than reserving autologous blood before the operation.

Adult↗
PubMed2003

Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases.

BACKGROUND: Extrahepatic disease has always been considered an absolute contraindication to hepatectomy for liver metastases. The present study reports the long-term outcome and prognostic factors of patients undergoing resection of extrahepatic disease simultaneously with hepatectomy for liver metastases. METHODS: From January 1987 to January 2001, 111 (30 per cent) of 376 patients who had hepatectomy for colorectal liver metastases underwent simultaneous resection of extrahepatic disease with curative intent. RESULTS: Surgery was considered R0 in 77 patients (69 per cent) and palliative (R1 or R2) in 34 patients (31 per cent). The mortality rate was 4 per cent and the morbidity rate 28 per cent. After a median follow-up of 4.9 years, the overall 3- and 5-year survival rates were 38 and 20 per cent respectively. The 5-year overall survival rate of patients with R0 resection only (n = 75) was 29 per cent. The difference in survival between patients with and without extrahepatic disease discovered incidentally at operation was significant, as was the number of liver metastases. CONCLUSION: Extrahepatic disease in patients with colorectal cancer who also have liver metastases should no longer be considered an absolute contraindication to hepatectomy. However, the presence of more than five liver metastases and the incidental intraoperative discovery of extrahepatic disease remain contraindications to hepatic resection.

Adolescent↗
PubMed2003

Portal vein resection and reconstruction prior to hepatic dissection during right hepatectomy and caudate lobectomy for hepatobiliary cancer.

BACKGROUND: Hepatobiliary cancer invading the hilar bile duct often involves the portal bifurcation. Portal vein resection and reconstruction is usually performed after completion of the hepatectomy. This retrospective study assessed the safety and usefulness of portal vein reconstruction prior to hepatic dissection in right hepatectomy and caudate lobectomy plus biliary reconstruction, one of the common procedures for radical resection. METHODS: Clinical characteristics and perioperative results were compared in patients who underwent right hepatectomy and caudate lobectomy plus biliary reconstruction with (ten patients) and without (11 patients) portal reconstruction from September 1998 to March 2002. RESULTS: All ten portal vein reconstructions were completed successfully before hepatic dissection; the portal cross-clamp time ranged from 15 to 41 (median 22) min. Blood loss, blood transfusion during the operation, postoperative liver function, morbidity and length of hospital stay were similar in the two groups. No patient suffered postoperative hepatic failure or death. CONCLUSION: This study demonstrates that portal vein reconstruction does not increase the morbidity or mortality associated with right hepatectomy and caudate lobectomy with biliary reconstruction. This approach facilitates portal vein reconstruction for no-touch resection of hepatobiliary cancer invading the hilar bile duct.

Aged↗
PubMed1989

A simplified single stage total hepatectomy in the rat with maintenance of gastrointestinal absorptive function.

A technique is described to remove the entire liver in a single stage with preservation of intestinal absorptive function. An inverted V-shape polyethylene cannula, either heparin bonded or silicon coated, was inserted into the portal vein and inferior vena cava to maintain venous return from the splanchnic and lower caval regions of the anhepatic rat. Blood glucose fell at a rate of 7 to 11 mg per hr per total plasma volume (4% body weight), usually resulting in hypoglycemia within the initial 2 hr. Euglycemia could be maintained in the first 3 hr after hepatectomy with hourly intravenous infusions of 2.5 to 5 mg per 100 gm body weight of glucose. Larger infusions of glucose (10 to 12.5 mg per hr per 100 gm body weight) were necessary for normal levels at later times. A 0.5 gm per 100 gm rat weight intestinal glucose bolus restored euglycemia for at least a 2-hr interval. Intestinal absorption of cholesterol and oleic acid was demonstrated in the anhepatic rat, although the latter was not so efficiently absorbed as in the control. The plasma cholesterol decreased with time in the anhepatic rat. Prompt increases were observed in plasma free fatty acid and glycerol concentrations after hepatectomy. Progressive increases in both direct and indirect plasma bilirubin levels were noted after hepatectomy. With appropriate maintenance of blood sugar, survival of 36 hr was observed. This procedure for single stage total hepatectomy in the rat can be performed in less than 30 min. The model is particularly useful for studies of the influence of the liver on postabsorptive metabolism.

Animals↗
PubMed1992

Effects of partial hepatectomy on hepatic insulinlike growth factor binding protein-1 expression.

Insulinlike growth factor binding proteins modulate the action of the insulinlike growth factors in various bioassays and may regulate the bioavailability of the insulinlike growth factors in vivo. Because the insulinlike growth factors may influence hepatic regeneration, we have examined the effect of partial hepatectomy on serum insulinlike growth factor binding proteins and on the abundance of insulinlike growth factor binding protein-1 messenger RNA in the liver. All rats were fasted before and after partial hepatectomy or sham operation to avoid the confounding effects of difference in food intake. Using a conventional protocol, 70% of the liver was removed, and groups of four or five rats were killed at different intervals after partial hepatectomy. Sham-operated rats served as controls. Pooled sera from each group of rats were analyzed by ligand blotting with 125I-insulinlike growth factor-I. Liver RNA from individual rats was analyzed by slot-blot and Northern-blot hybridization. A small decrease in the 39- to 42-kD insulinlike growth factor binding protein was apparent in sera from both the sham-operated and partial hepatectomized rats. In contrast, a dramatic increase (fivefold) in the 29-kD serum insulinlike growth factor binding protein (insulinlike growth factor binding protein-1) was apparent only in the partial hepatectomized rats. Hepatic insulinlike growth factor binding protein-1 messenger RNA abundance was significantly increased (1.99 +/- 0.18-fold; p less than 0.05) at 1 hr, reached a peak of 2.32 +/- 0.22-fold (p less than 0.01) at 3 hr after partial hepatectomy and returned to basal levels over the subsequent 6 to 12 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Intravenous administration of follistatin: delivery to the liver and effect on liver regeneration after partial hepatectomy.

When 1 microgram 125I-follistatin was administered into a rat intravenously, radioactivity levels in serum decreased rapidly. Analysis with a biexponential equation showed that the initial half-life and the terminal half-life were 4.0 and 130.8 minutes, respectively. After 2 hours of infusion, approximately 9% of the follistatin infused remained in the liver, which was much more than that in kidney, spleen, pancreas, intestine, or lung. Autoradiography of the liver obtained at 24 hours of infusion revealed that numerous grains were located in parenchymal cells. Radioactivity of 125I-follistatin in the liver remained elevated until 72 hours and declined markedly thereafter. When a booster shot of 125I-follistatin was administered at 72 hours, radioactivity in the liver at 120 hours was markedly increased compared with that in rats that received a single shot of 125I-follistatin. We then examined the effect of intravenous infusion of follistatin on liver regeneration after hepatectomy of 70%. Immediately after the hepatectomy, either 1 microgram follistatin or saline was infused intravenously. In some rats, a booster shot was infused at 72 hours. After 120 hours of hepatectomy of 70%, remnant liver weight, liver regeneration rate, and DNA content were significantly (P < .05) higher in rats that received a booster shot of follistatin at 72 hours than those in control rats. These results indicate that follistatin administered intravenously accumulates in the liver and promotes liver regeneration after partial hepatectomy.

Animals↗
PubMed1997

Preoperative determination of the surgical procedure for hepatectomy using technetium-99m-galactosyl human serum albumin (99mTc-GSA) liver scintigraphy.

Technetium-99m-diethylenetriaminepentaacetic acidgalactosyl human serum albumin (Tc-GSA) is a new liver scintigraphy agent which binds to the asialoglycoprotein receptors. We evaluated the preoperative assessment for hepatectomy using Tc-GSA liver scintigraphy. Ninety patients with hepatocellular carcinoma were admitted for elective hepatectomy. Tc-GSA scintigraphy was conducted after the intravenous injection of Tc-GSA, and maximal removal rate of Tc-GSA (GSA-Rmax) was calculated using a radiopharmacokinetic model. Measurement of GSA-Rmax, conventional liver function, and 15-minute retention rate of indocyanine green (ICGR15) was carried out preoperatively. The relationships between liver functions, histological activity index (HAI), ICGR15, and GSA-Rmax values were estimated. A significant correlation was obtained between GSA-Rmax and ICGR15 (r = .534, P < .0001). Preoperative discrepancies between GSA-Rmax and ICGR15 values were seen in 15 patients. In these cases, the GSA-Rmax values correlated well with the total HAI scores (r = .595, P < .02), but no significant correlation was seen between the ICGR15 and HAI scores. Two patients died of postoperative liver failure within 2 months of the operation. These two patients were found to have severe discrepancies between their preoperative GSA-Rmax and ICGR15 values. We concluded that GSA-Rmax might be useful for selecting candidates for hepatectomy and that extended hepatectomies (di- and tri-segmentectomy) are high-risk surgical procedures in the case of low GSA-Rmax scores (below 0.35).

Adult↗
PubMed1998

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats.

In a cirrhotic liver, the regenerative ability and specific functions are so impaired that excessive resection easily complicates postoperative liver dysfunction, which frequently leads to life-threatening multiple-organ failure. Hepatocyte growth factor (HGF), first identified as the most potent stimulator of DNA synthesis in primary hepatocytes, not only stimulates liver regeneration, but also accelerates hepatic function, improves fibrosis, and protects liver cells against injury. Therefore, we investigated the efficacy of preoperative portal branch ligation (PBL) (which can induce compensatory hypertrophy of the unaffected lobes) combined with a continuous HGF supply in the performance of extensive hepatectomy in cirrhotic rats. Cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN) three times per week for 3 weeks. Five days after the last injection, when 70% hepatectomy is lethal, the rats underwent portal ligation of the left lateral and median branches (corresponding to approximately 70% of the total volume of the liver). Simultaneously, they were continuously treated with either recombinant human HGF (rhHGF) or vehicle from an intraperitoneally implanted osmotic pump. Four days after the portal ligation, the occluded lobes were resected. The HGF treatment rapidly increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. The blood chemical analysis indicated that HGF significantly suppressed the posthepatectomy liver dysfunction. Most importantly, the HGF treatment markedly improved the survival rate of the rats at 48 hours after the major hepatectomy. In conclusion, PBL combined with a continuous HGF supply makes extensive hepatectomy possible in cirrhotic rats, mainly by promoting the hypertrophy of the unaffected lobes.

Animals↗
PubMed1983

Effects of partial hepatectomy on organ-specific toxic response to 1,2-dibromo-3-chloropropane (DBCP).

The organ-specific toxic potency of subcutaneously administered 1,2-dibromo-3-chloropropane (DBCP) was compared in partially hepatectomized and sham-operated rats over a dose range of 20--80 mg kg-1 to assess the roles of hepatic and extrahepatic metabolism in protection against acute renal and gonadal injury. Relative kidney weight and the severity of DBCP-induced renal proximal tubular cell necrosis were increased in rats subjected to a partial (70%) surgical hepatectomy 48 h prior to treatment with DBCP at 80 mg kg-1. Relative liver weight was reduced by DBCP in the hepatectomized, but not in the sham-operated rats. The severity of DBCP-induced (80 mg kg-1) hepatocellular centrilobular necrosis was greater in hepatectomized than in sham rats. DBCP reduced the relative weights of the testis and epididymis in a progressive manner and produced dose-dependent seminiferous tubular atrophy within 12 days of treatment. The morphologically apparent lesions of the testis and epididymis were enhanced by hepatectomy. The concentration of non-protein sulfhydryl groups (NPS) in rat liver was increased by partial hepatectomy. Because of the resulting decrease in liver size, however, the total amount of hepatic NPS per kg body weight 48 h post-surgery was lower than in sham rats. The surgery had no effect on renal, testicular or epididymal NPS concentrations of organ weights. Partial hepatectomy greatly increased pentobarbital and ethanol sleeping times, while sleep induction time for pentobarbital was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Hepatectomy for hepatocellular carcinoma: patient selection and postoperative outcome.

Hepatic resection and liver transplantation are considered the only curative treatments for hepatocellular carcinoma (HCC). Liver transplantation for HCCs < or =5 cm in diameter has been shown to produce favorable survival results, but its application is limited by the lack of donors. Hepatic resection remains the treatment of choice for patients who are not transplantation candidates because of large tumor, macroscopic vascular invasion, or advanced age. For small HCCs associated with Child's A cirrhosis, hepatic resection should still be considered the first-line treatment, but salvage transplantation for intrahepatic recurrence may be a feasible strategy. Recent improvement in surgical techniques and perioperative care has increased the safety and expanded the indication of hepatic resection for HCC to include large tumors that require extended hepatectomy in cirrhotic patients. Selection of appropriate candidates for hepatectomy depends on careful assessment of the tumor status and liver function reserve. Evaluation of the general fitness of patients is also critical because comorbid illness is an important cause of postoperative mortality, even if the patients have good liver function reserve. With careful patient selection and surgical expertise, the current operative mortality of hepatectomy for HCC is about 5% or less in major centers. Improved long-term survival results after resection of HCC have also been reported recently, with an overall 5-year survival rate of about 50%. The improved perioperative and long-term survival results have strengthened the role of hepatectomy as the mainstay of treatment for HCC despite the availability of a number of other treatment options for localized HCC.

Carcinoma, Hepatocellular↗
PubMed2004

One-year morbidity after donor right hepatectomy.

Live donors are becoming an increasingly important source of donor organs in liver transplantation; however, long-term functional aspects of recovery from donor right hepatectomy are unknown. We analyzed donor outcomes at 1-year follow-up. We performed a single-center retrospective analysis of 70 right hepatectomy donors. Six-week and 1-year postoperative follow-up results were compared to preoperative baseline values. Ultrasonography was performed in all donors at 6 weeks and as clinically indicated. All donors were alive and well at the end of the study period. Of 66 right hepatic donors, only 22 (32%) were fully compliant with a 1-year follow-up visit. All those not compliant were contacted by phone. All complications except 1 (late finding of portal vein thrombosis) occurred in the perioperative (90-day) period. The incidence of bile leak was 4.3%, incisional hernia 20%, and autologous transfusion 1.0%. There were no aborted procedures. In those compliant with full 1-year follow-up, total bilirubin, aspartate aminotransferase, and alanine aminotransferase were normal in 97%. A total of 5 donors were noted to have persistence of asymptomatic thrombocytopenia beyond the perioperative period (90 days). These were investigated with Doppler sonography. Sonography was unremarkable in 3 of the 5, while 2 had abnormal findings: splenomegaly alone in 1, and splenomegaly with portal vein thrombosis in the other. Magnetic resonance angiography was performed in both, and the patient with portal vein thrombosis underwent endoscopy, which failed to reveal varices. Neither has clinical portal hypertension. Both remain asymptomatic albeit with stable thrombocytopenia. In conclusion, the majority of complications after donor right hepatectomy occur in the perioperative period. Later findings may include asymptomatic thrombocytopenia, with an incidence possibly as high as 23%, though the significance of this finding remains uncertain. Larger-scale studies are needed to confirm the true incidence and clinical significance of persistent thrombocytopenia in the donor hepatectomy population. Strategies to improve compliance with 1-year follow-up visits need to be developed.

Adult↗
PubMed2005

Safety of donor right hepatectomy without abdominal drainage: a prospective evaluation in 100 consecutive liver donors.

Although the role of routine abdominal drainage after liver resection for tumors has been questioned, abdominal drainage after donor right hepatectomy for live donor liver transplantation (LDLT) has been a routine practice in most transplant centers. The present study aimed to evaluate the safety of the procedure without abdominal drainage. A prospective study was performed on 100 consecutive liver donors who underwent right hepatectomy for LDLT from July 2000 to September 2003. Biliary anatomy was carefully studied with intraoperative cholangiography using fluoroscopy. The middle hepatic vein was included in the graft in all except 1 patient. Parenchymal transection was performed using an ultrasonic dissector. The right hepatic duct was transected at the hilum and the stump was closed with 6-O polydioxanone continuous suture. Absence of bile leakage was confirmed with methylene blue solution instilled through the cystic duct stump. The abdomen was closed after careful hemostasis without drainage in all donors. The median age of the donors was 36 years (range 18-56 years). Median operative blood loss and operating time were 350 mL (range 42-1,400 mL) and 7.5 hours (range 5.2-10.7 hours), respectively. None of the donors required any blood or blood product transfusion. There was no operative mortality. The median postoperative hospital stay was 8 days (range 5-30 days). Postoperative morbidity occurred in 19 patients (19%), most of which were minor complications. No donor experienced bile leakage, intraabdominal bleeding, or collection. None required surgical, radiologic, or endoscopic intervention for postoperative complications, except for 1 donor who developed late biliary stricture that required endoscopic dilatation. All donors were well with a median follow-up of 32 months (range 11-50 months). In conclusion, with detailed study of the biliary anatomy and meticulous surgical technique, donor right hepatectomy can be safely performed without abdominal drainage. Abdominal drainage is not a mandatory procedure after donor hepatectomy in LDLT.

Abdomen↗
PubMed2004

Heparanase expression during normal liver development and following partial hepatectomy.

Heparan sulphate proteoglycans are major components of the liver extracellular matrix. Their cleavage by heparanase (endo-beta-glucuronidase) may thus be involved in liver-specific normal and pathological processes. Heparanase mRNA and protein were expressed during liver development but not in the mature healthy liver. A biphasic gain of heparanase expression, detected by immunostaining, western blotting, and real-time RT-PCR, was clearly noted following partial hepatectomy, peaking at 12 and 96-168 h and subsiding 2 weeks post-surgery. Expression of heparan sulphate gradually increased throughout the regeneration process. Unlike heparanase, baseline levels of matrix metalloproteinase-2 (MMP-2) were detected in the intact liver, increasing up to 4 days following partial hepatectomy and subsiding at day 10. Bands matching MMP-9 were absent prior to hepatectomy, but visible 2 h post-hepatectomy. Thioacetamide-induced liver fibrosis was associated with increased levels of MMP-9 and MMP-2, correlating with the severity of the disease. Elevated heparanase levels were noted in the early stages of fibrosis, with no further increase evident in rats exhibiting higher fibrotic grades. Taken together, these data suggest a role for heparanase during liver development and remodelling.

Animals↗