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PubMed2001

Cellular distribution and handling of liver-targeting preparations in human livers studied by a liver lobe perfusion.

We developed and tested a novel method for perfusing parts of human liver to study uptake and handling of drug-targeting preparations. These preparations, designed for the treatment of liver fibrosis in man, have been extensively studied in animals, but little is known about the uptake and handling by human livers. Human liver tissue was obtained from livers procured from multiorgan donors and from cirrhotic livers of patients. To assess tissue viability, perfusate glutamate-oxalacetate-transaminase (GOT), glutamate-pyruvate-transaminase (GPT), and lactate dehydrogenase (LDH) levels were determined. To assess tissue functionality, the uptake of taurocholic acid and phase I and II metabolism of lidocaine and 7-hydroxycoumarin were determined. Uptake of a drug-targeting preparation was studied with Dexa10-HSA, which is designed for targeting of dexamethasone to nonparenchymal cells in the liver. During a 90-min perfusion period, no elevation of either GOT, GPT, or LDH was found. Both healthy control livers and cirrhotic livers showed phase I and II drug metabolism and functional taurocholic acid uptake. Studies with Dexa10-HSA revealed that 60 min after administration, 40% of the dose had been taken up by control livers and only 5% by cirrhotic livers. In control livers, Kupffer and endothelial cells had taken up Dexa10-HSA, whereas in cirrhotic livers only Kupffer cells were responsible for the uptake. Viability parameters and liver function tests clearly showed the applicability of this method. In the perfusion set-up, we showed uptake of the drug-targeting preparation Dexa10-HSA by healthy and cirrhotic human liver tissue, although the distribution patterns differed. This demonstrates the need to study new concepts in (diseased) human tissue.

Anesthetics, Local↗
PubMed1999

Liver resection and needle liver biopsy cause hematogenous dissemination of liver cells.

We have investigated whether liver resection and needle liver biopsy cause dissemination of liver cells into peripheral blood circulation, using a reverse-transcription polymerase chain reaction (RT-PCR)-based assay targeted against alpha-fetoprotein (AFP) mRNA. Twelve patients with and 16 without primary liver cancer (PLC) undergoing liver resection were tested before skin incision, after liver mobilization, after hepatic parenchyma transection, after abdominal wall suture, and 4 days after surgery. Two patients with and 20 without PLC were tested before, 20 minutes after, and 24 hours after needle liver biopsy. Six of 14 patients with and 0 of 36 patients without PLC scored positive before intervention (P <.001). Liver cell spreading was induced at different times after surgery and liver biopsy in 14 of 14 patients with but also 23 of 36 without PLC (P <.05). We conclude that liver resection and needle liver biopsy induce release of cells from the liver, which are not necessarily liver tumor cells, into the peripheral blood circulation. This may be, however, an important mechanism of liver cancer cell dissemination deserving further investigations.

Adult↗
PubMed1991

Functional liver imaging with 99Tcm-galactosyl-neoglycoalbumin (NGA) in alcoholic liver cirrhosis and liver fibrosis.

Synthesis of 99Tcm-galactosyl-neoglycoalbumin (99Tcm-NGA), a recently described new radioligand with high specificity for hepatic binding protein (HBP), a galactose-residue specific receptor on hepatocytes, was carried out by covalent coupling of 2-imino-2-methoxyethyl-1-thio-beta-D-galactopyranoside to the primary amino groups of human serum albumin. NGA was purified by ultrafiltration and size exclusion high-pressure liquid chromatography (HPLC). Using a computer-based simulation program, time-activity data for the liver and precordium, blood radioactivity 2 min after i.v. injection of the radioligand, the association constant of 99Tcm-NGA-binding to HBP measured on human liver biopsies in vitro, and other patient-related parameters were put into a five-state non-linear model describing the pharmacokinetics of 99Tcm-NGA. By fitting the parameters of the model iteratively to the experimental data, an estimate of HBP concentration in the liver and of total liver blood flow was obtained. Using this model we studied 32 patients (53 +/- 11 years) with different clinical stages of alcoholic liver cirrhosis. Child B and Child C stage cirrhotic patients had a lower HBP concentration in the liver compared to control individuals (0.96 +/- 0.21 mumol l-1). The group with the most advanced cirrhosis (Child C stage) had a significantly lower HBP concentration (0.27 +/- 0.15 mumol l-1) than Child A patients (0.66 +/- 0.21 mumol l-1; P less than 0.01) and Child B patients (0.53 +/- 0.18 mumol l-1; P less than 0.05). In four patients with biopsy-proven liver fibrosis (0.84 +/- 0.20 mumol l-1) no difference in receptor concentration from normal individuals was estimated. Changes in liver blood flow were not significant between the groups. A direct comparison of HBP concentration estimated in vivo by 99Tcm-NGA functional imaging and HBP concentration measured in vitro on a surgically removed liver biopsy specimen from the same patient with a normal liver and liver cirrhosis showed good matching of these two values. The results suggest that in vivo estimation of HBP concentration in the liver by 99Tcm-NGA functional imaging might be a suitable method for determining liver cell mass.

Adult↗
PubMed1990

Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors.

Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single-photon computed tomography (SPECT), using 99mTc-colloid as tracer. The method was assessed in 11 patients by comparing the pre- and post-operative volume measurements with the volume of the resected liver mass. The correlation coefficient between these methods was 0.899 (P less than 0.01). Liver function was determined by measuring the galactose elimination capacity and the caffeine clearance. After a postoperative follow-up period of 50 days the liver had regenerated maximally to a volume of 75 +/- 2% of the preoperative liver mass. Maximal restoration of liver function was achieved 120 days after operation and amounted to 75 +/- 10% for the caffeine clearance and to 100 +/- 25% for the galactose elimination capacity. This study shows that SPECT is a useful method for assessing liver regeneration in patients after partial hepatectomy. Our study furthermore shows that caffeine clearance correlates well with total liver volume, whereas the galactose elimination capacity overestimates total liver volume after partial hepatectomy.

Adult↗
PubMed1981

Detection of liver IgG Fc receptors using soluble immune complexes of peroxidase-antiperoxidase. I. Detection in liver tissue from patients with liver diseases.

The presence of liver IgG Fc receptor sites was demonstrated in the liver tissue from 23 patients with liver diseases and 2 patients without liver lesions by the localization of soluble immune complexes of peroxidase-antiperoxidase (PAP). Cryostat sections of liver tissues were incubated with the complexes and the peroxidase activity was revealed histochemically. In the normal liver tissue, PAP were localized on the liver cell membrane, the Kupffer cells, and some of the sinusoidal walls. In acute hepatitis, a strongly positive reaction on swollen Kupffer cells was remarkable but positive reaction on the liver cell membrane was very weak. In chronic aggressive hepatitis, PAP were strongly positive on multiplied Kupffer cells and many PAP-positive infiltrated cells were observed at the area of piecemeal necrosis. However, the positive reaction on the liver cell membrane in patients with chronic aggressive hepatitis was generally fainter than in the normal cases without liver diseases. These results correlated well with the severity of liver cell necrosis. In chronic persistent hepatitis, the number of PAP-positive infiltrated cells in the portal area and positive Kupffer cells were fewer than in chronic aggressive hepatitis. Similar results were obtained with liver cirrhosis, and in particular, the liver cell membrane with regenerative nodules gave a positive reaction. A negative result was obtained by incubation with PAP-F(ab')2 alone. PAP reaction was significantly inhibited by pretreatment with aggregated human IgG, trypsin, and pronase but not with neuraminidase.

Hepatitis↗
PubMed2005

Signal intensity of the liver parenchyma in microbubble contrast agent in the late liver phase reflects advanced fibrosis of the liver.

BACKGROUND: Microbubble of Levovist accumulates in liver parenchyma, and the phenomenon has been reported as late liver-specific parenchymal. The aim of the present study was to compare the parenchymal enhancement effect of Levovist with the degree of liver dysfunction. PATIENTS AND METHODS: Sixty consecutive patients who consented to be treated were enrolled in this study. Pulse-inversion ultrasonography (US) in the liver parenchymal phase of enhancement with Levovist was performed in a preoperative examination. The mechanical index of pulse-inversion US was set at 1.3. The gray-scale intensity of the non-tumor area of the liver parenchyma at the level of the focal zone was measured. The hepatic fibrosis index was measured in each liver by morphometric analysis. The correlation between the gray-scale intensity of the non-tumor area of the liver parenchyma and the hepatic fibrosis index was assessed. RESULTS: There was a significant inverse correlation between the gray scale of the liver parenchyma and the hepatic fibrosis index (r = -0.809, P < 0.01). The average signal intensity of the liver parenchyma was 144.5 in a normal liver, 133.6 in chronic hepatitis, and 102.6 in liver cirrhosis, demonstrating a significant difference between a normal and cirrhotic liver (P < 0.01). CONCLUSIONS: The signal intensity of a microbubble disruption of the liver parenchyma in the late phase of enhancement with Levovist was considered to reflect the degree of hepatic fibrosis.

Adult↗
PubMed2003

Postoperative liver regeneration and complication in live liver donor after partial hepatectomy for living donor liver transplantation.

The safety of donor is the first priority during whole procedure in living donor liver transplantation. We evaluated the short-term results of partial living donor liver transplantation in the view of donor safety. We prospectively evaluated the extent of liver regeneration, the recovery of liver function, and the perioperative complications in 41 live liver donors for partial liver transplantation at our institution. We developed novel personal computer volumetry program for the evaluation of liver regeneration. Serial CAT scan was performed preoperatively, at postoperative day (POD) #7 and POD #30 and liver volume was measure by using volumetry program. The serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T.bil.) was serially monitored. There were 34 males and 7 females. The mean preoperative liver volume was 1320.6 cm3. The remained mean liver volume was 687.8 cm3 after harvest, and increased to 954.4 cm3 (144.6%) at POD #7, and 1169.5 cm3 (81.4%) at POD #30, which was 88.5% of preoperative total liver volume. The serum level of ALT/ AST and T.bil. peaked at POD #1 and declined thereafter, and finally returned to preoperative level at POD #30. The regeneration rate was significantly different by age, type and size of graft according to the donors. Six donors experienced postoperative complications and they were four pleural effusions, one wound infection and one case of bile duct stenosis that was treated by endoscopic nasal biliary drainage. All of them were right lobe donors. In conclusion, the donor liver regenerated up to 88.5% of preoperative volume with full recovery of liver function at POD #30. Right lobe donors suffered more complications and need more meticulous operative and postoperative care than left lobe or left lateral segment donors.

Adolescent↗
PubMed2002

Serum markers of liver fibrogenesis, and liver histology findings in patients with chronic liver diseases.

AIM OF THE STUDY: Investigation of the relationships between the grade and stage of chronic liver diseases irrespective of their etiology using some novel serum markers of liver fibrogenesis, the "classical" serum markers of liver necro-inflammatory injury (such as transaminases), and the histomorphological evaluation of liver biopsies. METHODS: Markers of liver fibrogenesis: serum metalloproteinase 1 (MMP-1), tissue inhibitor of MMP-1 (TIMP-1), and N-terminal propeptide of the procollagen III (PIIINP); "liver function tests" (LFTs): bilirubin, transaminases ALT, AST; ALP, GMT; and liver morphology findings: necro-inflammatory activity, fibrosis; were studied in the series of 32, 'naive', i.e. yet untreated patients (women/men--11/21) with various CLDs: chronic viral hepatitis B or C 13 (CHB 3, CHC 10), non-alcoholic steatohepatitis 9, liver steatosis 4, primary biliary cirrhosis 5, drug-induced hepatitis. The diagnoses were based on the clinical, laboratory and liver imaging (ultrasonography) findings and confirmed by the liver biopsy. CONCLUSIONS: Investigation of liver fibrogenesis serum markers (PIIINP, MMP-1, TIMP-1) in patients with various CLDs has shown statistically significant correlations of these parameters with "classical" serum markers of liver necro-inflammation (ALT, AST) and the results of histomorphological evaluation of the necro-inflammatory activity (parameters NAI, MEF) and fibrosis (parameter FI) in liver biopsies. (Tab. 4, Ref. 31.)

Adult↗
PubMed1985

[Serum concentrations of tissue polypeptide antigen and alpha 1-fetoprotein in patients with primary liver cancer, liver metastasis and liver cirrhosis].

Tissue Polypeptide Antigen (TPA) and alpha 1-fetoprotein (AFP) were determined in sera of 21 patients with hepatocellular carcinomas, in 20 patients with extrahepatic carcinomas and metastases of the liver, as well as in 26 patients with cirrhosis of the liver. TPA was increased (greater than 85 U/L) in all patients with malignant hepatomas, in 80% of patients with metastatic liver cancer and in 35% of patients with cirrhosis of the liver. The critical serum TPA level, above which only malignant liver tumours lay, was statistically evaluated and found to be 187 U/L. All patients with benign liver disease and half of the patients with metastatic liver disease showed TPA values lower than 187 U/L. All of the patients with hepatocellular carcinoma and half of the patients with metastatic liver cancer had TPA values greater than 187 U/L; all of our patients with cirrhosis of the liver, as well as half of the patients with metastatic liver cancer had lower TPA values. 86% out of all hepatoma patients showed increased AFP levels (greater than 9 ng/ml), whereby the AFP concentrations were in the range which is highly suggestive of hepatoma (greater than 174 ng/ml) in 67% of all patients with malignant hepatomas. Patients with metastatic liver cancer and cirrhosis of the liver had AFP levels lower than 174 ng/ml AFP. TPA is an unspecific tumour marker, which can be used together with AFP in the diagnosis of unclear defects in liver parenchyma, in supervision of cirrhosis, as well as in control assessment during chemotherapy or after tumour resection.

Antigens, Neoplasm↗
PubMed2000

Extracorporeal liver perfusion using human and pig livers for acute liver failure.

BACKGROUND: Patients with fulminant hepatic failure (FHF) often die awaiting liver transplantation. Extracorporeal liver perfusion (ECLP) has been proposed as a method of "bridging" such patients to transplantation. We report the largest experience to date of ECLP using human and porcine livers in patients with acute liver failure. METHODS: Patients with FHF unlikely to survive without liver transplantation were identified. ECLP was performed with human or porcine livers. Patients underwent continuous perfusion until liver transplantation or withdrawal of support. Two perfusion circuits were used: direct perfusion of patient blood through the extracorporeal liver and indirect perfusion with a plasma filter between the patient and the liver. FINDINGS: Fourteen patients were treated with 16 livers in 18 perfusion circuits. Nine patients were successfully "bridged" to transplantation. ECLP stabilized intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Arterial ammonia levels fell from a median of 146 to 83 micromol/liter within 12 hr and this reduction was maintained at least 48 hr. Pig and human ECLP lowered ammonia levels equally. Serum bilirubin levels also fell from a median of 385 to 198 micromol/liter over the first 12 hr but the response was not sustained as well with porcine livers. There was no immunological benefit to using the the filtered perfusion circuit. INTERPRETATION: These data demonstrate that ECLP is safe and can provide metabolic support for comatose patients with fulminant hepatic failure for up to 5 days. While labor and resource intensive, this technology is available to centers caring for patients with acute liver failure and deserves wider evaluation and application.

Adolescent↗
PubMed2002

Hepatocyte growth factor levels in liver and blood, and post-operative liver cell proliferation in patients with benign and malignant liver tumors after partial hepatectomy.

BACKGROUND: The purpose of our study was to investigate hepatocyte proliferation and the expression of hepatocyte growth factor (HGF) in liver tissue and blood from patients with benign and malignant liver tumors after partial hepatectomy. MATERIAL/METHODS: We studied 25 consecutive patients undergoing partial hepatectomy for metastatic colorectal adenocarcinoma (15 cases) and benign liver tumors (10 cases). Immunohistochemical examination for the presence of PCNA and HGF, c-MET/HGF-receptor expression was performed on formalin-fixed samples from: a) sections of resected fragments of liver tissue remote from the tumor; b) tumor tissue; c) remnant liver, 30 min after hepatectomy; d) fine needle aspiration liver biopsy, 7 days after liver resection. Circulating HGF and the level of AFP and GGT as biomarkers for liver cell regeneration were measured in the patients' blood at the same time. RESULTS: The proliferation rate of liver cells was higher in patients with malignant than benign liver tumors. This correlated with increased HGF in blood, but not with the expression of HGF and c-MET/HGF-R in liver tissue. The expression of HGF was detected in specimens from colorectal liver metastases. CONCLUSIONS: The mutual interactions between tumor and other cells may influence the proliferation of hepatocytes throughout the regenerative process in patients with colorectal carcinoma metastases after partial hepatectomy.

Adenocarcinoma↗
PubMed1994

Distribution of plasminogen activator inhibitor in normal liver, cirrhotic liver, and liver with metastases.

AIMS: To examine the distribution of PAI-1 antigen in normal and cirrhotic liver and liver with metastases. METHODS: Sections of normal and cirrhotic liver and liver with metastases were stained using the alkaline phosphatase antialkaline phosphatase (APAAP) technique and monoclonal antibody specific for plasminogen activator inhibitor (PAI-1). RESULTS: PAI-1 antigen was identified as discrete granules in the cytoplasm of hepatocytes in normal liver, particularly around portal tracts and central veins of the liver lobule. In cirrhotic liver a striking reduction of PAI-1 antigen was noted. In liver with metastases increased amounts of PAI-1 antigen were concentrated in hepatocytes around the margins of malignant deposits. CONCLUSIONS: Cirrhotic liver contains considerably less PAI-1 antigen than does normal liver, despite raised plasma concentrations of PAI-1. This may reflect release of hepatic PAI-1 into the circulation or decreased clearance of PAI-1 from the plasma. Secondary malignant deposits in the liver seem to stimulate production of PAI-1 in adjacent hepatocytes. This may influence the invasive process and may contribute to the thrombotic tendency associated with malignancy.

Carcinoma, Hepatocellular↗
PubMed2006

Serum cholinesterase activity helps to distinguish between liver disease and non-liver disease aberration in liver function tests.

The diagnostic usefulness of a single determination of serum cholinesterase activity to distinguish between overt liver disease and non-liver disease clinical problems in which a few of the traditional liver function tests are abnormal was assessed. Using three groups of subjects comprising liver disease, non-liver disease, and healthy controls, we have shown that serum cholinesterase activity helped to distinguish between liver disease and non-liver disease in subjects who had abnormality of a few liver function tests. Serum cholinesterase activity helped also to distinguish between the liver disease subjects and healthy controls. There was no statistically significant difference between the mean serum cholinesterase activities of non-liver disease subjects and healthy controls. We suggest that determination of serum cholinesterase activity is a cost-effective diagnostic means of differentiating between overt liver disease and non-liver diseases where there may be aberration of some liver function tests.

Journal Article↗
PubMed2006

Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation.

In advanced stages of polycystic liver disease, often associated with polycystic kidney disease, a curative therapy is liver or combined liver-kidney transplantation. However, little is known about long-term outcome and quality of life. Between 1990 and 2003, 36 patients (32 female, 4 male) with polycystic liver or combined liver-kidney disease underwent liver (n = 21) or liver-kidney (n = 15) transplantation at our center. Main indications for liver transplantation were cachexia, muscle atrophy, loss of weight, recurrent cyst infections, portal hypertension, and ascites. Apart from clinical parameters, 2 anonymous questionnaires (standard short form 36 and self-designed) addressing quality of life and social status were evaluated. Five patients (14 %) died due to sepsis or myocardial infarction with pneumonia, all within 61 days after transplantation. The follow-up time of the remaining 31 patients ranged from 5 to 156 months, with a mean of 62 months. Of the 23 (74%) answered the questionnaires, 91% of patients felt "much better" or "better," only 9% felt "worse" than before, and 52% of patients participated in sports regularly. Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after transplantation. Physical attractiveness and interest in sex increased as well. Professional occupation did not change for 71% of patients. Family situation before and after transplantation changed in 1 case only. Finally, 78% of patients said they would opt for transplantation again, while 17% were undecided; 1 patient would not repeat transplantation. In conclusion, patients with advanced polycystic liver or polycystic liver-kidney disease have an excellent survival rate and an improved quality of life after liver or combined liver-kidney transplantation.

Adult↗
PubMed1999

During liver regeneration following right portal embolization the growth rate of liver metastases is more rapid than that of the liver parenchyma.

BACKGROUND: The relative growth rates of human liver metastases are not known. The aim of this study was to determine in humans the growth rate of liver parenchyma during regeneration and the growth rate of liver metastases during the same process. METHODS: Among 556 patients hepatectomized for a malignant lesion, 48 underwent preoperative selective right portal vein embolization to induce hypertrophy of the left lobe. Five cases were selected because a liver metastasis was present inside the regenerating left lobe. The volumes of the liver metastasis and left lobe were measured with a three-dimensional technique on pre-embolization and postembolization computed tomography (CT) or CT arterial portography. The median interval between the two measurements was 34 (range 28-40) days. RESULTS: An increase occurred in the volume of the liver metastasis and the left lobe in the four patients with functionally intact liver parenchyma, but not in the patient with an impaired parenchyma. The volumetric increase of the normal liver varied from 59 to 127 per cent, compared with 60 to 970 per cent for the liver metastases. The ratio between the growth rate of the left lobe and the liver metastasis varied from 1.0 to 15.6. The growth rates of two metastases in the left lobe of a single patient were different. CONCLUSION: In functionally intact liver parenchyma, during hepatic regeneration or hypertrophy, the growth rate of metastases is more rapid that that of the liver parenchyma. However, a wide variation in growth rate is observed between patients and between metastases.

Aged↗
PubMed1997

Mast cells distribution in human liver disease and experimental rat liver fibrosis. Indications for mast cell participation in development of liver fibrosis.

BACKGROUND/AIMS: The development of liver fibrosis due to chronic liver diseases is thought to be mediated by inflammatory cells releasing fibrogenic mediators that activate fat-storing cells (Ito-cells). Recently, the involvement of mast cells in fibrogenesis has been suggested. We studied the distribution of these cells in normal human liver and human nonfibrotic and fibrotic liver disease as well as in normal rat liver and acutely and chronically injured rat liver (CCl4 model). METHODS: Mast cells were identified by histochemical and immunohistochemical methods. The immunoreactivity of liver and comparatively of rat peritoneal mast cells to the serpins alpha1-antitrypsin, alpha1-antichymotrypsin and antithrombin III was also studied. RESULTS: In normal human and rat liver, mast cells were rarely found in portal tracts, and there was no change in cell numbers in nonfibrotic human or acutely injured rat livers. In contrast, cirrhotic human and rat livers contained numerous mast cells in the portal tracts and the fibrous septa. They exhibited strong immunoreactivity to the serpins, as did rat peritoneal mast cells. CONCLUSIONS: The results indicate that in the late stages of liver fibrogenesis, mast cells may be involved by displaying protease inhibitory activity in the fibrotic septa.

Animals↗
PubMed1979

The mechanism of release of hepatic enzymes in various liver diseases. II. Altered activity ratios of GOT to GPT in serum and liver of patients with liver diseases.

The activities of glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and glutamate dehydrogenase (GLD) were determined in liver biopsy specimens and sera of patients with various liver diseases. Mitochondrial and cytosol isozymes of GOT were also separated for their assay. The activity ratio of GOT/GPT in serum was found to reflect the ratio in liver cytosol. The increased ratio in advanced or severe liver diseases, such as liver cirrhosis, was due to the greater decrease in liver cytosol GPT activity, this being pronounced in primary hepatoma. The activity of GLD decreased similarly but less markedly. The relatively greater decrease in GPT compared with GOT in advanced liver diseases was not mainly due to leakage of the enzyme from the liver, but to a specific mechanism associated with hepatic injury or its progression. Other pathological conditions of the liver such as those in obstructive jaundice and alcoholic liver injury also appeared to result in reduced liver GPT activity, which was reflected in the serum as an increased GOT/GPT ratio.

Alanine Transaminase↗
PubMed2001

Activation of hepatic stellate cells in liver tissue of patients with fulminant liver failure after treatment with bioartificial liver.

We studied the explanted livers from 12 patients with fulminant hepatic failure who were treated with a bioartificial liver and subsequently underwent orthotopic liver transplantation and from 18 patients who underwent orthotopic liver transplantation without previous treatment. Ten normal livers were used as controls. In addition to morphologic evaluation, an immunohistochemical analysis was performed with the monoclonal antibodies for alpha-smooth muscle actin and proliferation marker Ki-67. The expression of these markers was graded semiquantitatively from 0 to 3+ in a blinded fashion. The zonal distribution of activated hepatic stellate cells was also evaluated. In all cases, the hepatic stellate cells were activated and expressed alpha-smooth muscle actin. In all patients with submassive or massive liver cell necrosis, the distribution of activated hepatic stellate cells was predominantly in zone 1 of the acinus (periportal area). In contrast, in cases with early nodular regeneration and no significant fibrosis, the activated hepatic stellate cells were distributed throughout the liver parenchyma, involving zones 2 and 3 of the acinus. Expression of the proliferation marker Ki-67 was graded 3+ in all patients treated with the bioartificial liver who had orthotopic liver transplantation and 2+ in patients who underwent orthotopic liver transplantation only.

Actins↗