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PubMed1996

[A clinicopathological study of primary liver cancer associated with alcoholic liver injury].

We described a clinicopathological study of primary hepatoma associated with alcoholic liver diseases without viral liver diseases. In 150 patients with primary hepatoma, 6 patients (4%) have hepatoma associated with pure alcoholic liver disease, although 143 hepatoma were associated with chronic viral liver diseases and one was with primary biliary cirrhosis. All patients were male. The diagnosis of hepatoma was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Three cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in 3 cases and liver cirrhosis was in 3 cases. Chronic infections of hepatitis B and C viruses were ruled out by assaying serum virus markers. Autoimmune hepatitis and primary biliary cirrhosis were neglected by serum autoantibody. Hemochromatosis and Wilson's disease were also excluded. Hepatocellular carcinoma was diagnosed histologically in all the cases. Serum alpha-fetoprotein and PIVKA-II were positive in patients with advanced hepatocellular carcinoma. In cases with small hepatoma, the tumor was resected surgically in two cases and percutaneous ethanol injection against hepatoma was performed in one case. In these cases with small hepatoma, the patients were alive without tumor recurrence during observation period. In advanced hepatoma, transcatheter arterial infusion of anticancer agent was performed in two cases and no therapy was performed due to poor general condition in one case. One case was alive with recurrent hepatoma for 27 months, during which a therapy was repeated five times. Other 2 cases were died. The clinicopathological features of hepatoma associated with alcoholic liver disease were essentially same as those associated with chronic viral infection, although the incidence of hepatoma in alcoholic liver disease was lower than in viral liver disease. The mechanism of hepatocarcinogenesis in alcoholic liver disease was unclear and, therefore, further study of molecular biology and biochemistry was necessary.

Aged↗

PubMed1998

[Liver and artificial liver].

Despite good results of orthotopic liver transplantation in patients with fulminant hepatic failure the need still exists for an effective and safe artificial liver, able to temporarily take over the complex liver function so as to bridge the gap with transplantation or regeneration. Attempts to develop non-biological artificial livers have failed, mostly when controlled clinical trials were performed. In the last decade several different types of bioartificial livers have been devised, in which the biocomponent consists of freshly isolated porcine hepatocytes or a human hepatoblastoma cell line. The majority use semipermeable hollow fibers known from artificial kidney devices. The liver cells may lie either inside or outside the lumen of these fibers. In vitro analysis of liver function and animal experimental work showing that the bioartificial liver increases survival justify clinical application. Bioartificial livers are connected to patients extracorporeally by means of plasmapheresis circuit for periods of about 6 hours. In different trials about 40 patients with severe liver failure have been treated. No important adverse effects have not been reported in these phase I trials. Results of controlled studies are urgently needed. As long as no satisfactory immortalised human liver cell line with good function is available, porcine hepatocytes will remain the first choice, provided transmission of porcine pathogens to man is prevented.

Animals↗

PubMedDate not supplied

The effect of spleen volume on liver regeneration after hepatectomy--a clinical study of liver and spleen volumes by computed tomography.

BACKGROUND/AIMS: The relationship between liver regeneration and spleen volume after partial hepatectomy was studied with computed tomography (CT) in 13 patients with chronic liver disease (chronic active hepatitis: 2, pre-liver cirrhosis: 3, liver cirrhosis: 8). MATERIALS AND METHODS: Liver and spleen volumes were measured by abdominal CT before hepatectomy and 1 and 2 years after operation, and the percent volumes of the liver and spleen of abdominal capacity were compared. RESULTS: While the residual liver volume increased in all patients after 1 year, it continued to increase in 7 patients (percent recovery: 102 +/- 4.8%) but had decreased in 5 patients (90.0 +/- 4.8%) after 2 years. The mean spleen volume 2 years after hepatectomy was 2.8 +/- 0.9% in the former, and 6.0 +/- 1.2% in the latter. The percent increase in liver volume was inversely related to the spleen volume (r = -0.707). In a case of transcatheter splenic arterial embolization, the liver volume continued to be increase despite splenomegaly. CONCLUSION: Splenic volume is suggested to be related to the process of recovery of the liver.

Carcinoma, Hepatocellular↗

PubMed1994

Systemic and liver cytokine activation. Implications for liver regeneration and posthepatectomy endotoxemia and sepsis.

BACKGROUND: The liver is known to be an important site of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) production during infection, but local changes in these cytokines after liver resection are unknown. DESIGN: Fischer rats were subjected to 70% hepatectomy or sham operation to determine if hepatic resection alters liver cytokine production and subsequent response to infection. RESULTS: During liver regeneration, circulating IL-6 levels were mildly increased but no expression of TNF-alpha or IL-6 could be detected in the regenerating livers. However, the capacity for the regenerating liver to produce cytokines was intact, since intraperitoneal Escherichia coli endotoxin (2 mg/kg) produced liver cytokine messenger RNA levels in hepatectomized animals comparable to those in pair-fed controls. Systemic response to endotoxin and sepsis was also intact after hepatectomy, as circulating cytokine response was similar between hepatectomized and pair-fed animals after endotoxin administration as well as after cecal ligation and puncture. CONCLUSION: Hepatectomy elicits a circulating cytokine response without effects on liver IL-6 or TNF-alpha production. However, cytokine defense mechanisms are intact during noncomplicated liver regeneration, as indicated by normal TNF-alpha and IL-6 responses to endotoxemia or sepsis. Endotoxemia is a more potent stimulus for liver cytokine production than local trauma or liver regeneration, suggesting that not only the proximity to injury but also the severity and mechanisms of injury determine local cytokine responses.

Animals↗

PubMed1991

Immunophenotyping of lymphocytes in liver tissue of patients with chronic liver diseases by flow cytometry.

Immunological factors are important in the pathogenesis of a spectrum of hepatobiliary diseases. To characterize the nature of specific immunological responses in liver disease, we determined lymphocyte changes in liver tissue and in blood using flow cytometry. A total of 113 liver biopsy specimens was collected from patients with the following diseases: 19 chronic hepatitis B; 39 chronic non-A, non-B hepatitis; 27 alcoholic liver disease; 10 hepatic malignancy; 8 autoimmune hepatitis; 6 fatty liver and 4 primary biliary cirrhosis. The lymphocytes were isolated from the liver biopsy specimens by mechanical and enzymatic methods. The lymphocyte yield was 7,901 +/- 575 cells/mg of liver tissue. The viability of lymphocytes was 97.7% +/- 0.3%. Lymphocytes were stained with four pairs of two-color mixed fluorescein-conjugated monoclonal antibodies, including T4-T8 (CD4/CD8), T11-B1 (CD2-CD20), NKH1-T8 (CD56-CD8), IL-2R1-T11 (CD25-CD2), and the ratios were determined by an Epics Profile flow cytometer. Immunophenotyping of lymphocytes in whole blood samples was simultaneously analyzed. Variability in lymphocyte yield and different patterns of lymphocyte subsets were found in the liver biopsy specimens. The yields of lymphocytes from patients with chronic non-A, non-B and autoimmune hepatitis were highest, and the lowest yield was from patients with fatty liver. Patients with primary biliary cirrhosis, fatty liver and hepatic malignancy had relatively high ratios of CD4/CD8, CD56/CD8 and CD25/CD2; whereas patients with chronic hepatitis B, autoimmune hepatitis and non-A, non-B hepatitis had lower ratios of CD4/CD8, CD56/CD8 and CD25/CD2. No difference in lymphocyte ratios between the patients with cirrhotic and noncirrhotic alcoholic liver disease was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Separation↗

PubMed2005

Identification of in vivo P-glycoprotein mRNA decay intermediates in normal liver but not in liver tumors.

Post-transcriptional regulation at the level of mRNA stability is one important mechanism for over-expression of P-glycoprotein (Pgp) genes observed in cultured cells and in animals. A previous study has shown that mRNA half-lives for Pgp genes in normal liver were less than 2 h, in contrast to greater than 12 h measured in a transplantable liver tumor line. This lower turnover rate of Pgp mRNA may, in large part, contribute to the abundance of Pgp mRNA in liver tumors. The current study sought to investigate the underlying mechanism for the lower turnover rate of Pgp2 mRNA previously determined in liver tumors. As a first approach, we set out to understand the Pgp2 mRNA decay in both normal liver and liver tumors by first identifying and characterizing Pgp2 mRNA degradation intermediates. In this study, we showed that the sensitive ligation-mediated polymerase chain reaction (LM-PCR) method can be used to detect a homogenous pool of in vitro transcribed RNA down to 0.4 ng. By employing gene-specific primers in the LM-PCR method, we successfully identified four Pgp2 mRNA decay intermediates in normal liver. All four decay intermediates detected correspond to the 5' coding region of Pgp2 mRNA, and surprisingly no decay intermediates which correspond to 3' untranslated region, 3' coding region or middle coding region were found using LM-PCR. The identified decay intermediates are unique to the normal liver as they were absent or present at very low level in all three liver tumor samples analyzed. This observation supports our previous findings that the Pgp mRNA turnover rate is lower in liver tumors than in normal liver. These findings have implications for our understanding of the regulation of Pgp mRNA turnover in normal and malignant tissues.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2003

Sonographic evaluation of the anterior liver surface in chronic liver diseases using a 7.5-MHz annular-array transducer: correlation with laparoscopic and histopathologic findings.

PURPOSE: We studied the sonographic appearance of the anterior liver surface using an ultrasound scanner equipped with a 7.5-MHz annular-array transducer to determine the accuracy of this imaging modality in monitoring the course of chronic liver diseases. METHODS: We prospectively evaluated patterns of the liver surface in the sonograms of 77 consecutive patients with chronic liver diseases who had undergone sonographic examination with a 7.5-MHz annular-array transducer and a 3.75-MHz convex-array transducer over a 2-year period and compared these findings with those of laparoscopy (using previously described categories) and histopathology. RESULTS: Histopathologically confirmed disease prevalences for inactive chronic hepatitis, active chronic hepatitis, liver cirrhosis, and others were 10% (8/77), 56% (43/77), 29% (22/77), and 5% (4/77), respectively. The sonographic appearance of the liver surface with the 3.75-MHz transducer was classified as either a regular or an irregular pattern. The regular pattern corresponded to 69% (34/50) of the cases in laparoscopic category 200 or 300 and the irregular pattern with 85% (23/27) of the cases in category 400 or 500. The sonographic appearance of the liver surface with the 7.5-MHz transducer was classified as regular, unevenly irregular, diffusely irregular, or nodular. These 4 patterns detected 75% (24/32), 78% (14/18), 52% (12/23), and 75% (3/4) of the cases of laparoscopic categories 200, 300, 400, and 500, respectively. In a comparison of the sonographic patterns of the liver surface with the differential histopathologic findings, the regular sonographic pattern corresponded to 88% (7/8) of the cases of inactive chronic hepatitis, the unevenly irregular pattern with 35% (15/43) of the cases of active chronic hepatitis, and the diffusely irregular and nodular patterns (considered as 1 group) with 68% (15/22) of the cases of liver cirrhosis. CONCLUSIONS: Our results suggest that sonographic evaluation of the liver surface with a 7.5-MHz annular-array transducer using this classification provides detailed information on the evolution of chronic liver diseases that correlates with the laparoscopic and histopathologic findings and thus is a useful noninvasive method for monitoring the disease course to cirrhosis.

Biopsy, Needle↗

PubMed2003

Comparison between signal-to-noise ratio, liver-to-muscle ratio, and 1/T2 for the noninvasive assessment of liver iron content by MRI.

PURPOSE: To compare different MRI-derived parameters, i.e., liver signal-to-noise ratio (LSNR), liver-to-muscle ratio (LMR) and liver transversal relaxation rate (R2), in terms of their correlation with the ex vivo determined iron content in an experimental model of liver iron overload. MATERIALS AND METHODS: Multi-echo spin echo (SE) images of the liver were acquired at 4.7 T from a group of 33 male wistar rats subjected to a high iron content diet for feeding periods ranging from 2 to 50 days. Liver transversal relaxation time, liver signal-to-noise ratio, and liver-to-muscle ratio were measured over the same region of interest in order to get a direct comparison between these parameters. After MRI experiments, the rats were sacrificed and the liver iron content was measured ex vivo by atomic absorption spectroscopy. RESULTS: The iron content is better correlated to the LSNR than to the other parameters (LMR, R2). CONCLUSION: The finding that liver signal-to-noise ratio is better correlated to the iron content than the liver T2 relaxation rate is relevant for clinical applications of MRI because a T2 determination is more time-consuming, both for acquisition and postprocessing of images, than a simple SNR determination.

Animals↗

PubMed2004

Liver regeneration after adult living donor and deceased donor split-liver transplants.

As the number of living donor (LD) and deceased donor (DD) split-liver transplants (SLTs) have increased over the last 5 years, so too has the interest in liver regeneration after such partial-liver transplants. We looked at liver regeneration, as measured by computed tomography (CT) volumetrics, to see if there were significant differences among LDs, right-lobe LD recipients, and SLT recipients. We measured liver volume at 3 months postoperatively by using CT, and we compared the result to the patient's ideal liver volume (ILV), which was calculated using a standard equation. The study group consisted of 70 adult patients who either had donated their right lobe for LD transplants (n = 24) or had undergone a partial-liver transplant (right-lobe LD transplants, n = 24; right-lobe SLTs, n = 11; left-lobe SLTs, n = 11). DD (vs. LDs) were younger (P < 0.01), were heavier (P = 0.06), and had longer ischemic times (P < 0.01). At 3 months postoperatively, LDs had attained 78.6% of their ILV, less than the percentage for right-lobe LD recipients (103.9%; P = 0.0002), right-lobe SLT recipients (113.6%; P = 0.01), and left-lobe SLT recipients (119.7%; P = 0.0006). When liver size at the third postoperative month was compared with the liver size immediately postoperatively, LDs had a 1.85-fold increase. This was smaller than the increase seen in right-lobe LD recipients (2.08-fold), right-lobe SLT recipients (2.17-fold), and left-lobe SLT recipients (2.52-fold). In conclusion, liver regeneration, as measured by CT volume, seems to be greatest in SLT recipients. LD recipients seem to have greater liver growth than their donors. The reason for this remains unclear.

Adult↗

PubMed1975

Hepatoma, host liver, and normal rat liver lipids: distribution of isomeric monoene fatty acids in individual lipid classes.

Monoenoic acid fractions were isolated from phosphatidycholine, phosphatidylethanolamine, triglycerides, and cholesteryl esters of hepatoma 7288CTC, host liver, and normal liver from animals maintained on chow and fat free diets. Hexadecanoate (16:1), octadecenoate (18:1), and eisosenoate (20:1) fractions were analyzed quantitatively for their isomeric composition. The fat free diet had little or no effect relative to the chow diet on the isomeric composition of 16:1, 18:1, and 20:1 from any lipid class in either heptoma, host liver, or normal liver. Host livers were reduced in palmitoleic acid, and oleic and eicos-11-enoic acids were increased relative to normal liver. The 16:1 fraction from triglyceride of normal liver, host liver, and hepatoma contained 90, 80, and 75% palmitoleic acid, respectively. The 20:1 fraction from triglycerides of normal liver, host liver, and hepatoma contained ca. 55, 70, and 60% eicos-11-enoic acid, respectively, with the remainder consisting of eicos-13-enoic acid. The proportion of vaccenic acid in the 18:1 fraction was 60, 50, 20, and 25% for phosphatidylethanolamine, phosphatidylcholine, triglycerides, and cholesteryl esters, respectively, with oleic acid making up the balance. In contrast, all hepatoma lipid classes exhibited the same proportion of oleic (70%) and vaccenic (30%) acids. These data appear to be the first to demonstrate lipid class specificity for isomeric octadecenoic acids in normal liver and the loss of this specificity in a neoplasm.

Carcinoma, Hepatocellular↗

PubMed1990

Collagenase of hepatocytes and sinusoidal liver cells in the reversibility of experimental cirrhosis of the liver.

In order to explore the cellular source(s) and the behaviour of the collagenolytic activity previously described in rat liver homogenates, in the reversibility of experimental cirrhosis of the liver, enriched suspensions of hepatocytes and of sinusoidal liver cells were obtained by a procedure which employs low EDTA concentrations and no bacterial collagenase. Cell suspensions were prepared from three different groups of animals: 1) normal controls, 2) rats with CCl4-induced cirrhosis of the liver, and 3) rats with swine serum-induced cirrhosis of the liver. Animals were sacrificed in each group upon completion of treatment and also after 3, 6 and 12 months. In each liver wet weight and collagen concentration were determined, and collagenolytic activity of both enriched cell suspensions was measured separately. In addition, histological studies of liver tissue and ultrastructural examination of cell suspensions were performed by standard procedures. Enriched suspensions of both normal hepatocytes and sinusoidal liver cells display Ca2(+)-dependent collagenolytic activities. Both cell suspensions obtained from each of the two types of cirrhotic livers show normal or slightly increased average levels of collagenase activity at the time of treatment discontinuation, when average liver collagen content ranges from 6 to 10-fold over normal, suggesting that the normal collagenase/collagen ratio is disturbed and that collagenolytic activity is deeply decreased in relation to the actual liver collagen load.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients.

PURPOSE: Liver disease is a frequent complication in renal transplant recipients. To understand the nature and progression of hepatic disease in these patients, we performed percutaneous biopsies in 77 subjects who had chronic liver dysfunction in the posttransplant period. The purpose of the present investigation is to delineate the morphologic spectrum of chronic liver disease in the renal allograft recipients and to characterize the clinical and histologic progression of each of the different morphologic forms. PATIENTS AND METHODS: Between 1971 and 1990, 915 patients received renal transplants at the Hennepin County Medical Center, Minneapolis, Minnesota. One hundred nineteen (13%) of them had abnormal liver function that persisted for longer than 6 months. Percutaneous liver biopsies were performed in 77 of these patients, but adequate tissue for histologic evaluation was available in only 72. After the biopsy, the clinical and histologic course of each subject was monitored in relation to the baseline hepatic morphology. To assess the predictive value of serum enzymes in diagnosing the histologic lesions, the level of serum enzymes at the time of the biopsy was correlated with the morphologic diagnosis. In addition, several clinical, biochemical, etiologic, and histologic variables were screened for their association with histologic progression to liver cirrhosis. RESULTS: The morphologic diagnosis in the 72 specimens evaluated at baseline was as follows: fat metamorphosis in 8 (11%), chronic persistent hepatitis in 20 (28%), early chronic active hepatitis in 20 (28%), advanced chronic active hepatitis in 15 (21%), and hemosiderosis in 9 (12%). There was no statistical correlation between the serum enzyme levels and the histologic diagnosis. During a mean follow-up of 5.7 +/- 3.9 years, clinical progression to hepatic failure and death occurred in 35% of patients with early chronic active hepatitis, 55% with hemosiderosis, and 60% with advanced chronic active hepatitis. None of the patients with the morphologic diagnosis of fat metamorphosis or chronic persistent hepatitis died as a consequence of hepatic failure. Follow-up liver specimens were obtained in 34 (47%) of the original 72 subjects after a mean interval of 4.5 +/- 4.3 years. Of the 15 patients with the initial diagnosis of early chronic active hepatitis, 9 (60%) showed morphologic transition to advanced chronic active hepatitis, and in 1 of the 5 patients with hemosiderosis (20%), the lesion had resolved after successive phlebotomies. During the follow-up, 60% with early chronic active hepatitis (9 of 14), 66% with hemosiderosis (2 of 3), and 100% with advanced chronic active hepatitis (4 of 4) showed histologic progression to liver cirrhosis. On the contrary, no morphologic alterations were observed in the follow-up specimens of patients with fat metamorphosis or chronic persistent hepatitis. Of the different variables screened for their association with histologic progression, older age at transplant, female sex, and morphologic diagnosis of advanced chronic active hepatitis were found to be significant. CONCLUSION: Histologic diagnosis can be a useful marker in predicting the course of chronic liver disease after renal transplantation. Liver biopsy should be incorporated into the evaluation and management of chronic liver disease in renal transplant recipients.

Adult↗

PubMed2006

Assessment of residual error in liver position using kV cone-beam computed tomography for liver cancer high-precision radiation therapy.

PURPOSE: To evaluate the residual error in liver position using breath-hold kilovoltage (kV) cone-beam computed tomography (CT) following on-line orthogonal megavoltage (MV) image-guided breath-hold liver cancer conformal radiotherapy. METHODS AND MATERIALS: Thirteen patients with liver cancer treated with 6-fraction breath-hold conformal radiotherapy were investigated. Before each fraction, orthogonal MV images were obtained during exhale breath-hold, with repositioning for offsets>3 mm, using the diaphragm for cranio-caudal (CC) alignment and vertebral bodies for medial-lateral (ML) and anterior posterior (AP) alignment. After repositioning, repeat orthogonal MV images, orthogonal kV fluoroscopic movies, and kV cone-beam CTs were obtained in exhale breath-hold. The cone-beam CT livers were registered to the planning CT liver to obtain the residual setup error in liver position. RESULTS: After repositioning, 78 orthogonal MV image pairs, 61 orthogonal kV image pairs, and 72 kV cone-beam CT scans were obtained. Population random setup errors (sigma) in liver position were 2.7 mm (CC), 2.3 mm (ML), and 3.0 mm (AP), and systematic errors (Sigma) were 1.1 mm, 1.9 mm, and 1.3 mm in the superior, medial, and posterior directions. Liver offsets>5 mm were observed in 33% of cases; offsets>10 mm and liver deformation>5 mm were observed in a minority of patients. CONCLUSIONS: Liver position after radiation therapy guided with MV orthogonal imaging was within 5 mm of planned position in the majority of patients. kV cone-beam CT image guidance should improve accuracy with reduced dose compared with orthogonal MV image guidance for liver cancer radiation therapy.

Carcinoma, Hepatocellular↗

PubMed2004

Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure.

BACKGROUND/AIMS: Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. METHODS: A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity. RESULTS: The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed. A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure. CONCLUSIONS: Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure.

Acute Disease↗

PubMed1999

Sorbitol removal by the metastatic liver: a predictor of systemic toxicity of intra-arterial chemotherapy in patients with liver metastases.

BACKGROUND/AIM: Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine. METHODS: Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Student's t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability). RESULTS: Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy. CONCLUSIONS: Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.

Adult↗

PubMed2002

Lymphocyte recruitment to the liver in alcoholic liver disease.

The normal liver contains a large number of lymphocytes, which include not only specialized natural killer (NK) and NKT cells but also CD4 and CD8 T cells. Whereas some of these cells are terminally differentiated effector cells that are destined to die by apoptosis, many of them are not and include immunocompetent cells that traffic through the liver to provide continuing immune surveillance as well as epithelial-associated effector T cells. In alcoholic liver disease the number of lymphocytes in the liver increases and the type and distribution of these infiltrating cells will determine the nature of the inflammation. For instance, a predominance of parenchymal inflammation is a feature of alcoholic hepatitis, whereas a predominantly portal infiltrate is a feature of cirrhosis. In this article we discuss the molecular mechanisms that regulate the entry of lymphocytes to the inflamed liver in alcoholic hepatitis. Lymphocytes play a critical role in regulating the immune/inflammatory response to alcohol, and understanding how these cells are recruited to the liver has important implications for understanding the pathogenesis of alcoholic liver disease in which parenchymal infiltration is a critical determinant of disease progression. Aberrant recruitment and retention of lymphocytes in the liver may explain why some patients with alcoholic liver disease show progressive inflammatory damage whereas in others the disease takes a more indolent course. Similarly, leukocyte recruitment may present new therapeutic targets in which lymphocyte recruitment to the specific liver compartments can be inhibited, thereby minimizing tissue damage whilst leaving generalized lymphocyte recirculation intact. Potentially the most exciting potential is to modulate the nature of the lymphocyte subsets recruited to the liver, so that harmful cells are excluded and beneficial subsets are preferentially recruited.

Animals↗

PubMed1994

Proliferating cell nuclear antigen expression in Wistar rat livers. A retrospective immunohistochemical study of normal and neoplastic livers.

Formalin-fixed, paraffin-embedded liver specimens from 27 2-year-old Wistar rats, including 10 normal livers, 11 hepatocellular adenomas, 2 hepatocellular carcinomas, and 4 cystic cholangiomas, were immunostained using the streptavidin/peroxidase method and the PC10 monoclonal antibody (Mab), which recognizes an epitope on the proliferating cell nuclear antigen (PCNA). The following PCNA labeling index (LI) mean values were found for the above four groups of liver specimens: normal livers, 0.43 +/- 0.31%; hepatocellular adenomas, 1.51 +/- 0.59%; hepatocellular carcinomas, 24.80% +/- 10.28%; and cystic cholangiomas, 0.61 +/- 0.21%. Our findings indicate that PCNA LI clearly separates liver malignancies from other benign liver tumors, as well as from normal, non-neoplastic, liver tissues. Although the mean PCNA LI values seemed to reflect histological grading (i. e. normal, neoplastic benign, neoplastic malignant), overlapping between normal livers and hepatocellular adenomas was observed in five cases (i. e. in 2 normal livers and 3 hepatocellular adenomas, where the PCNA LI values varied between 0.74% and 0.96%). It thus appears that PCNA immunohistochemistry represents a promising tool for investigating liver cell proliferation in laboratory rats, and permits distinguishing between benign and malignant liver parenchymal tumors.

Animals↗

PubMed2000

Molecular mechanisms of augmenter of liver regeneration as immunoregulator: its effect on interferon-gamma expression in rat liver.

BACKGROUND: We have shown that the administration of exogenous Augmenter of Liver Regeneration protein in intact rats i) regulates mitochondrial gene expression by inducing the transcription and translation of the nuclear-encoded mitochondrial transcription factor A, and ii) inhibits the lytic activity of liver-resident Natural Killer cells. AIMS: The present investigation was carried out to study the effect, in intact rats, of exogenous administration of Augmenter of Liver Regeneration protein on Interferon-gamma, a cytokine produced by activated Natural Killer cells and known to control the expression of mitochondrial transcription factor A, a nuclear gene responsible for mitochondrial metabolism. METHODS: Interferon-gamma was measured as messenger RNA in liver-derived mononuclear leukocytes and as protein in liver-derived Natural Killer cells after a single injection of Augmenter of Liver Regeneration protein. RESULTS: The data obtained demonstrate that: i) in intact rats, Augmenter of Liver Regeneration protein administration induces a reduction of Interferon-gamma in the liver-resident Natural Killer cells and ii) the administration of Interferon-gamma in 70% hepatectomized rats is followed by a significant reduction both of the mitochondrial transcription factor A expression and of liver regeneration. CONCLUSIONS: These data demonstrate the pivotal role of Augmenter of Liver Regeneration as Growth Factor and as immunoregulator by controlling, through Interferon-gamma levels, the mitochondrial transcription factor A expression and the lytic activity of liver-resident Natural Killer cells.

Animals↗