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PubMed1998

Ultrasound-guided liver biopsy for parenchymal liver disease: an economic analysis.

The use of ultrasound (US) to assist in liver biopsy for nonfocal liver disease has been shown to significantly decrease the incidence of minor complications (defined as pain requiring treatment, hypotension, or bleeding). In this study, decision analysis was used to estimate the average additional net charge for US guidance. The risks for minor and major complications were extracted from the literature. The incidence of minor complications such as pain and bleeding not requiring hospitalization has been reported as 49% for blind liver biopsy and 39% for US-guided liver biopsy. Major complications requiring hospital admission occur in 4% of blind liver biopsies and 2% of US-guided liver biopsies. A decision tree was used to calculate the total charges of liver biopsy and its associated complications. The charge for treating an episode of minor complications was estimated at $605. The charge related to an episode of major complications was estimated at $1533. The total charge for an ultrasound-guided liver biopsy (except the added charge for the use of ultrasound) was $1770, or $102 less than the same charge for blind liver biopsy. The addition of ultrasound in performing liver biopsies for diffuse parenchymal liver disease is cost-saving if the additional charge of US is less than $102.

Biopsy↗
PubMed1998

Effect of S-adenosyl-L-methionine and dilinoleoylphosphatidylcholine on liver lipid composition and ethanol hepatotoxicity in isolated perfused rat liver.

We investigated whether S-adenosyl-L-methionine (SAMe), dilinoleoylphosphatidylcholine (DLPC), or SAMe + DLPC influence liver lipid composition as well as acute ethanol hepatotoxicity in the isolated perfused rat liver (IPRL). SAMe (25 mg/kg intramuscularly three times a day) was administered for five consecutive days, while DLPC was administered intraperitoneally for five days. The liver was then isolated, perfused with taurocholate to stabilize bile secretion, and exposed to 0.5% ethanol for 70 min. SAMe, without changing total phospholipid (PL) content, induced an increase in the phosphatidylcholine/phosphatidylethanolamine (PC/PE) molar ratio in both liver homogenate and microsomes and a significant enrichment of 16:0-20:4 and 18:0-20:4 PC molecular species. DLPC induced a significant enrichment of PL in liver homogenate and microsomes due to a contemporary increase in PC and PE. The PC enrichment specifically involved 16:0-20:4 and 18:0-20:4 PC molecular species besides the HPLC peak containing the administered 18:2-18:2 PC species. DLPC + SAMe increased the concentration of PC in liver homogenate and microsomes due to a specific enrichment of 16:0-22:6, 16:0-20:4, and 18:0-20:4 PC molecular species, and the HPLC peak containing the administered 18:2-18:2 PC species. Ethanol acute exposure in the control IPRLs for 70 min induced a depletion of cholesterol in both liver homogenate and microsomes without significant changes in the composition of PL classes and PC molecular species. SAMe, DLPC, or SAMe + DLPC counteracted the cholesterol depletion induced by ethanol, indicating that phospholipid changes promoted by these treatments all induce a major resistance of liver membranes to the effect of ethanol. Ethanol administration in control IPRLs induced a fivefold increase of AST and LDH release in the perfusate, depletion of glutathione in homogenates and mitochondria, decreased oxygen liver consumption, and inhibition of bile flow. These effects of ethanol were significantly antagonized by SAMe. In contrast, DLPC alone only minimally attenuated enzyme release in the perfusate and the inhibitory effect of ethanol on bile flow, but it failed to influence the depletion of total and mitochondrial glutathione or the depressed oxygen consumption induced by ethanol. DLPC, administered together with SAMe, added nothing to the protective effect of SAMe against ethanol hepatotoxicity and cholestasis. In conclusion, this study demonstrates that both SAMe and DLPC induced marked modifications in the lipid composition of liver membranes with a similar enrichment of polyunsaturated PC molecular species. Only SAMe, however, significantly protected against the hepatotoxic and cholestatic effect of acute ethanol administration, an effect associated with maintained normal glutathione mitochondrial levels and oxygen liver consumption. This indicates that the protective effect of SAMe against ethanol toxicity is linked to multiple mechanisms, the maintenance of glutathione levels probably being one of the most important.

Animals↗
PubMed2006

Intensive follow-up after liver resection for colorectal liver metastases: results of combined serial tumour marker estimations and computed tomography of the chest and abdomen - a prospective study.

The aim of the study was to prospectively evaluate an intensive follow-up programme using serial tumour marker estimations and contrast-enhanced computed tomography (CT) of the chest and abdomen in patients undergoing potentially curative resection of colorectal liver metastases. Seventy-six consecutive patients having undergone potentially curative resections of colorectal liver metastases in a single unit were followed up with a protocol of 3 monthly carcinoembryonic antigen and carbohydrate antigen 19-9 estimations and contrast-enhanced spiral CT of the chest, abdomen and pelvis for the first 2 years following surgery and 6 monthly thereafter. The median period of follow-up was 24 months (range 18-60). Recurrent tumour was classed as early if within 6 months of liver resection. Thirty-seven of the 76 patients (49%) developed recurrence on follow-up. Nineteen recurrences were in the liver alone (51%), 16 liver and extrahepatic (43%) and two extrahepatic alone (6%). Of the 19 patients with isolated liver recurrence, eight developed within 6 months of liver resection none of which were resectable. Of the 11 recurrences after 6 months, five (45%) were resectable. Of the 37 recurrences, CT indicated recurrence despite normal tumour markers in 19 patients. Tumour markers suggested recurrence before imaging in 12 and concurrently with imaging in 6. In the 12 patients who presented with elevated tumour markers before imaging, there was a median lag period of 3 months (range 1-21) in recurrence being detected on further serial imaging. Seventeen patients who developed recurrence had normal tumour markers before initial resection of their liver metastases. Of these 17, 10 (58%) had an elevation of tumour markers associated with recurrence. Over a median follow-up of 2 years following liver resection, the use of CT or tumour markers alone would have failed to demonstrate early recurrence in 12 and 18 patients respectively. A combination of tumour markers and CT detected significantly more (P < 0.05) recurrence than either modality alone. Tumour markers and CT should be used in combination in the follow-up of patients with resected colorectal liver metatases, including patients whose markers are normal at the time of initial liver resection.

Abdominal Neoplasms↗
PubMed1992

Glycogen phosphorylase isoenzymes from hepatoma 3924A and from a non-tumorigenic liver cell line. Comparison with the liver and brain enzymes.

Glycogen phosphorylase isoenzymes were isolated from normal rat liver, rat brain, the glycogen-poor Morris hepatoma (MH) 3924A, and the glycogen-rich non-tumorigenic liver cell line C1I. Electrophoretic and immunological characterization of the enzymes showed that tumour and C1I cells expressed a phosphorylase isoform similar to the brain type; the liver type was not detectable. All enzymes were obtained as dimers; the Mr of the subunits was 96,000 (liver), 93,000 (brain and MH 3924A) and 92,000 (C1I). Isoelectric focusing revealed a main band of pI 6.34 for liver phosphorylase a, pI 5.67 for the enzymes from MH 3924A and brain, and pI 5.68 for C1I phosphorylase. Partial kinetic characterization of the AMP-independent forms of the isoenzymes yielded Km values for glucose 1-phosphate of 3.5 +/- 0.5 mM (liver), 3.9 mM (brain), 1.9 +/- 0.3 mM (MH 3924A) and 2.5 +/- 0.5 mM (C1I); Km values for glycogen were 0.4 mM (liver) and 0.3 mM (MH 3924A and C1I), calculated as glucose equivalents. The AMP-independent phosphorylase was inhibited by glucose 6-phosphate (Glc6P) with Ki values of 0.32 +/- 0.03 mM (C1I), 0.50 +/- 0.04 mM (MH 3924A) and approximately 5 mM (brain). The inhibition could be abolished by 1 mM-AMP, indicating that AMP and Glc6P may partially compete for the same site on the protein. Liver phosphorylase a was not inhibited by up to 25 mM-Glc6P. In contrast with liver and brain isoenzymes, phosphorylase from the cell lines was not affected by NaF and Na2SO4. The data show that both the hepatocellular carcinoma and the non-malignant immortalized liver cells express a phosphorylase isoform different from the liver type. Furthermore, there is some evidence that the enzyme from MH 3924A and C1I cells is distinct from brain phosphorylase a, in spite of electrophoretic and immunological resemblance, and that this isoenzyme is subject to altered metabolic regulation.

Animals↗
PubMed2003

Bioartificial liver inoculated with porcine hepatocyte spheroids for treatment of canine acute liver failure model.

The aim of this study was to evaluate a novel bioartificial system in a canine model of acute liver failure. An acute liver failure model in canines was induced by an end-side portocaval shunt combined with common bile duct ligation and transection. The bioartificial liver system, which utilized blood perfusion through a hollow fiber bioreactor from BIOLIV A3A inoculated with 1.0 - 3.1 x 1010 porcine hepatocyte spheroids, was developed for the treatment of acute liver failure. Sixteen acute liver failure model canines were divided between a group treated with bioartificial liver (n=8) and a control group (n=8) for 5 h. Blood alanine aminotransferase (ALT), alkaline phosphatase (AKP), total bilirubin (TBi), direct bilirubin (DBi), prothrombin time (PT), ammonia levels, and the ratio of branched chain to aromatic amino acids (Fischer's ratio) were determined. ALT, AKP, TBi, DBi, and ammonia levels were significantly elevated, PT was significantly prolonged, and Fischer's ratio decreased significantly in the canine model of the two groups on day 14 after operation compared to baseline. There were no significant differences between the two groups in laboratory data before treatment. In canines treated with the bioartificial liver system, ALT, AKP, TBi, DBi, and ammonia levels decreased significantly, PT was significantly shortened, Fischer's ratio was significantly elevated after treatment, and the survival rate by day 7 after treatment was 100%. In canines in the control group, on the other hand, there were no significant differences in ALT, AKP, TBi, DBi, PT, and ammonia levels between pretreatment and posttreatment, though these indices decreased to a slight degree after treatment. The survival rate by day 7 after treatment was 62.5% in the control group. Fischer's ratio decreased after treatment. ALT, AKP, TBi, DBi, PT, and ammonia levels in the bioartificial liver system group were lower, and Fischer's ratio and survival rate were higher than those in the control group after treatment. These results indicate that the novel bioartificial liver system we developed has a significant impact on the course of canine acute liver failure model and has potential advantages for clinical use in patients with acute liver failure.

Animals↗
PubMed2004

[Liver transplantation for metabolic liver disease in adulthood].

The clinical presentation of metabolic liver disease is highly variable, covering acute liver failure, liver cirrhosis, hepatic cancer and various extrahepatic manifestations. Both natural course and prognosis after liver transplantation are substantially influenced by extrahepatic manifestations. In many types of metabolic liver disease, timely diagnosis allows for successful medical treatment. However, progressive liver failure and severe extrahepatic damage can be the indication for liver transplantation. In general, standard transplantation criteria also apply for metabolic liver disease. They have to be modified by disease-specific criteria, and extrahepatic damage may necessitate multiorgan transplantation. The overall prognosis after liver transplantation for metabolic liver disease is favorable. Furthermore, several metabolic defects are phenotypically cured by liver transplantation. Alternative treatments like hepatocyte transplantation or gene therapy are still in the experimental stage.

Adult↗
PubMed2000

Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver.

OBJECTIVE: To assess the influence of preoperative portal vein embolization (PVE) on the long-term outcome of liver resection for hepatocellular carcinoma (HCC) in injured liver. SUMMARY BACKGROUND DATA: On an healthy liver, PVE of the liver to be resected induces hypertrophy of the remnant liver and increases the safety of hepatectomy. On injured liver, this effect is still debated. METHODS: During the study period, 10 patients underwent preoperative PVE and 19 patients did not before resection of three or more liver segments for HCC in injured liver (cirrhosis or fibrosis). PVE was performed when the estimated rate of remnant functional liver parenchyma (ERRFLP) assessed by computed tomographic scan volumetry was less than 40%. RESULTS: In all patients, PVE was feasible. There were no deaths or complications. The ERRFLP after PVE was significantly increased compared with the pre-PVE value. Liver resection was performed after PVE in 9 of 10 patients, with surgical death and complication rates of 0% and 45%, respectively. PVE increased the number of resections of three or more segments by 47% (9/19). Overall actuarial survival rates with or without previous PVE (89%, 67%, and 44% vs. 80%, 53%, and 53% at 1, 3 and 5 years, respectively) and disease-free actuarial survival rates (86%, 64%, and 21% vs. 55%, 17%, and 17% at 1, 3, and 5 years respectively) after hepatectomy were comparable. CONCLUSION: With the use of PVE, more patients with previously unresectable HCC in injured liver can benefit from resection. Long-term survival rates are comparable to those after resection without PVE.

Carcinoma, Hepatocellular↗
PubMed2000

Improved graft survival of pediatric liver recipients transplanted with pediatric-aged liver donors.

BACKGROUND: Improving graft survival after liver transplantation is an important goal for the transplant community, particularly given the increasing donor shortage. We have examined graft survivals of livers procured from pediatric donors compared to adult donors. METHODS: The effect of donor age (<18 years or > or =18 years) on graft survivals for both pediatric and adult liver recipients was analyzed using data reported to the UNOS Scientific Registry from January 1, 1992 through December 31, 1997. Graft survival, stratified by age, status at listing, and type of transplant was computed using the Kaplan-Meier method. In addition, odds ratios of graft failure at 3 months, 1 year, and 3 years posttransplant were calculated using a multivariate logistic regression analysis controlling for several donor and recipient factors. Modeling, using the UNOS Liver Allocation Model investigated the impact of a proposed policy giving pediatric patients preference to pediatric donors. RESULTS: Between 1992 and 1997 pediatric recipients received 35.6% of pediatric aged donor livers. In 1998 the percent of children dying on the list was 7.4%, compared with 7.3% of adults. Kaplan-Meier graft survivals showed that pediatric patients receiving livers from pediatric aged donors had an 81% 3-year graft survival compared with 63% if children received livers from donors > or =18 years (P<0.001). In contrast, adult recipients had similar 3-year graft survivals irrespective of donor age. In the multivariate analysis, the odds of graft failure were reduced to 0.66 if pediatric recipients received livers from pediatric aged donors (P<0.01). The odds of graft failure were not affected at any time point for adults whether they received an adult or pediatric- aged donor. The modeling results showed that the number of pediatric patients trans planted increased by at most 59 transplants per year. This had no significant effect on the probability of pretransplant death for adults on the waiting list. Waiting time for children at status 2B was reduced by as much as 160 days whereas adult waiting time at status 2B was increased by at most 20 days. CONCLUSION: A policy that would direct some livers procured from pediatric- aged donors to children improves the graft survival of children after liver transplantation. The effect of this policy does not increase mortality of adults waiting. Such a policy should increase the practice of split liver transplantation, which remains an important method to increase the cadaveric donor supply.

Adolescent↗
PubMed2003

Role of ischemic preconditioning and the portosystemic shunt in the prevention of liver and lung damage after rat liver transplantation.

BACKGROUND: This study evaluates whether surgical strategies such as the portosystemic shunt and ischemic preconditioning can protect against hepatic and pulmonary injury associated with liver transplantation. METHODS: The effect of the portosystemic shunt, ischemic preconditioning, and both surgical procedures together were evaluated in rat liver transplantation. Alanine aminotransferase, hyaluronic acid levels in plasma, adenosine triphosphate and nucleotide levels in liver and edema, malondialdehyde levels, and myeloperoxidase activity were measured 24 hr posttransplantation. Plasmatic tumor necrosis factor (TNF) levels were measured as a possible proinflammatory factor responsible for hepatic and pulmonary damage associated with liver transplantation. RESULTS: Hepatocyte and cell endothelial damage were observed in liver grafts subjected to 8 hr of cold ischemia. This was associated with increased plasma TNF levels and lung inflammatory response. Portosystemic shunt application in the recipient protected endothelial cells but did not confer an effective protection from hepatocyte damage or reduce the increased plasma TNF levels and lung damage after liver transplantation. However, preconditioning of the donor liver conferred protection against both the endothelial cell and hepatocyte damage observed after liver transplantation. Preconditioning also attenuated the increased plasma TNF release and pulmonary damage. The combination of both surgical strategies resulted in levels of liver injury, TNF, and lung damage similar to those seen after liver transplantation. CONCLUSIONS: These findings indicate that ischemic preconditioning could be a preferred treatment to reduce hepatic and pulmonary damage associated with liver transplantation. However, this strategy may not be effective in several clinical situations requiring a portosystemic shunt.

Animals↗
PubMed2006

Attenuation of acute rejection in a rat liver transplantation model by a liver-targeted dextran prodrug of methylprednisolone.

BACKGROUND: The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in nontarget tissues. Therefore, selective delivery of MP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model. METHODS: The model consisted of a high responder rejection strain combination (Dark Agouti donors and Lewis recipients). Liver recipients were intravenously administered saline or a single subtherapeutic dose of MP (5 mg/kg) as the parent drug (MP) or its prodrug (DMP). Different groups were then monitored for graft survival or euthanized 5 or 9 days posttransplantation. Plasma chemistry, including alkaline phosphatase and bilirubin, allograft histology, and survival duration were determined. RESULTS: Untreated recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allografts, and a mean graft survival time (MST) of 10.5 days. MP treatment did not alter any of these parameters. In contrast, a single dose of DMP resulted in a decrease in plasma levels of liver injury markers, a decrease in histological grade of rejection on day 5, and a substantial increase in MST (27.5 days). CONCLUSIONS: These results demonstrate attenuation of acute rejection following local (allograft) immunosuppression with a single subtherapeutic dose of MP delivered as a liver-targeted prodrug. Dextran prodrugs may be useful for selective delivery of immunosuppressants to the liver following liver transplantation.

Acute Disease↗
PubMed2004

Liver iron deposits in hepatitis B patients: association with severity of liver disease but not with hemochromatosis gene mutations.

BACKGROUND AND AIMS: Iron deposits in the liver and abnormalities in serum iron biochemistry are frequently observed in patients with chronic liver diseases, but data for patients with hepatitis B virus (HBV) infection are scarce. Moreover, the role of HFE mutations in iron deposits in this condition remains unknown. The aim of the present study was to determine the prevalence of serum iron biochemical abnormalities and iron deposits in the liver of chronic HBV patients, and to evaluate the consequences for the activity and severity of liver disease. Additionally, we studied the role of HFE gene mutations in iron deposits. METHODS: Eighty-one male non-cirrhotic HBV patients were studied. Serum iron biochemistry, liver enzymes and C282Y/H63D mutations were investigated. Liver biopsies were scored for necroinflammatory activity (histological activity index [HAI]), fibrosis and iron deposits. RESULTS: Elevated transferrin saturation (TS) was found in 27.1% of patients and liver iron deposits in 48.7%; these deposits were mild in 68.4% and moderate in 31.6%. Patients with liver iron deposits exhibited significantly higher scores for HAI and fibrosis than those without iron deposits. HFE mutations were identified in 23.4% of patients (14 H63D heterozygotes, four H63D homozygotes, one compound mutation). No difference in the prevalence of C282Y and H63D mutations was observed between HBV patients (1.2% and 23.4%, respectively) and the general population (4.1% and 27.8%, respectively). No association was detected between HFE mutations and elevated TS or liver iron deposits. CONCLUSIONS: Elevated TS and liver iron deposits were frequent in non-cirrhotic HBV patients. Iron deposits were mainly mild and associated with higher activity and severity of liver disease, but not with HFE mutations.

Adolescent↗
PubMed1993

The evaluation of the isolated perfused liver as a model for the assessment of liver preservation.

An ex vivo isolated perfused porcine liver model was tested to assess its suitability for rapid, reliable and relatively cheap testing of organ preservation solutions for liver transplantation. The model consists of a machine driven recirculating system incorporating an organ chamber, blood pump and membrane oxygenator. Autologous blood was used for perfusion for a period of 2 h at a temperature of 37 degrees C. The model was tested with five groups of livers which had sustained varying degrees of injury ranging from minimally damaged to those known to be incapable of sustaining life when used for liver transplantation. The groups of livers were: (i) controls; (ii) preserved in University of Wisconsin solution (UW) for 6 h; (iii) preserved in an albumin-based extracellular fluid (ALB) for 6 h; (iv) preserved in UW for 18 h; and (v) preserved in ALB for 18 h. Bile production was found to be a reliable parameter of preservation damage. Changes in perfusate levels of aspartate aminotransferase, potassium, glucose and calcium also occurred in relationship to preservation damage. In contrast, weight gain of the liver, sequestration of the white cells and platelets in the liver, urea production and oxygen consumption were unreliable predictors of liver damage. Histology of biopsy specimens revealed apparently well preserved livers in all cases after preservation but before perfusion, but serious abnormalities after perfusion in long preserved livers, with features in these suggestive of damage to the sinusoidal endothelium. We believe that the model is a worthwhile adjunct to research into liver preservation.

Adenosine↗
PubMed2000

Development and evaluation of the Liver Disease Quality of Life instrument in persons with advanced, chronic liver disease--the LDQOL 1.0.

OBJECTIVES: Assessment of health-related quality of life (HRQOL) outcomes in studies of liver disease and liver transplantation is necessary. Reliable and valid disease-targeted HRQOL measures are thus needed. The objective of this study was to develop a reliable and valid self-report HRQOL instrument for ambulatory adults with chronic liver disease. METHODS: The Liver Disease Quality of Life instrument, LDQOL 1.0 (an HRQOL measure that uses the SF-36 as a generic core and 12 disease-targeted multi-item scales) was administered in a multicenter, cross-sectional field test to 221 ambulatory adults with advanced, chronic liver disease referred for primary liver transplantation evaluation. Disease-targeted scales included liver disease-related symptoms, liver disease-related effects on activities of daily living, concentration, memory, sexual functioning, sexual problems, sleep, loneliness, hopelessness, quality of social interaction, health distress, and self-perceived stigma of liver disease. We estimated the internal consistency reliability (Cronbach's alpha) for multi-item scales and construct validity. RESULTS: Interial consistency reliability coefficients were excellent, ranging from 0.62 to 0.95, with 19 of 20 scales >0.70. Multitrait scaling analysis provided strong support for item discrimination across scales, and exploratory factor analysis demonstrated distinguishable physical, mental, and social health dimensions. Significant associations were found between worse HRQOL and worse Child-Pugh class, worse self-rated liver disease severity, and increased number of disability days. CONCLUSIONS: The results of this multicenter field test provide support for the reliability and validity of the LDQOL 1.0 as an HRQOL outcome measure for individuals with chronic liver disease.

Chronic Disease↗
PubMed2007

Spectrum of liver histology in presumed decompensated alcoholic liver disease.

BACKGROUND: In presumed decompensated alcoholic liver disease (ALD; liver decompensation, heavy alcohol intake, and negative results of noninvasive screening for other causes), liver biopsy is often performed to assess severity of liver injury and to rule out other liver diseases. AIM: The aim of the study is to describe the spectrum of liver histology in such patients. METHODS: We reviewed all patients with presumed decompensated ALD seen between 1998 and 2004, in whom liver tissue was available for histology (N = 110). RESULTS: A total of 104 of the 110 patients had at least one of the histological features suggestive of ALD: fat, Mallory's hyalin, neutrophilic infiltrate, and hepatocyte ballooning. These features were more prevalent in tissue obtained within a month after presentation with decompensation than in that obtained before decompensation or more than 1 month after. These features were also associated with more severe liver dysfunction. Histology revealed a major additional diagnosis (Budd-Chiari syndrome) in only one case. In 41 patients biopsied within a month of first presentation with decompensation, Child score and Maddrey discriminant function (DF), but none of the histological features, were predictive of survival by Cox multivariate analysis. Of the 26 of these 41 patients with a Maddrey DF >32, 22 (85%) had alcoholic hepatitis. CONCLUSIONS: In patients with presumed decompensated ALD, other liver diseases are uncommon. Routine liver biopsy is of limited added value but biopsy should be considered in those in whom the noninvasive workup, or failure to recover despite abstinence, raises the possibility of other liver diseases.

Adult↗
PubMed2004

Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance.

BACKGROUND: The conditions associated with fatty liver disease presenting with normal liver enzymes and the mechanism involved in its development remain to be fully elucidated. AIMS: The aim of the present study was to test the hypothesis that fatty liver with normal liver enzymes occurs more frequently in arterial hypertensive patients and to establish whether this condition is associated with insulin resistance. PATIENTS: A total of 55 non-obese, non-diabetic, non-heavy alcohol drinking patients with arterial hypertensive and normal liver enzymes and 55 sex and age matched healthy subjects were enrolled into the study. METHODS: Plasma metabolic parameters, body mass index, and the presence of fatty liver were investigated. Insulin resistance was estimated from plasma insulin and glucose as the homeostasis model assessment index. Stepwise logistic regression and multivariate regression analysis were used on the combined sample to identify variables independently associated with fatty liver and insulin resistance. RESULTS: Hypertensive patients had a significantly higher prevalence of fatty liver (30.9% v 12.7%; p<0.041), higher insulin resistance (mean 2.27 (SD 1.81) v 1.56 (0.70); p = 0.022), and slightly higher body mass index (24.9 (3.0) v 24.0 (2.2); p = 0.043) than controls. Multivariate logistic regression identified insulin resistance (odds ratio 1.66 (95% confidence interval (CI) 1.03-2.52)) and body mass index (OR 1.22 (95% CI 1.00-1.49)) as factors independently associated with fatty liver. Multivariate regression analysis showed insulin resistance to be predicted by alanine transaminase (p = 0.002), presence of arterial hypertension (p = 0.029), and body mass index (p = 0.048). CONCLUSION: The higher prevalence of non-alcoholic fatty liver in non-obese hypertensive patients with normal liver enzymes appears to be related to increases in insulin resistance and body weight.

Adult↗
PubMed1995

Experimental study of liver injury after partial hepatectomy with intermittent or continuous hepatic vascular occlusion. Differences in tolerance to ischemia between normal and cirrhotic livers.

The degree of residual liver injury in normal and cirrhotic rats undergoing 70% hepatectomy with hepatic inflow occlusion was examined. The total duration of clamping was 60 min and animals were divided into 3 groups according to the ischemic modality: a 15-min intermittent clamping group (group I); a 30-min intermittent clamping group (group II), and a 60-min continuous clamping group (group III). In normal liver rats, the survival rates after operation in groups I, II and III were 90, 90 and 30%, respectively, compared to 70, 50 and 38%, respectively, in cirrhotic rats. The serum aspartate aminotransferase (AST) level increased markedly with prolongation of each period of clamping in rats with normal liver, showing higher AST levels than those with cirrhotic liver. The liver tissue adenosine-5'-triphosphate (ATP) levels and energy charge (EC) values decreased with prolongation of each period of clamping. Cirrhotic livers showed lower ATP levels and EC values than normal livers. Although there was no significant difference in the mitochondrial function between normal and cirrhotic livers in the group of the same form of ischemia, phosphorylative efficiency of mitochondria was maintained satisfactorily in normal groups I and II and in the cirrhotic group I. Even though cirrhotic livers showed a smaller necrotic response to ischemia than normal livers, they were more vulnerable to ischemia because of an inability to maintain energy metabolism. Therefore, when performing resection of a cirrhotic liver, a 15-min intermittent clamping method should be adopted.

Adenine Nucleotides↗
PubMed1991

Low uracil concentration in the liver might be responsible for the decreased antineoplastic activity of fluoropyrimidines in mice with CCl4-induced chronic liver dysfunction.

Some fluoropyrimidines are considered to be metabolized in liver microsomes. The present study was designed to assess the effect of chronic liver dysfunction on the antineoplastic activity of fluoropyrimidines. Chronic liver dysfunction was induced in BALB/c mice by 8 weeks of CCl4 injections. The 5-fluorouracil (5-FU)-sensitive MOPC-104E and 5-FU-resistant Meth-A cells were inoculated subcutaneously into the mice and then various fluoropyrimidines were administered intragastrically. The antitumor activity of the fluoropyrimidines decreased in mice with chronic liver dysfunction, although the concentration of 5-FU in the tumor of normal mice did not differ from that of mice with liver dysfunction. However, the concentration of uracil in the liver was decreased in mice with chronic liver dysfunction. On the other hand, the percent conversion of Tegafur [1-(2-tetrahydrofuryl)-5-FU] to 5-FU in the normal liver did not differ from that in the dysfunctional liver. These results suggest that low uracil concentrations in the liver may result from chronic liver dysfunction and lead to decreased antitumor efficacy of fluoropyrimidines.

Animals↗
PubMed2004

Liver-specific expression of the agouti gene in transgenic mice promotes liver carcinogenesis in the absence of obesity and diabetes.

BACKGROUND: The agouti protein is a paracrine factor that is normally present in the skin of many species of mammals. Agouti regulates the switch between black and yellow hair pigmentation by signalling through the melanocortin 1 receptor (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant regulatory mutations in the mouse agouti gene that cause the wild-type protein to be produced at abnormally high levels throughout the body. Mice harboring these mutations exhibit a pleiotropic syndrome characterized by yellow coat color, obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to hyperplasia and carcinogenesis in numerous tissues, including the liver. The goal of this research was to determine if ectopic expression of the agouti gene in the liver alone is sufficient to recapitulate any aspect of this syndrome. For this purpose, we generated lines of transgenic mice expressing high levels of agouti in the liver under the regulatory control of the albumin promoter. Expression levels of the agouti transgene in the liver were quantified by Northern blot analysis. Functional agouti protein in the liver of transgenic mice was assayed by its ability to inhibit binding of the alpha-melanocyte stimulating hormone (alphaMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were analyzed in control and transgenic mice. Control and transgenic male mice were given a single intraperitoneal injection (10 mg/kg) of the hepatocellular carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at 36 or 40 weeks after DEN injection and the number of tumors per liver and total liver weights were recorded. RESULTS: The albumin-agouti transgene was expressed at high levels in the livers of mice and produced a functional agouti protein. Albumin-agouti transgenic mice had normal body weights and normal levels of blood glucose and plasma insulin, but responded to chemical initiation of the liver with an increased number of liver tumors compared to non-transgenic control mice. CONCLUSIONS: The data demonstrate that liver-specific expression of the agouti gene is not sufficient to induce obesity or diabetes, but, in the absence of these factors, agouti continues to promote hepatocellular carcinogenesis.

Agouti Signaling Protein↗