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PubMed1985

Role of extracellular Ca2+ in toxic liver injury: comparative studies with the perfused rat liver and isolated hepatocytes.

The role of extracellular Ca2+ in toxic liver injury was examined in two in vitro models of the rat liver, the isolated perfused liver and isolated hepatocytes. The toxins t-butylhydroperoxide and carbon tetrachloride, as well as the Ca2+ ionophore, heptafluorodimethyloctanedione (FOD), were employed to induce cellular injury and death. Lipid peroxidation was also measured as the formation of thiobarbituric acid-reactive products. Cell death was measured by the release of lactate dehydrogenase in the perfused liver model and by the uptake of trypan blue in isolated hepatocytes. Toxin-induced cellular injury and death occurred in both in vitro models in the presence and absence of extracellular Ca2+, indicating that an influx of Ca2+ was not essential for toxic liver injury. The degree of toxicity seen in the perfused liver model was independent of increases or decreases in the total calcium concentration present in the liver tissue, providing further evidence that cell death is not dictated solely by changes in cellular calcium content. Isolated hepatocytes differed from the perfused liver, however, undergoing more lipid peroxidation and toxin-induced cell death when incubated in the absence of extracellular Ca2+ than in its presence. While suggesting that extracellular Ca2+ concentrations may have some influence on the expression of toxicity, these results demonstrate the nonessential role extracellular Ca2+ plays in the events leading to toxic liver injury.

Animals↗

PubMed1998

Early liver transplantation is crucial in children with liver disease and pulmonary artery hypertension.

BACKGROUND/AIMS: Early liver transplantation is crucial in children with liver disease and pulmonary artery hypertension. Some severe pulmonary vascular anomalies associated with portal hypertension disappear after isolated liver transplantation. Evolution of pulmonary artery hypertension due to plexogenic arteriopathy is controversial, as this association is still considered a contraindication to isolated liver transplantation. Outcome of pulmonary hypertension after isolated liver transplantation is reported in three patients with portal hypertension. METHODS: After echocardiographic diagnosis, the patients had a complete hemodynamic exploration, and two had a lung biopsy. After liver transplantation, the survivors had echocardiographic follow up and a second hemodynamic exploration. RESULTS: In two children, pulmonary pressures and resistances returned to near-normal values 1 and 6 years after successful isolated liver transplantation. The third patient, with the most severe arteriopathy, had to wait 1 year for a donor, and the attempted transplantation was complicated by ventricular tachycardia; death occurred 2 days after surgery. CONCLUSIONS: Liver transplantation can reverse pulmonary artery hypertension due to high pulmonary resistances complicating liver disease with portal hypertension, provided it is carried out at an early stage. Early detection of pulmonary hypertension by systematic echocardiography may thus be crucial in these children with portal hypertension.

Adolescent↗

PubMed1993

Liver transplantation for alcoholic liver disease.

The role of liver transplantation as a treatment for end-stage liver disease occurring in alcoholic patients is controversial. Earlier predictions that survival of alcoholic patients after liver transplantation was worse than that of non-alcoholic liver graft recipients, or that few alcoholic patients with serious liver disease could meet stringent selection criteria, have proved false. As a result, in many liver transplant programmes, alcoholic liver disease constitutes one of the most common diagnoses among patients proceeding to transplantation. Survival of alcoholic patients after transplantation is similar to that in non-alcoholic patients, i.e. up to 80% or more alive at 1 year. A multidisciplinary selection process has been introduced which includes careful psychiatric assessment to try to identify those patients most likely to maintain long-term abstinence after transplantation. Using this method, approximately 45% of alcoholic patients referred for transplantation have been selected for surgery. Furthermore, the survival rate of alcoholic patients not selected for transplantation because they were considered a poor prognostic risk for sobriety was significantly less than that of alcoholic patients undergoing liver transplantation. The ethical foundations for this multidisciplinary approach are explained in this chapter. Good data on recidivism after transplantation are few. In many programmes, including ours, instances of recidivism, defined as a relapse to a pathologic pattern of alcohol use, are uncommon and occur in 10% or less of alcoholic patients selected for liver transplantation, at least in the first 3 postoperative years. This figure underestimates the incidence of consumption of small amounts of alcohol. The data are limited also by the relatively short period of follow-up in most studies published to date. Whether recidivism will become more common as more patients are followed beyond 3 years remains to be seen.

Humans↗

PubMed2006

Cardiac surgery in children with end-stage liver disease awaiting liver transplantation.

BACKGROUND: Cardiac repair for congenital heart disease in children awaiting liver transplantation presents unique therapeutic challenges and dilemmas. We tested the hypothesis that operations in these children requiring cardiopulmonary bypass (CPB) were not associated with prohibitive morbidity and mortality. METHODS: Over the last 10 years (1994-2004), five infants were identified in our database with end-stage liver disease and awaiting liver transplantation that required cardiac surgery. Primary end point for the study was mortality. Secondary end points included morbidity and time to liver transplantation. The new pediatric end-stage liver disease (PELD) model was used to score liver disease severity. RESULTS: Three boys and two girls with mean age of 8.6 months (range, 1.5-21 months) and mean PELD of 18.0 (range, 10-29) required CPB for repair. The only early mortality in the series occurred after cardiac arrest during creation of a central shunt. The child expired two days later despite extracorporeal membrane oxygenation support. The patient had important myocardial hypertrophy. All other patients survived and underwent successful liver transplantation. CONCLUSIONS: Children with significant congenital heart disease awaiting liver transplantation can undergo safe cardiac repair with judicious perioperative support thereby reducing the risks of subsequent liver transplantation.

Comorbidity↗

PubMed2005

Up-regulation of ADRP in fatty liver in human and liver steatosis in mice fed with high fat diet.

The present study was performed to examine a role of adipose differentiation-related protein (ADRP) in the process of liver steatosis. Immunohistochemical findings indicated that ADRP expression is increased in the hepatocytes in patients with fatty liver when compared with normal liver. ADRP expression is localized in the surface of lipid droplets in the hepatocytes. Increased expression of ADRP mRNA and protein was similarly observed in fatty liver in ob/ob mice and the liver steatosis induced by high fat diet in mice. The up-regulation of ADRP mRNA and protein in the liver by high fat diet was identified in the surface of lipid droplets in a time-dependent manner. Recent studies demonstrated that up-regulation of PPARgamma in the hepatocytes is deeply involved in liver steatosis. To clarify whether ADRP expression is increased by PPARgamma activation in hepatocytes, we examined the effect of a PPARgamma ligand, troglitazone, on ADRP mRNA expression in HepG2 cells. ADRP mRNA expression was increased by troglitazone in dose- and time-dependent manners. All these results suggest that ADRP is up-regulated in liver steatosis in human and mice, and that high fat diet increases expression of ADRP through PPARgamma activation, followed by induction of liver steatosis.

Animals↗

PubMed2006

Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy.

PURPOSE: To measure the intrabreath-hold liver motion and the intrafraction and interfraction reproducibility of liver position relative to vertebral bodies using an active breathing coordinator (ABC) in patients with unresectable liver cancer treated with hypofractionated stereotactic body radiation therapy (SBRT). METHODS: Tolerability of ABC and organ motion during ABC was assessed using kV fluoroscopy in 34 patients. For patients treated with ABC, repeat breath-hold CT scans in the ABC breath-hold position were acquired at simulation to estimate the volumetric intrafraction reproducibility of the liver relative to the vertebral bodies. In addition, preceding each radiation therapy fraction, with the liver immobilized using ABC, repeat anteroposterior (AP) megavoltage verification images were obtained. Off-line alignments were completed to determine intrafraction reproducibility (from repeat images obtained before one treatment) and interfraction reproducibility (from comparisons of the final image for each fraction with the AP) of diaphragm position relative to vertebral bodies. For each image set, the vertebral bodies were aligned, and the resultant craniocaudal (CC) offset in diaphragm position was measured. Liver position during ABC was also evaluated from kV fluoroscopy acquired at the time of simulation, kV fluoroscopy at the time of treatment, and from MV beam's-eye view movie loops acquired during treatment. RESULTS: Twenty-one of 34 patients were screened to be suitable for ABC. The average free breathing range of these patients was 13 mm (range, 5-1 mm). Fluoroscopy revealed that the average maximal diaphragm motion during ABC breath-hold was 1.4 mm (range, 0-3.4 mm). The MV treatment movie loops confirmed diaphragm stability during treatment. For a measure of intrafraction reproducibility, an analysis of 36 repeat ABC computed tomography (CT) scans in 14 patients was conducted. The average mean difference in the liver surface position was -0.9 mm, -0.5 mm, and 0.2 mm in the CC, AP, and medial-lateral (ML) directions, with a standard deviation of 1.5 mm, 1.5 mm, and 1.5 mm, respectively. Ninety-five percent of the liver surface had an absolute differences in position between repeat ABC CT scans of less than 4.1 mm, 3.3 mm, and 3.3 mm in the CC, AP, and ML directions, respectively. Analysis of 257 MV AP images from patients treated using ABC revealed an average intrafraction CC reproducibility (sigma) of diaphragm relative to vertebral bodies of 1.5 mm (range, 0.6-3.9 mm). The average interfraction CC reproducibility (sigma) was 3.4 mm (range, 1.5-7.9 mm), indicating less day-to-day reproducibility of diaphragm position relative to vertebral bodies. The average absolute intra and interfraction CC offset in diaphragm position relative to vertebral bodies was 1.7 and 3.7 mm, respectively, with 86% of intrafraction and 54% of interfraction absolute offsets 3.0 mm or less. CONCLUSIONS: Intrafraction reproducibility of liver position using ABC is good in the majority of screened patients. However, interfraction reproducibility is worse, suggesting a need for image guidance.

Adult↗

PubMed2004

Development of a scaled up liver device incorporating cryo-preserved pig liver micro-organs.

BACKGROUND/AIMS: Currently there is no effective therapy for most patients with fulminant or end stage liver disease. METHODS: Pig liver micro-organs (LMOs), which preserve liver micro-architecture and ensure a maximal 150-200mum distance from a source of nutrients and gases have been prepared and a method to cryo-preserve them has been developed. A new scaled-up extra-corporeal liver device termed aLIVE-H in which LMOs are exposed to liver-like hemodynamic conditions has also been developed. The purpose of this work is to test the safety and function of cryo-preserved LMOs and how the hemodynamic properties of the scaled up aLIVE device affect their function. RESULTS: Pig LMOs in aLIVE-H, transcribe albumin and Factor V at similar levels, irrespective of their position within the bioreactor, indicating that the hemodynamic features of the aLIVE-H device allow for homogeneous plasma distribution and proper function at different locations. Cryo-preserved LMOs transcribe albumin and Factor V at levels comparable to those transcribed by a normal pig liver. Connecting the aLIVE-H bioreactor to normal pigs did not affect key blood components and biochemical parameters. CONCLUSIONS: An extra-corporeal liver device aLIVE-H which imitates the hemodynamic and functional properties of the normal liver and incorporates cryo-preserved LMOs has been developed and characterized. aLIVE-H was found to perform key synthetic liver functions.

Albumins↗

PubMed2004

The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes.

We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors). In human liver microsomes, there were no statistically significant differences (P > 0.05) in CYP activity as a function of age, gender, or ethnicity with one exception. 7-Ethoxyresorufin O-dealkylase (CYP1A2) activity was greater in males than females, which is consistent with clinical observation. Liver microsomal testosterone 6beta-hydroxylase (CYP3A4) activity was slightly greater in females than males, but the difference was not significant. However, in cryopreserved human hepatocytes, the gender difference in CYP3A4 activity (females = twice males) did reach statistical significance, which supports the clinical observation that females metabolize certain CYP3A4 substrates faster than do males. Compared with those from Caucasians and African Americans, liver microsomes from Hispanics had about twice the average activity of CYP2A6, CYP2B6, and CYP2C8 and half the activity of CYP1A2, although this apparent ethnic difference may be a consequence of the relatively low number of Hispanic donors. Primary cultures of hepatocytes were treated with beta-naphthoflavone, an inducer of CYP1A2, phenobarbital or rifampin, both of which induce CYP2B6, CYP2C9, CYP2C19, and CYP3A4, albeit it to different extents. Induction of these CYP enzymes in freshly cultured hepatocytes did not appear to be influenced by the gender or age of the donor. Furthermore, CYP3A4 induction in hepatocytes isolated from cirrhotic liver was comparable to that in normal hepatocytes, which supports the "healthy hepatocyte, sick environment" hypothesis of liver cirrhosis. This review summarizes these findings and discusses their implications for the use of human liver microsomes and hepatocytes for in vitro studies of drug metabolism and enzyme induction, which play a key role in drug development.

Aging↗

PubMed2005

Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis.

Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.

Adipocytes↗

PubMed2003

Blunt liver injury: from non-operative management to liver transplantation.

Therapeutic options for blunt hepatic trauma include both non-operative and operative management. We have reviewed our experience of the management of blunt hepatic trauma, from non-operative to liver transplantation. A total of 72 patients with blunt hepatic injury observed at the first surgical unit of Padua in a 3-year period (1998-2000) were analysed; we also included a patient who had a liver transplant in 1993 for severe liver trauma. Twenty-nine patients (39.7%) were treated conservatively, with a 93% success rate; 60.3% were treated surgically. Suture hepatorraphy was the most common procedure performed (52.3%). Advantages of non-operative management in our experience were the reduced need for transfusion (1.1U versus 4.3U) with 92% of patients not needing transfusion, and a reduced stay in the intensive care unit; there was no liver-related mortality. The overall morbidity in surgical patients was 30%, with 16% liver-related complications. Twelve surgical patients (27.2%) died, with a liver-related mortality of 18.2%. A large number of patients may present with an associated endo-abdominal injury, even in low-grade liver trauma, requiring rapid laparotomy. In high-grade hepatic trauma, the evolution toward liver failure is an indication for liver transplantation.

Adolescent↗

PubMed1998

Prevalence of antiphospholipid antibodies in patients with chronic liver disease related to alcohol or hepatitis C virus: correlation with liver injury.

Antiphospholipid antibodies (APAs) have been reported in various clinical conditions. However, the pathogenesis and clinical significance of these antibodies are still unclear. The objective of this study was to assess the prevalence of APAs in patients with chronic alcohol- or hepatitis C virus (HCV)-related liver disease and to evaluate their relation to the underlying liver disease. We prospectively studied 201 patients referred to an hepato-gastroenterology department, including 77 patients with a history of alcohol abuse (group I) and 124 with chronic HCV infection (group II), and 107 healthy subjects (control population). Liver biopsy was performed in all patients. In cirrhotic patients, the severity of the liver disease was assessed with the use of Child's classification, as modified by Pugh. Several biologic parameters, including lupus anticoagulant and anticardiolipin antibodies, were determined. Forty-eight percent of patients in group I and 33% of those in group II had APAs. Among cirrhotic patients, APAs were more frequent in patients with Child grade B or C than in those with grade A severity. In patients with chronic HCV-related liver disease, a correlation was found between APA levels and liver fibrosis (P = 0.009); no relation was found between APA levels and histologic liver disease activity (P = 0.25). In the control group, one subject was APA-positive. None had lupus anticoagulant. APAs seem to be frequently associated with chronic liver disease of various causes. These results suggest further investigations on the potential role of these antibodies in fibrosis or liver injury.

Adult↗

PubMed2002

Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis - amelioration by liver transplantation.

BACKGROUND/AIMS: Modification by advanced glycation renders macromolecules susceptible to elimination in the liver via scavenger receptors. Thus, in advanced liver disease an accumulation of advanced glycation end products (AGEs) in circulation might occur, due to the reduction of effective liver mass. METHODS: Plasma AGE levels (fluorescent AGEs-AGE-Fl and N(epsilon)-carboxymethyllysine - CML) were determined in 51 patients with liver cirrhosis (Ci) and 19 healthy controls. Five patients were followed 36 months after liver transplantation. RESULTS: In cirrhotic patients, markedly elevated concentrations of AGEs were revealed (AGE-Fl: control, 0.3+/-0.01 x 10(5) AU, Ci: 1.06+/-0.06 x 10(5) AU, P<0.01; CML, control: 431.7+/-16.3 ng/ml, Ci: 647.6+/-258.5, P<0.01). CML levels correlated with the severity of liver disease, as determined by clinical score (r=0.663, P<0.001), albumin level (r=0.704, P<0.001) and monoethylglycinexylide test (r=0.852, P<0.01). Reduced renal function contributed to the rise of CML in proportion to the degree of renal impairment. Liver transplantation resulted in about 50% decline of CML levels within 3 months, while impairment of renal function still persisted, underlying the central role of the liver for AGE removal. CONCLUSIONS: In liver Ci, hepatic removal of AGEs is impaired. With regard to the toxicity of AGEs, their accumulation could be of pathophysiological relevance.

Adolescent↗

PubMed1996

Liver biopsy in liver transplantation: no additional risk of infections in patients with choledochojejunostomy.

BACKGROUND/AIMS: This study aimed to determine whether there is an increased infectious risk following liver biopsy in liver transplant patients with choledochojejunostomy. METHODS: We evaluated the incidence of liver-biopsy-related sepsis in a consecutive series of 27 patients who underwent choledochojejunostomy, either during the transplant procedure (17 patients) or later following biliary complications (10 patients). We evaluated another 138 patients as a control group who had orthotopic liver transplantation during the same period and underwent duct-to-duct anastomosis. All liver biopsies had routine, prior ultrasound evaluation to detect dilated biliary ducts. RESULTS: In the 27 patients who underwent choledochojejunostomy, 96 liver biopsies were performed: the sepsis rate was 3.12% per biopsy (n = 96) or 7.4% per patient (n = 27). However, despite a normal ultrasound, subsequent ERCP demonstrated biliary obstruction in one patient. Thus the rate of sepsis was 2.1% per biopsy or 3.7 per patient. In the control group 338 liver biopsies were performed: the sepsis rate was 1.5% per biopsy (n = 338) or 2.9% per patient (n = 138). The difference was not significant. All septic episodes had positive blood cultures for a single enteric microorganism, and all responded to antibiotics CONCLUSIONS: Our data do not suggest that liver-transplanted patients with choledochojejunostomy are more at risk of sepsis following liver biopsy, providing there is no "occult" biliary obstruction; therefore, they do not require prophylactic antibiotics as has been suggested by other authors.

Adolescent↗

PubMed2000

Inhibitory effects of low doses of melatonin on induction of preneoplastic liver lesions in a medium-term liver bioassay in F344 rats: relation to the influence of electromagnetic near field exposure.

We have previously reported that exposures of F344 male rats to both 900 MHz and 1.5 GHz electro-magnetic near fields (EMFs) results in slightly decreased numbers and areas of glutathione S-transferase (GST-P)-positive liver foci, liver preneoplastic lesions in rats, in a medium-term liver bioassay (K. Imaida, M. Taki, T. Yamaguchi, T. Ito, S. Watanabe, K. Wake, A. Aimoto, Y. Kamimura, N. Ito, T. Shirai, Lack of promoting effects of the electromagnetic near-field used for cellular phones (929.2 MHz) on rat liver carcinogenesis in a medium-term liver bioassay, Carcinogenesis 19 (1998) 311-314; K. Imaida, M. Taki, S. Watanabe, Y. Kamimura, T. Ito, T. Yamaguchi, N. Ito, T. Shirai, The 1.5 GHz electromagnetic near-field used for cellular phones does not promote rat liver carcinogenesis in a medium-term liver bioassay, Jpn. J. Cancer Res. 89 (1998) 995-1002.). In both experiments, the melatonin serum levels were significantly decreased in both 900 MHz and 1.5 GHz exposed groups as compared with sham-exposed control group values. Therefore, changes of serum melatonin levels may modify the development of preneoplastic lesions in the livers of rats exposed by EMF. In order to clarify this question, the effects of different doses of melatonin (1, 5, 10 and 20 ppm in the drinking water) were analyzed in the same bioassay system employed for our previously reported EMF exposure studies. Six-week-old male F344 rats were given a single dose of diethylnitrosamine (DEN, 200 mg/kg b.w., i.p.). Starting 2 weeks later, they were treated with 0, 1, 5, 10 and 20 ppm melatonin in their drinking water for 6 weeks. Melatonin treatment were performed only during the night (between 18:00 to 09:00) in order to maintain their circadian rhythm, since serum melatonin levels are high at midnight. At week 3, all rats were subjected to a two-thirds partial hepatectomy. At week 8, the experiment was terminated and the animals were sacrificed. Serum hormone levels of melatonin, adrenocorticotropic hormone (ACTH), corticosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone at this time point were measured, only the first being elevated, while LH and testosterone were reduced. Although clear dose dependence was not apparent, both numbers and areas of GST-P-positive foci in the liver were decreased in the melatonin treated groups, this being significant for numbers in the 10 ppm melatonin group. Comparison of the current results with the previously reported findings for EMF exposure experiments, suggests that increase in melatonin serum levels is a possible reason for the associated tendency for decreased preneoplastic hepatocyte foci development.

Adrenocorticotropic Hormone↗

PubMed2000

MRI of liver: a comparison of CNR enhancement using high dose and low dose ferumoxide infusion in patients with colorectal liver metastases.

The purpose of this study was to compare the effects of high dose (HD) and low dose (LD) ferumoxides infusions on lesion-to-liver contrast-to-noise ratio (CNR) using four different T(2)-weighted MR sequences. Seventy-three patients with known colorectal liver metastases underwent T(2)-weighted fast spin echo (FSE) imaging before and after ferumoxides. After ferumoxides, T(2)-weighted dual echo (DE) and T(2)-weighted GRE FLASH images were also obtained. To evaluate the relationship between TE length and lesion-to-liver CNR, the same FLASH sequence was repeated in 18 LD patients after lengthening the TE. Ferumoxides was administered at a dose of 15 micromol/kg (HD) and 7.5 micromol/kg (LD) in 45 and 28 patients, respectively. The effects of HD and LD ferumoxides infusions were measured as the percentage signal intensity change (PSIC) in the liver and lesions, lesion-to-liver CNR and the change in lesion-to-liver CNR (DeltaCNR). In both LD and HD groups, all CNR values obtained after SPIO were significantly greater than those observed with unenhanced FSE (p < 0.01). There was no significant difference between the mean CNR values obtained with either dose for any sequence. With the FLASH sequence, CNR increased progressively with longer TE. At the longest TE of 26 ms, mean CNR was higher than that recorded with any of the other sequences. Although mean liver PSIC was significantly greater in the HD group than in the LD group (p < 0.01) because the mean lesion PSIC was also greater in the HD group, the mean DeltaCNR after ferumoxides was not significantly different in the two groups. LD SPIO enhanced MR significantly increases lesion-to-liver CNR compared with unenhanced images. At 1. 0 T, HD and LD ferumoxides infusions produce comparable lesion-to-liver CNR. Our results suggest that at 1.0 T ferumoxides may be administered at a dose of 7.5 micromol/kg without loss of image quality.

Aged↗

PubMed1997

Liver and tumour tissue concentrations of TNF-alpha in cancer patients treated with TNF-alpha and melphalan by isolated liver perfusion.

In this study we determined the level of tumour necrosis factor alpha (TNF-alpha) in liver and tumour tissue samples obtained from patients with colorectal metastases confined to the liver, who were treated with isolated liver perfusion with TNF-alpha and melphalan. We adapted a standard enzyme-linked immunosorbent assay kit for the quantification of TNF-alpha in serum to measure the amount of this cytokine in solid tissue. For this purpose, we developed a buffer that lysed the tissues without affecting the TNF-alpha present. The minimum detection level was about 2 pg of TNF-alpha per mg tissue. Using this technique, we found a significant increase in the TNF-alpha level after perfusion in the liver tissue of all evaluable patients, which may explain the transient liver toxicity we observed in all patients. In tumour tissue, a significant TNF-alpha increase was observed in one out of five patients. The level of TNF-alpha in all liver tissue samples and some of the tumours after treatment by isolated liver perfusion was much higher than the peak serum concentrations obtained after systemic administration of the maximum tolerated dose of TNF-alpha. Furthermore, we demonstrated that the level of TNF-alpha in the liver tissue samples was about seven to eight times higher than in tumour tissue. We concluded that regional liver treatment resulted in a relatively high local level of TNF-alpha, but also that this cytokine did not preferentially accumulate in tumour tissue.

Aged↗

PubMed1988

Activity of branched-chain 2-oxo acid dehydrogenase complex in rat liver mitochondria and in rat liver.

Four mitochondrial marker enzymes were used to show that: (1) high-protein (24%) diet increased the rat liver concentration and content of total branched-chain 2-oxo acid dehydrogenase complex (BCDC) by 31% by increasing mitochondrial specific activity of BCDC; (2) starvation increased the liver concentration of BCDC by 25% by decreasing liver weight; the liver content of mitochondria and the mitochondrial specific activity of BCDC were unchanged; (3) protein-free diet decreased rat liver BCDC concentration and content by 20%, by decreasing the liver concentration and content of mitochondria. Protein-free diet increased liver mitochondrial specific activities of L-glutamate, 2-oxoglutarate and NAD-isocitrate dehydrogenases. The validity of a mitochondrial method for the determination of the liver concentration of BCDC and the percentage in the active form in vivo is confirmed, and improvements are described. The experimental basis of criticisms of its use in this regard by Zhang, Paxton, Goodwin, Shimomura & Harris [(1987) Biochem. J. 246, 625-631] was not confirmed. The finding by Harris, Powell, Paxton, Gillim & Nagae [(1985) Arch. Biochem. Biophys. 243, 542-555], that starvation has no effect on the percentage of BCDC in the active form in rat liver, is confirmed.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed2000

Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C--a study of 527 patients at one establishment.

Patients with chronic hepatitis C infection show a gradual progression of fibrosis to liver cirrhosis and hepatocellular carcinoma (HCC). We studied whether the progression of liver fibrosis differed among Japanese subjects who were infected with different hepatitis C virus (HCV) genotypes. In 527 patients we examined whether there was a relationship between gender, age, history of blood transfusion, interval between date of blood transfusion and date of liver biopsy or date of diagnosis of HCC, serum alanine aminotransferase level, platelet count or HCV genotype, with the extent of liver fibrosis, classified into four stages (F1-F4). Moreover, we compared the mean rate of liver fibrosis progression per year in patients with each HCV genotype. Patients who had a higher fibrosis score tended to be older, have a lower platelet count and a longer interval since blood transfusion than those who had a lower fibrosis score. The mean rate of liver fibrosis progression was 0.12 +/- 0.15 stages per year after the blood transfusion. However, the progression rate of liver fibrosis in patients who had received a blood transfusion when they were > or = 30 years of age was 0.19 +/- 0.22, while the progression rate of liver fibrosis in the patients who had received a blood transfusion when they were < 30 years was 0.09 +/- 0.09. In conclusion, chronic hepatitis C is a progressive disease, and patients with genotype 1b, 2a and 2b have a similar rate of progression of liver fibrosis. Particular attention should be paid to patients who are infected with HCV when > or = 30 years of age, because intrahepatic fibrosis rapidly progresses in these patients.

Adult↗