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PubMed1996

Effect on the expression of c-met, c-myc and PPAR-alpha in liver and liver tumors from rats chronically exposed to the hepatocarcinogenic peroxisome proliferator WY-14,643.

The induction of rodent hepatic tumors by peroxisome proliferators (PP) appears to depend on focal growth of hepatocytes. Expression of the oncogenes c-met and c-myc is altered following regenerative stimuli in rat liver, suggesting involvement of their protein products in hepatocyte replication. In addition, increases in c-myc and c-met mRNA expression are observed in multiple types of human and rodent tumors, including hepatocellular carcinoma. A study was designed to test the hypothesis that development of PP-induced hepatic neoplasms occurs as a result of overexpression of c-met or c-myc. Male F344 rats were exposed to WY-14,643 for 22 or 78 weeks (1000 p.p.m. in the diet). Messenger RNA was extracted from liver tumors (78 weeks) and surrounding non-lesion liver of exposed rats and non-lesion liver from age-matched control rats. Levels of mRNA expression were compared using Northern analysis. Significant increases in c-met (approximately 6-fold) and c-myc (approximately 7-fold) mRNA levels were observed in liver tumors compared with liver from control rats. A slight but non-significant increase in mRNA for both of these genes was observed in tumors compared with surrounding non-lesion liver tissue (approximately 2-fold). Increases in mRNA expression of c-met (approximately 3-fold) and c-myc (approximately 5-fold) were also detected in non-lesion liver from WY-14,463-exposed animals compared with non-lesion liver from naive rats. PP exposure in rats increased c-met and c-myc expression in liver and liver tumors, but in a manner which does not correspond to the rapid proliferation of hepatocytes present in tumors. To determine the potential involvement of the PP-activated receptor in PP-induced hepatocarcinogenesis, tumors were also examined for PP-activated receptor expression relative to surrounding liver and liver from naive rats. PP-activated receptor-alpha mRNA levels were significantly increased (approximately 6-fold) in tumors compared with naive liver, but only slightly increased over surrounding non-lesion liver tissue. These results suggest that modulation of c-met, c-myc and PP-activated receptor-alpha are not major determinants of PP-induced hepatocarcinogenesis.

Animals↗
PubMed1978

Gangliosides of liver tumors induced by N-2-fluorenylacetamide. I. Ganglioside alterations in liver tumorigenesis and normal development.

Hyperplastic nodules and hepatocellular carcinomas were induced in livers of rats by a low-protein diet containing 0.05% of the carcinogen N-2-fluorenylacetamide. Ganglioside amounts and composition were determined for histologically different hepatocellular carcinomas and compared with those for control livers, hyperplastic nodules, and liver tissue surrounding hepatomas and nodules as well as those for livers of fetal, newborn, 1-week-old, weanling, and adult Sprague-Dawley rats. Ganglioside sialic acid levels were elevated above those of normal adult liver in all liver tissues following the carcinogen treatment regimen. Livers of fetal and newborn rats contained nearly twice the amount of ganglioside sialic acid on a protein or DNA basis as did livers of adult rats. Analyses of individual nodules and hepatomas revealed two populations of tumors in which the levels of ganglioside sialic acid were 2.3 and 3.8 times normal. Ganglioside sialic acid content was at hepatoma levels in small nodules. Individual gangliosides were evenly distributed between products of the monosialoganglioside and disialoganglioside pathways in normal liver with a ratio of [N-acetylneuraminic acid (sialic acid)] (NAN)-galactose (Gal)-N-acetylgalactosamine (GalNAc)-(NAN)-Gal-glucose (Glc)-ceramide (Cer) (GD1a) to Gal-GalNAc-(NAN)2-Gal-Glc-Cer (GD1b) of about one. In contrast, the monosialogangliosides predominated in liver tissues following administration of the carcinogen. Increased levels of specific monosialogangliosides were present in nodules, in liver of carcinogen-treated animals prior to the appearance of tumors, and in the liver tissues surrounding nodules and hepatomas. In single hepatomas, ganglioside patterns correlated with tumorigenicity. A well-differentiated hepatoma had a normal complement of most gangliosides but was deficient in trisialogangliosides. In a poorly diferentiated but well-circumscribed hepatoma, the relative levels of all higher gangliosides were reduced. The monosialoganglioside Gal-GalNAc-(NAN)-Gal-Glc-Cer (GM1) accounted for 80% of the total ganglioside in a poorly circumscribed and poorly differentiated hepatoma. The ganglioside pattern of fetal livers most closely resembled that of a poorly differentiated hepatoma. During the first week post natum, levels of all higher monosialogangliosides and disialogangliosides declined, but the decline was most pronounced for gangliosides GM1 and GD1a. The ratio of GM1 + GD1a to GD1b + NAN-Gal-GalNAc-(NAN)2-Gal-Glc-Cer or (NAN)3-Gal-Glc-Cer (GT), used as an index of the relative predominance of the monoslaloganglioside and disialoganglioside pathways, fell from 2.7 for fetal liver to 0.4 for adult liver. Pools of precursor gangliosides increased during development, transiently for GalNAc-(NAN)-Gal-Glc-Cer and for more than 3 weeks for NAN-Gal-Glc-Cer. When hyperplastic nodules and hepatocellular carcinomas were compared, a reverse pattern was observed. The ratio of GM1 + GD1a to GD1b + GT rose steadily to values of 2.7 and 11...

2-Acetylaminofluorene↗
PubMed2002

Isolated liver transplantation in infants with end-stage liver disease associated with short bowel syndrome.

OBJECTIVE: To evaluate experience with isolated orthotopic liver transplantation in children with liver failure associated with short bowel syndrome (SBS). SUMMARY BACKGROUND DATA: Infants who have liver failure as a result of SBS are frequently referred for consideration for combined liver and small bowel transplantation. In a few patients the liver disease develops despite a seemingly adequate bowel, which if given time and appropriate management has the potential for full enteral adaptation. There is a limited literature suggesting the utility of OLT without replacement of the native bowel. The advantages over combined liver and small bowel transplantation are clear: organ availability is greater, liver-reduction techniques are well established, lower immunosuppression is required, and there is greater experience in the care of children after orthotopic liver transplantation. METHODS: Eleven infants, considered to have a good prospect of eventual gut adaptation to full enteral nutrition if it were not for their advanced liver disease, underwent isolated orthotopic liver transplantation. Age range was 6.5 to 17.7 months. All patients had been dependent on parenteral feeding but had also shown significant enteral tolerance at some time before listing for transplantation. Advanced liver disease was apparent both clinically and on histologic examination. All were jaundiced and had low albumin levels, and most had coagulopathy. As a group the infants had growth retardation. Estimated remaining length of small bowel beyond the ligament of Treitz was in the range of 25 to more than 100 cm. Six infants retained their ileocecal valve. RESULTS: Thirteen liver transplants were performed in the 11 patients. A combination of whole livers (n = 6) and reduced-size grafts, of which three were from living-related donors, were used. Biliary anastomosis was duct-to-duct in eight instances and involved a short Roux limb in the others. Eight patients are alive with follow-up of 15 to 66 months. Three deaths have occurred after transplantation as a result of sepsis. Of eight surviving patients, only two continue to receive intravenous support and in both there is increasing enteral tolerance. Since transplantation, all surviving children have shown adequate growth with maintenance of pretransplant centiles. CONCLUSIONS: In selected infants with liver failure secondary to short bowel syndrome in whom complete enteral autonomy is anticipated, isolated liver transplantation can offer long-term survival.

Humans↗
PubMed1995

Cold ischemia-reperfusion injury of the liver. Role of the liver donor nutritional status in rats.

To verify the role of donor nutritional status on the quality of liver preservation after cold storage, we assessed hepatocyte and liver endothelial cell viabilities and functions in an isolated perfused rat liver model. Livers from fed and fasted Wistar rats were isolated and perfused either immediately after liver harvesting or after a 24-hr cold (4 degrees C) preservation in University of Wisconsin solution. Hyaluronic acid (150 ng/ml) and taurocholate (11.5 micrograms/ml) were infused into the reservoir, and their eliminations were assessed to evaluate liver endothelial cell function and hepatocyte function, respectively. Liver viability was estimated by intrahepatic resistance, oxygen consumption, bile secretion, and lactate dehydrogenase release. In addition, cell viabilities were evaluated by trypan blue staining. In fed-rat livers, glycogen content did not differ before or after the cold preservation, although a reduction was observed during the subsequent perfusion period. Liver glycogen content in fed rats was markedly higher than in the fasted rats at each time point studied. In fasted and fed rats, liver viability parameters and hepatocyte function were moderately altered, whereas liver endothelial cell function was markedly impaired after cold preservation. However, feeding had no influence on either hepatocyte or liver endothelial cell functions which were similarly altered in both nutritional conditions. The present data show that the nutritional status of liver donors does not play an important role in the preservation of liver endothelial cells after cold ischemia-reperfusion and, thus, should not affect the overall resistance of livers to hypothermic-ischemic injury.

Adenosine↗
PubMed2001

Increased risk and case fatality rate of pyogenic liver abscess in patients with liver cirrhosis: a nationwide study in Denmark.

BACKGROUND: Patients with liver cirrhosis are at increased risk of serious bacterial infections carrying a high case fatality rate. Case reports have suggested an association between liver cirrhosis and pyogenic liver abscess. AIMS: To estimate the risk and case fatality rate of pyogenic liver abscess in Danish patients with liver cirrhosis compared with the background population. METHODS: Identification of all patients with liver cirrhosis and pyogenic liver abscess over a 17 year period in the National Registry of Patients. Information on death was obtained from the Danish Central Person Registry. RESULTS: We identified 22 764 patients with liver cirrhosis and 665 patients with pyogenic liver abscess, of whom 21 were cirrhotics and 644 were non-cirrhotics. The crude incidence rate of liver abscess in cirrhotics was 23.3 (95% CI 14.4-35.6) per 100 000 person years. The age adjusted risk of liver abscess was increased 15-fold in patients with cirrhosis compared with the background population. The 30 day case fatality rates in patients with liver abscess and cirrhosis were 38.5% (13.9-68.4) in alcoholic cirrhosis and 62.5% (24.5-91.5) in non-alcoholic cirrhosis compared with 26.9% (23.5-30.5) in liver abscess patients from the background population. After adjustment for sex, age, and comorbidity, the relative risk of death was increased more than fourfold in alcoholic cirrhosis and non-alcoholic cirrhosis compared with the background population. CONCLUSIONS: Liver cirrhosis is a strong risk factor for pyogenic liver abscess associated with a poor prognosis.

Adult↗
PubMed2003

Development of highly functional long-term culture method of liver slice embedded in agarose gel for bioartificial liver.

It is difficult to a produce highly functional bioartificial liver (BAL) using only hepatocytes, because it is believed that liver-specific three-dimensional structure is necessary to maintain high function for BAL. But it is difficult to construct a culture system with liver-specific three-dimensional structure in vitro. To realize a highly functional culture system with liver-specific three-dimensional structure, we developed a culture system using liver slices that keep liver-specific architecture, such as liver lobule and hepatic microvascular system. Liver slices were embedded in agarose gel to maintain them under a moist and three-dimensional environment. We examined the viability and function of liver slices by using various shapes of agarose gel. Liver slices were cultured 1) under stationary condition (control), 2) directly embedded in gel, and 3) embedded in cylindrical gel for good drainage of medium and ventilation of air. The viability and function of the incubated liver slices were evaluated by LDH leakage, histomorphology, and immunohistochemistry. At 10 days, the morphological condition and function of liver slices embedded in cylindrical gel were maintained better than liver slices directly embedded in gel or in the stationary condition. We suggest that high functionality and morphological condition of liver slices could be maintained by embedding in cylindrical gel. In the future, it is possible that this method could be used to develop a highly functional bioartificial liver.

Animals↗
PubMed2004

Lamivudine prophylaxis of liver allograft HBV reinfection in HBV related cirrhotic patients after liver transplantation.

BACKGROUND: Liver allograft hepatitis B virus (HBV) reinfection and hepatitis B (HB) recurrence jeopardize the long-term survival of recipient and liver allograft. Lamivudine has been referred as a novel antiviral agent against HBV in HBV cirrhotic patients even in liver transplantation setting. We assessed the prophylatic effect of lamivudine on liver allograft HBV reinfection and clarified the dynamic changes of HBV markers in HBV related decompensated liver cirrhosis after liver transplantation. METHODS: Twenty-five recipients were divided into three groups: HBV active replication group (15 recipients), HBV inactive replication group (7), and control group (3). 100 mg/d lamivudine was administered preoperatively except in the control group. The HBV markers of serial sera and liver biopsy samples of the 25 recipients were evaluated regularly with enzyme-linked radioimmunoassay, HBV DNA fluorescent quantitative assay, immunohistochemical staining, labelled streptavidin biotin (LSAB) and digoxin labelled HBV DNA hybridization in situ. The dynamic alternation of HBV markers under lamivudine prophylaxis was observed. RESULTS: In the HBV active replication group who had received lamivudine 2 weeks before liver transplantation, serum HBV DNA positive converted to negative by 80%. HBsAg of all recipients disappeared after liver transplantation, but corresponding antibodies of HBV appeared within one week after the operation. HBsAb 9/15, HBcAb 13/15 and HBeAb 11/15 appeared and subsided gradually within 24 weeks. HBV DNA in sera was kept negative; HBsAg, HBcAg and HBV DNA hybridization in situ of liver biopsy samples remained negative after use of lamivudine. Ten of the 15 recipients showed clearance of HBV, and per se HBV markers were undetectable both in serum and liver biopsy samples between 12 to 44 weeks (24 weeks on average). The 1-, 2-year survival rates were 83% in this group. Two of the 15 recipients developed HBV allograft reinfection or recurrence of hepatitis 2 years after lamivudine monoprophylaxis (2/15, 13.3%). In the HBV inactive replication group, the outcome was similar to that of the HBV active group. The HBV antibody frequency was HBsAb 4/7, HBcAb 6/7, and HBeAb 2/7. Three of 7 recipients showed HBV clearance both in sera and liver biopsy samples, whereas in the control group all 3 recipients developed HBV allograft reinfection and recurrent hepatitis 8, 10, 12 months postoperatively; one of them died of fibrosing cholestatic hepatitis, and the remaining 2 recovered after additional lamivudine therapy. The overall allograft reinfection rate was 9.1% (2/22) and the overall 1-, 2-year survival rates were 87% in the lamivudine prophylaxis group. CONCLUSIONS: Lamivudine prophylaxis can prevent effectively liver allograft from HBV reinfection in patients with HBV-related decompensated liver cirrhosis even in HBV active replication recipient after liver transplantation. Its long-term outcome remains to be studied.

Adult↗
PubMed1988

Accumulation of iron and iron compounds in liver tissue. A comparative study of the histological and chemical estimation of liver iron.

Unsatisfactory results obtained by histological evaluation of liver tissue in iron loading diseases prompted us to study the distribution of the total liver iron, haem iron and ferritin iron in post mortem human liver tissue from two different sites of the same liver. The total liver iron content was measured by flameless atomic absorption spectroscopy in native liver homogenates and in acid digested liver tissue from 60 consecutive autopsies, and the results from the two methods were compared. From the standard deviation of the duplicate analyses, it was deduced that the liver iron is possibly inhomogeneously distributed. The CVduplo (22%) of total iron, measured in acid digested tissue was higher than the CVduplo (14%) of total iron in homogenates from liver tissue from which non-homogenized tissue e.g. vessel walls, fibrotic tissue, had been removed. The CVduplo of ferritin iron and haem iron in liver homogenate was 14% and 30% respectively. The ferritin iron increased with an increasing total iron content until saturation of ferritin iron appeared to be reached at 2.5 micrograms ferritin iron per mg liver protein. When the results of total non-heam liver iron measurements are expressed properly (amount of iron per amount of homogenized liver protein), the distribution of iron is found to be homogeneous in both normal and pathological liver tissues. It was concluded that the estimation of liver iron content by visual microscopic evaluation is unsatisfactory, and that more reliable results are obtained by atomic absorption spectrophotometry.

Ferric Compounds↗
PubMed1989

Hepatic aldehyde dehydrogenase activity in liver diseases, with particular emphasis on alcoholic liver disease.

Hepatic aldehyde dehydrogenase isozyme activity was measured in 51 patients with various types of liver diseases, including 24 patients with alcoholic liver disease, to elucidate the relationship between hepatic aldehyde dehydrogenase activity and liver disease, especially alcoholic liver disease. The levels of low-Km and total aldehyde dehydrogenase activity in the liver decreased both in alcoholic and nonalcoholic liver disease patients, who showed an isoelectric focusing pattern of the usual type. There was no significant difference in the aldehyde dehydrogenase activity between alcoholic and nonalcoholic liver disease. In alcoholic liver disease, the decrease in the activity was significantly correlated with the progression of liver histology. The activity in liver cirrhosis was significantly lower than that in the other types of alcoholic liver disease. In nonalcoholic liver disease patients, the unusual type of hepatic aldehyde dehydrogenase activity observed was not different from the unusual type observed in nonhepatobiliary disease patients. These results indicate that the reduction of hepatic low-Km aldehyde dehydrogenase activity is a change that occurs subsequent to liver damage. Genetic abnormality in aldehyde dehydrogenase may not be important in the pathogenesis of alcoholic liver injury.

Aldehyde Dehydrogenase↗
PubMed2004

Technique for expanding the donor liver pool: heat shock preconditioning in a rat fatty liver model.

Fatty liver is a common predisposing risk factor for postoperative liver failure and accounts for most discarded livers during triage of donors. We investigated the effect of heat shock preconditioning (HPc) on recipient survival in a rat fatty liver transplantation model. Fatty liver donor rats were exposed to brief whole-body hyperthermia (10 minutes at 42.5 degrees C) and allowed to recover. HPc induced heat shock proteins (HSPs) (HSP72, HSP90, and heme oxygenase [HO]-1) in donor livers, with levels peaking 12 to 48 hours after HPc. Subsequently, donor livers were harvested 24 hours after HPc, placed in cold storage for 10 hours, and transplanted into normal rats. At 3 hours posttransplantation, HPc reduced serum liver enzymes in the recipients and almost completely suppressed the release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10. Histologic evaluation 3 and 24 hours after transplantation showed that HPc significantly reduced hepatic inflammation and hepatocellular necrosis without affecting the steatotic appearance of hepatocytes. One week after transplantation, control non-heat-shocked and heat-shocked fatty liver recipients exhibited survival rates of less than 10% and more than 80%, respectively. The evaluation of the survival of recipients receiving fatty livers at different times after HPc showed that the protective effect of HPc was significant when donor livers were transplanted 3 to 48 hours after HPc, with the maximum effect seen 6 to 48 hours after HPc. In conclusion, HPc is a promising avenue to salvage rejected donor fatty livers and enhance the survival rate of fatty liver recipients. We estimate that this technique could increase the annual donor pool by 600 livers.

Animals↗
PubMed2001

Fatty liver in liver transplantation and surgery.

Steatosis of the liver is common in Western countries, affecting about 25% of donors for liver transplantation and 20% of patients undergoing liver resection. Transplantation of livers with severe steatosis (> 60%) is associated with a high risk of primary nonfunction, and these livers should not be used for organ donation. In contrast, transplantation with livers containing mild steatosis (< 30%) yields results similar to those of transplantation performed with nonfatty livers. The outcome of livers with moderate steatosis (30 to 60%) are varying, and the use of these organs depends on the existence of additional risk factors. Similarly, liver resection in patients with steatosis is associated with a risk of postoperative mortality when compared with patients with nonfatty livers (14% versus 2%). Although hepatic steatosis is an important risk factor for surgery, little is known about the mechanisms of injury. In animal experiments, steatosis is associated with decreased ATP production and a disturbance of sinusoidal flow. Further contributing factors may include Kupffer cell dysfunction and leukocyte adhesion. Fatty hepatocytes have reduced tolerance against ischemic injury with a predominant necrotic form of cell death. In addition, the ability of hepatocytes to regenerate after major tissue loss is impaired in the steatotic liver. Very few protective strategies are known. Ischemic preconditioning and intermittent clamping protect the human liver against prolonged periods of ischemia. These techniques appear to be particularly protective in the steatotic liver. New insights into the mechanisms of liver failure in steatotic organs are needed to decrease the risk of surgery and increase the pool of organ donors.

Contraindications↗
PubMed2003

Effects of different mitogens on intrasplenic liver tissue transplants in comparison to orthotopic liver.

Ectopic liver cell transplants, when compared to orthotopic liver, can serve as a tool to study topic influences on liver cell differentiation, multiplication, function and responsiveness to xenobiotics. The aim of the present study was to evaluate, if characteristic effects of mitogens are exerted in both liver and intrasplenic liver cell transplants in a similar manner. Fetal liver tissue suspensions were transplanted into the spleens of adult male syngenic rats. Four months later, transplant recipients and controls were treated with fluorene (FEN), fluorenone (FON), 2-acetylaminofluorene (AAF), N-nitrosodibenzylamine (NDBA) or the solvent 48 hours before sacrifice. The following parameters were assessed within livers and spleens: mitotic activity of hepatocytes, glycogen content, cytochrome P450 (P450) isoforms expression, P450 mediated monooxygenase functions, tissue content of lipid peroxides (LPO) and of reduced and oxidized glutathione (GSH; GSSG). In both orthotopic livers and intrasplenic transplants FEN, FON or NDBA administration increased the mitotic activity of the hepatocytes. Treatment with the mitogens caused a distinct and characteristic induction of the P450 isoforms expression and of the respective monooxygenase functions in the livers and (with certain differences) also in the transplants. FEN and FON slightly increased, AAF and NDBA reduced liver glycogen content. The latter effect was also seen in the transplants. NDBA administration caused a slight increase in tissue LPO content in livers, but not in spleens. Additionally, AAF or NDBA treatment led to an elevation of liver (but not of spleen) GSH and GSSG concentrations. The results of the present investigation show that characteristic effects of mitogens on orthotopic liver occur with certain differences also in ectopic liver cell transplants.

2-Acetylaminofluorene↗
PubMed1998

Internal bioartificial liver with xenogeneic hepatocytes prevents death from acute liver failure: an experimental study.

OBJECTIVE: To demonstrate that a bioartificial liver, using allogeneic or xenogeneic hepatocytes protected from rejection by a semipermeable membrane, could prevent death from acute liver failure. SUMMARY BACKGROUND DATA: An implantable bioartificial liver using isolated hepatocytes could be an alternative to orthotopic liver transplantation to treat patients with acute liver failure. It could serve either as a bridge until liver transplantation or as the main treatment until recovery of the native liver. However, allogeneic or xenogeneic hepatocytes that could be used in clinical applications are spontaneously rejected. METHODS: Acute liver failure was induced in rats by 95% liver resection. Twenty-five million hepatocytes harvested in rats (allogeneic) or guinea pigs (xenogeneic) were encapsulated in a semipermeable membrane to protect them from rejection. The hollow fibers containing hepatocytes were transplanted into the peritoneum of recipient rats. Survival rates were compared between rats transplanted or not with hepatocytes. RESULTS: In groups not transplanted with viable hepatocytes, 73% to 93% of rats died after 95% liver resection. The mortality rate was reduced to 39% in rats transplanted with allogeneic hepatocytes and 36% in rats transplanted with xenogeneic hepatocytes. The bioartificial liver could be removed 1 month after transplantation, when regeneration of the native liver was complete. Allogeneic and xenogeneic hepatocytes remained viable. CONCLUSIONS: The implantable bioartificial liver was able to prevent death in this model of acute liver failure. This could be an important step toward clinical application of the method.

Animals↗
PubMed2002

Etiology and outcome of acute liver failure: experience from a liver transplantation centre in Montreal.

BACKGROUND: Acute liver failure is a rare condition in which massive liver injury is associated with the rapid development of hepatic encephalopathy. Although viral hepatitis and drug-induced liver injury are the most common causes, no specific etiology is found in a substantial proportion of cases reported from Europe and the United States. AIM: To determine the etiology and outcome of patients with acute liver failure in the authors' institution. PATIENTS AND METHODS: The charts of 81 consecutive patients admitted to Saint-Luc between 1991 and 1999 were reviewed. RESULTS: The etiology was viral in 27 cases (33.2%), toxic or drug-induced in 22 (27.2%), of unknown origin in 22 (27.2%) and due to various causes in 10 (12.3%) (autoimmune, vascular, cancer). Of the 81 patients, 16% survived without liver transplantation, and 84% died or underwent liver transplantation. Survival without liver transplantation differed according to the mode of presentation: the survival rate was 27% in patients with hyperacute liver failure, 7% in those with acute liver failure and 0% in those with subacute liver failure. Among the 38 patients who underwent liver transplantation, survival one year after transplantation was 71%. In the 30 patients who died without liver transplantation, the main causes of death were cerebral edema and sepsis. CONCLUSIONS: Acute liver failure is associated with a high mortality, and liver transplantation is the treatment of choice. In a significant proportion of cases, the etiology remains undetermined and is probably related to yet unidentified hepatotropic viruses.

Adult↗
PubMedDate not supplied

Use of mammalian liver cells for artificial liver support.

Advances in orthotopic liver transplantation have improved the survival rate of both acute and chronic liver failure patients to nearly 70%. However, the success of this treatment modality has created an international organ shortage. Many patients die while awaiting transplantation in part due to the minimal capacity to store viable transplantable livers beyond 24 h. Additionally, for many areas of the world, routine use of whole liver transplantation to treat liver disease is impractical due to the demands on both financial and technical resources. Potentially, these issues may be alleviated, at least in part, by the use of liver cell transplantation or cellular-based liver assist devices. The well-documented regenerative capacity of the liver may obviate the need for whole organ transplantation in some instances of acute failure, if the patient may be provided temporary metabolic support. Although other patients ultimately may require transplantation, a longer period of time to find a suitable organ for transplantation may be gained by that supportive therapy. The field of liver cell transplantation may offer solutions to patients with inherited metabolic deficiencies or chronic liver disease. The potential to treat an hepatic disorder by using only a fraction of the whole liver would increase the number of whole organs available for orthotopic liver transplantation. Research in the fields of hepatocyte based intra- and extra-corporeal liver support is providing evidence that these therapeutic modalities may ultimately become routine in the treatment of severe liver disease. A historic overview of that technology along with its current status is discussed.

Animals↗
PubMed1995

Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver.

Iron was systematically studied in the nontumorous liver of 24 patients with hepatocellular carcinoma (HCC) developed on a noncirrhotic liver compared with 4 control groups (cirrhosis with and without HCC, liver metastasis, and normal liver) matched according to age, sex, and presence of chronic alcoholism. Assessment of liver iron was made by (1) histology according to iron distribution and quantification (total iron score: 0 to 60), and (2) biochemistry (liver iron concentration-N < 36 mumol/g) with calculation of the hepatic iron index (liver iron concentration/age). Patients with hepatocellular carcinoma developed on a noncirrhotic liver presented with (1) histological iron in 83%; (2) parenchymal iron excess significantly more frequent (90%) than in controls; (3) total iron score (15 +/- 12) and liver iron concentration (81 +/- 96) significantly greater than in controls; and (4) hepatic iron index significantly increased (1.4 +/- 1.5) when compared with control groups, except for the hepatocellular carcinoma complicating cirrhosis group (0.9 +/- 1.1). This study (1) shows a mild but unquestionable parenchymal iron excess in the nontumorous liver of most patients presenting with hepatocellular carcinoma developed on a noncirrhotic liver and, at a lesser extent, on cirrhosis, (2) should incite others to study the putative role of iron in the development of liver cancer both in patients with cirrhosis and those without it, whatever the cause of the underlying liver disease, and (3) add argument to take into account and to treat any liver iron excess, even when mild.

Adolescent↗
PubMed2003

Relationship between portal venous flow and liver regeneration in patients after living donor right-lobe liver transplantation.

The purpose of this study is to evaluate the relationship between portal venous (PV) velocity and degree of liver regeneration in humans after living donor liver transplantation (LDLT). Between July 1997 and September 2002, a total of 15 adult-to-adult LDLTs with right-lobe grafts were performed, and 13 of these patients were enrolled in this study. Postoperative PV dynamics differed according to the primary liver disease; therefore, patients were divided into two groups: a fulminant hepatic failure (FHF) group (n = 4) and a liver cirrhosis (LC) group (n = 9). Right-lobe donors (n = 13; D group) were used as controls. Doppler ultrasound was used to measured changes in PV velocity preoperatively; postoperative days (PODs) 1, 3, 7, 14, and 28; and 3 months after LDLT. To assess hepatic regeneration, the increase in liver volume ratio (postoperative liver volume to standard liver volume [SLV]) was measured. PV velocity after LDLT in the LC group increased sharply until POD 7, whereas those in the FHF and D groups were constant. In the first 3 months after LDLT, mean PV velocity was greater in the LC group than the other groups, reflecting the persistent hyperdynamic state in chronic end-stage liver disease. Liver regeneration also was more rapid in the LC group than the FHF and D groups and reached 100% as early as 2 weeks posttransplantation, whereas both the FHF and D livers reached approximately 80% of SLV at 3 months. PV velocity POD 7 correlated significantly with regeneration of the partial-liver allograft at 1 month (r = 0.84; P =.0091). In conclusion, the PV persistent hyperdynamic state in the LC group could directly trigger early liver regeneration in partial-liver allografts after LDLT.

Adolescent↗
PubMed2005

Resolution of liver fibrosis in chronic CCl4 administration in the rat after discontinuation of treatment: effect of silymarin, silibinin, colchicine and trimethylcolchicinic acid.

The purpose of this work was to obtain a suitable model of fibrosis, in which spontaneous reversion was minimal, to study the ability of silymarin, silibinin, colchicine and trimethylcolchicinic acid (TMCA) to reverse it. Reversal of liver fibrosis was studied in male Wistar rats after one, two or three months of CCl(4) administration (0.4 g/kg intraperitoneally, three times per week), by discontinuation of the toxin for 2 months. Silymarin (50 mg/kg), silibinin (50 mg/kg), colchicine (10 microg/rat) and trimethylcolchicinic acid (100 microg/rat) were administered daily, by gavage, after 3 months of CCl(4) administration. Collagen content was determined by measuring hydroxyproline in liver samples; glycogen, was determined utilizing the anthrone reagent; Mallory's trichromic stains of liver sections were performed. The best scheme of treatment was obtained when CCl(4) was administered during three months (collagen increased 6 times). Discontinuation of the toxin for two months produced a significant but relative small reduction of fibrosis (collagen was still 4.5 times over control). Colchicine, TMCA, silymarin or silibinin treatment showed no significant fibrolitic effect. This scheme of treatment may be an excellent tool to study the ability of drugs to reverse fibrosis. The hepatoprotective properties of silymarin, silibinin, colchicine and trimethylcolchinic acid may be irrelevant to reverse established cirrhosis.

Alanine Transaminase↗