Hepatic Liver Failure Research Articles

Can 3D imaging modeling recognize functional tissue and predict liver failure? A retrospective study based on 3D modelling of the major hepatectomies after hepatic modulation

BackgroundThanks to the introduction of radiomics, 3d reconstruction can be able to analyse tissues and recognise true hypertrophy from non-functioning tissue in patients treated with major hepatectomies with hepatic modulation.The aim of this study is to evaluate the performance of 3D Imaging Modelling in predict liver failure.MethodsPatients submitted to major hepatectomies after hepatic modulation at Sanchinarro University Hospital from May 2015 to October 2019 were analysed.Three-dimensional reconstruction was realised before and after surgical treatment. The volumetry of Future Liver Remnant was calculated, distinguishing in Functional Future Liver Remnant (FRFx) i.e. true hypertrophy tissue and Anatomic Future Liver Remnant (FRL) i.e. hypertrophy plus no functional tissue (oedema/congestion) These volumes were analysed in patients with and without post hepatic liver failure.ResultsTwenty-four procedures were realised (11 ALPPS and 13 PVE followed by major hepatectomy). Post hepatic liver failure grade B and C occurred in 6 patients. The ROC curve showed a better AUC for FRFxV (74%) with respect to FRLV (54%) in prediction PHLF > B. The increase of anatomical FRL (iFRL) was superior in the ALPPS group (120%) with respect to the PVE group (73%) (p = 0,041), while the increase of functional FRFX (iFRFx) was 35% in the ALLPS group and 46% in the PVE group (p > 0,05), showing no difference in the two groups.ConclusionThe 3D reconstruction model can allow optimal surgical planning, and through the use of specific algorithms, can contribute to differential functioning liver parenchyma of the FLR.

Exosomes from Placenta-Derived Mesenchymal Stem Cells Are Involved in Liver Regeneration in Hepatic Failure Induced by Bile Duct Ligation.

Although the liver has a regenerative capacity, hepatic failure is a severe and irreversible chronic disease. Placenta-derived mesenchymal stem cells (PD-MSCs) have distinctive features, such as recycling of the placenta waste after birth, ease of accessibility, abundant cell numbers, and strong immunosuppressive properties. Previously, we reported that PD-MSCs can regenerate the liver in hepatic failure through antifibrotic and autophagic mechanisms. Many reports have investigated whether exosomes, which are formed by the budding of vesicular bodies and are emitted into the blood, from stem cells have therapeutic potential in various diseases. C-reactive protein (CRP) is produced in hepatocytes and secreted via vessels. Therefore, the objectives of this study were to compare the expression of CRP in exosomes of a hepatic failure rat model (bile duct ligation, BDL) and to evaluate the therapeutic effect by their correlation between CRP and angiogenesis depending on PD-MSC transplantation. The exosomes were analyzed in a BDL rat model with transplantation of PD-MSCs through LC-MS analysis and precipitation solution. The exosomes, CRP, and factors related to these molecules were evaluated and quantified in exosomes as well as investigated by real-time PCR, Western blot, and immunofluorescence (IF) in vivo and in vitro. CRP was present in exosomes from serum of a rat model and increased by PD-MSC transplantation. In the exosomes, CRP upregulated the factors related to the Wnt signaling pathway and angiogenesis in the BDL rat liver-transplanted PD-MSCs. Also, CRP regulated the Wnt pathway and vascularization in rat hepatocytes by interacting with endothelial cells. Therefore, our findings indicate that CRP in exosomes excreted by PD-MSCs functions in angiogenesis via the Wnt signaling pathway.

Right extended hepatectomy for hilar cholangiocarcinoma: A case report

Radical resection in a case of hilar cholangiocarcinoma is the only curative option. However resection in a hilar cholangiocarcinoma is a challenging procedure because of the low resectability rate. Only a few cases of hilar cholangiocarcinoma are operable because of the advanced nature of disease at presentation. Furthermore, the extent of surgery makes it a complicated process to attempt. We recently had a patient who underwent an open extended right hepatectomy and hepaticojejunostomy for a type IIIa hilar cholangiocarcinoma.
 The tumor was 20 mm in diameter and was located between the right hepatic duct and common hepatic duct. Radiological examination showed that the hepatic artery was not involved but the right portal vein was invaded by the tumor. CT volumetry was done and the future liver remnant was only 20% in the jaundiced patient. Preoperative drainage was done with percutaneous transhepatic biliary drainage from the left side. Portal vein embolization was done to augment future liver remnant to 30%.
 The patient underwent an extended right hepatectomy (right trisectionectomy combined with caudate lobectomy). The operation time was nearly 300 min, and the intraoperative blood loss was about 500 ml. However, in the postoperative period, the patient developed post hepatic liver failure which was managed successfully with conservative treatment. The postoperative hospital stay was 23 days.
 The final diagnosis was hilar cholangiocarcinoma with no nodal metastasis (pT2bN0M0) stage II (American Joint Committee on Cancer, AJCC).

Volume\u2013Function Analysis (LiMAx Test) in Patients with HCC and Cirrhosis Undergoing TACE\u2014A Feasibility Study

BackgroundTransarterial chemoembolization (TACE) is an important therapy for hepatocellular carcinoma (HCC) in cirrhosis. In particular in advanced cirrhosis, post-TACE hepatic failure liver (PTHF) failure may develop. Currently, there is no standardization for the periinterventional risk assessment. The liver maximum capacity (LiMAx) test assesses the functional liver capacity, but has not been investigated in this setting.AimsThe aim of this study was to prospectively evaluate periinterventional LiMAx and CT volumetry measurements in patients with cirrhosis and HCC undergoing repetitive TACE.MethodsFrom 06/2016 to 11/2017, eleven patients with HCC and cirrhosis undergoing TACE were included. LiMAx measurements (n = 42) were conducted before and after each TACE. Laboratory parameters were correlated with the volume–function data.ResultsThe median LiMAx levels before (276 ± 166 µg/kg/h) were slightly reduced after TACE (251 ± 122 µg/kg/h; p = 0.08). This corresponded to a median drop of 7.1%. Notably, there was a significant correlation between LiMAx levels before TACE and bilirubin (but not albumin nor albumin–bilirubin [ALBI] score) increase after TACE (p = 0.02, k = 0.56). Furthermore, a significantly higher increase in bilirubin in patients with LiMAx ≤ 150 µg/kg/h was observed (p = 0.011). LiMAx levels at different time points in single patients were similar (p = 0.2).ConclusionIn our prospective pilot study in patients with HCC and cirrhosis undergoing multiple TACE, robust and reliable LiMAx measurements were demonstrated. Lower LiMAx levels before TACE were associated with surrogate markers (bilirubin) of liver failure after TACE. Specific subgroups at high risk of PTHF should be investigated. This might facilitate the future development of strategies to prevent occurrence of PTHF.

Ingestion of an Entire Vaping Device

Since 2014, vaping devices or “e-cigarettes” have become the most commonly used tobacco product in the pediatric population (1). Primary health concerns among patients who vape typically include associated lung disease and injury (2). There have, however, been cases of pediatric ingestions of vaping device refill cartridges or liquids containing nicotine or tetrahydrocannabinol leading to vital instability, altered mental status, and even hepatic liver failure (3,4). Here, we report a case of a patient who ingested an entire vaping device. A previously healthy 15-year-old boy presented to us after he had accidentally swallowed his vaping device. On arrival to our facility, he was asymptomatic and physical examination was unremarkable. An x-ray was consistent with a foreign body in his gastric region (Fig. 1A). His urine drug screen was positive for cannabinoids and his serum cotinine level, a metabolite of nicotine, was elevated to 165 ng/mL indicating recent exposure. Poison control recommended no intervention apart from device removal. The device was retrieved endoscopically via a 2.5 × 5.5 cm polypectomy snare and measured 10 cm in length and 2 cm in width (Fig. 1B, C). The patient was discharged without complications. This case illustrates an unexpected potential danger of vaping devices.FIGURE 1: XXX.

The role of genetic and epigenetic factors in non alcoholic fatty liver disease (NAFLD) pathogenesis

Background and aimNonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries, as well as the most common indication for hepatic liver failure in these countries. In this study, we aimed to determine the clinical prognostic significance of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M polymorphism as the genetic dimension in the pathogenesis of NAFLD, the miRNA-122 level as the epigenetic dimension, and to use the miRNA-122 level in NAFLD patients as a biological marker. Material and metodThis study included 40 patients with NAFLD diagnosis who underwent various tests and 20 control groups. At the beginning of the study, the patient's was obtained written informed consent. Age and gender, bady mass ındex (BMI), insulin resistance (IR), aspartate aminotransferase (AST), alanin aminotransferase (ALT) levels were recorded in the patient and control group. ResultsMiRNA-122 level, PNPLA3 I148M polymorphism and various parameters were compared. No statistically significant results were found between miRNA-122 levels when the patient and control group were compared as a result of our study (p = .090). No significant results were found between patient and control group for PNPLA3 I148M polymorphism (p = .087). ConclusionIn the light of this obtained data, progress in NAFLD management will benefit us from further scientific studies in terms of providing new diagnostic biomarkers and therapeutic targets.

Currently Circulating Genotypes of Hepatitis E Virus in India, 2014–2018

AbstractPurpose: Hepatitis E virus (HEV) is an emerging pathogen causing acute viral hepatitis worldwide. Clinical manifestations often occur in young adults with an increased mortality rate among pregnant women. HEV genotypes 1 and 4 are mainly reported among humans and swines, respectively. Aims: The aim was to study the currently circulating genotypes of HEV in India. Materials and Methods: A retrospective cross-sectional study was carried out at Manipal Institute of Virology to know the circulating genotypes of hepatitis E, spanning over 5 years from August 2014 to September 2018. The serum samples screened serologically positive and confirmed positive for active infection by real-time reverse transcriptase-polymerase chain reaction (PCR) (Real Star® HEV RT-PCR Kit 2.0, Altona Diagnostics, GmbH, Hamburg, Germany) were further subjected to nested conventional PCR targeting the RdRp gene of non-structural ORF1 region. The purified PCR product was sequenced in BigDye Terminator v3.1 Cycle Sequencing Kit (Life Technologies, Thermo Fisher Scientific, USA). The chromatograms obtained by sequencing were analysed using Sequencher 5.4.6, and HEV FASTA sequences were compared with reference sequences for HEV in GenBank Nucleotide Blast. Results: During the study period, there were 317 cases of laboratory-confirmed cases of acute viral hepatitis comprising 202, 70, 43 and 2 cases of hepatitis A, E, B and C, respectively. Serum samples of 70 acute hepatitis cases were positive for anti-hepatitis E IgM. According to the clinical case classification, there were 66 cases of acute viral hepatitis and four cases of fulminant hepatic liver failure. The mean age of the patients was 30.3 years (standard deviation = 12.5). The samples from various parts of India were genotyped as 1a. Conclusion: The HEV genotypes 1a was observed to be the currently circulating strain in the regions studied.

Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome.

Mutations in mitochondrial DNA (mtDNA) have been linked to a variety of metabolic, neurological and muscular diseases which can present at any time throughout life. MtDNA is replicated by DNA polymerase gamma (Pol γ), twinkle helicase and mitochondrial single-stranded binding protein (mtSSB). The Pol γ holoenzyme is a heterotrimer consisting of the p140 catalytic subunit and a p55 homodimeric accessory subunit encoded by the nuclear genes POLG and POLG2, respectively. The accessory subunits enhance DNA binding and promote processive DNA synthesis of the holoenzyme. Mutations in either POLG or POLG2 are linked to disease and adversely affect maintenance of the mitochondrial genome, resulting in depletion, deletions and/or point mutations in mtDNA. A homozygous mutation located at Chr17: 62492543G>A in POLG2, resulting in R182W substitution in p55, was previously identified to cause mtDNA depletion and fatal hepatic liver failure. Here we characterize this homozygous R182W p55 mutation using in vivo cultured cell models and in vitro biochemical assessments. Compared to control fibroblasts, homozygous R182W p55 primary dermal fibroblasts exhibit a two-fold slower doubling time, reduced mtDNA copy number and reduced levels of POLG and POLG2 transcripts correlating with the reported disease state. Expression of R182W p55 in HEK293 cells impairs oxidative-phosphorylation. Biochemically, R182W p55 displays DNA binding and association with p140 similar to WT p55. R182W p55 mimics the ability of WT p55 to stimulate primer extension, support steady-state nucleotide incorporation, and suppress the exonuclease function of Pol γ in vitro. However, R182W p55 has severe defects in protein stability as determined by differential scanning fluorimetry and in stimulating function as determined by thermal inactivation. These data demonstrate that the Chr17: 62492543G>A mutation in POLG2, R182W p55, severely impairs stability of the accessory subunit and is the likely cause of the disease phenotype.

Experimental study on acute hepatotoxicity in beagles induced by Amanita exitialis

Objective To establish acute hepatotoxic model induced by Amanita exitialis and to study the characteristics of acute toxic liver failure induced by mushrooms containing peptide toxins, in hope for providing some help to experimental research on poisoning induced by mushrooms containing peptide toxins. Methods UPLC-MS/MS(Ultra performance liquid chromatography- tandem mass spectrometry) method was used to detect peptide toxins in Amanita exitialis. To establish acute toxic liver hepatic failure model, the beagles were fed with 60 mg/kg of lyophilized powder of Amanita exitialis fungus which encapsulated in starch capsules. Toxic sighs were observed, coagulation function, hepatic and renal function, liver histopathological morphology, peptide toxin concentration in plasma and urine were detected during the experiment. Results Total peptide toxins in Amanita exitialis was (3 482.6 ± 124.94) mg/kg. All the beagles had toxic signs including vomiting and diarrhea in 12-48 h after ingestion. On 24 h after ingestion, the beagles’ ALT, AST, TBIL, ALP, PT and APTT levels increased obviously. On 36 h after ingestion, the beagles’ ALT, AST, PT and APTT values reached their peaks (ALT: 283.2±112.9 Kallmann unit; AST: 223.9±93.8 Kallmann units; PT: 132.9±152.6 s; APTT: 131.4±153.9 s). On 48 h after ingestion, the beagles’ TBIL and ALP levels reached their peaks (TBIL: 23.3±14.6 mol/L; ALP: 274.5±115.5 U/L). The beagles’ TBIL, TP and APTT returned to normal 1 week after ingestion, their ALT, AST and ALP levels returned to normal 3 weeks after ingestion. Three dogs died during 24-72 h after ingestion. Liver histopathological morphology study showed hemorrhagic necrosis of hepatocytes. Peptide toxins can be detected in plasma within 24 h after ingestion. Peptide toxins can be detected in urine within 96 h after ingestion. Conclusion Amanita peptide toxins can cause hemorrhagic necrosis of liver cells and lead to acute liver failure. This model is consistent with clinical pathophysiological process of acute toxic liver failure induced by mushrooms containing peptide toxins, and it can be applied to the study of diagnosis and treatment of poisoning induced by mushrooms containing peptide toxins. Key words: Mushroom poisoning; Amanita exitialis; Amanita peptide toxins; Beagles; Hepatotoxicity; Hemorrhagic necrosis of liver cells; Acute hepatic failure; Toxin detection; Model

Effect of bone marrow mesenchymal stem cell transplantation on expression of Caspase1 and IL-18 in rats with acute hepatic liver failure

Effect of bone marrow mesenchymal stem cell transplantation on expression of Caspase1 and IL-18 in rats with acute hepatic liver failure

The nuclear receptor FXR regulates hepatic transport and metabolism of glutamine and glutamate

Hepatic transport and metabolism of glutamate and glutamine are regulated by intervention of several proteins. Glutamine is taken up by periportal hepatocytes and is the major source of ammonia for urea synthesis and glutamate for N-acetylglutamate (NAG) synthesis, which is catalyzed by the N-acetylglutamate synthase (NAGS). Glutamate is taken up by perivenous hepatocytes and is the main source for the synthesis of glutamine, catalyzed by glutamine synthase (GS). Accumulation of glutamate and ammonia is a common feature of chronic liver failure, but mechanism that leads to failure of the urea cycle in this setting is unknown. The Farnesoid X Receptor (FXR) is a bile acid sensor in hepatocytes. Here, we have investigated its role in the regulation of the metabolism of both glutamine and glutamate. In vitro studies in primary cultures of hepatocytes from wild type and FXR −/− mice and HepG2 cells, and in vivo studies, in FXR −/− mice as well as in a rodent model of hepatic liver failure induced by carbon tetrachloride (CCl 4), demonstrate a role for FXR in regulating this metabolism. Further on, promoter analysis studies demonstrate that both human and mouse NAGS promoters contain a putative FXRE, an ER8 sequence. EMSA, ChIP and luciferase experiments carried out to investigate the functionality of this sequence demonstrate that FXR is essential to induce the expression of NAGS. In conclusion, FXR activation regulates glutamine and glutamate metabolism and FXR ligands might have utility in the treatment of hyperammonemia states.

Tolerogenic dendritic cells and myeloid-derived suppressor cells: Potential for regulation and therapy of liver auto- and alloimmunity

Organ transplantation is now established as an accepted treatment for end-stage liver disease, acute fulminant hepatic liver failure and hepatocellular carcinoma. While early graft acceptance rates have increased markedly due to improved immunosuppressive drug regimens, rates of late graft failure remain largely unchanged. Recent findings suggest that in addition to alloimmunity, chronic rejection of liver allografts may also reflect de novo autoimmune hepatitis or recurrence of pre-existing hepatic autoimmune disease. Dendritic cell (DC)- based therapy is a promising experimental approach to promotion of transplant tolerance and the treatment of autoimmune diseases. Newly emerging evidence also demonstrates the potential efficacy of myeloid-derived suppressor cells (MDSC) in the antigen (Ag)-specific regulation of T-cell responses. Herein, we discuss current understanding of liver autoimmunity post-transplantation, along with current approaches for the development of tolerogenic DC, and the potential use of MDSC for the development of stable, Ag-specific tolerance.

Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure

Early identification of those patients with fulminant hepatic liver failure (FHF) who need a transplant greatly helps in their management. A number of prognostic criteria have recently been proposed, including arterial blood lactate and serum phosphate concentrations. To validate their use, we retrospectively studied 83 consecutive patients with FHF admitted to our intensive treatment unit between August 2000 and March 2003. A total of 48 patients (58%) survived with medical management only (group I) and 35 patients (42%) failed to survive spontaneously (group II). This group included 19 patients (23%) who underwent orthotopic liver transplantation (LT), and 16 patients (19%) who died without undergoing LT (group IIa). A total of 5 patients (6%) who underwent liver transplantation died. Within paracetamol overdose (POD) and non-POD subgroups, phosphate concentrations were not significantly higher in group II patients (P = 0.08 and P = 0.27, respectively), when compared to group I patients. In multivariate analysis, post admission 12-hour lactate level was the only predictor of survival for the POD subgroup, whereas in non-POD patients, 12-hour lactate and admission bilirubin levels were significant in predicting patients' outcome. In conclusion, we found that while serum phosphate concentrations have limited clinical utility as prognostic markers, persistently elevated arterial blood lactate levels despite adequate fluid resuscitation are indicators of a poor prognosis in FHF.

Indications for liver transplantation in chronic liver diseases

Surgical resection of the diseased liver together with the implantation of a new donor organ allows patients with chronic liver failure to survive longer as well as to achieve a better quality of life. In life-threatening acute and chronic hepatic failure liver transplantation represents the only causal and long-term therapeutic option. This is also true for several genetically defined liver diseases. Five-year survival approaches 70 % in most cases. Three of four patients regain a nearly normal life with complete reintegration into their professional work. Drawbacks of this therapeutic option relate to a life-long dependence on drugs and medical services as well as to the risks associated with the surgical procedure and the side-effects of a continuous drug-induced immunosuppression. Mortality and morbidity are considerably increased during the first three months after operation. These limitations and the dramatically low availability of donor organs necessitate the application of all conservative measures before a transplantation procedure should be performed. However, the surgical option should be evaluated early enough to allow for a good chance of success. Profound knowledge of prognosis and medical treatment of each individual liver disease is a prerequisite for correct indication and timing of liver transplantation.

Significance of Fas antigen-mediated apoptosis in human fulminant hepatic failure.

The aim of this study was to elucidate the role of apoptosis in human fulminant hepatic failure. We studied the expression of Fas antigen on liver tissues, Fas ligand in lymphocytes, and soluble Fas ligand in patients' serum. On finding apoptotic cells in fulminant hepatic failure liver, we first examined them using the TUNEL method. Subsequently, the expression of Fas was studied by immunostaining. Simultaneously, Fas ligand presenting on both liver-infiltrated cells and peripheral lymphocytes was studied by reverse transcription-polymerase chain reaction, and soluble Fas ligand in sera was measured by ELISA. By using the TUNEL method, we first demonstrated that many apoptotic cells existed in fulminant hepatic failure but not in normal ones. Our immunohistochemistry study showed that many hepatocytes in fulminant hepatic failure strongly expressed Fas. In addition, Fas ligand on both liver-infiltrating lymphocytes and peripheral lymphocytes in fulminant hepatic failure patients was detected. The serum level of soluble Fas ligand was significantly increased in fulminant hepatic failure (mean value, 2.91 ng/ml in fulminant hepatic failure [n = 10], 1.62 ng/ml in acute hepatitis [n = 10], and 0.27 ng/ml in healthy controls [n = 10]). Furthermore, this serum level of sFas ligand was significantly associated with prothrombin time both in acute hepatitis and fulminant hepatic failure. The present results indicate that Fas-mediated apoptosis may be one of the triggers for the induction of fulminant hepatic failure.

Significance of Fas antigen-mediated apoptosis in human fulminant hepatic failure

OBJECTIVE: The aim of this study was to elucidate the role of apoptosis in human fulminant hepatic failure. We studied the expression of Fas antigen on liver tissues, Fas ligand in lymphocytes, and soluble Fas ligand in patients’ serum. METHODS: On finding apoptotic cells in fulminant hepatic failure liver, we first examined them using the TUNEL method. Subsequently, the expression of Fas was studied by immunostaining. Simultaneously, Fas ligand presenting on both liver-infiltrated cells and peripheral lymphocytes was studied by reverse transcription-polymerase chain reaction, and soluble Fas ligand in sera was measured by ELISA. RESULTS: By using the TUNEL method, we first demonstrated that many apoptotic cells existed in fulminant hepatic failure but not in normal ones. Our immunohistochemistry study showed that many hepatocytes in fulminant hepatic failure strongly expressed Fas. In addition, Fas ligand on both liver-infiltrating lymphocytes and peripheral lymphocytes in fulminant hepatic failure patients was detected. The serum level of soluble Fas ligand was significantly increased in fulminant hepatic failure (mean value, 2.91 ng/ml in fulminant hepatic failure [n = 10], 1.62 ng/ml in acute hepatitis [n = 10], and 0.27 ng/ml in healthy controls [n = 10]). Furthermore, this serum level of sFas ligand was significantly associated with prothrombin time both in acute hepatitis and fulminant hepatic failure. CONCLUSIONS: The present results indicate that Fas-mediated apoptosis may be one of the triggers for the induction of fulminant hepatic failure.

USE OF MARS IN THE TREATMENT OF ACUTE LIVER FAILURE. PRELIMINAR MONOCENTRIC EXPERIENCE

The bioartificial liver (BAL), with depurative and synthetic capacities, and the molecular absorption recycling system (MARS) caracterized by the only depuration function through hybrid layers foe detoxics tield up to the albumin transportation are two different extracorporeal methods today aviable for the treatment of acute liver failure. The BAL using hepatocites derived from hepatoblastoma or from animals is loaded by the risk of the apparence of antibodies for the exposure to specific species antigens, in limitating the application in a longe period. MARS, conditioned from the impossibility of synthesis, can be used for an illimitated time. Aim of our study is to report our experience in using MARS in three patients with acute liver failure secondary to PNF (case 1), FHF due to HBV infection (case 2), Autoimmune acute hepatitis (case 3). All patients were in the waiting list for an urgent liver transplant. The parameters of hepatic and renal function, the coagulation values, ammoniemia and albuminemia have been monitorized before and after treatment that lasted 8.1±1.5 hours. The three patients were in hepatic coma and underwent to the EEG. For the lack of hepatic synthesis has always been set up substitutive therapy. Neither hemodinamic complications or varations of the albuminemia have been observed during the treatment. Patient nr. 2 has been successfully transplanted. The results of our study are reported in the table 1. We conclude that MARS treatment should be safe and that it could be used in hepatic liver failure as bridge to the liver transplantaion or as artificial depurative support waiting for the recovery of normal hepatic function, as it can remove the toxic substances like ammonium and bilirubine.Table

A Reversible Model of Acute Hepatic Failure by Temporary Hepatic Ischemia in the Pig

Background. To evaluate new therapies for human fulminant hepatic failure, a suitable large animal model is needed. The purpose of this study was to develop a reversible surgical model of acute hepatic liver failure by transient ischemia in pigs.Materials and methods. Under general anesthesia, an end-to-side portacaval shunt was performed in 17 pigs and tape was laid around the hepatoduodenal ligament. Two days after construction of the functional portacaval shunt, 13 ambulant pigs underwent transient total liver ischemia by tightening of the tape around the hepatoduodenal ligament for 5.5 h. During ischemia, 10% glucose was continuously infused intravenously to prevent hypoglycemia.Results. Ten animals (77%) died with hepatic coma after a mean duration of 22.5 ± 1.9 h. The 3 remaining animals survived more than 5 days and were sacrificed. In dying animals, encephalopathy was observed 14 ± 1.7 h after the onset of ischemia. During ischemia, similar progressive decrease of fibrinogen, platelets, prothrombin time, and factors V and VII activities was observed in dying and surviving animals. Just before death, mean prothrombin and factors V and VII activities were respectively 22 ± 2, 21 ± 4.4, and 24 ± 5%. At 22 h, plasma ammonia and lactate levels were respectively 705 ± 93 μmol/L and 10.5 ± 0.4 mmol/L in dying animals and 249 ± 75 μmol/L and 2.9 ± 0.1 mmol/L in surviving animals (P < 0.01). Estimation of the percentage liver cells necrosed was 74 ± 4.7% in the survivors and 86 ± 5.5% in animals who died of hepatic coma (NS).Conclusions. This model is reproducible and reversible and should allow the quantitative evaluation of new technologies, such as bioartificial liver, for the support of hepatic failure in humans.

Lack of hepatocyte growth factor receptor (c-met) gene expression in fulminant hepatic failure livers before transplantation.

To gain insight into liver regeneration mechanisms in fulminant hepatic failure, we compared gene expression of hepatocyte growth factor, its receptor c-met, c-myc, and albumin in human normal (4 cases) and fulminant (14 cases) livers by reverse transcription-polymerase chain reaction. In normal livers, hepatocyte growth factor gene was not expressed, whereas c-met, c-myc and albumin genes were always expressed. In fulminant hepatic failure, hepatocyte growth factor gene was expressed in 1 of 14 cases, c-met in none of 14 cases, c-myc in 10 of 14 cases, and albumin in 3 of 14 cases. By immunofluorescence, c-met protein was revealed in normal but not in fulminant hepatic failure liver tissue. Liver tissue is unlikely to account for high hepatocyte growth factor plasma levels typical for fulminant hepatic failure. Lack of its receptor (c-met) expression may explain a poor response of fulminant hepatic failure livers to exogenous hepatocyte growth factor that normally promotes liver growth and regeneration.