Fulminant Hepatic Failure Group Research Articles

Intestinal Dendritic Cells Are Altered in Number, Maturity and Chemotactic Ability in Fulminant Hepatic Failure.

Fulminant hepatic failure (FHF) is defined as rapid acute liver injury, often complicated with spontaneous bacterial peritonitis (SBP). The precise onset of FHF with SBP is still unknown, but it is thought that SBP closely correlates with a weakened intestinal barrier. Dendritic cells (DCs) play a crucial role in forming the intestinal immune barrier, therefore the number, maturity and chemotactic ability of intestinal DCs were studied in FHF. Mouse intestinal and spleen DCs were isolated by magnetic-activated cell sorting (MACS) and surface markers of DCs, namely CD11c, CD74, CD83 and CD86, were identified using flow cytometry. Immunohistochemistry and Western blotting were performed to detect the distribution and expression of CC-chemokine receptor 7 (CCR7) and CC-chemokine receptor 9 (CCR9), as well as their ligands-CC-chemokine ligand 21 (CCL21) and CC-chemokine ligand 25 (CCL25). Real-time PCR was used to detect CCR7 and CCR9 mRNA, along with their ligands-CCL21 and CCL25 mRNA. Flow cytometry analysis showed that the markers CD74, CD83 and CD86 of CD11c+DCs were lower in the D-galactosamine (D-GalN) group and were significantly decreased in the FHF group, while there were no significant changes in the expression of these markers in the lipopolysaccharide (LPS) group. Immunohistochemistry results showed that staining for CCR7 and CCR9, as well as their ligands CCL21 and CCL25, was significantly weaker in the D-GalN and FHF groups compared with the normal saline (NS) group or the LPS group; the FHF group even showed completely unstained parts. Protein expression of CCR7 and CCR9, as well as their ligands- CCL21 and CCL25, was also lower in the D-GalN group and decreased even more significantly in the FHF group. At the gene level, CCR7 and CCR9, along with CCL21 and CCL25 mRNA expression, was lower in the D-GalN group and significantly decreased in the FHF group compared to the NS and LPS groups, consisting with the protein expression. Our study indicated that intestinal DCs were decreased in number, maturity and chemotactic ability in FHF and might contribute to a decreased function of the intestinal immune barrier in FHF.

Intestinal dendritic cells change in number in fulminant hepatic failure.

To investigate the change in intestinal dendritic cell (DC) number in fulminant hepatic failure (FHF). An animal model of FHF was created. Intestinal CD11b/c was detected by immunohistochemistry and Western blot. Quantitative real-time polymerase chain reaction (PCR) was used to detect intestinal integrin-α mRNA expression. Intestinal CD83, CD86, CD74, CD3 and AKT were detected by immunohistochemistry, Western blot and PCR. Phosphorylated-AKT (p-AKT) was detected by immunohistochemistry and Western blot. In the FHF group [D-galactosamine (D-Galn) + lipopolysaccharide (LPS) group], the mice began to die after 6 h; conversely, in the D-Galn and LPS groups, the activity of mice was poor, but there were no deaths. Immunohistochemistry results showed that in FHF, the expression of CD11b/c (7988400 ± 385941 vs 1102400 ± 132273, P < 0.05), CD83 (13875000 ± 467493 vs 9257600 ± 400364, P < 0.05), CD86 (7988400 ± 385941 vs 1102400 ± 13227, P < 0.05) and CD74 (11056000 ± 431427 vs 4633400 ± 267903, P < 0.05) was significantly increased compared with the normal saline (NS) group. Compared with the NS group, the protein expression of CD11b/c (5.4817 ± 0.77 vs 1.4073 ± 0.37, P < 0.05) and CD86 (4.2673 ± 0.69 vs 1.1379 ± 0.42, P < 0.05) was significantly increased. Itg-α (1.1224 ± 0.3 vs 0.4907 ± 0.19, P < 0.05), CD83 (3.6986 ± 0.40 vs 1.0762 ± 0.22, P < 0.05) and CD86 (1.5801 ± 0.32 vs 0.8846 ± 0.10, P < 0.05) mRNA expression was increased significantly in the FHF group. At the protein level, expression of CD74 in the FHF group (2.3513 ± 0.52) was significantly increased compared with the NS group (1.1298 ± 0.33), whereas in the LPS group (2.3891 ± 0.47), the level of CD74 was the highest (P < 0.05). At the gene level, the relative expression of CD74 mRNA in the FHF group (1.5383 ± 0.26) was also significantly increased in comparison to the NS group (0.7648 ± 0.22; P < 0.05). CD3 expression was the highest in the FHF group (P < 0.05). In the FHF, LPS and D-Galn groups, the expression of AKT at the protein and mRNA levels was elevated compared with the NS group, but there was no statistical significance (P > 0.05). The p-AKT protein expression in the FHF (1.54 ± 0.06), LPS (1.56 ± 0.05) and D-Galn (1.29 ± 0.03) groups was higher than that in the NS group (1.07 ± 0.03) (P < 0.05). In FHF, a large number of DCs mature, express CD86, and activate MHC class II molecular pathways to induce a T cell response, and the AKT pathway is activated.

Outcomes of Orthotopic Liver Transplantation in Non-malignant End-stage Liver Diseases

BackgroundOrthotopic liver transplantation (OLT) is an effective treatment for patients who have end-stage liver disease. The aim of this study is to compare outcomes of OLT in fulminant hepatic failure (FHF) and non-fulminant hepatic failure (non-FHF) patients. MethodsA retrospective review of adult patients who underwent OLT for non-malignant end-stage liver diseases between 2002 and 2011 at Siriraj Hospital was performed. All explanted liver histopathology results were reviewed. The clinical factors and overall results of OLT were analyzed. ResultsOf the 137 patients, 72 patients had non-malignant diagnoses. Eleven patients were diagnosed with FHF, whereas 61 patients were in the non-FHF group. The most common indication for liver transplantation was chronic viral hepatitis. One- and 5-year survival rates (95% confidence interval) in the FHF group were 91% (51%–99%) and 91% (51%–99%), respectively, whereas those in the non-FHF group were 74% (61%–83%) and 66% (52%–77%), respectively. Multivariate cox regression analysis revealed no statistically significant difference of survival between both groups (P = .34). ConclusionsThe post-OLT outcomes in non-malignant patients were comparable between FHF and non-FHF groups in terms of survival. OLT remains the only therapeutic option for the FHF patients.

Effects of Large-Pore Hemofiltration in a Swine Model of Fulminant Hepatic Failure

Among the different potential mechanisms that could lead to brain edema and intracranial hypertension in fulminant hepatic failure (FHF), the inflammatory hypothesis implies that systemic inflammation might be in part responsible for an increase in cerebral blood flow (CBF) and brain water content. In this study, the authors used a validated ischemic FHF swine model to evaluate the effects of 80 kDa large-pore membrane hemofiltration (LPHF) on intracranial pressure (ICP) and CBF, in relation with the clearance of proinflammatory cytokines and blood liver tests, as primary end points. Fifteen pigs were randomized into one of three groups: SHAM, FHF, and FHF + LPHF. All experiments lasted 6 h. In the FHF groups, liver failure was induced by liver ischemia. After 2 h, the FHF + LPHF group underwent 4 h of a zero-balance continuous veno-venous hemofiltration using a 0.7-m(2), large-pore (78 Å) membrane with a cutoff of 80 kDa. ICP, CBF, mean arterial pressure, central venous pressure, and heart rate were continuously monitored and recorded. Arterial aspartate aminotransferase, total bilirubin, creatinine, international normalized ratio, glucose, lactate and serum cytokines interleukin (IL)-6, IL-10, and tumor necrosis factor-α were measured at T0, T120, and T360. Over the 6 h following liver ischemia, the FHF group developed a significant increase in ICP. This ICP rise was not observed in the SHAM group and was attenuated in the FHF + LDHF group. However, the ICP levels were not different at T360 in the FHF + LDHF group compared to the FHF group. No significant effect of LPHF on liver tests or levels of proinflammatory cytokines could be demonstrated. In this model, 80 kDa LPHF was not efficient to control FHF intracranial hypertension and to decrease serum cytokine levels.

Evaluation of a reversibly immortalized human hepatocyte line in bioartificial liver in pigs

An appropriate cell source is essential for the clinical application of bioartificial liver (BAL) system. This study aimed to test a reversibly immortalized human hepatocyte line (HepLi-4) in our newly validated choanoid fluidized bed bioreactor based BAL in pigs with fulminant hepatic failure (FHF). 15 FHF pigs were allocated to three groups: a BAL group receiving BAL treatment with HepLi-4 cells; a sham BAL group receiving cell-free BAL treatment; and a FHF group receiving intensive care only. Expression of liver-specific genes in HepLi-4 cells before and after BAL was analyzed, adult human hepatocytes acted as a reference. In BAL group, Fischer index was higher and serum indirect bilirubin level was lower compared with two control groups. Survival time in BAL group was longer than that in two control groups, but the difference was not statistically significant. Gene expression analysis showed that the transcript levels of liver-specific genes in HepLi-4 were retained after BAL, but significant variations were observed between HepLi-4 and human hepatocytes. HepLi-4 showed beneficial metabolic effects on FHF pigs in BAL, but is still not an appropriate cell source for BAL. More insights into interpreting the conditions for hepatocyte differentiation are needed. Key words : Reversible immortalization, hepatocytes, bioartificial liver, fulminant hepatic failure.

Bioartificial liver system based on choanoid fluidized bed bioreactor improve the survival time of fulminant hepatic failure pigs

Bioartificial liver (BAL) support system has been proposed as potential treatment method for end-stage liver diseases. We described an improved BAL system based on a choanoid fluidized bed bioreactor containing alginate-chitosan encapsulated primary porcine hepatocytes. The feasibility, safety, and efficiency of this device were estimated using an allogeneic fulminant hepatic failure (FHF) model. FHF was induced with intravenous administration of D-galactosamine. Thirty FHF pigs were divided into three groups: (1) an FHF group which was only given intensive care; (2) a sham BAL group which was treated with the BAL system with empty encapsulation, and (3) a BAL group which was treated with the BAL system containing encapsulated freshly isolated primary porcine hepatocytes. The survival times and biochemical parameters of these animals were measured, and properties of the encapsulations and hepatocytes before and after perfusion were also evaluated. Compared to the two control groups, the BAL-treated group had prolonged the survival time and decreased the blood lactate levels, blood glucose, and amino acids remained stable. No obvious ruptured beads or statistical decline in viability or function of encapsulated hepatocytes were observed. This new fluidized bed BAL system is safe and efficient. It may represent a feasible alternative in the treatment of liver failure.

Viral Load, Antibody Titers and Recombinant Open Reading Frame 2 Protein-Induced Th1/Th2 Cytokines and Cellular Immune Responses in Self-Limiting and Fulminant Hepatitis E

Objectives: Hepatitis E virus (HEV) is the predominant cause of water-borne epidemics, sporadic acute viral hepatitis (AVH) in adults and fulminant hepatic failure (FHF) among pregnant women and other adults in India. This preliminary study was designed to examine the association of viral load and certain host immune responses with uneventful recovery or progression to FHF. Methods: Viral load, anti-HEV antibody titers, rORF2p-induced Th1/Th2 cytokines levels and cellular immune responses were assessed in 47 patients with self-limiting hepatitis E and 14 FHF-E cases. The controls included 16 anti-HEV-IgM and IgG-negative healthy individuals. Results: In AVH category, the viral load was 2.4 × 10⁴ ± 1.92 × 10⁴ copies/ml while except for one, all FHF patients were negative for HEV RNA; anti-HEV-IgM and IgG titers were higher in the FHF group. Lymphocyte proliferative response to rORF2p was comparable in both groups. As compared to AVH, significantly higher levels of both Th1 (IFN-γ, IL-2 and TNF-α) and Th2 (IL-10) cytokines were recorded in FHF patients. Analysis of sequential samples differentiated FHF recovered and fatal patients with respect to IFN-γ and IL-12. Conclusion: The results document increased Th1/Th2 responses and anti-HEV titers in FHF patients that warrant in-depth immunological studies.

Metabolic Profiling Analysis of a d-Galactosamine/Lipopolysaccharide-Induced Mouse Model of Fulminant Hepatic Failure

The purpose of this study was to characterize the changes in metabolic intermediates and to investigate the metabolic profile of a mouse model of fulminant hepatic failure (FHF), induced by D-galactosamine/lipopolysaccharide (GalN/LPS). Plasma metabolite levels were detected using gas chromatography/time-of-flight mass spectrometry, and the acquired data were transferred into Simca-P and processed using principal components analysis (PCA). In total, 45 metabolites were identified from the 267 distinct compounds found in the study. Whereas significant differences were noted in the plasma levels of the control and FHF groups, no differences in gluconeogenesis or glycolysis were noted following GalN/LPS treatment. Our data also suggest that the production of ketone bodies, and the tricarboxylic acid and urea cycles, was inhibited. PCA data suggest that 5-hydroxyindoleacetic acid, glucose, beta-hydroxybutyrate, and phosphate parameters had the highest weights on each of the principal components, and that they were the most important metabolites contributing to the separation of groups. In conclusion, this metabonomic approach can be used as a powerful tool to characterize changes in metabolic intermediates and to search for metabolic markers under certain pathophysiological conditions, such as FHF. Our data also demonstrate that a combination of 5-hydroxyindoleacetic acid, glucose, beta-hydroxybutyrate, and phosphate concentrations in the plasma is a potential marker for FHF, as well as for the early prognosis of FHF.

TypeIinositol 1, 4, 5-triphosphate receptors increase in kidney of mice with fulminant hepatic failure

To delineate the mechanisms of renal vasocon-striction in hepatorenal syndrome (HRS), we investigated the expression of type I inositol 1, 4, 5-triphosphate receptors (IP3RI) of kidney in mice with fulminant hepatic failure (FHF). FHF was induced by lipopolysaccharide (LPS) in D-galactosamine (GalN) sensitized BALB/c mice. There were 20 mice in normal saline (NS)-treated group, 20 mice in LPS-treated group, 20 mice in GalN-treated group, and 60 mice in GalN/LPS-treated group (FHF group). Liver and kidney tissues were obtained at 2, 6, and 9 h after administration. The liver and kidney specimens were stained with hematoxylin-eosin for studying morphological changes under light microscope. The expression of IP3RI in kidney tissue was tested by immunohistochemistry, Western blot and reverse transcription (RT)-PCR. Kidney tissues were morphologically normal at all time points in all groups. IP3RI proteins were found localized in the plasma region of glomerular mesangial cells (GMC) and vascular smooth muscle cells (VSMC) in kidney by immunohistochemical staining. In kidney of mice with FHF at 6 h and 9 h IP3RI staining was up-regulated. Results from Western blot demonstrated consistent and significant increment of IP3RI expression in mice with FHF at 6 h and 9 h (t=3.16, P<0.05; t=5.43, P<0.01). Furthermore, we evaluated IP3RI mRNA expression by RT-PCR and observed marked up-regulation of IP3RI mRNA in FHF samples at 2 h, 6 h and 9 h compared to controls (t=2.97, P<0.05; t=4.42, P<0.01; t=3.81, P<0.01). The expression of IP3RI protein increased in GMC and renal VSMC of mice with FHF, possibly caused by up-regulation of IP3RI mRNA.

Impact of Viral Hepatitis on Apo- and Lipoprotein Status in Blood

Objectives:To investigate the effect of viral hepatitis on serum levels of apo- and lipoproteins in different forms of liver diseases. Materials and Methods: One hundred and thirty adult patients and 100 healthy age- and gender-matched control individuals participated in this study. Patients were grouped according to four types of liver disease: acute viral hepatitis, chronic active hepatitis (CAH), cirrhosis of the liver and fulminant hepatic failure. Results: Hepatitis B virus, C virus and E virus (HEV) infections were recorded in different combinations in these patients, but viral infections of hepatitis A and D were not seen in any of the patient groups. The results of lipo- and apoprotein analysis showed different patterns. The low-density lipoprotein value was high in the CAH group. In the other three groups, low-density lipoprotein level was comparable to the control value. The high-density lipoprotein level (p = 0.02) was significantly low in all groups except in the cirrhosis group. Apo-A was significantly reduced in the acute viral hepatitis and fulminant hepatic failure groups, whereas Apo-B level was low in the CAH and cirrhosis groups. The lipoprotein (a) level in these groups was low, compared to control. Conclusion: No apparent relationship was observed between etiological viruses and ensuing changes in lipid/lipoprotein profile.

Separate analysis of asialoglycoprotein receptors in the right and left hepatic lobes using 99mTc-GSA SPECT in patients with acute hepatic damage

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the sinusoidal surfaces of hepatocytes. However, regional expression and clinical significance of the ASGPR in acute hepatic damage is presently unknown. Our aim was to clarify the clinical significance of the regional expression of ASGPR in human livers with acute hepatitis (AH) and fulminant hepatic failure (FHF). Eighteen volunteers, 42 patients with AH and 10 with FHF were studied using a newly developed, conventional (99m)Tc-GSA SPECT analysis. Using Cantlie's line as a guide, ASGPR expression was analyzed separately in the right and left hepatic lobes, as well as in the whole liver, using novel indices (the liver uptake ratio [LUR] and liver uptake density [LUD], which reflect the amount and density of ASGPRs in the liver, respectively). Mean LUR and LUD values for the whole liver and the right and left lobes decreased in accordance with the severity of acute hepatic damage. In the FHF group, the reduction in LUR and LUD values in the right lobes was more significant than in the left lobes. The LUR and LUD values for the whole liver correlated well with hepatic functional reserve and total bilirubin levels. The right LUR and LUD values in particular correlated well with these parameters. A time-course observation of 13 patients with either AH or FHF revealed that the expression of ASGPRs in the right lobe recovered faster than in the left. We first evaluated the regional expression of AGSPRs by (99m)Tc-GSA SPECT analysis in both AH and FHF patients, which is a clinically useful and reliable indicator for assessing the severity of regional hepatic damage and evaluating regional liver regeneration.

Predictors of clinical outcome in children undergoing orthotopic liver transplantation for acute and chronic liver disease

The current United Network for Organ Sharing (UNOS) policy is to allocate liver grafts to pediatric patients with chronic liver disease based on the pediatric end-stage liver disease (PELD) scoring system, while children with fulminant hepatic failure may be urgently listed as Status 1a. The objective of this study was to identify pre-transplant variables that influence patient and graft survival in those children undergoing LTx (liver transplantion) for FHF (fulminant hepatic failure) compared to those patients transplanted for extrahepatic biliary atresia (EHBA), a chronic form of liver disease. The UNOS Liver Transplant Registry was examined for pediatric liver transplants performed for FHF and EHBA from 1987 to 2002. Variables that influenced patient and graft survival were assessed using univariate and multivariate analysis. Kaplan-Meier analysis of FHF and EHBA groups revealed that 5 year patient and graft survival were both significantly worse (P < 0.0001) in those patients who underwent transplantation for FHF. Multivariate analysis of 29 variables subsequently revealed distinct sets of factors that influenced patient and graft survival for both FHF and EHBA. These results confirm that separate prioritizing systems for LTx are needed for children with chronic liver disease and FHF; additionally, our findings illustrate that there are unique sets of variables which predict survival following LTx for these two groups.

Evaluation of a bioartificial liver based on a nonwoven fabric bioreactor with porcine hepatocytes in pigs

We developed a bioartificial liver (BAL) based on a direct hemoperfusion typed nonwoven fabric bioreactor containing porcine hepatocytes. In this study, the efficacy of our BAL was evaluated with a pig fulminant hepatic failure (FHF) model. FHF was induced with intravenous administration of D-galactosamine (1.3 g/kg) in each pig. Twelve hours post D-galactosamine injection, fifteen pigs were divided into: a BAL group (n = 5), in which pigs received the BAL treatment with 1.0 to 1.3 x 10(9) hepatocytes for 6 h, a sham BAL group (n = 5), in which pigs received the BAL treatment without hepatocytes, and a FHF group (n = 5), in which pigs only received intensive care. Parameters related to liver function and animal survival up to 168 h were determined. In the BAL group, blood ammonia and plasma lactate levels were lower, and serum glucose levels and Fischer index were higher than those in the other two groups. Survival time of pigs in the BAL group was significantly prolonged as compared with the sham BAL and the FHF group. The BAL based on a nonwoven fabric bioreactor containing porcine hepatocytes appears to be effective in the treatment of FHF in pigs.

Hemodynamic parameters in a surgical devascularization model of fulminant hepatic failure in the minipig.

Animal models of fulminant hepatic failure (FHF) are important for studying the pathophysiology of this process and for evaluation of the efficacy of artificial and bioartificial liver support systems. In experiments, hemodynamic parameters were monitored in a group of minipigs with FHF induced by surgical devascularization, and compared with those in a control group. During the experiment, animals were analgosedated and were on mechanical lung ventilation. Crystalloid and colloidal solutions were administered and norepinephrine in continuous infusion was applied if mean arterial pressure (MAP) decreased below 60 mm Hg despite adequate intravascular volumes. An increase in heart rate, and decreases in MAP and systemic vascular resistance, compared with the baseline, occurred in the FHF group from 6 h after surgery. A comparison of FHF and control groups revealed no significant differences in systemic vascular resistance and MAP until after 12 h after surgery (systemic vascular resistance index: 953 FHF vs. 1658 controls; p < 0.05; MAP: 58.1 FHF vs. 76 controls; p < 0.05). No significant differences in CI were seen between the FHF group and controls. FHF animals survived for about 13 h after surgery, i.e. a period, which we consider long enough to test a support device. The parameters are believed to be quite adequate, as we were able to maintain satisfactory hemodynamic stability in all experimental animals with induced acute hepatic failure.

Transcranial Doppler sonography in fulminant hepatic failure

The clinical course of patients with fulminant hepatic failure (FHF) is often worsened by the presence of cerebral edema and endocranial hypertension. In spite of the multiple studies using Transcranial Doppler Sonography (TCDS), few have shown the cerebral blood flow (CBF) pattern among patients with encephalopathy resulting from FHF. Objective Our objective was to characterize the CBF pattern in these patients through the use of TCDS to provide therapeutic strategies. Method The TCDS pattern was assessed in five patients diagnosed with FHF and compared with a control group who displayed critical neurologic conditions not associated with FHF. Pulsatile index, systolic, diastolic, and mean velocity of the middle cerebral artery were measured. Results The mean age of patients with FHF was 45.4 years. One hundred percent were women, with viral hepatitis as the predominant etiology. A cerebral hypoperfusion pattern was found in 80% of the FHF group and 40% of the control group. In the former group there was no evidence of hyperemia, as there was among 20% of the control group. The mean values of velocity and pulsatile index were 36.6 cm/sec and 2.4, respectively, in the FHF group and 47.8 cm/s and 1.8 in the control group ( P = 0.268, P = 0.402). Conclusions FHF patients show a predominance of cerebral hypoperfusion pattern with mean velocities lower than normal values and an increased pulsatile index. We recommend that clinicians take appropriate measures to improve cerebral perfusion and avoid hypoxia. Hyperventilation as a first level measure is contraindicated.

Hepatic expression and serum levels of thrombomodulin reflect the extent of liver injury in rats with fulminant hepatic failure and extensive hepatectomy

In order to evaluate the biological significance of thrombomodulin (TM) in the serum and its expression in the liver, changes in TM were investigated in rats with fulminant hepatic failure (FHF) or after extensive hepatectomy. Forty-two rats were divided into four groups as follows: control (sham, n=6), 70% hepatectomy (70% Hx, n=12), 90% hepatectomy (90% Hx, n=12) and fulminant hepatic failure (FHF, n=12). The soluble-TM levels in the 90% Hx and FHF groups were significantly higher than that in the 70% Hx group. In the FHF group, the soluble-TM level 24 h after induction was significantly higher than that at 12 h ( P<0.05). Moreover, the level of soluble TM was significantly higher in the FHF group than that in the 90% Hx group, while hyaluronic acid was not increased at statistical significance. The expression of TM in the liver intensified with time in both FHF and 90% Hx groups, which was more pronounced in zone 3 of the liver in FHF group than in the 90% Hx group. In conclusion, elevation of s-TM in the serum and expression of TM in the sinusoidal endothelial cell are useful markers of hepatic failure and its sinusoidal endothelial injury, especially in the state of FHF, since the presence of necrotic liver tissue is the only difference between FHF and 90% Hx in the model of the rats.

Increased turnover of Gc-globulin in patients with hepatic encephalopathy.

A low serum level (< 100 mg/L) of the actin-scavenger Gc-globulin is a prognostic marker of non-survival in fulminant hepatic failure (FHF). It is unknown whether decreased production or increased consumption (or both) is responsible for the low Gc-globulin levels. Ten patients with FHF and four patients with acute or chronic liver disease (AOCLD) with hepatic encephalopathy (HE) grades II-IV were included. Eight patients with cirrhosis (chronic liver disease, CLD) without HE served as controls. Total, free, and actin-bound Gc-globulin were measured in samples from an artery, a central vein, and a hepatic vein. In 12 patients (9 FHF, 3 AOCLD), concentrations were measured before and after high volume plasmapheresis (HVP). Total Gc-globulin was reduced to 21%, 40%, and 43% of the normal level in the FHF, AOCLD, and CLD groups, respectively, whereas bound Gc-globulin was within normal range in all patients. The Gc:actin complex ratio was increased 3.8, 2.5, and 1.9-fold compared with normal levels. Total, free, and bound serum Gc-globulin levels did not differ among arterial, systemic venous, or hepatic venous blood. Total Gc-globulin rose to >100 mg/L in all patients after HVP, whereas bound Gc-globulin remained unchanged. The Gc-globulin production rate in FHF and AOCLD patients was increased to 4.1 +/- 1.3 mg/min compared to literature values of 0.6 mg/min in healthy individuals. The estimated half-life of total Gc-globulin was shorter in the patients compared to healthy individuals (127 +/- 56 min and 870 min, respectively). Gc-globulin levels were reduced in patients with FHF and AOCLD because a 7-fold increase of Gc-globulin production rate could not compensate for the accelerated clearance. Bound Gc-globulin was maintained within normal levels in all circumstances studied, indicating a possible regulatory role of this parameter in the clearance of actin.

Energy expenditure in acetaminophen-induced fulminant hepatic failure.

To determine energy expenditure in critically ill patients suffering from acetaminophen-induced fulminant hepatic failure and compare it with values obtained in matched, healthy control subjects and in patients studied during the anhepatic period of elective liver transplantation. Prospective, controlled, observational study. A ten-bed intensive therapy unit and a liver transplant unit at a University teaching hospital. Sixteen patients suffering from acetaminophen-induced fulminant hepatic failure who were sedated, paralyzed, and mechanically ventilated; 16 age-, gender-, and weight-matched, awake, healthy control subjects; and 16 patients with chronic liver disease, undergoing elective liver transplantation, who were studied during the anhepatic period of surgery. None. The mean energy expenditure was calculated in each case for a 30-min period, using indirect calorimetry. In the patients undergoing liver transplantation, measurements were performed after clamping the hepatic veins and recipient hepatectomy. Energy expenditure was markedly increased in the fulminant hepatic failure group (mean energy expenditure, 4.05 [SD 0.52] kJ x kg(-1) x hr(-1)), in comparison with healthy control subjects (mean, 3.44 [0.27] kJ x kg(-1) x hr(-1); mean difference, 18%; p < .001) and in comparison with patients during the anhepatic period of liver transplantation (mean, 3.15 [0.61] kJ x kg(-1) x hr(-1); mean difference, 29%; p < .001). These differences were even more pronounced when a correction factor for differences in core temperature was included in the calculation. Harris-Benedict predictions of energy expenditure were unreliable in the patients with acute liver failure. No correlations were found among energy expenditure and hemodynamic variables, the requirement for vasoconstrictors, or the presence of renal failure. Despite the loss of functioning liver cell mass, the metabolic rate is substantially increased in patients with acetaminophen-induced fulminant hepatic failure. This finding is consistent with the marked systemic inflammatory response, which accompanies acute hepatic failure. The Harris-Benedict equation is unreliable when an estimation of energy expenditure is required in patients with this condition.

Acute pancreatitis and fulminant hepatic failure

Background: The association of acute pancreatitis with fulminant hepatic failure (FHF) was first recognized in 1973. Since then, few studies have described the clinical profile of the FHF patient with acute pancreatitis. Identification of the distinguishing attributes of pancreatitis in combination with FHF will provide a more sound basis for clinical management. The purposes of this study were to identify distinguishing clinical characteristics of acute pancreatitis in FHF and to compare outcomes with those of patients with acutely decompensated chronic liver disease and acute pancreatitis (DECOMP). Study Design: This was a retrospective survey of 30 patients with FHF and 30 with DECOMP admitted during the period July 1995 to July 1997. Results: The prevalence of acute pancreatitis in FHF and DECOMP was 33% and 23%, respectively. Acute pancreatitis was associated with severe hepatocellular synthetic dysfunction, renal insufficiency, requirement for endotracheal intubation, increased acuity of illness at the time of ICU admission, more rapid decompensation during the disease, and significantly greater mortality in both the FHF and DECOMP groups. Conclusions: In both FHF and DECOMP, acute pancreatitis increases disease acuity and mortality. Acute pancreatitis does not occur with significantly greater frequency in FHF. Implementation of orthotopic liver transplantation may not be warranted in this setting.

Hepatitis D virus (HDV) infection in severe forms of liver diseases in north India.

Preliminary reports indicate that hepatitis D virus (HDV) infection exists in India. However, its prevalence in patients with different types of liver diseases has not been studied in detail. The aim of this study was to evaluate the status of HDV infection in severe types of liver disease in India. Using commercial kits for various hepatitis viral markers, the present study was undertaken to determine the serological status of hepatitis B virus (HBV) and hepatitis D virus (HDV) markers in 208 patients with severe liver diseases. This total included 110 cases with fulminant hepatic failure (FHF), 65 cases with subacute hepatic failure (SHF) and 33 cases with chronic active hepatitis (CAH). The hepatitis B surface antigen (HBsAg) carrier population, indicated by the presence of HBsAg without IgM anti-HBc (hepatitis B core) in serum, was recorded in 23.6%, 24.6% and 60.6% cases of FHF, SHF and CAH groups, respectively. HBV infection, as indicated by serum positivity of IgM anti-HBc in the FHF and SHF groups and HBsAg and/or IgM anti-HBc in the CAH group, was detected in 19.1%, 23.1% and 69.7% of cases from these three groups, respectively. IgM anti-HDV, demonstrating active/recent HDV infection, was found in 8.1% cases of FHF and 9.2% cases of SHF patients. HDV as a superinfection in HBsAg carriers was noted in 4.5% and 4.6% cases, respectively of FHF and SHF groups. Similarly, HDV-HBV coinfection, diagnosed by simultaneous presence of IgM anti-HBc and IgM anti-HDV in the FHF and SHF groups, was recorded in 3.6% and 4.6% of cases from these two groups, respectively. In the CAH group, HDV infection was observed in 9.2% cases. HDV infection, recorded in less than 10% of patients with different liver diseases in India, seems to be an unimportant factor in inducing severe liver diseases in this country.