Fulminant Hepatic Failure Patients Research Articles

Evaluation of hepatitis E antigen kinetics and its diagnostic utility for prediction of the outcomes of hepatitis E virus genotype 1 infection

ABSTRACT HEV-Ag ELISA assay is a reliable diagnostic test in resource-limited areas. HEV genotype 1 (HEV-1) infections are either self-limited or progress to fulminant hepatic failure (FHF) and death if anti-HEV therapy is delayed. Limited data is available about the diagnostic utility of HEV Ag on HEV-1 infections. Herein we aimed to study the kinetics of HEV Ag during HEV-1 infections at different stages, i.e., acute HEV infection, recovery, and progression to FHF. Also, we evaluated the diagnostic utility of this marker to predict the outcomes of HEV-1 infections. Plasma of acute hepatitis E (AHE) patients were assessed for HEV RNA by RT-qPCR, HEV Ag, and anti-HEV IgM by ELISA. The kinetics of HEV Ag was monitored at different time points; acute phase of infection, recovery, FHF stage, and post-recovery. Our results showed that the level of HEV Ag was elevated in AHE patients with a significantly higher level in FHF patients than recovered patients. We identified a plasma HEV Ag threshold that can differentiate between self-limiting infection and FHF progression with 100% sensitivity and 88.89% specificity. HEV Ag and HEV RNA have similar kinetics during the acute phase and self-limiting infection. In the FHF stage, HEV Ag and anti-HEV IgM have similar patterns of kinetics which could be the cause of liver damage. In conclusion, the HEV Ag assay can be used as a biomarker for predicting the consequences of HEV-1 infections which could be diagnostically useful for taking the appropriate measures to reduce the complications, especially for high-risk groups.

Prognostic, clinical, and therapeutic importance of RANTES-CCR5 axis in hepatitis A infection: A multiapproach study.

Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of the RANTES-chemokine receptor type 5 (CCR5) signaling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in silico, in vitro and patient cohort-based approach.In silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using real-time quantitative reverse transcription PCR (qRT-PCR), enzyme-linked immunosorbent assay, and flow-cytometry-based methods. In the HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5. The HAV-VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. Reduced monocyte and T-cell activation were observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with proinflammatory responses. Hyper Th1-biased immune responses, marked by high interleukin (IL)-12/IL-10 ratio were observed in FHF cases, which were also characterized by upregulated tumor necrosis factor-alpha (TNF-α) expression and reduced interferon-gamma expression. In vitro, RANTES was protective against HAV infection but resulted in upregulated TNF-α expression. Although viral load increased upon the regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV-infected cells. Our study suggests the importance of RANTES-CCR5 signaling and linked-immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk-reduction strategy in FHF patients. Our findings, therefore, have important implications for the management of high-risk HAV infections.

Up‐regulation of microRNA‐30b/30d cluster represses hepatocyte apoptosis in mice with fulminant hepatic failure by inhibiting CEACAM1

Recently, impacts of microRNAs have been unraveled in human diseases, and we aimed to confirm the role of miR-30b/30d in fulminant hepatic failure (FHF). Expression of miR-30b/30d and CEACAM1 in serum of FHF patients and healthy people was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Mice FHF models were established by injection of D-Galn and lipopolysaccharide, and were treated with miR-30b/30d mimics. Oxidative stress, liver injury, and inflammatory reaction in mouse liver tissues were measured using oxidative stress-related factor kits, hematoxylin-eosin staining and enzyme-linked immunosorbent assay, respectively. Moreover, cell cycle distribution and apoptosis of hepatocytes of mice were determined by flow cytometry, and the target relation between miR-30b/30d and CEACAM1 was confirmed by bioinformatic method and dual luciferase reporter gene assay. MiR-30b/30d expression was positively, and CEACAM1 expression was negatively related to prognosis of FHF patients. Up-regulation of miR-30b/30d attenuated oxidative stress, liver injury, and inflammatory reaction, and improved survival rate of FHF mice. Furthermore, elevated miR-30b/30d ameliorated apoptosis and cell cycle arrest of hepatocytes of FHF mice. CEACAM1 was a target gene of miR-30b/30d. This study highlights that up-regulated miR-30b/30d attenuates the progression of FHF by targeting CEACAM1, which may be helpful to FHF treatment.

Factors predictive of outcome before and after transplantation for fulminant hepatic failure

Objective: We aimed to evaluate prognostic factors for patients with fulminant hepatic failure (FHF) referred to liver transplantation (LT). Methods: We retrospectively studied 156 adult patients (82 female, mean age 37.73±15.84 y) with FHF referred to urgent transplantation at our Institution. Etiologies were virus in 15% of cases, drug-induced in 41%, autoimmune in 13%, cryptogenic in 27% and other in 4%. LT was indicated according to O'Grady criteria. Analysis of outcome after LT included deceased donor data. Results: Mortality rate before LT was 45%. At prioritization, non-survivors showed higher grade of encephalopathy (82.9% × 61.7%), creatinine (2.37±2.02 × 1.51±1.45 mg/dL) lactate (60.0±42.9 × 39.3±28.3 mg/dL), MELD (40.0±12.9 × 33.7±11.9), rate of kidney failure (80.0% × 46.1%), dialysis (37.5% × 18.0%) and cryptogenic etiology (41.7% × 19.6%) and less autoimmune hepatitis (4.17% × 17.8%) compared to survivors. Multiple logistic regression identified renal failure and INR as independent prognostic factors for death before LT. Cox model evaluating 30-day outcome after LT of 107 patients identified patients grade of encephalopathy, jaundice-encephalopathy interval, lactate, arterial pH and renal failure, and donor BMI, creatinine, sodium, glucose, AST, pH and DRI as possible factors of worse prognosis. Multivariate cox regression identified receptor lactate >41 mg/dL and arterial pH <7.368, and donor BMI >26.2 kg/m2, creatinine >0.68 mg/dL, glucose >42 mg/dL and AST >24 UI/L as independent indicators of mortality after LT (Figure). Conclusion: At prioritization to LT, FHF patients with a poor liver function condition associated to prolonged INR and renal impairment have higher chance of death before transplantation. On the other hand, survival after LT is associated to patient lactate levels and pH at prioritization and to donor obesity, levels of creatinine, glucose and AST.

The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies

Objective: Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies. Methods: Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations. Results: Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose. Conclusions: There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.

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.

Prognostic Value of Model for End-Stage Liver Disease Scores in Patients with Fulminant Hepatic Failure

BackgroundThis study was undertaken to investigate risk factors of mortality in patients with fulminant hepatic failure (FHF). MethodsFifty-three patients with FHF treated from January 2006 to April 2011 were allocated to a spontaneous survival group (group 1), a death without liver transplantation (LT) group (group 2), and an LT group (group 3). To analyze risk factors associated with mortality in FHF, we excluded group 3 patients. Clinical features, Model for End-Stage Liver Disease (MELD) scores, and King's College Hospital criteria at the time of hepatic encephalopathy in group 2 were compared with those of group 1. ResultsThe causes of FHF were acute viral infection (n = 29, hepatitis A:B, 28:1), drugs (n = 18; including 4 acetaminophen and 14 herbal medication), autoimmune (n = 4), and miscellaneous (n = 2). Of the 53 patients, 19 were allocated to group 1, 18 to group 2, and 16 to group 3. According to univariate analysis, risk factors for mortality in group 2 were acute renal failure requiring renal replacement therapy and a MELD score ≥30 at the time of hepatic encephalopathy. However, by multivariate analysis, a MELD score ≥30 was the only independent risk factor for mortality in group 2 (P = .042; hazard ratio, 4.500). ConclusionsA MELD score ≥30 was found to be the only independent risk factor of mortality in FHF patients without LT. Therefore, the findings of this study suggest that these patients may need emergent LT for survival.

Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion with human blood.

Patients in fulminant hepatic failure currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for such patients is the use of extracorporeal perfusion with porcine livers as a form of "liver dialysis". During a 72-h extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified porcine sialoadhesin expressed on Kupffer cells as the lectin responsible for binding N-acetylneuraminic acid on the surface of the hRBC. We evaluated whether blocking porcine sialoadhesin prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. Ex vivo studies were performed using wild type pig livers perfused with isolated hRBCs for 72-h in the presence of an anti-porcine sialoadhesin antibody or isotype control. The addition of an anti-porcine sialoadhesin antibody to an extracorporeal porcine liver xenoperfusion model reduces the loss of hRBC over a 72-h period. Sustained liver function was demonstrated throughout the perfusion. This study illustrates the role of sialoadhesin in mediating the destruction of hRBCs in an extracorporeal porcine liver xenoperfusion model.

Resection after preoperative chemotherapy or chemoradiation therapy for unresectable pancreatic cancer – Single center experience

A 29-year-old man was referred to our hospital with fulminant hepatic failure (FHF) and stage III hepatic coma (somnolence and confusion). Living donor liver transplantation (LDLT) was planned for 2 days after admission to our hospital. However, on the day after admission, he lapsed into stage IV hepatic coma: no right reflexes and no response to pain stimuli. Emergency cranial computed tomography revealed a subarachnoid hemorrhage (SAH), but no aneurysm was seen on magnetic resonance angiography. We speculated that the cause of the SAH may have been bleeding of intracranial veins secondary to coagulopathy and overextension of a vein due to brain edema. We considered that only LDLT could improve the coagulopathy and brain edema. The patient recovered consciousness on postoperative day (POD) 2 and was finally discharged from the hospital without neurological deficit on POD 85. This case suggested that SAH is not a prohibiting factor for LDLT in an FHF patient if the cause of the SAH is venous bleeding.

Therapeutic effects of blood purification in treatment of fulminant hepatic failure

ObjectivesTo evaluate the clinical effects of blood purification for treating fulminant hepatic failure (FHF). MethodsThirty-three severe FHF patients with hepatic encephalopathy (HE) above grade III were subjected to a combined blood purification treatment in addition to the comprehensive liver protection therapy. Patients underwent continuous hemofiltration on a daily basis during the daytime followed by sequential treatment with plasma exchange or hemodialysis every 2–3 days. The therapeutic effects of this treatment were evaluated. ResultsAfter treatment with blood purification, restoration of consciousness (those who abandoned the treatment without restoration of consciousness were excluded) was achieved in 6 of 8 cases (75%) in acute liver failure (ALF) group, 3 of 3 cases (100%) in subacute liver failure (SALF) group, and 9 of 14 cases (64.29%) in acute/subacute on chronic liver failure (A/SCLF) group. Of all cases, 11 patients restored consciousness after 7 days in a coma. The rate of long-term survival (those who abandoned the treatment were excluded) was 3/7 (42.86%) for ALF group, 2/2 (100%) for SALF group, and 1/11 (9.09%) for A/SCLF group. The levels of hemoglobin and platelet in peripheral blood were significantly reduced after blood purification. ConclusionsTreatment of FHF patients with daily continuous hemofiltration during the daytime is effective in treating HE and in improving health status in the early stages of the disease. Long-term prognosis also benefits from this treatment. The rate of consciousness recovery and long-term survival is highest in SALF group followed by ALF group. This treatment is less effective in A/SCLF patients. It should be noted that blood purification procedure may cause damage to blood cells.

Blocking Porcine Sialoadhesin Improves Extracorporeal Porcine Liver Xenoperfusion

Background: Patients in fulminant hepatic failure (FHF) currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for patients in FHF is the use of extracorporeal perfusion with porcine livers as a form of “liver dialysis”. During a 72 hour extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells (KC) bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified sialoadhesin (Sn) on the surface of porcine KC as the lectin responsible for binding N-acetylneuraminic acid (Neu5Ac) on the surface of the hRBC. In order for extracorporeal porcine liver perfusion to be used as a therapy for patients in liver failure, all forms of anti-human rejection must be resolved. We evaluated whether targeting Sn prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. Methods:In vitro experiments were performed wherein cultured porcine macrophages (pMΦ) were pretreated with the anti-porcine Sn monoclonal antibody, 1F1. pMΦ were subsequently assayed for their ability to bind hRBC. Next, ex vivo experiments were performed wherein six wild type pig livers were perfused with isolated hRBCs for 72 hours. In one group, three livers were treated with 1F1. As a control group, three livers were treated with an antibody of the same isotype but with no known specificity for Sn. Results: We have shown that treatment of cultured pMΦ with 10ug/ml of 1F1 abolishes the ability of the pMΦ to bind hRBC (p < 0.001). Additionally, we have shown that the addition of 1F1 to an extracorporeal porcine liver xenoperfusion model significantly reduces the loss of hRBC over a 72 hour period (p < 0.01). Sustained liver function was demonstrated by continued bile production and other markers. Conclusions: This study suggests that the destruction of human erythrocytes in an extracorporeal porcine liver xenoperfusion model is, in part, mediated by Sn expressed on the surface of porcine KC. Furthermore, this data illustrates that the addition of anti-Sn antibody to the circulation of a pig-to-human xenoperfusion may inhibit the destruction of human erythrocytes by porcine KC. Future studies should be conducted utilizing livers derived from Sn deficient pigs.

Early prognostic markers for fatal fulminant hepatic failure cases with viral hepatitis: Proton nuclear magnetic resonance spectroscopic studies of serum

BackgroundFulminant hepatic failure is associated with liver metabolic derangements which could have fatal consequences. The aim of the present study is to identify serum markers for early prediction of the outcome. MethodsProton nuclear magnetic resonance spectroscopic studies of serum of fulminant hepatic failure patients due to viral hepatitis with grade II/III of encephalopathy (twenty-four: ten prospective and fourteen retrospective) and twenty-five controls were undertaken. Of the twenty-four patients, fifteen survived with medical management alone while nine had fatal outcome. ResultsThe results demonstrated significantly elevated indices of amino acids (alanine, lysine, glutamine, histidine, tyrosine, phenylalanine and 1,2-propanediol) in fatal cases compared to survivors and controls. Principal component analysis showed clear separation of fatal and surviving cases. Liver function parameters were significantly deranged in patients but they failed to provide early significant differences between surviving and fatal cases. Compared to Model for End-stage Liver Disease scores, Principal Component Analysis appear to be better as an early prognostic indicator. Biochemical mapping of pathways suggested interruptions in amino acid metabolism and urea cycle. ConclusionsProton nuclear magnetic resonance studies of serum have the potential of rapidly identifying patients with irreversible fulminant hepatic failure requiring liver transplantation as life saving option.

Hepatitis E virus from India exhibits significant amino acid mutations in fulminant hepatic failure patients

In India, hepatitis E virus (HEV) is the predominant cause of acute viral hepatitis (AVH) and fulminant hepatic failure (FHF) among pregnant women and adults. The present study evaluates association, if any, of the mutations in the viral genome with disease outcome. Ten genotype-1 complete genomes (five each from AVH and FHF patients) were sequenced. Phylogenetic analysis showed a distinct cluster including all five FHF-HEV sequences from western India (present study), one FHF isolate from northern India, and one AVH isolate detected in 2010 (present study). HEV genotype-1 sequences from fulminant cases exhibited 150 significantly different (p≤0.05) nucleotide substitutions when compared to all genotype-1-AVH sequences as well as isolates from the Indian subcontinent. At six positions, all FHF sequences showed identical substitutions (1 non-synonymous). Six amino acid changes in ORF1; F179S, A317T, T735I, L1110F, V1120I, and F1439Y were significantly associated with HEV-type-1 FHF. The data suggests that the nucleotide substitutions recorded and/or L1110F and V1120I amino acid substitutions in helicase domain may play important role in determining outcome of HEV infection.

Potentiality of Immobilized Pig Hepatocyte Spheroids in Bioartificial Liver System

Various extracorporeal bioartificial liver (BAL) systems have been developed. To treat fulminant hepatic failure (FHF) patients. Direct cell-cell interaction is one of the major factors influencing the functions of cultured hepatocytes, which increase with progressing of cell aggregation in this study, we investigated the effects of plasma viability and function single and spheroid pig hepatocytes in vitro. Hepatocytes were cultured as spheroids by suspension culture in spinner flasks. We obtained pig plasma from animals in hepatic failure. Immobilized single pig hepatocytes exposed to the toxic pig plasma lost viability and liver function. However, immobilized pig hepatocyte spheroids showed stable ammonia removal functions and urea synthesis and lower lactate dehydrogenase, glutamine oxaloacetate transaminase, and glutamine pyruvate transminase levels during BAL operation. At 5 hours, the ammonia concentration in plasma decreased to 370 and 150 μg/dL by immobilized single and spheroid hepatocytes, respectively, the concentrations at which they were maintained thereafter. The urea concentrations in plasma were 44 versus 72 μg/dL in immobilized single versus spheroid hepatocytes respectively, at 5 hours of operation. Spheroid hepatocytes not only showed in vivo structure, but also maintained high levels of liver-specific functions. The spheroid-based BAL system may be a good candidate to treat FHF patients.

Activated lymphocytes and high liver expression of IFN‐γ are associated with fulminant hepatic failure in patients

To study immunological mechanisms of fulminant hepatic failure (FHF) derived from extensive liver lesions, 14 patients with FHF induced by different aetiologies were investigated by observance of both lymphocyte phenotyping and cytokine levels. Five patients bearing benign acute hepatitis B (AHB) and seven healthy liver donors (HC) were used as controls. Samples of liver and blood from both FHF patients and HC were obtained during transplantation procedures. Plasma levels of IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ, TNF-α, MCP-1, RANTES and MIP-1α were quantified using a multiplex immunoassay. Cell characterization was carried out by flow cytometry. IFN-γ staining was performed on liver sections using immunofluorescence methods. An increase of peripheral frequency of natural killer (NK) cells expressing early activation markers (CD69, HLA-DR and CD38) and adhesion molecule CD44 was observed in FHF patients. Elevated frequency of T lymphocytes CD4(+) and CD8(+) expressing CD38 and adhesion molecules CD29 and CD44 was also observed in FHF. Additionally, an increase of natural killer T cells (NKT) was detected in FHF patients. High plasma cytokine levels were not statistically different between FHF and AHB patients. In comparison to HC, a strong liver expression of IFN-γ was detected in FHF patients. The increased frequency of CD4(+) CD44(+) and IL-8 cytokine was found in patients with poor prognosis. These findings indicate the involvement of NK and NKT cells as well as T lymphocytes CD4(+) and CD8(+) in the inflammatory process inducing FHF, confirmed by the high hepatic expression of IFN-γ.

Molecular detection and sequence analysis of hepatitis E virus in patients with viral hepatitis from North India

Viral hepatitis is a major cause of mortality and morbidity in developing countries. Hepatitis E virus (HEV) is responsible for both sporadic and epidemic outbreaks of viral hepatitis in India. Here a total of 843 samples were collected: 685 from patients with acute viral hepatitis (AVH), 70 from patients with fulminant hepatic failure (FHF), 53 from patients with chronic liver disease (CLD), 11 from patients with antituberculosis therapy (ATT)–induced jaundice, and 24 from pregnant women. When tested for anti-HEV IgM, 58.3% of the pregnant women, 41.4% of the patients with FHF, 38.6% of the patients with AVH, 9.4% of the patients with CLD, and 18.2% of the patients with ATT-induced jaundice tested positive. We found that 34% and 16% of the acute hepatitis patients and fulminant hepatitis patients, respectively, showed no reactivity to the existing viral hepatitis markers and were thus grouped as non A to E. Among the HEV IgM–positive cases, males outnumbered females (62.8% versus 37.1%). HEV RNA was found in 35% of fulminant and 9.4% of acute hepatitis patients. From phylogenetic analysis, we observed that all the isolates were clustered within genotype 1. Critical analysis placed the acute isolates along with strains under subtype Ia, while the fulminant isolates clustered along with the FHF strain (X98292) under subtype Ic. The segregation of HEV isolates from AVH and FHF patients into different subtypes raises interesting questions on the molecular basis of HEV disease severity.

Ferritin/alanine aminotransferase ratio as a possible marker for predicting the prognosis of acute liver injury

Serum levels of ferritin and heme oxygenase (HO)-1 are both markers of macrophage activation. We evaluated simple markers for predicting the prognosis of severe acute liver injury in which macrophage activation plays an important role. Subjects comprised 114 patients with acute liver injury, admitted to the liver unit of Nagasaki Medical Center between January 2001 and September 2010. Subjects included 11 patients with fulminant hepatic failure (FHF), 82 patients with ordinary acute hepatitis (AH), and 21 patients with severe-form AH (AHS). We determined serum levels of ferritin, HO-1 and other biochemical makers, and analyzed relationships between clinical outcomes of patients and each of these parameters alone and in combination. Median serum ferritin levels were significantly higher in FHF (25900ng/mL) and AHS (3060ng/mL) than in AH (700ng/mL; P<0.01 each). Median HO-1 levels were also significantly higher in FHF (123ng/mL) and AHS (51ng/mL) than in AH (19ng/mL; P<0.01 each). Similarly, median ferritin/alanine aminotransferase (F/A) ratio was significantly higher in FHF (6.7) than in AHS (1.6, P<0.05) or AH (0.5, P<0.01). Among the 11 FHF patients, three recovered, seven died and one underwent liver transplantation. The ability of F/A ratio to distinguish non-survivors from survivors was analyzed using receiver operating characteristics curves. A cut-off level of 3.12 provided high sensitivity (87.5%) and specificity (81.2%). These results suggest that F/A ratio offer a quick and simple marker for predicting the prognosis of acute liver injury.

Serum levels of platelet‐derived growth factor‐BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure

In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF). Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls. Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050±1572 pg/mL vs 4521±2419 pg/mL vs 8506±5500 pg/mL, VEGF; 39±38 pg/mL vs 144±122 pg/mL vs 205±121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r=0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r=0.79), PT activity (r=0.37) and D.Bil/T.Bil ratio (r=0.50), while serum VEGF levels were significantly correlated with platelet counts (r=0.68) and PT activity (r=0.38). We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.

Viral Hepatitis in India: A Report from Delhi

Present study reports the etiological spectrum of viral hepatitis in different types of liver diseases in north India. Sera from a total number of 370 adult patients belonging to various liver diseases were analysed for different markers of hepatitis virus A, B, C, D and E infections. These sera were also tested to detect Torque Teno Virus (TTV) infection in them. The results of analysis show hepatitis A virus (HAV) infection to be rare with hepatitis B virus (HBV) and hepatitis C virus (HCV) as the predominant cause of acute and chronic liver diseases. Similarly, hepatitis E virus (HEV) infection is quite common in acute viral hepatitis (AVH) and fulminant hepatic failure (FHF) patients. Hepatitis D virus (HDV) infection could not be detected in these patients. TTV-DNA was detected in high proportions in all the disease groups. All types of viral hepatitis in these liver diseases have been discussed for various aspects.

A novel scoring system for prognostic prediction in d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure BALB/c mice

BackgroundIt is frequently important to identify the prognosis of fulminant hepatic failure (FHF) patients as this will influence patient management and candidacy for liver transplantation. Therefore, a novel scoring system based on metabonomics combining with multivariate logistic regression was developed to predict the prognosis of FHF mouse model.MethodsBALB/c mice were used to construct FHF model. Parts of plasma were collected at 4, 5, and 6-h time points after treatment, respectively, and detected using gas chromatography/time-of-flight mass spectrometry (GC/TOFMS). The acquired data were processed using partial least square discriminant analysis (PLS-DA). The metabolic markers identified were used to construct a scoring system by multivariate regression analysis.Results28 mice of survival group and 28 of dead group were randomly selected and analyzed. PLS regression analysis showed that both the PLS models of 5 h and 6 h after d-galactosamine/lipopolysaccharide treatment demonstrated good performances. Loadings plot suggested that phosphate, beta-hydroxybutyrate (HB), urea, glucose and lactate concentrations in plasma had the highest weightings on the clustering differences at the three time points. By the multivariate logistic regression analysis, the death/survival index (DSI) was constructed based on relative concentrations of HB, urea and phosphate. It provided general accurate rate of prediction of 93.3% in the independent samples.ConclusionsThe novel scoring system based on metabonomics combining with multivariate logistic regression is accurate in predicting the prognosis of FHF mouse model and may be referred in clinical practice as a more useful prognostic tool with other available information.