Early indicators of prognosis in fulminant hepatic failure

The successful use of orthotopic liver transplantation in fulminant hepatic failure has created a need for early prognostic indicators to select the patients most likely to benefit at a time when liver transplantation is still feasible. Univariate and multivariate analysis was performed on 588 patients with acute liver failure managed medically during 1973-1985, to identify the factors most likely to indicate a poor prognosis. In acetaminophen-induced fulminant hepatic failure, survival correlated with arterial blood pH, peak prothrombin time, and serum creatinine--a pH less than 7.30, prothrombin time greater than 100 s, and creatinine greater than 300 mumol/L indicating a poor prognosis. In patients with viral hepatitis and drug reactions three static variables [etiology (non A, non B hepatitis or drug reactions), age less than 11 and greater than 40 yr, duration of jaundice before the onset of encephalopathy greater than 7 days] and two dynamic variables (serum bilirubin greater than 300 mumol/L and prothrombin time greater than 50 s) indicated a poor prognosis. The value of these indicators in determining outcome was tested retrospectively in a further 175 patients admitted during 1986-1987, leading to the construction of models for the selection of patients for liver transplantation.     

Prognostic factors for fatal outcomes prior to receiving liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure

BACKGROUND AND AIM: Many patients continue to die due to the rapid development of cerebral edema and/or multiple organ failure prior to receiving a liver transplantation. METHODS: We investigated the prognostic factors associated with 1-week fatal outcomes after the diagnosis of fulminant hepatic failure, which were associated with fatal outcomes prior to receiving liver transplantation, in 104 patients with non-acetaminophen-related fulminant hepatic failure. RESULTS: With a multivariate logistic regression analysis, age (>40 years), systemic inflammatory response syndrome (SIRS) and plasma prothrombin activities (40 years), cause of fulminant hepatic failure (viral hepatitis), plasma prothrombin activity (相似文献   

Inhibitors of hepatic DNA synthesis in fulminant hepatic failure

In certain etiological groups of patients with fulminant hepatic failure, poor survival may be due to lack of liver regeneration.In vitro experiments have shown that fulminant hepatic failure serum is cytotoxic to rabbit hepatocytes and inhibits DNA synthesis on short-term incubation with isolated regenerating rat hepatocytes. When fulminant hepatic failure serum is injected into partially hepatectomized rats at the time of maximal DNA synthesis, [³H]thymidine incorporation into hepatic DNA is reduced significantly. The effect is greater with sera obtained from patients with fulminant hepatic failure due to non-A, non-B hepatitis or an adverse drug reaction and is associated with a<10,000-dalton fraction. No stimulation of DNA synthesis is observed with injection of the >10,000-dalton serum fraction into normal rats. In preliminary experiments, no increase in epidermal growth factor production has been found in liver failure. Overall, the substances present in fulminant hepatic failure serum appear to be inhibitory rather than stimulatory for liver cell regeneration.Presented at the Proceedings of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Systemic inflammatory response syndrome strongly affects the prognosis of patients with fulminant hepatitis B

Background Hepatitis B virus infection is the most frequent cause of fulminant hepatic failure. Recently, systemic inflammatory response syndrome has been reported to be important in patients with fulminant hepatic failure. However, prognostic factors for fulminant hepatitis B have not been fully examined. In this study, we analyzed prognostic factors for fulminant hepatitis B in order to accurately identify patients with fatal outcomes. Methods Of 110 consecutive patients with fulminant hepatic failure, 36 (33%) were diagnosed with fulminant hepatitis B. Five of the 36 patients received liver transplants, and we analyzed prognostic factors associated with fatal outcomes in the other 31 patients, who consisted of 15 men and 16 women with a median age of 45 (range, 20–74) years. Results Eleven patients (35%) survived without liver transplantation, and the remaining 20 (65%) died. Nonsurvivors were older and had a higher prevalence ratio of systemic inflammatory response syndrome than survivors. Treatments were similar between survivors and nonsurvivors. Using a multivariate Cox proportional hazard model, age (>45 years), systemic inflammatory response syndrome, and ratio of total to direct bilirubin (>2.0) were associated with fatal outcomes. In particular, 1-week and overall survival rates of patients with systemic inflammatory response syndrome at the time of diagnosis were 39% and 8%, respectively, while those of patients without systemic inflammatory response syndrome were 94% and 56%, respectively. Conclusions Systemic inflammatory response syndrome strongly affects the short-term prognosis of patients with fulminant hepatitis B, and patients with systemic inflammatory response syndrome might need urgent liver transplantation.     

Elevated Resistive Index in the Hepatic Artery as a Predictor of Fulminant Hepatic Failure in Patients with Acute Viral Hepatitis: A Prospective Study Using Doppler Ultrasound

To assess the sensitivity and specificity of the resistive index of the hepatic artery, which is related to the vascular resistance of the artery, for the prediction of fulminant hepatic failure, we performed Doppler ultrasonography examinations on the hepatic arteries of 72 patients with acute viral hepatitis (25 of whom developed fulminant hepatic failure and 47 of whom recovered without developing fulminant hepatic failure) as well as the hepatic arteries of age- and sex-matched controls. The mean resistive index of the hepatic arteries in patients who developed fulminant hepatic failure was significantly larger than that of patients who recovered without developing fulminant hepatic failure (P < 0.01). When a resistive index cutoff level of 0.74 was used, an 84% sensitivity and a 94% specificity were obtained for the prediction of fulminant hepatic failure. An elevated resistive index of the hepatic artery may be useful for predicting the patient's clinical outcome and determining the need for a liver transplantation in patients with acute viral hepatitis.     

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.     

Prevalence of TT virus in patients with fulminant hepatic failure in Japan

A novel virus (TT virus) was isolated from patients with posttransfusion hepatitis of unknown etiology. We studied the prevalence of TT virus in 26 patients with fulminant hepatic failure without risk factors, including blood transfusion, and also examined 106 healthy blood donors as controls. We assayed serum TT virus DNA by seminested polymerase chain reactions and also examined the genotypes of this virus. Serum was obtained at admission from patients with fulminant hepatic failure. Serum samples at admission from seven (27%) of the 26 patients were positive for TT virus DNA. There were no differences in clinical findings, duration from onset to coma, or results of laboratory tests in patients with and without TT virus DNA. However, all 7 patients with TT virus died, whereas 9 of the 19 patients without TT virus died. The outcome for patients with fulminant hepatic failure and TT virus was significantly worse than for patients without the virus (P = 0.0227). TT virus was also detected in 29 (27%) of the 106 healthy blood donors. The genotype of the TT virus was mainly 1a in both groups. There were no differences in the rate of positivity and the genotypes of TT virus between patients with fulminant hepatic failure and healthy blood donors. TT virus infection may not cause severe hepatitis, such as fulminant hepatic failure, but it may indicate a poor outcome in such patients. Received: September 14, 1998 / Accepted: May 28, 1999     

Serological markers in fulminant hepatitis B.

Serological markers for hepatitis B virus infection have been examined in 34 patients with acute hepatitis B, 17 of whom developed fulminant hepatic failure. Hepatitis B surface antigen concentrations were significantly lower and hepatitis Be antigen was less frequently detectable in patients with fulminant hepatic failure compared with those with acute hepatitis (median 0.64 micrograms, range 16-0 and median 32 micrograms and range 100-4 micrograms respectively, p less than 0.001; HBeAg detected in 12% and 88% respectively, p less than 0.001). The IgM component of hepatitis B core antibody was significantly higher in the patients with fulminant hepatic failure with median values of 500 IU/ml compared with those with uncomplicated hepatitis (median 202 IU/ml, p less than 0.05 Wilcoxon's rank test). Three patients who developed a fulminant course had detectable levels of either anti-HBs or anti-HBe. These results are consistent with enhanced antibody responses to all three hepatitis B virus antigens and more rapid clearance of the latter during fulminant hepatic failure.     

TT virus infection in patients with fulminant hepatic failure

OBJECTIVE: A new DNA virus, which has been designated the TT virus, was discovered in 1997. It is not clear whether TT virus is a cause of any of the types of hepatitis. We conducted a case-control study to test the hypothesis that the presence of TT virus is a necessary condition for the development of fulminant hepatic failure in people who have non-A, -B, or -C hepatitis. METHODS: We studied 55 patients with fulminant hepatic failure [28 men, 27 women, mean (+/- SD) age, 47 +/- 15 yr], 32 patients with acute hepatitis (18 men, 14 women, mean age, 38 +/- 15 yr), and 200 healthy subjects (106 men, 94 women, mean age, 42 +/- 14 yr). TT virus DNA was detected in sera by a nested polymerase chain reaction using a primer set for genotype 1. RESULTS: TT virus was more frequently detected in patients with fulminant hepatic failure [in 33 of 55 (60%); 95% confidence interval (CI), 47-73%] than in those with acute hepatitis [in 8 of 32 (25%); 95% CI, 10-40%; p = 0.0016] or in healthy subjects [in 50 of 200 (25%); 95% CI, 19-31%; p < 0.0001]. TT virus was detected at a significantly higher rate in non-A, -B, or -C fulminant hepatic failure [in 18 of 22 (82%); 95% CI, 66-98%] than in fulminant hepatic failure of A, B, or C type [45%, 28-62%, 15/33; p = 0.007] or in non-A, -B, or -C acute hepatitis [24%, 3-44%, 4/17; p = 0.0003]. The logistic regression analysis selected TT virus (p = 0.0009), age (p = 0.0116), and etiology (p = 0.0309) as independent variables associated with fulminant hepatic failure (coefficient of determination, 0.2335). CONCLUSIONS: TT virus comparatively plays a role in the pathogenesis of non-A, -B, or -C fulminant hepatic failure.     

Accurate prediction of fulminant hepatic failure in severe acute viral hepatitis: multicenter study

Background: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. Methods: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. Results: In the retrospective study, we established the following discrimination equation: Z = −0.89 + 1.74 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. Conclusions: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis. Received: September 4, 2001 / Accepted: May 31, 2002 Acknowledgments. Supported by a grant from the Ministry of Health and Welfare of Japan. Reprint requests to: M. Yoshiba     

Levels of the human hepatocyte growth factor in serum of patients with various liver diseases determined by an enzyme-linked immunosorbent assay.

We have found a hepatotrophic factor in plasma or sera of patients with fulminant hepatic failure and have purified human hepatocyte growth factor from plasma of these patients. In this study we developed an enzyme-linked immunosorbent assay with high specificity and sensitivity for human hepatocyte growth factor in human serum. This assay for serum human hepatocyte growth factor is a sandwich method consisting of three steps. The standard curve for human hepatocyte growth factor appeared to be linear in the range of 0.20 to 12.50 ng purified human hepatocyte growth factor/ml (2.35 to 147 pmol/L). The assay took about 4 hr. Serum human hepatocyte growth factor values in patients with fulminant hepatic failure measured by enzyme-linked immunosorbent assay showed a strong positive correlation with that by bioassay using rat hepatocytes in primary culture. The mean value of serum human hepatocyte growth factor for 30 normal subjects was 0.24 +/- 0.12 (S.D.) ng/ml; that for 23 patients with fulminant hepatic failure was 8.06 +/- 1.76 (S.E.M.) ng/ml- greater than 30 times greater than the mean value for normal subjects. Serum human hepatocyte growth factor levels in patients with acute hepatitis, chronic hepatitis and cirrhosis were found to be slightly higher than those in normal subjects, but only the increase in serum human hepatocyte growth factor of acute hepatitis patients was statistically significant. The enzyme-linked immunosorbent assay for serum human hepatocyte growth factor should prove useful for serum human hepatocyte growth factor level measurement in patients with various liver diseases.     

A double-blinded,randomized trial of hydrocortisone in acute hepatic failure

The Acute Hepatic Failure Study Group (AHFSG) has conducted a double-blinded, randomized evaluation of hydrocortisone in patients with acute hepatic failure. From July 1975 through August 1978, a 38-month period, 18 medical centers in the United States and one in Canada participated in this trial. A total of 64 patients were accessed and found eligible to participate in the study; two of them were subsequently eliminated from our analysis. Eighteen patients received placebo; 23 received 400 mg hydrocortisone per day, and 21 patients were administered 800 mg hydrocortisone per day. We did not observe any therapeutic effect of hydrocortisone, and the survival rates for placebo versus 400 mg and versus 800 mg hydrocortisone per day were 22%, 9%, and 24%, respectively. Fulminant hepatitis associated with drug hepatotoxicity or non-A, non-B hepatitis seemed to have a worse prognosis than fulminant B, although these differences were not significant. Serum -fetoprotein had a modest prognostic value of survival and seemed to be limited to fulminant B. The AHFSG recommends, therefore, that corticosteroid use in acute hepatic failure with hepatic encephalopathy be discontinued.Supported in part by grants from the National Institute of Health (HL-23420 and CA-30209)     

Evaluation of liver function for the application of preoperative portal vein embolization on major hepatic resection

BACKGROUND/AIMS: Although preoperative portal vein embolization has been employed for hepatectomy to increase the safety of the surgery, patient selection criteria for hepatectomy following portal vein embolization have still not been established. In this study liver functional tests before and after portal vein embolization were evaluated in order to determine their influence on the outcome of subsequent hepatectomy and the prognostic potential of this approach. METHODOLOGY: Forty-five patients, who had undergone major hepatic resection after embolizing the right portal branch, were divided into the following 3 groups according to their postoperative course: complication(-), complication(+), and liver failure group. Clinical, analytical, and hemodynamic parameters obtained before and after portal vein embolization were compared between the three groups. RESULTS: Significant differences were found between the complication(-) group and the liver failure group for 8 factors, and statistically significant cut-off points distinguishing the liver failure group could be determined. Based upon values measured before PVE these were: 1) portal pressure > 16 cmH2O; 2) pre-PVE serum cholinesterase < 160 U/L; 3) pre-PVE serum hyaluronate > 130 ng/mL. Based on values measured after PVE they were: 1) a hypertrophic ratio of the left lobe < 1.21; 2) post-PVE ICGR15 (%) > 16%; 3) a portal pressure measured immediately after PVE > 25 cmH2O; 4) post-PVE serum cholinesterase < 160 U/L; 5) post-PVE serum hyaluronate > 160 ng/mL. Discriminant function analysis in a stepwise manner showed that the portal pressure and serum levels of hyaluronate measured before and after portal vein embolization were the most useful in prediction of the outcome of the following hepatectomy. CONCLUSIONS: Patients whose data match the above criteria before portal vein embolization should be excluded as candidates for major hepatic resection with portal vein embolization. Even after portal vein embolization in patients whose data match post-portal vein embolization criteria major hepatic resection may have to be abandoned, or the extent of the hepatic resection reconsidered.     

Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators.

The value of coagulation factor V and VIII/V levels as prognostic indicators was assessed in 27 patients with fulminant hepatic failure and compared with other predictive indices. Admission factor V levels were significantly reduced in 22 patients with paracetamol induced hepatic failure compared with a healthy control group (median 9.5% v 103%, respectively; p less than 0.001) and with lower values in non-A non-B hepatitis (median 2.7%). Values in the seven patients who died after paracetamol overdose, considered together with the four who underwent liver transplantation (group median 5.1%), were significantly lower than in the 11 who survived (median 11.8%; p less than 0.01). Median admission factor VIII was higher in those who died or received a transplant than in those who survived (298% v 162%; p less than 0.05), with both results higher than in healthy volunteers (median 104%; p less than 0.01) but lower than in non-A non-B hepatitis (median 340%). The ratio of factor VIII/V on admission was less than 30 in all patients who survived paracetamol overdose (median 17) with corresponding values greater than 30 in 10 of 11 of those who died (median 39). A factor V result less than or equal to 10% on admission predicted an adverse outcome in 10 of 11 fatal cases, a 91% sensitivity which was greater than for the previously defined indicator of an arterial blood pH less than 7.30 on admission (sensitivity 82%). Prothrombin time at admission or on day 4 did not usefully predict outcome in our series. Predictive accuracy was 73% and 82% for factor V and admission acidosis respectively and 95% for factor V in conjunction with admission coma grade III or IV and factor VIII (ratio > 30). These criteria may be useful in selecting patients with paracetamol induced fulminant hepatic failure for transplantation.     

Fulminant hepatic failure caused by ecarazine hydrochloride (a hydralazine derivative)

The cause of fulminant hepatic failure is reported to be unknown in more than half the cases in Japan. We recently reviewed 23 cases of fulminant hepatic failure that had been treated at our hospital. The cause of disease had been regarded as unknown before this study. It was found that seven of these patients had been under ecarazine hydrochloride therapy when they developed fulminant hepatic failure. We examined the reasons why fulminant hepatic failure in these seven patients had not been previously attributed to ecarazine, and found that it could be explained by the following factors: (1) the time from the start of ecarazine therapy to the onset of hepatic failure was long; (2) in all cases, hepatic failure developed more than 10 days after the clinical recognition of hepatitis; and (3) characteristic signs of drug-induced hepatic failure such as a skin rash and positive lymphocytes stimulation test with the drug were absent in all cases. Fulminant hepatic failure in these cases could be characterized by: (1) rapid decrease in serum alanine transaminase (ALT) level after discontinuation of ecarazine, (2) prolonged jaundice despite discontinuation of ecarazine, (3) high incidence of anti-nuclear antibody (ANA) (57%), and (4) histological findings of extensive hepatocellular necrosis ranging from bridging necrosis to massive necrosis. Of the seven patients, four died of fulminant hepatic failure. These four patients had received high doses of ecarazine hydrochloride for prolonged periods. Our data suggest that there may be many cases in which the cause of fulminant hepatic failure or acute hepatitis was not previously determined that can be attributed to long- term drug therapy for chronic diseases. (Hepatology 1996 Mar;23(3):465-70)     

Fulminant hepatitis and the new G/GBV-C flavivirus

A new virus within the family Flaviviridae, 'hepatitis' G/GBV-C, has been incriminated by several authors as a causative factor of idiopathic or cryptogenic fulminant hepatitis, a syndrome of presumed viral aetiology. Review of worldwide data from 22 studies on 364 cases indicates that G/GBV-C infection is present in approximately 20% of idiopathic cases but a similar or even higher prevalence is detected in fulminant hepatitis of viral B, D or C aetiology, reflecting a high rate of parenteral viral exposure rather than a specific aetiology of fulminant hepatic failure. An aetiopathogenic role of G/GBV-C in fulminant hepatitis seems to be further refuted by the analysis of other data in the literature. The presence of G/GBV-C infection in fulminant hepatic failure is largely a result of secondary infection or coinfection. The aetiopathogenetic mystery of cryptogenic or idiopathic fulminant hepatitis remains unsolved.     

Galactose elimination capacity as a prognostic index in patients with fulminant liver failure.

In 25 patients with fulminant hepatic failure the prognostic value of a quantitative liver function test, the galactose elimination capacity, was assessed and comapred with routine liver function tests and clinical features. The galactose elimination capacity was significantly higher (P less than 0-05) in the five patients who survived than in the 20 patients who died. None of the other liver function tests, was significantly different. The values of the galactose elimination capacity overlapped considerably between survivors and non-survivors, but all patients with a galactose elimination capacity below 12-8 mumol galactose/min and kg body weight died. The disease among most patients who died having a galactose elimination capacity greater than 13 mumol ran a subacute course. It is suggested that quantitative liver function tests be included when new treatments of fulminant hepatic failure are investigated.     

Fulminant Hepatic Failure in an African Setting: Etiology, Clinical Course, and Predictors of Mortality

This is prospective cross-sectional study on 37 patients presenting to different hospitals in Khartoum state, Sudan, sought to determine the etiology, clinical course, and predictors of mortality in patients presenting with fulminant hepatic failure (FHF). Patients were subclassified into hyperacute, acute, and subacute FHF; all sera were tested for hepatitis A, B, C, and E; negative samples were tested for antinuclear antibodies and anti-smooth muscle antibodies. The commonest etiologic factors included seronegative hepatitis (38%), hepatitis B virus (22%), severe Plasmodium falciparum malaria (8%), autoimmune hepatitis (8%), hepatitis E virus (5%), anti-tuberculous drugs (5%), and lymphomatous infiltration of the liver (5%). The mortality rate was high at 84%. Poor prognostic factors included presentation with grade III/IV encephalopathy, evidence of bacterial infection, and a prolonged prothrombin time of >25 seconds over the controls.