Management of fulminant hepatic failure

There has been considerable public concern that emissions from intensive livestock farming may have hazardous effects on human health, particularly on the respiratory system. From October 1991 to September 1992, data on consultations of asthmatic children (up to 8 years) were obtained by a network of 25 GP and paediatric practices in South Oldenburg, a region with one of the highest livestock densities in Germany. Comparable data from a similar network of 75 practices in 3 adjacent regions (Brunswick, Hanover, Verden) with average livestock density served as a reference. In South Oldenberg, 2084 consultations of 542 asthmatic children were observed, with asthma being the reason for visit in 734 of the contacts (36%). The boy-girl ratio was 2.1:1 among index patients and 1.9:1 among consultations. Consultation rate was 25.2 contacts by asthmatic children per 1,000 total consultations of children up to 8 years in South Oldenburg, compared to 17.8 per 1,000 in Hanover, 15.7 per 1,000 in Brunswick and 13.6 per 1,000 in Verden. Consultations due to asthma scored 11.2/1,000 in South Oldenburg, 10.8/1,000 in Hanover, 7.2/1,000 in Brunswick and 6.5/1,000 in Verden. Asthmatic patients in South Oldenburg were younger (mean age 38 vs. 42 months) than those observed in the reference regions. There were no regional patterns in sex ratio, severity of asthma, respiratory allergies or atopic dermatitis. As this is an ecological study design, inferences concerning the cause of the observed regional differences can only be weak. We therefore propose a case-control study in order to obtain exposure and health data on an individual level.     

Treatment of fulminant hepatic failure with intravenous prostaglandin E1

We studied 32 patients with the thickened lesions of the wall of the gallbladder by using dynamic MRI. We tried the differential diagnosis of gallbladder lesions according to the time intensity curve (TIC) and enhanced pattern. TIC of carcinoma was elevated more seeply from plain to arterial phase than the inflammatory diseases. The Inflammatory diseases were keeping three-layer structures of the wall of the gallbladder, but gallbladder carcinoma destroys the wall-structure. We could diagnose as direct liver invasion of the carcinoma clearly. We could exactly diagnose adenomyomatosis in dynamic MRI by small low intensity spots within the wall of the gallbladder. In the patients with gall stones, the wall of the gallbladder were more clearly observed in dynamic MRI compared with US and EUS.     

Early prognostic biochemical indicators of fulminant hepatic failure

This article reviews related studies from the authors' laboratory, which focus on the regulation of vascular Na+,K+-ATPase in hypertension. Earlier studies, including the authors', suggested that Na-pump activity in cardiovascular tissues is subject to regulation during hypertension; most of these studies report a stimulation of the vascular enzyme during established stages of hypertension. To test hypothesis that in vascular smooth muscle, strain resulting from elevated pressure may be a signal initiating a cascade of events leading to increased expression of Na+,K+-ATPase, the authors used cell culture and the Flexercell Strain Unit to apply cyclical stretch to rat aortic smooth muscle cells (ASMC) for several days. These studies demonstrated that mechanical strain induces the upregulation of both the alpha-1 and alpha-2 subunits of Na+,K+-ATPase. Mechanisms underlying these changes appear to involve a transient increase in intracellular sodium entering the cell through stretch-activated channels. Calcium entering the cell via L-type channels did not affect stretch-induced upregulation of the alpha isoforms. In addition, protein kinase C inhibition resulted in inhibition of the Na-pump during stretch, but not under nonstretch conditions. The authors conclude that the stretch component of vascular pressure upregulates the Na+,K+-ATPase catalytic subunits. Intracellular sodium may be a signal for this regulation. In addition, phosphorylation by PKC may be important in stretch-induced short-term regulation of the vascular Na-pump.     

Living-related liver transplantation and neurological outcome in children with fulminant hepatic failure

In vivo, endothelial cells (ECs) are subjected to a complex mechanical environment composed of shear stress, pressure, and circumferential stretch. The aim of this study was to subject bovine aortic ECs to a pulsatile pressure oscillating from 70 to 130 mm Hg (mean of 100 mm Hg) in combination with pulsatile shear stresses from 0.1 to 6 dyne/cm2 (1 dyne/cm2=0.1 N/m2) with or without a cyclic circumferential stretch of 4% for 1, 4, and 24 hours. The effect of highly reversing oscillatory shear stress (range -3 to +3 dyne/cm2, mean of 0.3 dyne/cm2) typical of regions prone to the development of atherosclerotic plaques was also studied at 4 and 24 hours. Endothelin-1 (ET-1) and endothelial constitutive nitric oxide synthase (ecNOS) mRNA expression was time and mechanical force dependent. ET-1 mRNA was maximal at 4 hours and decreased to less than static culture expression at 24 hours, whereas ecNOS mRNA increased over time. Pressure combined with low shear stress upregulated ET-1 and ecNOS mRNA compared with static control. Additional increase in expression for both genes was observed under a combination of higher shear stress and pressure. A cyclic circumferential stretch of 4% did not induce a further increase in ET-1 and ecNOS mRNA at either low or high shear stress. Oscillatory shear stress with pressure induced a higher expression of ET-1 mRNA but lower expression of ecNOS mRNA compared with unidirectional shear stress and pressure. We have shown that the combination of pressure and oscillatory shear stress can downregulate ecNOS levels, as well as upregulate transient expression of ET-1, compared with unidirectional shear stress. These results provide a new insight into the exact role of mechanical forces in endothelial dysfunction in regions prone to the development of atherosclerosis.     

Reduced serum Gc-globulin concentrations in patients with fulminant hepatic failure: association with multiple organ failure

OBJECTIVE: To evaluate the association between admission serum concentrations of the actin-scavenger, Gc-globulin, and the subsequent development of multiple organ failure in patients with fulminant hepatic failure. DESIGN: Retrospective study. SETTING: A hepatologic intensive care unit. PATIENTS: Seventy-nine patients with hepatic encephalopathy grade 3 or 4. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum admission concentrations of both total and nonactin-complexed (free) Gc-globulin were determined. The development of cardiovascular failure, renal failure, pulmonary failure, intracranial hypertension, and infections were recorded in each patient. Both total and free Gc-globulin values were significantly lower in the patients, compared with normal controls. The Gc-globulin values were significantly reduced in patients who subsequently developed cardiovascular failure (p < .01), intracranial hypertension (p < .001), and infections (p < .001), compared with those patients who did not. No differences were found between patients with and without pulmonary or renal failure. Patients with total Gc-globulin values in the lowest quintile had on average 2.6 organ failures, whereas patients with Gc-globulin concentrations in the highest quintile had 0.9 organ failures. The corresponding figures for the lowest and highest quintiles of free Gc-globulin were 3.0 and 1.1 organ failures, respectively. Both total and free Gc-globulin were inversely correlated to the number of organ failures (p < .005 in both cases). Patients with multiple organ failure (> or = 2 organ failures) had significantly reduced Gc-globulin values compared with patients without multiple organ failure (p < .0001). CONCLUSIONS: In patients with fulminant hepatic failure, the lowest admission Gc-globulin concentrations were associated with the subsequent development of cardiovascular failure, intracranial hypertension, and infections. Lack of Gc-globulin correlated significantly with the development of multiple organ failure and may be pathogenetically involved in this condition.     

The beneficial effects of ciprofloxacin on survival and hepatic regenerative activity in a rat model of fulminant hepatic failure

Recently, we reported that ciprofloxacin, an antimicrobial agent with gamma-aminobutyric acid (GABA(A)) receptor antagonist properties, significantly increases hepatic regenerative activity in animal models of alcohol-induced liver disease and cirrhosis. In the present study, we documented the effects of ciprofloxacin on survival and hepatic regeneration in a D-galactosamine (D-gal)-induced model of acute hepatic injury in rats. One hundred nineteen adult, male Sprague-Dawley rats (n = 19-20/group) were treated with intraperitoneal D-gal (total dose: 2.5 g/kg), followed by gastric gavage with either saline, ciprofloxacin (10, 50, or 100 mg/kg), norfloxacin (250 mg/kg), or intraperitoneal putrescine (300 micromol/kg), a potent hepatic growth promoter. Mortality rates were then documented over a 4-day period. An additional 45 rats (n = 15/group) received a sublethal dose of D-gal (1.0 g/kg), followed by gastric gavage with either saline or ciprofloxacin (100 mg/kg), or intraperitoneal putrescine (300 micromol/kg). In these rats, hepatic regenerative activity was documented at 12, 24, and 60 hours post-D-gal by 3H-thymidine incorporation into hepatic DNA and proliferating cell nuclear antigen (PCNA) staining. In the survival study, a dose-response effect of ciprofloxacin on survival was observed (ciprofloxacin: 10 mg/kg, 10%; 50 mg/kg, 26%; and 100 mg/kg, 35%) with the results in the 100-mg/kg-treated group being significant when compared with the 5% survival rate in saline-treated controls (P < .05). Survival figures in the norfloxacin- and putrescine-treated groups were not significantly improved (15% and 25%, respectively). In the regeneration study, compared with the D-gal + saline-treated control group, DNA synthesis rates at 60 hours were increased in the D-gal + ciprofloxacin and D-gal + putrescine groups (10.2 +/- 3.3 vs. 18.2 +/- 5.1 and 18.8 +/- 6.8 x 10(3) dpm/mg DNA respectively; P < .05). The results of PCNA staining also supported enhanced hepatic regeneration in the ciprofloxacin-treated group at 60 hours (saline, 13.4 +/- 3.7; ciprofloxacin, 47.4 +/- 7.3; and putrescine, 8.4% +/- 2.8% hepatocytes staining positive). Ciprofloxacin at a dose of 100 mg/kg significantly improves survival and hepatic regenerative activity in this animal model of acute hepatic injury.     

Detection of hepatitis C virus with RNA polymerase chain reaction in fulminant hepatic failure

The role of hepatitis C virus (HCV) infection in fulminant hepatic failure is controversial. The frequency of serum HCV RNA positivity in previously reported patients with fulminant hepatic failure (FHF) of indeterminate cause ranged from 0 to 12% in the United States and Europe and from 43% to 59% in Asia. We assessed serum HCV RNA using polymerase chain reaction (PCR) and oligoprimers from the 5'UTR of the HCV genome in 26 consecutive patients with FHF. Another laboratory independently performed PCR on 21 of the serum samples using different oligoprimers from the 5'UTR and NS3 region of the HCV genome. Serum HCV RNA was detected in two of seven (28%) patients with hepatitis B, 9 of 15 (60%) with an indeterminate cause, and in none with hepatitis A (n = 2) or drug-induced hepatotoxicity (n = 2). HCV RNA PCR results were concordant between both laboratories in 17 of 21 (81%) of samples. In patients with an indeterminate cause, HCV RNA positivity was significantly associated with the transmission risk factor of low socioeconomic status and Hispanic ethnicity. Eighteen patients underwent liver transplantation (LT) and 15 (83%) survived. Among patients with FHF of indeterminate cause, recurrent or acquired HCV infection after transplantation occurred in three of five (60%) and one of four (25%) patients, respectively. Three of four (75%) patients with hepatitis C virus infection post-LT also developed histologic hepatitis. HCV appears to be the causative agent of a substantial number of cases of FHF classified as indeterminate in the Los Angeles area. Differences in patient populations or risk factors may explain the discordant incidences of HCV infection in FHF observed among different programs.     

Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate analysis

Results of eight multicenter, randomized, placebo-controlled, double-blind, parallel-group studies were pooled to assess the efficacy of the angiotensin II-receptor blocker irbesartan over the dose range of 1 to 900 mg. A total of 2955 adults with a seated diastolic blood pressure of 95 to 110 mm Hg were randomized to treatment with oral irbesartan once daily or placebo for 6 to 8 weeks. Office blood pressure was measured at trough (24+/-3 hours after the last dose) and peak (3+/-1 hours after the last dose) by mercury sphygmomanometry. Demographic characteristics (mean blood pressure; 151/101 mm Hg; mean age, 54 years; 63% male; and 82% white) were similar across all dose groups. After the groups were pooled, antihypertensive efficacy was assessed by therapeutic response (trough seated diastolic blood pressure <90 mm Hg or a reduction from baseline of > or = 10 mm Hg) and by modeling of the maximum reductions in trough and peak seated diastolic and systolic blood pressure. Antihypertensive effects increased with increasing doses and reached a plateau at > or = 300 mg. Irbesartan 150 mg provided placebo-subtracted reductions in trough seated systolic and diastolic blood pressure of approximately 8 and approximately 5 mm Hg, respectively, with 56% of patients displaying a favorable response. In conclusion, irbesartan provides clinically significant blood pressure lowering, with a clear relationship between (log) dose and antihypertensive effect.     

Functional analysis of HBV genomes from patients with fulminant hepatitis

Two previous case reports suggest that hepatitis B virus (HBV) core promoter variants with a high replication competence contribute to the pathogenesis of fulminant hepatitis B (FHB). We recently found in HBV genomes from patients with FHB an accumulation of mutations within the core promoter region. Therefore, the aim of this study was to investigate the phenotype of these HBV variants. Replication competence and expression of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) of viral genomes from seven patients with FHB and one patient with fulminant recurrent hepatitis after liver transplantation were analyzed by transfection experiments in human hepatoma cells. Compared with wild-type virus, the HBV variants from the seven patients with FHB produced similar or slightly lower levels of intracellular replicative intermediates and extracellular viral particles. In contrast, the HBV genomes from the patient with fulminant recurrent hepatitis synthesized and secreted significantly more HBV DNA. All genomes tested expressed similar or even higher levels of HBeAg compared with wild-type virus, except for those from four patients with a precore stop codon mutation in the respective dominant viral populations. The level of HBsAg produced by all variant genomes was similar or reduced compared with wild-type virus. These data indicate that in some cases HBV variants with enhanced replication competence and/or a defect in HBeAg expression may contribute to the development of FHB. However, neither phenotype is an essential prerequisite; thus, an additional role of other viral or host factors in the pathogenesis of FHB is suggested.     

A case of non A, non B, non C hepatitis that relapsed into fulminant hepatic failure

We describe a 12 year-old patient that relapsed into fulminant non A, non B, non C (NANBNC) hepatitis 10 weeks post-clinical recovery. A complete clinical and pathological evaluation, including an ultra-structural examination of a liver biopsy was consistent with the diagnosis of NANBNC hepatitis. The patient relapsed into hepatic failure and required transplantation. NANBNC hepatitis may have a relapsing form that can lead to hepatic failure requiring transplantation. Consultants in hepatology should have a high degree of clinical awareness and maintain prolonged patient follow-up.     

The risk of transmitting HCV, HBV or HIV by blood transfusion in Victoria

OBJECTIVE: To report the incidence rate of hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV in Victorian repeat blood donors and to derive the residual risk of transmission of the viruses by screened blood transfusion. DESIGN: The interval from the previous whole blood donation was extracted retrospectively from Victorian Red Cross Blood Bank records for each of the 358332 repeat donations given between March 1994 and December 1995. Records of repeat donors found positive for the viruses in this period were traced to the previous seronegative donation and accepted if screened by the same test. For each virus, the number of previous donations screened by the same test was calculated and the sum of all donation intervals used to derive the incidence of infection in the repeat donor population. Published intervals after infection (when a donation can be infective although seronegative) were used to calculate the risk of release of a seronegative unit which would be infective. PARTICIPANTS AND SETTING: Homologous blood donors at the Red Cross Blood Bank of Victoria. MAIN OUTCOME MEASURES: Incidence rate of HBV, HCV and HIV in regular blood donors and risk of infective donations being seronegative. RESULTS: The incidence of infection in repeat donors was: HBV: 1.67 per 100000 person-years; HCV: 1.89 per 100000 person-years; and HIV: 1.31 per 100000 person-years. The risk of a seronegative repeat donation being infective was: HBV: 2.71 per million donations (adjusted to 6.45 to account for viraemias which remain seronegative); HCV: 4.27 per million donations; and HIV: 0.79 per million donations. CONCLUSION: The risk of transmitting HCV, HBV or HIV by repeat blood donors is low and compares favourably with overseas data. Repeat donors have an incidence rate of HIV and HBV comparable to that of the general population, but the incidence rate of HCV is lower for repeat donors than in the general population.     

A comparison between the Fick method and indirect calorimetry for determining oxygen consumption in patients with fulminant hepatic failure

OBJECTIVE: To compare the Fick method of determining oxygen consumption (VO2) with a gas exchange method in a group of patients in whom the cardiac output and mixed venous oxygen saturation values were consistently high. DESIGN: A prospective, observational study. SETTING: A ten-bed intensive therapy unit at a university teaching hospital. PATIENTS: Seventeen patients suffering from fulminant hepatic failure who required ventilatory support and invasive hemodynamic monitoring. All patients were sedated and paralyzed throughout the study period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VO2 was determined simultaneously by indirect calorimetry and by the Fick method five or six times in each patient over a 5-hr period after resuscitation with fluids and, if clinically indicated, norepinephrine infusion. The agreement between the methods was poor (limits of agreement +19 to -101 mL/min/m2) and the Fick method consistently underestimated gas exchange measurements (mean bias 41 mL/min/m2). The bias varied widely, both between and within individual patients. The reproducibility of the Fick-derived VO2 was worse than the indirect calorimetry measurements, indicating that the dispersion of data attributable to measurement error was greater with the Fick method. CONCLUSIONS: Under clinical conditions, the agreement between Fick calculations and indirect calorimetry measurements of VO2 in hyperdynamic patients with fulminant hepatic failure was extremely poor. The reproducibility of Fick calculations was less than the reproducibility derived by gas exchange measurements because of the large measurement errors that may occur with the Fick method when the cardiac output is large and the arterial-venous oxygen content difference is small. Fick calculations systematically underestimate gas exchange measurements. The Fick method is inaccurate and unreliable when an estimation of VO2 is required in patients with this hemodynamic pattern.     

Kinetics of [14C]cholic acid in fulminant hepatic failure: a prognostic test

The kinetics of intravenously injected [14C]cholic acid have been investigated in 14 patients with fulminant hepatic failure, 24 to 36 hr after the development of grade IV encephalopathy. Radioactivity was measured in plasma samples and in the individual plasma bile acid fractions after separation by thin layer chromatography. Plasma disappearance curves of the free [14C]cholic acid were calculated by an iterative nonlinear least squares fitting procedure using a computer. The disappearance of total plasma radioactivity was similar in all patients and greatly prolonged compared with healthy subjects. However, the plasma disappearance of free [14C]cholic acid was significantly faster in the 8 patients who recovered consciousness than in the 6 who did not. Plasma disappearance of free [14C]cholic acid correlated highly significantly with the proportion of conjugated [14C]cholate in plasma. All patients in whom more than 70% of plasma radioactivity was in the conjugated fraction 3 hr after injection survived and left hospital, whereas all of those in whom less than 55% was conjugated died. Measuring the percentage conjugation of [14C]cholate 3 hr after injection may therefore be a useful test of residual liver function in hepatic failure, as a guide to prognosis and in evaluating new forms of treatment.     

Seroprevalence of HBV, HCV and HDV hepatitis markers in 500 patients infected with the human immunodeficiency virus

The serological status for both hepatitis B, C and D viruses was analyzed for 500 HIV seropositive patients and for 1037 of a control group. The prevalence was 31.4% for anti HCV, 13.8% for HBs Ag and 69.0% for one or more HBV markers in HIV positive patients and respectively 2.5%, 2.7% and 13.1% in control group. The markers for hepatitis D were founded among 21% of the HBs Ag carriers (patients and control group), correlated with drug i.v. use. The prevalence of anti-HCV was 71.6% in subjects who had blood-borne HIV infection and 1.5% in those with sexually acquired infection. The prevalence in control group was 10.2% and 1.7% respectively according to the same risk factors. The prevalence of HBs Ag was higher among HIV positive patients with sexual risk (17.5%) than with blood exposition (9.9%) and a variation in the same direction is observed in control group (3% v.s. 1%). The relation between markers for hepatitis B and hepatitis C was negative.