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.     

Comparison of the one-gram d-[14C]xylose breath test to the [14C]bile acid breath test in patients with small-intestine bacterial overgrowth

In twelve patients with culture-proven bacterial overgrowth of the small intestine, the ability of a newly-developed one-gram d-[14C]xylose breath test to detect bacterial overgrowth was compared to that of the [14C]bile acid breath test. All patients manifested excessive production of breath 14CO2 after the administration of one gram [14C]xylose, with 83% of the patients being abnormal within the first hour of testing. In contrast, during the [14C]bile acid breath test, four of the twelve patients had no period of excessive 14CO2 production (above the 95% confidence range of controls). Nutrient malabsorption (fat, cobalamin, xylose) was seen with both true-positive and false-negative bile acid breath tests. The one gram [14C]xylose breath test, utilizing a substrate with more predominant absorption in the proximal small intestine and which can be catabolized by Gram-negative aerobic bacteria, appears to have a greater degree of sensitivity and specificity than the bile acid breath test in detecting the presence of small-intestine bacterial overgrowth.     

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.     

Posttransplantation chronic hepatitis in fulminant hepatic failure

Non-A, non-B or seronegative hepatitis is the leading indication for liver transplantation in patients with fulminant hepatic failure (FHF). We examined protocol annual review liver allograft biopsy specimens in consecutive adult patients transplanted for FHF in an attempt to determine the extent of the histological changes. One hundred eleven biopsy specimens from 41 patients transplanted for fulminant seronegative hepatitis and 34 from a comparison group of 16 patients transplanted for other causes of FHF (11 paracetamol overdose, 2 idiosyncratic drug reaction, 3 Wilson's disease) were available. Specimens were analyzed using standard proforma without knowledge of the original diagnosis. Chronic hepatitis was present in 29 patients (71%) transplanted for fulminant seronegative hepatitis (23 mild, 3 moderate, and 3 severe) compared with 5 patients (31%, all mild) transplanted for other causes of FHF. Twenty-five patients (61%) grafted for seronegative FHF had fibrosis (13 mild, 9 moderate, and 3 severe) in contrast to 4 fibrosis (25%) (all mild) in the comparison group. Excluding early allograft failure because of primary graft nonfunction or vascular complications, six patients with seronegative FHF required retransplantation (2 = chronic rejection; 1 = severe hepatitis with panacinar necrosis, resembling original liver; and 3 = chronic hepatitis with precirrhotic fibrosis and prominent cholestasis of unknown cause). One patient in the comparison group had a second graft (chronic rejection). Posttransplantation chronic hepatitis is more frequent and severe in patients transplanted for seronegative hepatitis. Graft survival may be adversely influenced by the development of chronic hepatitis, which may represent persistent or recurrent disease.     

Synthesis of UDP-N-[1-14C]acetyl D-glucosamine and UDP-N-[1-14C]acetyl-D-galactosamine from [1-14C]acetate

Procedures for the preparation of UDP-N-[1-14C]acetyl-D-glucosamine and UDP-N-[1-14C]acetyl-D-galactosamine with very high specific activities are described. The overall yield based on the amount of [1-14C]acetate used is greater than 80%. The N-acetyl-D-glucosamine-alpha-1-phosphate used in this synthesis is prepared by phosphorylation of tetraacetyl-D-N-acetylglucosamine with crystalline phosphoric acid. N-acetyl-D-glucosamine-alpha-1-phosphate is then deacetylated in anhydrous hydrazine with hydrazine sulfate as a catalyst. D-glucosamine-alpha-1-phosphate is N-acetylated with [14C]acetate using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling agent. The acetylated product is coverted to the UDP derivative with yeast UDP-N-acetyl-D-glucosamine pyrophosphorylase. UDP-N-[1-14C]acetylgalactosamine is prepared by acetylation of UDP-galactosamine using [1-14C]acetate and N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline. UDP-galactosamine is prepared enzymatically using galactokinase and galactose-1-phosphate uridyltransferase. The labeled products, isolated and characterized by ion-exchange and paper chromatography, were active as substrates in glycosyl transferase systems.     

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.     

Simultaneous assessments of exocrine pancreatic function by cholesteryl-[14C]octanoate breath test and measurement of plasma p-aminobenzoic acid

Two noninvasive tests for assessing pancreatic exocrine function, the cholesteryl-[14C]octanoate breath test and the HPLCN-benzoyl-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test, were simultaneously performed in nine patients with pancreatic exocrine insufficiency due to chronic pancreatitis and in nine healthy volunteers. 14CO2 output in breath and plasma PABA concentration rose slowly in patients but increased rapidly in healthy subjects. The measurement time giving the best discrimination between both groups was 120 min for the cholesteryl-[14C]octanoate breath test and 90 min for the plasma PABA test. At these points, both single-sample tests had essentially identical diagnostic sensitivity. The diagnostic sensitivities of the two single-sample tests were equal to that of the cumulative 6-h urinary PABA recovery and the cumulative 6-h urinary PABA/PAS ratio. We conclude that, for both the cholesteryl-[14C]octanoate breath test and the plasma PABA test, a single test sample is sufficient for rapid detection of impaired exocrine pancreatic function.     

Evaluation of [14C]aminopyrine breath test, peripheral clearance of [99mTc]EHIDA, and serum bile acid levels in liver function and disease

The purpose of this study is to evaluate the diagnostic value of the following tests in the assessment of patients with chronic liver disease (CLD) and cholestatic syndrome (CS): (1) aminopyrine breath test, measuring 14CO2 excretion in the expired air, (2) peripheral clearance of [99mTc]EHIDA, and (3) postprandial levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). The results indicate that: (1) 14CO2 2-hr excretion rate is a specific and sensitive marker of liver function, with good correlation with postprandial bile acid levels, [99mTc]EHIDA retention, and the conventional tests of serum albumin and prothrombin time. (2) Peripheral clearance and retention of [99mTc]EHIDA increased in both groups of CLD and CS vs controls, but it does not discriminate between the two. (3) Postprandial bile acids were elevated in CLD, particularly those of GCDCA, whereas GCA levels were significantly elevated in CS compared with CLD. This may be due to increased synthesis and entry into the blood. (4) The combination of [14C]aminopyrine breath test and postprandial levels of GCDCA enhance the diagnostic value, specificity, and sensitivity in the assessment of patients with CLD.     

Factor VII levels as a guide to prognosis in fulminant hepatic failure

Levels of clotting factors II, V, and VII were measured on admission and then daily in 12 patients with grade IV hepatic coma due to fulminant hepatic failure. Factor VII levels obtained within 36 hours of the development of grade IV coma were not of value in predicting which patients would subsequently recover consciousness. Four of the latter group had levels below 9% at this time while the levels in three of the seven fatal cases were higher. Serial determinations were of more value and levels rose rapidly in those patients who ultimately made a complete recovery.     

The incorporation of [14C]glucosamine into dolichol diphosphate N-acetyl[14C] glucosamine by unbroken liver cells in culture

Urinary testosterone and epitestosterone were assayed in 60 men: 7 normals and 53 patients with chronic prostatitis (of these 8 patients had prostatis free of complications, 45 had prostatitis with disturbances of generative and copulative functions). In 73.1% of patients considerable reduction of testosterone excretion was revealed. Reduction of testicular endocrine function is in direct correlative dependence on severity of clinical symptoms, duration of disease and form of chronic prostatis. Disturbances of genital hormone metabolism are of considerable importance in case of chronic prostatitis and its complications.     

Compartmentation of [14C]glutamate and [14C]glutamine oxidative metabolism in the rat hippocampus as determined by microdialysis

Metabolic compartmentation of amino acid metabolism in brain is exemplified by the differential synthesis of glutamate and glutamine from the identical precursor and by the localization of the enzyme glutamine synthetase in glial cells. In the current study, we determined if the oxidative metabolism of glutamate and glutamine was also compartmentalized. The relative oxidation rates of glutamate and glutamine in the hippocampus of free-moving rats was determined by using microdialysis both to infuse the radioactive substrate and to collect 14CO2 generated during their oxidation. At the end of the oxidation experiment, the radioactive substrate was replaced by artificial CSF, 2 min-fractions were collected, and the specific activities of glutamate and glutamine were determined. Extrapolation of the specific activity back to the time that artificial CSF replaced 14C-amino acids in the microdialysis probe yielded an approximation of the interstitial specific activity during the oxidation. The extrapolated interstitial specific activities for [14C]glutamate and [14C]glutamine were 59 +/- 18 and 2.1 +/- 0.5 dpm/pmol, respectively. The initial infused specific activities for [U-14C]glutamate and [U-14C]glutamine were 408 +/- 8 and 387 +/- 1 dpm/pmol, respectively. The dilution of glutamine was greater than that of glutamate, consistent with the difference in concentrations of these amino acids in the interstitial space. Based on the extrapolated interstitial specific activities, the rate of glutamine oxidation exceeds that of glutamate oxidation by a factor of 5.3. These data indicate compartmentation of either uptake and/or oxidative metabolism of these two amino acids. The presence of [14C]glutamine in the interstitial space when [14C]glutamate was perfused into the brain provided further evidence for the glutamate/glutamine cycle in brain.     

Effects of a meal on plasma clearance of [14C]glycocholic acid and indocyanine green in man

1. The fasting plasma disappearance curve of [14C]glycocholic acid after intravenous injection was compared in nine normal subjects with that obtained 100 min after a standard liquid test meal. 2. Plasma disappearance curves of indocyanine green were determined in 13 normal subjects under the same conditions. 3. Plasma clearances were significantly increased after the meal for both [14C]glycocholic acid (median 455 ml min--1 m--2, range 376--672 increased to 704, 528--1968; P less than 0.01) and indocyanine green (359, 227--473 increased to 435, 358--985; P less than 0.01). 4. Median initial volume of distribution was unaltered, but in four subjects it was greatly increased after the meal, although no alteration in plasma volume, measured with Evans blue dye, was observed. 5. The increased postprandial plasma clearance of glycocholic acid is probably due to an increase in liver blood flow, and suggests that in health this part of the enterohepatic circulation of bile acids also varies with meals.     

Liver transplantation for fulminant hepatic failure in the pediatric patient

BACKGROUND: Small-bowel transplantation is an alternative to home parenteral nutrition (HPN) in patients with gut failure. Our aim was to report the indication, diagnosis, morbidity, mortality, and intestinal adaptation in the total cohort of Danish patients receiving HPN at any time during the 5 years between 1 January 1991 and 31 December 1995. The data were analysed against the option of transplantation. RESULTS: HPN was given to 129 patients; 59 (46%) had inflammatory bowel disease (15% died), 26 (20%) had cured cancers (42% died), and 44 (34%) had other diseases (dysmotility, surgical complications, infarcts, and so forth; 27% died). Of these, 60% were new in the HPN program, but only 19% received HPN all 5 years; 31 % had terminated HPN, 19% permanently, and 25% died. Only four deaths were HPN-related. In December 1995, 73 patients were receiving HPN in Denmark, for a prevalence of 13.9 per million, which is the highest in Europe but 10-fold lower than in the United States. CONCLUSIONS: Gut failure was the only indication for HPN in Denmark. Weight loss without gut failure, such as disseminated cancer and acquired immunodeficiency syndrome, was not an indication for HPN. Survival after small-bowel transplantation should be assessed against a sizeable mortality among candidates receiving HPN, and this depends on diagnosis and age. In an HPN population comparable with the Danish, a quarter is likely to die within a period of 5 years, a quarter will terminate HPN, and the others survive with HPN. Small-bowel transplantation can be a lifesaving procedure in the small fraction of foreseeable HPN-related deaths, mainly caused by liver failure. Transplantation will not improve survival in most adult HPN patients, and only an improved quality of life after transplantation justifies this procedure in most HPN patients.     

Disposition of [14C]avitriptan in rats and humans

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans. The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans. Renal excretion was a minor route of elimination in both species, with the majority of the dose being excreted in the feces. After a single oral dose, urinary excretion accounted for 10% of the administered dose in rats and 18% of the administered dose in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats. Avitriptan was extensively metabolized after oral administration, with the unchanged drug accounting for 32% and 22% of the total radioactivity in plasma in rats and humans, respectively. Plasma terminal elimination half-life was approximately 1 hr in rats and approximately 5 hr in humans. The drug was extensively distributed in rat tissues, with a tendency to accumulate in the pigmented tissues of the eye.     

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.     

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.