Kevin D. Mullen

Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon

We treated 10 patients who had chronic non-A,non-B hepatitis with recombinant human alpha interferon in varying doses (0.5 to 5 million units) daily, every other day, or three times weekly for up to 12 months. In 8 of the 10 patients, elevated serum aminotransferase levels decreased rapidly during therapy and eventually fell into the normal or nearly normal range. In two of these patients, the interferon therapy was stopped after four months, and in both cases, a prompt return of aminotransferase activities to pretreatment values occurred. Prolonged treatment was associated with a sustained improvement in aminotransferase levels; in three cases, biopsy specimens obtained after one year of therapy showed marked improvement in hepatic histology, even though low doses of alpha interferon had been used. These preliminary findings, although not adequately controlled, suggest that long-term, low-dose alpha interferon therapy may be effective in controlling the disease activity in some patients with chronic non-A,non-B hepatitis. A prospective controlled trial is now needed to assess the role of interferon therapy in this disease.

Randomized, controlled trial of recombinant human α-interferon in patients with chronic hepatitis B

Forty-five patients with chronic hepatitis B were entered into a randomized controlled trial of recombinant human alpha-interferon therapy. All patients had hepatitis B surface antigen in serum for at least 1 yr and had stable serum levels of both hepatitis B virus deoxyribonucleic acid and hepatitis B e antigen. During the 4-mo period of therapy, 10 of 31 (32%) treated patients and only 1 of 14 (7%) control patients became negative for serum hepatitis B virus deoxyribonucleic acid and deoxyribonucleic acid polymerase. All 10 patients who became negative for serum hepatitis B virus deoxyribonucleic acid subsequently had a marked improvement in serum aminotransferase activities and lost hepatitis B e antigen from serum, and 9 of them had improvement in liver histology. Comparison of responders to nonresponders indicated that female sex and a high initial level of serum aspartate aminotransferase correlated best with response to interferon therapy. These findings indicate that a 4-mo course of recombinant alpha-interferon can induce a remission in disease in approximately one-third of patients with chronic hepatitis B.

Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure

Three separate, but allosterically interacting, sites on the gamma-aminobutyric acid (GABA) supramolecular complex in the brain were pharmacologically blocked in rabbits with hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure to determine whether decreased GABAergic neurotransmission can ameliorate the syndrome of hepatic encephalopathy. Bicuculline (a GABAA receptor blocker), Ro 15-1788 (a benzodiazepine receptor antagonist), or isopropylbicyclophosphate (a chloride channel blocker) consistently induced a transient but unequivocal decrease in the clinical severity of the encephalopathy and also corrected the abnormal pattern of the visual evoked response associated with hepatic encephalopathy. Rabbits with hepatic encephalopathy exhibited increased resistance to the convulsive effects of bicuculline. In encephalopathies induced in rabbits by gamma-vinyl-GABA (an inhibitor of GABA catabolism) or diazepam (a benzodiazepine receptor agonist), abnormalities of the visual evoked response similar to those found in hepatic encephalopathy occurred and were corrected by bicuculline and Ro 15-1788, respectively. These findings suggest that in hepatic encephalopathy due to fulminant hepatic failure (a) there is increased GABAergic tone, (b) an amelioration of encephalopathy can be induced by blockade of GABA or benzodiazepine receptors, (c) benzodiazepine receptor antagonists may be of clinical value in the management of hepatic encephalopathy, and (d) an endogenous substance with GABA potentiating properties may be present in hepatic encephalopathy.

Hepatic encephalopathy: Application of visual evoked responses to test hypotheses of its pathogenesis in rats

A previous study of the patterns of visual evoked responses (VERs) in rats was interpreted as providing support for the synergistic neurotoxins hypothesis of the pathogenesis of hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF). In contrast, other studies of the patterns of VERs in rabbits with different encephalopathies were interpreted as providing support for the concept that increased GABA-ergic tone may contribute to the neural inhibition of HE due to FHF. To attempt to resolve the discordant findings in these studies, additional studies of VERs have been undertaken in rats. To induce increased tissue levels of ammonia, mercaptans and fatty acids which are found in HE due to FHF, carefully predetermined doses of urease, dimethyldisulphide and octanoic acid were administered. The (pre-seizure) encephalopathy induced by these three agents was associated with abnormalities of the VER waveform that were fundamentally different from the abnormalities of the VER waveform associated with HE due to thioacetamide-induced FHF. However, the VER waveform in this model of HE due to FHF resembled closely that associated with pentobarbital-induced encephalopathy. These findings are in satisfactory agreement with those in the previous analogous studies in rabbits. They do not provide support for the synergistic neurotoxins hypothesis of the pathogenesis of HE, but are entirely consistent with increased GABA-ergic tone contributing to the neural inhibition of HE due to FHF.

Randomized Controlled Trial of a Four Month Course of Recombinant Human Alpha Interferon in Patients with Chronic Type B Hepatitis

Chronic infection with hepatitis B virus (HBV) is major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma world-wide (1). No therapy has yet been proven to be of definite benefit in improving the natural outcome of this infection. The most promising modality of treatment for this condition has been prolonged courses of alpha interferon (IFNα) (2,3). Other agents have either not been successful in achieving the aims stated above or have resulted in unacceptable side effects (4,5). In pilot studies, treatment of chronic type B hepatitis with IFNα has been shown to result in a response rate of between 22–40% (6,7). We undertook a randomized controlled trial of a four month course of recombinant human IFNα (rIFNα) in patients with chronic type B hepatitis.

Quinine Hepatotoxicity: An Underrecognized or Rare Phenomenon?

Quinine-induced hepatic injury has been reported very rarely. We report a case involving a patient with an apparent hypersensitivity to quinine, manifested by a clinical syndrome mimicking a viral illness and a mixed hepatocellular-cholestatic liver injury pattern. We briefly review the unusual literature on this topic, which features many cases of hypersensitivity to the optical isomer of quinine, quinidine; yet, to our knowledge, there has only been one prior report of quinine hepatotoxicity.

Precipitation of overt encephalopathy in the portacaval shunted rat : towards the development of an adequate model of chronic portal systemic encephalopathy

Objective: To assess the feasibility of developing a model of overt portal‐systemic encephalopathy (PSE) in rats with a surgically constructed portacaval anastomosis (PCA). Design: The ability of increasing the load of nitrogenous substances in the gastrointestinal tract and/or further decreasing hepatocellular function to induce overt encephalopathy in rats with a PCA was determined. Methods: The load of nitrogenous substances in the gastrointestinal tract was increased by feeding a pure horse‐meat diet or by gavaging with blood. Partial hepatectomy and the induction of cirrhosis were used to decrease hepatocellular function further. The severity of encephalopathy was assessed using a neurobehavioural scale. Results: Overt encephalopathy was not induced in rats by a PCA alone, by a PCA plus a horse‐meat diet, by a PCA plus induction of cirrhosis, or by a PCA plus a 50% hepatectomy. Predominantly mild, but overt, encephalopathy was induced in rats with a PCA alone by gavaging with blood and a higher incidence of more severe overt encephalopathy was induced in rats with a PCA combined with either cirrhosis or partial hepatectomy by gavaging with blood. Although these models of PSE were associated in some instances with plasma ammonia concentrations about 25 times higher than normal, no seizures were observed. Conclusion: A syndrome that resembles overt PSE in humans can be induced in the rat with a PCA by further reducing hepatocellular function and also gavaging with blood. Although the rat with a PCA has been extensively used as a model in studies relating to the pathogenesis of PSE, a syndrome resembling overt PSE in humans cannot readily be induced in rats with a PCA.

Cortical benzodiazepine receptor binding in a rabbit model of hepatic encephalopathy: The effect of Triton X-100 on receptor solubilization

Increased benzodiazepine (BZ) receptor density has been reported in brains of rabbits with hepatic encephalopathy (HE) due to galactosamine (GalN)-induced fulminant hepatic failure (FHF). These data were generated using detergent-Triton X-100-treated neural membranes. While performing further studies it was noted that the increase in BZ receptor density was not demonstrable when Triton X-100 preparation was not employed. Accordingly the binding of [3H] flunitrazepam, a BZ ligand, to neural membranes from cortices of normal rabbits and rabbits with HE due to (GalN)-induced FHF was studied with and without detergent preparation. Scatchard plot analysis of the binding data indicated that when no detergent was employed, the apparent affinity and density of BZ receptors were similar for control membranes and membranes from animals in HE. BZ receptors from animals in HE were shown to be more resistant to solubilization by Triton than control membranes. These findings (a) afford a potential explanation for the apparent increase in density of BZ receptors in this model when Triton treatment of neural membranes is utilized and (b) suggest that recent evidence for increased GABAergic tone in the syndrome of HE is not dependent on an increased density of BZ receptors.

Hepatic Encephalopathy and Benzodiazepine Receptor Ligands

Benzodiazepine (BZ) receptor ligands interact with specific binding sites on the GABAA receptor/chloride channel complex on neurons in the central nervous system (CNS) (1) (Figure 1). Such ligands could contribute to or ameliorate hepatic encephalopathy (HE) if the supra-molecular complex itself is involved in this syndrome. The complex includes distinct receptors for BZ ligands and GABA, and a chloride ionophore on which there are binding sites for barbiturates and cage convulsants, such as Picrotoxin. Activation of the effector component of this complex, the chloride channel, is mediated by the binding of GABA to its receptor and is potentiated by the binding of a BZ agonist or a barbiturate to discrete loci on the complex. Activation induces conformational changes in the complex which result in opening of the chloride channel and hyperpolarization of the neuron (1) (Figure 1). This GABA-gated chloride ion conductance is the basis of GABA-mediated inhibitory neurotransmission or “GABAergic tone.”

Synaptic membrane complex carbohydrates in experimental hepatic encephalopathy

To evaluate further the status of synaptic plasma membranes (SPMs) in the brain in the syndrome of hepatic encephalopathy (HE) lipid- and protein-bound sialic acid and ganglioside and protein composition were investigated in SPMs from the brains of six rabbits with galactosamine-induced fulminant hepatic failure and five normal rabbits. HE was associated with no appreciable changes in the Chromatographic pattern of gangliosides or the concentration of protein-bound sialic acid, but the syndrome was associated with a 20% increase in lipid-bound sialic acid and, as assessed electrophoretically, an increase in the concentration of a protein with a molecular weight of about 70 kDa. Thus, changes in the composition of complex carbohydrates and protein in SPMs occur in a model of HE. The findings raise the possibility that nonhumoral factors, such as increased sialylation of glycolipids, contribute to the generation of abnormal neurotransmission in HE.