Search

The aims of this study were to determine whether long-term oral administration of the opiate antagonist nalmefene is associated with any beneficial effects in patients with pruritus secondary to cholestatic liver disease and to assess the safety of long-term administration of this drug to these patients. Fourteen patients with unrelieved chronic pruritus of cholestasis were studied. Scratching activity, independent of limb movements, was recorded continuously for 24-hour periods before and during treatment with an initial ameliorating dose of nalmefene. Simultaneously, during these periods, visual analogue scores (VASs) of pruritus were recorded every 4 hours while patients were awake. The dose of nalmefene, which initially was 2 mg orally twice daily, was increased during the study, usually until a satisfactory clinical response was achieved. Five patients experienced a transient opioid withdrawal-like reaction that did not preclude continuing with nalmefene therapy. Serum biochemical indices of cholestasis did not change appreciably during treatment. Thirteen patients reported amelioration of the perception of pruritus on nalmefene. In 5 patients, exacerbations of pruritus occurred approximately 4 weeks after an initial ameliorating dose had been reached; these exacerbations were managed by increasing the dose. Baseline mean values for VAS and scratching activity were higher than corresponding means during nalmefene therapy in 13 (P = .002) and 12 (P = .013) patients, respectively. Possible tolerance to nalmefene occurred in 3 patients. Three patients experienced marked exacerbation of pruritus after nalmefene therapy was suddenly discontinued. Blood levels of nalmefene were consistent with normal pharmacokinetics of the drug. These results suggest that nalmefene may have a favorable risk-to-benefit ratio when it is administered orally long-term to patients with the pruritus of cholestasis.

Levels of benzodiazepine receptor ligands were measured in plasma samples from 25 patients in various stages of hepatic encephalopathy due to fulminant liver failure who were not exposed to pharmaceutical benzodiazepines immediately before or during hospitalization. Chromatographic analysis of extracted plasma samples revealed one to nine fractions containing material that competitively inhibited [3H]flumazenil binding to benzodiazepine receptors with the pharmacological properties of benzodiazepine receptor agonists. Two of these peaks were positively identified as the 1,4-benzodiazepines diazepam and N-desmethyldiazepam on the basis of chromatographic, ultraviolet and mass spectral evidence. The plasma levels of diazepam and N-desmethyldiazepam were significantly increased above control values in stage 4 hepatic encephalopathy, whereas total benzodiazepine receptor ligand concentrations were increased above control in stages 1 through 4. A significant but weak linear correlation was found between the relative increase in the levels of diazepam, N-desmethyldiazepam and total benzodiazepine receptor ligands and the severity of hepatic encephalopathy. Thus increased concentrations of benzodiazepine receptor ligands appear to contribute to the enhancement of GABAergic neurotransmission in hepatic encephalopathy, particularly in stage 4. These results constitute further support for a role for benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy associated with acute liver failure.

Endopeptidase 24.11 (enkephalinase), an enzyme known to be present in plasma and liver, is capable of metabolizing a substantial number of bioactive peptides. We measured plasma endopeptidase 24.11 activity in normal subjects and in patients with chronic hepatocellular disease or chronic cholestatic liver disease. The mean level of plasma endopeptidase 24.11 activity was 13 times higher in cholestatic patients than in controls or patients with hepatocellular disease (p < 0.01). Plasma endopeptidase 24.11 activity in patients correlated closely with traditional serum markers of cholestasis, including levels of alkaline phosphatase, gamma-glutamyltranspeptidase and aminopeptidase (p < 0.01 for all). However, plasma endopeptidase 24.11 activity correlated poorly with serum ALT aminotransferase level (p = NS), indicating that it is not a marker of hepatocellular disease. The lack of overlap between plasma endopeptidase 24.11 activity in cholestatic patients and noncholestatic liver disease controls suggests that this enzyme activity is a useful biochemical marker of cholestasis. In addition, because of the broad spectrum of peptides metabolized by endopeptidase 24.11, increased plasma endopeptidase 24.11 activity may contribute to the pathophysiology of the syndrome of cholestasis.

The blood-brain-barrier plays an essential role in regulating the entrance of substances into the brain. To date, permeability of the blood-brain barrier has not been studied in models of cholestatic liver injury, although levels of substances known to enhance vascular permeability (bile acids, substance P, histamine) are elevated in cholestasis. Two rat models of cholestasis were studied: bile duct resection (5 days after surgery) and alpha-naphthylisothiocyanate treatment (45 mg/kg/day for 7 days). The mean value for whole brain blood-to-brain transfer constant in bile duct resection rats was about 50% less than corresponding values in sham-operated and unoperated control rats (p < or = 0.05, respectively). Reductions in blood-to-brain transfer constant of similar magnitude were found in the caudate nuclei, cortexes and hippocampi of bile duct-resected rats. Blood-to-brain transfer constant values in alpha-naphthylisothiocyanate-treated rats were also about 50% less in whole brain and specific brain regions than corresponding control values. A precedent for a decrease in blood-to-brain transfer constant is the dexamethasone-treated rat, in which the phenomenon has been attributed to a decrease in cerebral capillary endothelial cell membrane fluidity. We confirmed that blood-to-brain transfer constant values are reduced by about 50% in dexamethasone-treated rats. A decrease in membrane fluidity affords a rational explanation for a decrease in blood-to-brain transfer constant in cholestasis as a consequence of the dynamic equilibrium between elevated plasma levels of cholesterol in cholestasis and cell membranes exposed to the circulation.

We report a patient with concurrent superficial carcinomas of the esophagus and stomach. The tumors occurred in a 68-year-old woman. The esophageal tumor was an intramucosal squamous cell carcinoma, and the gastric tumor an intramucosal adenocarcinoma, type III in the Japanese classification of early gastric cancer. This is the first reported case of associated superficial esophageal and gastric cancers originating from a Western country. Such an association may be more frequent than realized, and therefore it is important to examine both the stomach and esophagus if a patient has one of these tumors.

Symptomatology and objective findings of Sjögren's syndrome were evaluated in 38 consecutive patients with primary biliary cirrhosis. Symptoms of Sjögren's syndrome were present in 18 (47.4%) patients, but were severe enough to warrant therapy in only four (10.5%). Nineteen patients consented to evaluation for Sjögren's syndrome, which included Schirmer's I test, measurement of parotid flow rate and serum autoantibodies, labial minor salivary gland biopsy and human leukocyte antigen typing. Histological changes diagnostic of Sjögren's syndrome were present in five patients (26.3%). All five patients had symptoms of Sjögren's syndrome and three had abnormal Schirmer's I tests, but none had corneal ulcerations or decreased parotid flow rates. Results of serological tests and human leukocyte antigen typing were not similar to those described in patients with primary Sjögren's syndrome but were similar to those described in patients with rheumatoid arthritis and Sjögren's syndrome. These findings indicate that Sjögren's syndrome associated with primary biliary cirrhosis is a form of secondary Sjögren's syndrome resembling that associated with rheumatoid arthritis.

Behavioral and electrophysiological evidence implicating the GABA-benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy was obtained using an improved rat model of hepatic encephalopathy caused by thioacetamide-induced fulminant hepatic failure. After the administration of thioacetamide together with supportive therapy, acute hepatocellular failure developed in rats as a result of massive hepatocellular necrosis without evidence of renal failure or hypoglycemia. The evolution of hepatic encephalopathy in this model was sufficiently slow to readily permit the staging of the syndrome. Prominent features of the encephalopathy include a marked reduction in open field activity and an abnormal visual evoked response. Both the deficits in spontaneous motor function and visual evoked response abnormalities of rats in stages III to IV hepatic encephalopathy were significantly improved after the administration of the benzodiazepine receptor ligands flumazenil or Ro 15-4513. Doses of flumazenil or Ro 15-4513 that produced these effects in rats with hepatic encephalopathy had no detectable action on either the behavior or the visual evoked responses of normal rats. The ability of benzodiazepine receptor ligands to ameliorate both the behavioral depression and the visual evoked response abnormalities associated with hepatic encephalopathy in the thioacetamide-induced rat model suggest an involvement of the GABA/benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy. In addition, the similarity of these observations to those in rabbits with hepatic encephalopathy caused by galactosamine-induced fulminant hepatic failure is compatible with the hypothesis that the mechanisms of hepatic encephalopathy in these two distinct models share a common final pathway, the allosteric enhancement of GABAergic tone through the benzodiazepine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

gamma-Aminobutyric acid (GABA) is a potent inhibitory neurotransmitter which is synthesized by the enteric bacterial flora and delivered into portal venous blood. To determine whether the liver is likely to play an important role in regulating serum GABA levels, the uptake and metabolism of [3H]GABA by three populations of cells isolated from rat liver were studied. GABA was specifically taken up by hepatocytes but not by endothelial or Kupffer cells. Uptake by hepatocytes was saturable, as well as time and sodium dependent. At 0.5 degrees C, a temperature at which binding of GABA to the cell surface is considered to be the predominant component of the uptake process, the apparent affinity constant (Km) was 0.82 microM and a minimum value for binding velocity (Vmax) was 0.13 microM per min per 5 X 10(5) cells. Uptake of [3H]GABA by hepatocytes was markedly inhibited by excess unlabeled GABA (95%), alpha-aminoisobutyric acid (66%) and bicuculline (58%), but was inhibited much less by alanine (16%) and leucine (29%). These findings suggest that GABA binds specifically to the high affinity acceptor of the A amino acid transport system of rat hepatocytes. Impaired function of this transport system in liver failure could contribute to increased circulating levels of GABA.

Monooctanoin, a cholesterol gallstone solvent, has been gaining wide acceptance as an effective safe agent for dissolving retained common bile duct stones when infused into the biliary tract. A woman with choledocholithiasis who received infusions of this agent into the biliary tract on three different occasions developed systemic side effects on each occasion. The severity of the side effects necessitated discontinuation of monooctanoin therapy.

We have studied five long-term survivors of allogeneic bone marrow transplantation. All exhibited prolonged serum biochemical evidence of hepatic dysfunction during 2- to 5-year periods of follow-up. Two patients developed chronic cholestasis without pruritus. The serum of a third patient became chronically positive for HBsAg. A fourth patient developed an acute hepatic syndrome and high titers of antibody to cytomegalovirus. Nuclear, mitochondrial, and smooth muscle antibodies were not detected. Seven liver biopsies, obtained from three of the patients, all revealed a hepatocellular necroinflammatory lesion suggestive of chronic active hepatitis, a paucity of interlobular bile ducts, and intrahepatic cholestasis. Possible etiologies for these hepatic changes include reactivation of chronic non-A, non-B hepatitis and chronic graft-versus-host disease per se. Our study emphasizes the diagnostic problems posed by hepatic dysfunction occurring in an immunosuppressed multiply-transfused patient after bone marrow transplantation.

To complement analogous studies using conventional ligand-membrane binding assays, the densities of gamma-aminobutyric acid and benzodiazepine receptors in the brain have been assessed using an autoradiographic technique in an animal model of hepatic encephalopathy. Hepatic encephalopathy due to fulminant hepatic failure was induced in rabbits by the intravenous injection of galactosamine. The specific binding of three radiolabeled ligands was assessed densitometrically in several microregions of cerebral cortex, hippocampus and cerebellum. [3H]Muscimol was used to assess gamma-aminobutyric acid receptor density and [3H]flunitrazepam or [3H]Ro 15-1788 was used to assess benzodiazepine receptor density. No significant differences were observed between the magnitude of binding of the three ligands to each of the microregions of brain from control rabbits and rabbits in Stage III or IV hepatic encephalopathy. These findings suggest that the behavioral expression of hepatic encephalopathy in the model studied is not dependent upon an increase in the number of gamma-aminobutyric acid or benzodiazepine receptors, but do not conflict with the hypothesis that gamma-aminobutyric acid-ergic tone is increased in hepatic encephalopathy.

To determine whether abnormalities of lymphocyte function in primary biliary cirrhosis are due to altered function of immunoregulatory T cell subpopulations, phenotypic and functional characteristics of CD4+ T cells were examined. The proportion of CD4+ T cells expressing the Leu-8 and CD45R antigens was normal in patients with primary biliary cirrhosis. The capacity of CD4+, Leu-8- T cells to provide helper function for pokeweed mitogen-stimulated immunoglobulin synthesis by B cells in vitro was similar in patients and controls. However, in contrast to normal individuals and patients with other liver diseases, CD4+, Leu-8+ T cells from six of 10 patients with primary biliary cirrhosis did not suppress, but enhanced immunoglobulin synthesis. Whereas treatment of CD4+ T cells from normal individuals with anti-Leu-8 monoclonal antibody enhanced their suppressor function, similar treatment of CD4+ T cells from patients with primary biliary cirrhosis did not increase their suppressor function. To determine whether the abnormal regulatory function of CD4+, Leu-8+ T cells was due to a defect of cell activation, the proliferative response of CD4+ T cell subpopulations to mitogenic stimulation was examined. The proliferative responses of CD4+, Leu-8- T cells from patients with primary biliary cirrhosis and controls were similar, but the proliferative responses of CD4+, Leu-8+ T cells from patients with primary biliary cirrhosis were lower than those of control cells.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a patient with advanced primary biliary cirrhosis associated with Sjögren's syndrome, xanthelasma, and extensive, painful xanthomata involving cutaneous lipid deposits on her face, abdomen, hands, and buttocks and extensor surfaces over many joints. Despite conventional dietary and drug therapy, these lesions progressed rapidly over 3 years. There was symptomatic improvement of the xanthomata, but no objective amelioration of the xanthomatosis with the use of plasmapheresis over an 18-month period. Liver transplantation was undertaken for decompensated chronic liver disease and poor quality of life due to complications of xanthomatosis. Twelve months after transplantation, all xanthomata and xanthelasma and symptoms attributable to xanthomata had disappeared. Liver transplantation is a drastic but successful remedy for complications of abnormal lipid metabolism associated with primary biliary cirrhosis.

The status of the excitatory glutamatergic neurotransmitter system in hepatic encephalopathy has been studied. Synaptic membranes (SM) were prepared from the brains of normal rabbits, hyperammonemic normal rabbits, and rabbits with fulminant hepatic failure. Data on the specific binding of glutamate to SM indicated that fulminant hepatic failure was associated with a decrease in the number of glutamate receptors on SM from cerebral cortex, cerebellum, and particularly the hippocampus, without any associated change in the affinity of these receptors. In contrast, hyperammonemia was associated with an increase in the affinity and no decrease in the number of glutamate receptors on SM from the hippocampus. These findings indicate that the effects of hyperammonemia and fulminant hepatic failure on cerebral glutamate receptors are fundamentally different. The decreased number of glutamate receptors in hepatic encephalopathy might reflect a decreased sensitivity of glutamatergic neurons to glutamate-mediated neural excitation, a phenomenon that could contribute to the neural inhibition of hepatic encephalopathy.

The antiviral drug, acyclovir, has been used in the treatment of chronic type B hepatitis. High serum concentrations of acyclovir are required to achieve inhibition of hepatitis B viral replication. Because only 15 to 20% of an oral dose is absorbed, it is necessary to administer acyclovir by intravenous infusion. 6-Deoxyacyclovir, an analog of acyclovir, is well absorbed when given orally, and is converted to acyclovir by xanthine oxidase which is present in the gut and liver. This study has examined the hepatic disposition of 6-deoxyacyclovir in a 100 ml recirculating (12 ml per min) perfused rat liver system. Following administration of a bolus dose of 5 mumoles 6-deoxyacyclovir to the reservoir, perfusate concentrations of 6-deoxyacyclovir declined monoexponentially, as the metabolite acyclovir appeared in the perfusate. Addition of the xanthine oxidase inhibitor allopurinol (5 mg) to the perfusate reservoir prior to the administration of 6-deoxyacyclovir resulted in impaired hepatic metabolism of 6-deoxyacyclovir, as demonstrated by a 47% reduction in systemic clearance rate (4.5 +/- 0.4 to 2.4 +/- 0.9 ml per min; p less than 0.05) (mean +/- S.E., n = 6) and a 1.8-fold increase in terminal elimination half-life of 6-deoxyacyclovir (23.5 +/- 2.7 to 42.7 +/- 4.1 min; p less than 0.05), accompanied by a 30% reduction in appearance of acyclovir. The efficient hepatic conversion of 6-deoxyacyclovir to the active antiviral drug, acyclovir, provides a rationale for trials of oral 6-deoxyacyclovir in the treatment of chronic type B hepatitis.

It has previously been shown in an animal model of hepatic encephalopathy (HE) that the number of receptors for the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), increases and that the number of receptors for the excitatory neurotransmitter, glutamate, decreases. To determine the functional status of other neurotransmitter systems in HE, measurements were made of the specific binding of other neurotransmitters to synaptic membranes prepared from the brains of normal rabbits and rabbits in HE due to galactosamine-induced acute liver failure. The development of HE was associated with: (i) a decrease in the density (Bmax) of receptors for the two excitatory amino acid neurotransmitters, aspartate and kainic acid; (ii) an increase in the Bmax of both the low and high affinity binding site for strychnine, a marker for the inhibitory neurotransmitter glycine; (iii) a decrease in the affinity (Kd) of receptors for dopamine, and (iv) no appreciable change in either the specific binding of [3H]D-ala2-methionine enkephalinamide or [3H]naloxone, markers for opiate receptors, or in the Bmax or the Kd of receptors for acetylcholine. If it is assumed that the sensitivity of the brain to neurotransmitters varies directly with the density of neurotransmitter receptors, HE may be associated with increased sensitivity to inhibitory amino acid neurotransmitters and decreased sensitivity to excitatory amino acid neurotransmitters. Thus, the observed changes in neurotransmitter receptors in HE afford a feasible pathophysiological basis for the mediation of the neural inhibition of HE.

Six patients with chronic type B hepatitis were treated with adenine arabinoside 5'-monophosphate at a dosage of 10 to 15 mg per kg per day for 10 days. All demonstrated an immediate and marked decrease in serum hepatitis B virus DNA and DNA polymerase, and 5 of the 6 became negative for both markers by the end of the period of therapy. One patient remained negative for hepatitis B virus DNA and DNA polymerase when therapy was discontinued. This patient subsequently exhibited clinical, serum biochemical, and histological remission in disease activity concurrent with seroconversion from hepatitis B e antigen to antibody. In the remaining five patients, serum hepatitis B virus DNA and DNA polymerase returned to pretreatment values soon after therapy was stopped, and these patients demonstrated no significant changes in clinical, biochemical, serological, or histological features of the disease. Side effects of the therapy were mild and transient. These results suggest that a 10-day course of adenine arabinoside 5'-monophosphate is not adequate to induce permanent amelioration of infection and disease activity in the majority of patients with chronic type B hepatitis.

Peripheral blood mononuclear cells from 7 patients with primary biliary cirrhosis and 7 healthy control subjects were studied for their ability to produce antibodies to mitochondrial antigens in vitro. Peripheral blood mononuclear cells were collected by lymphapheresis and cultured with or without pokeweed mitogen for 10 days. The culture supernatants were then tested for antibodies to mitochondrial antigens by both immunofluorescence microscopy and a microtiter ELISA. Peripheral blood mononuclear cells from 5 of 7 patients with primary biliary cirrhosis but from none of the healthy controls produced antibodies to mitochondrial antigens spontaneously (without pokeweed mitogen stimulation). In contrast, peripheral blood mononuclear cells from 6 of 7 patients with primary biliary cirrhosis and from 6 of 7 control subjects synthesized detectable levels of antibodies to mitochondrial antigens after stimulation with pokeweed mitogen. In general, peripheral blood mononuclear cells from the primary biliary cirrhosis patients produced higher titers of antibodies to mitochondrial antigens in culture than cells from healthy controls. Furthermore, the antibodies to mitochondrial antigens reactivity produced by peripheral blood mononuclear cells of primary biliary cirrhosis patients exhibited a specificity for the M2 mitochondrial antigen which is present on the inner membrane of mitochondrial cristae and which is closely associated with a mitochondrial ATPase activity. In contrast, the antibodies to mitochondrial antigens reactivity produced by peripheral blood mononuclear cells of healthy controls appeared to be directed at a broader range of mitochondrial antigens. These findings indicate that, inpatients with primary biliary cirrhosis, there is a marked expansion of B lymphocyte clones that produce an antibody to a specific mitochondrial antigen.