bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies on the Composition of the Mononuclear Cell Infiltrates in Liver From Patients With Chronic Active Delta Hepatitis
Authors: Chu Chia-Ming , Liaw Yun-Fan
Published: March 2007

To evaluate the immune process involved in the pathogenesis of liver cell damage in chronic hepatitis delta virus infection, a panel of monoclonal antibodies against pan T cells (Leu 4), inducer/helper T cells (Leu 3a+3b), suppressor/cytotoxic T cells (Lue 2a), B cell (Leu 12), monocyts/macrophages (Leu M3) and NK/K cells (Leu 7) was used to characterize the subsets of the mononuclear cell infiltrates in livers from 12 patients with chronic type D hepatitis, with special emphasis on the areas of periportal piecemeal necrosis and intralobular necrosis. A control group of 12 patients with chronic type B hepatitis was also studied for comparison. The results revealed that the livers from patients with chronic type D hepatitis showed a prominent mononuclear cell infiltration in portal/periportal and intralobular areas. Furthermore, the vast majority of the mononuclear cell infiltrates in liver were T cells, which constituted more than 80% of the cells in the areas of periportal piecemeal necrosis and intralobular necrosis and about 60% of the cells in the portal tract, whereas B cells, monocytes/macrophages and NK/K cells were relatively uncommon. Among T cell populations, the inducer/helper T cells were predominant in the portal tract, and, by contrast, the suppressor/cytotoxic T cells were predominant in the areas of piecemeal necrosis and intralobular necrosis. The distribution of the mononuclear cell subsets in relation to the different topographical areas of the liver in patients with chronic type B hepatitis was essentially the same as that observed in chronic type D hepatitis. Our findings therefore suggest that T cell–mediated immunity might play a role in the pathogenesis of chronic type D hepatitis, similar to that suggested for chronic type B hepatitis.
In Vitro Replication and Expression of Hepatitis B Virus From Chronically Infected Primary Chimpanzee Hepatocytes
Authors: Jacob James R. , Eichberg Jorg W. , Lanford Robert E.
Published: March 2007

Primary chimpanzee hepatocytes were maintained in vitro utilizing a serum–free medium. Hepatocyte functions were sustained throughout the culture period as demonstrated by the synthesis and secretion of liver–specific plasma proteins characteristic for differentiated hepatocytes. Hepatocyte cultures established from a chimpanzee chronically infected with human hepatitis B virus exhibited the synthesis and secretion of hepatitis B virus proteins into the medium. In addition, the de novo replication of hepatitis B virus was documented by the recovery of virus, exhibiting an endogenous DNA polymerase activity, from the tissue culture medium. Therefore, both the long–term maintenance of differentiated hepatocytes and the expression of hepatitis B virus from these primary cultures were sustained in the serum–free medium.
The Rat Liver Microcirculation in Alcohol–Induced Hepatomegaly
Authors: Mastaï Ricardo , Huet P.-Michel , Brault Antoine , Belgiorno Jocelyne
Published: March 2007

It has been suggested that hepatocyte enlargement can lead to compression of the extracellular space (sinusoidal and interstitial) and induce portal hypertension. However, this hypothesis has never been tested by measuring the vascular and extravascular spaces in the intact liver. The aim of the present study was to investigate the effects of chronic alcohol intake on the hepatic microcirculation using Goresky's multiple–indicator dilution technique in the isolated perfused rat liver. Female rat littermates were pair–fed either ethanol (n = 7) or an isocaloric carbohydrate diet (n = 7) for 21 days. As expected, chronic alcohol intake produced a significant increase in liver/body weight ratio (+32%, p < 0.01) and hepatocyte size (+45%, p < 0.001), which was accompanied by a marked increase in the cellular water space (control: 3.3 ± 0.6 ml; ethanol–fed: 4.9 ± 0.9 ml; p < 0.001). When expressing data per total liver, the sinusoidal space was similar in the two groups (control: 1.87 ± 0.2; ethanol–fed: 1.95 ± 0.2 ml; not significant), whereas the interstitial space was increased in alcohol rats compared to controls (albumin space +58%, p < 0.01; sucrose space +51%, p < 0.01). In alcoholic rats, the sinusoidal space was probably stretched, with an overall reduced transversal diameter, as suggested by the reduced values found when data were expressed per gm of liver weight. However, despite this finding and the enlargement of the liver and hepatocytes observed in alcoholic rats, similar values were obtained between the two groups for the portal perfusion pressure and thus the intrahepatic vascular resistance. The present data show that the enlargement of the liver and hepatocytes due to chronic alcoholic intake: (i) does not develop at the expense of the total vascular space and unexpectedly increases the interstitial space, and (ii) under our experimental conditions, does not modify the overall resistance of the liver.
A Multicenter, Randomized, Double–Blind Trial of Somatostatin in the Management of Acute Hemorrhage From Esophageal Varices
Authors: Valenzuela Jorge E. , Schubert Timothy , Fogel Ronald M. , Strong Richard M. , Levine Joel , Mills Peter R. , Fabry Thomas L. , Taylor Linda W. , Conn Harold O. , Posillico James T.
Published: March 2007

A prospective, randomized, placebo–controlled, double–blind, multicenter clinical trial of intravenous somatostatin (Stilamin®; Serono Laboratories, Inc., Randolph, MA) was performed in 102 patients with actively bleeding esophageal varices from August, 1985, to November, 1986. Patients had major hemorrhage indicated by hematemesis or melena and evidence of significant blood loss. For entry, patients had to have endoscopic demonstration of active bleeding from esophageal varices or stigmata of recent hemorrhage and bright red blood in the gastric aspirate with no other source of bleeding found. Randomized patients received identical appearing somatostatin or placebo for a 30–hr study period. Those given somatostatin received a 250–μg bolus and a 250–μg per hr infusion with repeat bolus and doubling of the infusion if the bleeding was not controlled. In retrospect, 18 patients could not be evaluated.

Of the 84 evaluable patients, 48 received somatostatin and 36 placebo. They were comparable in age, gender, severity of liver disease and history of variceal bleeding. Transfusion requirements were similar in both groups. Bleeding stopped for 12 consecutive hr during 30 hr of the study period in 31 (65%) of the somatostatin group vs. 30 (83%) of the placebo group (p = 0.06). The median time to cessation of bleeding was 2 hr in the placebo group and 3 hr in the somatostatin group. Deaths following the study period were nine (25%) in the placebo group and 15 (31%) in the somatostatin group. Within the limitations of the present study, we conclude that somatostatin was ineffective in the management of active bleeding of esophageal varices.
Pharmacokinetics of Benzodiazepine Antagonist Ro 15-1788 in Cirrhotic Patients With Moderate or Severe Liver Dysfunction
Authors: Pomier-Layrargues Gilles , Giguère J.-François , Lavoie Joël , Willems Bernard , Butterworth Roger F.
Published: March 2007

Ro 15-1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15-1788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score >10, Group II) and eight patients with severe liver dysfunction (Pugh score > 10, Group III). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15-1788 over 5 min, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15-1788 had a high plasma clearance [16.3 ± 2.6 ml per min per kg (mean ± S.D.)], a short half–life (45.7 ± 8.5 min), a large volume of distribution (0.62 ± 0.09 liter per kg) and a low plasma protein binding (45 ± 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (–57 and -74%, respectively); the volume of distribution was unchanged in Group II and moderately increased in Group III (+37%). The elimination half–life was markedly prolonged in Groups II and III (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p < 0.001). The plasma protein binding of Ro 15-1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group II; +44% in Group III). These findings emphasize the need for adjustment of Ro 15-1788 dosage in cirrhotic patients, particularly in those with severe liver failure.
Rejection in Liver Transplantation
Authors: Klintmalm Goran B.G. , Nery Joseph R. , Husberg Bo S. , Gonwa Thomas A. , Tillery Glenn W.
Published: March 2007

One hundred four liver transplant recipients were retrospectively reviewed for the incidence of liver allograft rejection, the response to antirejection therapy and the impact of rejection on graft and patient survival. Liver biopsies were performed weekly during episodes of graft dysfunction and to follow response to treatment. Baseline immunosuppression consisted of cyclosporine and low–dose prednisolone. Rejection was treated with steroids and with OKT3 as rescue. Azathioprine was given to patients with preoperative or perioperative renal insufficiency and was added to patients' treatment after the first sign of rejection.

Seven complications were observed in approximately 1,100 liver biopsies, only one necessitating surgery. We found that 39.4% of the patients never experienced acute rejection, and 60.6% had at least one episode of acute rejection. Overall, 42.3% of the patients had only one episode of acute rejection, 13.5% had two, 3.8% had three and 1% had five episodes of acute rejection. Sixty of 63 first acute rejection episodes occurred within 21 days of transplant. Primary disease, sex or patient age had no significant influence on the incidence of rejection. There was a lower incidence of rejection (p < 0.005) in patients transplanted after October, 1986, despite lower mean cyclosporine levels. Mean cyclosporine level during the first postoperative month was 679 ng per ml vs. a mean level of 910 ng per ml prior to October, 1986, when the immunosuppressive protocol was altered. Antirejection therapy was very effective in that only two of the 63 patients had graft failure due to acute rejection. Both of these patients were subsequently retransplanted. One patient died directly as a result of the acute rejection. In six patients (4.8%), chronic rejection was diagnosed, 29 to 545 days after transplantation. Two of these patients never had previous acute rejection but had suffered severe viral infections. Four of the six chronic rejection patients had primary sclerosing cholangitis as their primary disease. One patient underwent a suspected hyperacute rejection and was successfully retransplanted. We conclude that rejection is a major cause for morbidity after liver transplantation but is presently only a minor cause for mortality. The importance of the primary disease and viral infections in the development of chronic rejection needs further study.
Interaction of Hemopexin, Albumin and Liver Fatty Acid–Binding Protein With Protoporphyrin
Authors: Knobler Elizabeth , Poh-Fitzpatrick Maureen B. , Kravetz Donna , Vincent William R. , Muller-Eberhard Ursula , Vicent Styliani H.
Published: March 2007

Equilibrium constants for the binding of protoporphyrin to serum albumin and hemopexin and liver cytosolic fatty acid–binding protein of the rat were determined fluorometrically. The experimental equilibrium constant [106
M
-1 (mean ± S. D.)] values were 8.4 ± 1.3, 10.0 ± 2.4 and 34.0 ± 3.0 for albumin, hemopexin and liver fatty acid–binding protein, respectively. Statistical analysis showed the equilibrium constant of binding of protoporphyrin to liver fatty acid–binding protein to be significantly (p < 0.01) higher than that to albumin and hemopexin. The data suggest that in patients with erythropoietic protoporphyria an equilibrium gradient may exist which favors the uptake by hepatocytes of plasma protoporphyrin as a result of its greater affinity for intracellular liver fatty acid–binding protein.
Prevalence of Hepatocellular Carcinoma and Relation to Cirrhosis: Comparison of Two Different Cities of the World—Trieste, Italy, and Chiba, Japan
Authors: Tiribelli Claudio , Melato Mauro , Crocè Lory S. , Giarelli Luigi , Okuda Kunio , Ohnishi Kunihiko
Published: March 2007

A comparative, descriptive study on the prevalence of hepatocellular carcinoma either associated or not with cirrhosis was undertaken between the cities of Trieste, Italy, and Chiba, Japan. Data were derived from 12,340 and 2,052 autopsies consecutively performed in Trieste and Chiba during 1980 to 1984 and 1975 to 1985, respectively. During these years, more than 70% of all deaths were studied by autopsy in Trieste. Clinical cases of hepatocelluar carcinoma admitted to the Chiba University Hospital were also analyzed to correct for the bias induced by the relatively small number of autopsies in Chiba. Serum hepatitis B surface antigen was more frequent in Chiba, whereas alcohol intake was greater in Trieste. From the comparison of the data, we conclude: (i) hepatocellular carcinoma was associated with cirrhosis in the large majority of the cases both in Trieste (87%) and Chiba (81%); (ii) in both sexes, the average age of hepatocellular carcinoma patients was significantly older (p < 0.005) in Trieste than in Chiba; (iii) in the autopsy series, cirrhosis was more frequent in Trieste (9.7%) than in Chiba (1.5%); (iv) in Chiba, hepatocellular carcinoma was more frequent than cirrhosis not complicated by hepatocellular carcinoma (6.9 vs. 1.5%) at necroscopy, and (v) the age–standardized rate of hepatocellular carcinoma was significantly (p < 0.01) higher in Trieste than in Chiba. These geographical differences might be related to the different type of cirrhosis observed in Trieste (alcoholic) and Chiba (postnecrotic).
Association of Primary Sclerosing Cholangitis and Celiac Disease: Fact or Fancy?
Authors: Schrumpf Erik
Published: March 2007

The association of primary sclerosing cholangitis and celiac disease was observed in three patients, an association not previously reported. All three patients were men who presented with chronic cholestatic liver disease at ages 32, 46, and 62 years, respectively. In each patient, endoscopic retrograde cholangiography showed the typical findings of primary sclerosing cholangitis. Histologic features of liver biopsy were compatible with the diagnosis. Two patients had associated chronic ulcerative colitis. All three patients complained of frequent loose stools and weight loss; subsequent testing showed severe steatorrhea (204 to 323 mmolfd of fecal fat on a 100 g fat diet). Total villous atrophy was found in all three patients on histologic examination of the small bowel. Celiac disease was diagnosed at the time of presentation in two patients who had primary sclerosing cholangitis and was diagnosed three years after the onset of primary sclerosing cholangitis in the third patient. The celiac disease responded to a gluten–free diet in each patient whereas the primary sclerosing cholangitis was not affected by dietary treatment. The possibility of a chance association of primary sclerosing cholangitis and celiac disease cannot be accurately assessed but seems unlikely given the rarity of both diseases. The relationship between the two diseases remains unknown, although an immunologic connection is suspected. Celiac disease should be considered in the differential diagnosis of severe steatorrhea in patients with primary sclerosing cholangitis.
Insulin and Steatonecrosis: Are They Related?
Authors: Amatruda John M. , Salhanick Arthur I.
Published: March 2007

Hepatic steatosis and steatonecrosis occur in non–alcoholic individuals, usually in a setting of obesity, type II diabetes mellitus, and after jejunoileal bypass. We propose an hypothesis for the pathogenesis of these hepaic lesions based on an observation in peritoneal dialysis patients.

Hepatic histology was examined at autopsy in eleven patients with type I diabetes mellitus and renal failure who had received intraperitoneal insulin in conjunction with continuous ambulatory perritoneal dialysis (CAPD). Steatosis in a unique subcapsular distribution occurred in 10 of 11 patients treated with intraperitoneal insulin and in none of 9 controls receiving CAPD without insulin. Three of the 11 had steatonecrosis, 2 of whom had Mallory bodies.

We suggest that isulin has an important role in the pathogenesis of steatosis and steatoncrosis. In CAPD patients the lesions occurred only under the capsule where concentrations of insulin are high secondary to its intraperitoneal administration. In obese patients the lesions occur throughhout the liver where insulin concentrations are high because of elevated levels in the portal vein. Free fatty acids (FFA) are oxidized in the liver by a pathway that is blocked by insulin. In the presence of insulin, FFA are preferentially esterified into triglycerides which accumulate in large quantities leading to steatosis; small amounts of FFA escaping local control may lead to membrane injury and steatonecrosis. Steatosis and/or steatonecrosis will occur when there is insulin secretion sufficient to block FFA oxidation but not sufficient to block FFA mobilization from adipose tissue. This situation occurs in obesity associated with type II diabetes where adipose tissues are resistant to insulin, and in obesity after jejunoileal–bypass where continued eating and insulin secretion occurs in the face of marked weight loss.
Portacaval Anastomosis: the Longest Shunt
Authors: Conn Harold O.
Published: March 2007

A 34–year–old patient with cryptogenic cirrhosis underwent a portacaval shunt after four episodes of upper gastrointestinal bleeding. His subsequent course is remarkable not onle because of its 26–year duration, but also because of the absence of any subsequent hepatic decomensation such as jaundice, ascites, coagulopathy or encephalopathy. Currently, the shunt is patent.
Extrahepatic Replication of Duck Hepatitis B Virus: More Than Expected
Authors: Hosoda Kazuhiko , Omata Masao , Uchiumi Katsuo , Imazeki Fumio , Yokosuka Osamu , Ito Yoshimi , Okuda Kunio , Ohto Masao
Published: March 2007

Replication of duck hepatitis B virus in extrahepatic tissue such as pancreas, kidney and spleen has been well documented. To assess whether there is more widespread extraheptic virus replication, we assayed brain, heart, lung, thymus, pancreas, kidney, spleen and intestine of 1– to–wk–old ducklings for the presence of duck hepatitis B virus DNA and mRNA by blotting in in situ methods. Replicative intermediates and single–stranded duck hepatitis B virus DNA and RNA transcripts were detected in the brain, lung, heart, intestine, kidney, pancreas and spleen. In situ hybridization showed evidence of viral replication in the lung epithelium, germinal center of spleen, acinar cell of pancreas and tubular epithelium of kidney.

These data suggest that extrahepatic duck hepatitis B virus replication is more widespread than previously thought. It is yet to be determined whether widespread extrahepatic replication is unique to duck hepatitis B virus infection or is a common feature of other mammalian hepatitis B–like viruses. (HEPATOLOGY 1990; 11: 44-48.)
Plasma Gaba–Like Activity in Rats With Hepatic Encephalopathy Is Due to Gaba and Taurine
Authors: Maddison Jill E. , Leong Dorothy K. , Dodd Peter R. , Johnston Graham A.R.
Published: March 2007

Significant discrepancy exists between radioreceptor and high–performance liquid chromatographic estimates of plasma GABA concentrations in animal models of hepatic encephalopathy. A possible explanation for this discrepancy is the presence in plasma of a substance that can inhibit [3H]–GABA binding but is not GABA itself. The aim of this study was to determine whether any of the amino acids that are increased in the plasma of animal models of acute and chronic hepatic encephalopathy (glutamine, glutamate, phenylalanine, tyrosine, citrulline and taurine) can significantly inhibit [3H]–GABA binding and contribute to the GABA–like activity of plasma aliquots.

At final assay concentrations equivalent to plasma concentrations found in hepatic encephalopathy, only taurine was found to significantly inhibit [3H]–GABA binding to whole rat brain synaptosomal membranes (36% inhibition at 30 μmol/L final assay concentration). The concentration of taurine that resulted in 50% inhibition (final assay concentration) was 158 μmol/L, corresponding to a plasma concentration of 1.58 mmol/L. Taurine inhibition of [3H]–GABA binding was competitive because the receptor density was unaltered, but the receptor affinity decreased with increasing concentration of taurine.

Plasma GABA–like activity (determined by radioreceptor assay) and plasma GABA and taurine concentrations (determined by high–performance liquid chromatography) were measured in 18 rats with acute or chronic hepatic encephalopathy and 9 control rats. Plasma GABA–like activity and plasma GABA and taurine concentrations were significantly increased in rats with hepatic encephalopathy compared with control rats.

A comparison of the percent inhibition of [3H]–GABA binding expected by known concentrations (determined by high–performance liquid chromatography) of taurine and GABA in each plasma sample indicated that the inhibition of [3H]–GABA binding by plasma aliquots could be entirely attributed to the presence of GABA and taurine in plasma. Therefore the plasma “GABA–like factor” in animal models of hepatic encephalopathy is taurine. The implications of this finding to the pathogenesis of hepatic encephalopathy are unknown at present.
The Effect of Liver Dysfunction on Colchicine Pharmacokinetics in the Rat
Authors: Leighton Jonathan A. , Bay Michael K. , Maldonado Alma L. , Johnson Raymond F. , Schenker Steven , Speeg K. V.
Published: March 2007

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P–450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham–operated controls), α–naphthylisothiocyanate–induced intrahepatic cholestasis and galactosamine–induced diffuse hepatocelluar necrosis.

The control group had a colchicine clearance of 77.33 ml/min. kg ± 8.27 ml/min kg, a half–life of 16.68 min ± 0.97 min and a volume of distribution of 1.84 L/kg ± 0.15 L/kg.

Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p < 0.05) and half–life to increase by 38% (p < 0.05). Volume of distribution did not change.

At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p < 0.05), terminal half–life increased to 513.7 min ± 106.6 min (p < 0.05) and volume of distribution increased by 175% (p < 0.05). Colchicine pharmacokinetics in sham–operated rats were not statistically different from the above mentioned controls.

After α–naphthylisothiocyanate administration, colchicine clearance decreased by 55% (p < 0.05), the halflife increased by 56% (p < 0.05) and the volume of distribution decreased by 30% (p < 0.05).

After administration of galactosamine, 1,000 mg/kg, colchicine clearance decreased by 62% (p < 0.05), half–life increased to 144.72 min ± 35.30 min (p < 0.05) and volume of distribution increased by 124% (p < 0.05).

These data show that experimental hepatic injury in the rat significantly impairs colchicine pharmacokinetics. They also support the hypothesis that the liver is a major route of colchicine elimination.
Enhancement of Portal Pressure Reduction by the Association of Isosorbide–5–Mononitrate to Propranolol Administration in Patients With Cirrhosis
Authors: Garcia-Pagan Joan Carles , Navasa Miquel , Bosch Jaime , Bru Conxita , Pizcueta Pilar , Rodes Joan
Published: March 2007

This study investigated whether oral doses of isosorbide–5–mononitrate, a preferential venous dilator that decreases portal pressure, could enhance the effects of propranolol on portal hypertension. Taking part in the stuty were 28 patients with cirrhosis and portal hypertension. Twenty patients (group 1) had hemodynamic measurements in baseline conditions after beta–blockade by intravenous administration of propranolol and after receiveing oral doses of isosorbide–5–mononitrate. The remaining eight patients (group 2) were given oral isosorbide–5–mononitrate while receiving chronic propranolol therapy. In group 1, propranolol significantly reduced portal pressure (estimated as the gradient between wedged and free hepatic venous pressures) from 21.5 ± 3.9 to 18.6 ± mm Hg (–13.7%, p <0.001), azygos blood flow (–38%, p < 0.001), hepatic blood flow (-12.8%, p < 0.05), cardiac output (-24.5%, p < 0.001) and heart rate (-18.4%, p < 0.001) without significant changes in mean arterial pressure. Addition of oral isosorbide–5–mononitrate caused a further and marked fall in portal pressure (to 15.7 ± 3.1 mm Hg, p < 0.001), without additional changes in azygos blood flow but with significant additional reductions in hepatic blood flow (-15.5%, p < 0.05), cardiac out put (-11.5%, p < 0.001) and mean arterial pressure (-22%, p < 0.001). The additional effect of isosorbide–5–mononitrate on portal pressure was especially evident in patients who did not respond to propranolol (decrease in portal pressure less than 10%, n = 9), the final reduction in portal pressure after combined therapy being similar in propranolol responders (-26%) and nonresponders (-27%). In group 2, the association of isosorbide–5–mononitrate to chronic propranolol therapy also caused a further significant reduction in portal pressure, from 17.1 ± 3.1 to 15.4 ± 2.1 mm Hg (p < 0.05). Study results indicate that isosorbide–5–mononitrate enhances the beneficial effects of propranolol on portal hypertension in patients with cirrhosis.
Rabbit Hepatocytes in Primary Culture: Preparation, Viability and Use in Studies of Propranolol Metabolism
Authors: Walpole Horace E. , Lee William M. , Walle Thomas , Walle Kristina U. , Wilson Michael J. , Kennedy John W.
Published: March 2007

Isolated hepatocyte cultures have become a frequently used model system for investigating drug metabolism. Although rat and hamster hepatocytes are frequently used for this purpose, metabolism in these species differs in many respects from human metabolism. A species with a metabolism more closely resembling that of humans might be more useful. Our in vivo experiments demonstrated that the metabolism of propranolol in the rabbit is more similar to that in humans than in rats or hamsters. We therefore examined the usefulness of rabbit parenchymal liver cells for studies of propranolol metabolism. A detailed method is presented for their preparation and culture, along with data on their viability, structure and protein synthesizing capability. One– or two–day–old hepatocyte cultures were exposed to 10 μmol/L 3H–propranolol from 30 min to hr; metabolites were identified by gas chromatography–mass spectrometry and quantitated by high–performance liquid chromatography. Propranolol metabolism was linear over 1 hr, with 15% of the substrate metabolized during this time. The cytochrome P–450 pathways, which result in ring oxidation and sidechain oxidation, were expressed in a reproducible fashion similar to that found in vivo in humans. The arylhydrocarbon hydroxylase inhibitor α–naphthoflavone (100 μmol/L) inhibited side–chain oxidation of propranolol by 90% without affecting ring oxidation. In contrast, cholorpromazine (100 μmol/L) was shown to inhibit ring oxidation of propranolol by 85% without affecting sidechain oxidation. Cimetidine (250 μmol/L) inhibited both pathways by about 50%. These observations suggest that rabbit hepatocyte metabolic pathways more closely resemble human cell metabolism and thus may be a more useful adjunct that rat or hamster hepatocytes in the study of drug–drug interactions when combined with in vivo studies in humans. (Hepatology 1990;11:394-400.)
Epidemiology of Primary Biliary Cirrhosis in A Defined Rural Population in the Northern Part of Sweden
Authors: Danielsson Äke , Boqvist Lennart , Uddenfeldt Per
Published: March 2007

The northern part of Sweden is sparsely populated and must be regarded as a rural region. An investigation into the incidence and prevalence of primary biliary cirhosis was conducted and the course of the disease was followed. In total, 111 patients with primary biliary cirrhosis were identified for the 10–yr period 1973 to 1982 in the northern health region of Sweden. The mean annual incidence amounted to 13.3 per million and the point prevalence was 151 per million, which is the highest reported so far. There was a significantly higher prevalence in the most northern county of Sweden, both with respect to total number of primary biliary cirrhosis patients and symptomatic patients. Asymptomatic patients amounted to 37%. During the study period 25 patients out of the 111 died (23%), 14 as a direct consequence of the liver disease. Three patients died of primary hepatocellular carcinom, one having an asympatomatic liver disease without cirrhosis. Primary biliary cirrhosis seems to be more common in Sweden, especially in the northern part, than it is elsewhere. A high frequency of extrahepatic symptoms (85%), mainly musculoskeletal, was recorded. These symptoms may lead to the first contact with the health service, rather than signs of liver disease. Thus, an increasing number of patients are diagnosed with asymptomatic liver disease, who must be followed to check for the eventual development of symptoms.(Hepatology 1990;11:458-464.)
Hepatic Mycobacterial Disease and Aids
Authors: Light Richard W.
Published: March 2007

We reviewed the clinical data, hepatic histology, and microbiological features of 21 patients with previously documented acquired immune deficiency syndrome who had liver biopsies. Diagnoses of specific infections were made on liver biopsy in 11/21 patients (57%). Granulomas were found in 10/21 patients (48%) and were most often a manifestation of infection with Mycobacterium avium–intracellulare. Elevated levels of serum alkaline phosphatase and longer duration of diagnosed illness were significantly associated with the presence of granulomatous disease.
The Effect of Anti–α–Fetoprotein–Adriamycin Conjugate on A Human Hepatoma
Authors: Galun Eithan , Shouval Daniel , Adler Ruth , Shahaar Michal , Wilchek Meir , Hurwitz Esther , Sela Michael
Published: March 2007

Conjugates between chemotherapeutic agents and antibodies, linked by a dextran bridge, were previously shown to be effective in suppression of hepatoma growth in vitro and in vivo. However, scaling up of production of such conjugates may lead to a high degree of variation in molar ratios of drug to antibody in different batches. In this study, an alternative link between drug and antibody was evaluated. A conjugate between adriamycin and murine IgGl monoclonal antibodies to human α–fetoprotein was prepared using a polyglutamic–acid bridge. The simple and reproducible method of linking adriamycin to a specific site on the antibody enabled the binding of the drug to α–fetoprotein with a high yield (63% to 68%); the molar ratio of drug/antibody was in the range of 110: 1 to 120: 1. The conjugate retained its capacity to bind to purified α–fetoprotein. Incorporation of [3H]–thymidine or [3H]–leucine into hepatoma cells, which express α–fetoprotein, was inhibited by the conjugate, compared with unconjugated antibody. Furthermore, 90% of this pharmacological activity was preserved, compared with free adriamycin. In vitro, the inhibitory activity of the polyglutamic acid conjugate was higher than that of a conjugate in which dextran was used as the linker between drug and antibody. In vivo, both conjugates were equally effective in suppression of hepatoma growth transplanted subcutaneously in athymic mice. However, this effect lasted only during the treatment period of 2 to 3 wk. Six days after discontinuation of therapy, reacceleration of tumor growth was observed regardless of the conjugate used. These preliminary results suggest that polyglutamic acid may be used as an alternative link to dextran for conjugation of anti–α–fetoprotein to adriamycin. However, use of monoclonal anti–α–fetoprotein for delivery of adriamycin to the hepatocellular carcinoma transplanted in athymic mice causes only partial remission of tumor growth. Therefore conjugates containing monoclonal antibodies to different cell surface antigens, administered sequentially or simultaneously, may have to be evaluated as well.(HEPATOLOGY 1990; 11:578:584.)
Inhibition of α–Ketoglutarate Dehydrogenase Activity by A Distinct Population of Autoantibodies Recognizing Dihydrolipoamide Succinyltransferase in Primary Biliary Cirrhosis
Authors: Fregeau David R. , Prindiville Thomas , Coppel Ross L. , Kaplan Marshall , Dickson Rolland E. , Gershwin Eric M.
Published: March 2007

Sera from patients with primary biliary cirrhosis contain autoantibodies that recognize mitochondrial proteins. Five of the target autoantigens have now been identified as enzymes of three related multienzyme complexes: the pyruvate dehydrogenase complex, the branched chain α–ketoacid dehydrogenase complex and the α–ketoglutarate dehydrogenase complex. Each complex consists of component enzymes designated E1, E2 and E3. In this report, we confirm that primary biliary cirrhosis sera react with dihydrolipoamide succinyltransferase, the E2 component of α–ketoglutarate dehydrogenase complex. Seventy–three of 188 (39%) primary biliary cirrhosis sera reacted with α–ketoglutarate dehydrogenase complex–E2 when immunoblotted against purified α–ketoglutarate dehydrogenase complex; one of these sera also reacted with the E1 component. In addition, primary biliary cirrhosis sera possessing α–ketoglutarate dehydrogenase complex–E2 reactivity specifically inhibited enzyme function of α–ketoglutarate dehydrogenase complex. Enzyme activity was not affected by primary biliary cirrhosis sera that contained autoantibodies to pyruvate dehydrogenase complex–E2 and/or branched chain α–ketoacid dehydrogenase complex–E2, which lacked α–ketoglutarate dehydrogenase complex–E2 reactivity. Furthermore, affinity–purified primary biliary cirrhosis sera against α–ketoglutarate dehydrogenase complex–E2 inhibited only α–ketoglutarate dehydrogenase complex activity but did not alter enzyme activity of either pyruvate dehydrogenase complex or branched chain α–ketoacid dehydrogenase complex. Finally, α–ketoglutarate dehydrogenase complex–E2 specific affinity–purified antisera did not react on immunoblot with any component enzymes of pyruvate dehydrogenase complex or branched chain α–ketoacid dehydrogenase complex. These data demonstrate that the E2 component of α–ketoglutarate dehydrogenase complex is recognized by a distinct population of autoantibodies separate from autoantibodies that recognize pyruvate dehydrogenase complex–E2 or branched chain α–ketoacid dehydrogenase complex–E2. Our data further suggest that these autoantibodies are directed toward a functional domain of this enzyme.(HEPATOLOGY 1990;11:975–981.).
Prevention of Ursodeoxycholate Hepatotoxicity in the Rabbit by Conjugation With N –Methyl Amino Acids
Authors: Schmassmann Adrian , Hofmann Alan F. , Angellotti Antonietta M. , Ton-Nu Huong-Thu , Schteingart Claudio D. , Clerici Carlo , Rossi Steven S. , Rothschild Marcus A. , Cohen Bertram I. , Stenger Richard J. , Mosbach Erwin H.
Published: March 2007

The effect of dietary administration of four different amino acid (N–acyl) conjugates of ursodeoxycholic acid on biliary bile acid composition, liver tests and hepatic morphology by light microscopy was examined in the rabbit. Each group of four to five rabbits received a chow diet supplemented with a single conjugate of ursodeoxycholic acid ursodeoxycholylglycine, ursodeoxycholyl–sarcosine, ursodeoxycholyltaurine or ursodeoxycholyl–N–methyltaurine for 3 wks at a dose of 50 mg/kg/day; a control group received chow alone. After 3 wks of feeding, animals receiving ursodeoxycholyl–glycine or ursodeoxycholyl–taurine had hepatotoxicity associated with abnormal liver tests. Lithocholic acid made up 11% ± 2.7% of biliary bile acids in the ursodeoxycholyl–glycine and 10% ± 2.2% in the ursodeoxycholyl–taurine group. In contrast, animals receiving ursodeoxycholyl–sarcosine or ursodeoxycholyl–N–methyltaurine had neither hepatotoxicity nor abnormal liver tests and the proportion of lithocholic acid in biliary bile acids increased much less. Complementary studies showed that ursodeoxycholyl–sarcosine and ursodeoxycholyl–N–methyltaurine were not biotransformed during hepatic transport and were resistant to deconjugation and dehydroxylation in the rabbit. These experiments indicate that the N–methyl amino acid conjugates of ursodeoxycholic acid are nontoxic in the rabbit and resist deconjugation and dehydroxylation. Such resistance decreases formation of lithocholic acid in the colon, thus reducing its accumulation and consequent induction of hepatotoxicity.(HEPATOLOGY 1990;11:989–996.).
Ursodeoxycholic Acid in the Treatment of Primary Biliary Cirrhosis: First Controlled Data
Authors: Borum Marie , Fromm Hans
Published: March 2007

We studied the effect of ursodeoxycholic acid on 18 women and 2 men with primary biliary cirrhosis, mainly stages I and II. After a 3–mo observation period, patients were randomized to a 9–mo treatment period with ursodeoxycholic acid, 10 mg/kg · day, or placebo. Two patients on placebo left the study. In all patients on ursodeoxycholic acid, mean values of serum glutamate dehydrogenase, aspartate and alanine aminotransferases, alkaline phosphatase, and γ–glutamyl transpeptidase fell significantly by 48%–79% after 18-24 wk; 7 of 10 showed a mean decrease of 35% in immunoglobulin M after 24 wk. Prothrombin time, serum bilirubin, albumin, the antipyrine breath test, and plasma disappearance of indocyanine green were normal initially and did not change. Total serum bile acid concentrations increased; ursodeoxycholic acid became the predominant bile acid. No significant improvement occurred in the placebo group. Hepatic histology improved in 6 patients of the ursodeoxycholic acid group but deteriorated in 4 patients receiving placebo. In studies with erythrocyte membranes, changes in electron spin resonance revealed that ursodeoxycholic acid was less toxic than chenodeoxycholic or deoxycholic acid, and coaddition of ursodeoxycholic acid prevented their toxic effect.
Collagen Type I and Iii Occur Together in Hybrid Fibrils in the Space of Disse of Normal Rat Liver
Authors: Geerts Albert , Schuppan Detlef , Lazeroms Sylvia , De Zanger Ronald , Wisse Eddie
Published: March 2007

Collagen type I and procollagen type III were localized at the ultrastructural level on ultrathin frozen sections of rat liver by the protein A-gold technique using affinity–purified primary antibodies. Both collagen type I and procollagen type III were localized on nearly all solitary and bundled fibrils in the space of Disse. Simultaneous localization of collagen type I and procollagen type III by a double–labeling procedure using protein A-gold probes of different sizes unequivocally demonstrated the presence of both collagens in the same fibrils.

Measurement of the diameter of large numbers of collagen fibrils in the space of Disse of the rat liver showed a unimodal distribution of the fibril diameters around an average value of 62.4 nm (S.D. = 12.8 nm), and 91% of the collagen bundles contained less than 30 fibrils. Additional measurements on epoxy resin-embedded material of five biopsy specimens of normal human liver showed a comparable unimodal distribution of the fibril diameters around an average value of 57.2 nm (S.D. = 9.6 nm), and 74% of the bundles contained less than 60 fibrils. The latter observation demonstrates that human liver contains broader interstitial collagen bundles than rat liver.

From these results, we conclude that the space of Disse of normal rat and human liver contains a uniform population of striated interstitial collagen fibrils. In the rat liver, these fibrils contain both collagen type I and procollagen type III. Therefore the concept that procollagen type III is predominantly localized in small diameter fibrils or bundles, whereas collagen type I is preferentially localized in thick ones, does not hold. (Hepatology 1990;12:233-241).
Benign Recurrent Intrahepatic Cholestasis: Failure of S–Adenosylmethionine Therapy
Authors: Conn Harold O. , Ghent C. N.
Published: March 2007

S–Adenosylmethionine (800 mg i.v. per day) was used to treat two brothers and a brother and sister from each of two kindreds with benign recurrent intrahepatic cholestasis. Symptoms, routine tests of liver function, concentrations of total bile acids, and the oral clearances of [11,12–2H]chenodeoxycholic acid and [24–13C]cholic acid were determined before and after treatment with S–adenosylmethionine. S–Adenosylmethionine did not ameliorate symptoms or biochemical parameters of cholestasis but reduced bile acid clearances in 3 of 4 subjects. Transaminase levels in both subjects of one kindred rose during treatment. These limited, preliminary observations suggest that S–adenosylmethionine may be ineffective in the therapy of benign recurrent intrahepatic cholestasis and may be hepatotoxic in some patients.
Biliary tract disease in aids: Aids vs. nonaids
Authors: Simon Douglas , Brandt Lawrence J.
Published: March 2007

Endoscopic retrograde cholangiopancreatography (ERCP) was performed in twenty-six AIDS patients to evaluate either abdominal pain suggestive of biliary tract disease, fever, serum alkaline phosphatase elevation, or a combination of these findings. Twenty patients (77%) had abnormal cholangiograms and four distinct patterns were identified: (1) papillary stenosis (n = 3); (2) sclerosing cholangitis (n = 4); (3) sclerosing cholangitis with papillary stenosis (n = 10); and (4) long extrahepatic bile duct strictures (n = 3). Ampullary biopsy and culture identified an AIDS-related pathogen (CMV, MAI and cryptosporidium) or malignancy (lymphoma, Kaposi's sarcoma) in eleven patients (55%). No features differentiated patients with normal from patients with abnormal cholangiograms. Noninvasive biiary tract imaging studies (CT, ultrasound), however, showed ductal dilation in 75% of patients with abnormal cholangiograms compared with 16% in those with normal cholangiograms (p <0.001). Endoscopic sphincterotomy (ES) in 12 patients with either papillary stenosis or the combination of sclerosing cholangitis and papillary stenosis produced a significant reduction in right upper abdominal pain, although serum alkaline phosphatase continued to increase (mean follow-up = 3.9 months). Ten of the 12 patients undergoing ES had sclerosing cholangitis, perhaps explaining this lack of response of the serum alkaline phosphatase. Of the 12 patients who had ES, five died of AIDS-related complications within nine months of the procedure (a mean of 4.8 months), four were lost to follow-up by four months, and three were alive at 12 months. Of the eight patients who did not have ES, five were alive at one to six months and three died within five months (mean 1.7 months) after the procedure. This paper expands our knowledge of biliary tract abnormalities in HIV-infected individuals and suggests that ES may improve biliary tract associated abdominal pain.
Hepatocyte plasma membrane glycosphingolipid reactive with sera from patients with autoimmune chronic active hepatitis: Its identification as sulfatide
Authors: Toda Gotaro , Ikeda Yusei , Kashiwagi Masuo , Iwamori Masao , Oka Hiroshi
Published: March 2007

Sera from patients with autoimmune chronic active hepatitis were found to contain IgG-class antibody to the acidic glycosphingolipid fraction from rabbit hepatocyte plasma membrane by solid-phase enzyme-linked immunosorbent assay. Using serum positive for the antibody as a probe, we isolated the target antigen by Iatrobeads column chromatography. Analysis by thinlayer chromatography and negative ion fast atombombardment mass spectrometry revealed that the antigen was sulfatide. The presence of antisulfatide antibody was also confirmed by immunoblotting. The reactivity of the serum with sulfatide was diminished by preincubation of the serum with galactosylceramide-6-sulfate and sulfatide, indicating that the antibody reacted with sulfated galactosylceramide regardless of the position of the sulfate residue. The antibody was found in 92.3%, 42.9%, 15.8%, 14.2%, 0% and 0%, respectively, of patients with autoimmune chronic active hepatitis, primary biliary cirrhosis, cirrhosis, systemic lupus erythematosus, chronic active hepatitis and chronic persistent hepatitis. Thus antisulfatide antibody was characteristic of autoimmune-type chronic liver diseases. Antisulfatide antibody was absorbed by rabbit hepatocyte plasma membrane. Preincubation of sera with sulfatide immobilized on Sepharose decreased their reactivities with not only sulfatide but also rabbit plasma membrane and rat hepatocytes. Therefore sulfatide may be a target antigen of the antibody to hepatocyte surface membrane. (HEPATOLOGY 1990;12:664-670).
Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: Analysis by detection of antibody to hepatitis C virus
Authors: Kiyosawa Kendo , Sodeyama Takeshi , Tanaka Eiji , Gibo Yukio , Yoshizawa Kaname , Nakano Yoshiyuki , Furuta Seiichi , Akahane Yoshihiro , Nishioka Kusuya , Purcell Robert H. , Alter Harvey J.
Published: March 2007

To clarify the relationship between hepatitis C virus infection and the development of hepatocellular carcinoma as sequelae of non-A, non-B posttransfusion hepatitis, 231 patients with chronic non-A, non-B hepatitis (96 with chronic hepatitis, 81 with cirrhosis and 54 with hepatocellular carcinoma) were analyzed for antibody to hepatitis C virus and were compared with 125 patients with chronic hepatitis B (50 with chronic hepatitis, 46 with cirrhosis and 29 with hepatocellular carcinoma). Antibody to hepatitis C virus was detected in 89.6%, 86.4% and 94.4% of patients with non-A, non-B hepatitis-related chronic hepatitis, cirrhosis and hepatocellular carcinoma, respectively, compared with 6%, 17.4% and 34.5% with similar diseases related to hepatitis B. A history of transfusion was documented in 52%, 33% and 42% of anti-hepatitis C virus-positive cases of chronic hepatitis, cirrhosis and hepatocellular carcinoma. The mean intervals between the date of transfusion and the date of diagnosis of anti-hepatitis C virus—positive chronic hepatitis, cirrhosis and hepatocellular carcinoma were 10, 21.2 and 29 yr, respectively. In 21 patients with transfusion-associated hepatocellular carcinoma, anti-hepatitis C virus was present in each serial sample available for testing, including samples obtained up to 14 yr before the diagnosis of hepatocellular carcinoma. These data suggest the slow, sequential progression from acute hepatitis C virus—related non-A, non-B hepatitis through chronic hepatitis and cirrhosis to hepatocellular carcinoma and support a causal association between hepatitis C virus and hepatocellular carcinoma. (HEPATOLOGY 1990; 12:671-675).