bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of recurrent bleeding in cirrhotics with recent variceal hemorrhage: Prospective, randomized comparison of propranolol and sclerotherapy
Authors: Fleig Wolfgang E. , Stange Eduard F. , Hunecke Roland , Schönborn Wolfgang , Hurler Ulrike , Rainer Kordula , Gaus Wilhelm , Ditschuneit Hans
Published: March 2007

To compare the efficacy of endoscopic paravariceal sclerotherapy and oral propranolol in the prevention of recurrent upper gastrointestinal bleeding, 78 cirrhotic patients were randomly assigned to either treatment after an endoscopically proven bleed from esophageal varices. After randomization, but before treatment had been started, a total of eight patients had to be withdrawn from the study due to early rebleeding (requiring emergency sclerotherapy) or violations of the protocol. Among the 70 patients analyzed (36 sclerotherapy, 34 propranolol), both treatment groups were comparable with respect to demographic, clinical and laboratory data. The groups also did not differ with respect to continued alcohol intake. Sclerotherapy was performed twice weekly using 1% polidocanol as the sclerosing agent until the varices were eradicated or well-covered by fibrous tissue. Propranolol was given twice daily at a dose reducing the resting heart rate by 25% (60 to 320 mg per day; mean ± SD = 161 ± 80 mg per day). Patients were followed for up to 2 years with visits at 3 monthly intervals (mean follow-up = sclerotherapy, 14 months; propranolol, 9.2 months). Life table analysis of patients without rebleeding from nonvariceal sites revealed a tendency in favor of propranolol; however, the difference did not reach statistical significance. No significant difference was observed between sclerotherapy and propranolol in the proportion of patients rebleeding from esophageal varices or from all sources of upper gastrointestinal bleeding. Furthermore, survival was similar in both treatment groups. A small esophageal perforation due to sclerotherapy was observed in one patient, and one propranolol patient had to discontinue the medication due to severe bradycardia. Other complications of sclerotherapy and side effects of propranolol were minor. Propranolol reduced variceal size significantly within 3 months of treatment. No such decrease was observed in a subgroup of patients who rebled under propranolol, and in the untreated control group of an ongoing trial of prophylactic sclerotherapy. We conclude that propranolol and sclerotherapy are of comparable value in preventing recurrent upper gastrointestinal bleeding in cirrhotics.
The diagnosis of hepatic metastases: Converting a chance into a choice
Authors: Meyer Klemens B. , Kassirer Jerome P.
Published: March 2007

Clinicians frequently perform tests to determine whether patients have liver metastases. Optimal use of a laboratory test requires that the clinician know the test's operating characteristics (its sensitivity and specificity) and have an estimate of the pretest probability that disease is present. We have surveyed studies that examined the value of four biochemical and three imaging tests in establishing a diagnosis of hepatic metastases in patients who underwent an invasive procedure to establish the presence or absence of disease. We have pooled the data from these studies to arrive at values for the sensitivity and specificity of each of these tests, and calculated the predictive values for these tests over a wide range of pretest probabilities of disease. Several examples illustrate how this information may be used clinically. We provide a framework for the optimal interpretation of these commonly ordered tests and indicate the data needed for their complete analysis.
Liver disease in aids
Authors: Brettman Lee R.
Published: March 2007

Abnormal liver chemistries, unexplained fevers, or hepatomegaly prompted 36 liver biopsies on 34 patients with the acquired immunodeficiency syn-drome. The most common finding was the presence of hepatic granulomas, seen in 13 of the biopsy specimens. Eight of these granulomas were illdefined, and 5 were more clearly associated with mycobacterial disesse. Portal fibrosis and fatty infiltration were comon, but a paucity of significant inflammatory activity was seen despite elevated aspartate aminotransferase levels, perhaps related to the underlying imunoincompetent status. Other noteworthy histopathologic findings included 1 patient each with peliosis hepatitis and cryptococcal hepatitis. Electron-microscopic evidence of cytoplasmic tubular structures or viral particles were seen within the hepatocytes of 2 patients. It is concluded that a broad spectrum of hepatic histopathology may be seen in the acquired immunodeficiency syndrome, and that liver biopsy may be diagnostically valuable in the clincial investigation of such patients.
The role of propranolol in congestive gastropathy of portal hypertension
Authors: Hosking Shorland W. , Kennedy Hugh J. , Seddon Ian , Triger David R.
Published: March 2007

Heavy diffuse bleeding from congested gastric mucosa (congestive gastropathy) was treated by propranolol (dose = 24 to 480 mg per day) in 14 consecutive patients with portal hypertension. Thirteen patients (93%) stopped bleeding within 3 days. Gastric mucosal cherry red spots (a sign of severe gastropathy) were unchanged in 5 patients, became less obvious in 4 and appearances returned to normal in 5. Propranolol was discontinued electively in seven patients after 2 to 6 months; four of these patients rebled from the same lesion and stopped bleeding when propranolol was recommenced. No patient has rebled from congestive gastropathy while receiving propranolol during follow-up of 12 to 42 (median = 23) months.

A further 24 patients with nonbleeding congestive gastropathy received 160 mg long-acting propranolol per day in a double-blind placebo controlled cross-over trial. Twenty-two patients completed the study; in nine patients, endoscopic grading of congestive gastropathy improved after propranolol compared to three after placebo (p < 0.05). Although the mechanism of action is not understood, propranolol appears to have a clinically significant role in the management of nonvariceal gastric bleeding in portal hypertension.
Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: A prospective study of factors associated with rebleeding
Authors: Poynard Thierry , Lebrec Didier , Hillon Patrick , Sayegh Raymond , Bernuau Jacques , Naveau Sylvie , Chaput Jean-Claude , Klepping Claude , Rueff Bernard , Benhamou Jean-Pierre
Published: March 2007

In a previous randomized trial, we demonstrated that propranolol prevented recurrent gastrointestinal bleeding in patients with cirrhosis. We have undertaken the present study in a new group of patients to ascertain the factors associated with rebleeding. Among 232 patients with cirrhosis admitted for gastrointestinal bleeding, 127 were included. They received propranolol orally at a dose reducing the heart rate by 25%. The median follow-up period was 682 days. The following factors were studied: cause of cirrhosis; severity of cirrhosis; hepatocellular carcinoma recognized after inclusion; compliance; persistent decrease in heart rate; dose of propranolol; alcohol abstinence; previous history of hemorrhage; time interval from hemorrhage to onset of propranolol administration, and source of bleeding. The percentage of patients free of rebleeding was 71% at 1 year and 57% at 2 years. Only five factors were significantly and independently associated with rebleeding: occurrence of hepatocellular carcinoma; lack of compliance; lack of persistent decrease in heart rate; lack of abstinence, and previous history of bleeding. In conclusion, this study confirms the results of our previous trial and suggests that certain factors play a role in the mechanism of rebleeding in patients receiving propranolol.
Increased prolyl hydroxylase activity and collagen synthesis in hepatocyte cultures exposed to superoxide
Authors: Hussain Zamirul M. , Watson John A. , Bhatnagar Rajendra S.
Published: March 2007

Primary monolayer cultures of rat hepatocytes at confluence were exposed to an exogenously added source of superoxide, and its influence on collagen synthesis was examined. Superoxide was generated by the addition of dihydroxyfumarate to the culture medium. Exposure of hepatocytes to dihydroxyfumarate greatly stimulated the activity of prolyl hydroxylase and the synthesis of collagen. A significant increase in prolyl hydroxylase activity was observed with 5 μg per ml dihydroxyfumarate in 24 hr relative to that in the untreated cultures. Maximum stimulation of greater than 3-fold compared to the control value was elicited by 25 μg per ml dihydroxyfumarate. When scavengers of superoxide such as superoxide dismutase and Cu(Lys)2 were added in the medium, the increase in prolyl hydroxylase activity induced by dihydroxyfumarate was nearly abolished. Experiments with actinomycin D indicated that synthesis of new RNA was involved in the stimulation of prolyl hydroxylase activity. Analysis of collagen synthesis in cultures exposed to dihydroxyfumarate also showed a marked increase compared to that of the untreated cultures. The presence of superoxide dismutase in the medium significantly reduced the increase in collagen synthesis. Our results indicate that superoxide mediates the stimulation of collagen synthesis in hepatocytes. These findings may provide a possible explanation for excess collagen formation during induced liver fibrosis.
Characterization of ciprofibrate and clofibric acid as peroxisomal proliferators in primary cultures of rat hepatocytes
Authors: Feller Dennis R. , Singh Yogendra , Shirhatti Vilas R. , Kocarek Thomas A. , Liu Cuo-Tung , Krishna Gopal
Published: March 2007

We have determined the comparative activities of peroxisomal proliferators, ciprofibrate and clofibric acid on various hepatic parameters associated with endoplasmic reticulum, mitochondria and peroxisomes in primary cultures of rat hepatocytes. We have measured the activities of carnitine acetyltransferase and fatty acylCoA oxidase, and the amount of 60 and 80 kD polypeptides as biochemical markers of the peroxisomal function; laurate hydroxylase and cytochrome P-450 as markers of the endoplasmic reticulum; and carnitine palmitoyltransferase as a marker of mitochondria in primary cultures of hepatocytes. Ciprofibrate (0.01 to 0.3 mM) and clofibric acid (0.1 to 3 mM) produced similar changes in several components of cultured hepatocytes within 72 hr. Increases of protein (18 and 11%), carnitine palmitoyltransferase (23 and 97%), cytochrome P-450 (37 and 49%), carnitine acetyltransferase (484 and 614%), fatty acylCoA oxidase (529 and 931%) and laurate hydroxylase (624 and 671%) were obtained in hepatocytes after a 72-hr exposure to 0.1 mM ciprofibrate and 1.0 mM clofibric acid, respectively. In cultured hepatocytes, ciprofibrate was about 30-fold more active than clofibric acid for the stimulation of carnitine acetyltransferase, laurate hydroxylase and fatty acylCoA oxidase activities. Ciprofibrate was also more potent than clofibric acid as an inducer of the 60 and 80 kD proteins in hepatocytes. The maximal drug-induced increases in carnitine acetyltransferase activity were not additive, and the induction of carnitine acetyltransferase by ciprofibrate was blocked by addition (1 μg per ml) of cycloheximide or actinomycin D. Changes in protein and RNA synthesis preceded the drug-induced increases of carnitine acetyltransferase activity. Druginduced increases in peroxisomes of hepatocytes were also confirmed by 3,3′-diaminobenzidine staining and electron microscopic examination. These results show that: (i) measurements of carnitine acetyltransferase, fatty acylCoA oxidase, laurate hydroxylase activities and 80 kD polypeptide in primary cultures of rat hepatocytes are useful criteria for characterizing the effects of peroxisome proliferating agents; (ii) ciprofibrate is more active as a peroxisomal proliferating agent than clofibric acid in hepatocyte cultures; and (iii) the isolated, cultured rat hepatocyte system is valuable as an adjunct to the in vivo model for studying biochemical mechanisms of peroxisome proliferation and hepatotoxicity for this class of agents.
Effect of corticosteroid therapy on levels of antibody to hepatitis B core antigen in patients with chronic type B hepatitis
Authors: Sjogren Maria H. , Hoofnagle Jay H. , Waggoner Jeanne G.
Published: March 2007

Serum levels of antibody to hepatitis B core antigen and IgM antibody to hepatitis B core antigen were tested in 15 patients who participated in a randomized, placebo-controlled trial of a 28-day course of prednisolone therapy. During treatment, serum levels of antibody to hepatitis B core antigen and IgM antibody to hepatitis B core antigen decreased in all 10 treated patients, but in none of five controls (p < 0.05). Also during therapy, ALT activity decreased by an average of 50% and serum IgG levels by 30% (both p <: 0.05). Serum levels of hepatitis B virus DNA and DNA polymerase activity did not change significantly. Four to 10 weeks after discontinuation of prednisolone, a rebound of serum ALT and IgM antibody to hepatitis B core antigen levels occurred, which usually resolved within the subsequent months of follow-up evaluation. In three patients, however, there was a prolonged exacerbation of the disease following prednisolone withdrawal; in these three, levels of IgM antibody to hepatitis B core antigen and ALT remained elevated above pretreatment values. The close correlation between changes in serum ALT activity and IgM antibody to hepatitis B core antigen levels suggests that corticosteroids can modulate disease activity in chronic type B hepatitis by suppression of the host-immune response to hepatitis B virus antigens.
Plasma gaba, gaba-like activity and the brain gaba-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy
Authors: Maddison Jill E. , Dodd Peter R. , Morrison Murray , Johnston Graham A. R. , Farrell Geoffrey C.
Published: March 2007

Plasma γ-aminobutyric acid (GABA)-like activity, plasma GABA and the brain GABA-benzodiazepine receptor complex were studied in rats with chronic hepatic encephalopathy. Portal vein ligation (after prior subcutaneous transposition of the spleen) results in complete portal bypass of splanchnic blood. In addition, significant hepatocellular damage was superimposed on this model of portosystemic shunting by ligation of the common bile duct. Plasma GABA-like activity (determined by radioreceptor assay) and true plasma GABA concentrations (determined by high-performance liquid chromatography) were found to be significantly increased in both portal vein-ligated and portal vein and bile duct-ligated rats, compared with controls. However, plasma GABA-like activity was consistently greater than the concentration of true GABA in the plasma of all rats. This suggested the presence of a GABA-like factor in plasma that can inhibit [3H]GABA binding, but is not GABA itself. The concentration of this GABA-like factor was significantly increased in the plasma of rats with chronic hepatic encephalopathy

Despite the significant increase in plasma GABA-like activity and plasma GABA concentrations, there was no alteration in the affinity or density of the physiologically relevant, low-affinity brain GABA binding site in the rats with portal vein ligation, with or without bile duct ligation. There was also no significant alteration in brain benzodiazepine binding in these rats. GABA enhancement of benzodiazepine binding was unchanged in the portal vein-ligated rats. However, the maximal enhancement of benzodiazepine binding was decreased in the rats with portal vein and bile duct ligation.

There appears to be no substantial evidence that brain GABAergic neurotransmission is increased in these models of chronic hepatic encephalopathy.
Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: A double-blind, randomized clinical trial
Authors: Uribe Misael , Campollo Octavio , Vargas Florencia , Ravelli Gian Paolo , Mundo Fernando , Zapata Laura , Gil Sofia , Garcia-Ramos Guillermo
Published: March 2007

A double-blind, controlled trial to study the efficacy of acidifying enemas of lactitol, a new galactoside-sorbitol disaccharide, and lactose vs. nonacidifying tapwater enemas was performed in 45 episodes of acute portal-systemic encephalopathy. At the time of randomization, all patients had encephalopathy of at least Grade 2+ severity, delay in the performance of number connection tests and hyperammonemia. A sequential analysis was performed which revealed after the inclusion of the first 20 patients, a significant failure of the non-acidifying enemas as compared to the lactitol enemas (p < 0.004). The tap-water enema group was, therefore, suspended but the rest of the study continued after rerandomization for lactose and lactitol groups. A favorable response to treatment was obtained in 19 (86%) of the patients receiving lactitol enemas and in 14 (78%) of those receiving lactose enemas. A similar significant improvement in portal-systemic encephalopathy parameters and index was observed after both treatments. Both types of acidifying enemas induced a significant pH decrease in stool (p < 0.05). These data suggest that acidifying agents like lactose and lactitol are effective and superior to tap-water enemas for the treatment of acute nitrogenous portal-systemic encephalopathy.
Interaction of human liver connective tissue cells, skin fibroblasts and smooth muscle cells with collagen gels
Authors: Monteiro Alvaro N. A. , Borojevic Radovan
Published: March 2007

Interactions of liver connective tissue cells, skin fibroblasts and smooth muscle cells with collagen gels in vitro were studied and compared.

Liver connective tissue cells showed the lowest rate of migration into the gel and the highest speed of gel contraction, reflecting their high adhesiveness to the substrate as compared to the other cell lines studied.

The analysis of their ultrastructural morphology showed that liver connective tissue cells and smooth muscle cells developed cytoskeletal and cytoplasmic organelle polarities, in response to the contact with gel surface. This polarity was lost when cells were embedded in the gel. Skin fibroblasts did not show this characteristic, neither on top nor in the gel.

Although liver connective tissue cells have been recognized as analogous to smooth muscle cells, they represent a defined cell population, present in fibrotic livers, with specific behavior and with particular relationship to the extracellular matrix.
Leukotrienes as mediators in frog virus 3-induced hepatitis in rats
Authors: Hagmann Wolfgang , Steffan Anne-Marie , Kirn André , Keppler Dietrich
Published: March 2007

The role of leukotrienes was investigated in frog virus 3-induced hepatitis in rats. Frog virus 3 elicited an enhanced generation of cysteinyl leukotrienes in vivo as monitored by measurement of N-acetyl-leukotriene E4 as the major endogenous metabolite of cysteinyl leukotrienes secreted into rat bile. N-Acetyl-leukotriene E4 concentrations were elevated for more than 4 hr after frog virus 3 injection. In vitro experiments using cultured rat liver Kupffer cells of high purity indicated that these cells can produce and metabolize leukotrienes and are thus a possible source of leukotrienes elicited in vivo by frog virus 3. The selective 5-lipoxygenase inhibitor AA 861 and the dual inhibitor of arachidonate lipoxygenase and cyclooxygenase, BW 755C, reduced the hepatocellular injury after a high dose of frog virus 3 by about 50 and 80%, respectively, as judged from plasma activities of ALT and sorbitol dehydrogenase at 24 hr after frog virus 3 administration. Our in vivo and in vitro studies argue in favor of an important role of leukotrienes as mediators in frog virus 3 hepatitis in rats.
RNA transcripts of hepatitis B virus in hepatocellular carcinoma
Authors: Imazeki Fumio , Yaginuma Katsuyuki , Omata Masao , Okuda Kunio , Kobayashi Midori , Koike Katsuro
Published: March 2007

The states of hepatitis B virus DNA, RNA transcripts and antigens (HBsAg and HBcAg) were studied in the liver with hepatocellular carcinoma by blot hybridization and immunohistological methods. We used whole hepatitis B virus DNA and gene specific probes (S, C and X genes) for hybridization. Integrated viral DNA was found in all five tumors, but episomal DNA was not detected in the neoplastic tissue. In the nonneoplastic cirrhotic liver, episomal DNA was found in four cases and integrated viral DNA in four cases. A large amount of hepatitis B virus-specific RNA transcripts was demonstrated in nonneoplastic liver of all five cases. Two major transcripts, 2.4 and 3.4 kb in length, were identified. The former hybridized with the S gene probe and the latter with the C gene probe, suggesting that they were messenger RNAs for HBsAg and HBcAg, respectively. In contrast to nonneoplastic liver, RNA transcripts were found in the neoplastic portion in only two cases, small in quantity; they primarily hybridized with S and X, but not with C genes. Novel species of 4.0 and 3.9 kb transcripts were found in the neoplastic and the nonneoplastic portions, respectively, in one case. They may represent fusion transcripts of integrated viral DNA and cellular flanking sequences.
The nature of cell death in piecemeal necrosis: Is order emerging from chaos?
Authors: Powell Lawrie W.
Published: March 2007

Electron microscopic studies of acidophilic or Councilman-like bodies in the liver show that they are manifestations of apoptosis. The morphology and biochemistry of apoptosis suggest a process of active cellular self-destruction rather than degeneration. The incidence of apoptosis indicates that it is normally involved in the regulation of organ size and, in addition, may be triggered by specific pathological stimuli. Cell death produced in vitro by various types of cell-mediated immune injury occurs by apoptosis

The occurence of apoptosis in hepatic disease is illustrated and discussed. That it constitutes the only clearly identifiable mode of cell death in most types of acute and chronic hepatitis and in primary biliary cirrhosis is in accord with current concepts of the pathogenesis of these conditions. Furthermore, the morphological features of apoptosis may explain long-standing enigmas in the histology of hepatitis--the cryptic nature of the cell death in piecemeal “necrosis” and the apparent drop-out of large numbers of hepatocytes in many cases of acute hepatitis without overt evidence of necrosis. Apoptosis represents rapid budding of a cell to form numerous globules, the largest of which appear to be acidophilic bodies. All apoptotic fragments are quickly removed by adjacent cells without evident inflammation, permitting the process to occur inconspicuously.
Lack of hepatic transferrin receptor expression in hemochromatosis
Authors: Sciot Raf , Paterson Alan C. , Van Den Oord Joost J. , Desmet Valeer J.
Published: March 2007

The major part of hepatocellular iron is derived from uptake of transferrin-bound iron by means of nonspecific fluid-phase endocytosis and specific, saturable binding on high-affinity transferrin receptors. We investigated the expression of transferrin receptors on hepatocytes in liver biopsies of 22 cases of hemochromatosis (21 primary hemochromatosis and 1 secondary hemochromatosis), using immunohistochemical demonstration of the human transferrin receptor with the specific monoclonal antibody OKT9. Fifty liver biopsies (normal and pathological) without demonstrable iron storage (Perls' stain negative) served as controls. In the controls, membranous and/or cytoplasmic transferrin receptor expression was always present on hepatocytes, albeit in variable numbers and patterns without obvious relation to the underlying liver disease. In 19 of 22 hemochromatosis cases with severe iron overload, OKT9 immunoreactivity on hepatocytes was completely absent. Three hemochromatosis cases showed few hepatocytes positive for OKT9. One showed mild iron overload, while the second, a successfully treated case, was free of iron. The remaining hemochromatosis case was a known alcoholic with severe iron overload. Since OKT9 binding to the transferrin receptor is not blocked by previous binding of transferrin, the findings show that in advanced hemochromatosis hepatocytes do not express transferrin receptors. This finding is in keeping with the inverse relation between transferrin receptor expression and exogenous iron supply in various cell cultures.

These results indicate that in hemochromatosis, apparently as a result of progressive iron overload, transferrin receptor expression on hepatocytes disappears. This leaves the hepatocytes with a nonsaturable mechanism for uptake of transferrin-bound iron (fluid-phase pinocytosis) and with uptake of potentially more toxic forms of nontransferrin-bound iron, which may represent up to 30% of serum iron in fully established hemochromatosis.
Two different subtypes of antimitochondrial antibodies are associated with primary biliary cirrhosis: Identification and characterization by radioimmunoassay and immunoblotting†
Authors: Manns Michael , Gerken Guido , Kyriatsoulis Apostolos , Trautwein Christian , Reske Konrad , Zum Büschenfelde Karl-Hermann Meyer
Published: March 2007

Antimitochondrial antibodies from patients with primary biliary cirrhosis react with different mitochondrial polypeptides as demonstrated by Western blots. The IgG fractions of a patient with primary biliary cirrhosis Stage I reacting exclusively with a pair of polypeptides at 48,000 daltons (p 48) on Western blot and from a patient with Stage III primary biliary cirrhosis reacting exclusively with a single 62,000 dalton polypeptide (p 62) were labeled with 125I; two radio-immunoassays were established detecting antimitochondrial antibodies against p 62 and p 48, respectively. Autologous sera blocked the assay, but the two reference sera did not block each other. Fourteen of 40 patients with primary biliary cirrhosis reacted with p 62, 6/40 with p 48 and 20 sera with both antigens. Sera from 200 patients with various hepatic and nonhepatic diseases were negative for anti-p 62 and anti-p 48. This collection of sera included 5 patients with nonhepatic autoimmune disorders, 3 with drug-induced pseudo-lupus syndrome and 2 with syphilis II, which were positive for antimitochondrial antibodies by immunofluo-rescence. Mitochondrial autoantigens p 62 and p 48 were both localized on mitoplasts, presumably inner mitochondrial membranes; they were thermolabile, trypsin- and chymotrypsin-sensitive, but resistant to DNAase, RNAase and neuraminidase treatments. In cesium chloride density gradients, p 62 floated at 1.28 gm per cm3 and p 48 at 1.30 gm per cm3. Thus, radio-immunoassays have been developed that specifically detect two distinct primary biliary cirrhosis-specific subtypes of antimitochondrial antibodies: anti-p 62 and anti-p 48. All primary biliary cirrhosis sera were positive for at least one of these antimitochondrial antibodies subtypes. The reaction of antimitochondrial antibodies with mitochondrial antigens p 62 and p 48 is due to different autoantibody subtypes and not due to identical determinants on different polypeptides.
Pancreatic hormones and amino acid levels following liver transplantation
Authors: Francavilla Antonio , Polimeno Lorenzo , Van Thiel David H. , Todo Saturo , Kam Igal , Lynch Stephen , Starzl Thomas E.
Published: March 2007

Glucose intolerance, hyperinsulinemia, peripheral insulin resistance and hyperglucagonemia are common in patients with advanced liver disease. These abnormalities in the plasma levels of the pancreatic hormones, insulin and glucagon have been thought to be responsible, at least in part, for the abnormal plasma ratio of branched-chain amino acids to aromatic amino acids. To evaluate this issue, plasma levels of glucose, insulin, glucagon, C-peptide and the branched-chain and aromatic amino acids were measured before and serially after orthotopic liver transplantation in 9 humans and 5 dogs. The abnormal plasma amino acid levels rapidly improved and achieved normal levels following orthotopic liver transplantation. Insulin levels also became normal following orthotopic liver transplantation, despite enhanced insulin secretion documented by an even further increased level of C-peptide. In contrast, the baseline abnormal plasma glucagon levels which are commonly seen in cirrhotics became even more abnormal following orthotopic liver transplantation. Despite this progressive increase in the abnormally elevated plasma glucagon levels, plasma amino acid levels, both branched-chain and aromatic, became normal. These data demonstrate that before and after orthotopic liver transplantation, there is: (i) no relationship between the changes in plasma levels of glucagon and changes observed in the plasma level of amino acids; and (ii) plasma insulin and amino acid levels change in the same direction. In addition, these changes in plasma insulin and amino acid levels following orthotopic liver transplantation occur despite enhanced secretion of insulin evidenced by the progressive increase in plasma levels of C-peptide.
Glycoside conjugation in microsomes from hepatic and renal carcinoma of man†
Authors: Matern Heidrun , Fiebig Heinz-Herbert , Matern Siegfried
Published: March 2007

Human hepatoma which had been xenografted into nude mice have been estimated for their ability to catalyze glucuronic acid and glucose conjugation of endogenous compounds and p-nitrophenol. The xenobiotic p-nitrophenol was glucuronidated with a comparable rate in microsomes from human hepatoma, human liver and host liver. With regard to glucuronic acid or glucose conjugation of the endogenous compounds of bile acids, bilirubin and steroid hormones, glucosidation of bile acids was the only conjugation mechanism that was not decreased or deficient in microsomes from hepatoma, but showed about a 2-fold increase in reaction rate compared to normal human liver. Human hepatoma and host liver were shown to respond to phenobarbital treatment which led to about a 2-fold increase in UDP-glucuronosyltransferase activity toward bilirubin in hepatoma and in host liver. Compared to normal tissues, alterations in the pattern of glycoside conjugating enzymes were not only observed in microsomes from human hepatoma, but also in microsomes from human adenocarcinoma of the kidney, exhibiting negligible UDP-glucuronosyltransferase activities toward bile acids and steroid hormones. Bile acid glucoside formation was measurable in kidney adenocarcinoma with an activity which was similar to the activity observed in hepatoma. In comparison to normal renal tissue, glucose-conjugating activity toward bile acids decreased about 2-fold in kidney adenocarcinoma.
Gallstone disease without gallstones: A partial answer
Authors: Small Donald M.
Published: March 2007

Although bile acid and bile lipid metabolism have been studied in established cholelithiasis, little is known about them in patients destined to develop gall stones, but in whom the stones have not yet appeared (prestone gall stone disease). After confirmed complete gall stone dissolution and withdrawal of treatment, gall stones recur frequently. Before the stones reappear, these patients have ‘poststone gall stone disease.’ In 13 such patients we confirmed complete gall stone dissolution with two normal cholecystograms and in 11 of the 13 by normal ultrasonography, measured bile acid and bile lipid composition in fasting duodenal bile, bile acid synthesis from marker corrected three day faecal bile acid excretion, bile acid pool size using an abbreviated isotope dilution technique, ‘steady-state’ bile lipid secretion using a duodenal amino acid perfusion system and then calculated the enterohepatic cycling frequency of the bile acid pool and the relationship between pool size and body weight. The results confirm that after withdrawal of treatment the biliary cholesterol saturation index reverts to levels (1.6 ± SEM 0.4) comparable with those before dissolution therapy first began (1.6 ± 0.2; NS). The mean bile acid pool size in the 13 patients of 4.4±0.5 mmol was comparable with that in untreated gall stone patients. Pool size was significantly smaller in the nine non-obese patients (3.5 ± 0.3), than in the four obese (6.0 ± 0.8; p < 0.05). It also correlated significantly with body weight (r = 0.72) and with %IBW (r = 0.79). The coefficients of variation for biliary bile acid, phospholipid and cholesterol secretion were high, but the mean hourly secretion rates were of the same order as those seen in untreated gall stone patients studied with the amino acid duodenal perfusion stimulus. These results provide a baseline for assessing the response to postdissolution treatment and may indicate metabolic events leading to gall stone formation.
Is fulminant B hepatitis more common among infants born to e antigen-negative carrier mothers?
Authors: Okuda Kunio
Published: March 2007

A total of 105 cases of fulminant hepatitis sen during the period fom January 1979 to December 1983 and filed by the pediatric services of major hospitals throughout Japan with the diagnostic criteria set by the 12th Inuyama Liver Symposium were analyzed. The male:Female atio was 2:1. Fifty-six per cent of he cases werre younge than 2 years and 29.5% were thought to be due to hepaitis B infection. The majority of B-type fulminant heptitis cases younger than 6 months not related to blood transfusion had been born to HBeAg-negative caie mohers. The overall ftality was 85.7% and there was no difference betwen the acutte and subacute varieties of fulminant hepatic failure.
α1-Adrenergic effects and liver regeneration
Authors: Cruise Jennifer L. , Knechtle Stuart J. , Bollinger Randal R. , Kuhn Cynthia , Michalopoulos George
Published: March 2007

The effects of several treatments involving α-adrenergic mechanisms upon the early stages of rat liver regeneration were examined. Catecholamine concentrations in rat plasma were measured at various times after hepatectomy and were found to be elevated relative to those in plasma from sham-operated rats. Surgical hepatic denervation or injection of an α1-adrenergic receptor antagonist (prazosin) reduced incorporation of [3H] thymidine into liver DNA during the first 24 hr after partial hepatectomy. Chronic guanethidine injections (3 to 6 weeks) reduced liver catecholamine levels, but did not affect its ability to regenerate.

The inhibition of regenerative DNA synthesis by prazosin was preceded by an alteration in the binding of epidermal growth factor to regenerating liver, which was apparently the result of an increased number of epidermal growth factor receptors. Thus, α1-adrenergic blockade, which affects both epidermal growth factor receptor binding and subsequent DNA synthesis in hepatocyte primary cultures, can also modulate these processes during liver regeneration in vivo.
Hepatic heme synthesis in a new model of experimental hemochromatosis: Studies in rats fed finely divided elemental iron
Authors: Bonkovsky Herbert L. , Healey John F. , Lincoln Beth , Bacon Bruce R. , Bishop David F. , Elder George H.
Published: March 2007

Rats fed chow containing finely divided elemental iron (from carbonyl-iron) develop hepatic iron overload resembling human hereditary hemochromatosis in that deposition of iron is primarily in periportal hepatocytes and with hepatic iron concentrations sufficiently high to be associated in the human disease with hepatic fibrosis or cirrhosis. In recent studies using this model, we reported changes in hepatic hemoproteins and heme oxygenase, the rate-controlling enzyme of heme breakdown. We now report effects of iron-loading on three enzymes of heme synthesis: 5-aminolevulinate synthase; the first and rate-controlling enzyme of the pathway, 5-aminolevulinate dehydrase (or porphobilinogen synthase), and uroporphyrinogen decarboxylase, the activity of which is decreased in porphyria cutanea tarda, a liver disease in which iron is known to play an important but still poorly understood role. Of the three enzymes, only activity of the dehydrase was altered by iron-loading: it was decreased significantly as early as 1 week after starting iron feeding, and with marked iron overload was 30 to 32% of control values. The degree of decrease was inversely related (r = −0.77 to −0.88) to the degree of iron overload and was partially reversed within 1 to 3 days when feeding of the iron-supplemented diet was stopped. The decrease in dehydrase activity was not attributable to lack of reduced glutathione or other disulfide-reducing agents or to zinc deficiency; nor was evidence found for inhibition by iron compounds or other possible inhibitors present in iron-loaded livers. Immunochemical studies showed that the amount of 5-aminolevulinate dehydrase protein decreased in parallel to its decrease in activity, suggesting that iron-loading produced a reversible imbalance between the rate of synthesis and breakdown of the enzyme.
Biochemical characteristics of isolated rat liver stellate cells
Authors: Yamada Masao , Blaner William S. , Soprano Dianne Robert , Dixon Joseph L. , Kjeldbye Hild M. , Goodman Dewitt S.
Published: March 2007

Hepatic stellate cells play a quantitatively important role in hepatic retinoid metabolism and storage in rats maintained under normal nutritional conditions. Studies were conducted to further explore the biochemical characteristics of hepatic stellate cells. Stellate cells were isolated in high purity and yield from the livers of normal rats. The isolated cells had the morphology expected (on electron micrographs) for stellate cells, and were enriched in retinoids and in the intracellular retinoid-binding proteins. The composition of the stellate cell lipid droplets was examined. These lipid droplets were isolated in high purity and integrity from frozen and thawed stellate cell preparations by differential centrifugation. We estimate that the lipid composition of stellate cell lipid droplets consisted of approximately 42% retinyl ester, 28% triglyceride, 13% cholesterol (total) and 4% phospholipid. Thus, stellate cell lipid droplets contain substantial levels of both cholesterol and triglyceride, in addition to retinyl esters. Stellate cell homogenates were assayed for both retinol-binding protein and transthyretin by specific radioimmunoassays. Within the detection limits of these radioimmunoassays, we were unable to detect the presence of either retinol-binding protein (<9 ng per 106 cells) or transthyretin (<11 ng per 106 cells) in the stellate cell preparations. Total RNA, prepared from the isolated stellate cells, was examined by Northern blot analysis for retinol-binding protein mRNA and transthyretin mRNA, using cDNA probes for retinol-binding protein and transthyretin. Within the sensitivity of these assays, retinol-binding protein mRNA and transthyretin mRNA were not detected in stellate cells. These findings suggest that stellate cells do not synthesize or accumulate retinol-binding protein.
Effect of colchicine and phalloidin on the distribution of three plasma membrane antigens in rat hepatocytes: Comparison with bile duct ligation
Authors: Durand-Schneider Anne-Marie , Maurice Michèle , Dumont Micheline , Feldmann Gérard
Published: March 2007

The hepatocyte plasma membrane presents a morphological and functional regionalization into three domains: the sinusoidal; the lateral, and the canalicular. The mechanisms responsible for the biogenesis and maintenance of this regionalization are poorly understood. In this work, we have used colchicine and phalloidin, two drugs known to interfere with the secretory processes in hepatocytes, to study whether they also affect the transport of membrane proteins. The localization of three plasma membrane antigens was studied by light and electron microscopy using monoclonal antibodies identifying either the sinusoidal (A39) or the lateral (B1) or the canalicular (B10) domains in normal hepatocytes. In rats injected with colchicine (0.25 mg per 100 gm), A39 moved from the sinusoidal membrane to the lateral and canalicular ones, whereas B10 was displaced from the canalicular to the sinusoidal and lateral membranes, resulting after 8 hr in an almost equal labeling of the three domains with both antibodies. In rats injected daily for 7 days with phalloidin (50 μg per 100 gm), A 39 became mainly localized on the bile canalicular membrane instead of the sinusoidal one; B10 predominated on the canalicular membrane as in controls but in places it labeled the sinusoidal and lateral domains as well. In bile duct-ligated rats studied for comparison for 4, 10 or 21 days, A39 and B10 localizations evolved as after phalloidin, but the changes were more marked. B1 was not affected by any of the treatments. In conclusion, colchicine, phalloidin and bile duct ligation do not seem to hinder the antigens in reaching the plasma membrane, but induce a redistribution of two of them, suggesting a disturbance in the biogenesis and/or control of the plasma membrane regionalization. Such an abnormal distribution could be involved in—or contribute to—the initiation of cholestasis.
Hepatic extraction of renin: Quantitation and characterization in the isolated perfused rat liver
Authors: Keiser Joan A. , Romero Juan C. , Kost Louis J. , Larusso Nicholas F.
Published: March 2007

Since the liver is thought to be the major organ for the metabolism of renin, the rate-limiting enzyme in the renin-angiotensin cascade, we examined the kinetics and regulation of renin extraction by the isolated perfused rat liver. Partially purified, hog kidney renin was continuously infused into isolated rat livers perfused in a nonrecirculating manner with serum-free medium. Concentrations of renin in the portal and hepatic veins were measured by radioimmunoassay and first-pass hepatic extraction calculated. In livers from normal rats, steady-state, first-pass hepatic extraction of porcine renin ranged from 12.3 ± 0.9 to 25.5 ± 3.9% of the infused dose; at high renin infusion rates, hepatic extraction was saturable. Administration of captopril, a converting enzyme inhibitor, decreased hepatic extraction of renin by approximately 60%; enalaprilat, another converting enzyme inhibitor, had no effect. First-pass hepatic extraction of renin was also inhibited by the bile acid, taurocholate, in a dose-dependent manner. However, bilateral nephrectomy, which reduced endogenous plasma renin activity to unmeasurable levels, had no significant effect on hepatic extraction of renin by livers isolated from nephrectomized rats. These results demonstrate directly that the liver extracts renin in a dose-dependent and saturable manner, although the precise mechanism of uptake remains to be determined.
Chemoimmunotherapy of experimental hepatic metastases
Authors: Williams David L. , Sherwood Edward R. , McNamee Rose B. , Jones Ernest L. , Browder William I. , di Luzio Nicholas R.
Published: March 2007

Previous studies from our laboratory have demonstrated that particulate glucan is efficacious in the therapy of a syngeneic murine reticulum cell sarcoma (M5706), which specifically metastasizes from its primary site to the liver. The present study was undertaken to examine the therapeutic efficacy of a newly developed soluble glucan, in combination with cyclophosphamide in the treatment of hepatic metastatic disease. Male C57Bl/6J mice were injected subcutaneously on Day 0 with 1 × 104 sarcoma cells. Glucan (200 mg per kg i.v.), cyclophosphamide (45 mg per kg i.p.) or glucan and cyclophosphamide were administered beginning on Day 20, when hepatic metastases were evident, and continued at 3-day intervals up to Day 50. Combined therapy with glucan and cyclophosphamide resulted in reduction of hepatic metastatic lesions on Day 36, compared to control. Survival data revealed that the combination of glucan and cyclophosphamide significantly (p < 0.001) extended median survival time and the time to 100% mortality in an additive fashion, when compared to either therapy alone. Glucan-cyclophosphamide therapy was also effective in decreasing primary tumor weight to a level that was significantly (p < 0.05) less than when therapy was initiated. In vitro studies revealed that Kupffer cell tumoricidal activity against sarcoma was increased (p < 0.05) following glucan and cyclophosphamide. Glucan and cyclophosphamide also enhanced bone marrow proliferation and splenocyte response to mitogens in vitro. Additionally, glucan was observed to exert a direct cytostatic effect on sarcoma in vitro. Our results denote that soluble glucan-cyclophosphamide exerts antitumor activity by: (i) activation of Kupffer cell cytolytic activity; (ii) enhancing cell-mediated immunity, and (iii) exerting a direct cytostatic effect on sarcoma M5076.
Acute non-B hepatitis in the Israel defence forces: Comparison of some epidemiologic features before and after the usage of preexposure immune serum globulin prophylaxis
Authors: Matzkin Haim
Published: March 2007

Large-scale epidemics of non-B (HBsAg-negative) hepatitis have occurred in the Israel Defense Forces prior to post- and preexposure immune serum globulin administration. Presently, hepatitis morbidity rates have stabilized around 1 to 2 per 1,000. Several years after vaccine initiation, a comparison of epidemiological features was made in order to redefine risk groups. Seasonal morbidity, sex, ethnic origin and educational status (as a representative of socioeconomic level) were not different after the preexposure immunization compared to the preimmunization era. Therefore, a more selective immunization is proposed.
Interleukin 1: Regulation of hepatic carbohydrate metabolism by insulin or insulinomimesis
Authors: Owen Oliver E.
Published: March 2007

The purpose of this study was to investigate the effect of interleukin 1 (IL 1) on glucocorticoid-regulated hepatic metabolism. Steroid binding in liver cytosol, plasma glucose, plasma corticoster-one, and phosphenolpyruvate carboxykinase (PEPCK) activity were assayed in C3H/HeJ mice after IL 1 administration. Mice received 5 pyrogenic U (PU) of rabbit IL 1 i.p. and were sacrificed 4 hr later. In adrenal-intact mice, steroid binding and plasma glucose were significantly decreased (63 and 64% of control) and plasma corticosterone was significantly elevated threefold. In adrenalectomized mice, IL 1 (5 PU) treatment produced similar results in steroid binding (66% of control) and plasma glucose (71% of control). PEPCK was measured in intact mice fasted overnight and treated with 5 PU of IL 1. PEPCK was induced in fasted control animals (23.1 ± 1.4 U/mg) vs fed control animals (15.9 ± 0.7 U/mg). IL 1 treatment inhibited the induction of PEPCK in fasted animals (13.4 ± 2.0 U/mg) and caused a significant decrease in steroid binding (78% of fasted control) and plasma glucose (82% of fasted control). No difference in plasma corticosterone was seen in IL 1-treated mice and fasted control mice. These data indicate that IL 1 decreases intracellular steroid receptors, resulting in decreased induction of PEPCK and subsequent reduced gluconeogenesis and plasma glucose. We propose that IL 1 plays a regulatory role in glucocorticoid-regulated hepatic metabolism.
Oriental hornet venom-induced hepatic injury: The first animal-produced hepatotoxin?
Authors: ZIMMERMAN HYMANJ
Published: March 2007

The hepatotoxic effect of venom sac extract (VSE) of the Oriental hornet has already been demonstrated using the well-known models of experimental toxicology: in vivo, isolated in situ and in vitro. The present work deals with a series of 48 rats treated daily with 5 mg VSE/kg body weight for 1-14 days. Serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT) were measured. Liver tissue fractionation was performed. Detailed information on the topographical and functional aspects of some enzyme changes was obtained in respect to the number of envenomations. The biochemical alterations are partially reversible. The biochemically proven liver damage induced by VSE correlated well with previous electron microscopic observations of damage to mitochondria and cell membranes.