bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic Effects of Glucagon in Portal Hypertension
Authors: Silva Guillermo , Navasa Miquel , Bosch Jaime , Chesta Jaime , Pizcueta Pilar M. , Casamitjana Rosa , Rivera Francisca , Rodes Joan
Published: March 2007

It has been suggested that glucagon contributes to the pathogenesis of portal hypertension by increasing portal blood flow. This study examined this issue by assessing the hemodynamic effects of a pharmacological dose of glucagon (1 mg, intravenously) in patients with cirrhosis and portal hypertension (n = 10) and in subjects without significant liver disease (controls = n = 5). Patients with cirrhosis had much higher glucagon levels than control subjects (875 ± 167 vs. 186 ± 25 pg/ml, p < 0.01) and showed blunted hemodynamic responses after glucagon administration. This occurred despite greater circulating glucagon levels, probably because of a significant prolongation of the plasma half–life of exogenously administered glucagon (4.9 ± 0.4 vs. 2.7 ± 0.1 min, p < 0.1). Control subjects had marked increases in heart rate (+19% ± 4%, p < 0.01), cardiac index (+16% ± 4%, p = 0.01) and arterial pressure (+ 10% ± 3%, p < 0.05), but corresponding changes in patients with cirrhosis (+ 7% ± 1%, +6% ± 1%, and +6% ± 2%, respectively) were significantly less pronounced (p = 0.05), and there was a negative correlation between basal glucagon levels and the response of heart rate to glucagon injection (r = –0.804, p < 0.001). Resistance to the systemic effects of glucagon in cirrhosis may thus be caused by a down–regulation of vascular glucagon receptors. In addition, glucagon adminstration caused a significant increase in portal pressure (from 18.1 ± 1.1 to 19.0 ± 1.2 mm Hg, p < 0.01), as well as in azygos blood flow (from 0.54 ± 0.03 to 0.64 ± 0.04 L/min, +19% ± 4%, p < 0.02), reflecting increased portocollateral blood flow. These findings are consistent with the hypothesis that glucagon is one of the factors contributing to the splanchnic vasodilatation and increased portal pressure of cirrhosis.
Mhc Antigen Expression in Human Liver Grafts: Its Role in Rejection
Authors: Snover Dale C.
Published: March 2007

The present study documents major histocompatibility complex (MHC) Class I and II expression during early acute rejection of human liver grafts. Serial graft biopsies (pretransplant, time zero, and 1 week) were studied. Ten patients received azathioprine (AZA) and prednisone; the other six patients were treated with quadruple therapy (azathioprine, cyclosporine A, prednisone, and cyclophosphamide). To study the specificity of changes in MHC antigen expression, biopsies of six patients with minor or no morphologic abnormalities served as controls. In addition, phenotypes of inflammatory cells present during rejection were analyzed using a panel of monoclonal antibodies. The results show that during acute rejection expression of MHC Class I and II antigens increased significantly in the AZA–treated patients, in a pattern similar to that seen in the patients treated with quadruple therapy, showing enhanced MHC Class I expression on hepatocytes, bile duct epithelium, and sinusoidal endothelium, and Class II antigen on Kupffer cells and sinusoidal endothelium. Bile duct epithelium was consistently positive for Class II antigen; no significant difference with the nonrejection group was observed. T cells are the predominant inflammatory cells during rejection with equal quantities of CD4 + and CD8 + cells. A majority of the infiltrating T cells show expression of Class II antigen but do not react with antiinterleukin–2 receptor antibody. This may be the result of immunosuppressive therapy or a simple reflection of the temporary expression of interleukin–2 receptors during lymphocyte activation. The authors hypothesize that the induction of MHC antigens on bile duct epithelium leads to rejection whereas the expression on hepatocytes represents an epiphenomenon.
Intracellular Acidosis: Can It Delay the Inevitable?
Authors: Moseley Richard H.
Published: March 2007

The relationships between extracellular pH (pHo), intracellular pH (pHi), and loss of cell viability were evaluated in cultured rat hepatocytes after ATP depletion by metabolic inhibition with KCN and iodoacetate (chemical hypoxia). pHi was measured in single cells by ratio imaging of 2′, 7′ –biscarboxy–ethyl–5, 6–carboxyfluorescein (BCECF) fluorescence using multiparameter digitized video microscopy. During chemical hypoxia at pHo of 7.4, pHi decreased from 7.36 to 6.33 within 10 min. pHi remained at 6.1-6.5 for 30-40 min. (plateau phase). Thereafter, pHi began to rise and cell death ensued within minutes, as evidenced by nuclear staining with propidium iodide and coincident leakage of BCECF from the cytoplasm. An acidic pHo produced a slightly greater drop in pHf, prolonged the plateau phase of intracellular acidosis, and delayed the onset of cell death. Inhibition of Na+/H+ exchange also prolonged the plateau phase and delayed cell death. In contrast, monensin or substitution of gluconate for Cl- in buffer containing HCO3
- abolished the pH gradient across the plasma membrane and shortened cell survival. The results indicate that intracellular acidosis after ATP depletion delays the onset of cell death, whereas reduction of the degree of acidosis accelerates cell killing. We conclude that intracellular acidosis protects against hepatocellular death from ATP depletion, a phenomenon that may represent a protective adaptation against hypoxic and ischemic stress.
Phenobarbital Influences the Development of Sodium Retention in Liver Disease Induced by Bile Duct Ligation in the Rat
Authors: Wensing Georg , Branch Robert A.
Published: March 2007

The onset of sodium retention in phenobarbital/carbon tetrachloride–induced cirrhosis in rats is preceded by a linear decrease in hepatic function as assessed by the aminopyrine rate constant of elimination. Sodium retention occurs when liver function decreases below a critical aminopyrine rate constant of elimination threshold of 1 min- × 10-3. The objective of this study was to investigate this relationship in a different experimental model of cirrhosis in rats and to learn whether alteration of drug–metabolizing activity by hepatic enzyme induction changes the threshold for urinary sodium retention. Cirrhosis was induced in untreated and phenobarbital–treated rats by bile duct excision. Liver function, assessed by the aminopyrine breath test, and urinary sodium excretion on a constant salt diet were measured weekly for up to 4 wk. In untreated rats, the aminopyrine breath test rate constant of elimination was reduced by about 40% within 1 wk of surgery. Aminopyrine rate constant of elimination then decreased more slowly, but linearly. Urinary sodium excretion was initially unchanged, but sodium retention occurred after 2.5 wk and was maintained until the end of the experiment. Phenobarbitaltreated rats had greater initial aminopyrine rate constant of elimination, but we saw a similar fall in aminopyrine rate constant of elimination of about 40% within 1 wk of bile duct excision to a value still above baseline aminopyrine rate constant of elimination of untreated controls. Aminopyrine rate constant of elimination remained at a plateau for 3.5 wk without changes in urinary sodium excretion. After 3.5 wk, a sudden decrease in aminopyrine rate constant of elimination was associated with the sudden onset of sodium retention. Aminopyrine rate constant of elimination was 1.2 min-1 × 10-2 in both groups when sodium retention occurred. There was no change in serum sodium, serum creatinine or creatinine clearance after sodium retention. These results suggest that the threshold of liver function below which sodium retention occurs is independent of the experimental model of cirrhosis. The observation that phenobarbital induction does not alter the threshold, despite increasing the metabolism of aminopyrine, and that it delays the onset of sodium retention indicates that induction with this drug also influences the hepatic determinant of renal function to a similar extent as oxidative metabolism.(HEPATOLOGY 1990; 11:773–778.)
Micronodular Transpormation (Nodular Regenerative Hyperplasia) of the Liver: A Report of 64 Cases Among 2,500 Autopsies and A New Classification of Benign Hepatocellular Nodules
Authors: Wanless Ian R.
Published: March 2007

Nodular regenerative hyperplasia is defined by he–patocellular nodules distributed throughout the liver in the absence of fibrous septa between the nodules. Most reports have been single cases so that the prevalencend clinical significance of nodular regenerative hyperplasia is uncertain. In this study, the hepatic histology of 2,500 consecutive autopsies was reviewed. A spectrum of nodular regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively similar but lesser degrees of noduler transformation was found with nodular regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively similar but lesser degrees of nodular transformation in a further 10.2%. Nodular transformation was also seen in 47% of livers with cirrhosis and 69% with portal veins was seen in all cases with nodlular regenerative byperplasal, but only 4.7% of these had evidence of portal hypertension.

The prevalence of various clinical states was compared in nodular regenerative hyperplasia and in controls. The reslults confirm, extend and quantify the spectrum of associated diseases. Nodular regenerative hyperplasia occurs in 5. 6% of individuals over age 80 and with increased frequency in patients with arteritis, polymyalgia rheumatica, massive tumor infiltration and mineral oil deposition. Nodular tumor infiltrtion and mineral oil deposition. Noduler regenerative hyperplasia appears to be the hepatic analogue of arterial and arteriolar nephrosclerosis.

A new classification of nodular transformation is proposed that encompasses the specturm of lessions described here and the previously defined entities of focal nodular hyperplasia, parial nodular transformation and “cirrhosis telangiectasia hepatis.” The major conclusion is that nodular regenerative yperplasia is a secendary and nonspecific tissue adaptation to tation to heterogeneous distribution of blood flow and does not represent a specific entity.(HEPATOLOGY 1990; 11:787–797.)
Liver Gene Expression During Chronic Dietary Iron Overload in Rats
Authors: Pietrangelo Antonello , Rocchi Emilio , Schiaffonati Luisa , Ventura Ezio , Cairo Gaetano
Published: March 2007

To clarify the pathogenesis of hepatic iron toxicity, we investigated the effect of chronic dietary iron overload on the expression of several genes in rat liver. After 10 wk of iron treatment, when only minor histological features of liver damage were appreciable, the level of pro–α2(I)–collagen mRNA was already higher than in control liver and increased further at 30 wk of treatment. Also, the relative amount of L ferritin subunit mRNA was enhanced early by iron load and was even more elevated at the latest time point considered, whereas neither H ferritin subunit nor transferrin mRNA levels were affected by iron treatment. In contrast, after chronic iron treatment, no variations were found in the steady–state level of mRNAs transcribed from liver–specific and preferentially expressed genes (albumin, α–fetoprotein, apolipoprotein A–1), growth–related genes (c–myc, c–Ha–ras and c–fos) and stress–induced genes (heat shock protein 70). These results suggest that chronic dietary iron overload in rats can specifically activate target genes in the liver (i. e., L ferritin and procollagen) in the absence of either histological signs of severe liver damage or alterations in differentiated liver functions.(HEPATOLOGY 1990; 11:798–804.)
Localization of the Heme–Binding Protein in the Cytoplasm and of A Heme–Binding Protein–Like Immunoreactive Protein in the Nucleus of Rat Liver Parenchymal Cells: Immunocytochemical Evidence of the Subcellular Distribution Corroborated by Radioimmunoassay and Immunoblotting
Authors: Fahimi Dariush H. , Voelkl Alfred , Vincent Styliani H. , Muller-Eberhard Ursula
Published: March 2007

The abundant heme–binding protein of the liver, probably identical with Z–protein or liver fatty acid–binding protein, has an apparent molecular weight of 14,000 Da and is presumably involved in the intracellular transport of a variety of compounds. The cellular and subcellular distribution of HBP in the liver was studied in adult male and female rats by postembedding immunocytochemistry using the protein A–gold technique. By light microscopic examination heme–binding protein is present exclusively in parenchymal cells and not found in the sinusoidal lining cells or other cells in portal tracts. Immunoreactivity for heme–binding protein is uniformly strong throughout the liver lobule in female rats but is markedly reduced in the pericentral region in male animals. By immunoelectron microscopy heme–binding protein immunoreactivity is localized in cytoplasm and nuclear matrix. The mitochondria and peroxisomes and the secretory apparatus are free of the label. In nuclei, gold labeling is confined to the interchromatin region (euchromatin) and nucleoli; condensed chromatin (heterochromatin) and nucleolus–associated chromatin are negative. The subcellular localization was substantiated by radioimmunoassay and immunoblotting of nuclear and cytosolic fractions. Immunoblotting shows that the heme–binding protein–like immunoreactive protein in the nucleus has a slightly larger molecular weight than that in the cytoplasm.(HEPATOLOGY 1990; 11:859–865.)
More About Mast Cells and Fibrosis in Porphyria Cutanea Tarda
Authors: Claman Henry N.
Published: March 2007

We quantitated numbers of mast cells in the sclerotic skin noted on the dorsa of the hands of 10 patients with porphyria cutanea tarda (PCT), and compared them with those of diffuse scleroderma and healthy controls. Mast cell counts in scleroderma and healthy controls. Mast cell counts in sclerodermoid skin of PCT patients were significantly greater than those in involved skin of 9 patients with diffuse scleroderma in its late stage and also greater than those in normal skin of 8 controls. When mast cell density was analyzed according to the depth of the dermis, an 84% increase was noted in the uppermost layer (0-0.2 mm in depth) and a 150% increase in the second uppermost layer (0.2-0.4 mm in depth) in the patients with PCT when compared with those in the corresponding sites of the controls. These results suggest a possible role of mast cells in the pathogenesis of sclerodermoid skin of PCT.
Depressed Liver Regeneration After Partial Hepatectomy of Germ–Free, Athymic and Lipopolysaccharide–Resistant Mice
Authors: Cornell Robert P. , Liljequist Barbara L. , Bartizal Kenneth F.
Published: March 2007

A hypothesis has been proposed by this laboratory that endogenous gut–derived lipopolysaccharide is responsible for systemic endotoxemia in animals with acute liver injury particularly after partial (67%) hepatectomy. Systemic lipopolysaccharide and possibly fibrin aggregates or tissue debris then elicit release of cytokines from phagocytizing macrophages and/or monocytes that may be essential for normal liver regeneration. To test this hypothesis liver regeneration was assessed in germ–free euthymic mice that lack the gram–negative bacterial source of lipopolysaccharide, as well as being deficient in lymphoid tissue and relatively resistant to endotoxin. To complement the germ–free animals, conventional athymic nude BALB/c mice and conventional lipopolysaccharide–resistant C3H/HeJ mice were also examined. Liver regeneration, quantified by [3H] thymidine incorporation into hepatic DNA after partial hepatectomy was performed on mice anesthetized with ether, was significantly depressed in germ–free euthymic and conventional athymic BALB/c mice and delayed in conventional lipopolysaccharide–resistant C3H/HeJ mice, as compared with conventional control BALB/c and C3H/HeN animals. Pretreatment of conventional euthymic control mice with lipopolysaccharide 24 hr before surgery significantly stimulated hepatic DNA synthesis after 67% liver resection. Germ–free euthymic, conventional athymic, and conventional lipopolysaccharide–resistant mice pretreated with endotoxin did not manifest significant stimulation of liver regeneration. Evidence is reviewed that cytokine release in response to endotoxin was depressed in germ–free euthymic, conventional athymic, and conventional lipopolysaccharide–resistant mice as compared with conventional euthymic controls. The inability to release cytokines in response to gut–derived endotoxin in the three murine strains studied or the paucity of endogenous lipopolysaccharide in germ–free animals may explain the significant depression or delay of liver regeneration as compared with conventional euthymic control mice.(HEPATOLOGY 1990;11:916–922.).
Effects of Branched–Chain Amino Acids on Nitrogen Metabolism in Patients With Cirrhosis
Authors: Weber Fredrick L. , Bagby Brenda S. , Licate Lucilla , Kelsen Steven G.
Published: March 2007

This study was conducted to determine whether an amino acid solution enriched with branched–chain amino acids altered protein catabolic rates and plasma ammonia in patients with cirrhosis. Nine stable subjects were given two peripheral intravenous infusions: a standard amino acid solution (solution A) and a branched–chain–enriched solution containing 97% more leucine (solution B). Each solution was given for separate 9–day (group 1, n = 6) or 3–day (group 2, n = 3) periods. Amino acid solutions delivered 0.7 gm protein kg-1 day-1. Diets provided an additional 0.3 gm protein plus maintenance calories. Protein turnover was assessed by a primed continuous infusion of [1–14C] leucine in six patients (three patients in group 1 and three patients in group 2). Nitrogen balance and urinary 3–methyl histidine excretion were determined in group 1 patients. Compared with solution A, solution B increased leucine flux and leucine oxidation but had no significant effect on protein synthesis or catabolism based on the plasma specific activity of either leucine or α–ketoisocaproic acid. The additional leucine infused with solution B was quantitatively oxidized. Nitrogen balance did not differ with the two solutions and there was also no difference in the urinary excretion of 3–methyl histidine, suggesting that muscle protein catabolism was unchanged. Plasma ammonia concentration decreased significantly during the infusion of solution B and was associated with a slight fall in plasma glucagon concentration. The results indicated that a branched–chain–enriched amino acid solution did not alter protein synthesis or catabolism although it did lower the plasma ammonia when compared with a standard amino acid formula in stable cirrhotic patients.(HEPATOLOGY 1990;11:942–950.).
Splanchnic and Renal Extraction of Circulating Type Iii Procollagen Aminoterminal Propeptide in Patients With Normal Liver Function and in Patients With Alcoholic Cirrhosis
Authors: Bentsen Kirsten D. , Henriksen Jens H. , Bendtsen Flemming , Hørslev-Petersen Kim , Lorenzen Ib
Published: March 2007

Splanchnic and renal extraction of circulating aminoterminal propeptide of type III procollagen and related antigens were studied in 12 patients with normal liver function and in 19 patients with alcoholic cirrhosis during catheterization.

Type III procollagen peptide in serum was measured in two assays: the Type III Procollagen Peptide Radioimmunoassay Kit, a new assay that selectively determines the intact propeptide (and larger type III propeptide–holding antigens) and the Type III procollagen Fab assay that measures both the intact propeptide and the smaller fragments that quantitatively dominate in serum.

A significant decrease in the concentration of the intact propeptide between the artery and the hepatic vein was found in the group with normal liver function (p < 0.01) and in patients with cirrhosis (p < 0.01). In patients with cirrhosis, however, the splanchnic extraction ratio of the intact propeptide (median = 0.04, range = –0.03 to 0.16) was significantly lower than in patients with normal liver function (median = 0.17, range = 0.05 to 0.36, p. < 0.01). The concentration of the intact propeptide in the hepatic vein was positively correlated to hepatic pressure (n = 18, r = 0.51, p < 0.05) and inversely correlated to indocyanine green clearance (n = 15, r = –0.61, p < 0.05). No splanchnic extraction could be demonstrated in the Type III propeptide Fab assay.

A significant renal extraction was found in the Fab assay, but not in Type III Procollagen Peptide Radioimmunoassay Kit. Similar extraction ratios were observed in both healthy patients (median = 0.11, range = 0.00 to 0.21) and cirrhotic patients (median = 0.14, range = 0.06 to 0.22).

Thus intact circulating type III procollagen peptide is extracted in the liver, and the extraction ratio is decreased in alcoholic cirrhosis. Smaller type III procollagen peptide–related antigens are extracted from the circulation by the kidneys.(HEPATOLOGY 1990;11:957–963.).
Vasopressin/Nitroglycerin Infusion Vs. Esophageal Tamponade in the Treatment of Acute Variceal Bleeding: A Randomized Controlled Trial
Authors: Teres Josep , Planas Ramon , Panes Julia , Salmeron Joan Manel , Mas Antoni , Bosch Jaime , Llorente Covadonga , Viver Josep , Feu Faust , Rodés Joan
Published: March 2007

Vasopressin infusion and esophageal tamponade are still widely used to arrest variceal bleeding, but no objective evidence exists on the superiority of either of the two procedures. In this study, 108 cirrhotic patients bleeding from varices were included in a prospective, randomized trial to investigate the comparative effectiveness and safety of balloon tamponade (using the Sengstaken–Blakemore tube for esophageal varices and the Linton–Nachlas tube for gastric varices) (n = 52) and intravenous vasopressin infusion (0.4 to 0.8 μ/min) plus intravenous nitroglyeerin infusion (40 to 400 μg/min) (n = 56). Both treatments were maintained for 24–hr. The hemostatic efficacy according to the intention to treat was 86.5% for tamponade and 66% for pharmacological therapy (p < 0.01). No significant differences were found with respect to rebleeding during the first 72 hr after treatment, mortality rate or side effects. These results suggest that esophageal tamponade is more effective than vasopressin/nitroglycerin infusion in the treatment of variceal bleeding in cirrhotic patients.(HEPATOLOGY 1990;11:964–968.).
Prostanoids and Leukotrienes in Experimental Feline Cholecystitis
Authors: Kaminski Donald L. , Daneshmand Hootan , Dean Philip , Deshpande Yashwant G.
Published: March 2007

Current information suggests that arachidonic acid metabolites are involved in the development of cholecystitis. The purpose of this study was to evalute eicosanoid formation during the development of experimental cholecystitis in cats. Lysophosphatidylcholine is found in the gallbladders of patients with cholecystitis and is known to be a cytolytic, membrane damaging substance. Anesthetized cats underwent gallbladder perfusion with and without 1.5 mmol/L lysophosphatidylcholine. Additional experiments were performed when calcium ionophore was added to the perfusates and experiments were performed when cats were treated with indomethacin and underwent perfusion with lysophosphatidylcholine. Changes in the gallbladder were determined by evaluating mucosal water transport as measured by determining the changes in concentration in a nonabsorbable marker, by protein secretion and by β–glucuronidase accumulation in gallbladder tissue as an index of inflammation. Eicosanoid formation was evaluated by measuring perfusate concentrations and gallbladder homogenate concentrations by radioimmunoassay of prostaglandin E, 6 keto prostaglandin F 1 α, leukotriene B4 and leukotriene C4. Lysophosphatidylcholine perfusion reversed the control patterns of absorption and produced water exsorption, produced an efflux of protein into the perfusate and increased β–glucuronidase activity. These changes were accompanied by increased production of prostaglandin E and 6 keto prostaglandin F1α in gallbladder perfusate and homogenate. The concentration of leukotrience C4 in gallbladder effusate was increased by lysophosphatidylcholine when compared with control values. Indomethacin inhibited the protein efflux, decreased β–glucuronidase levels and decreased prostaglandin E and 6 keto prostagladin F1 α formation when compared with values produced by lysophosphatidylcholine alone. Cyclooxygenase inhibition did not alter the secretion of water into the gallbladder or perfusate leukotriene C4 concentrations. Lysophosphatidylcholine alters gallbladder mucosal function, and these changes may be mediated by arachidonic acid metabolites.(HEPATOLOGY 1990;11:1003–1009.).
A Comparison of the Molecular Structure of Integrated Hepatitis B Virus Genomes in Hepatocellular Carcinoma Cells and Hepatocytes Derived From the Same Patient
Authors: Ogata Norio , Tokino Takashi , Kamimura Tomoteru , Asakura Hitoshi
Published: March 2007

To elucidate critical genetic elements in the development of hepatocellular carcinoma associated with hepatitis B virus DNA integration, a single integrant in hepatocellular carcinoma cells and one species of multiple integrants in hepatocytes, both obtained from the same patient, were compared structurally using molecular cloning techniques. Both hepatitis B virus integrants showed similar inverted repeat sequences consisting of two defective virus genomes. The recombination of viral DNAs seemed to be mediated by short regions of base homology near the direct repeat 1 and at other regions of the virus genomes in both integrants. The virus component in the junction with host DNAs was the cohesive end region in each identical end of the viral integrant in hepatocellular carcinoma cells and in one end of the viral integrant in hepatocytes. The structure of the integrant in hepatocellular carcinoma cells was characterized by an inverted, duplicated conformation composed not only of integrated virus genomes but also of flanking cellular sequences. It was shown to be the so–called “alpha dimer” of satellite DNA. In contrast, the flanking, nonreiterated cellular DNA in the hepatocyte–derived clone did not show discernible rearrangement.

These findings suggest that a common mechanism underlies the integeration of hepatitis B virus DNA so that a similar organization of inverted repeat genomes is found in hepatocellular carcinoma cells and in hepatocytes. The unstable nature of cellular DNA where DNA integration occurs may be important in generating chromosome alterations found in hepatocellular carcinoma (HEPATOLOGY 1990;11:1017–1023.).
Risk Factors for the Development of Hepatic Cysts in Autosomal Dominant Polycystic Kidney Disease
Authors: Gabow Patricia A. , Johnson Ann M. , Kaehny William D. , Manco-Johnson Michael L. , Duley Irene T. , Everson Gregory T.
Published: March 2007

Hepatic cysts are a major manifestation of autosomal dominant polycystic kidney disease. This study examined 239 autosomal dominant polycystic kidney disease patients and 189 unaffected family members to define the factors that influence the presence and severity of hepatic cysts. Autosomal dominant polycystic kidney disease patients with hepatic cysts were older than autosomal dominant polycystic kidney disease patients without such cysts (44.6 ± 1.1 yr vs. 32.9 ± 1.1 yr; p < 0.0001). The number of hepatic cysts increased with age (r = 0.43; p < 0.0001). Women were more likely to have massive hepatic cystic disease (> 15 cysts) than men (p < 0.04). Women also had larger maximal cyst men (p < 0.04). Women also had larger maximal cyst size (4.2 ± 0.4 cm vs. 2.7 ± 0.3 cm; p < 0.004). Women with hepatic cysts were more likely to have been pregnant (p < 0.001) and to have had more pregnancies (2.9 ± 0.3 pregnancies vs. 1.6 ± 0.2 pregnancies; p < 0.0009). Kidney volume (p < 0.0001), number of cysts (p < 0.004), percentage of cystic parenchyma (p < 0.001) and predominant cyst size (p < 0.001) were greater and creatinine clearance was lower (64.5 ± 3.1 ml/min/1.73 m2 vs. 94.5 ± 3.4 ml/min/1.73 m2; p < 0.001) in autosomal dominant polycystic kidney disease patients with hepatic cysts. By logistic regression, the frequency of hepatic cysts was related to increased age, increased severity of renal cystic disease and decreased creatinine clearance. Number and size of hepatic cysts correlated with the occurrence of pregnancy, female gender, increased age and severity of the renal lesion. In conclusion, the hepatic expression of the autosomal dominant polycystic kidney disease gene appears to be modulated by age, female gender, pregnancy, severity of the renal lesion and kidney function.(HEPATOLOGY 1990;11:1033–1037.).
Increased Prooxidant Action of Hepatic Cytosolic Low–Molecular–Weight Iron in Experimental Iron Overload
Authors: Britton Robert S. , Ferrali Marco , Magiera Christopher J. , Recknagel Richard O. , Bacon Bruce R.
Published: March 2007

In the iron–loaded liver there may be an increase in the putative intracellular transit pool of iron, components of which could be catalytically active in stimulating lipid peroxidation. To study the levels of low–molecular–weight, catalytically active iron in the liver, cytosolic ultrafiltrates were tested in an assay containing rat liver microsomes and NADPH. Malondialdehyde production was used as an index of lipid peroxidation. This assay system was sensitive enough to detect 0.25 μmol/L ferrous iron; progressive but nonlinear increases in malondialdehyde were produced as the iron concentration was increased to 5 μmol/L. Ultrafiltrates from hepatic cytosol of iron–loaded rats had greater prooxidant action than did those from controls. When added to the assay, deferoxamine, an iron chelator, completely suppressed the prooxidant action of hepatic ultrafiltrates, showing that this activity is iron–dependent. Deferoxamine administered intraperitoneally to control animals at a dose of 1 gm/kg completely inhibited the prooxidant effect of hepatic ultrafiltrates prepared from rats killed after 1, 2 and 3 hr. Partial inhibition was observed at 4 hr; by 6 hr the inhibitory effect of deferoxamine was completely lost. Administration of deferoxamine (1 gm/kg intraperitoneally, 1 hr before killing) completely inhibited the prooxidant action of hepatic ultrafiltrates in moderately iron–loaded rats and control but had no protective effect in heavily iron–loaded rats. These results support the concept that iron overload results in an increase in a hepatic cytosolic pool of low–molecular–weight iron that is catalytically active in stimulating lipid peroxidation. This pool can be chelated transiently in vivo by deferoxamine in moderate, but not heavy, iron overload.(HEPATOLOGY 1990;11:1038–1043.).
Low–Dose Corticosteroid Therapy After Multiple Relapses of Severe Hbsag–Negative Chronic Active Hepatitis
Authors: Czaja Albert J.
Published: March 2007

To evaluate the efficacy of low–dose corticosteroid therapy after multiple relapses of severe HBsAg negative chronic active hepatitis, 22 patients who had relapsed on 3.4 ± 0.4 occasions (range = two to seven relapses) were treated with the lowest dose of medication necessary to ameliorate symptoms and maintain serum AST activity below five–fold normal. Results were compared with those in 31 patients who had received conventional retreatments after 3.4 ± 0.3 relapses (range = two to eight relapses). During 44 ± 7 mo of low–dose therapy (range = 9 to 149 mo), one patient (5%) entered sustained remission, 16 patients (72%) continued treatment, two patients (9%) died of liverrelated complications and one patient (5%) died of a nonliver–related cause. Drug–related side effects improved in 11 of 13 patients who had acquired them during conventional therapy (85%). The median dose of prednisone was 7.5 mg daily (range = 1 to 17.5 mg) with and without azathioprine. Thirteen patients received long–term treatment consisting of 10 mg or less of prednisone only. Patients receiving conventional treatment entered remission more frequently than those on low–dose therapy (97% vs. 36%, p < 0.001) but they relapsed after drug withdrawal (53% vs. 87%, p > 0.1), required continuous therapy (55% vs. 72%, p > 0.1) and died of liver–related complications (10% vs. 9%) as commonly as those receiving low–dose therapy. We conclude that low–dose corticosteroid therapy in patients who have experienced multiple relapses has similar efficacy and less morbidity than conventional retreatments.(HEPATOLOGY 1990;11:1044–1049.).
Hepatitis B Virus and Hepatitis D Virus Replication in Hbsag–Positive Fulminant Hepatitis
Authors: Mas Antoni , Buti María , Esteban Rafael , Sánchez-Tapias José M. , Costa Josep , Jardí Rosendo , Bruguera Miquel , Guardia Jaime , Rodés Joan
Published: March 2007

Hepatitis B virus DNA and hepatitis D virus RNA, the most sensitive markers of hepatitis B and hepatitis D virus replication, were sought by molecular hybridization with radioactive probes in serial serum samples from 29 consecutive patients with HBsAg–positive fulminant hepatitis. Nineteen patients had evidence of hepatitis D virus infection, as assessed by the presence in serum of delta antigen, anti–delta antibodies, or both. Hepatitis B virus DNA was found in only two patients: one was a chronic HBsAg carrier with hepatitis D virus superinfection and the other had fulminant hepatitis caused by hepatitis B and hepatitis D coinfection. Hepatitis D virus RNA was detected in three patients: two with hepatitis B and hepatitis D coinfection and also in the HBsAg carrier with positive hepatitis B virus DNA and hepatitis D virus superinfection. None of 10 patients with hepatitis B virus infection alone had detectable viral nucleic acids in serum. Overall, viral nucleic acids were detected in the sera of 4 of the 29 patients (14%). Hepatitis D virus antigenemia did not indicate hepatitis D virus replication because hepatitis D virus RNA was not detected in 9 of 12 patients with hepatitis D virus antigen in their sera. The low frequency of viral replication found in fulminant hepatitis B or D may explain the low recurrence rate of viral hepatitis in patients with fulminant hepatitis who have received liver transplantations.(HEPATOLOGY 1990;11:1062–1065.).
Hormonal Responses to Large Paracentesis: Are Discordant Results Due to Technologic Differences?
Authors: Rodes Joan
Published: March 2007

The use of paracentesis has recently been reproposed as a safe and effective alternative to diuretics for management of ascites. We have investigated the clinical and biochemical effects of large–volume paracentesis in 19 cirrhotics with tense ascites, and the relative changes in the hormones involved in sodium and water renal handling. Plasma renin activity (PRA), aldosterone (PA), and arginine vasopressin (AVP) levels and conventional liver and renal function tests were measured before and 1, 2 and 7 days after the paracentesis. No complications were observed, but patients regained 37% of the weight lost after 1 wk. Percent weight regained was significantly and directly correlated with PA concentration measured before the paracentesis. No changes were recorded after paracentesis in biochemical and clinical data, except for a significant drop in diastolic blood pressure. No changes in AVP levels were observed. A signficant increse in PA occured after paracentesis, with a maximum peak after 48 h. The increase in PA was not accompanied by changes in PRA, but was associated with a reduction of urinary sodium excretion. A relevant fraction of body aldosterone was confined to the ascitic fluid. We conclude that the clinical results of a large–volume paracentesis can be predicted in part on the basis of PA measurement, and that removal of ascites is followed by an increase of PA of uncertain origin and effectiveness.
Abnormal Pressor Response to Vasopressin in Patients With Cirrhosis: Evidence for Impaired Buffering Mechanisms
Authors: Moreau Richard , Hadengue Antoine , Soupison Thierry , Mechin Guy , Assous Michel , Roche-Sicot Jacqueline , Sicot Christian
Published: March 2007

In patients with cirrhosis, vasopressin infusion induces sustained vasoconstriction and elevation of arterial pressure. The vasopressor effect could be caused by impairment of mechanisms normally aimed at buffering increases in arterial pressure (reflex bradycardia and decreases in arteriolar resistance). We studied the acute effects of continuous vasopressin infusion (0.4 IU/min) on systemic hemodynamics in seven patients with cirrhosis and in six patients without cirrhosis (controls). Vasopressin effects on systemic O2 consumption were also studied. In both groups, vasopressin infusion induced similar peak increases in arterial pressure, followed by similar decreases in heart rate and cardiac output. However, cirrhotic patients and controls differed 30 min after the start of vasopressin infusion. At 30 min, mean arterial pressure, diastolic arterial pressure and systemic vascular resistance remained significantly higher than preinfusion values in patients with cirrhosis. No decrease in systemic O2 consumption occurred in cirrhotic patients. In controls, at 30 min, mean arterial pressure and diastolic arterial pressure had returned to baseline. Systemic vascular resistance was not significantly higher than the preinfusion value and systemic O2 consumption had significantly decreased to below preinfusion values. We conclude that the vasopressor effect of vasopressin is abnormally sustained in patients with cirrhosis. This might be caused by insufficient buffering of vasopressin–induced arteriolar constriction rather than by abnormal vagal control of heart rate. In turn, as suggested by the lack of a decrease in systemic O2 consumption, persistent arteriolar constriction might be related to abnormally sustained sympathetic vascular tone in patients with cirrhosis. (Hepatology 1990;12:7-12).
Identification of Homozygous Hemochromatosis Subjects by Measurement of Hepatic Iron Index
Authors: Summers Kim M. , Halliday June W. , Powell Lawrie W.
Published: March 2007

The value of measurement of hepatic iron concentration and determination of the hepatic iron index in distinguishing homozygotes from heterozygotes for hemochromatosis was examined. The study group included 42 homozygotes with an unequivocal diagnosis of hemochromatosis and six individuals who had initial equivocal results but were established as homozygous after extensive follow–up. These were compared with 15 heterozygotes with no sign of increasing body iron stores who had undergone liver biopsy because of an initial suspicion of raised iron levels. In these subjects a hepatic iron concentration of greater than 75 μmol/gm dry weight was clearly indicative of homozygous hemochromatosis. Body iron accumulation was age–related both in homozygotes and in these heterozygotes with mild biochemical abnormalities (r = 0.476; p = 0.001 and r = 0.689; p = 0.01, respectively), with a rate of accretion of approximately 5 μmol/gm dry weight/year in homozygotes and 0.9 μmol/gm dry weight/year in heterozygotes. Thus, lower values in young subjects may be consistent with homozygosity, and higher values in older individuals are consistent with heterozygosity. To overcome this problem, the hepatic iron index (hepatic iron concentration divided by age in years) was analyzed and found to separate the two groups effectively, with no homozygote having an index of less than 1.9 and no heterozygote having an index of greater than 1.5. These results in a series of patients who have been followed for a median of 3 yr (range = 1 to 30 yr) validate the use of the hepatic iron index to discriminate hemochromatosis homozygotes from heterozygotes with raised levels of serum ferritin, transferrin saturation or both. (Hepatology 1990;12:20-25).
Prevention of Hepatocyte Injury and Lipid Peroxidation by Iron Chelators and α–Tocopherol in Isolated Iron–Loaded Rat Hepatocytes
Authors: Sharma Bipin K. , Bacon Bruce R. , Britton Robert S. , Park Chanho H. , Magiera Christopher J. , O'Neill Rosemary , Dalton Nicholas , Smanik Patricia , Speroff Theodore
Published: March 2007

These experiments were performed to characterize the relationship between lipid peroxidation and hepatocyte viability in iron overload. Hepatocytes were isolated from rats with chronic dietary iron overload and the effects of in vitro iron chelation on lipid peroxidation, cell viability and ultrastructure were studied over a 4–hr incubation period. Cell viability was significantly reduced at 3 and 4 hr in iron–loaded hepatocytes compared with controls and was preceded by an increase in iron–dependent lipid peroxidation. Similarly, extensive degenerative ultrastructural changes were observed in iron–loaded hepatocytes compared with controls after 4 hr of incubation. In vitro iron chelation with either deferoxamine or apotransferrin protected against lipid peroxidation, loss of viability and ultrastructural damage in iron–loaded hepatocytes. The addition of an antioxidant, α–tocopherol, also protected against lipid peroxidation and preserved cell viability over a 4–hr incubation. The protective effects of iron chelators and α–tocopherol support a strong association between iron–dependent lipid peroxidation and hepatocellular injury in iron overload. (Hepatology 1990;12:31-39).
Histopathology of α1–Antitrypsin Liver Disease in A Transgenic Mouse Model
Authors: Geller Stephen A. , Nichols Stephen W. , Dycaico Mark J. , Felts Katherine A. , Sorge Joseph A.
Published: March 2007

Transgenic mice were constructed using human α1–antitrypsin M and Z genomic clones. Livers of the M lineage mice showed slight cellular pleomorphism and immunohistochemically demonstrable finely granular α1–antitrypsin material in hepatocytes. Z lineage mice with five gene copies per haploid mouse genome (Z # 1) demonstrated fine granular α1–antitrypsin material and a few large globules. In contrast, Z lineage mice with 12 gene copies per haploid mouse genome (Z # 2) demonstrated hepatocytes filled with homogeneous, eosinophilic globules that were strongly reactive with diastase and periodic acid-Schiff and antibody to α1–antitrypsin. Scattered microscopic polymorphonuclear leukocyte accumulations were seen that contained extracellular α1–antitrypsin material, but there was neither histological nor serological evidence of mouse infectious hepatitis. In young animals, small clusters of hepatocytes lacking α1–antitrypsin material were seen. These cells were the dominant population in older animals and formed nodular arrangements. Fibrosis was not demonstrable in neonatal and young animals or in any of the controls, but perisinusoidal fibrosis was seen in older Z # 2 mice. Groups of hepatocytes without α1–antitrypsin material showed dysplastic changes. We conclude that the transgenic mouse is a reliable and useful model in which to study the effects of α1–antitrypsin in the liver because it demonstrates changes similar to those in the human disease. (Hepatology 1990;12:40-47).
Immunohistochemical Study of Adhesion Molecules in Liver Inflammation
Authors: Volpes Riccardo , van den Oord Joost J. , Desmet Valeer J.
Published: March 2007

Using monoclonal antibodies and in situ immunohistochemistry, we studied the distribution of “accessory” adhesion molecules (i.e., intercellular adhesion molecule–1 and leukocyte function-associated antigen–3) in 114 liver biopsy specimens with various inflammatory liver diseases and in 12 control liver biopsy samples without inflammation. The distribution of these adhesion molecules was compared with the presence on inflammatory cells of their natural ligands, lymphocyte function-associated antigen–1 and cluster of differentiation antigen–2, respectively.

In normal liver, intercellular adhesion molecule–1 and leukocyte function-associated antigen–3 reacted weakly with sinusoidal lining cells, portal vessel endothelium and scattered mononuclear inflammatory cells, whereas hepatocytes were constantly negative.

In contrast, all 114 biopsy samples of acute or chronic liver diseases revealed strong expression of intercellular adhesion molecule–1 and leukocyte function-associated antigen–3 on sinusoidal lining cells and on hepatocytes in areas of inflammation. Hepatocellular membrane positivity resulted in a “honeycomb pattern” of staining, which was panacinar in acute hepatitis and focal in chronic persistent or aggressive hepatitis. In various other chronic liver diseases, a multifocal periportal and intraacinar honeycomb pattern was detected. In all cases, a close topographical correlation was found between hepatocellular expression of intercellular adhesion molecule–1 and leukocyte function-associated antigen–3 on one hand and the presence of inflammatory cells expressing lymphocyte function-associated antigen–1 and cluster of differentiation antigen–2 on the other.

These data suggest that in inflammatory liver diseases adhesion between hepatocytes and inflammatory cells is mediated by two different pathways of cellular interaction, involving intercellular adhesion molecule–1/lymphocyte function-associated antigen–1 and leukocyte function-associated antigen–3/cluster of differentiation antigen–2. This may result in increased adherence and may facilitate antigen presentation to and activation of inflammatory cells. In this way, hepatocytes may play an active immunoregulatory role in the recruitment and retention of inflammatory cells during an immune response. (Hepatology 1990;12:59-65).
Histochemical and Immunohistochemical Evidence for Hepatic Zone 3 Distribution of Alcohol Dehydrogenase in Rats
Authors: Kato Shinzo , Ishii Hiromasa , Aiso Sadakazu , Yamashita Shuji , Ito Daisuke , Tsuchiya Masaharu
Published: March 2007

The distribution of alcohol dehydrogenase in the hepatic acinus was examined by both histochemical and immunohistochemical approaches. The immunohistochemical method using anti-alcohol dehydrogenase antibody indicated zone 3 predominance of this enzyme in the hepatic acinus, whereas a conventional histochemical method showed slight zone 1 predominance. However, when the histochemical technique was improved by using 2% glutaraldehyde instead of formalin for fixation and by adding phenazine methosulfate (0.33 mmol/L) to the staining incubation mixture, this method also supported zone 3 predominance of alcohol dehydrogenase. Evidence for zone 3 distribution of alcohol dehydrogenase may be of value in elucidating the mechanism of zone 3 liver damage by alcohol. (Hepatology 1990;12:66-69).
Characterization of A Phenotypically and Functionally Distinct Subset of Large Granular Lymphocytes (Pit Cells) in Rat Liver Sinusoids
Authors: Vanderkerken Karin , Bouwens Luc , Wisse Eddie
Published: March 2007

Pit cells, or large granular lymphocytes, with natural tumoricidal activity are found in the sinusoids of normal rat liver. Hepatic large granular lymphocytes are heterogeneous and can be subdivided into two subsets. These subsets were compared with peripheralblood large granular lymphocytes and were found to differ phenotypically and functionally. Phenotypical differences included lower expression of the asialo–GM1 marker of natural killer cells, lower cellular density and many more small cytoplasmic granules in hepatic large, granular lymphocytes. Low–density hepatic large, granular lymphocytes were five to eight times more cytotoxic than blood large, granular lymphocytes on a per–cell basis as measured against YAC–1 cells and colon carcinoma cells. In addition, hepatic large, granular lymphocytes were able to lyse P–815 target cells, which are resistant to blood natural killer cells. Large, granular lymphocytes isolated from the liver also contained a subset with intermediate phenotypical and functional characteristics, possibly representing a transitional form between blood and “liverspecific” large, granular lymphocytes. The liver thus contains a specific population of highly activated or further differentiated large granular lymphocytes. (Hepatology 1990;12:70-75).