bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum titers of pre-S(2) antigen in patients with acute and chronic type B hepatitis: Relation to serum aminotransferase activity and other hepatitis b virus markers
Authors: Kurai Kiyohiko , Iino Shiro , Koike Kazuhiko , Mitamura Keiji , Endo Yasuo , Oka Hiroshi
Published: March 2007

The peptide which is encoded by the pre-S(2) region of hepatitis B virus DNA, the pre-S(2) antigen, was determined quantitatively by an enzyme immunoassay system employing monoclonal antibodies. The prevalence and titer of pre-S(2)Ag were 91.9% (91/99) and 10,356 ± 19,053 units (mean ± S.D., arbitrary units) for hepatitis B e antigen (HBeAg)-positive patients with acute and chronic HBV infection and 86.0% (74/86) and 952 ± 1,565 units for HBeAg-negative subjects. In four patients with acute hepatitis B, pre-S(2)Ag titers changed in parallel with HBV DNA levels, and the disappearance of pre-S(2)Ag from serum was associated with a rapid fall of ALT levels into the normal range, whereas the fluctuation of pre-S(2)Ag titer correlated with persistence of ALT elevations. In all of the 19 episodes of acute exacerbation of hepatitis which occurred in nine patients with chronic active hepatitis B, a significant elevation of pre-S(2)Ag titer was observed, closely overlapping an increase or appearance of HBV DNA, and its peak preceded peaks of ALT by 1 to 11 weeks (mean ± S.D.=4.26 ± 2.57 weeks). These observations suggest that quantitative measurement of pre-S(2)Ag would be useful for estimation of the magnitude of HBV replication and would help predict the prognosis of acute hepatitis B and of acute exacerbation in chronic hepatitis B.
Studies of GB hepatitis agent in tamarins
Authors: Karayiannis Peter , Petrovic Lidija M. , Fry Mark , Moore Duncan , Enticott Mike , McGarvey Michael J. , Scheuer Peter J. , Thomas Howard C.
Published: March 2007

Three tamarins (Saguinus labiatus), two of which had previously been infected with hepatitis A virus and parenteral non-A, non-B hepatitis, were inoculated intravenously with the agent of GB hepatitis. All three animals developed alanine aminotransferase abnormalities 2, weeks after inoculation. Peak alanine aminotransferase levels were recorded 4 weeks postinoculation. These declined thereafter but continued to fluctuate at abnormal levels for 32 weeks. Liver biopsies showed liver cell swelling and inflammation with focal necrosis. Portal tracts and areas around central veins were heavily infiltrated with mononuclear cells. A fourth animal (no previous exposure to hepatitis viruses) inoculated with GB was killed on Day 15 postinoculation. Serum and extracts of liver and feces from this day were used as inocula for three other animals. Only the serum and liver extract transmitted GB hepatitis. The fecal specimen did not transmit and a fecal extract taken at a later date from another animal was also noninfectious.

GB hepatitis virus is distinct from the viruses causing Type A and blood-borne non-A, non-B-hepatitis. Although the virus is present in serum and has previously been transmitted per os, it is not shed in feces.
The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients
Authors: Hay Eileen J. , Czaja Albert J. , Rakela Jorge , Ludwig Jurgen
Published: March 2007

To determine the nature of unexplained chronic serum aspartate aminotransferase elevations of a mild to moderate degree in asymptomatic patients, we performed systematic clinical, biochemical and histologic examinations in 47 individuals who had been screened for virus-, alcohol-or drug-related disease. Serum aspartate aminotransferase levels ranged from 3-to 8-fold normal (mean: 156 ± 7 units per liter) for at least 6 months (mean: 30 ± 6 months). Serum alanine aminotransferase levels were also increased but to a lesser degree in most patients. Thirty-four patients (72%) had histologic features of chronic active hepatitis, including 16 with cirrhosis. Ten patients (21%) had steatohepatitis and three (6%) had miscellaneous disorders. Patients with chronic active hepatitis and cirrhosis could not be distinguished from counterparts without cirrhosis by individual clinical or laboratory findings. Antinuclear or smooth muscle antibodies were detected in 18 of the patients with chronic active hepatitis (53%). All patients with steatohepatitis were women, and they had laboratory changes at presentation, including seropositivity for antinuclear antibodies, that overlapped with those of patients with chronic active hepatitis. We conclude that asymptomatic patients with unexplained chronic aspartate aminotransferase elevations of a mild to moderate degree frequently have chronic active hepatitis and that many have cirrhosis. Immunoserologic findings compatible with autoimmune hepatitis are commonly present. Steatohepatitis is the most frequent alternative diagnosis, especially in women, and it is not excluded by the presence of antinuclear antibodies. Differentiation of the disorders is possible only by histologic examination.
Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood
Authors: Mieli-Vergani Glorgina , Lobo-Yeo Ava , McFarlane Barbara M. , McFarlane Ian G. , Mowat Alex P. , Vergani Diego
Published: March 2007

Children with primary sclerosing cholangitis or autoimmune chronic active hepatitis have similar high levels of immunoglobulin G and non-organ-specific autoantibodies and may have similar histological features. To investigate a possible immunopathogenesis of primary sclerosing cholangitis, we have studied a series of regulatory and/or effector immune mechanisms in eight children with primary sclerosing cholangitis, comparing them to 14 children with autoimmune chronic active hepatitis and 24 healthy children as controls. Antibodies to a liver membrane protein preparation were found in all children with autoimmune chronic active hepatitis tested and in seven of eight with primary sclerosing cholangitis, whereas antibodies against the hepatic asialoglycoprotein receptor were present in three of six patients with autoimmune chronic active hepatitis and in two of the eight with primary sclerosing cholangitis. Lymphocyte cytotoxicity values to autologous hepatocytes were similarly elevated in primary sclerosing cholangitis (median: 50%; range: 38 to 83%) and in autoimmune chronic active hepatitis (median: 52%; range 37 to 87%) compared to controls (median: 8%; range: 0 to 27%) (p<0.01 for both). In contrast, T suppressor cell number and function were normal in patients with primary sclerosing cholangitis (median: 23%; range: 19 to 28%; and median: 54%; range: 44 to 61%), but significantly decreased in patients with autoimmune chronic active hepatitis (median: 15%; range: 9 to 21%; and median: 9%; range: −40 to +21%) when compared to controls (median: 24%; range: 16 to 29%; and median: 53%; range: 8 to 77%) (p<0.01 for both). While the percentage of T lymphocytes expressing the activation marker HLA-DR was similarly increased in primary sclerosing cholangitis (median: 5%; range: 2 to 6%) and in autoimmune chronic active hepatitis (median: 5%; range: 1 to 10%) compared to controls (median: 3%; range: 1 to 5%, p<0.01 for both), the percentage of T lymphocytes expressing interleukin 2 receptors was greatly increased in autoimmune chronic active hepatitis (median: 19%; range: 12 to 22%) but normal in primary sclerosing cholangitis (median: 0%; range: 0 to 1%). These data suggest that liver-damaging effector mechanisms are similar in primary sclerosing cholangitis and autoimmune chronic active hepatitis but that factors leading to autoimmunity differ. Whereas in autoimmune chronic active hepatitis. autoimmunity probably derives from defective T-dependent immune regulation, in primary sclerosing cholangitis it could result from B lymphocyte activation bypassing T cells.
A histometric analysis of chronically rejected human liver allografts: Insights into the mechanisms of bile duct loss: Direct immunologic and ischemic factors
Authors: Oguma Shiro , Belle Steven , Starzl Thomas E. , Demetris Jake A.
Published: March 2007

Conspicuous pathologic features of chronic liver allograft rejection include bile duct loss and chronic obliterative arteriopathy. A quantitative histometric analysis was performed to document the extent of bile duct loss, the size of the “vanished” ducts and the extent of chronic obliterative arteriopathy and to determine whether there was any relationship between chronic obliterative arteriopathy and bile duct loss. All failed liver allograft specimens with chronic rejection were reviewed and categorized according to the degree of chronic obliterative arteriopathy, assessed by the degree of luminal narrowing of hilar hepatic artery branches. Histometric analysis of the grafts revealed: (i) there was a loss of small portal arterioles (<35 μm); (ii) bile ducts which should accompany arteries <35, 35 to 54 or 55 to 74 μm in diameter were missing, with the greatest decrease occurring among the smallest ducts; (iii) bile duct loss was seen in the absence of significant large vessel chronic obliterative arteriopathy, and (iv) the severity of arteriole and bile duct loss, as well as the size of the vanished ducts, was directly proportional to the degree of chronic obliterative arteriopathy. Furthermore, the size of the “vanished” bile ducts in liver allografts appeared to differ from the size of ducts destroyed in primary biliary cirrhosis. These studies offer indirect, but suggestive proof that two mechanisms are operative in the bile duct loss seen in chronic rejection: direct lymphocytotoxicity and ischemic damage.
Anoxic hepatocyte injury: Role of reversible changes in elemental content and distribution†
Authors: Berger Marc L. , Reynolds Rolland C. , Hagler Herbert K. , Bellotto Dennis , Parsons Dorabeth , Mulligan Kevin J. , Buja Maximilian L.
Published: March 2007

Examination of anoxic isolated hepatocytes by light and electron microscopy indicated that initial morphologic changes were largely localized to the periphery of the cells. This early phase consisted of surface bleb formation but was not accompanied by alterations in parameters of plasma membrane integrity (leakage of cellular enzymes, exclusion of trypan blue). The time course of changes in structure was temporally related to alterations in the elemental distribution and content of various subcellular compartments. These studies, which employed electron probe X-ray microanalysis, demonstrated that rapid increases in the sodium and chlorine content and decreases in the potassium content of the cytoplasm, mitochondria and nucleus occurred, whereas no change in the calcium content of any subcellular compartment was detected. Concurrently, two cellular functions known to be dependent upon ion homeostasis, sodium-dependent taurocholate uptake and mitochondrial respiratory control, became markedly impaired. Reoxygenation within 30 min resulted in the restoration of both elemental distribution and the latter two functions to baseline. These data are consistent with the hypothesis that some early functional changes may be mediated by altered ion homeostasis. In contrast, additional studies indicated that sodium and water fluxes could be dissociated from the appearance of plasma membrane blebs. Thus, this study provides direct evidence that the structural and functional changes of early anoxic hepatocyte injury cannot be explained by a single mechanistic cascade, but apparently involve multiple mechanisms which may not be directly linked.
Discrepancy between portal pressure and systemic hemodynamic changes after incremental doses of propranolol in a wake portal hypertensive rats
Authors: Koshy Abraham , Girod Catherine , Lee Samuel S. , Hadengue Antoine , Cerini Raimondo , Lebrec Didier
Published: March 2007

The effects of increasing doses of propranolol were studied in awake portal hypertensive rats in order to elucidate the relative effects of the β-blocker on systemic and splanchnic circulation. Hemodynamic responses to 0.1, 0.2 and 0.4 mg per min infusions of propranolol were compared with placebo in awake rats with portal hypertension due to portal vein stenosis. Heart rate significantly and progressively decreased from 356 ± 13 to 293 ± 10 beats per min (mean ± S.E.). Cardiac output significantly decreased from 54 ± 3 to 42 ± 3 ml per min per 100 gm body weight at the highest dose. Significant decrease in portal tributary blood flow from 27 ± 1 to 18 ± 1 ml per min, at 0.4 mg per min dose, was due not only to the decrease in cardiac output but also to a significant increase in portal tributary vascular resistance from 269 ± 17 to 368 ± 31 dyne per sec per cm5 × 103. However, portal pressure showed only an insignificant decrease from 14.9 ± 1.1 to 14.1 ± 1.4 mmHg. The reduction in portal pressure being minimal, in spite of a significant decrease in portal tributary blood flow, is explained by an increase in combined hepatic and collateral resistance from 44 ± 2 to 66 ± 4 dyne per sec per cm5 × 103, p<0.05, at 0.4 mg per min dose. We conclude that the systemic and splanchnic effects of propranolol show discrepancy at two levels. First, portal tributary blood flow is reduced more than expected by the decrease in cardiac output because of an increase in portal tributary vascular resistance. Second, despite the marked decrease in portal tributary blood flow, the reduction in portal pressure is minimal because of an increase in combined hepatic and collateral vascular resistance. We suggest, furthermore, that the discrepancy at these two levels may be more or less apparent depending on the dose of propranolol utilized.
The multiple-indicator dilution technique for characterization of normal and retrograde flow in once-through rat liver perfusions†
Authors: St-Pierre Marie V. , Schwab Andreas J. , Goresky Carl A. , Lee Wai-Fong , Pang Sandy K.
Published: March 2007

The technique of normal and retrograde rat liver perfusion has been widely used to probe zonal differences in drug-metabolizing activities. The validity of this approach mandates the same tissue spaces being accessed by substrates during both normal and retrograde perfusions. Using the multiple-indicator dilution technique, we presently examine the extent to which retrograde perfusion alters the spaces accessible to noneliminated references. A bolus does of 51Cr-labeled red blood cells, 125I-albumin, 14C-sucrose and 3H2O was injected into the portal (normal) or hepatic (retrograde) vein of rat livers perfused at 10 ml per min per liver. The outflow perfusate was serially collected over 220 sec to characterize the transit times and the distribution spaces of the labels. During retrograde perfusion, red blood cells, albumin and sucrose profiles peaked later and lower than during normal perfusion, whereas the water curves were similar. The transit times of red blood cells, albumin and sucrose were longer (p<0.005), whereas those for water did not change. Consequently, retrograde flow resulted in significantly larger sinusoidal blood volumes (45%), albumin Disse space (42%) and sucrose Disse space (25%) than during normal flow, whereas the distribution spaces for total and intracellular water remained unaltered. The distension of the vascular tree was confirmed by electron microscopy, by which occasional isolated foci of widened intercellular recesses and spaces of Disse were observed. Cellular ultrastructure was otherwise unchanged, and there was no difference found between normal and retrograde perfusion for bile flow rates, AST release, perfusion pressure, oxygen consumption and metabolic removal of ethanol, a substrate with flow-limited distribution, which equilibrates rapidly with cell water (hepatic extraction ratios were virtually identical: normal vs. retrograde, 0.50 vs. 0.48 at 6 to 7.4 mM input concentration). These findings suggest that the functional and metabolic capacities of the liver remain unperturbed during retrograde perfusion, rendering the technique suitable for the investigation of zonal differences in drug-metabolizing enzymes.
The effect of age upon liver volume and apparent liver blood flow in healthy man
Authors: Wynne Hilary A. , Cope Lance H. , Mutch Elaine , Rawlins Michael D. , Woodhouse Kenneth W. , James Oliver F. W.
Published: March 2007

The aim of this study was to determine the effect of aging upon liver volume and apparent liver blood flow in healthy man. Sixty-five subjects between 24 and 91 years of age were recruited. Liver volume was quantitated by a gray scale B ultrasound scan method. Apparent liver blood flow was determined from the plasma clearance of indocyanine green, based on an assumption of no change in hepatic extraction of the dye with age.

A significant negative correlation was observed between age and both liver volume and apparent liver blood flow (p <0.001), whether expressed in absolute terms or per unit body weight. Similarly, a significant negative correlation was observed between apparent liver blood flow per unit volume of liver (liver perfusion) and age (p<0.005).

The reduction in liver volume, apparent liver blood flow and perfusion may at least partly account for the decline in the clearance of many drugs undergoing liver metabolism which has been noted to occur with aging in man.
Incomplete compensation of enhanced hepatic oxygen consumption in rats with alcoholic centrilobular liver necrosis
Authors: Tsukamoto Hidekazu , Xi Xiao Ping
Published: March 2007

Centrilobular hypoxia mediated by enhanced hepatic consumption of oxygen has been hypothesized to be a factor of pathogenetic importance in ethanol-induced liver injury. In the present study, this hypothesis was tested in a rat model which developed alcoholic centrilobular liver necrosis. Male Wistar rats were infused with high fat diet plus ethanol or isocaloric glucose for 7 weeks, a duration which resulted in induction of balloon cell degeneration, focal necrosis, and inflammation in the centrilobular region of the liver of the ethanolfed animals. Hepatic blood flow, oxygen consumption and oxygen delivery were determined by the radiolabeled microsphere method and measurement of oxygen content in arterial, portal venous, and hepatic venous blood. Hepatic oxygen consumption was markedly increased by 159% in the ethanol-fed animals compared to that in the controls when results were expressed as relative to body weight. Even after these results were standardized per gram of liver weight, hepatic oxygen consumption was still significantly elevated in the ethanol-fed group, but the magnitude of the elevation was reduced to 70%, due to marked hepatomegaly observed in these animals. There was a concomitant 59% increase in hepatic oxygen delivery in the ethanol-fed rats when expressed per kilogram of body weight, and this effect was attributable entirely to increased portal blood flow. However, the increment of this increase in oxygen delivery was much too small to compensate for the 159% increase in oxygen consumption. In addition, this increase in hepatic oxygen delivery was no longer observable when the results were reexpressed based on the liver weight. These uncoordinated changes in hepatic oxygen consumption and delivery resulted in significantly increased oxygen extraction by livers of the ethanol-fed animals (65.2± 6.4 vs. 43.2± 6.0%) and a 40% reduction in oxygen content in hepatic venous blood of these animals. The observed pathophysiology supports the hypothesis of ethanol-induced centrilobular hypoxia and may contribute to pathogenetic mechanisms of the centrilobular liver necrosis seen in this rat model of alcoholism.
Serum high-density lipoprotein particles of alcohol-fed rats are deficient in apolipoprotein E
Authors: Lin Renee C. , Lumeng Lawrence , Phelps Vickie L.
Published: March 2007

Effects of chronic ethanol consumption on serum lip-oproteins have been studied in the rat. The serum levels of triglycerides, cholesterol, phospholipids and apolipo-proteins AI and AIV increased significantly after 1 week of ethanol feeding, and they remained elevated up to 7 weeks of alcohol drinking. By contrast, serum total apolipoprotein E decreased or, sometimes, did not change. Very-low-density lipoprotein cholesterol, triglycerides and very-low-density lipoprotein apolipoprotein E of the alcohol-fed rats increased in parallel and were about 2-to 2.5-fold over the controls. Whereas high-density lipoprotein cholesterol, phospholipids, apolipoprotein AI and AIV increased 1.2-fold by chronic alcohol feeding, the level of high-density lipoprotein apolipoprotein E decreased to 70% of that of the control rats. The rates of secretion of apolipoprotein AI, E and AIV into the culture medium by hepatocytes isolated from ethanol-fed rats were 1.8-, 1.3-and 1.1-fold higher than those from control rats. These data indicate that (i) chronic ethanol feeding increases very-low-density lipoprotein and high-density lipoprotein in the rat; (ii) serum high-density lipoprotein particles of the ethanol-fed rats are deficient in apolipoprotein E, and (iii) chronic ethanol feeding increases hepatic secretion of apolipoprotein AI, E and AIV. Since the steady-state serum level of apolipoprotein E decreases or remains unchanged in the presence of increased hepatic apolipoprotein E secretion, this imbalance suggests that alcohol feeding either accelerates the rate of degradation of serum apolipoprotein E or suppresses apolipoprotein E synthesis by nonhepatic tissues.
Thyroid hormones and the hepatic handling of bilirubin. I. Effects of hypothyroidism and hyperthyroidism on the hepatic transport of bilirubin mono- and diconjugates in the wistar rat
Authors: Van Steenbergen Werner , Fevery Johan , De Vos Rita , Leyten Roger , Heirwegh Karel P. M. , De Groote Jan
Published: March 2007

The effects of thyroidectomy and of thyroid hormone administration on the hepatic transport of endogenous bilirubin were investigated in the Wistar R/APfd rat. Hypothyroidism resulted in an enhanced hepatic bilirubin UDP-glucuronosyltransferase activity and in a decreased p-nitrophenol transferase activity. It caused a cholestatic condition with a 50% decrease in bile flow and bile salt excretion, and an increased proportion of conjugated bilirubin in serum. The biliary output of unconjugated and monoconjugated bilirubins decreased in parallel by about 65%, whereas the excretion rate of the diconjugate dropped by only 47%, resulting in an increased di-to monoconjugate ratio in bile. Hyperthyroidism was characterized by a decreased bilirubin and an increased p-nitrophenol transferase activity, and by an augmented bilirubin output in bile. The output of unconjugated and monoconjugated bilirubins increased in parallel by about 50 or 100%, whereas the excretion of the diconjugate increased by only 20 to 50%, depending on the dose of thyroxine administered; this resulted in a decreased di-to monoconjugate ratio in bile. A linear positive relationship was found between bilirubin UDP-glucuronosyltransferase activity and the ratio of bilirubin di-to monoconjugates present in bile or formed by in vitro incubation of liver homogenates at low concentration of bilirubin (10 to 15 μM), indicating that bile pigment composition is mainly determined by the conjugation activity in the liver. The inverse relationship observed between hepatic β-glucuronidase activity and the ratio of di-to monoconjugates in bile warrants further investigation to analyze whether this enzyme activity also plays a possible role in the changes in bile pigment composition in hypo-and hyperthyroid rats.
The nonspecificity of electroencephalographic triphasic waves: The emperor defrocked
Authors: Conn Harold O. , Levy Lewis L.
Published: March 2007

A blind analysis of 56 EEGs with triphasic wave patterns was performed to determine the diagnostic specificity of individual electrographic features. EEG and clinical variables analyzed included longitudinal topography, phase lags, symmetry, background activity, reactivity, longitudinal bipolar phase reversal sites, responses to photic stimulation and mental status at the time of recording. The only statistically significant finding for any of the diagnostic groups tested was the presence of severe background slowing in cases of hepatic encephalopathy (P<0.001). We found no evidence to suggest that other features may contribute to a more highly characteristic pattern for hepatic encephalopathy. None of the features studied reliably distinguished hepatic encephalopathy from other forms of metabolic encephalopathy.
Localization of ammonia-metabolizing enzymes in human liver: Ontogenesis of heterogeneity
Authors: Moorman Antoon F. M. , Vermeulen Jacqueline L. M. , Charles Robert , Lamers Wouter H.
Published: March 2007

Immunohistochemical analysis of human liver (8 to 94 years) shows a compartmentation of ammonia-metabolizing enzymes across the acinus. The highest concentration of carbamoylphosphate synthetase (ammonia) is found in the parenchymal cells around the terminal portal venules. Glutamine synthetase is found in a small pericentral compartment two to three cells thick. In contrast to observations in rat liver, in human liver a well-recognizable intermediate zone can be distinguished in which neither enzyme can be detected. This intermediate zone is not yet established at the age of 8 years but can be recognized in livers from 25 years onward.

Carbamoylphosphate synthetase can already be detected in the liver of human fetuses at 5 weeks of development. The enzyme distribution reveals a random heterogeneity among the hepatocytes, suggesting that not all hepatocytes start to accumulate carbamoylphosphate synthetase at the same time. From 9 weeks of development onward, the enzyme becomes homogeneously distributed throughout the liver parenchyma until at least 2 days after birth. Glutamine synthetase cannot be detected during this period. In addition, the definitive architecture of the acinus is not yet completed at birth.

These results therefore support the idea that in human liver, metabolic zonation with respect to NH3 metabolism exists as it does in rat liver. Furthermore, the data show that this functional compartmentation becomes established concomitant with the development of the acinar architecture. The fact that enzymic zonation is not yet established in the perinatal period may have important consequences for the regulation of ammonia fixation and pH homeostasis in preterm infants and neonates.
The effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in rats†
Authors: Whitington Peter F. , Kehrer Beat H. , Whitington Susan H. , Shneider Benjamin , Black Dennis D.
Published: March 2007

A major factor in poor bioavailability of cyclosporine in children undergoing orthotopic liver transplantation appears to be poor absorption of the drug. Our hypothesis is that the Roux-en-Y choledochojejunostomy used for biliary drainage in these children causes cyclosporine malabsorption by reducing the length of bowel available for absorption and by distally displacing the entry of bile into the intestine. In these experiments, we determined the effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in Sprague-Dawley rats.

Experimental rats (n = 24) were prepared for study by constructing self-emptying jejunal blind loops. Sham rats (n = 9) had jejunal transection and reanastomosis. Control rats (n = 26) had no operation. Two to 4 weeks later, chronic biliary-enteric fistulae were formed in all animals. In experiments, [3H]cyclosporine was delivered into the duodenum while the site of bile delivery varied. Hourly and cumulative [3H]cyclosporine excretion into bile was quantitated, which our preliminary data show to be a valid estimate of absorption. In control rats, bile was delivered into the duodenum or was replaced with saline and sucrose solution. In experimental rats, bile was infused either into the duodenum, which tested bowel shortening only, or into the proximal end of the blind loop, which tested the combined effects of bowel shortening and distal displacement of bile entry. In sham rats, bile was infused into the duodenum, which controlled for previous abdominal surgery, or into the mid-jejunum, which tested for distal bile entry only.

Two effects of biliary enteroenterostomy on cyclosporine absorption were observed. First, distal displacement of bile entry into the intestinal lumen reduced drug absorption by about 50%. Compared to control rats with duodenal bile (n = 15), which excreted 14.8 ± 3.3% of the label into bile in 24 hr, and sham rats with duodenal bile (n = 4), which excreted 14.6 ± 1.3%, experimental animals with loop bile (n = 13) excreted 7.7 ± 2.1% and sham rats with midjejunal bile (n = 5) excreted 7.2 ± 1.8%. Control rats with no bile (n = 11) excreted 3.2 ± 1.6%. Second, reduction of bowel length by constructing the enteroenterostomy reduced absorption by 25%. Experimental rats with duodenal bile (n = 11) excreted 11.2 ± 2.5%. These data suggest that the surgical approach to biliary reconstruction after orthotopic liver transplantation in children can contribute to poor cyclosporine bioavailability.
Effects of vitamin E deficiency on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload†
Authors: Bacon Bruce R. , Britton Robert S. , O’Neill Rosemary
Published: March 2007

Peroxidative decomposition of organelle membrane phospholipids with subsequent organelle dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. We studied the effects of different α-tocopherol concentrations on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. There was no evidence of mitochondrial lipid peroxidation (conjugated dienes) or alteration in mitochondrial oxidative metabolism in α-tocopherol-deficient rats with normal hepatic iron levels. Significant reductions in mitochondrial respiratory control ratios and oxidative phosphorylation ratios were seen in association with increased conjugated dienes in all three groups of iron-loaded rats regardless of the α-tocopherol status (deficient, normal or excess); thus, the α-tocopherol deficiency associated with dietary iron overload in this experimental model is not responsible for the mitochondrial abnormalities observed. In addition, chronic parenteral administration of α-tocopherol to iron-loaded animals, which increased hepatic levels of this substance 3-fold, did not ameliorate the hepatic mitochondrial lipid peroxidation or the defects in mitochondrial oxidative metabolism resulting from iron overload.
Stimulation of DNA synthesis in hepatocytes by kupffer cells after partial hepatectomy
Authors: Katsumoto Fujio , Miyazaki Kohji , Nakayama Fumio
Published: March 2007

The role of Kupffer cells during reparative regeneration of rat liver was investigated with an in vitro experimental model. Conditioned media from primary cultures of Kupffer cells isolated from intact and regenerating liver were added to primary cultures of hepatocytes, and [3H]thymidine incorporation into DNA was studied. Kupffer cell-conditioned media from intact liver and regenerating remnant liver significantly stimulated DNA synthesis in hepatocytes as compared with control media (p<0.05). Moreover, the stimulating activity of Kupffer cells prepared from regenerating liver at 6 and 12 hr after partial hepatectomy was significantly higher than that of Kupffer cells from untreated rats (p<0.05). The activity was found in serum-free conditioned media. This stimulating activity exponentially increased as the increase of the number of the cultured cells, indicating that the stimulating activity was released directly by cultured Kupffer cells. These results suggest that Kupffer cells stimulate DNA synthesis in hepatocytes by producing and releasing certain factor(s) at an early stage of liver regeneration after partial hepatectomy.
Atrial natriuretic factor and renin-aldosterone in volume regulation of patients with cirrhosis†
Authors: Gerbes Alexander L. , Wernze Heinrich , Arendt Rainer M. , Riedel Angelika , Sauerbruch Tilman , Paumgartner Gustav
Published: March 2007

The role of the atrial natriuretic factor and of the main counteracting sodium-retaining principle, the renin-aldosterone system, in acute volume regulation of cirrhosis of the liver has been investigated. Central volume stimulation was achieved in 21 patients with cirrhosis, 11 without and 10 with ascites, and 25 healthy controls by 1-hr head-out water immersion. Immersion prompted a highly significant (p<0.001) increase of atrial natriuretic factor plasma concentrations in cirrhotic patients without ascites from 8.5 ± 1.3 fmoles per ml to 16.5 ± 2.6 fmoles per ml, comparable to the stimulation in control subjects (6.0 ± 0.6 fmoles per ml to 13.6 ± 2.6 fmoles per ml). In cirrhotic patients with ascites, atrial natriuretic factor increase (from 7.7 ± 1.3 fmoles per ml to 11.4 ± 2.3 fmoles per ml) was blunted (p<0.05). Plasma renin activity and plasma aldosterone concentration were elevated in cirrhotic patients, especially in the presence of ascites. Following immersion, plasma renin activity and plasma aldosterone concentration were reduced similarly in all groups. Water immersion induced a more pronounced natriuresis and diuresis in control subjects than in cirrhotic patients. Neither atrial natriuretic factor nor plasma renin activity nor plasma aldosterone concentration alone correlated to sodium excretion. However, atrial natriuretic factor to plasma aldosterone concentration ratios were closely correlated to basal and stimulated natriuresis in cirrhotic patients, particularly in those with ascites. These data suggest that atrial natriuretic factor and the renin-aldosterone system influence volume regulation in patients with cirrhosis.
Relationship between oxygen transport and oxygen uptake in patients with cirrhosis: Effects of vasoactive drugs
Authors: Moreau Richard , Lee Samuel S. , Hadengue Antoine , Ozier Yves , Sicot Christian , Lebrec Didier
Published: March 2007

To elucidate the relationship between oxygen transport and uptake in cirrhosis, we studied the effects of three vasoactive drugs that change O2 transport. Systemic hemodynamics, blood gases and lactate concentration were measured in patients with alcoholic cirrhosis before and after intravenous dobutamine, propranolol and nitroglycerin. Nine patients received successively dobutamine and then propranolol. Ten patients received nitroglycerin. Three other patients without cirrhosis (controls) received dobutamine. In patients with cirrhosis, dobutamine infusion was accompanied by a significant increase in cardiac output (+21%), systemic O2 transport (+21%) and O2 uptake (+12%), whereas O2 extraction ratio and arterial lactate concentration did not change significantly. Propranolol administration was followed by a significant decrease in cardiac output (−24%) and systemic O2 transport (−25%) and a significant increase in O2 extraction ratio (+19%), whereas O2 uptake and arterial lactate concentration did not change. Nitroglycerin infusion was accompanied by a significant decrease in cardiac output (−21%), systemic O2 transport (−26%) and O2 uptake (−10%), whereas O2 extraction ratio (+18%) and arterial lactate concentration (+31%) significantly increased. In control patients, dobutamine infusion was accompanied by an increase in cardiac output and in systemic O2 transport and by a decrease in O2 extraction ratio, whereas O2 uptake was not modified. These results suggest that O2 uptake may be abnormally dependent on O2 transport in patients with cirrhosis.
β-blockade prevents recurrent gastrointestinal bleeding in well-compensated patients with alcoholic cirrhosis: A multicenter randomized controlled trial
Authors: Colombo Massimo , de Franchis Roberto , Tommasini Maurizio , Sangiovanni Angelo , Dioguardi Nicola
Published: March 2007

To assess the efficacy of β-blockers in preventing rebleeding in selected cirrhotic patients and to compare the tolerance, safety and patient compliance of a selective and a nonselective β-blocker, 94 patients were randomly assigned to propranolol (32 patients), atenolol (32 patients) or placebo (30 patients). Randomization was made at least 15 days after the bleeding episode. Propranolol was given orally at increasing doses until the resting pulse rate was reduced by approximately 25%. Atenolol was given at a fixed dose of 100 mg per day. Patients were followed up for a mean of 357 days. Rebleeding occurred in 14 patients in the placebo group, 10 in the atenolol group and eight in the propranolol group. The incidence of rebleeding was significantly lower in patients receiving propranolol than in those on placebo (propranolol vs. placebo: p = 0.01, logrank test). Atenolol was less effective than propranolol (atenolol vs. placebo: p = 0.065, logrank test). Bleeding-free survival was better for patients on active drugs than for those on placebo (propranolol vs. placebo=p = 0.01, atenolol vs. placebo: p = 0.05, logrank test). Retrospective analysis revealed that, whatever the type of treatment, abstinence from alcohol was crucial in preventing rebleeding. We conclude that β-blocker treatment is effective in preventing rebleeding from esophageal varices in carefully selected alcoholic cirrhotic patients who survive at least 2 weeks after acute variceal hemorrhage and stop drinking.
Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: Presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections
Authors: Korba Brent E. , Wells Frances V. , Baldwin Betty , Cote Paul J. , Tennant Bud C. , Popper Hans , Gerin John L.
Published: March 2007

During long-term studies of the natural history of woodchuck hepatitis virus infection, five cases of histologically confirmed, primary hepatocellular carcinoma were observed in a total of 92 woodchucks which had recovered, by analysis of viral serologic markers (WHsAG−, anti-WHc+, anti-WHs+), from experimental acute woodchuck hepatitis virus infections 20 to 30 months prior to the detection of hepatocellular carcinoma. No hepatocellular carcinoma was observed in 167 uninfected controls at least 3 years of age and held in the same laboratory environment. Southern blot hybridization analysis of liver tissue taken from four of these recovered woodchucks revealed the presence of low levels (0.1 to 0.3 copies per cell) of integrated woodchuck hepatitis virus DNA in hepatocellular carcinoma (four of four animals) and nonneoplastic tissue (three of four animals). Similarly, hepatocellular carcinoma tissue obtained from two wild-caught, naturally infected and serologically recovered woodchucks also contained low levels of integrated woodchuck hepatitis virus DNA. Liver tissues from another 27 of these 92 recovered woodchucks (without hepatocellular carcinoma) were examined for woodchuck hepatitis virus nucleic acids 13 to 31 months following experimental woodchuck hepatitis virus infection. Nonreplicating woodchuck hepatitis virus DNA was present in the liver of eight (30%) and in the peripheral blood lymphocytes from eight (30%) of these 27 animals. These results were in marked contrast to the analysis of woodchuck hepatitis virus DNA in the liver tissue of chronic woodchuck hepatitis virus carriers (20 experimentally infected and nine naturally infected). In these animals, high levels of replicating woodchuck hepatitis virus DNA (up to 2,000 copies per cell) were observed in all hepatocellular carcinoma and nonneoplastic liver tissue. Integrated woodchuck hepatitis virus DNA was found in eight of 60 individual hepatocellular carcinomas detected in 29 chronic carriers, 15 to 40 months postinfection. Integrated woodchuck hepatitis virus DNA was present in the nonneoplastic tissue from four of these 29 chronic woodchuck hepatitis virus carriers.
Defective function of lymphokine-activated killer cells and natural killer cells in patients with hepatocellular carcinoma
Authors: Saibara Toshiji , Onishi Saburo , Sakaeda Hiroshi , Yamamoto Yasutake
Published: March 2007

Lymphokine-activated killer activity and natural killer activity in hepatocellular carcinoma patients were assessed. Maximum lymphokine-activated killer activity was induced at 3 to 5 days of incubation, and lymphokine-activated killer activity tended to increase in a manner dose dependent of recombinant interleukin-2. However, the maximum increase of lymphokine-activated killer activity in hepatocellular carcinoma was not as high as that of normal subjects or liver cirrhosis patients. Lymphokine-activated killer activity was impaired in hepatocellular carcinoma as compared to that in normal subjects. Hepatocellular carcinoma seemed to consist of two groups: i.e. a high-lymphokine-activated killer activity group and a low-lymphokine-activated killer activity group. Reduction of natural killer activity was also observed in hepatocellular carcinoma as compared with that in normal subjects and patients with liver cirrhosis. No correlation could be demonstrated between natural killer activity and lymphokine-activated killer activity in normal subjects, liver cirrhosis patients and hepatocellular carcinoma patients. With regard to the presence of HBsAg or α-fetoprotein concentration in the sera, there was no significant difference in natural killer and lymphokine-activated killer activity in hepatocellular carcinoma patients. Patients with a small mass lesion showed a low lymphokine-activated killer activity, and depressed lymphokine-activated killer activity was not necessarily related to tumor size. In comparison with the high-lymphokine-activated killer group, the low-lymphokine-activated killer group showed a significant decrease in γ-inter-feron production and a preserved function of indocyanine green clearance.
Enzyme profile of rat bile ductular epithelial cells in reference to the resistance phenotype in hepatocarcinogenesis†
Authors: Mathis Georg A. , Walls Sandra A. , D’Amico Paul , Gengo Thomas F. , Sirica Alphonse E.
Published: March 2007

An extensive bile ductular cell hyperplasia with the formation of well-differentiated bile ductules is the most prominent feature of rat liver at 6 to 15 weeks after bile duct ligation. We have improved our previous cell isolation procedure and are now routinely able to obtain from such livers high yields of viable bile ductular epithelial cells. These cells were characterized with respect to their specific activities of γ-glutamyl transpeptidase and β-glucuronidase and of select Phase I and Phase II enzymes of biotransformation. At the time of their isolation, only a very small number of the bile ductular epithelial cells were observed to be in DNA synthesis. In addition, in histological sections prepared from intact hyperplastic bile ductular tissue isolates, only the bile ductular epithelial cells exhibited histochemical staining for γ-glutamyl transpeptidase activity. Typically, greater than 95% of the cells isolated from this tissue were also found to be histochemically positive for γ-glutamyl transpeptidase activity, and no hepatocytes were seen contaminating this cell population. Biochemically, the isolated bile ductular cells exhibited a γ-glutamyl transpeptidase specific activity that was 100 times higher than that of hepatocytes isolated at the same time from the bile duct-ligated rats and more than 300 times higher than the specific activity of the enzyme of freshly isolated normal rat hepatocytes. The bile ductular cells also expressed a β-glucuronidase specific activity that was higher than that measured in normal rat hepatocytes, but in contrast to normal liver, they did not contain a detectable amidopyrine demethylation (Phase I) activity. On the other hand, they exhibited specific activities for the Phase II enzymes UDP-glucuronosyl-transferase and glutathione S-transferase that were relatively close in amounts to those obtained with hepatocytes from the bile duct-ligated rats. Substrate and/or inhibitor studies further suggested that the forms of the Phase II enzymes expressed by the bile ductular cells were similar to those shown by immunohistochemistry to be present in the interlobular bile ducts of normal untreated rats. Our findings represent the first direct biochemical measurements of Phase II enzyme activities of isolated bile ductular epithelial cells and indicate possible mechanisms which may favor their resistance to the cytotoxic and mito-inhibitory effects of at least some types of hepatocarcinogenic and hepatotoxic chemicals.
Chlamydia trachomatis and ascites: Going with the flow?
Authors: Shabot Marc J.
Published: March 2007

Chlamydia trachomatis as an etiological agent in the Fitz-Hugh-Curtis syndrome has recently been reported; however, the condition has not been typically associated with ascites. We report a case of Chlamydia trachomatis perihepatitis in a young woman who had exudative ascites as a predominant clinical feature of her disease. Laparoscopy revealed characteristic “violin string” adhesions which were also identified on abdominal computerized scan.
Quantification of cholesterol nucleation-promoting activity in human gallbladder bile: A “homeopathic” approach?
Authors: Mazer Norman A.
Published: March 2007

We have developed a simple method to quantitate cholesterol nucleation promoting activity in bile. The method makes use of the fact that gallbladder bile of cholesterol gallstone patients contains potent nucleation promoting activity. Gallbladder bile samples were serially diluted, routinely from 1/25 to 1/6,400. The diluted samples were mixed with a supersaturated model bile and the nucleation time (NT) of the mixtures was determined. The greatest dilution that resulted in a significant shortening of the NT was called the nucleation promoting activity titre (NPAT). The determination is independent of the original lipid content of the bile sample. The NPAT was measured in 14 gallbladder bile samples derived from patients with cholesterol gallstones and 9 controls. In all samples promoting activity was found. In the samples from the stone patients the NPAT was significantly elevated as compared to the patients without cholesterol stones (p = 0.01). Our results suggest that the cholesterol saturation index and the activity of cholesterol nucleation promoting factors are the most important factors in the pathogenesis of cholesterol gallstone disease. Assessment of the NPAT allows the differentiation of groups of patients with a normal cholesterol saturation index who are at risk for gallstone formation due to a high NPAT.
Human embryotoxicity of pyrrolizidine-containing drugs
Authors: Huxtable Ryan J.
Published: March 2007

Hepatic veno-occlusive disease is the most frequent cause of hepatic vein obstruction in children. Only the small and medium veins are involved. The initial vascular lesion is endothelial edema, followed by phlebosclerosis and occlusion of the small vessels, leading to secondary necrosis of liver cells, progressive fibrosis, and ultimately cirrhosis. The disease was first recognized in Jamaica in 1954, and subsequently reported from other parts of the world. It arises from the ingestion of pyrrolizidine alkaloids found in various herbal medicines and in poorly winnowed wheat. Several plants have been implicated, in particular the genera Senecio, Crotalaria, and Heliotropium. More recently, similar pathologic changes have been observed after hepatic irradiation, bone marrow transplantation, and use of chemotherapeutic drugs. We report a newborn infant with fatal hepatic vaso-occlusive disease. Pyrrolizidine alkaloids were identified in the herbal medicine bought by the mother at a pharmacy and consumed daily during the entire pregnancy.