bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathological Observations of Intrahepatic Peribiliary Glands in 1,000 Consecutive Autopsy Livers. Ii. A Possible Source of Cholangiocarcinoma
Authors: Terada Tadashi , Nakanuma Yasuni
Published: March 2007

It remains unclear whether atypical epithelial lesions, including carcinomas and precancerous lesions, develop in intraheptic peribiliary glands. This question was tested in this study. One thousand livers from consecutive autopsies were surveyed and 201 livers with bile duct carcinomas or metastatic malignant neoplasms were excluded because atypical epithelial lesions of the glands were difficult to distinguish from the primary or metastatic malignant cells. Consequently, 799 livers were examined for the atypical epithelial lesions by histological, mucin–histochemical and immunohistochemical methods. The atypical epithelial lesions were divisible into papillary hyperplasia, atypical hyperplasia and carcinomatous transformation. Of the 799 livers, papillary hyperplasia was only found in six livers (0.8%), papillary hyperplasia and atypical hyperplasia coexisted in four livers (0.5%) and carcinomatous transformation and atypical hyperplasia coexisted in one liver (0.1%). Mucinhistochemical study showed that the intracytoplasmic location of mucin was different between carcinomatous transformation and normal peribiliary glands. From an immunohistochemical standpoint, epithelial cells of the atypical epithelial lesions showed stronger immunoreactivities to carcinoembryonic antigen, carbohydrate antigen 19–9 and DU–PAN–2 than those of normal intrahepatic peribiliary glands. These findings suggest that intrahepatic cholangiocarcinomas arising from intrahepatic peribiliary glands actually exist, and that papillary and atypical hyperplasia of the peribiliary glands may precede this type of cholangiocarcinoma. (Hepatology 1990;12:92-97).
The Demography of Primary Biliary Cirrhosis in Ontario, Canada
Authors: Witt-Sullivan Helga , Heathcote Jenny , Cauch Karen , Blendis Laurence , Ghent Cameron , Katz Allen , Milner Ruth , Pappas Chris S. , Rankin James , Wanless Ian R.
Published: March 2007

The demographics of primary biliary cirrhosis in Ontario, Canada, are described. Two hundred and twenty–five primary biliary cirrhosis patients were identified by 85 of 502 gastroenterologists (or internists) practicing in Ontario acute care hospitals that have 150 or more beds. Two hundred and six patients were verified as being antimitochondrial antibody–positive, resulting in an incidence of 3.26 per million per year and a prevalence of 22.39 per million. Questionnaire data were obtained on 88.5% of these patients. Twenty–nine percent of the patients were found to be asymptomatic. Geographical clustering and racial predisposition were not seen. No increase in breast cancer prevalence was noted. By the time the diagnosis of primary biliary cirrhosis was established, the patients had consulted a median number of 3.5 physicians. Fatigue was reported as the most disabling symptom. The diagnosis of primary biliary cirrhosis in patients referred from across the province of Ontario was independently confirmed by us, using standard criteria (antimitochondrial antibody testing and liver biopsy), and was found to be reliable. (Hepatology 1990; 12:98-105).
Basal Energy Production Rate and Substrate Use in Stable Cirrhotic Patients
Authors: Merli Manuela , Riggio Oliviero , Romiti Adriana , Ariosto Franco , Mango Lucio , Pinto Giorgio , Savioli Massimiliano , Capocaccia Livio
Published: March 2007

The basal energy production rate was measured using indirect calorimetry in 25 stable cirrhotic patients and 10 controls of comparable age. The endogenous substrate oxidation was also calculated by measuring urinary nitrogen excretion. The energy production rate was similar in cirrhotic patients and controls. The origins of liver disease and the degree of liver damage did not seem to influence the energy production rate. On the other hand, in cirrhotic patients, as in controls, a significant correlation was present between the energy production rate and parameters of body size, such as body weight and fat–free mass. As a consequence, cirrhotic patients with poor nutritional status, with a reduced fat–free mass, showed a lower energy production rate. The measured energy production rate was compared with the resting energy expenditure estimated by formulas commonly used in healthy individuals. The good agreement found between the measured energy production rate and calculated energy expenditure suggests that these formulas may be applied to stable cirrhotic patients in clinical practice. In cirrhotic patients, the oxidation of endogenous fat is the main contributor to basal energy production rate. The fat oxidation rate does not appear to be influenced by the hormonal pattern found in the cirrhotic patients. However, a significant correlation was present between fat oxidation and plasma free fatty acid levels. This confirms that the prevalent fat use in cirrhotic patients is supported by the greater availability of fat–derived substrates. (Hepatology 1990;12:106-112).
Uptake of Thymidine Labeled on Carbon 2: A Potential Index of Liver Regeneration by Positron Emission Tomography
Authors: Vander Borght Thierry M. , Lambotte Luc E. , Pauwels Stanislas A. , Dive Charles C.
Published: March 2007

Noninvasive measurement of liver regeneration with positron emission tomography has been attempted with 11C–thymidine; however, results were unsatisfactory using thymidine labeled on its methyl group. To evaluate whether the specificity of the method could be improved by modifying the labeling position of the tracer, thymidine labeled on its methyl group with 3H and thymidine labeled on its carbon 2 with 14C were injected in 22 hepatectomized rats either 1 hr (when DNA synthesis is not increased) or 24 hr after the surgical procedure (when the rate of DNA synthesis is maximal). Liver samples taken 10, 30 and 120 min after injection showed that, in contrast to 3H–radioactivity, 14C–radioactivity measured in whole tissue allowed a clear discrimination between regenerating and nonregenerating livers. In addition, 14Cradioactivity measured in whole tissue of regenerating livers correlated with the DNA radioactivity 10, 30 and 120 min after injection of the tracer. In contrast, no such correlation was found with the methyl–labeled thymidine. Analysis of the radioactive material present in the nonDNA fraction using ion exchange disks and high–performance liquid chromatography showed that 2–C-labeled thymidine was incorporated into DNA without accumulation of labeled metabolites whereas, for the methyl–labeled thymidine, almost all radioactivity was related to degradative products. Therefore the evaluation of the liver regeneration with the 2–C-labeled thymidine, which does not require cellular fractionation, should be suited for noninvasive measurement with positron emission tomography. (Hepatology 1990;12:113-118).
Hepatic Expression of Intercellular Adhesion Molecule–1 (Icam–1) in Viral Hepatitis B
Authors: Volpes Riccardo , van den Oord Joost J. , Desmet Valeer J.
Published: March 2007

The in situ distribution patterns of intercellular adhesion molecule–1 and human leukocyte antigen–DR antigens were studied in serial sections of 61 liver biopsy specimens from patients with hepatitis B virus infection using immunohistochemical techniques. In addition, the topographical relationship between the display of HBcAg on one hand and the expression of intercellular adhesion molecule–1 by hepatocytes on the other was analyzed with a double–staining immunohistochemical procedure in 14 selected liver biopsy samples showing chronic persistent or chronic active hepatitis and signs of active hepatitis B virus replication as reflected by the presence of variable amounts of HBcAg in a nuclear or cytoplasmic pattern of immunoreactivity.

Coexpression of intercellular adhesion molecule–1 and human leukocyte antigen–DR antigens by hepatocytes correlated positively with the site and extent of the inflammatory infiltrate, which was composed of lymphocytes expressing lymphocyte function-associated antigen–1. In healthy HBsAg–positive carriers without inflammatory liver disease, no intercellular adhesion molecule–1 or human leukocyte antigen–DR expression was found on hepatocytes; in acute hepatitis, intercellular adhesion molecule–1 and human leukocyte antigen–DR were strongly expressed throughout the liver parenchyma on liver cell membranes and on sinusoidal lining cells. In chronic persistent and chronic active hepatitis and in active cirrhosis, intercellular adhesion molecule–1 and human leukocyte antigen–DR showed membranous positivity on focal clusters of hepatocytes in areas of periportal or intraacinar inflammation.

Double–staining for HBcAg and intercellular adhesion molecule–1 revealed variable numbers of HBcAg–positive hepatocytes expressing intercellular adhesion molecule–1 on their cell membranes; these cells may represent the “cytotoxic” model, in which cell–cell interactions between lymphocyte function-associated antigen–1-positive lymphocytes and hepatitis B virus-infected hepatocytes are facilitated. Furthermore, intercellular adhesion molecule–1-positive hepatocytes lacking HBcAg were found in areas of inflammation, indicating that the virus itself does not directly trigger intercellular adhesion molecule–1 expression. These intercellular adhesion molecule–1-positive, HBcAg–negative liver cells might “guide” lymphocytes through the parenchyma toward virally infected target cells. Finally, in many cases, variable numbers of HBcAg–positive liver cells lacked membranous intercellular adhesion molecule–1 expression; these cells may represent the “tolerogenic” model, in which incomplete clearance of virally infected hepatocytes adds to the chronic nature of hepatitis B virus infection. (Hepatology 1990;12:148-154).
Auxiliary Liver Transplantation: A Negative Viewpoint
Authors: Shaked Abraham A. , Busuttil Ronald W.
Published: March 2007

Auxiliary heterotopic liver transplantation is theoretically attractive because it leaves the recipient's liver in place. The surgical trauma of hepatectomy is avoided, and failure of the graft does not necessarily lead to the death of the patient or a second, emergency transplantation. Another advantage is that matching the body sizes of the donor and the recipient is not mandatory, which increases the number of possible donors. However, previous clinical results of auxiliary liver transplantation have been poor.

We performed auxiliary partial liver transplantation in six consecutive patients with end–stage chronic liver disease who were not accepted for orthotopic liver transplantation because they had massive ascites, deficient clotting function, cachexia, or poor pulmonary reserve. The donor liver was transplanted to the right subhepatic region after removal of segments II and III, and it was provided with portal and arterial blood. There were no major changes in hemodynamic measurements during surgery. The mean hospital stay after transplantation was 22.7 days (range, 14 to 29). After a mean follow–up period of 14 months (range, 5 to 23), all patients were alive, with good graft function as demonstrated by scintigraphy, Doppler ultrasonography, and synthesis of clotting factors.

From these observations we conclude that auxiliary partial liver transplantation is an attractive alternative to orthotopic liver transplantation in high–risk patients. Its role in other patients who need liver transplants remains to be defined.
Fine Specificity of Human Antibody Response to the Pres1 Domain of Hepatitis B Virus
Authors: Alberti Alfredo , Cavalletto Daniela , Chemello Liliana , Beluss Fabio , Fattovich Giovanna , Pontisso Patrizia , Milanes Gabriele , Ruol Arturo
Published: March 2007

The preS1 domain of hepatitis B virus envelope proteins contains a site of attachment to the hepatocyte membrane that has been shown to evoke virusneutralizing antibodies. Using synthetic peptides, we have examined kinetics and specificity of the antibody response to preS1 during acute and chronic HBV infection. Antibodies against two continuous B cell epitopes, p (21-32) and p (32-47), which overlap with the virus receptor for hepatocytes, were detected in 17 (28%) and 28 (47%) patients, respectively, of 60 patients who were tested during acute hepatitis B. Serial testing demonstrated these anti–preS1 specificities in more than 50% of patients who became virus free. By contrast, five patients with chronic evolution of hepatitis B and 61 of 66 patients with an established chronic HBV infection were negative, independent of serological profile and liver disease activity. Fifteen (22.7%) patients with chronic hepatitis B were positive for antibody to the C–terminus p (94-117) preS1 sequence that, unlike the acute–phase anti–(21-32) and anti–(32-47) reactivities, did not behave as a virusprecipitating antibody. Acute–phase sera were found to also contain virus–precipitating antibodies directed against conformational preS1 epitopes. These results indicate that the preS1 site, which contains the binding activity for the hepatocyte membrane, elicits an early antibody response during acute hepatitis B. A defect in such antibody repertoire may participate in the chronicity process as a result of continuing reinfection of hepatocytes by circulating virions. (Hepatology 1990;12:199-203).
Prevalence and Prediction of Osteopenia in Chronic Liver Disease
Authors: Bonkovsky Herbert L. , Hawkins Michael , Steinberg Karen , Hersh Theodore , Galambos John T. , Henderson Michael J. , Millikan William J. , Galloway John R.
Published: March 2007

To obtain information on the prevalence and clinical and laboratory correlates of osteopenia in patients with chronic liver disease, we measured bone densities and 30 selected laboratory variables in 133 subjects (70 men, 63 women) with liver disease. Thirty–two had alcoholic liver disease, 18 had primary biliary cirrhosis, 16 had primary sclerosing cholangitis, 48 had other forms of cirrhosis (cryptogenic, posthepatitic) and 19 had chronic hepatitis or fibrosis without cirrhosis. Bone densities of the lumbar spine and three sites of the proximal femur (neck, Ward's triangle, greater trochanter) were estimated by dual–photon absorptiometry. Bone densities at all sites were significantly correlated to one another (r = 0.4 to 0.9; 95% confidence intervals = 0.24-0.54 to 0.81-0.90; p < 0.0001 for all). Compared with an age– and gendermatched reference group, patients with liver disease had highly significant decreases in bone densities (>2 standard deviations below control values; p < 0.0008 at all sites). Decreases were particularly marked (24% to 42%) at Ward's triangle, the site of the femoral neck particularly prone to fracture. The prevalence of decreased bone densities ranged from 10% to 56%, depending on the site studied and the nature of the liver disease. Among 30 laboratory variables studied, there were significant (p < 0.05) correlations with bone densities at more than one site for urinary creatinine (r = 0.21, 0.25), urinary calcium (r = -0.18, –0.23), serum total alkaline phosphatase (r = -0.18, –0.27) and the liver–1 isozyme of serum alkaline phosphatase (r = -0.19, –0.26). We conclude that osteopenia is prevalent in patients with chronic liver disease, particularly in those with reduced skeletal muscle mass (reflected in lower creatinine excretions) and higher serum alkaline phosphatases. However, because correlations are relatively low between laboratory variables and bone densities, the laboratory variables tested are not useful to predict which patients with chronic liver disease have osteopenia. Thus the way to determine the presence and severity of osteopenia in these patients is to measure bone density. (Hepatology 1990;12:273-280).
Microscopic Incipient Hepatocellular Carcinoma Found Incidentally in A Routine Liver Biopsy Specimen
Authors: Hirooka Noboru , Nitta Yoshiro , Tsunoda Takabumi , Kitazawa Eiji , Sato Junichi , Machii Akira , Murakami Yoshitsugu , Takahashi Manabu , Kondo Fukuo
Published: March 2007

A microscopic atypical focus suggestive of hepatocellular carcinoma is reported. The lesion, 0.3 mm in diameter, was found by chance in a liver biopsy specimen taken from a cirrhotic patient; it was characterized histologically by cytoplasmic basophilia, hypercellularity (high nucleus–to–cell ratio) and microacinar structures. The reticulin framework of the focus was relatively sparse compared with the surrounding noncancerous area. The focus had developed in a regenerative nodule apparently no different from other regenerative nodules of the cirrhosis and showed no accompanying preneoplastic lesion such as adenomatous hyperplasia.

A thorough search for the primary lesion, including ultrasonographic imaging and superselective hepatic arteriography, demonstrated no mass lesion in the liver.

Therefore, the lesion may have been an incipient de novo hepatocellular carcinoma, and this may be the first report of such a lesion discovered in a biopsy sample. (Hepatology 1990;12:291-294).
Lack of Metabolic Effects of Cholecystokinin on Hepatocytes
Authors: Kost Louis J. , Gores Gregory J. , Sayles John M. , Miller Laurence J. , Lemasters John J. , Herman Brian , Larusso Nicholas F.
Published: March 2007

We previously reported that the liver was the major organ that extracts small, biologically active, circulating forms of cholecystokinin. Although our work indicated extensive degradation of cholecystokinin extracted from plasma during its transit across the hepatocyte, it was unclear whether cholecystokinin might also have a physiological effect on this cell before its intracellular degradation. Therefore we tested the hypothesis that cholecystokinin has a direct biological effect on hepatocytes. Using freshly isolated or cultured hepatocytes, we studied whether cholecystokinin–octapeptide alters protein synthesis, affects amino acid transport or influences cytosolic free calcium concentrations. Using liver slices, we also determined the effect of cholecystokinin–octapeptide on cyclic nucleotide levels. Cholecystokininoctapeptide, up to a concentration of 1 μmol/L, had no effect on the incorporation of radiolabeled amino acids into total hepatocyte protein; in contrast, comparable molar amounts of insulin stimulated protein synthesis by as much as 37% (ED50 = 1.5 × 10-10 mol/L). Although insulin and glucagon stimulated the transport into hepatocytes of 14C–α–aminoisobutyric acid, a nonmetabolizable amino acid analog, cholecystokinin–octapeptide had no effect. Cholecystokinin–octapeptide also did not affect either the concentration of calcium in individual hepatocytes, as measured by digitized video microscopy using Fura–2, or the levels of cyclic AMP or cyclic GMP in liver slices. Our results show that cholecystokinin has no effect on protein synthesis, on amino acid transport or on hepatocyte calcium and cyclic nucleotide levels. These and our previous data suggest that the primary outcome of hepatic extraction of cholecystokinin is hormone degradation. (Hepatology 1990;12:301-305).
Norepinephrine–Induced Cholestasis in the Isolated Perfused Rat Liver Is Secondary to Its Hemodynamic Effects
Authors: Lenzen Romana , Funk Andreas , Kolb-Bachofen Viktoria , Strohmeyer Georg
Published: March 2007

In this study we examined the effect of pharmacological doses of various α–adrenergic agents on hepatic portal perfusion, organic anion uptake and bile secretion using the isolated perfused rat liver. Addition of norepinephrine at portal perfusate concentrations ranging from 0.01 to 100 μmol/L induced a dose–related increase in portal pressure with a twofold increment at the highest concentration. This was accompanied by an inhibition of hepatocellular uptake of taurocholate by 16.8% ± 1.8% and of sulfobromophthalein (BSP) by 32.9% ± 3.0% compared with controls. Moreover, a 22.5% ± 3% decrease in bile flow rate and a 22.8% ± 4% inhibition of biliary excretion of taurocholate were observed. Addition of other α–adrenergic agonists (epinephrine, dopamine and phenylephrine) at similar concentrations produced the same hepatic effects as observed with norepinephrine. During infusion of these α–adrenergic agents, trypan blue infusion revealed a patchy perfusion pattern of the liver surface compared with the homogeneously stained organs in controls. The hemodynamic alterations could be confirmed by electron microscopy examination that demonstrated that increased portal pressure produced by norepinephrine was associated with sinusoidal shunting. All hemodynamic, metabolic and biliary changes induced by norepinephrine could be entirely prevented by concomitant infusion of the α–antagonist phentolamine, thus indicating that norepinephrineinduced hepatic effects were mediated by α–receptors. In contrast, simultaneous addition of papaverine, an unspecific vasodilator, prevented the hemodynamic and the biliary changes of norepinephrine, but failed to modify the metabolic effects of the drug. These results indicate that norepinephrine–induced cholestasis in the isolated perfused rat liver accompanies the hemodynamic changes, thus supporting the concept that the drug has no direct effect on hepatic bile formation. (Hepatology 1990;12:314-321).
Nonabsorbable Disaccharides Plus Neomycin in Hepatic Encephalopathy: Do They Enhance Each Other?
Authors: Capocaccia Livio , Riggio Oliviero
Published: March 2007

The beneficial effect of disaccharides, lactulose and lactitol, in prevention and treatment of hepatic encephalopathy is well established but their use in combination with neomycin is still controversial. We studied in vitro the fecal bacterial growth, acid and gas formation in presence of lactitol (beta–galactosidesorbitol) and neomycin alone or in combination. The results indicate that neomycin only inhibits the growth of susceptible bacteria (E. coli, Staph. aureus) which, conversely, are poor lactitol fermenters. The resistent organisms (Lactobacillus acidophilus, Clostridium perfringens) that are efficient disaccharide fermenters continue to metabolize lactitol still when antibiotic is added. Addition of lactitol 10% increased the inhibitory effect of neomycin on bacterial growth by 25-50% within 60-70 min. These preliminary data suggest that lactitol and neomycin may have additional or synergistic effects in vivo when used together in presence of favourable intestinal microbial environment.
The Streaming Liver: Can the Age of A Hepatocyte Be Determined From Its Position on the Portohepatic Radius?
Authors: Lamers Wouter H.
Published: March 2007

Hepatocyte age was estimated from its distance from the portal tract. We have previously shown that hepatocytes are formed adjacent to the portal tract and stream toward the terminal hepatic vein, advancing at a daily velocity of 2 μm. Thus, the farther a cell from the portal tract, the older it is. This relationship between cell age and distance served here for the study of age–dependent changes in the hepatocyte, particularly nuclear area and DNA content. DNA content was derived from the absorbance of Feulgen–stained nuclei in 5–μm–thick tissue sections. Absorbance and nuclear area were measured with a cytophotometer. Since most nuclei of the tissue section were sliced, DNA content was estimated also in intact nuclei which were sampled by fine needle aspiration, and stained with either Feulgen or propidium iodide. Feulgen–stained nuclei were scanned by a cytophotometer, while the DNA content of propidium iodide–stained nuclei was measured by flow cytometry. Absorbance was expressed in relationship to the mean absorbance of diploid periportal littoral cells. Littoral absorbance was delined as one absorbance unit. A high correlation between nuclear absorbance and area was observed in nuclear suspensions (adjusted r–square 0.79), so that nuclear area may serve as a good predictor of nuclear DNA content, which is valuable in routine sections which are stained with H and E. Most periportal hepatocytes were polyploid and their mean absorbance was 1.68 units. Nuclear absorbance increased with cell distance from the portal tract. Within 100 pm it rose from 1.68 to 1.92 units. Nuclear area increased by 13%. Since the cell covers the 100 pm distance in 60 days, its absorbance increases daily by 0.006 units. Yet since the advancing hepatocyte gets older as it advances, nuclear absorbance increases with hepatocyte age, and so does nuclear area.
The response of atrial natriuretic factor and sodium excretion to dietary sodium challenges in patients with chronic liver disease
Authors: Warner Leonard C. , Campbell Peter J. , Morali Gilles A. , Logan Alexander G. , Skorecki Karl L. , Blendis Laurence M.
Published: March 2007

Despite intensive investigation, the pathogenesis of sodium retention in patients with chronic liver disease is not fully known. We have studied 19 chronic liver disease patients, 13 without (group 1) and six with (group 2) histories of clinical sodium retention (ascites or edema) by varying dietary sodium intake. The patients were placed on a 20 mmol/day constant diet for 1 wk, followed by a constant 100 mmol/day sodium diet for 1 wk under strict metabolic conditions. After 5 days of equilibration on each diet, blood and urine samples were collected for plasma atrial natriuretic factor levels and urinary sodium excretion. Group 1 patients (n = 6) achieved near sodium balance in 5 days on both a 20-mmol (urinary sodium output = 17 ± 3 mmol/day) and a 100-mmol sodium diet (urinary sodium output = 80 ± 5 mmol/day). Atrial natriuretic factor levels in these patients tended to be elevated, but the increase was not significantly greater than that in normal control subjects (10 ± 4 pg/ml to 19 ± 4 pg/ml) on the same diets. In contrast, group 2 patients (n = 5) were in significant positive sodium balance on both the 20 mmol/day sodium diet (mean urinary sodium output = 9.5 ± 3.3 mol/day) and the 100 mmol/day sodium diet (urinary sodium output = 37 ± 13 mmol/day). This occurred despite significantly elevated baseline atrial natriuretic factor levels and a significant increase in plasma atrial natriuretic factor levels after sodium challenge (62 ± 9 pg/ml, p < 0.05) on a 100 mmol/day sodium diet. These results indicate that renal resistance to the natriuretic actions of atrial natriuretic factor occurs in this group of patients with a history of sodium retention. In preascitic, uncomplicated chronic liver disease patients corrected sinusoidal pressure was positively correlated with atrial natriuretic factor levels (n = 13, r = 0.75; p < 0.01). These results suggest that, in these patients, intrasinusoidal portal hypertension may have a role in the development of sodium retention and that sodium homeostasis is maintained on various sodium diets at the expense of a gradual elevation in atrial natriuretic factor levels. (Hepatology 1990;12:460-466).
Natriuretic hormone activity in the urine of cirrhotic patients
Authors: La Villa Giorgio , Asbert Mónica , Jiménez Wladimiro , Ginés Pere , Claria Joan , Lopez Clara , Planas Ramon , Llach Josep , Gaya Joan , Rivera Francisca , Gentilini Paolo , Arroyo Vicente , Rodés Joan
Published: March 2007

The ability of urine extracts to inhibit sodium and potassium-activated ATPase, cross-react with antidigoxin antibodies and induce natriuresis in rats was investigated in 10 healthy subjects, 10 cirrhotic patients without ascites (compensated cirrhotics), 27 nonazotemic cirrhotic patients with ascites and 10 cirrhotic patients with ascites and functional renal failure to assess whether reduced activity of natriuretic hormone contributes to sodium retention in cirrhosis. No significant differences were seen between healthy subjects and compensated cirrhotic patients in any of these parameters (sodium and potassium-activated ATPase inhibition = 178.5 ± 19.8 vs. 247.4 ± 48.7 nmol equivalent of ouabain/day; digoxinlike activity = 43.9 ± 6.1 vs. 48.0 ± 5.6 ng equivalent of digoxin/day; natriuretic activity = 0.36 ± 0.15 vs. 0.63 ± 0.27 μmol/min). Cirrhotic patients with ascites with and without functional renal failure showed significantly higher values of sodium and potassium-activated ATPase inhibition (708.1 ± 94.0 and 529.2 ± 53.9 nmol equivalent of ouabain/day, respectively), digoxinlike activity (136.9 ± 7.2 and 116.3 ± 7.9 ng equivalent of digoxin/day) and natriuretic activity (1.78 ± 0.48 and 1.93 ± 0.37 μmol/min) than healthy subjects and compensated cirrhotic patients. We saw no significant differences between these two groups of cirrhotic patients with ascites with respect to these parameters. In the cirrhotic patients studied, sodium and potassium-activated ATPase inhibition and antidigoxin antibodies directly correlated with the degree of impairment of hepatic and renal function, plasma renin activity and plasma levels of aldosterone and norepinephrine. These results show that natriuretic hormone activity is increased in cirrhotic patients with ascites and suggest that sodium retention in these patients cannot be attributed to a deficiency in this hormone. An alternate explanation, however, is that the increased activity of natriuretic hormone in patients with cirrhosis and ascites, which may represent a compensatory response, is not sufficient to antagonize the renal effects of sodium-retaining forces. (Hepatology 1990;12:467-475).
Effects of propranolol on gastric microcirculation and acid secretion in portal hypertensive rats
Authors: Piqué Josep M. , Pizcueta Pilar , Pérez Ayuso ROSA M. , Bosch Jaime
Published: March 2007

Rats with chronic portal hypertension have an increased gastric mucosal blood flow and an impaired acid secretory response to pentagastrin stimulation. This study investigated the effects of propranolol, a drug widely used in the treatment of portal hypertension, on gastric mucosal blood flow and acid secretion in portal hypertensive rats with partial portal vein occlusion. In study I, gastric mucosal blood flow, measured by hydrogen gas clearance, and acid output were determined in basal conditions and after the administration of propranolol (0.3 mg/kg/min) or vehicle infusion in portal hypertensive and sham-operated rats. Gastric mucosal blood flow was significantly higher (p < 0.005) in portal hypertensive rats than in sham-operated rats, and it was significantly reduced (p < 0.05) after propranolol infusion in portal hypertensive rats (39 ± 2 vs. 35 ± 3 ml/min/100 gm). Basal acid output was not significantly modified with propranolol infusion, either in portal hypertensive or sham-operated animals. In study II, acid output was measured in portal hypertensive rats in basal conditions, during pentagastrin (20 μ/kg/hr) infusion and after the combined infusion of pentagastrin and propranolol (or vehicle). Pentagastrin infusion significantly increased (p < 0.001) acid output, but propranolol did not modify stimulated gastric acid secretion. In conclusion, propranolol induced a slight but significant reduction in gastric mucosal blood flow and did not change basal or stimulated gastric acid secretion. (Hepatology 1990;12:476-480).
Desensitization of myocardial β-adrenergic receptors in cirrhotic rats
Authors: Lee Samuel S. , Marty Jean , Mantz Jean , Samain Emmanuel , Braillon Alain , Lebrec Didier
Published: March 2007

Cardiac responses to catecholamines are known to be attenuated in chronic liver disease. To elucidate the role of β-adrenergic receptor alteration in this phenomenon, we measured heart rate responsiveness to isoprenaline and myocardial β-adrenergic receptor-binding characteristics in three groups of rats: those that were sham operated, those that had portal vein stenosis and those that were cirrhotic because of bile duct ligation. Responsiveness to isoprenaline was evaluated in conscious rats by the dose of isoprenaline needed to increase basal heart rate by 50 beats/min and by the maximal heart rate response. β-Receptor characteristics in heart membranes were derived from 125I-iodocyanopindolol binding data. Compared with sham-operated controls, cirrhotic rats needed a significantly higher dose of isoprenaline to raise basal heart rate by (50 beats/min). (102.3 ± 19.1 vs. 28.3 ± 11.3 ng/kg) and lower maximal heart rate response (104 ± 29 vs. 158 ± 61 beats/min). In addition, myocardial β-receptor density was significantly lower in cirrhotic rats (26.5 ± 4.6 vs. 37.5 ± 10.3 fmol/mg protein) and the dissociation constant was higher (31.6 ± 17.0 vs. 14.0 ± 2.5 pmol/L). Analysis of β1/β2 subpopulations revealed that the decreased total β-receptor density was entirely due to selective β1-receptor down-regulation. β-Receptor affinity for agonist was not altered in cirrhotic rats. Rats with portal vein stenosis showed no significant differences in either isoprenaline responsiveness or β-receptor characteristics when compared with controls. These results indicate that β-adrenergic receptor down-regulation may be responsible for the myocardial hyporesponsiveness to catecholamines observed in cirrhosis. (Hepatology 1990;12:481-485).
Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes
Authors: Galle Peter R. , Theilmann Lorenz , Raedsch Richard , Otto Gerd , Stiehl Adolf
Published: March 2007

Primary human hepatocytes were used to study bile salt hepatotoxicity and the hepatoprotective potential of ursodeoxycholate in vitro. Hepatocytes were obtained by collagenase perfusion of healthy human liver tissue and were treated with glycochenodeoxycholate for 24 hr 1 day after plating. Clear signs of cytotoxicity were observed at concentrations of about 100 μmol/L glycochenodeoxycholate. Toxicity was determined by release of alkaline phosphatase, γ-glutamyl transferase, AST, ALT or lactate dehydrogenase into the culture medium, by measuring DNA synthesis of the cultured liver cells and by testing the viability of the hepatocytes using trypan-blue dye exclusion. Addition of ursodeoxycholate, which by itself proved to be of little toxicity, significantly reduced the hepatotoxic effects of glycochenodeoxycholate: 72% ± 6% of the cells survived treatment with 500 μmol/L glycocheno-deoxycholate alone, but addition of 100 μmol/L ursodeoxycholate increased the survival rate to 87% ± 4% (p < 0.05). Moreover, all enzymes tested were secreted at a significantly lower level when ursodeoxycholate was present. Similarly, the cellular DNA synthesis was maintained at significantly higher levels as a result of ursodeoxycholate treatment. We conclude that (a) primary human hepatocytes are a suitable model for studying hepatotoxicity of bile salts in vitro, (b) ursodeoxycholate reduces hepatotoxicity of other bile salts and (c) ursodeoxycholate can act hepatoprotectively by itself (i.e., alteration of the metabolism of other bile salts is not necessarily required). (Hepatology 1990;12:486-491).
Ursodeoxycholic acid-induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis
Authors: Stiehl Adolf , Rudolph Gerda , Raedsch Richard , Moller Bernd , Hopf Ulrich , Lotterer Erich , Bircher Johannes , Fölsch Ulrich , Klaus Jürgen , Endele Richard , Senn Martin
Published: March 2007

Ursodeoxycholic acid treatment of patients with primary biliary cirrhosis may lead to relief of pruritus and improvement of biochemical liver tests. The changes in serum and urinary bile acids induced by ursodeoxycholic acid treatment were studied. After 29 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (750 to 1,000 mg/day) for 6 to 12 mo because of an increase in ursodeoxycholic acid, total plasma bile acids increased from 30.5 ± 6 μmol/L (mean ± S.E.M.) to 52.7 ± 11.7 μmol/L (p < 0.01). The increase in total plasma bile acids correlated significantly with concentrations of plasma bile acid before treatment (p < 0.01). The concentrations of endogenous bile acids decreased, mainly because of a decrease of cholic acid. During treatment, glycine conjugation increased and taurine conjugation decreased, whereas sulfation and glucuronidation of bile acids were unchanged.

In 10 patients with primary biliary cirrhosis in stages III and IV, urinary excretion of bile acids was also studied. After treatment, ursodeoxycholic acid and its 3-β isomer and C-1-hydroxylated and C-6-hydroxylated derivatives were also excreted. During treatment, urinary excretion of endogenous bile acids decreased.

The increase of ursodeoxycholic acid and the decrease of endogenous bile acids may both be related to the improvement of biochemical liver tests in precirrhotic stages of the disease. In cirrhosis, endogenous bile acids in plasma remained high and changes in liver tests were small. (Hepatology 1990;12:492-497).
Mechanisms of transport of nontransferrin-bound iron in basolateral and canalicular rat liver plasma membrane vesicles
Authors: Wright Teresa L. , Lake John R.
Published: March 2007

Although most iron in plasma is bound to transferrin, recent evidence suggests that the nontransferrin-bound fraction contributes to hepatic iron loading and toxicity seen in iron-overload disorders. Our studies of isolated perfused rat liver previously demonstrated saturable uptake of nontransferrin-bound iron that continues despite hepatic iron overload. To further characterize the mechanism of transport of this form of iron, we measured binding of 55Fe-labeled ferrous ascorbate to rat liver plasma membrane vesicles under varying conditions. Binding of 5 μmol/L iron by both basolateral and canalicular membranes was time-dependent and linear for the first 5 sec. Initial rate of binding of ferrous ascorbate to basolateral membrane vesicles was temperature dependent and increased by calcium but, in contrast to the perfused rat liver, was not inhibited by other divalent cations. Binding velocities by basolateral membrane vesicles were saturable at increasing iron concentration (Km = 33 μmol/L, Vmax = 16 pmol/mg protein/sec). Ferrous iron binding by canalicular membrane vesicles was also temperature dependent, but initial association rates were not saturable over the concentration range studied (2 to 20 μmol/L).

We conclude that nontransferrin-bound iron associates with basolateral liver plasma membrane vesicles by a saturable mechanism sensitive to temperature and calcium and consistent with a membrane carrier. Other divalent cations do not inhibit membrane association but may compete for a subsequent cytosolic binding site. (Hepatology 1990;12:498-504).
Mitochondrial structure and function in CCl4-induced cirrhosis in the rat
Authors: Krählenbühl Stephan , Reichen Jürg , Zimmermann Arthur , Gehr Peter , Stucki Jörg
Published: March 2007

To investigate whether the impairment of mitochondrial function in cirrhosis is due to a reduction in liver cell mass or whether mitochondrial function is altered specifically, we analyzed mitochondrial volume and surface density of mitochondrial membranes in control and cirrhotic rats by stereological means. Cirrhosis was induced by long-term exposure to phenobarbital and CC14. Hepatocellular and mitochondrial volumes were reduced to a similar extent, by 39% and 40%, respectively, in cirrhotic animals (p < 0.01). Thus the fraction of hepatocytes occupied by mitochondria did not differ between the two groups. Both total outer (31 ± 3 vs. 19 ± 6 m2; p < 0.01) and inner (87 ± 24 vs. 45 ± 12 m2; p < 0.01) mitochondrial membranes were significantly reduced. Membrane surface was normal per unit of mitochondrial volume, however, suggesting intact mitochondrial structure. Matrix and outer membrane enzyme activities expressed per compartment did not differ between control and cirrhotic animals. Inner membrane, in contrast, had an increased enzyme content per unit area both for cytochrome oxidase (10.3 ± 2.9 vs. 13.0 ± 1.6; p < 0.05) and ATPase (13.7 ± 1.4 vs. 21.2 ± 2.9; p < 0.01). Basal oxygen consumption measured in the perfused liver in situ was significantly reduced in cirrhotic livers (1.6 ± 0.1 vs. 1.1 ± 0.4 μmol/min−1/gm−1) but was unchanged when expressed per square meter of inner membrane. Our results demonstrate that impaired mitochondrial function is mainly due to loss of hepatocellular mass. Increased enzyme activity per unit surface area of inner mitochondrial membrane may be important to maintain mitochondrial function of the cirrhotic liver. (Hepatology 1990;12:526-532).
A hypercoagulable state follows orthotopic liver transplantation
Authors: Stahl Robert L. , Duncan Alexander , Hooks Michael A. , Henderson Michael J. , Millikan William J. , Warren Dean W.
Published: March 2007

Orthotopic liver transplantation may be associated during the postoperative period with hepatic artery thrombosis, a catastrophic occurrence generally necessitating emergency retransplantation. To assess the contribution of the coagulation mechanism to this complication, the levels of procoagulant and anticoagulant proteins were followed in 41 liver transplant patients during the first 10 postoperative days. The mean activities of all procoagulant factors reach normal values on day 1 except for factors V and VII, which achieve normal activity by day 3. Supernormal levels of factór VIII activity and antigen are noted (peak values on day 5 of 334% ± 113% and 481% ± 260%, respectively). The anticoagulant proteins show delayed recovery, with deficient antithrombin III levels seen in 81% of patients on day 3 and 57% on day 5. Similarly, proteins C and S are subnormal in 24% and 21%, respectively on day 3, and 20% and 10%, respectively, on day 5. During this period, elevated levels of thrombin/antithrombin complexes are encountered, reflecting in vivo activation of the coagulation mechanism. Activated thrombin is, therefore, being generated at a time when a decrease in the major regulatory anticoagulant proteins exists. These data suggest an imbalance between the hemostatic and thrombotic mechanisms and indicate a sustained prothrombotic state that may contribute to the risk for hepatic artery thrombosis. Using a regimen of low-dose heparin and fresh frozen plasma infusion, no thromboses have been seen in 65 consecutive liver transplants. (Hepatology 1990;12:553-558).
Assessment of lidocaine metabolite formation as a quantitative liver function test in children
Authors: Gremse David A. , A-Kader Hassan H. , Schroeder Timothy J. , Balistreri William F.
Published: March 2007

Lidocaine, an aminoethylamide, undergoes deethylation in the liver after intravenous injection, resulting in the formation of monoethylglycinexylidide. Serum monoethylglycinexylidide concentration can be measured by a simple, rapid fluorescent polarization immunoassay. We sought to determine whether lidocaine metabolism, as indicated by monoethylglycinexylidide formation, could be used as a quantitative index of hepatic function. Therefore we measured monoethylglycinexylidide formation in 10 healthy children and in 28 children with chronic liver disease. Patients with chronic liver disease were divided by disease severity as being at low, moderate or high risk for deterioration based on a clinical scoring system for liver transplant candidates. In healthy controls, the peak monoethylglyclnexylidide concentration 15 min after injection of lidocaine (1 mg/kg) was 97 ± 12 μg/L (mean ± S.E.). However, monoethylglycinexylidide concentration was decreased in 28 children with chronic liver disease (32 ± 5 μg/L, p < 0.001). Furthermore, this value was inversely proportional to the severity of liver disease. The mean difference in monoethylglycinexylidide concentration between the low-risk and high-risk groups was statistically significant (42 ± 6 vs. 11 ± 4 μg/L, respectively, p < 0.01). We conclude that the rate of formation of the lidocaine metabolite monoethylglycinexylidide is decreased in patients with chronic liver disease and is inversely related to disease severity. Therefore measurement of monoethylglycinexylidide concentration after lidocaine injection may be used as a quantitative assessment of liver function in children. We speculate that monoethylglycinexylidide formation may be a useful prognostic index in children with liver disease. (Hepatology 1990;12:565-569).
Clinical course of spontaneous reactivation of hepatitis B virus infection in patients with chronic hepatitis B
Authors: Levy Philippe , Marcellin Patrick , Martinot-Peignoux Michèle , Degott Claude , Nataf Joëlle , Benhamou Jean-Pierre
Published: March 2007

The purposes of this study were (a) to describe the clinical and biochemical manifestations associated with spontaneous reactivation of hepatitis B virus as defined by the reappearance of hepatitis B virus DNA in serum using dot-blot hybridization and (b) to determine whether the clinical and biochemical manifestations associated with hepatitis B virus reactivation were different in patients with and without human immunodeficiency virus-1 infection. During 1 yr, 110 French patients were admitted to Hôpital Beaujon for chronic hepatitis B. Fourteen were found to have hepatitis B virus reactivation; of these, three were anti-human immunodeficiency virus-1-positive. These 14 patients were HBsAg-positive for 60 mo (range = 6 to 180 mo). Clinical manifestations related to reappearance of hepatitis B virus DNA were present in 11 patients. HBeAg/anti-HBe status did not change in nine patients in whom hepatitis B virus reactivation would not have been recognized without hepatitis B virus DNA testing. Cirrhosis was present in nine patients. Four patients, of whom two were anti-human immunodeficiency virus-1-positive, had fulminant liver failure. Two patients died; one was anti-human immunodeficiency virus-1-positive. One patient was given an emergency transplant. We conclude that (a) spontaneous hepatitis B virus reactivation is a common complication in white patients infected with hepatitis B virus during adulthood; (b) many cases of reactivation, recognized by reappearance of hepatitis B virus DNA using dot-blot hybridization, would have gone unrecognized if diagnosis had been based only on the reappearance of HBeAg; (c) the clinical spectrum associated with hepatitis B virus reactivation ranges from absence of manifestations to fulminant liver failure; (d) severe liver injury can develop in patients with immune deficiency caused by human immunodeficiency virus-1 infection; and (e) emergency transplantation may be indicated in some patients with hepatitis B virus reactivation and fulminant liver failure (Hepatology 1990;12:570-574).
Hepatitis C-associated hepatocellular carcinoma
Authors: Hasan Fuad , Jeffers Lennox J. , De Medina Maria , Reddy Rajender K. , Parker Talley , Schiff Eugene R. , Houghton Michael , Choo Quilim , Kuo George
Published: March 2007

In the United States, a large percentage of patients with hepatocellular carcinoma are serologically negative for hepatitis B. We conducted a retrospective study to determine the prevalence of hepatitis C antibody in the sera of 59 patients with hepatocellular carcinoma who were HBsAg-negative and had no evidence of alcoholic liver disease, primary biiary cirrhosis, autoimmune hepatitis, hemochromatosis or α1-antitrypsin deficiency. Twenty patients (34%) were hepatitis C antibody-positive and hepatitis B core antibody-negative. All twenty patients had underlying cirrhosis, and seven (35%) had histories of transfusions. Eleven (19%) additional patients were also hepatitis C antibody-positive but were hepatitis B core antibody-positive as well. Twenty-one (36%) patients were both hepatitis C antibody- and hepatitis B core antibody-negative and seven (12%) were hepatitis C antibody-negative but hepatitis B core antibody-positive.

The prevalence of hepatitis C antibody was also determined among three other population groups serving as controls and found to be 14% in 28 HbsAg-positive patients with hepatocellular carcinoma, 44% in 76 patients with cryptogenic cirrhosis and 0.5% in 200 consecutive volunteer blood donors.

We conclude that hepatitis C antibody is prevalent among patients with hepatocellular carcinoma and may therefore be a common causative agent of this disease. A significant number of patients with and without cirrhosis, negative for hepatitis C antibody and hepatitis B core antibody, remain without a discernible cause for this malignancy. Perhaps a second-or third-generation test will detect hepatitis C antibody in some of these patients. (Hepatology 1990;12:589-591).