bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of glucose on hepatic conversion of aminonitrogen to urea in patients with cirrhosis: Relationship to glucagon
Authors: Hamberg Ole , Vilstrup Hendrik
Published: March 2007

Glucose reduces the hepatic conversion of aminonitrogen to urea, quantified by the functional hepatic nitrogen clearance (i.e., the slope of the linear relation between urea synthesis rate and blood α-aminonitrogen concentration). This is due to a direct effect of glucose and to inhibition of glucagon. In this study, the effect of glucose on functional hepatic nitrogen clearance was examined during spontaneous hormone responses and during hormonal control by somatostatin. In 7 control subjects (study 1) and 9 patients with cirrhosis (study 2), functional hepatic nitrogen clearance was assessed twice in each subject: during infusion of alanine and during alanine administration superimposed on a continuous glucose infusion (blood glucose, on average = 8.4 mmol/L). In study 3, 6 patients with cirrhosis had functional hepatic nitrogen clearance determined on three occasions: during infusions of alanine and of alanine superimposed on infusion of somatostatin with either euglycemia or hyperglycemia (blood glucose = 8.4 mmol/L). In the control subjects (study 1), functional hepatic nitrogen clearance was 32.5 ± 1.9 L/hr, and glucose reduced it to 18.4 ± 0.9 L/hr (p < 0.01). In the cirrhotic patients, functional hepatic nitrogen clearance was only 9.8 ± 1.3 L/hr (p < 0.01 vs. controls), and glucose did not change it. In the control subjects, glucose reduced the glucagon response to alanine from 204 ± 36 ng/L to 106 ± 8 ng/L (p < 0.05). In the cirrhotic patients the mean fasting glucagon level was increased twofold (180 ± 21 ng/L). The response to alanine increased to 968 ± 265 ng/L; it was not reduced by glucose. In study 3, somatostatin and hyperglycemia reduced functional hepatic nitrogen clearance from 13.2 ± 1.5 L/hr to 6.4 ± 0.7 L/hr (p < 0.01). Somatostatin and euglycemia reduced functional hepatic nitrogen clearance to 9.2 ± 1.2 L/hr (p < 0.01 vs. alanine and hyperglycemia). The results show that the reduction by glucose of hepatic aminonitrogen conversion is lost in cirrhotic patients. The markedly increased glucagon response to alanine was not suppressed by glucose. Inhibition of the glucagon response by somatostatin reestablished the glucose effect, which was in part due to inhibition of glucagon in itself. Thus hepatic aminonitrogen conversion in cirrhosis depends on increased glucagon levels. The hormone-independent effect of glucose is preserved if the hyperglucagonemia is abolished, but the spontaneous high glucagon level overrules the glucose effect. The results indicate reduced hepatic contribution to the nitrogen-sparing effect of glucose in cirrhotic patients. (Hepatology 1994;19:45-54).
Gastrointestinal transit in cirrhotic patients: Effect of hepatic encephalopathy and its treatment
Authors: van Thiel David H. , Fagiuoli Stefano , Wright Harlan I. , Chien Mei-Chen , Gavaler Judith S.
Published: March 2007

Chronic hepatic encephalopathy is highly responsive to changes in diet, to antibiotic therapy and to ingestion of nondigestible disaccharides. The precise pathophysiology of chronic hepatic encephalopathy in individual cases is highly variable, although ammonia toxicity and production of neurotransmitterlike substances in the gut have been proposed to contribute to the overall syndrome of chronic hepatic encephalopathy. The support for this hypothesis is based on the empiric observation that reduction in protein intake, a catharsis or both are effective treatments for chronic hepatic encephalopathy. This study was performed to evaluate the effect of mild subclinical and low-grade (grade 0 to 1) chronic hepatic encephalopathy on gastric emptying and oral-cecal transit times. Thirty patients were studied. Ten had no evidence of chronic hepatic encephalopathy, as determined with a battery of neuropsychiatric studies (group 1); 10 had subclinical hepatic encephalopathy, as judged on the basis of abnormal neuropsychiatric test performance but normal neurological examination (group 2); and 10 had grade 1 hepatic encephalopathy. Each underwent a liquid gastric emptying study and a lactulose oral-cecal transit time study. No significant differences between groups were evident in the results of the gastric emptying studies. In contrast, the time required for a lactulose load to reach the cecum was significantly greater in the patients with hepatic encephalopathy (p < 0.01) and increased as a function of the hepatic encephalopathy grade. More interesting was that when those patients with hepatic encephalopathy were treated for 1 wk with oral neomycin (2 gm/day) and reduction in protein intake to 40 gm/day, the oral-cecal transit time declined significantly to levels seen in subjects without clinical or neuropsychiatric evidence of chronic hepatic encephalopathy. These data suggest that (a) chronic hepatic encephalopathy is associated with prolongation of oral-cecal transit that cannot be attributed to delay in gastric emptying and (b) treatment of chronic hepatic encephalopathy with antibiotics and protein restriction reduces oral-cecal transit. These data suggest but do not prove that chronic hepatic encephalopathy is a self-perpetuating disease process wherein progressive delay in oral-cecal transit allows for greater enteric production of ammonia and other putative encephalogenic materials of dietary origin. (Hepatology 1994;19:67-71).
Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites
Authors: Angeli Paolo , Pria Manuela Dalla , de Bei Erica , Albino Grazia , Caregaro Lorenza , Merkel Carlo , Ceolotto Giulio , Gatta Angelo
Published: March 2007

Although some clinical studies seem to prove the efficacy of nonantialdosteronic potassium-sparing diuretics in the treatment of ascites, no controlled study has compared the efficacy of these drugs with that of antialdosteronic diuretics. Forty nonazotemic cirrhotic patients were randomized to receive amiloride (group A, n = 20) or potassium canrenoate (group B, n = 20). The initial doses of amiloride and potassium canrenoate were 20 mg and 150 mg, respectively. The doses were increased in stepwise fashion to 60 and 500 mg/day, respectively, if no response ensued. Nonresponders to the highest doses of each drug were later treated with potassium canrenoate and amiloride, respectively. Seven of 20 group A patients responded to amiloride, whereas 14 of 20 group B patients responded to potassium canrenoate (p < 0.025). Seven of 13 non-responders to amiloride later responded to potassium canrenoate, whereas only two of the nonresponders to potassium canrenoate later responded to amiloride. The diuretic responses to amiloride and potassium canrenoate were related to the activity of the reninaldosterone system. All responders to amiloride (n = 9) had normal values of plasma aldosterone. All nonresponders to amiloride who later responded to potassium canrenoate (n = 7) had increased levels of plasma aldosterone. Moreover, on comparison of all responders (n = 21) and nonresponders (n = 12) to potassium canrenoate, a higher degree of renal proximal sodium reabsorption (with consequent limitation of sodium delivery to the distal tubule) was found to be the main difference. These results indicate that (a) amiloride is less effective than potassium canrenoate in the treatment of ascites in cirrhotic patients and (b) amiloride may represent an alternative to potassium canrenoate only in patients without increased activity of the renin-aldosterone system. (Hepatology 1994;19:72-79).
Hepatic iron and zinc concentrations after portacaval shunting for nonalcoholic cirrhosis
Authors: Adams Paul C. , Bradley Colin , Frei Jaroslav V.
Published: March 2007

Hepatic iron and zinc concentrations were determined in 26 consecutive nonalcoholic cirrhotic patients who had previously undergone portacaval shunting and then liver transplantation and 37 control patients. Stainable iron was graded on a scale of 0 to 4; 11 shunt patients and 3 control patients had grade 2 to 4 iron staining. Mean hepatic iron concentration was significantly increased (20.1 ± 4.1 μmol/gm) in the shunt group compared with the control group (9.1 ± 2.3 μmol/gm) (normal value, < 35 μmol/gm) (p = 0.015, Student’s t test). Mean hepatic iron index (hepatic iron/age) was 0.5 ± 0.10 in the shunt group and 0.19 ± 0.04 in the control group (p = 0.002). One shunt patient had a hepatic iron index of greater than 2. Hepatic zinc was not significantly different between the shunt group (2.42 ± 0.18 μmol/gm) and the control group (2.56 ± 0.14 μmol/gm). Serial biopsy specimens were analyzed in 17 cases (6 shunt, 11 controls), and the mean annual rate of iron accumulation was significantly greater in shunt patients (4.75 μmol/gm/yr) than in control cases (0.93 μmol/gm/yr, p = 0.037). Although increased stainable iron was ccmmon after portacaval shunting, quantitative iron analysis demonstrated increased hepatic iron concentrations in only 6 of 26 shunt patients and 3 of 37 control patients (p = 0.14, x2 test). Quantitative hepatic iron analysis demonstrated in this study that portacaval shunt patients have far less accumulated iron than hemochromatosis patients and are unlikely to have tissue injury resulting from iron overload. (Hepatology 1994;19:101-105).
Hepatic venular stenosis after orthotopic liver transplantation
Authors: Dhillon Amar P. , Burroughs Andrew K. , Hudson Mark , Shah Neil , Rolles Keith , Scheuer Peter J.
Published: March 2007

Fibrous stenosis of hepatic venules and other features of venous outflow obstruction, including zone 3 congestion and hemorrhage, are sometimes seen after orthotopic liver transplantation. Similar changes associated with endothelial damage have recently been ascribed to azathioprine toxicity and may be forerunners of chronic rejection. Other potential causative agents such as viral hepatitis have yet to be considered. We reviewed 49 liver biopsy specimens from 21 consecutive patients after orthotopic liver transplantation, in whom full data including further follow-up biopsy samples were available. Hepatic venous stenosis was identified in seven patients who had received azathioprine and two additional patients in whom this change could not be ascribed to azathioprine. Stenosis was always associated with zone 3 hemorrhage and congestion and was first noted between 5 and 30 days after transplantation in all but two cases; in these two patients they were first noted after 72 and 133 days. Cellular rejection, including endotheliitis involving terminal hepatic venules, was found in five of the seven patients who had received azathioprine. Chronic (ductopenic) rejection was not seen during a follow-up period of between 97 and 540 days. In three of the nine patients with hepatic venular stenosis, zone 3 changes persisted, and in two of these azathioprine could not be held responsible. Of the 12 patients without hepatic venular stenosis, 10 had received azathioprine. Two of these 12 patients had peliosis-like foci but no other vascular abnormalities. Both also had moderate cellular rejection. Hepatic venular stenosis was found in 43 of patients after liver transplantation; this was usually associated with azathioprine administration and concomitant cellular rejection. Hepatic venular stenosis was usually transient despite continued azathioprine administration. Transient hepatic venular stenosis could be caused by endothelial damage associated with endotheliitis in terminal venules as part of the process of cellular rejection. Rejection frequently coincides with azathioprine administration. Other causative agents such as recurrent viral hepatitis are required to explain persistent hepatic venular stenosis. (Hepatology 1994;19:106-111).
Genetic alterations at the splice junction of p53 gene in human hepatocellular carcinoma
Authors: Hsu Hey-Chi , Huang A-Min , Lai Po-Lin , Chien Wei-Ming , Peng Shian-Yang , Lin Shu-Wha
Published: March 2007

The tumor-suppressor gene p53 may transactivate the transcription of genes that down-regulate cellular growth-related genes and may become oncogenic as a result of the production of mutant proteins or the loss of its protein expression. This study reports that alterations of the highly conserved consensus intervening sequences at the splice junctions may lead to the inactivation of the p53 gene. Analyses with the combined polymerase chain reaction and single-strand conformational polymorphism and direct DNA sequencing of DNAs amplified by means of asymmetric polymerase chain reaction demonstrated sequence alterations at the splice junctions of introns 5 and 7 in four human hepatocellular carcinomas, with a single base substitution at the splice junction in three and a 10-bp deletion starting from the dinucleotide AG of the acceptor site of intron 5 in the fourth. Restriction fragment length polymorphism analysis disclosed allele loss in all three informative cases. The p53 mRNA concentrations were remarkably reduced or undetectable in two hepatocellular carcinomas, whereas the two tumors (cases 2 and 3) that had single base changes at the acceptor site of intron 7 had both normal and abnormally sized p53 mRNAs. Immunocytochemistry failed to detect the wild-type and mutant p53 proteins in all four tumors. Western-blot analysis disclosed an abnormal, larger p53 protein of 55 kD in the tumor of case 3. These findings suggest that the inactivation of p53 gene caused by the genetic alterations at the splice junction may occur more often than perceived and plays an important role in human hepatocarcinogenesis because of the inactivation of the p53 gene by way of the loss of the protein or production of an abnormal protein. (Hepatology 1994; 19:122-128).
Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient: Preliminary report of a prospective study†
Authors: Azoulay D. , Castaing D. , Dennison A. , Martino W. , Eyraud D. , Bismuth H.
Published: March 2007

The aim of this prospective nonrandomized study was to assess the immediate and short-term sequelae of transjugular intrahepatic portosystemic shunting on the circulatory hyperdynamic state of the cirrhotic patient. Twelve transjugular portosystemic shunting procedures were performed in 12 cirrhotic patients for sclerotherapy failure (10 cases) and/or intractable ascites (4 cases). Self-expandable stents 10 mm in diameter were used in all cases. Portal pressure measurement and right-heart catheterization were performed before and 30 min and 1 mo after the procedure. The portoatrial pressure gradient decreased from 15 ± 3 to 7 ± 3 mm Hg 30 min after surgery (p < 0.0001) to 8 ± 3 mm Hg 1 mo after surgery (p < 0.001, in comparison with basal values). The cardiac index increased from 4.5 ± 1.3 to 5.7 ± 1.5 L/min·m2 30 min after surgery (p < 0.001) to 7.4 ± 1.4 L/min μ2 1 mo after surgery (p < 0.001). Systemic vascular resistance decreased from 808 ± 323 to 646 ± 209 dyne·sec·cm−5 30 min after surgery (p < 0.01) to 467 ± 101 dyne·sec·cm−5 1 mo after surgery (p < 0.05). This study demonstrates that transjugular portosystemic shunting rapidly and significantly worsens the hyperdynamic circulatory state of the cirrhotic patient. Although apparently noninvasive, this procedure should be considered with caution in cirrhotic patients with limited cardiac reserve. (Hepatology 1994;19:129-132).
Combination of extracorporeal shock-wave lithotripsy and dissolution of gallbladder stones with methyl tert-butyl ether: A randomized study
Authors: Neubrand Michael , Holl Joseph , Sackmann Michael , Klüppelberg Ulrich , Pauletzki Jürgen , Paumgartner Gustav , Sauerbruch Tilman
Published: March 2007

We conducted a prospective randomized study in gallstone patients to determine whether a combination of extracorporeal shock-wave lithotripsy and subsequent dissolution with methyl tert-butyl ether increases the success rate of methyl tert-butyl ether dissolution and shortens treatment time compared with monotherapy with methyl tert-butyl ether. Fifty patients were randomized into two groups. Twenty-five patients underwent extracorporeal shock-wave lithotripsy before contact dissolution with methyl tert-butyl ether, and 25 patients were treated with methyl tert-butyl ether alone. All patients had at least three stones or stones larger than 30 mm that were radiolucent on x-ray and had densities of less than 140 Hounsfield Units (HU) on computed tomography. Overall, the combined approach neither shortened the treatment time significantly vs. monotherapy with methyl tert-butyl ether nor reduced the time of hospitalization. The success rate was slightly but not significantly increased compared with that of methyl tert-butyl ether therapy alone. The recurrence rate was similar in the two groups after a median follow-up of 1 yr. However, when subgroups of patients with at least one stone larger than 15 mm or with stones with densities of more than 60 HU were analyzed, the clearance rate after 5 mo was significantly higher (p < 0.005 and p < 0.025, respectively) in patients subjected to a combination of extracorporeal shock-wave lithotripsy and methyl tert-butyl ether dissolution. Extracorporeal shock-wave lithotripsy and methyl tert-butyl ether did not expose patients to more adverse effects than did treatment with methyl tert-butyl ether alone. (Hepatology 1994;19:133-137).
Neoexpression of Lewis Y antigen is a sensitive phenotypic change of the damaged intrahepatic bile ducts
Authors: Sasaki Motoko , Kono Naoko , Nakanuma Yasuni
Published: March 2007

We examined the expression of Lewis antigens, particularly Lewis Y, on the intrahepatic biliary epithelial cells in normal livers and various hepatobiliary diseases with immunohistochemical and immunoelectron microscopic methods. In normal livers, Lewis Y was consistently and generally negative in the bile ductules and small bile ducts, respectively. This antigen was frequently and strongly expressed on these ducts and ductules showing variable pathological changes such as necroinflammation and proliferation in a majority of hepatobiliary diseases independent on their etiology, whereas a majority of normal-appearing bile ducts and ductules in these pathological conditions were negative. Immunoelectron microscopically, gold particles suggesting the presence of Lewis Y were demonstrated on microvilli facing the biliary lumen, lateral cell membranes, secretory granules and Golgi apparatus of abnormal biliary epithelial cells in various hepatobiliary diseases. These data suggest that neoexpression of Lewis Y antigen is a highly sensitive, nonspecific phenotypic change of carbohydrate residues occurring in the abnormal biliary epithelial cells in various hepatobiliary diseases. (Hepatology 1994;19:138-144).
Effect of ursodeoxycholic acid on intracellular pH in a bile duct epithelium-like cell line†
Authors: Strazzabosco Mario , Poci Carlo , Spirlí Carlo , Sartori Leonardo , Knuth Alexander , Crepaldi Gaetano
Published: March 2007

Recent studies in perfused livers and isolated hepatocytes indicate that ursodeoxycholic acid-induced HCO3-rich hypercholeresis originates at the ductule/duct level. The bile duct epithelium may be involved in bile alkalinization by passively reabsorbing the protonated unconjugated ursodeoxycholic acid, by directly secreting in response to an ursodeoxycholic acid-induced increase in acid/base transporter activity or by taking up UDCA− in exchange for a base equivalent. To investigate these processes in more detail, we studied the effects of ursodeoxycholic acid on intracellular pH in SK-ChA-1, a well-differentiated human cholangiocarcinoma cell line similar to bile duct epithelium in terms of intracellular pH regulatory mechanisms and morphological markers. Intracellular pH changes were monitored with a microfluorimetric setup using the fluorescent indicator 2′ −7′-bis(2-car-boxyethyl)−5, 6, carboxy fluorescein. Administration of 50 to 1,000 μmol/LUDCA in the absence of HCO3 caused dose-dependent intracellular acidification (intracellular pH = −0.13 ± 0.03 pH/U after 500 μmol/L ursodeoxycholic acid). Acidification was not prevented by preincubation of cells with 0.5 mmol/L 4,4-diisothiocy-anatostilbene-2,2,-disulfonic acid (DIDS) for 30 min or by furosemide administration (1 mmol/L), thus ruling out the stimulation of Cl/HCO3 exchange or the presence of an ursodeoxycholic acid/base exchange. Ursodeoxycholic acid also acidified human fibroblasts, a cell type with no transport capability for ursodeoxycholic acid. In addition, direct measurement of the activities of the three major acid/base transporters in SK-ChA-1 cells (Na+/H+ exchange, sodium-dependent and sodium-independent Cl/HCO3 exchange) failed to show significative differences between cells treated with 500 μmol/L UDCA and controls. In conclusion, ursodeoxycholic acid administration does not primarily stimulate the activities of acid/base transporters responsible for HCO3 secretion by bile duct epithelium. Rather, similar to what has previously been shown in hepatocytes, ursodeoxycholic acid induces intracellular acidification in SK-ChA-1 cells and in fibroblasts. This effect is likely mediated by nonionic diffusion of the weak acid ursodeoxycholic acid. These data confirm that ursodeoxycholic acid can be passively reabsorbed by the biliary epithelium, consistent with the cholehepatic-shunt hypothesis. (Hepatology 1994;19:145-154).
Vasoactive effect of endothelin-1 on rat liver in vivo †
Authors: Okumura Shigetoshi , Takei Yoshiyuki , Kawano Sunao , Nagano Kouichi , Masuda Eiji , Goto Moritaka , Tsuji Shingo , Michida Tomoki , Chen Sheng-Song , Kashiwagi Toru , Fusamoto Hideyuki , Kamada Takenobu , Sato Nobuhiro
Published: March 2007

The purpose of this study was to evaluate the role of endothelin-1 in modulating hepatic microcirculation and liver damage. Rats were infused with endothelin-1 at doses ranging from 30 to 1,000 pmol/kg over 1 min through an indwelling cannula placed in the portal vein. In control rats, saline solution was infused at the same rate. Alterations in hepatic microcirculation were measured with an in vivo microscopy system. Serum lactate dehydrogenase activity, an indicator of hepatic damage, was measured 1 hr after endothelin-1 infusion. Immediately after infusion of endothelin-1, we noted a rapid increase in portal pressure, which remained increased for up to 30 min after endothelin-1 infusion. In contrast, systemic blood pressure remained unchanged, even at 1,000 pmol/kg of endothelin-1. Sinusoidal width was reduced and sinusoidal erythrocyte velocity was diminished in a dose-dependent manner. Oxygen saturation of blood in sinusoids was decreased in a dose-dependent manner, reaching values around 40 of control with 1,000 pmol/kg endothelin-1. The degree of decrease in oxygen saturation of blood in sinusoids had an excellent correlation with the calculated blood flow in the liver tissue. Serum lactate dehydrogenase levels were three to four times control values when endothelin-1 was administered at 1,000 pmol/kg. Thus endothelin-1 decreased hepatic tissue oxygenation associated with sinusoidal vasoconstriction. At high concentrations of endothelin-1, this decrease results in hepatocellular damage. (Hepatology 1994;19:155-161).
Vitamin A deficiency potentiates carbon tetrachloride-induced liver fibrosis in rats
Authors: Seifert Wilfried F. , Bosma Anne , Brouwer Adriaan , Hendriks Henk F. J. , Roholl Paul J. M. , van Leeuwen Rick E. W. , van Thiel-De Ruiter Christa G.F. , Seifert-Bock Ingrid , Knook Dick L.
Published: March 2007

Earlier studies have shown that retinoid administration suppresses the generation of hepatic fibrosis and stimulates its regression in normal (i.e., vitamin A-sufficient) carbon tetrachloride-treated rats. This study focuses on the possible role of a marginal or deficient vitamin A status on carbon tetrachloride-induced fibrosis. This experimental study in rats shows that vitamin A status, reflected by hepatic retinoid content (retinol and retinyl esters), modulates the development of hepatic fibrosis induced by carbon tetrachloride. In rats with low hepatic retinoid levels (12 ± 0.9 μg/gm liver), carbon tetrachloride-induced liver fibrosis was more pronounced than in rats with sufficient hepatic retinoid levels (1,065 ± 327 μg/gm liver). Enhanced liver fibrogenesis was confirmed both morphologically and by a higher hydroxyproline content of the liver. It was associated with a reduced liver weight and the development of parenchymal regeneration nodules. Furthermore, carbon tetrachloride treatment itself reduced the hepatic retinoid content in rats independently of the liver vitamin A status before treatment and increased serum retinol levels in vitamin A-sufficient rats. The results show that the vitamin A status of the liver plays an important role in hepatic fibrogenesis. Low hepatic vitamin A levels, which can be the result not only of low dietary intake but also of interference with vitamin A metabolism by agents such as ethanol and carbon tetrachloride, may be a risk factor for the development of liver fibrosis. We suggest that retinoids modulate collagen synthesis and deposition irrespective of the degree of hepatocellular necrosis induced by carbon tetrachloride. The reduction of retinoid levels in fat-storing cells and fibroblast-like cells by an enhanced secretion of retinol from the liver into the circulation during carbon tetrachloride treatment may stimulate the transformation of these cells to fibroblasts and, in this way, contribute to fibrogenesis of the liver. (Hepatology 1994;19:193-201).
Small-for-size liver transplanted into larger recipient: A model of hepatic regeneration
Authors: Francavilla Antonio , Zeng Qihua , Polimeno Lorenzo , Carr Brian I. , Sun Dantong , Porter Kendrick A. , van Thiel David H. , Starzl Thomas E.
Published: March 2007

Orthotopic liver transplantation was performed in 60 recipient rats weighing 200 to 250 gm. Sixty rats of the same strain were used as liver donors, 30 weighing 100 to 140 gm (small for size) and the other 30 weighing 200 to 250 gm (same size). After 1, 2, 3, 4, 7 and 14 days (n = 5 each) DNA synthesis, nuclear thymidine labeling and mitoses were increased in both the small-for-size and same-size groups, but significantly more in the former. These changes were maximal after 48 to 72 hr, similar to but later than the well-known regeneration response after partial hepatectomy, which peaks at 24 hr in rats. Indirect indexes of regeneration of the transplanted livers also were measured: plasma or serum ornithine decarboxylase; insulin and glucagon serum levels; estradiol and testosterone serum levels (and their nuclear and cytosolic receptors); and transforming growth factor-β, c-Ha-ras and c-jun mRNA expressions. With the small-for-size transplantation, these followed the same delayed pattern as the direct regeneration parameters. The small livers gradually increased in size over the course of 1 to 2 wk and achieved a volume equal to that of the liver originally present in the recipient. In contrast, no significant liver weight gain occurred in the transplanted livers from same-size donors despite the evidence of regeneration by direct indexes, but not by most of the surrogate parameters, including ornithine decarboxylase. (Hepatology 1993;19:210-216).
Cytokine stimulation of nitric oxide formation and differential regulation in hepatocytes and nonparenchymal cells of endotoxemic rats
Authors: Spitzer Judy A.
Published: March 2007

Some disease processes in which increased endotoxin and cytokine levels exist (e.g., sepsis and infantile diarrhea) are also associated with increased levels of blood nitrates, the stable and products of nitric oxide. Available evidence suggests that the effects of an endotoxic environment, with its attendant complex cytokine networks, on liver function are mediated in part by modulation of hepatic nitric oxide synthesis. This hypothesis was tested by means of studying nitric oxide formation and its regulation in liver parenchymal and nonparenchymal cells of rats that had been continuously infused with endotoxin for 30 hr. Hepatocytes of such rats responded to in vitro stimulation for 20 hr by single cytokines, tumor necrosis factor, interleukin-1β and interferon-γ with enhanced nitric oxide formation. In combination, interferon-γ and endotoxin had greater synergistic effect on hepatocytes than did tumor necrosis factor and endotoxin. Kupffer cells of these endotoxic rats responded to 20 hr of interferon-γ stimulation with the same enhanced nitric oxide formation we documented previously for endotoxin. Potentiation of the effect, through combination of endotoxin and interferon-γ, was not as marked as it was with hepatocytes. Challenge of Kupffer cells with tumor necrosis factor or interleukin-1β evoked no response. Hepatocytes and Kupffer cells of time-matched, saline solution-treated rats were unresponsive to endotoxin or cytokine stimulation. Small quantities of nitric oxide were produced by endothelial cells spontaneously; this production was somewhat enhanced in cells of the endotoxin-infused rats by a 20-hr in vitro endotoxin challenge. Studies with inhibitors suggest that enhanced nitric oxide formation by endotoxic hepatocytes and Kupffer cells in response to in vitro endotoxin stimulation is differentially regulated. Our findings indicate modulation of nitric oxide generation by cytokines in vitro in various liver cell types of endotoxic rats. A similar scenario may exist in vivo because of the prevailing inflammatory response to endotoxin administration. (Hepatology 1994;19:217-228).
Salicylamide sulfate cell entry in perfused rat liver: A multiple-indicator dilution study
Authors: Xu Xin , Schwab Andreas J. , Iii Ford Barker , Goresky Carl A. , Pang Sandy K.
Published: March 2007

The hepatocellular entry of salicylamide sulfate conjugate, which binds to both red blood cells and albumin, was examined with the multiple-indicator dilution technique in the perfused rat liver, with medium containing both 20 red cells and 1 albumin (set A), red cells only (set B), albumin only (set C) and neither red cells nor albumin (set D). [14C]Salicylamide sulfate, 51Cr-labeled red cells (a vascular reference), 125I-labeled albumin, [3H]sucrose or [58Co] ethylenediaminetetraacetic acid (EDTA) (high and low molecular weight interstitial references, respectively) and 3H2O or D2O (a cellular reference) were injected as a bolus into the portal vein. Among all sets of outflow data, the earliest immediate vascular recoveries for the [14C] salicylamide sulfate were lower than those for the vascular reference. For sets A and B, the upslopes precessed those for the 58Co-EDTA curve, then crossed over the 58Co-EDTA curves, with lower magnitude peaks occurring at the same time as those for labeled albumin, whereas for sets C and D, in which red cells were absent, the upslopes of [14C]salicylamide sulfate lagged behind those for labeled albumin and [3H]sucrose, reaching lower magnitude peaks coincidental in time with those for labeled sucrose. The precession of the [14C]salicylamide sulfate curve over 58Co-EDTA or [3H]sucrose in the presence (sets A and B) but not in the absence (sets C and D) of red cells and the absence of precession with albumin alone (set C) suggest that a red cell effect on the upslope is more evident than that for albumin. For all experiments, the downslopes of the sulfate curve crossed over those of the labeled red cells, albumin, 58Co-EDTA and sucrose curves and then the water curve at around the peak. The downslopes of the [14C]salicylamide sulfate were similar to those for labeled water, suggesting rapid cellular influx and efflux of salicylamide sulfate. Quantitative evaluation with a barrier-limited space-variable transit-time model for rapidly equilibrating red cell and albumin binding accounted for the upslope effects on [14C]salicylamide sulfate behavior and demonstrated its relatively high liver cell permeability. Values for the unbound permeability surface area product (0.029 to 0.036 ml sec−1·gm−1) were not different, regardless of the presence or absence of red cells and albumin, and slightly exceeded values for hepatic blood flow (0.0186 ± 0.0016 ml sec−1·gm−1). Comparable influx (0.083 to 0.14 sec−1) and efflux (0.10 to 0.18 sec−1) coefficients were obtained, suggesting rapid cellular entry and efflux of salicylamide sulfate. The ratio of the derived rate constants, which corresponds to the concentration ratio across the membrane, was 0.40 to 0.55. The findings contrast sharply with those for acetaminophen sulfate, which enters liver cells poorly. (Hepatology 1994; 19:229-244).
Does hepatitis C virus cause hepatocellular carcinoma?
Authors: Blum Hubert E.
Published: March 2007

Background and Methods.

To detect potentially curable cases of hepatocellular carcinoma, outpatients with chronic hepatitis or compensated liver cirrhosis who were seen at the Center for Adult Diseases (Osaka, Japan) were examined periodically by means of ultrasonography and measurement of serum alpha-fetoprotein. Risk factors for hepatocellular carcinoma were identified with a Cox proportional-hazards model.

Results.

A total of 917 patients, 40 to 69 years old, were registered from May 1987 to March 1991. By the end of September 1991, liver cancer had developed in 54. The three-year cumulative risk of liver cancer was 12.5 percent for 240 patients with liver cirrhosis at enrollment and 3.8 percent for 677 patients with chronic hepatitis. Cox regression analysis showed that the risk of liver cancer was increased almost sevenfold in patients with hepatitis B surface antigen (rate ratio, 6.92; 95 percent confidence interval, 2.92 to 16.39) and fourfold in patients with hepatitis C antibody (rate ratio, 4.09; 95 percent confidence interval, 1.30 to 12.85). A high alpha-fetoprotein value at enrollment was also a risk marker for liver cancer.

Conclusions.

Patients with hepatitis C virus infection have a greatly increased risk of liver cancer. Further studies are required to clarify the roles of other risk factors, including drinking and smoking habits.
What’s wrong when it isn’t right: Situs inversus and genetic control of organ position
Authors: Fishman Laurie N. , Lavine Joel E.
Published: March 2007

A recessive mutation was identified in a family of transgenic mice that resulted in a reversal of left-right polarity (situs inversus) in 100 percent of the homozygous transgenic mice tested. Sequences that flanked the transgenic integration site were cloned and mapped to mouse chromosome 4, between the Tsha and Hxb loci. During early embryonic development, the direction of postimplantation turning, one of the earliest manifestations of left-right asymmetry, was reversed in homozygous transgenic embryos. This insertional mutation identifies a gene that controls embryonic turning and visceral left-right polarity.
Detection of antigens related to hepatitis C virus RNA encoding the NS5 region in the livers of patients with chronic type C hepatitis
Authors: Tsutsumi Mikihiro , Urashima Sachio , Takada Akira , Date Takayasu , Tanaka Yujiro
Published: March 2007

Hepatitis C virus is a positive single-strand RNA virus distantly related to flaviviruses. Therefore RNA replicase, an RNA-dependent RNA polymerase, may be essential for the replication of hepatitis C virus, as well as other RNA viruses. In this study we synthesized the recombinant polypeptide (HCV-NS5 antigen) with a 576 bp cDNA encoding a part of the NS5 region of the HCV genome that has the Gly-Asp-Asp motif. The antibody against this polypeptide was obtained from rabbit serum. In Western-blot analysis with NS5 IgG HCV antibody, an 84-kD protein was clearly detected as a single band in the microsomal fraction but not in the nuclear and mitochondrial fractions or in the cytosol fraction. Immunohistochemically, HCV-NS5 antigen was clearly stained in the cytoplasm of hepatocytes but not in the nucleus or cell membrane. Moreover, as determined on immunoelectron microscopy, HCV-NS5 antigen was demonstrated with fine granular distribution along the endoplasmic reticulum but not in other organelles, including the nucleus and mitochondria. Immunoreaction in other cell types was negative. These results indicate that replication of HCV may occur only in hepatocytes and that HCV-NS5 may be produced in the endoplasmic reticulum of these cells. HCV-NS5 antigen was stained only in the livers of hepatitis C virus-positive patients but not in sections from patients with chronic type B hepatitis or alcoholic fibrosis. In chronic type C liver disease, the overall detection rate of HCV-NS5 antigen was 56 (33 in chronic persistent hepatitis, 52 in chronic active hepatitis and 86 in cirrhosis). These results indicate that the replication of HCV may occur more frequently in the advanced than in the early stages of type C hepatitis. Recently, interferon has been used for treatment of chronic type C hepatitis. However, it is very difficult to determine when HCV is eliminated from the liver, even if hepatitis C virus RNA is not detected in serum. Immunostaining of HCV-NS5 antigen in liver biopsy sections may be helpful in evaluating the cessation of HCV replication. (Hepatology 1994;19:265-272).
Hepatitis C viremia in chronic liver disease: Relationship to interferon-α or corticosteroid treatment
Authors: Magrin Silvio , Craxi Antonio , Fabiano Carmelo , Simonetti Rosa Giovanna , Fiorentino Germana , Marino Liliana , Diquattro Orazia , Marco Vito Di , Loiacono Oreste , Volpes Riccardo , Almasio Piero , Urdea Mickey S. , Neuwald Paul , Sanchez-Pescador Ray , Detmer Jill , Wilber Judith C. , Pagliaro Luigi
Published: March 2007

We assessed the pattern of hepatitis C viremia in chronic liver disease by studying 100 hepatitis C virus antibody-positive patients: 48 with chronic hepatitis, 21 with cirrhosis and 31 with hepatocellular carcinoma and cirrhosis. Serum hepatitis C virus RNA was detected by means of both the conventional nested polymerase chain reaction and a newly developed assay based on branched DNA that can also quantify viremia. Hepatitis C virus RNA was found in 94 of 100 patients with polymerase chain reaction and in 71 of 100 patients with branched-DNA (p < 0.001). Mean viremia level (× 103 genome equivalents/ml ± S.D.), as assessed with the branched-DNA test, was 5,700 ± 7,618 in the 48 patients with chronic hepatitis, 3,340 ± 3,633 in the 21 patients with cirrhosis and 1,768 ± 2,770 in the 31 patients with hepatocellular carcinoma (p < 0.02). We also analyzed retrospectively the relationship between viremia and treatment. Fifty-five patients (41 chronic hepatitis, 14 cirrhosis) underwent interferon-α treatment. Mean viremia level was comparable among the 30 responders (5,644 ± 8,207) and the 25 nonresponders (5,519 ± 6,208) to interferon, but it was significantly lower (1,841 ± 1,864) in the 12 of 30 responders (11 chronic hepatitis, 1 cirrhosis) who maintained remission up to 1 yr after cessation of interferon treatment. Fourteen patients (7 chronic hepatitis, 7 cirrhosis) with autoantibodies (12 antinuclear, 2 anti-liver-kidney microsomal) were treated with prednisone. The mean viremia level significantly increased after 3 mo of treatment, even in face of ALT decrease. In conclusion, serum hepatitis C virus RNA is detectable in almost all patients with hepatitis C virus antibody-positive chronic liver disease, polymerase chain reaction being more sensitive than the branched-DNA test. Hepatitis C viremia is lowest in patients with advanced liver disease. A low pretreatment value of viremia could identify patients with chronic hepatitis who will derive long-term benefit from interferon. Corticosteroids generally increase viremia in hepatitis C virus antibody-positive, autoantibody-positive chronic hepatitis, independent of ALT response. (Hepatology 1994;19:273-279).
High sustained response rate and clearance of viremia in chronic hepatitis C after treatment with interferon-α2b for 60 weeks
Authors: Reichard Olle , Foberg Ulla , Frydén Aril , Mattsson Lars , Norkrans Gunnar , Sönnerborg Anders , Wejstål Rune , Yun Zhi-Bing , Weiland Ola
Published: March 2007

To evaluate the effect of prolonged interferon-α treatment on serum aminotransferase levels and hepatitis C virus RNA in serum, 40 patients with chronic hepatitis C virus infection were treated with 3 MU interferon-α2b thrice weekly for 60 wk. Before treatment all patients had elevated serum ALT levels for at least 1 yr, antibodies to HCV by second-generation tests and liver histological findings consistent with chronic hepatitis C. Before treatment hepatitis C virus RNA was found in serum in 39 of 40 (97.5) patients. Normalization of ALT levels at treatment cessation was seen in 24 of 40 (60) patients, of whom 15 of 24 (62.5) had sustained ALT responses up to 24 wk after treatment. At follow-up, 24 wk after treatment, hepatitis C virus RNA was cleared from serum in 17 of 40 (42.5) patients, including all sustained responders, one nonsustained responder and one nonresponder. We conclude that 60 wk of treatment with interferon-α2b seems to induce a high percentage of sustained response, which coincides with cessation of viral replication. (Hepatology 1994; 19:280-285).
T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections
Authors: Ferrari Carlo , Valli Antonietta , Galati Lucia , Penna Amalia , Scaccaglia Patrizia , Giuberti Tiziana , Schianchi Claudia , Missale Gabriale , Marin Maria Grazia , Fiaccadori Franco
Published: March 2007

Twenty-nine patients with chronic hepatitis C and 15 asymptomatic hepatitis C virus antibody-positive subjects who clinically recovered from hepatitis C virus infection were studied for their peripheral blood lymphomononuclear cell proliferative response to hepatitis C virus structural and nonstructural antigens (core, envelope, nonstructural 4 and nonstructural 5) expressed in yeast as superoxide dismutase fusion proteins, in an initial attempt to define some of the features of the virus-specific immune response. Hepatitis C virus core was the most immunogenic antigen for human leukocyte antigen class II-restricted T cells in both groups of patients studied, and the proliferative response to it was the most vigorous and the most frequently expressed in comparison with the other antigens tested. The specificity of the results was supported by the lack of response to hepatitis C virus antigens by healthy uninfected controls and confirmed by recognition of recombinant core proteins of different origin (yeast and baculovirus) by polyclonal T-cell lines produced by T-cell stimulation with yeast-derived core. Each of the antigens tested was able to induce significant although variable levels of proliferative response, indicating that all can be immunogenic at the T-cell level. Significant proliferative responses to core, nonstructural 4 and nonstructural 5 antigens were more frequently detected in subjects who were able to eradicate infection than in patients with chronic hepatitis C, although the difference was statistically not significant. No difference was observed between the two groups of patients with respect to the response to the putative envelope antigens. (Hepatology 1994;19:286-295).
Growth hormone, insulin-like growth factor-1 and insulin resistance in cirrhosis
Authors: Shmueli Ehoud , Stewart Murray , George K. , Alberti M. M. , Record Christopher O.
Published: March 2007

Cirrhosis is characterized by paradoxical growth hormone secretion in response to glucose and insulin infusion. To ascertain whether this abnormality contributes to insulin resistance, euglycemic hyperinsulinemic glucose clamps were performed on six patients with cirrhosis and six normal control subjects. Each patient with cirrhosis underwent two clamps in random order, a clamp with somatostatin (250 μg/hr) together with insulin and glucagon replacement, and a control clamp without somatostatin. The normal subjects underwent the control clamp only. During the control clamp, growth hormone levels were considerably higher in the patients with cirrhosis (6.1 ± 0.4 vs. 0.5 ± 0.4 mU/L, p < 0.02), and glucose uptake was considerably lower (3.29 ± 0.56 vs. 9.52 ± 1.14 mg/kg/min, p < 0.001). Indirect calorimetry indicated that the defect was accounted for by lower nonoxidative glucose disposal (1.23 ± 0.45 vs. 6.00 ± 0.73, p < 0.001). Peripheral glucose uptake, exemplified by forearm glucose uptake (0.27 ± 0.04 vs. 1.22 ± 0.42 mg/100 ml/min, p < 0.02), and calculated insulin sensitivity (24 ± 8 vs. 114 ± 20 μl/kg/min per mU/L) were particularly diminished. In the patients with cirrhosis somatostatin suppressed growth hormone levels (6.1 ± 1.2 to 1.2 ± 0.4 mU/L, p < 0.05). However, no significant changes occurred in whole-body glucose uptake (3.29 ± 0.56 vs 3.01 ± 0.54 mg/kg/min), forearm glucose uptake (0.27 ± 0.04 vs 0.30 ± 0.01 mg/100 ml/min) or insulin sensitivity (24 ± 8 vs. 35 ± 10 μl/kg/min/mU/L, p = 0.42). Suppression of abnormal growth hormone secretion by somatostatin over 5 hr does not alter insulin sensitivity or glucose uptake in cirrhosis. (Hepatology 1994;19:322-328).
Early and late changes in fasting and absorptive plasma amino acids and ammonia after distal splenorenal shunt in cirrhosis
Authors: Trevisani Franco , Bernardi Mauro , Arienti Vincenzo , Scrivano Pietro , Mazziotti Alighieri , Cavallari Antonino , Patrono Daniela , Piazzi Sandro , Gozzetti Giuseppe , Gasbarrini Giovanni
Published: March 2007

Levels of plasma amino acids, ammonia, glucagon and insulin and their 5-hr responses to a protein feeding were evaluated before and sequentially (3 mo and 1 yr) after distal splenorenal shunt in 10 patients with cirrhosis belonging to Child-Pugh’s class A or B. An index of glucagon effectiveness (plasma glucose/glucagon) was also calculated. These parameters were related to liver test results, portal vein diameter and mental state, and they were compared with those found in seven patients undergoing sclerotherapy of esophageal varices with comparable liver function (control group). Liver test results and levels of plasma insulin did not change in either group. Shunt significantly increased levels of fasting tyrosine, methionine, ornithine, arginine, histidine, ammonia and glucagon with respect to the control group; it also significantly decreased levels of leucine, valine, glucagon effectiveness and portal vein diameter. The elevation of levels of tyrosine, ammonia and the sum of arginine and ornithine was correlated directly with the increase in glucagon and inversely with the decline in glucagon effectiveness. Tyrosine increase was also correlated with the reduction of portal vein diameter. One shunted patient showed mild hepatic encephalopathy. Protein feeding did not worsen the mental state of patients before and after the operation. Surgery significantly increased the 5-hr response to the meal of gluconeogenic amino acids; its rise was again correlated with the changes in glucagon plasma levels and effectiveness. Although the absorptive levels of plasma ammonia were significantly higher 1 yr after surgery, its 5-hr response barely rose. In cirrhotic patients with a relatively preserved liver function, distal splenorenal shunt progressively worsened the fasting plasma profile of nitrogen compounds and the response to protein ingestion of gluconeogenic amino acids. The decline of portal blood flow and glucagon effectiveness may be causal factors. Despite this, the “cerebral” tolerance to a moderate oral load of protein was not reduced by surgery. (Hepatology 1994;19:329-338).