bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of extrahepatic cholestasis on liver regeneration after partial hepatectomy in the rat
Authors: Aronson D. C. , Chamuleau R. A. F. M. , Frederiks W. M. , Bosman O. K. , Oosting J.
Published: August 2010

Abstract: Liver regeneration after partial hepatectomy was studied in four groups of rats: control rats (n=12), rats with 1 week of common bile duct obstruction (n=11), rats with restoration of bile flow after 1 week of obstruction (n=9) and a sham‐operated group (n=7). Parameters of DNA synthesis – thymidine kinase activity and in vivo bromodeoxyuridine incorporation – were measured at partial hepatectomy (T=0), and 24 and 48 h after partial hepatectomy. During common bile duct obstruction, DNA synthesis was already stimulated at T=0, but partial hepatectomy in common bile duct obstruction rats induced a delayed DNA synthesis. After 1 week of restoration of bile flow, normal DNA synthesis had returned at T=0, but DNA synthesis after partial hepatectomy was still delayed. The sham‐operated rats showed a normal regeneration response after partial hepatectomy assessed by bromodeoxyuridine incorporation but delayed as assessed by thymidine kinase activity, partly due to the impaired physical condition of the animals. The present data support the hypothesis that during cholestasis, regeneration promoting, and inhibitory factors accumulate in the liver, their balance determining whether regeneration after partial hepatectomy will occur in a normal, enhanced or delayed way.
Contact solvents for common bile duct stones. Study in an in vitro system
Authors: Guitaoui Mustapha , Montet Anne‐Marie , Takács Tamás , Montet Jean‐Claude
Published: August 2010

Abstract: Cholesterol and brown pigment stones found in the common bile duct are often radiolucent and therefore indistinguishable. The purpose of this study was to define contact solvent systems able to dissolve both stone types. The influence of mucolytic agents on in vitro pigment stone dissolution was first determined. It was shown that dithioerythritol induced more rapid dissolution than N‐acetylcysteine. Alternating treatment with an aqueous alkaline solvent (pH=9.5), composed of sodium deoxycholate 50 mM, ethylenediaminetetraacetate 26 mM and dithioerythritol 50 mM, for 45 min, and an organic solvent methyl tert‐butyl ether/dimethyl sulfoxide (90/10) for 15 min, was more effective for bilirubin, cholesterol, and fatty acid solubilization (p<0.01) than using these solvents separately. The dissolution of brown stones was nearly completed within 9 h and that of mixed cholesterol stones was obtained within 3 h. We conclude that the alternating treatment described is very effective for the rapid in vitro dissolution of the two major stone types present in the bile ducts, and deserves further assessment in vivo.
Normotest and abnormal prothrombin in liver transplantation
Authors: Nakao Akimasa , Iwaki Yuichi , Virji Mohammed A. , Kita Yoshiaki , Demetris A. Jake , Iwatsuki Shunzaburo , Starzl Thomas E.
Published: August 2010

Abstract: Postoperative changes in coagulation parameters, including the abnormal plasma prothrombin level, were studied in 95 patients who underwent liver transplantation, and the results were compared with the clinical outcome. The patients were classified into four groups: Group I had a satisfactory postoperative course, (n=76), Group II suffered graft failure or death at 31 days or more after transplantation (n=9); Group III suffered graft failure or death from 8 to 30 days after transplantation (n=4); and Group IV suffered graft failure or death within 7 days of transplantation (n=6). The Normotest, which closely reflected liver graft function, showed an increase immediately after transplantation in Group I, II, and III, but showed a marked decrease in Group IV. In patients with severe acute cellular rejection, the plasma level of abnormal prothrombin (desgamma‐carboxy prothrombin) was compared with the histology of the liver biopsy specimen. When liver graft function was good after orthotopic transplantation, the Normotest value recovered to the normal range of 70% or more. Subsequently, graft function remained good when the desgamma‐carboxy prothrombin level stayed low, whereas acute cellular rejection was indicated by an elevation of des‐gamma‐carboxy prothrombin. When the Normotest value was lower than 20% for the first 2 days after transplantation, graft failure was likely. Because des‐gamma‐carboxy prothrombin was not produced by graft with early failure, the des‐gamma‐carboxy prothrombin level also remained low. Thus, the Normotest value and the des‐gamma‐carboxy prothrombin level were both useful parameters for assessing hepatic function and rejection after transplantation.
A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease
Authors: Uchimura Yasuyo , Sata Michio , Kage Masayoshi , Abe Hirohiko , Tanikawa Kyuichi
Published: August 2010

Abstract: To clarify the relationship between hepatitis C virus infection and excessive alcohol intake, we carried out histological examination of the liver in 46 alcoholics with chronic hepatitis C virus infection and compared the findings in 55 patients with chronic hepatitis C, 38 with alcoholic liver disease, and 27 with chronic hepatitis B. The majority of alcoholics with chronic hepatitis C virus infection displayed virus‐related histological changes very similar to those in chronic hepatitis C, including frequent lymphoid follicles (34.7%) or aggregates (93.3%) in the portal tracts, mild necroinflammatory change (76.1%) in the parenchyma, and lymphocytosis in sinusoids (82.7%). Liver cell dysplasia and irregular regenerative activity of hepatocytes were rarely observed. The effects of alcohol on the liver were found to be minimal in the majority. These findings could suggest that the hepatic injury in the majority of alcoholics with chronic hepatitis C virus infection in Japan is due to persistent hepatitis C virus infection rather than to alcoholic injury. In addition, our study disclosed that the perivenular fibrosis which is designated as a histological characteristic of alcoholic liver disease is frequently observed in chronic hepatitis C. These similarities suggest that a similar fibrogenesis is present in chronic hepatitis C and alcoholic liver disease.
Early effects of high doses of retinol (vitamin A) on the in situ cellular metabolism in rat liver
Authors: Lettinga K. D. , Gutter W. , Van Noorden C. J. F. , Schellens J. P. M. , Frederiks W. M.
Published: August 2010

Abstract: Understanding of the possible toxicity associated with hypervitaminosis A becomes increasingly important in view of the popularity of vitamin A supplementation. Hypervitaminosis A for many years may eventually lead to hepatocellular damage. In the present study, rats were treated for 7 days with high doses of retinol to study the early effects on the metabolism of different types of liver cells using (enzyme) histochemistry, immunohistochemistry and electron microscopy. Excessive intake of vitamin A activates Kupffer cells and induces accumulation of lipid droplets in fat‐storing cells as well as proliferation of these cells. Moreover, it affects the metabolic heterogeneity in the liver lobules, but does not lead to apparent cell damage. Based on the changes in marker enzymes for different metabolic processes, it is concluded that the capacity for breakdown of purines, the antioxidant capacity, the potential for phagocytosis and the regulation of ammonia levels were largely decreased. Increased alkaline phosphatase activity in hepatocytes pointed to an activated process of transport of retinol esters over the bile canalicular membrane. The possible causes of these metabolic changes have been described in the discussion.
Structural and functional features of bile canaliculi in adult rat hepatocyte spheroids
Authors: Yumoto Atsuko Uchida , Watanabe Sumio , Hirose Miyoko , Kitamura Tsuneo , Yamaguchi Yasushi , Sato Nobuhiro
Published: August 2010

Abstract: Spheroids of adult rat hepatocytes are spherical cell aggregates which retain three‐dimensional architecture and hepatocyte specific functions. In this study, we investigated the detailed structure and function of bile canaliculi in spheroids. Hepatocytes were prepared from adult rat liver and cultured with epidermal growth factor (50 ng/ml). Hepatocytes formed floating spheroids 4 days after inoculation. The morphology of hepatocyte spheroids was investigated after fluorescent staining for actin using confocal laser scanning microscopy and electron microscopy. To study the function of bile canaliculi, the transcellular transport of fluorescein diacetate was observed. These experiments were performed in a control group and in a group treated with the actin inhibitor cytochalasin B. In a control group, spheroids contained bile canalicular structures which were surrounded by actin filaments. Added fluorescent dye was secreted and pooled in bile canaliculi. Cytochalasin B caused marked distention of bile canaliculi and prominent accumulation of secreted fluorescent dye in dilated bile canaliculi. This phenomenon was based on the impairment of contractile movement of bile canaliculi. These results demonstrate that hepatocyte spheroids maintain functional and morphological peculiarity, and therefore this model may be useful in investigation of the mechanism of bile formation and intrahepatic cholestasis.
Does the measurement of portal flow velocity have any value in the identification of patients with cirrhosis at risk of digestive bleeding?
Authors: Cioni G. , Tincani E. , Cristani A. , Ventura P. , D'Alimonte P. , Sardini C. , Turrini F. , Abbati G. L. , Romagnoli R. , Ventura E.
Published: August 2010

Abstract: Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. In most cases haemorrhage originates from oesophageal varices or from congestive gastropathy, and the evaluation of the bleeding risk is based on oesophagogastroduodenoscopic data. The aim of this prospective study was to determine whether the measurement of portal flow velocity by Duplex‐Doppler, compared with endoscopic data, can help in detecting patients with cirrhosis at risk of bleeding. One hundred and seventy‐three patients underwent endoscopy to ascertain the size of the varices and the severity of congestive gastropathy. For each patient maximal portal flow velocity measurements were obtained. No difference in portal flow velocity was observed between patients with or without oesophageal varices or congestive gastropathy. During a 2‐year observation period, 27 patients (15.6%) had at least one episode of acute digestive bleeding. Stepwise multiple logistic regression analysis demonstrated a correlation between oesophageal varices and congestive gastropathy endoscopic grading and the incidence of bleeding; only the former was entered into the final regression equation (p>0.001). No relationship between the max portal flow velocity value and incidence of bleeding was found. This study shows that portal flow velocity is unrelated to the degree of the endoscopic abnormalities in patients with liver cirrhosis and that it has no value in the identification of patients with cirrhosis at risk of upper gastrointestinal bleeding.
Treatment of woodchuck hepatitis virus infection in vivo with 2‘,‐3’‐dideoxycytidine (ddC) and 2‘,‐3’‐dideoxycytidine monophosphate coupled to lactosaminated human serum albumin (L‐HSA ddCMP)
Authors: Zahm F. E. , D'Urso N. , Bonino F. , Ponzetto A.
Published: August 2010

Abstract: Dideoxycytidine (ddC) is a nucleoside analogue active against human immunodeficiency virus and with in vitro activity against human hepatitis B virus. We investigated the ability of ddC to inhibit one of the Hepadnaviridae, the woodchuck hepatitis virus and compared the results with the effect obtained by a conjugate of lactosaminated human serum albumin 2′,‐3′‐dideoxycytidine monophosphate (L‐HSA ddCMP). This compound specifically enters the hepatocyte via the asialoglycoprotein receptor. We treated five chronic woodchuck hepatitis virus carriers with intravenous injections of 0.5 mg/kg body weight of ddC for 5 consecutive days, and under the same protocol five woodchucks with 10.4 mg/kg L‐HSA ddCMP, a dose equivalent to 0.25 mg/kg of free ddC. A reduction of serum woodchuck hepatitis virus DNA (5–125 fold) was observed during therapy in three out of five animals receiving ddC and in two of the five animals treated with L‐HSA ddCMP. In responding wood‐chucks, virus DNA levels rebounded immediately after stopping therapy. No signs of toxicity were observed during or after the course of therapy. These preliminary results of short‐term treatment indicate that ddC has anti‐viral activity against woodchuck hepatitis virus. When the dose was reduced by 50%, L‐HSA ddCMP showed anti‐viral activity to an even lesser degree.
Seroprevalence of HBV (anti‐HBc, HBsAg and anti‐HBs) and HDV infections among 9006 women at delivery*
Authors: Bart P. A. , Jacquier P. , Zuber P. L. F. , Lavanchy D. , Frei P. C.
Published: August 2010

Abstract: Serum samples from 9006 women, who delivered in Switzerland in 1990 and 1991, were collected around the country. Of these women, 62.7% were Swiss and 37.3% originated from foreign countries. Samples were first screened for anti‐HBc and those found positive were further tested for HBsAg, anti‐HBs and anti‐HDV Anti‐HBc was found in 640 of the 9006 women (overall prevalence, 7.1%; Swiss, 3.3%; foreigners, 13.5%). Of these 640 positive samples, 61 (9.5%) were positive for HBsAg (without anti‐HBs), 467 (73.0%) positive for anti‐HBs (without HBsAg) and 8 (1.3%) positive for both HBsAg and anti‐HBs. The remaining 104 were thus anti‐HBc positive without HBsAg or anti‐HBs. These 104 specimens with the so‐called “isolated anti‐HBc” reactivity represented 1.2% of the whole population or 16.3% of the 640 anti‐HBc positive mothers. All were HBV DNA negative (PCR). Anti‐HDV antibody was found in only five women. HBsAg was seen in 38 of the cord‐blood samples from the anti‐HBc positive mothers. In this large sampling, we observed a relatively high seroprevalence of HBV infection. Cases with isolated anti‐HBc reactivity, being HBV DNA negative by PCR, were probably non‐infectious at the time of blood collection.
Incidence of post‐transfusion hepatitis in Taiwan before and after introduction of anti‐HCV testing
Authors: Chang Ting‐Tsung , Young Kung‐Chia , Yang Yu‐Jen , Lai Kuo‐An , Wu Hua‐Lin , Wu Mingo‐Ho , Chen Mao‐Yuan , Lin Xi‐Zhang , Lin Ching‐Yih , Shin Jeng‐Shiann
Published: August 2010

Abstract: The effectiveness of second‐generation anti‐hepatitis C virus antibody (anti‐HCV) screening of blood donations for the prevention of non‐A, non‐B post‐transfusion hepatitis (NANB PTH) was assessed. A prospective study of 192 transfusion recipients was performed to compare the incidence of NANB PTH after the introduction of the second‐generation anti‐HCV test with the incidence before its introduction. We used a polymerase chain reaction to detect HCV‐RNA and HBV‐DNA in the sera of patients with NANB PTH. The incidence of acute post‐transfusion hepatitis C was 11% (8 of 71) before the screening for anti‐HCV as compared with 2.5% (3 of 121) after the screening (p<0.05). Viremia was detected within the first five weeks of infection in 10 patients with acute post‐transfusion hepatitis C. However, there was no significant difference in the incidence of non‐A, non‐B, non‐C (NANBNC) PTH before screening (3 of 71, 4.2%) compared with after screening (3 of 121, 2.5%). Usually, NANBNC PTH was not clinically important. Anti‐HCV screening of blood donors significantly reduces the incidence of post‐transfusion hepatitis C, but not the incidence of NANBNC PTH.
Liver failure in erythropoietic protoporphyria associated with choledocholithiasis and severe post‐transplantation polyneuropathy
Authors: Lock G. , Holstege A. , Mueller A. R. , Christe W. , Doss M. O. , Schölmerich J. , Neuhaus P.
Published: August 2010

Abstract: In a 58‐year‐old woman with erythropoietic protoporphyria, asymptomatic liver involvement had been diagnosed 12 years earlier. For more than 20 years the patient had been known to have symptomatic gallstones. A mild polyneuropathy of the lower limbs had been diagnosed several years ago. In December 1992, she presented with colicky upper abdominal pain, dyspepsia and mild jaundice. Diagnosis of beginning cholestasis in erythrohepatic protoporphyria and coincidental choledocholithiasis was made. A causal relation between choledocholithiasis and deterioration of liver function was assumed. Endoscopic extraction of the bile duct stones, however, could not prevent the development of terminal hepatic failure. Biochemically, an excessive protoporphyrinemia and coproporphyrinuria were found. Five weeks after presentation, the patient underwent orthotopic liver transplantation. Immediately after the operation she developed a severe axonal neuropathy with cranial nerve involvement. One year after transplantation, her general condition has markedly improved, but there is still a disabling polyneuropathy. Recently, there were single reports on patients with very similar neurological symptoms following liver transplantation in erythropoietic protoporphyria. This case supports the assumption of a distinct protoporphyrin‐induced neural damage in severe hepatic failure.
Short‐ and long‐term hemodynamic response to octreotide in portal hypertensive patients: a double‐blind, controlled study
Authors: Zironi G. , Rossi C. , Siringo S. , Galaverni C. , Gaiani S. , Piscaglia F. , Bolondi L.
Published: August 2010

Abstract: This randomized, double‐blind, placebo‐controlled study on the hemodynamic effect of two different doses of octreotide administered subcutaneously was conducted among 20 cirrhotic portal hypertensive patients. The wedged hepatic venous pressure, the hepatic venous pressure gradient, the mean portal venous flow velocity, the resistive index of the superior mesenteric artery, the heart rate and the mean arterial pressure were simultaneously evaluated by hepatic vein catheterization and Doppler flowmetry at baseline, 30 and 45 min after a subcutaneous injection of octreotide [0.10 mg (7 patients), 0.05 mg (7 patients)] and of a placebo (6 patients). The portal blood flow velocity, the resistive index of the superior mesenteric artery, the heart rate and the mean arterial pressure were also measured 2, 4, 6 and 8 h after the injection. The hemodynamic changes observed 30 min after the injection did not differ from those at 45 min and the changes at 2, 4, and 6 h were similar to those at 8 h. A statistically significant decrease, in comparison to the placebo group, was observed 45 min after the injection of the two doses of octreotide in the wedged hepatic venous pressure (cumulative median decrease: —10%, p<0.005), in the hepatic venous pressure gradient (cumulative median decrease: —10%, p<0.005) and in the mean portal flow velocity (cumulative median decrease: —11%, p<0.005). A significant increase in the resistive index of the superior mesenteric artery was observed 45 min after the injection of the two doses of octreotide (cumulative median increase: + 10%, p<0.005). Lower, but significant changes in the mean portal flow velocity and in the resistive index of the superior mesenteric artery persisted until 8 h after the injection of the two doses of octreotide (cumulative median decrease of mean portal flow velocity: —7%, p<0.005 and cumulative median increase of resistive index of the superior mesenteric artery: +4%, p<0.005). Changes in the wedged hepatic venous pressure, the hepatic venous pressure gradient, the mean portal flow velocity and the resistive index of the superior mesenteric artery showed a great variability among patients. These changes were more pronounced in patients injected with the lower dose with no relationship with the plasma drug concentrations. Responder patients showed a significant higher baseline mean portal flow velocity in comparison with nonresponders (15.2±1.7 cm/s vs 11.3 ±1.3 cm/s; p<0.005).
Large encapsulated hepatocellular adenoma in a male
Authors: Ramakrishna Banumathi , Sitaram V. , Khanduri Prakash
Published: August 2010

Abstract: A case of hepatocellular adenoma arising in the left lobe of the liver in a 53‐year‐old man, not associated with any predisposing factor, is presented.
Circulating HCV‐RNA, HCV genotype, and liver histology in asymptomatic individuals reactive for anti‐HCV antibody and their follow‐up study
Authors: Okanoue T. , Yasui K. , Sakamoto S. , Minami M. , Nagao Y. , Itoh Y. , Kagawa K. , Kashima K.
Published: August 2010

Abstract: The present study was aimed to clarify the virologic status, liver histologies, and the results of follow‐up liver tests in symptom‐free individuals with anti‐HCV antibodies and normal liver tests. Forty‐nine individuals with normal liver tests and positive second generation anti‐HCV antibody assay were entered into this study. Cases with hepatitis C viremia were evaluated for HCV genotype, amount of circulating HCV‐RNA, and liver histology and were followed‐up for more than one year. Of the forty‐nine individuals, 36 had hepatitis C viremia, indicated by polymerase chain reaction (PCR) assay. Liver histology was as follows: 3 had non‐specific changes, 25 had chronic persistent hepatitis (CPH), and 8 had chronic active hepatitis (CAH). Twenty‐four cases with CPH and CAH developed an elevated AST and/or ALT concentration (> 30IU/1) between 12 and 32 months of follow‐up. The amount of circulating HCV‐RNA ranged from 102 to 107 copies/50 μl serum. The distribution of HCV genotypes was nearly the same as that for symptomatic CAH. These data suggest that the histological examination and follow‐up examination are very important for following symptom‐free individuals with hepatitis C viremia because there are some candidates for interferon therapy among them. There are few individuals who will remain healthy among asymptomatic HCV carriers.
Quantitative measurement of human tissue hepatic blood volume by C15O inhalation with positron‐emission tomography
Authors: Taniguchi Hiroki , Masuyama Mamoru , Koyama Hiroshi , Oguro Atsushi , Takahashi Toshio
Published: August 2010

Abstract: In order to estimate the tissue liver function, tissue hepatic blood volume was measured quantitatively and non‐invasively using C15O inhalation in conjunction with positron‐emission tomography. Fifty‐eight patients with normal liver function, 14 patients with chronic hepatitis, 28 patients with hepatic cirrhosis, and 4 patients with obstructive jaundice were studied by positron‐emission tomography scan after the single breath inhalation of 20 mCi of high specific activity 15O‐labeled carbon monoxide. The mean tissue hepatic blood volume was significantly greater in patients with normal livers than in patients with chronic hepatitis or hepatic cirrhosis (mean: 20.5, 18.2, and 16.1 ml per 100 cm3, respectively, p=8.6×10‐8). Tissue hepatic blood volume (tHBV) correlated with the reaction of the mesenchymal system and protein synthesis, because there was a potent correlation between tHBV and hepatic fibrosis. In normal livers, we were able to demonstrate significant differences in tissue hepatic blood volume among liver segments.
Serum angiotensin converting enzyme and C4 protein of complement as a combined diagnostic index in alcoholic liver disease
Authors: Sopeña Barnardo , Martínez‐Vázquez César , Fernández‐Rodríguez Conrado M. , de la Fuente Javier , Rivera Alberto , Rodríguez Miguel , Gómez Mary‐Carmen , Prieto Jesús
Published: August 2010

Abstract: Diagnosis of liver cirrhosis relies on hepatic biopsy. So far, attempts have failed to achieve a serologic test that differentiates cirrhosis from other hepatic conditions. The aim of this work was to assess the diagnostic value of the ratio of serum angiotensin converting enzyme activity (SACE) and the levels of protein C4 of serum complement (SACE/C4) in differentiating cirrhotic from noncirrhotic alcoholic liver diseases. In this study, 68 active alcoholic patients (17 with fatty liver or minimal changes, 11 with acute alcoholic hepatitis and 40 with cirrhosis) were included. Twenty healthy subjects were studied as a control group. Liver biopsy was performed in all patients. SACE levels were significantly higher in the group with cirrhosis when compared with the group of patients without cirrhosis and the control. On the other hand, serum C4 level decreased as liver damage progressed. SACE values above 25 IU/1 had a sensitivity of 92.5 percent (95 percent confidence interval, 87.5 to 97.5) and a specificity of 79 percent (95% percent confidence interval, 70.5 to 87.5), in detecting those patients with liver cirrhosis. The sensitivity further increased to 95 percent (95 percent confidence interval, 90.5 to 99.5) and the specificity to 100 percent when the SACE/C4 ratio was used and a cutoff point of 145 was chosen. To conclude, in alcoholics SACE is specifically elevated in patients with cirrhosis, and the SACE/C4 ratio is a excellent biochemical index for the diagnosis of cirrhosis in alcoholic patients.
Influence of phospholipid on bile salt binding to calcium hydroxyapatite and on the poisoning of nascent hydroxyapatite crystals
Authors: Okido Masayuki , Soloway Roger D. , Crowther Roger S.
Published: August 2010

Abstract: Glycine‐conjugated, dihydroxy bile salts inhibit calcium hydroxyapatite (HAP) formation by binding to and poisoning nascent crystal embryos. Their taurine‐conjugated counterparts bind less well to hydroxyapatite and do not inhibit its formation; but more hydrophobic, synthetic analogs of the taurine conjugated bile salts are inhibitors of hydroxyapatite formation. Because hydrophobicity is an important determinant of the ability of bile salts to inhibit hydroxyapatite crystal growth, experiments were performed to study the effect of the physiologically important mixed micelles of bile salt and phospholipid. Taurodeoxycholate/phosphatidylcholine (10:1) mixed micelles bound to HAP at lower total lipid concentrations than did pure taurodeoxycholate. At low total lipid concentrations, phosphatidylcholine (PC) binding appeared to predominate, suggesting that PC had a higher affinity than did taurodeoxycholate (TDC) for the HAP surface. Although glycodeoxycholate (3 mM) significantly (>95%) inhibited hydroxyapatite precipitation, higher concentrations of taurodeoxycholate, either alone or mixed with phosphatidylcholine, did not affect hydroxyapatite formation. These results suggest that biliary phospholipids do not modulate the ability of bile salts to inhibit hydroxyapatite crystal growth.
Hospital prevalence of asymptomatic primary biliary cirrhosis: 4‐year study based on analysis of 4468 consecutive in‐patients
Authors: Magrini Andrea , Nicodemo Sabino , Puoti Claudio
Published: August 2010

Abstract: To assess the hospital prevalence of asymptomatic primary biliary cirrhosis (PBC), routine determination of serum alkaline phosphatase (AP), liver function tests (albumin, bilirubin, prothrombin time) and serum liver biochemistry (aminotransferases, gamma‐glutamyltranspeptidase) were performed in 4468 consecutive in‐patients (2332 men, 2136 women; mean age 57 years, range 16–94 years) admitted to our medical department from April 1991 to May 1995. In patients with an increase of serum AP levels, antimitochondrial antibody (AMA) testing, ultrasonography or CT scan, HIDA biliary scintiscan, bone scintiscan and endoscopic retrograde cholangio‐pancreatography (ERCP) were performed to exclude any disorders other than PBC. Fourteen out of the 4468 patients (0.3%) showed an asymptomatic increase of AP levels (i.e., detected by chance at the entry and not earlier investigated). In 12 of 14 cases the increase of AP was not related to PBC. Asymptomatic PBC was found in 2 of 4468 patients (0.04%). When only the “risk group” (women over 40 years) is considered, the prevalence rate increases to 0.12% (2/1644 women). Our data, while not assessing the true prevalence of asymptomatic PBC in the general population, suggest that symptomless PBC is much more common than has been thus far supposed.
Rsa I polymorphism at the cytochrome P4502E1 locus is not related to the risk of alcohol‐related severe liver disease
Authors: Agúndez José , Ladero José , Díaz‐Rubio Manuel , Benítez Jullo
Published: August 2010

Abstract: Ethanol‐inducible cytochrome P4502E1 is the main pathway in the non‐alcohol dehydrogenase oxidation of ethanol. Its coding gene, CYP2E1, is polymorphic at the Rsa I restriction site in the 5′‐flanking region. The mutant genotype c2c2 has a higher transcriptional activity than the genotypes c1c1 or c1c2. Heavy drinkers carrying the c2 allele might be at a higher risk of alcoholic cirrhosis since they might synthesize greater amounts of acetaldehyde, the compound believed responsible for hepatotoxicity of ethanol. With the aim of establishing if the c2 allele increases the risk of cirrhosis in heavy drinkers, we studied 58 (6 female) chronic heavy drinkers with liver cirrhosis and 137 healthy normal controls of the same ethnic (white Spaniards) origin. After extraction of DNA from white blood cells, alleles c1 and c2 of CYP2E1 were identified by restriction fragment length polymorphism (RFLP) with endonuclease Rsa I. Fifty‐six patients and 130 controls were classified as homozygous c1c1 and two and seven, respectively, as heterozygous c1c2. No homozygous c2c2 were detected. The c2 allele frequencies were 0.017 in patients and 0.026 in controls (non‐significant differences). We conclude that the Rsa I RFLP polymorphism is probably not related to the risk of cirrhosis in Spanish heavy drinkers.
Intrahepatic expression of pro‐inflammatory cytokine mRNAs and interferon efficacy in chronic hepatitis C
Authors: Fukuda Ryo , Ishimura Norihisa , Ishihara Shunji , Chowdhury Aktaruzzaman , Moriyama Nobuyuki , Nogami Chie , Miyake Tatsuya , Niigaki Misa , Tokuda Alejandro , Satoh Shuichi , Sakai Shino , Akagi Shuji , Watanabe Makoto , Fukumoto Shiro
Published: August 2010

Abstract: To investigate the relationship between intrahepatic cytokine expression and interferon (IFN) response in chronic hepatitis C [CH(C)], interleukin (IL)‐1ß,‐2,‐4,‐6,‐8, interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α and TNF‐ß mRNAs were investigated semiquantitatively by reverese transcription polymerase chain reaction using serial liver biopsies taken before and after IFN‐α treatment from 24 patients with CH(C), including 12 responders and 12 non‐responders. Before IFN treatment, IL‐2, TNF‐ß, IFN‐γ and IL‐8 mRNA were associated with severe hepatitis activity whereas IL‐4 mRNA was associated with weak hepatitis activity, regardless of IFN response. IL‐2, TNF‐ß and IFN‐γ mRNAs were significantly greater in IFN non‐responders. After IFN treatment a complete response to IFN was significantly associated with the disappearance of these pro‐inflammatory cytokines, whereas non‐responders retained the expression of cytokine mRNA as before IFN treatment. Our results indicated that IFN‐α treatment may modulate the intrahepatic cytokine network, and this may be one mechanism of IFN‐α that reduces hepatitis activity, aside from an anti‐viral effect. A difference in cytokine network may be involved in IFN response in CH(C).
Expresion of cell adhesion molecule CD44 in primary tumors of the liver: an immunohistochemical study
Authors: Washington Kay , Telen Marilyn J. , Gottfried Marcia R.
Published: August 2010

Abstract: CD44, a widely distributed integral membrane protein, has been implicated in tumor invasion and metastatic spread in some human carcinomas and lymphomas. In this study, 35 cases of hepatocellular carcinoma from 32 patients (11 cholangiocarcinomas, 9 hepatic adenomas, and 5 cases of focal nodular hyperplasia, a non‐neoplastic lesion) were examined by imunohistochemical methods for expression of CD44. The mouse monoclonal antibody A3D8 was used on formalin‐fixed, paraffin‐embedded tissue; this antibody does not distinguish between standard CD44 and splice variants. Positive membrane staining was seen in 13 of 35 cases of hepatocellular carcinoma (12 of 32 patients), 8 of 11 cases of cholangiocarcinoma, and 1 of 9 cases of hepatic adenoma. The strongest staining for CD44 was seen in two cases of fibrolamellar carcinoma, but CD44 expression was otherwise not related to degree of tumor differentiation. All five cases of focal nodular hyperplasia were negative for CD44. In non‐neoplastic liver, hepatocytes were negative; sinusoidal lining cells and portal lymphocytes were positive; bile ducts and proliferating bile ductules were focally positive in some cases. Anatomic stage at time of presentation was similar in both groups of patients, with most patients presenting with stage III or IV disease. A trend towards slightly longer survival in patients whose hepatocellular carcinomas were CD44 negative was noted. These results show that aberrant CD44 expression is present in a subset of hepatocellular carcinomas and in most cholangiocarcinomas. The relationship between CD44 expression and tumor spread is unclear in this group of tumors, but is unlikely to be a simple association between CD44 expression and metastatic potential.
Serum alanine aminotransferase level in relation to hepatitis B and C virus infections among blood donors
Authors: Tsai Jung‐Fa , Jeng Jen‐Eing , Ho Mei‐Shang , Wang Ching‐Shan , Chang Wen‐Yu , Hsieh Min‐Yuh , Lin Zu‐Yau , Tsai Juei‐Hsiung
Published: August 2010

Abstract: To assess the serum alanine aminotransferase (ALT) activity in relation to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among blood donors, antibodies to HCV (anti‐HCV) and hepatitis B surface antigen (HBsAg) were detected in 400 blood donors with normal ALT level (≤750 μmol/s per liter), and 76 blood donors with raised ALT level. The prevalence of anti‐HCV (10.5%) and HBsAg (28.9%) in the latter was higher than that (2.0% and 17.5%, respectively) in the former (p<0.001 and p<0.03, respectively). There was a trend that indicated that the risk of anti‐HCV positivity increased with increasing age (p<0.001). Thirty of 76 (39.5%) donors with raised ALT level were positive for anti‐HCV or HBsAg. Compared with HBsAg‐positive donors, donors with anti‐HCV had higher serum ALT levels (p<0.01) and greater mean age (p<0.01). Multivariate analysis indicated that both anti‐HCV (odds ratio: 6.2; 95% confidence interval: 2.2–17.8) and HBsAg (odds ratio: 2.2; 95% confidence interval: 1.3–3.9) were significantly associated with raised serum ALT activity. The estimated population‐attributable risk was 8.6% for anti‐HCV, and 13.8% for HBsAg. In conclusion, although HBV and HCV infections are independent risk factors of raised ALT activity among blood donors, they play a minor role in the etiology of raised ALT activity.
Recombinant interferon‐α‐2a for treatment of chronic hepatitis C: results of a multicenter randomized controlled dose study
Authors: Imai Y. , Kawata S. , Tamura S. , Ito N. , Seki K. , Nishiuchi M. , Shinji Y. , Kiriyama K. , Himeno S. , Minami Y. , Kashihara T. , Kawakami F. , Maeda H. , Yabuuchi I. , Nishioka M. , Shirai Y. , Fukuda K. , Kiso S. , Ito T. , Igura M. , Doi Y. , Matsuzawa Y.
Published: August 2010

Abstract: To compare the efficacy of low and relatively high dosages of recombinant interferon (IFN)‐α‐2a in Japanese patients with chronic hepatitis C, as well as to characterize the type of patients who will respond well to a low‐dosage treatment, 88 patients with histologically proven chronic hepatitis C were randomly assigned to two treatment groups; one treated with IFN‐α‐2a 6 MU daily for 2 weeks followed by 6 MU three times weekly for 22 weeks (6‐MU group), and another given the same initial treatment followed by 3 MU three times weekly for 22 weeks (3‐MU group). The rate of sustained normalization of ALT 6 months after the cessation of treatment was 33% in the 3‐MU group and 40% in the 6‐MU group (p=0.64). In addition, there was no difference in elimination of serum HCV‐RNA 6 months after the cessation of treatment between the 3‐MU group (26%) and 6‐MU group (29%). Multivariate stepwise regression analysis revealed that serum HCV‐RNA level (p=0.0035) and platelet count (p=0.0009) were independent variables useful in predicting a sustained response of ALT. The sustained response rate of ALT in patients with a serum HCV‐RNA level less than 105 copies/ml and serum platelet level above 15×104/μl was 71%, whereas that in patients with a serum HCV‐RNA level above 105 copies/ml and serum platelet level less than 15×104/μl was 12%. These results indicate that a high rate of sustained response to IFN therapy can be expected in chronic hepatitis C patients with a low serum level of HCV‐RNA and a high level of platelets, even if treated with a low dose of IFN.
Modulation of Kupffer cell and peripheral blood monocyte activity by in vivo treatment of rats with all‐trans‐retinol
Authors: Hoglen Niel C. , Abril Edward A. , Sauer John‐Michael , Earnest David L. , McCuskey Robert S. , Lantz R. Clark , Mobley Scott A. , Sipes Glenn I.
Published: August 2010

Abstract: Previous studies have shown that large doses of vitamin A potentiate chemical‐induced liver injury and that the Kupffer cell is directly involved in this potentiation. Therefore, these studies were designed to determine if Kupffer cells isolated from vitamin A treated male Sprague‐Dawley rats (75 mg/kg/day for 3–7 days as all‐ trans‐retinol) had altered activity and function. Respiratory activity of Kupffer cells isolated from rats treated with vitamin A for 3 to 7 days markedly increased. Similarly, phagocytic activity was significantly elevated (up to 9‐fold) after exposure to vitamin A for 3 to 7 days. Production of reactive oxygen species, measured by luminol‐enhanced chemiluminescence of Kupffer cells isolated after 7 days of vitamin A exposure, was significantly higher than that of control cells when stimulated with opsonized zymosan. Also, the release of superoxide anion by individual Kupffer cells isolated from vitamin A treated rats was nearly three times greater than that of control cells. Basal production of tumor necrosis factor‐alpha (TNF‐α) and prostaglandin E2 (PGE2) production were significantly elevated in Kupffer cells isolated from rats treated with vitamin A. Lastly, peripheral blood monocytes (PBMC) isolated from rats treated with vitamin A for 7 days had a significantly greater respiratory activity, as well as TNF‐α and PGE2 production, than PBMC isolated from control rats. Our data suggest that large doses of vitamin A enhance both Kupffer cell and PBMC function. Upregulation of the activity by these phagocytic cells may play a role in the vitamin A potentiation of chemical‐induced liver injury.
Transforming growth factor α (TGF‐α) expression correlates with DNA replication in regenerating rat liver whatever the hepatectomy extent
Authors: Scotté Michel , Laquerrière Annie , Masson Sylvie , Hiron Martine , Ténière Paul , Hémet Jacques , Lebreton Jean‐Pierre , Daveau Maryvonne
Published: August 2010

Abstract: Liver regeneration is a physiological mechanism that leads to restoration of the hepatic parenchyma following hepatectomy or toxic injury. As a two‐third hepatectomy is the usual model to analyse this phenomenon, few studies have compared liver regeneration after minor vs major hepatectomy. We have used a quantitative RT‐PCR technique to study the hepatic transcription of the TGF‐α gene in rats submitted to 30% or 80% hepatectomy, and we have correlated this transcription with the regenerative response assessed by flow cytometry and Ki‐67 expression. The level of TGF‐α expression and the regenerative response were different, according to the volume of liver removed, and were statistically correlated (r =0.679, p = 0.002). TGF‐α expression and phase S peaked at day 2 vs 6 in the 80% vs 30% hepatectomized rat groups, respectively. Ki‐67 expression occurred at 2 h post‐hepatectomy in the two groups of rats and was observed until day 14 mainly in the 80% hepatectomy group. Our results indicate that TGF‐α expression in regenerating liver is strongly correlated with hepatocyte mitosis, that a delayed regenerative response occurs following 30% hepatectomy and that the course of regeneration differs between minor vs major hepatectomy.
GB virus C infection in patients who underwent liver transplantation
Authors: Ross R. S. , Viazov S. , Kruppenbacher J. P. , Elsner S. , Sarr S. , Lange R. , Eigler F.‐W. , Roggendorf M.
Published: August 2010

Abstract: To elucidate the impact of an infection with the recently discovered GB virus C (GBV‐C) on the clinical course after orthotopic liver transplantation (OLT), we studied eight patients who were GBV‐C RNA positive after transplantation. Five individuals had been viraemic before transplantation, three became GBV‐C RNA positive thereafter. A control group comprised eight patients without pre‐ or post‐transplant GBV‐C infection. GBV‐C RNA was detected by reverse‐transcription followed by nested polymerase‐chain‐reaction (PCR) with primers corresponding to the NS5 genome region. Nested PCR products were sequenced directly. The five patients infected with GBV‐C before transplantation remained GBV‐C RNA positive throughout the time of observation. Pre‐ and post‐transplant GBV‐C RNA titres were almost identical. Phylogenetic analysis revealed a very close relationship between the pre‐ and post‐transplant viral nucleotide sequences indicating persistent GBV‐C infection. No signs of hepatitis could be detected after transplantation in all GBV‐C infected patients. However, four out of eight GBV‐C RNA positive patients had a clinical course complicated by severe cholestasis, which was not observed in the control group. Although GBV‐C infection does not lead to an increase in the rate of post‐transplant hepatitis, it might be associated with severe unexplained cholestatic courses after OLT.
Bafilomycin A1, a specific inhibitor of V‐type H+‐ATPases, inhibits the acidification of endocytic structures and inhibits horseradish peroxidase uptake in isolated rat sinusoidal endothelial cells
Authors: Harada Masaru , Shakado Satoshi , Sakisaka Shotaro , Tamaki Seishu , Ohishi Masahito , Sasatomi Kurumi , Koga Hironori , Sata Michio , Tanikawa Kyuichi
Published: August 2010

Abstract: The role of vacuolar type H+‐ATPases (v‐ATPases) and pH gradient between the endocytic compartments and cytoplasm in the endocytosis of horseradish peroxidase, a mannose‐terminated glycoprotein, was investigated morphologically in isolated rat sinusoidal endothelial cells. Toward this purpose, a specific inhibitor of v‐ATPases, bafilomycin A1, was used to inhibit v‐ATPases in the vacuolar system. Uptake of horseradish peroxidase was examined by electron microscopy. Fluorescent staining by acridine orange showed that bafilomycin A1 inhibited the acidification of the endocytic compartments. Horseradish peroxidase was taken up via mannose receptors and was distributed in the endocytic structures in the isolated sinusoidal endothelial cells. Uptake of horseradish peroxidase was significantly inhibited by bafilomycin A1, and this finding was confirmed by morphometrical analysis. These results suggest that: a) v‐ATPases are necessary for acidification of the endocytic compartments in the sinusoidal endothelial cells and b) the pH gradient between the endocytic compartments and the cytoplasm that is generated by v‐ATPases is necessary for the receptor‐mediated endocytosis of a mannose‐terminated glycoprotein, horseradish peroxidase.
Clonality of large regenerative nodules in liver cirrhosis
Authors: Piao Zhe , Park Young Nyun , Kim Hoguen , Park Chanil
Published: August 2010

Abstract: The role of the large regenerative nodule (RN) in hepatocarcinogenesis is not clear, although the incidence of hepatocellular carcinoma (HCC) is high in cirrhotic liver. This study was aimed at clarifying the preneoplastic nature of large RN without atypia. We analyzed the clonality of HCCs and large RNs, ranging in size from 0.6 to 1.2 cm, of cirrhotic liver by X‐linked human androgen receptor (HUMARA) gene assay, using the principle of random X chromosome methylation and inactivation in females. Eleven cases of HCC and five cases of large RN without atypia from ten female patients were selected. All HCCs, large RNs and paired non‐tumorous tissue from adjacent liver were selectively microdissected from deparaffinized hematoxylin and eosin stained slides. Genomic DNA was isolated and digested with Hha I. Polymerase chain reaction (PCR) amplification of the HUMARA gene was performed using a PCR mixture containing [α‐32P]‐dCTP. The PCR products were separated by gel electrophoresis and analysed by autoradiography. HUMARA was informative in nine out of ten female patients. In the informative 10 HCCs from nine patients, 9 HCCs were monoclonal and one case was polyclonal. The HCC case that showed polyclonality contained many inflammatory cells in the tumor. All of the large RNs were polyclonal. No allelic loss of chromosome 18q was present in the large RNs in constrast to the 3 out of 7 HCCs, which showed allelic deletion in chromosome 18q. We conclude that all or most of the cells composing the large RNs without atypia are polyclonal and the size of a nodule may not be important in hepatocarcinogenesis. This clonality assay may be informative for the differentiation between regenerative and preneoplastic nodules in cirrhotic liver.
Clinicopathological study of primary biliary cirrhosis negative for antimitochondrial antibodies
Authors: Nakanuma Yasuni , Harada Kenichi , Kaji Kyousuke , Terasaki Shuichi , Tsuneyama Koichi , Moteki Sekio , Van de Water Judy , Leung Patrick S.C. , Gershwin M. Eric
Published: August 2010

Abstract: Primary biliary cirrhosis (PBC) is characterized by the occurrence of antimitochondrial antibodies (AMA) and the progressive destruction of intrahepatic bile ducts, followed by biliary cirrhosis. However, there are about 5% of PBC patients who show clinicopathological features of PBC but are negative for AMA. In this study, clinicopathological features, as well as antibody reactivity against recombinant (r)‐mitochondrial polypeptides, were examined in 30 AMA negative PBC patients and 38 AMA positive PBC patients, in whom the presence of AMA had been determined by indirect immunofluorescence (IF). There were few differences in the clinical and serological features between both groups. Histopathologic features, including staging, bile duct lesions and granuloma, were also similar in both groups. Among the 30 IF‐tested AMA negative patients, 29 were also negative against beef heart mitochondrial proteins, but 24 reacted to one or more of the following r‐polypeptides, as determined by immunoblotting: E1 alpha of pyruvate dehydrogenase complex, the E2 subunit of pyruvate dehydrogenase complex, and the branched‐chain 2‐oxo‐acid dehydrogenase complex. The remaining six AMA‐negative patients were asymptomatic, and histologically resembled having stage 1 of the disease, with relatively mild lymphocytic piecemeal necrosis. One case was positive for anti‐smooth muscle antibody. The other clinicopathological features of these patients were similar to those of other AMA negative patients. The present study found that a majority of the AMA‐negative patients fulfilling other clinicopathological criteria of PBC, had features similar to the AMA‐positive PBC patients, and that a majority of IF AMA‐negative patients were positive for r‐polypeptides of the 2‐oxo‐acid dehydrogenase complex. It seems that nearly all the AMA negative patients possess a broad spectrum of antibody profile of AMA, in addition to clinicopathological and serological features.