bluuebunny/crossref_metadata_2025 huggingface dataset:
Inapparent “wild‐type” and “e‐minus variant” HBV infection in patients with HCV‐related chronic hepatitis
Authors: Sardo Maria Adriana , Rodinò Guiseppina , Brancatelli Santa , Pernice Maurizio , Campo Salvatore , Squadrito Giovanni , Russo Francesco , Raimondo Giovanni
Published: August 2010

We analysed DNA extracted from liver biopsy specimens and serum samples from 42 HCV‐RNA‐positive/HBsAg‐negative subjects with chronic hepatitis. Twenty‐eight of them were anti‐HBs/anti‐HBc‐positive (group A), while 14 were negative for all HBV markers (group B). HBV sequences were found in hepatic DNA of 12 cases (11 of group A, one of group B), but in the serum of only two cases of group A. Sequencing analysis of pre‐core region of HBV‐DNA showed the presence of wild‐type HBV in three cases, HBeAg‐defective HBV in three cases, and the coexistence of both viral populations in six cases. These results indicate that HBV and HCV infection may coexist in HBsAg‐negative chronic hepatitis, particularly in anti‐HBs/anti‐HBc‐positive patients. However, HBV replication appears suppressed in these cases, and this state of latency may involve both wild and HBeAg‐defective HBV types.
Cytokeratin inclusions in alcoholic liver disease and their relation to the amount of alcohol intake
Authors: Savolainen V. T. , Lalu K. , Penttilä A. , Virtanen I. , Karhunen P. J.
Published: August 2010

ABSTRACT: In the present study, the frequency and the distribution pattern of immunoreactive hepatocytic cytokeratin (CK) inclusions was investigated using the monoclonal antibody (MAb) CAM 5.2 detecting CKs 8, 18 and 19. The CK antigenicity of the inclusions was confirmed on frozen sections with MAbs for the CKs 7, 8, 17, 18 and 19. The frequency of hepatocytic CK aggregates was compared to the presence of non‐alcoholic and alcoholic liver disease (ALD) as well as to the average all‐year daily ethanol intake of 195 consecutive males subjected to medicolegal autopsy. Hepatocytic CK inclusions were infrequent in patients with normal liver histology, portal fibrosis and/or portal inflammation. In ALD, however, inclusions were observed in 35.6% of patients with fatty liver, in 63.2% of patients with alcoholic hepatitis, in 30.8% of patients with bridging fibrosis and in 60.0% of patients with liver cirrhosis. In all specimens studied, the inclusions were reactive only for CKs 8 and 18, CKs 7, 17, and 19 being unreactive. The frequency of inclusion bodies increased, paralleling increasing average all‐year daily alcohol consumption. Compared to non‐drinkers, a daily intake of between 40 and 80 g of absolute alcohol was associated with a statistically significantly (relative risk, RR=6.6) increased risk of formation of aggregates. Similarly, daily consumption exceeding 80 g was related to increased (RR=6.0) frequency of CK aggregates. The frequency of full‐blown “classical” Mallory bodies (MBs) was, however, increased (RR=8.9) only in patients with a daily intake exceeding 160 g. These results indicate that CK inclusions are unequivocally related to the presence of ALD in longitudinal autopsy series. Their frequency in autopsy series was, however, significantly lower than their frequency in previous studies comprising hospitalised patients diagnosed as having alcoholic liver disease. Furthermore, our results suggest that a daily ethanol intake between 40 and 80 g can increase the risk of appearance of smaller CK inclusions, although the risk of occurrence of “classical” full‐blown MBs was associated only with heavy drinking exceeding 160 g of absolute alcohol daily.
Human immunodeficiency virus infection and hepatitis C pathology
Authors: Guido Maria , Rugge Massimo , Fattovich Giovanna , Rocchetto Piero , Cassaro Mauro , Chemello Liliana , Noventa Franco , Giustina Giuliano , Alberti Alfredo
Published: August 2010

ABSTRACT: To investigate the possible influence of human immunodeficiency virus (HIV) infection on hepatitis C virus‐related liver disease, liver morphology was evaluated in 160 HBsAg‐negative patients with chronic hepatitis C, including 68 HIV‐positive and 92 HIV‐negative cases. No differences were detected in the severity of necro‐inflammatory hepatic lesions between HIV‐negative and HIV‐positive patients when the CD4+ lymphocytes count exceeded 400 cells/mm3. In contrast, HIV‐positive patients with CD4+ lymphocytes below 400/mm3 showed a significantly lower grade of portal inflammation and piecemeal necrosis. These results suggest that liver lesions in hepatitis C may largely depend on immunomediated mechanisms.
Lymphoblastoid interferon therapy in chronic hepatitis C: biochemical, virological and histological evaluation of two different doses
Authors: Picciotto A. , Callea F. , Varagona G. , Bardellini E. , Borzone S. , De Conca V. , Vallarino E. , Giudici‐Cipriani A. , Vitali A. , Grasso A. , Palombino M. A. , Dodero M. , Marenco G. , Menardo G. , Celle G.
Published: August 2010

Sixty patients of both sexes with biopsy‐proven chronic hepatitis C were randomized to receive lymphoblastoid interferon 3 MU or 6 MU three times weekly for 6 months. A follow‐up period of 3 months at the end of the therapy was scheduled. Thirty‐two patients (53.3%) normalized alanine aminotransferase at the end of the therapy. Of these, 17 received 3 MU (56.7%) and 15 (50%) received 6 MU. Eighteen of the 32 patients (56.2%) relapsed in the follow‐up period after treatment. No significant difference in relapse rate was observed between the two groups. The overall percentage of the non‐responder patients was 36.6%. The treatment was discontinued because of non‐compliance and/or side effects in six patients (10%): three in the 3‐MU group and three in the 6‐MU group. An improvement in liver histology was observed in about a quarter of chronic active hepatitis patients whose overall diagnosis changed to chronic persistent hepatitis. Knodell's score system showed a significant improvement (p<0.05) with regard to peripheral necrosis, fibrosis and total score. HCV‐RNA was positive at the beginning in all patients and it became undetectable in almost all responder patients. In some cases there was no correlation between viraemia and biochemical signs of liver disease. Our study shows that 6 MU does not increase the response rate compared to 3 MU. Moreover, the lower dose is able to improve the liver histology and to abolish the HCV viraemia in responder patients.
Mannan‐binding protein and complement dependent opsonization in alcoholic cirrhosis
Authors: Homann C. , Garred P. , Hasselqvist P. , Graudal N. , Thiel S. , Thomsen Å. C.
Published: August 2010

Mannan‐binding protein is synthesized by the liver and functions in first‐line host defence by opsonizing mannose‐rich microorganisms due to activation of the classical complement pathway independent of Clq, and by an intrinsic ability to opsonize and mediate phagocytosis. We have investigated whether the increased susceptibility to bacterial infections in patients with cirrhosis could be explained by low plasma concentrations of mannan‐binding protein and impaired complement‐dependent opsonization. We examined 51 patients with compensated alcoholic cirrhosis, 34 who were decompensated and 16 healthy controls. Irrespective of group, we found a significant correlation (p<0.05) between plasma mannan‐binding protein concentration and deposition of the complement opsonin C4 on mannan from baker's yeast. In contrast to what was expected, this kind of opsonization and plasma levels of mannan‐binding protein were significantly increased in the patients with decompensated cirrhosis (p=0.01 and p=0.007, respectively). A significant correlation (0<0.05) was found between mannan‐binding protein and erythrocyte sedimentation rate, fibrinogen and haptoglobin in these patients. Though the correlations were weak (rho=0.49, rho=0.48 and rho=0.40, respectively), the elevated levels of mannan‐binding protein in the patients with decompensated cirrhosis may reflect an acute phase reaction. It is concluded that plasma levels of mannan‐binding protein are increased in patients with decompensated cirrhosis and that complement‐dependent opsonization of mannan does not seem to be compromized in patients with alcoholic cirrhosis.
The French experience of treatment of chronic type D hepatitis with a 12‐month course of interferon alpha‐2B. Results of a randomized controlled trial
Authors: Gaudin Jean‐Louis , Faure Pascal , Godinot Hubert , Gerard Françoise , Trepo Christian
Published: August 2010

Hepatitis due to hepatitis delta virus (HDV) infection is generally associated with severe histological abnormalities and rapid progression of the disease. To assess the efficacy of recombinant interferon‐a2b in treatment of chronic delta hepatitis, 22 patients were entered into a randomized controlled trial: 11 received interferon‐a2b subcutaneously three times weekly for 12 months (5 MU/m2 for 4 months and then 3 MU/ m2 for a further 8 months) and 11 were untreated. All patients were followed up for 6 months after the completion of therapy. Nine treated patients completed the trial: one was withdrawn with hyperthyroidism and one committed suicide. Serum ALT levels were normalized or significantly reduced, always within 3 months of initiating treatment, and remained so in 73% of treated patients at the 4th month and in 54.5% at the 12th month, compared with 18% and 18%, respectively, in the untreated group. Moreover, in seven of nine treated patients, interferon was associated with the clearance of serum HDV‐RNA, associated with amelioration of the histological picture, whereas this occurred in only four of 11 untreated patients. On cessation of therapy, all patients but one experienced a biological and/ or virological relapse over the 6‐month follow up. In conclusion, our data confirm that HDV is sensitive to inhibition by interferon‐a2b, although the schedule used did not achieve permanent control of the disease. The adverse effects of interferon require consideration; in particular, care will be needed to avoid serious psychiatric side effects.
Cytochemical detection of a class 3 aldehyde dehydrogenase in human hepatocellular carcinoma
Authors: Chieco Pasquale , Stecca Barbara , Bolondi Luigi , Melchiorri Cinzia , Gaiani Stefano , Barbara Luigi
Published: August 2010

The development of hepatocellular carcinoma in rodents treated with different chemical compounds is associated with the appearance in the cytosol of neoplastic liver cells of an unusual aldehyde dehydrogenase isozyme of class 3 (ALDH‐3) which is very active with aromatic aldehydes. This tumor‐associated isozyme is readily detected by enzyme cytochemistry using the substrate benzaldehyde with NADP as coenzyme. To determine whether human hepatocellular carcinomas express ALDH‐3, the activity of this isozyme was examined in frozen sections from 68 echo‐guided human liver biopsies. In 54 cases the guided biopsy was performed on one or more nodules suggestive for hepatocellular carcinoma found at ultrasonography within the liver parenchyma. The remaining 14 patients were affected by chronic active hepatitis or cirrhosis. An intense enzymatic activity was ascertained in 5 out of 36 hepatocellular carcinomas. In non‐neoplastic liver, in macroregenerative nodules and in metastatic adenocarcinomas enzymatic activity was not detectable. ALDH‐3‐positive tumors were typical hepatocellular carcinomas (histological grade II and III). These results suggest that ALDH‐3 is a phenotype associated with malignancy in human liver tumors.
Hepatic purine and pyrimidine metabolism: implications for antiviral chemotherapy of viral hepatitis
Authors: Shaw Timothy , Locarnini Stephen A.
Published: August 2010

Abstract:The use of nucleoside analogues as antiviral agents is expanding. For most nucleoside analogues, intracellular phosphorylation is the major prerequisite for activity. Antiviral activity may be limited by poor uptake, absence of appropriate activating enzymes, catabolism, and competition from endogenous nucleotides. Appreciation of these factors, which are species‐, tissue‐ and cell‐specific is important in the understanding of the pharmacology and toxicology of nucleoside analogues. The use of nucleoside analogues against the agents of viral hepatitis is inherently problematic for many reasons including active hepatic nucleoside catabolism, probable absence of virus‐specific activating enzymes, competition from endogenous nucleotides synthesisedde novoor derived from RNA turnover, and factors related to mitochondrial toxicity. Despite these drawbacks, some nucleoside analogues have been found efficacious against hepatitis B virus and it is likely that as knowledge of their mechanism of action accumulates, their efficacy can be improved both by rational drug design and by use in combination with other drugs, including interferon.
Functional differences between activated and normal rat liver macrophages: LPS uptake capacity by flow cytometric analysis in contrast with TNF‐α release
Authors: Kayano Kozo , Sakaida Isao , Kubota Masafuml , Yasunaga Mitsuru , Okita Kiwamu
Published: August 2010

Abstract:Activated liver macrophages are considered to play an important role in the development of liver injuries. Functional differences between activated and normal rat liver macrophages were investigated. In addition, from the therapeutic point of view, the effects of prostaglandin E1, prostaglandin I2and E3330 ((2E)‐3‐[5‐(2,3‐dimethoxy‐6‐methyl‐1,4‐benzoquinoyl)]‐2‐nonyl‐2‐propenoic acid) on the functions of liver macrophages were also determined. Rat liver macrophages were primed byPropionibacterium acnesand activated by a small dose of lipopolysaccharide. Lipopolysaccharide uptake capacity was evaluated quantitatively by flow cytometric analysis. Tumor necrosis factor‐α activities were measured by bioassay. There were no significant differences in lipopolysaccharide uptake capacity between activated and normal liver macrophages, while activated liver macrophages had a significantly (P<0.01) higher capacity in the release of tumor necrosis factor‐α. Prostaglandin E1and E3330 inhibited tumor necrosis factor‐α release without suppressing lipopolysaccharide uptake capacity. In this study we have clarified the functional differences between activated and normal liver macrophages. The beneficial effects of prostaglandin E1and E3330 on the functions of liver macrophages were also demonstrated.
Haemostatic and immunological sequelae of portacaval shunt in rats
Authors: Robson S. C. , Jaskiewicz K. , Engelbrecht G. , Kahn D. , Hickman R. , Kirsch R. E.
Published: August 2010

Abstract: We have evaluated the link between haemostatic abnormalities and immune dysfunction in liver disease by evaluating parameters of cellular and humoral immunity in conjunction with coagulation profiles in rats following portacaval anastomosis, induction of portal hypertension by portal vein stenosis or by sham surgical procedures. Twelve weeks following surgery, portacaval shunted rats were markedly anaemic (8.9±0.6 g/dl; controls 12.3±1.4 g/dl, p>0.05), had low plasma fibrinogen levels (0.6±0.3 g/l, controls 2.5±0.2 g/l p>0.05) and markedly elevated fibrin(ogen) degradation products (FDP) titres (1/40–1/80; controls >1/10. p>0.05). Portal vein stenosed rats were less anaemic (11.5±0.8 g/dl), had near normal fibrinogen levels (2.1±0.3 g/l) but elevated FDP levels (1/40–1/80). Both portacaval shunted and portal vein stenosed rats had elevated serum IgG levels (35.1±14.1 g/l; 29.2±13.9 g/l respectively; control values 20±5.9 g/l p>0.05 for comparison with both experimental groups). Intrinsic lymphocyte proliferation to T and B cell mitogens was markedly depressed in the portacaval anastamosed rats when compared to controls. Serum factors inhibitory to control lymphocyte proliferation were noted in the shunted rats. Phagocytosis of complement and immunoglobulin sensitised sheep RBC by Kupffer cells purified from rats that had undergone portacaval shunting was markedly reduced (p>0.05). The increased degree of phagocytosis following exposure to LPS‐endotoxin (50 μg/ml) was proportionate in degree to the control group. Spontaneous release of bioactive lymphocyte activating factors (IL‐1 and IL‐6) by purified rat sinusoidal cell populations was decreased in the portacaval shunted group, and decreased still further following stimulation with LPS (50 μg/ml) in vitro. The observation that many of the haemostatic and immunological abnormalities associated with chronic liver disease are present in rats with surgically created portacaval shunts or with induced portal hypertension, lends credence to the hypothesis that shunting of portal blood is, at least in part, responsible for many of the systemic manifestations associated with chronic liver disease.
Gastric and colonic inflammatory and vasoactive mediators in experimental portal hypertension
Authors: Ackerman Zvi , Karmeli Fanny , Amir Gail , Rachmilewitz Daniel
Published: August 2010

Abstract: Rats with portal hypertension and experimental liver disease may exhibit increased susceptibility of the gastric mucosa to damage by noxious agents, and increased bacterial translocation through the bowel wall. The aim of this study was to determine mucosal gastric and colonic generation of vasoactive substances, because they may contribute to the altered mucosal function. Rats with partial vein ligation (n=7), complete bile duct ligation (n=6) and sham‐operated rats (n=10) were studied. Three weeks following surgery rats were anesthetized, splenic pulp pressure was measured, stomachs and colons were removed and mucosa was extracted for determination of prostaglandin E2, thromboxane B2, leukotriene B4, leukotriene C4 and endothelin‐l by radioimmunoassay (ng/g) and platelet activating factor activity (pg/10 mg) by platelet aggregation. Pulp pressure was >13 mmHg in partial vein ligated rats and bile duct ligated rats and 6 mmHg in sham‐operated rats. No macroscopic or microscopic lesions were seen any of the removed tissues. Gastric mucosal prostaglandin E2 and thromboxane B2 generation were decreased by 35% and 7%, respectively, in bile duct ligated rats (bile duct ligated versus sham‐operated, p>0.05 for prostaglandin E2 and thromboxane B2). Gastric leukotriene B4 and C4 generation, platelet activating factor activity and endothelin‐l content did not differ significantly among the three groups. A different pattern of changes was observed in the colon. Colonic leukotriene B4 generation and endothelin‐1 content were increased in bile duct ligated rats by 105% and 210%, respectively (bile duct ligated versus sham‐operated, p>0.05 for leukotriene B4 and endothelin‐l). The decreased gastric mucosal prostaglandin E2 generation of bile duct ligated rats may render the gut mucosa of these animals relatively ischemic and vulnerable to damage by noxious agents. The increased colonic leukotriene B4 generation and the increased endothelin‐l content of the colonic mucosa of bile duct ligated rats may promote inflammatory and ischemic changes in the colonic mucosa and may enable bacterial translocation.
Genotype, serum level of hepatitis C virus RNA and liver histology as predictors of response to interferon‐α 2α therapy in Japanese patients with chronic hepatitis C
Authors: Mizokami Masashi , Orito Etsuro , Gibo Yukio , Suzuki Kaoru , Ohba Ken‐ichi , Ohno Tomoyoshi , Lau Johnson Y. N.
Published: August 2010

Abstract: To determine whether pretreatment HCV‐RNA level, hepatitis C virus genotypes, alanine aminotransferase and histology correlate with subsequent response to interferon‐α therapy or not, serum HCV‐RNA levels and genotype were determined by branched DNA signal amplification assay and genotype‐specific polymerase chain reaction in 43 patients with chronic active hepatitis C. Response to recombinant interferon‐α 2α (504 million units in total) was defined as complete and sustained CR→SR, n=12), complete response followed by relapse (CR→Rel, n=17), and no response (NR, n=10), excluding dropouts (n=4). Patients who showed CR→SR had a lower HCV‐RNA level (0.438 × 106 eq/ml) compared to CR→Rel (2.452 × 106 eq/ml, p=0.008) and NR (4.882 × 106 eq/ml, p=0.009). A higher proportion of patients with CR→SR had type 2a HCV (67%) compared to the CR→Rel (28%) and the NR (0%). There was a trend for type 1b hepatitis C virus infection to have higher serum HCV‐RNA levels. There was no correlation between pretreatment HCV‐RNA level and alanine aminotransferase. However, no relation between pretreatment HCV‐RNA level and liver histology was observed; a high proportion of patients with CAH2a showed CR→SR, compared to those with CAH2b (p=0.001). Moreover, the patients with CAH2b who had low level hepatitis C virus viremia did not show CR→SR. These data indicate that pre‐treatment serum HCV‐RNA levels, genotype and liver histology are good predictors of subsequent response to interferon‐α therapy in Japanese patients with chronic hepatitis C virus infection.
Effect of diethylmaleate on bile secretion and ultrastructural appearance of hepatocytes in normal rats and mutant rats with defective organic anion secretion
Authors: Dumont Micheline , D'Hont Corinne , Feldmann Gérard , Rogier Edith , Moreau Alain , Jansen Peter L. M. , Erlinger Serge
Published: August 2010

Abstract: Diethylmaleate is an organic anion secreted into bile as a glutathione conjugate. Its transport by the hepatocyte is associated with dilatation of the Golgi apparatus and the appearance of small vesicles in the pericanalicular area. It has been speculated that the Golgi apparatus could play a role in the intracellular transport and/or the biliary canalicular secretion of diethylmaleate. The purpose of this work was to determine whether the alterations in the Golgi apparatus and the pericanalicular vesicles could mediate the canalicular secretion of diethylmaleate. Diethylmaleate biliary secretion and diethylmaleate‐induced bile flow were measured in Sprague‐Dawley rats, and in TR‐ rats which have an inherited defect in the excretion into bile of organic anions, including glutathione conjugates. Livers of both Sprague‐Dawley and TR‐ rats were examined by electron microscopy, to characterize the changes in intracellular organelles. In Sprague‐Dawley rats, as previously described, diethylmaleate administration was associated with an increase in bile flow, which was parallel in time to the secretion into bile of diethylmaleate conjugates. Electron microscopic examination of the liver after diethylmaleate administration showed dilatation of the Golgi saccules. In contrast, in TR‐ rats, the increase in bile flow and the secretion of diethylmaleate conjugates were nearly absent. Nevertheless, electron microscopic examination showed a dilatation of the Golgi saccules similar to that observed in Sprague‐Dawley rats. TR‐ rats, in addition to the changes in the Golgi apparatus, had marked dilatation of the endoplasmic reticulum. These results show that biliary secretion of diethylmaleate conjugates was severely impaired in TR‐ rats, in spite of a dilatation of the Golgi apparatus and of the endoplasmic reticulum. We conclude that it is unlikely that the alterations in the Golgi apparatus (and the endoplasmic reticulum) induced by diethylmaleate play a role in the canalicular secretion of diethylmaleate. We do not exclude the possibility that these organelles could play a role in intracellular transport of this compound. Alternatively, these alterations could be due to a “toxic” effect of diethylmaleate accumulation in hepatocytes.
Distribution of hepatitis C virus RNA in the liver and its relation to histopathological changes
Authors: Kojima Shigeru , Tanaka Yujiro , Enomoto Nobuyuki , Marumo Fumiaki , Sato Chifumi
Published: August 2010

Abstract: To investigate a cellular mode of HCV‐infection in the liver and its pathological implications in relation to histopathological changes or clinical data, we studied the distribution of HCV‐RNA in the livers of 21 patients with HCV‐related chronic liver disease (chronic active hepatitis, 14 cases; cirrhosis, 7 cases) using the in situ hybridization technique. In situ hybridization was performed on 4% paraformaldehyde‐fixed frozen sections with digoxigenin‐labeled DNA probe deduced from the core region of HC–J4. In situ hybridization showed positive signals in the liver specimens of 20/21 cases. The signals were localized in the cytoplasm of hepatocytes. The distribution pattern of positive cells was individually different, whereas the pattern was identical in the right and left lobes. There were no correlations of the HCV‐positive cell number with serum aminotransferase levels at biopsy or with genotypes of HCV. The positive hepatocytes were occasionally associated with infiltrating mononuclear cells, and they were sparsely distributed in the area of piecemeal necrosis. These findings suggest that factors such as host immunoreaction to the virus may be more important than its direct cytopathy in the pathogenesis of chronic hepatitis C virus infection.
Do serum ALAT values reflect the inflammatory activity in the liver of patients with chronic viral hepatitis?
Authors: Cahen D. L. , Van Leeuwen D. J. , Ten Kate F. J. W. , Blok A. P. R. , Ousting J. , Chamuleau R. A. F. M.
Published: August 2010

Abstract: A retrospective study was carried out in 40 patients with chronic viral hepatitis, to assess whether serum alanine aminotransferase reflects the inflammatory process in the liver. Twenty liver biopsy specimens were included for each disease. Five histological aspects were scored: periportal inflammation, lobular inflammation, ballooning, Councilman bodies and lymphocyte follicles. Logarithmic values of alanine aminotransferase were correlated with each aspect using the Spearman correlation coefficient. For the hepatitis B cohort a statistical significant correlation was found between alanine aminotransferase and periportal inflammation (p=0.0001), lobular inflammation (p=0.0002) and Councilman bodies/area (p=0.003). In the hepatitis C study population alanine aminotransferase correlates with both periportal inflammation (p=0.007) and lymphocyte follicles/Area (p=0.02). In conclusion, these results suggest that alanine aminotransferase can be used as an indicator of inflammatory activity. A prospective study is needed, to further analyze the use of alanine aminotransferase, as a monitor of disease activity in patients with chronic viral hepatitis.
Risk of HBV reinfection after liver transplantation in HBsAg‐positive cirrhosis: Primary hepatocellular carcinoma is not a predictor for HBV recurrence
Authors: Mazzaferro Vincenzo , Regalia Enrico , Montalto Fabrizio , Pulvirenti Andrea , Brunetto Maurizia Rossana , Bonino Ferruccio , Lerut Jean , Gennari Leandro
Published: August 2010

Abstract:Two hundred and twenty‐eight patients who underwent orthotopic liver transplantation for hepatitis B‐related cirrhosis in 11 European Liver Transplant Centers were collected. The male/female ratio was 184/44, with a median age of 41 years (13–66). In 55 patients (24%) hepatocellular carcinoma was associated with liver disease. All cases were stratified for pre‐orthotopic liver transplantation viral characteristics: HBV‐DNA neg/HBeAg neg: 106 patients (47%), HBV‐DNA neg/Delta pos: 80 (35.5%), HBV‐DNA pos/HBeAg pos: 28 (12.5%), other 14 (5%). In 49 patients (21.4%) post‐orthotopic liver transplantation passive prophylaxis with anti‐HBs immunoglobulins was not followed, while in 179 patients the anti‐HBs serum titer was kept above 100–200 mU/ml. Overall 5‐year actuarial survival of the series was 54%. One hundred and eighty‐five patients were evaluable for HBsAg reappearance in the serum at various intervals after orthotopic liver transplantation. Overall 3‐year HBV‐free survival of these patients was 55%. There was a significant difference in 3‐year HBV‐free survival between HBV‐DNA neg (52%), HBV‐DNA pos (13%) and Delta pos (73%) patients (p: 0.03). Sixty‐three percent of patients in the prophylaxis group were HBV‐free, compared to only 25% of untreated patients (p>0.001). Three‐year HBV‐free survival in patients with or without HCC was 44% and 59%, respectively. Cox‐multivariate analysis revealed that only post‐transplantation prophylaxis (p: 0.003) and pre‐transplantation viral activity (p: 0.004) can be considered as independent factors affecting HBV recurrence. Candidates with hepatocellular carcinoma in HBV‐cirrhosis should not be excluded from orthotopic liver transplantation, supporting the idea of a higher risk of post‐transplantation viral reactivation.
Expression of apolipoprotein A‐1 mRNA in normal intrahepatic biliary tree
Authors: Ohta Tetsuo , Numata Masayuki , Yamamoto Miyuki , Iseki Shoichi , Tsukioka Yuhji , Kayahara Masato , Nagakawa Takukazu , Miyazaki Itsuo
Published: August 2010

Abstract: Our previous study demonstrated that apolipoprotein A‐1 (apo A‐1) immunoreactive peptides were located diffusely in the cytoplasm, not only of human normal hepatocytes, but also of intrahepatic bile ducts and peribiliary glands. It is important to determine whether the presence of these immunoreactive peptides in intrahepatic biliary tree is caused by pinocytosis from the bile, or by intracellular protein synthesis. Thus, we investigated whether apo A‐1 is synthesized by cells that line the biliary tree. Normal human liver samples obtained at surgery were used, and the expression and distribution of apo A‐1 mRNA in normal human liver tissues were examined, using in situ hybridization histochemistry with a 35S‐labeled oligonucleotide probe specific for apo A‐1. On the autoradiogram, many silver grains were found to be distributed uniformly in hepatocytes. In addition, an appreciable apo A‐1 mRNA signal was also observed in both the surface epithelial lining of the bile ducts and the epithelial cells of the peribiliary glands. In conclusion, these findings suggest that the apo A‐1 found in bile is secreted both by hepatocytes and by intrahepatic bile duct cells and peribiliary glands.
Low proliferative activity in macroregenerative nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis
Authors: Theise Neil D. , Marcelin Kerline , Goldfischer Michael , Hytiroglou Prodromos , Ferrell Linda , Thung Swan N.
Published: August 2010

Abstract: Macroregenerative nodules are commonly thought to be hyperplastic lesions, deriving both their large size and premalignant potential from an increased proliferative rate. We have previously suggested an alternate model of macroregenerative nodule development in which neither size nor premalignant potential of macroregenerative nodules would depend on increased proliferation. We tested this hypothesis by examining the proliferative activity in macroregenerative and surrounding cirrhotic nodules. Methods: Eighteen macroregenerative nodules, including five type I and 13 type II, were immunostained for proliferating cell nuclear antigen (PCNA). Type II macroregenerative nodules included ten with diffuse large (7) or small (3) liver cell dysplasia only and eight containing nodule‐ in‐nodule lesions. Five nodule‐in‐nodule lesions met the histologic criteria for hepatocellular carcinoma. PCNA labeling indices (PCNA‐LIs; percentage positive hepatocyte nuclei/500 randomly counted cells) were determined in macroregenerative nodules and the four largest adjacent cirrhotic nodules. Nodule‐in‐nodule lesions were assessed separately from the background macroregenerative nodule. Results: 4/5 type I and 12/13 type II macroregenerative nodules (exclusive of NIN lesions) had PCNA‐LIs lower than the mean of surrounding cirrhotic nodules. All nodule‐in‐nodule lesions, whether atypical or overtly malignant, had PCNA‐LIs greater than any surrounding nodules. In conclusion, macroregenerative nodules have PCNA‐LIs indistinguishable from, and often lower than, surrounding cirrhotic nodules. Increased proliferative activity only occurs with the development of atypia and transition to hepatocellular carcinoma. Conclusion: Macroregenerative nodules derive neither their size nor their premalignant potential from on‐going rapid proliferation, a finding consistent with our alternate hypothesis of macroregenerative nodule development.
Ischemic hepatitis secondary to the spontaneous rupture of a hepatocellular carcinoma in a patient with cirrhosis
Authors: Castiella Agustín , Cancio Manuel , García‐Bengoechea Manuel , Lobo Carmen , Bujanda Luis , Arenas Juan I.
Published: August 2010

Abstract: A patient with alcoholic cirrhosis who developed fatal ischemic hepatitis induced by hemorrhagic shock, due to the spontaneous rupture of a hepatocellular carcinoma, is reported. This was the first manifestation of the hepatic neoplasm. To our knowledge, this is the first case report of ischemic hepatitis of this origin.
Innervation of the liver: morphology and function
Authors: Tiniakos D. G. , Lee J. A. , Burt A. D.
Published: August 2010

Abstract: Although it has been known for many years that the liver receives a nerve supply, it is only with the advent of immunohistochemistry that this innervation has been analysed in depth. It is now appreciated not only that many different nerve types are present, but also that there are significant differences between species, especially in the degree of parenchymal innervation. This has stimulated more detailed investigation of the innervation of the human liver in both health and disease. At the same time, functional studies have been underlining the important roles that these nerves play in processes as diverse as osmoreception and liver regeneration. This article briefly reviews current understanding of the morphology and functions of the hepatic nerve supply.
Iron stores, response to α‐interferon therapy, and effects of iron depletion in chronic hepatitis C
Authors: Piperno Alberto , Sampietro Maurizio , D'Alba Roberta , Roffi Luigi , Fargion Silvia , Parma Stefania , Nicoli Carlo , Corbetta Noemi , Pozzi Massimo , Arosio Valeria , Boari G. , Fiorelli Gemino
Published: August 2010

Abstract: We studied 81 patients with chronic hepatitis C to investigate the relationship between iron and α‐interferon response. Sixty‐one patients (group A) were given α‐interferon irrespective of iron status, whereas 20 (group B) with iron overload, were iron depleted before α‐interferon therapy. In group A, 21 patients responded to α‐interferon and 40 were non‐responders. Increased iron indices were significantly more frequent in non‐responders than responders. Multivariate analysis showed that among the independent variables evaluated, only γ‐GT and liver iron concentration predicted therapy outcome. After phlebotomy treatment, serum alanine aminotransferase fell significantly both in patients of group B (196±122 IU/1 vs 82±37 IU/1, p<10‐6) and in 12 non‐responders of group A (198±89 IU/1 vs 107±81 IU/1, p<10‐6). In 16 iron depleted patients, eight from each group, subsequent treatment with α‐interferon produced a response in only one patient. These results suggest that increased liver iron is a negative prognostic factor for a‐interferon response in chronic hepatitis C. Iron depletion had a beneficial effect on serum alanine aminotransferase in all the patients treated, but did not improve the response to α‐interferon.
Role of sympathetic cardiovascular tone in control of arterial pressure in rats with cirrhosis
Authors: Kirstetter Philippe , Moreau Richard , Soupison Thierry , Cailmail Stéphane , Hartleb Marek , Lebrec Didier
Published: August 2010

Abstract: Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg · kg‐1 · min‐1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356±50 vs 166±30 pg/ml, p=0.04) than in normal rats (186±23 vs 86±31 pg/ml, p=0.06) and rats with portal vein stenosis (103±37 vs 93±5 pg/ml, p=0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg · kg‐1 · min‐1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (‐25±2%) than in normal rats (‐11±1%) and in rats with portal vein stenosis (‐13±2%) (p=0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis.
Immunogenicity and reactogenicity of a combined hepatitis A/B candidate vaccine: first results
Authors: Kallinowski B. , Bock H. L. , Clemens R. , Theilmann L.
Published: August 2010

Abstract: We evaluated immunogenicity and reactogenicity of an inactivated, combined hepatitis A/B candidate vaccine in 50 seronegative volunteers. Each volunteer received a total of three doses of vaccine (720 EIU HAV and 20 μg HBs antigen) according to a 0, 1 and 6 month vaccination schedule. One month after the first injection, the seroconversion rate was 90% (45/50) for anti‐HAV and 28% (14/50) for anti‐HBs, respectively. After the booster dose, at month 7, the seroconversion rate was as high as 100% (49/49) for anti‐HAV and 94% (46/49) for anti‐HBs. The geometric mean titres increased with each dose of vaccine administered. Mild, and mostly local side effects were reported in 54% of the volunteers after the first injection and in less than 10% after the third injection. Our results show that this inactivated, candidate hepatitis A/B vaccine is highly immunogenic and well‐tolerated.
Rapid hepatic failure associated with a contracted liver mimicking cirrhosis in a case of nasopharyngeal carcinoma with liver metastasis
Authors: Hwang Yue‐Ting , Chen Pei‐Jer , Kao Jia‐Horng , Wang Tzung‐Dau , Wang Hsih‐Hsi , Chu Jan‐Show , Su Ih‐Jen , Chen Ding‐Shinn
Published: August 2010

Abstract: A 46‐year‐old women had an undifferentiated nonkeratinizing nasopharyngeal carcinoma, locally controlled by radiotherapy. Initially, she had normal liver function tests and normal hepatic ultrasonography. Seven months later, she experienced a rapidly progressive hepatic failure manifested by the development of ascites, elevation of serum bilirubin level, and prolongation of prothrombin time. Imaging studies showed a contracted liver and serum biochemical tests were compatible with chronic liver disease, except for an increase of alkaline phosphatase and γ‐glutamyl transpeptidase levels. An endoscopic retrograde cholangiogram was compatible with changes of sclerosing cholangitis. The patient died of hepatic decompensation within two months. A liver necropsy disclosed diffuse infiltration of carcinoma cells into the hepatic sinusoids and obliterative angio‐invasion of the tumor cells with massive fibrotic stroma replacing almost all hepatocytes. In situ hybridization demonstrated expression of Epstein‐Barr virus transcripts EBER1 in the tumor cells and proved a metastatic nasopharyngeal carcinoma. The contracted liver is likely to be explained by the tumor‐associated desmoplastic change and the obliterative angio‐invasion of the tumor. It is important to be aware that, although rare, such an unusual pattern of liver metastasis may mimick cirrhosis clinically and cause rapid hepatic failure in patients with nasopharyngeal carcinoma.
Mononeuritis multiplex: a rare complication of acute hepatitis A
Authors: Safadi Rifaat , Ben‐Hur Tamir , Shouval Daniel
Published: August 2010

Abstract: A 28‐year‐old man suffered from acute severe hepatitis A virus infection, documented by serologic diagnosis. During the clinical and enzymatic recovery phase, mononeuritis multiplex that involved the left ulnar and right lateral cutaneous nerves developed. It presented by sensorimotor disturbances in left arm and right thigh. Mononeuritis multiplex has been frequently described in patients with chronic hepatitis B, either isolated or associated with periarteritis nodosa. However, it has not been reported in association with hepatitis A infection.
Oxygen radical formation, proliferative activity and phagocytic capacity of cultivated macrophages from cirrhotic rat livers
Authors: Vogl Siegfried , Petermann Henning , Dargel Rolf
Published: August 2010

Abstract: A method to isolate and cultivate macrophages from macronodular‐cirrhotic rat livers was developed in order to characterize them biochemically, by comparing various functional parameters in macrophage cell cultures from controls and cirrhotic livers. Cells were prepared from female Wistar rats, made cirrhotic by treatment with thioacetamide, by means of a pronase‐collagenase digestion method followed by a nycodenz gradient and elutriation. The yield of macrophages was 8.9×106 cells/g for controls and 10.6×106 cells/g for cirrhotic livers. The vitality of the cells was >95%. Forty‐eight hours after cultivation, the purity of the cell fractions amounted to 94% and 91% in controls and in the experimental group, respectively. Nitric oxide synthesis was more markedly stimulated by lipopolysaccharide (LPS) in cultures from cirrhotic livers than in those from controls (25×4 vs 5.8×1 nmol/106 cells/72 hours). Interferon‐gamma (IFN‐γ) induced the nitric oxide synthase more rapidly in macrophage cultures from cirrhotic livers than in controls. The production of superoxide anions by macrophages from cirrhotic livers stimulated by zymosan was significantly lower by about 40% when compared with the controls. Incorporation of 3H‐thymidine was increased to 250% in cultivated macrophages from thioacetamide‐treated rats in comparison with macrophages from untreated animals. The stimulated phagocytic activity of cultivated macrophages from cirrhotic livers did not differ significantly from that of the controls. The data presented provide evidence that it is possible to isolate and to cultivate macrophages from macronodular‐cirrhotic livers with high yield and vitality. They are characterized by enhanced proliferation, reduced formation of superoxide anions, and increased production of nitric oxide.
Determination of functional portal‐systemic shunting in patients submitted to hepatic angiography
Authors: Molino G. , Battista S. , Bar F. , Garello E. , Avagnina P. , Grosso M. , Spalluto F.
Published: August 2010

Abstract:Angiographic visualization of the hepatic vascular bed by selective angiography can be profitably complemented with the evaluation of functional portal‐systemic shunting by D‐sorbitol bioavailability. Seventeen patients requiring diagnostic arterial catheterization were studied: most of them had biopsy‐proven liver cirrhosis. Patients were studied at rest and after overnight fasting on two subsequent days, in which a sterile pyrogen‐free solution (1.5%) of D‐sorbitol was administered by direct infusion (15 mg/min for 20 min) into the superior mesenteric artery and an antecubital vein, respectively. The fractional bioavailability (Fma) of Dsorbitol was calculated as the ratio between the net cumulative urinary outputs obtained after infusion through the catheter into the superior mesenteric artery and the systemic vein, respectively. A good correlation was found between the estimated fractional portal‐systemic shunting, which in the present study ranged between 1.4% and 96.7%, and a suitable index scoring the clinical evidence of collateral circulation. Since the hepatic removal of D‐sorbitol is not affected by sinusoidal capillarization and its hepatic extraction ratio is quite high and only slightly modified by reduction in the number or functional activity of hepatocytes, the measured Fma can be assumed as a parameter reflecting the entity of portal‐systemic shunting. The test is safe and inexpensive, and appears potentially useful in several situations in which portal‐systemic shunting is pathophysiologically relevant.
Cardiovascular status after postural change in compensated cirrhosis: an argument for vasodilatory concept
Authors: Hartleb Marek , Rudzki Krystian , Karpel Ewa , Becker Alina , Waluga Marek , Boldys Hubert , Nowak Andrzej , Nowak Stanislaw
Published: August 2010

Abstract:It seems that hypervolemia and vasodilatation coincide in compensated cirrhosis, but neither rank nor importance of these factors has been fully clarified in adaptive response to postural change. We studied, with gated equilibrium radionuclide angiography and thoracic electrical bioimpedance the hemodynamic status of 19 patients with compensated cirrhosis and 18 healthy subjects in upright and supine positions. In the upright position, the cirrhotic patients were hypotensive and had decreased peripheral vascular resistance despite increased cardiac output. The transition to the supine position was accompanied by a significant fall in the heart rate and an increase in the stroke volume in both controls (92±22 to 63±10 beats/min, and 38±9 to 62±19 ml/m2, respectively) and cirrhotic patients (101±20 to 79±13 beats/min, and 44±15 to 63±19 ml/m2, respectively). Besides, the diastolic arterial pressure fell in controls from 89±9 mmHg to 81 ± 11 mmHg;p<0.01, while it remained unchanged in cirrhotic patients (77±17 vs 82±13 mmHg). In the supine position, the cirrhotic patients presented tachycardia and left ventricular hyperkinesy (increased velocity of left ventricular filling and emptying). In conclusion, these results show that in compensated cirrhosis the decreased arterial tone and peripheral blood pooling are important factors of adaptive hemodynamic reaction to postural change.
Effect of ursodeoxycholic acid on liver iron stores and distribution in rats with normal or iron‐supplemented diet
Authors: Loréal Olivier , Chenoufi Norchen , Turlin Bruno , Haziza‐Pigeon Christelle , Robert Jean‐Yves , Lescoat Gérard , Mathiex‐Fortunet Hélène , Deugnier Yves , Brissot Pierre
Published: August 2010

Abstract: Iron excess is a potential liver‐damaging factor, and bile salts can increase iron digestive absorption and iron biliary excretion. The aim of this study was to investigate in rats the effect of ursodeoxycholic acid, a bile salt used in the treatment of chronic liver disease, on the hepatic iron stores in normal and iron‐overload conditions. UDCA was administered by gavage to Sprague‐Dawley rats. Iron hyperabsorption and overload were obtained by 5% carbonyl iron addition in diet. Hepatic iron stores and distribution were evaluated by liver iron concentration measurement and histologic assessment, respectively. Whatever the iron content of the diet, liver iron concentration was not modified by UDCA administration compared with the control groups. Iron distribution was not modified by UDCA in rats with normal diet. The total iron score was only transiently lowered by UDCA in iron supplemented rats compared with the control group at 1 month. In conclusion, chronic UDCA administration does not modify liver iron stores and distribution in rats with both normal or increased digestive iron absorption. These data suggest that UDCA is unlikely to increase hepatic iron stores in treated patients and that the benefit of UDCA treatment is probably not related to a decreasing effect of liver iron content.