bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis C virus markers in patients with long‐term biochemical and histological remission of chronic hepatitis
Authors: Saracco Giorglo , Abate Maria Lorena , Baldl Maurizio , Calvo Pier Luigi , Manzini Paola , Brunetto Maurizia Rossana , Oliveri Filippo , Kuo George , Chien David , Houghton Michael , Verme Giorgio , Rizzetto Mario , Bonino Ferruccio
Published: August 2010

We measured hepatitis C virus (HCV) RNA and antibodies against HCV recombinant proteins (C22/S1, E1/S2, E2/NS1, C33/NS3, C100/NS4, NS5) in serial serum samples from 22 interferon‐treated patients with a long‐term follow up (range: 36–44 months). Eleven of them showed persistently normal liver function tests and a significant histological amelioration or a complete resolution of chronic hepatitis (long‐term responders, LTRs). In the remaining 11 patients (non‐responders (NRs)) liver function tests normalized temporarily during therapy or remained unchanged. At the end of the follow up (3 years), viraemia was undetectable in six of 11 LTRs (54.6%). HCV‐RNA was always detectable in the serum of NRs (p = 0.017). At admission, anti‐C22/S1, anti‐E1/S2, anti‐E2/NS1, anti‐C33/NS3, anti‐C100/NS4 and anti‐NS5 were detected in 95.4%, 40.9%, 77.3%, 95.4%, 72.7%, and 77.3% of the patients, respectively. Three years after suspension of therapy, anti‐C100/NS4 was undetectable in five of six (83.3%) LTRs who cleared HCV‐RNA and in only one with ongoing viraemia (20%). Anti‐E2/NS1 was undetectable in 54.5% of LTRs and in no NRs (p = 0.067). Anti‐E1/S2 was detected more frequently in LTRs than in NRs (81.8% vs 45.5%). Serum levels of anti‐C22/S1, C33/NS3 and NS5 did not change during therapy and the follow up in either group of patients. The clearance of viraemia in LTRs was associated with that of anti‐C100/NS4 (p = 0.017). Serum HCV‐RNA and anti‐C100/NS4 appear suitable tools for monitoring patients who respond to therapy. More than 40%) of LTRs remained HCV‐RNA‐positive in spite of the biochemical remission of their liver diseases.
HBcAg and HBsAg expression in ductular cells in chronic hepatitis B
Authors: Delladetsima J. K. , Vafiadis I. , Tassopoulos N. C. , Kyriakou V. , Apostolakl A. , Smyrnoff T.
Published: August 2010

The possible involvement of bile duct epithelium (BDE) in chronic hepatitis B was examined by immunohistochemical investigation of HBcAg and HBsAg expression in biliary cells in 47 liver biopsies with both viral antigens detectable in hepatocytes. HBsAg‐ and HBsAg‐positive cells were identified in nine and five cases, respectively, in atypical and occasionally in typical ductules in cases of acute excacerbation, chronic active hepatitis and active cirrhosis. Atypical ductules were usually located in areas of periportal fibrosis and in cirrhotic septa. Liver cell plates expressing viral markers and undergoing ductular transformation (positive reaction of hepatocytes to BDE‐specific, wide‐spectrum keratin) were also observed in acinar zone 1, at the periphery and within parenchymal nodules in a number of cases. The presence of both viral antigens in atypical ductules in cases of advanced chronic liver disease most probably expresses the persistence of the virus in cells deriving from biliary metaplasia of infected hepatocytes. However, the detection of the virus in a few typical ductules is indicative of a direct viral infection. According to these findings, ductular cells seem to serve as a suitable host for HBV, their genotype permitting viral replication and antigen production.
Acetylsalicylate (ASA)‐induced mitochondrial dysfunction and its potentiation by Ca2+
Authors: Tomoda T. , Takeda K. , Kurashige T. , Enzan H. , Miyahara M.
Published: August 2010

Although it has been suggested that acetylsalicylate (ASA)‐induced mitochondrial dysfunction plays an important role in the pathogenesis of Reye's syndrome, administration of ASA alone does not cause this syndrome in therapeutic doses. We noted, however, that Ca2+ plays important roles in the regulation of cellular functions. ASA at concentrations of 250 μM or less, which had little effect on succinate‐linked respiration, impaired Ca2+ accumulation in liver mitochondria by causing an increase in Ca2+ release. ASA plus Ca2+, which in concentrations of 150 μM or less alone had little effect on mitochondrial respiration, inhibited state 3 respiration and dinitrophenol‐induced uncoupling of respiration. In addition, ASA plus Ca2+ increased state 4 respiration and ATPase activity. These results indicate that ASA plus Ca2+ impaired mitochondrial ATP synthesis, and suggest that ASA and ASA‐induced Ca2+ increases in cytosol form a vicious circle of effects. Furthermore, oral administration of ASA (150 mg/kg for 5 days running) to rats did not affect mitochondrial structure or liver function, but resulted in aberrations of mitochondrial respiration. These results suggest that even therapeutic doses of ASA may induce alteration in mitochondrial function.
Changes in receptor‐mediated endocytosis in liver sinusoidal cells after partial hepatectomy in the rat
Authors: Kamimoto Y. , Tanabe D. , Tashiro S. , Hiraoka T. , Miyauchi Y.
Published: August 2010

Liver sinusoidal cells play an important role in host defense by clearing particulate matter and macromolecules from the circulation. In this study, receptor‐mediated endocytosis in sinusoidal cells was examined in two‐thirds hepatectomized rats using 125I‐labeled formaldehydetreated bovine serum albumin (fBSA) as an endocytable macromolecule. The liver‐weight to body‐weight ratio in hepatectomized rats returned to the control value 10 days after hepatectomy. The endocytotic index for fBSA in sinusoidal cells decreased significantly to 0.0210±0.0017 (controls, 0.0598±0.0019) on the first day, then returned to the control level at 5 days (0.0554±0.0030). The changes in hepatic uptake for fBSA showed a similar time course of the endocytotic index. A transient increase in the uptake of fBSA per unit weight of liver of 22–39% above control occurred 2 to 3 days after hepatectomy. In contrast to fBSA, the endocytotic index in hepatocytes evaluated with 125I‐labeled asialofetuin reached the minimum level on the second day, and then recovered to the control level 10 days after hepatectomy. These results suggest that endocytosis of fBSA by sinusoidal cells decreases after hepatectomy and rapidly recovers to normal before the completion of liver regeneration, whereas endocytosis of asialofetuin by hepatocytes decreases following hepatic resection and returns to normal when regeneration is substantially complete.
Histological outcome in patients with chronic hepatitis C given a 60‐week interferon alfa‐2b treatment course
Authors: Reichard Olle , Glauman Hans , Norkrans Gunnar , Wejstål Rune , Fryden Aril , Schvarcz Robert , Weiland Ola
Published: August 2010

Forty patients with chronic hepatitis C virus (HCV) infection were treated with 3 MU interferon alfa‐2b given subcutaneously for 60 weeks. A biochemical response with normalization of serum alanine aminotransferase (s‐ALT) levels was seen in 24 patients (60%) at treatment cessation. A sustained response with continuously normal s‐ALT levels during 24 weeks of follow up was seen in 15 of these 24 patients (62%), all of whom also became HCV RNA negative in serum. Histological changes in the pre‐ and posttreatment liver biopsies were assessed using a numerical scoring system. Biochemical responders had a significant decrease in all four scored categories: portal inflammation, piecemeal necrosis, spotty necrosis and fibrosis. Non‐responders had a significant decrease in piecemeal necrosis and spotty necrosis, whereas the scores for portal inflammation and fibrosis remained unchanged. There was no significant difference in any of the scored categories in the pretreatment biopsy between responders and non‐responders. We conclude that patients suffering from chronic HCV infection who responded biochemically and virologically to interferon treatment also improved their liver histology. Necroinflammatory activity decreased to some extent in biochemical non‐responders, possibly giving them some benefit from the treatment, but not to the same extent as responders. No specific histological pretreatment findings were predictive of biochemical response to interferon treatment.
Fluctuations in viremia, aminotransferases and IgM antibody to hepatitis B core antigen in chronic hepatitis B patients with disease exacerbations
Authors: Mels Guido Colloredo , Bellati Giorgio , Leandro Gioacchino , Brunetto Maurizia Rossana , Vicari Omar , Borzlo Mauro , Piantino Paolo , Fornaciari Giovanni , Scudeller Guido , Angeli Giovanni , Bonino Ferruccio , Ideo Gaetano
Published: August 2010

We studied the relationships between the serum levels of viremia, aminotransferases and IgM anti‐HBc, measured by monthly quantitative assays, in 52 untreated chronic hepatitis B patients (41 anti‐HBe+, 11 HBeAg+) followed up for 12–20 months. Forty hepatitis exacerbations were observed in 17/41 anti‐HBe+ (41.5%) and in 6/11 HBeAg+ patients (54.5%) (p = NS); all but one were clinically asymptomatic. We analyzed the fluctuations in the serum levels of the three parameters before, during and after the hepatitis exacerbations and found this chronological sequence of events in 96.2% of them: HBV‐DNA increase→ALT flare→IgM anti‐HBc increase. These results suggest that both antiviral immune reactions and ALT flares were triggered by quantitative variations in viremia. HBV‐DNA baseline levels before flares were lower in anti‐HBe+ (3.9±1.2 pg/ml) than in HBeAg+ patients (35.3±5.4 pg/ml) (p<0.0001) and there was an inverse correlation between basal values and viremia level increases at the time of disease exacerbations (p< 0.001). This suggests that for a hepatitis exacerbation to occur, low basal viremia needed to increase markedly, while moderate increases in HBV‐DNA serum levels were sufficient to trigger ALT flares in patients with elevated basal viremia. In conclusion, asymptomatic hepatitis B exacerbations are frequent in the natural history of chronic HBV infection, and monthly monitoring of HBV‐DNA, ALT and IgM anti‐HBc appears to be a suitable method to evaluate their frequencies and entities. This method can be a helpful guide for clinical and therapeutic decision‐making in the single patient with chronic hepatitis B.
HCV‐marker‐positive autoimmune‐type chronic active hepatitis: a possible relation between HCV infection and liver autoreaction
Authors: Zeniya Mikio , Aizawa Yoshio , Watanabe Fumitoki , Kawabe Tomonobu , Hara Masaki , Sakaguchi Masami , Toda Gotaro
Published: August 2010

This study focused on 32 patients who were diagnosed as having autoimmune hepatitis based upon clinical and histological factors. Fifteen of these patients were positive for HCV‐RNA and for one of the HCV‐related markers tested, including anti‐C100, ELISA II, and RIBA 2 (Group 2). The remaining 17 patients were negative for all HCV‐related markers (Group 1). Clinical factors in the two groups, including the frequency of autoantibodies, serum levels of aminotransferase and gammaglobulin, HLA phenotypes, and the response to corticosteroid treatments, were compared. The titer of serum anti‐nuclear antibodies and the level of serum aminotransferase at initial diagnosis were significantly higher in Group 1 than in Group 2. Furthermore, the genetic background of the two groups, as indicated by HLA phenotypes, differed. All cases in Group 1 were HLA‐DR4‐positive, whereas only 60% of those in Group 2 cases had HLA‐DR4. Also, all cases in Group 1 but only 66.7% of the cases in Group 2 showed good clinical responses to corticosteroid treatment. Finally, no cases of HCV‐related‐marker‐positive autoimmune hepatitis (Group 2) had antibodies for LKM, suggesting that these cases were clinically different from type II autoimmune hepatitis. These data indicated that immunosuppressive treatment might be the preferred initial treatment in patients who either satisfy the criteria for AIH or who are sero‐positive for an HCV‐marker.
Detection of human androgen receptor mRNA in hepatocellular carcinoma by in situ hybridisation
Authors: Negro Francesco , Papotti Mauro , Pacchioni Donatella , Galimi Francesco , Bonino Ferruccio , Bussolati Gianni
Published: August 2010

Recent evidence suggests that anti‐androgen therapy may be useful in patients with androgen receptor (AR)‐positive hepatocellular carcinomas (HCC), as determined by a steroid binding assay. To evaluate the AR expression of HCC, in both histological and cytological material, we developed a non‐radioisotopic in situ hybridisation (NISH) assay specific for the human AR mRNA. A synthetic oligonucleotide complementary to positions 661–695 of the human AR coding sequence was end‐labelled with digoxigenin‐dUTP and revealed by an alkaline phosphatase‐conjugated anti‐digoxigenin antibody. We analysed 22 formalin‐fixed, paraffin‐embedded HCC, obtained at surgery, together with the corresponding non‐neoplastic liver tissues (19 cases). In six cases, cell blocks obtained by fine‐needle aspiration (FNA) prior to surgery were also available. Positive controls included seminal vesicles and prostate tissues. Sixteen HCCs (73%) expressed a variable amount of AR mRNA, with the proportion of positive cells ranging from very few to more than 90%. Normal hepatocytes were stained weakly and focally in eight cases (42%). Appropriate controls, inclusive of immunohistochemical detection of the AR protein in selected cases, established the specificity of the assay. Data obtained on FNA specimens were predictive of the results on histologic material. However, in two cases the NISH assay was negative on the cytological specimen but stained rare hepatocytes within the surgically resected tumor. In conclusion, NISH is a novel procedure for rapid and specific assessment of the expression of AR in HCC tissue. Its clinical significance, in terms of predictivity of response to anti‐androgen treatment, needs to be assessed in large correlative studies.
Histological evolution of chronic hepatitis C. Factors related to progression
Authors: Vaquer Pere , Canet Ramon , Llompart Alfred , Riera Joan , Obrador Antoni , Gayá Jaume
Published: August 2010

We have evaluated the histological progression of liver disease in 29 untreated patients with chronic hepatitis C. All patients were positive to antibodies to hepatitis C virus by ELISA2 and RIBA2. Two liver biopsies were carried out for each patient, with an interval ranging between 12 and 126 months (mean 50.2±30.7). In all cases the usual histological classification was applied and the histological activity index scoring system according to Knodell et al. was determined. Fifteen cases worsened (51.7%), 12 cases showed no histological changes (41.4%) and two patients improved (6.9%). Cirrhosis was found in five patients (18.5%) in the second liver biopsy. Epidemiological, clinical, biochemical and histological parameters were compared between the group without histological progression and the group with impairment in liver histology. Factors related to histological worsening were: more advanced age (p=0.002), high levels of aspartate aminotransferase (p=0.04), high global histological activity index (p=0.03) and piecemeal necrosis and bridging necrosis scores (p=0.02) at first biopsy. The histological activity index can be applied to assess the natural history of chronic viral hepatitis, and is a good tool to evaluate the prognosis. Thus chronic hepatitis C virus infection is a histologically progressive disease in at least half the cases.
Immunohistochemical analysis of retinoblastoma gene product (pRB) expression in malignant and non‐malignant liver diseases
Authors: Kawakita Nobuyoshi , Seki Shuichi , Sakaguchi Hiroki , Yanai Atsushi , Nakatani Kazuki , Yamada Takao , Kitada Takuya , Sakai Yasuhiko , Kuroki Tetsuo , Kobayashi Kenzo , Monna Takeyuki
Published: August 2010

ABSTRACT: The retinoblastoma gene product is a nuclear phosphoprotein that undergoes cell cycle‐dependent changes in its phosphorylation status. To analyze the expression of retinoblastoma gene product in the process of liver regeneration and the initiation of hepatocellular carcinoma, we studied immunohistochemically the expression of retinoblastoma gene product and DNA polymerase alpha (DPA) in 33 patients with various liver diseases. Only a few hepatocytes positive for retinoblastoma gene product were found in undamaged, nonregenerating liver tissues, whereas many hepatocytes positive for retinoblastoma gene product were detected in specimens of regenerating liver obtained from patients with acute or chronic liver diseases. Similarities were found between distribution patterns of hepatocytes positive for retinoblastoma gene product and those of hepatocytes positive for DPA, and a highly significant positive correlation was found between the number of hepatocyte nuclei stained for retinoblastoma gene product per 1000 nuclei examined (R‐LI) and the number of hepatocyte nuclei stained for DPA per 1000 nuclei examined (D‐LI) in tissues obtained from patients with nonmalignant liver disease. Hepatocellular carcinoma cells positive for DPA were detected in the 14 hepatocellular carcinoma specimens tested. In ten of these specimens, hepatocellular carcinoma cells positive for retinoblastoma gene product were found but not in the other four. For all hepatocellular carcinoma specimens, R‐LI was proportional to D‐LI. Thus in both nonmalignant and malignant liver, retinoblastoma gene product increased in proportion to proliferation of hepatocytes or hepatocellular carcinoma cells.
Long‐term histologic and viral changes in patients with chronic hepatitis C who responded to alpha interferon
Authors: Marcellin Patrick , Boyer Nathalie , Degott Claude , Martinot‐Peignoux Michèle , Duchatelle Veronique , Giostra Emile , Areias Jorge , Erlinger Serge , Benhamou Jean‐Pierre
Published: August 2010

ABSTRACT: We assessed the long‐term outcome in 24 patients with chronic hepatitis C who responded to alpha interferon. All patients were followed up for 12 months, and 16 patients were followed up 41±9 months. During the follow‐up period, 18 of the 24 patients (75%) relapsed (serum ALT levels increased again); 16 had an early relapse within the 6 months and two had a late relapse 21 and 36 months after therapy; one cirrhotic patient with relapse died. Serum HCV RNA remained detectable in the two patients before the late relapse and in three of the six patients with sustained biochemical response. Histologic assessment 13 to 31 months after therapy showed a decrease in activity in most patients, even in some of those with relapse, but the decrease in portal inflammation was more marked (p<0.05) in patients with sustained biochemical response. Liver HCV RNA was not detectable in the two sustained responders who were negative for serum HCV RNA. Despite biochemical remission induced by interferon therapy, HCV replication persists in many patients with a potential risk of late relapse. In contrast, some patients have no long‐term detectable HCV RNA, suggesting clearance of HCV. Long‐term histologic improvement of portal inflammation in most patients confirms the beneficial effect of interferon.
Macroregenerative nodules in cirrhosis are not associated with elevated serum or stainable tissue alpha‐fetoprotein
Authors: Theise Neil D. , Fiel Isabel M. , Hytiroglou Prodromos , Ferrell Linda , Schwartz Myron , Miller Charles , Thung Swan N.
Published: August 2010

We have explored the relationship of serum alpha‐fetoprotein and macroregenerative nodules (MRNs), possible precursor lesions of hepatocellular carcinoma (HCC), and sought to demonstrate alpha‐fetoprotein (AFP) expression in these nodules. One hundred and sixty‐eight sequential adult cirrhotic resected livers were examined and MRNs were identified by standard criteria. Pretransplant serum AFP was available for 158 of these patients (normal <20 ng/ml). One hundred and seventy‐two randomly selected lesions, including ordinary and atypical MRNs, some containing microfoci of HCC, and HCCs were stained for AFP by immunohistochemistry. In the series, 12 cases had grossly apparent HCCs, four associated with high serum alpha‐fetoprotein (p<0.006). Forty‐four cases had MRNs, 32 without grossly apparent HCC. Five of these 32 cases were associated with high serum AFP (not significant). Immuno‐staining for AFP was seen in three specimens of HCC and in a cirrhotic nodule from a patient without HCC, but not in MRNs. 1) Neither the presence of MRNs – whether ordinary, atypical, or containing micro‐foci of HCC – nor that of gross HCC is ruled out by a normal serum AFP. 2) Elevated serum AFP is not associated with the presence of MRNs. 3) MRNs rarely stain for tissue AFP.
The role of the spleen in endotoxin‐induced liver injury
Authors: Hiraoka Eisaku , Nonami Toshiaki , Kurokawa Tsuyoshi , Kobayashi Hiroyuki , Takagi Hiroshi
Published: August 2010

In these experiments, the role of the spleen in endotoxin‐induced liver injury was evaluated, using rats which underwent splenectomy or splenic vein ligation with antecedent spleno‐systemic shunt. Male Wistar rats were divided into three groups: a sham‐operated group, a splenectomy group, and a splenic vein ligation group. In each animal, 48 h after surgery, 5 mg/kg lipopolysaccharide (LPS) were injected intravenously. Six rats from each group were sacrificed 6 or 12 h after LPS administration. Bronchoalveolar lavage fluid (BALF) and arterial blood were also collected. Splenectomy reduced the liver injury as indicated by the serum lactate dehydrogenase level. A decrease in liver tissue adenosine triphosphate and increase in lipid peroxide were induced by LPS administration and inhibited by splenectomy. Splenectomy also reduced alveolar protein release as indicated by the protein level in BALF. Splenic vein ligation provided similar protective effects on the liver, but did not affect lung injury. From these results, it appears that the spleen plays a significant role in endotoxin‐induced liver injury, and a mediator derived from the spleen is likely associated with development of liver injury. This mediator may be cleared or inactivated by not only splenectomy but also splenic vein ligation.
Association of primary sclerosing cholangitis, thymoma and hypogammaglobulinemia
Authors: Yoshioka Ryoji , Sato Yukio , Kogure Atsuko , Ohira Hiromasa , Takagi Tohru , Kuroda Masahito , Miyata Masayuki , Obara Katsutoshi , Nishimaki Tomoe , Kasukawa Reiji
Published: August 2010

A 64‐year‐old Japanese woman with thymoma has been suffering from diarrhea and increased alkaline phosphatase levels without jaundice. Her serum immunoglobulin levels of IgM and IgG were less than half of the normal levels, with an increase in CD8 (suppressor/cytotoxic) T cell percentage and a decrease in CD4 (helper) T cell percentage, resulting in a lower CD4/CD8 ratio of 0.31. These immunological features are in accordance with those of hypogammaglobulinemia complicating thymoma. Cholangiography and a liver biopsy specimen disclosed the presence of primary sclerosing cholangitis (PSC). PSC has been recognized in various immunodeficiency syndromes and this case shows that thymoma complicated by hypogammaglobulinemia is associated with PSC.
Type VI collagen gene expression in experimental liver fibrosis: quantitation and spatial distribution of mRNAs, and immunodetection of the protein
Authors: Takahara Terumi , Sollberg Stephen , Muona Päivi , Uitto Jouni
Published: August 2010

Type VI collagen is a minor but essential matrix component in the liver. In this study, we utilized an acute and a chronic injury model to clarify the process of liver fibrosis in rats by administration of carbon tetrachloride. Collagen gene expression, with particular emphasis on type VI collagen, was studied by molecular hybridization techniques. The α2(VI) collagen mRNA levels were markedly elevated on day 3 of acute injury and were approximately at the same high level at 7 and 14 weeks of chronic injury, as determined by Northern hybridizations and slot‐blot analyses. Marked enhancement of type I collagen gene expression was similarly noted at these time points The activation of collagen gene expression in acute injury, as determined by in situ hybridization, was particularly prominent in the vicinity of the central veins. Indirect immunofluorescence demonstrated marked accumulation of type VI collagen protein as early as day 3 of acute injury, and the reaction appeared to be initiated in the proximity of central veins. These results indicate that type VI collagen gene expression, together with other connective tissue components, including type I collagen, is activated in the early stages of the fibrotic process. Type VI collagen accumulation may contribute to the distorted architecture and functional impairment of the liver in hepatic fibrosis.
Systemic AA amyloidosis induced by oral contraceptive‐associated hepatocellular adenoma: a 13‐year follow up
Authors: Cosme Angel , Horcajada Juan Pablo , Vidaur Fernando , Ojeda Evelia , Torrado Julio , Arenas Juan Ignacio
Published: August 2010

Abstract: We report a case of a woman who showed hepatic and renal AA amyloidosis with a liver adenoma associated with the use of oral contraceptives. A nephrotic syndrome secondary to the renal amyloidosis underwent complete remission 7 years after the withdrawal of oral contraceptive therapy. Twenty‐nine months after the initial presentation, the patient was admitted with acute upper abdominal pain and abdominal tenderness. The abdominal ultrasound revealed a subphrenic fluid collection, and a presumptive diagnosis of a ruptured hepatic adenoma was made. The liver adenoma diminished from 8 cm to 1 cm over a 13‐year follow up after the discontinuance of oral contraceptive therapy.
Clearance of serum hepatitis C virus RNA after interferon therapy in relation to virus genotype
Authors: Kanai Koichi , Kako Makoto , Aikawa Tatsuya , Kumada Takashi , Kawasaki Tsunehisa , Hatahara Terumasa , Oka Yuji , Mizokami Masashi , Sakai Takahiro , Iwata Koichiro , Okamoto Hiroaki , Mayumi Makoto
Published: August 2010

Abstract: The effect of recombinant interferon‐alfa on serum HCV RNA levels in Japanese patients with chronic hepatitis C was investigated. At 24 weeks of treatment, 41 (32.5%) of 126 patients lost HCV RNA from serum, and aminotransferases were normalized in 31 (75.6%) of these 41 cases. HCV genotypes were categorized into four types (Type I, II, III, IV); the frequencies among the patients were: Type I: 0%, Type II: 70.6%, Type III: 20.6%, and Type IV: 6.3%. At the end of the 24‐week treatment, HCV RNA levels were remarkably decreased in Type III patients and became undetectable in 18 (69.2%) of 26. In contrast, only 18 (20.2%) of 89 patients with Type II and two of eight with Type IV lost HCV RNA from sera. The relation between HCV genotype (Type III) and response to IFN therapy was also confirmed using a logistic regression model. HCV genotype seems to be an important factor in determining the response to IFN in patients with chronic hepatitis C.
Primary biliary cirrhosis: lung involvement
Authors: Costa Cristina , Sambataro Angela , Baldi Sergio , Modena Vittorio , Todros Luca , Libertucci Daniela , Coni Francesco , Fusaro Enrico , Revello Flavio , Murgia Angelo , Rizzetto Mario , Recchia Serafino , Bonino Ferruccio , Verme Giorgio , Rosina Floriano
Published: August 2010

Abstract: Sub‐clinical lung impairment, mostly represented by a reduced diffusion of alveolar gases, is a recognised complication of advanced primary biliary cirrhosis. The aim of the study was to evaluate the prevalence and type of pulmonary involvement in primary biliary cirrhosis and the relationship between lung function abnormalities and selected epidemiological and clinical variables. Sixty‐one patients with different stages of primary biliary cirrhosis consecutively seen in our outpatient clinic were evaluated. The advancement of primary biliary cirrhosis was characterised by the histological stage, the presence of signs of portal hypertension and the Mayo Risk Score: a Cox regression model using serum bilirubin and albumin levels, prothrombin time, age and degree of oedema as selected variables. We measured static and dynamic lung volumes, by means of a spirometer, and diffusing capacity for carbon monoxide. Rheumatological disorders were evaluated by an independent rheumatologist. No patient complained of respiratory symptoms. Airway obstruction was present in one patient. In 24 patients (39%) the alveolar diffusion capacity was reduced. We did not find any significant relationship between diffusing capacity and smoking habits, advancement of liver disease and concomitant Sjogren syndrome. Reduced diffusion capacity showed a significant correlation with the presence of complete or incomplete CREST syndrome (p<0.01) and with the presence of circulating anti‐centromere antibodies (p<0.05). Alveolar diffusion capacity is frequently impaired in patients with primary biliary cirrhosis, usually in the absence of clinical manifestations. These alterations mostly affect patients with concomitant CREST syndrome. Prospective studies are needed to evaluate if these abnormalities will eventually lead to clinical symptoms and if their progression could be influenced by different therapeutic regimens for primary biliary cirrhosis.
Short‐term cardiovascular effects of somatostatin in patients with cirrhosis
Authors: Gaudin Christophe , Moreau Richard , Champigneulle Bruno , Soubrane Olivier , Kleber Gerhard , Lebrec Didier
Published: August 2010

Abstract: Somatostatin is used to treat variceal hemorrhage in patients with cirrhosis and portal hypertension. Its systemic hemodynamic effects, however, are not yet well defined. Since cardiomyopathy or pulmonary artery hypertension may occur in patients with cirrhosis, definition of the systemic hemodynamic effects of somatostatin or its analogue octreotide is of clinical importance. The aim of this study was to evaluate the effects of somatostatin, at different doses and under different conditions of administration, on the systemic hemodynamics in 17 patients with cirrhosis. Two sets of experiments were performed. In the first, eight patients received two different bolus doses (100 and 250 μg) of somatostatin. The second set of experiments was designed to study the hemodynamic effects of the combination of a bolus and an infusion of somatostatin. Nine other patients received one bolus of 250 μg of somatostatin, followed by a 250 μg/h infusion for 65 min. A second bolus of 250 μg of somatostatin was injected in these patients after 35 min of infusion. Before and for 30 min after each bolus, systemic hemodynamics were measured. Following a bolus of somatostatin, a dose‐dependent decrease in heart rate (from 77±3 to 73±5 beats/min with 100 μg, and from 78±4 to 68±5 beats/min with 250 μg, p<0.05) and increases in systemic and pulmonary artery pressures were observed. The combination of an infusion and a bolus of somatostatin significantly reduced the increases in systemic and pulmonary artery pressures. These results suggest that a combination of an infusion and a bolus of somatostatin might have less deleterious effects on systemic hemodynamics than a bolus alone.
Transient hepatic fibrin‐ring granulomas in a patient with acute hepatitis A
Authors: Yamamoto Takeshi , Ishii Motoyasu , Nagura Hiroshi , Miyazaki Yutaka , Miura Masahito , Igarashi Takehiko , Toyota Takayoshi
Published: August 2010

Abstract: A case of acute hepatitis A associated with fibrin‐ring granulomas in the liver is presented. Because a relationship between acute hepatitis A infection and granuloma formation had not previously been established, liver specimens were examined from both the hepatitic and recovery phases. Numerous fibrin‐ring granulomas were observed in the parenchyma during the hepatitic phase. The cellular components of the granulomas were largely macrophages and CD4‐positive T‐cells. Granulomas had disappeared completely by the recovery phase. These results suggest that fibrin‐ring granulomas were caused by hepatitis A virus infection. This virus may activate macrophages and CD4‐positive T‐cells through an as‐yet undetermined mechanism.
Mitochondrial antigen/antibody systems in primary biliary cirrhosis: revisited
Authors: Berg P. A. , Klein R.
Published: August 2010

Abstract: Methods for the evaluation of the four antimitochondrial antibody subtypes in primary biliary cirrhosis ‐ anti‐M2, ‐M4, ‐M8, ‐M9 ‐ are described. The importance of the application of different preparations for the demonstration of complement fixing antibodies and the detection of antibodies by ELISA or Western blotting is emphasized. Complement fixing antigens can be prepared by discontinuous isopynic sucrose density gradient centrifugation using mitochondrial subfractions derived either from beef heart (M2), rat liver (M4), or pig kidney (M8). Anti‐M9 antibodies do not fix complement. For ELISA, the pyruvate dehydrogenase or the AT‐Pase‐associated antigen fraction (M2), the sulfite oxidase fraction (M4), and the chromatographically purified M8‐fraction should be used. The same antigen fractions are suitable for Western blotting, but anti‐M4 and anti‐M8 cannot be visualized by this method. For the demonstration of anti‐M9 by ELISA and Western blotting a purified fraction prepared from rat liver has to be applied. Correlating antimitochondrial antibody‐subtypes with clinical condition and the natural course, there is convincing evidence that especially the presence of complement fixing antibodies against the subtypes M2, M4, and M8 is a reliable indicator for a more active course. Patients expressing only anti‐M9 (without anti‐M2) have biochemically all the typical features also found in classical anti‐M2 positive primary biliary cirrhosis patients, but seem not to advance to late stages. Since these antimitochondrial antibody‐subtypes are present even in very early stages without changing their pattern during the course, antimitochondrial antibody‐profiles can also be taken as early prognostic parameters. The evaluation of the immunological activity by antimitochondrial antibody‐subtype testing may further facilitate the decision whether therapy with ursodeoxycholic acid should be combined with steroids and/or immunosuppressive agents. The role of mitochondrial autoantigens in the induction of this chronic destructive bile duct process is also discussed. The concept is put forward that not bile ducts but naive(?) B‐cells expose the different mitochondrial antigens, thereby stimulating autoreactive T‐cells to provide a second signal for antibody production. The degree of breakage of tolerance to the different mitochondrial epitopes may be one crucial factor which determines the diversity of antimitochondrial antibody‐subtypes in patients with primary biliary cirrhosis.
Granulomas in primary sclerosing cholangitis
Authors: Ludwig Jurgen , Colina Francisco , Poterucha John J.
Published: August 2010

Abstract: Granulomas in liver biopsy specimens from adult patients with chronic ductopenic cholestatic liver disease are a characteristic feature of primary biliary cirrhosis. However, we found a similar combination of abnormalities in 7 out of 100 native livers (7%) from patients who had orthotopic liver transplantation for primary sclerosing cholangitis. In a control group of native livers from 100 patients with primary biliary cirrhosis, the prevalence of granulomas was exactly the same, 7%. In the primary sclerosing cholangitis group, 13 additional livers showed a granulomatous epithelioid cell response, with or without foreign body type giant cells, to extravasated bile. All granulomas were noncaseating and non‐necrotizing; they consisted of epithelioid cells and often contained giant cells. Perigranulomatous lymphocytic infiltrates were generally mild to moderate. The granulomas involved portal tracts, scars, and hepatic parenchyma. Biopsy experience revealed that granulomas can be found in all stages of the disease. In contradistinction to the granulomas in primary biliary cirrhosis, the granulomas in primary sclerosing cholangitis did not represent granulomatous cholangitis – that is, they were not a feature of the duct destruction. The etiology of these lesions is not clear, but in some cases we found strong morphologic evidence that granulomas may form as a response to the leakage of bile or bile components. No evidence of infection or of sarcoidosis was found. Although adverse drug responses cannot be ruled out with certainty, review of the clinical histories made that mechanism unlikely. Thus, the presence of granulomas in chronic ductopenic cholestatic liver disease is not pathognomonic for primary biliary cirrhosis and, in rare instances (on average, in 3–4% of the biopsy samples), may be a feature of primary sclerosing cholangitis.
Hepatotoxicity of intravenous Cyclosporin A in patients with acute ulcerative colitis on total parenteral nutrition
Authors: Actis G. C. , Debernardi‐Venon W. , Lagget M. , Ottobrelli A. , Ponzetto A. , Rocca G. , Boggio‐Bertinet D. , Balzola F. , Bonino F. , Verme G.
Published: August 2010

Abstract: A group of 24 patients underwent a 7–14‐day course of continuously infused Cyclosporin A (2 mg · kg‐1 · day‐1) to treat a severe attack of ulcerative colitis. In 19 of them, including eight treated with total parenteral nutrition, we retrospectively analyzed the serum aminotransferase (AST/ALT) levels at the beginning and at the end of Cyclosporin infusion. The baseline levels of AST/ALT in the group were 19.9±3.2 and 31.4±6.4; on stopping Cyclosporin infusion, they were 43±15.8 and 119±56, respectively. Six patients showed an ALT change above 1.5 times the upper limit of reference. They included five of the eight patients treated with total parenteral nutrition (62.5%). In one of the six, ALT rose to 1000 U/l and was accompanied by full‐blown febrile cholangitis (proven by liver biopsy). This episode was preceded by excessive accumulation of Cyclosporin in blood. The development of liver toxicity was independent of the length of Cyclosporin treatment, nor did it impair drug efficacy. Thus, in these patients total parenteral nutrition and Cyclosporin were synergistic, causing twice the frequency of liver damage (62.5%) reported for ulcerative colitis patients on total parenteral nutrition alone (37%). Total parenteral nutrition should not be used to support patients needing Cyclosporin for autoimmune disease. However, too high a dose of Cyclosporin may cause liver disease per se.
Changes in laminin content in livers of patients with alcoholic liver disease
Authors: Tsutsumi Mikihiro , Urashima Sachio , Nakase Katsunori , Takada Akira
Published: August 2010

Abstract: An increase in serum laminin levels has been reported in patients with liver disease; however, the mechanisms for this increase have not yet been clarified. In the present study, the laminin content of liver biopsy specimens obtained from patients with alcoholic liver disease and nonalcoholic liver disease was determined with a one‐step sandwich enzymeimmunoassay system, using monoclonal antibodies for human placental laminin. Hepatic laminin content was significantly higher in patients with liver disease than in normal controls. In alcoholic liver disease, the content in patients with mild fibrosis was lower than in patients with advanced types of alcoholic liver disease. In non‐alcoholic liver disease, the hepatic laminin content tended to increase in parallel with the progression of fibrosis. The laminin content in alcoholic liver disease was significantly higher than in the corresponding type of non‐alcoholic liver disease. Hepatic total collagen content increased in parallel with the progression of fibrosis in both alcoholic liver disease and non‐alcoholic liver disease. The ratio of laminin to total collagen content was highest in alcoholic liver disease showing mild fibrosis and decreased in parallel with the progression of fibrosis. In contrast, the ratio was low in all types of nonalcoholic liver disease. The ratio in patients with alcoholic liver disease was significantly higher than in those with the corresponding non‐alcoholic liver disease. Hepatic laminin content increased in parallel with the increase in hepatic type IV collagen in alcoholic liver disease, and the correlation was statistically significant. However, a similar correlation was not found in non‐alcoholic liver disease. These results indicate that the response of laminin synthesis to alcoholic liver disease is strong in mild fibrosis and reached a plateau at a relatively early stage of fibrosis. The stimulation for laminin synthesis in non‐alcoholic liver disease is different from that in alcoholic liver disease.
Long‐term favourable outcome of portal hypertension complicating primary systemic amyloidosis
Authors: Horsmans Y. , Brenard R. , Ferrant A. , Lagneaux G. , Geubel A. P.
Published: August 2010

Abstract: An unusual case of systemic amyloidosis complicated by portal hypertension is reported. In this condition, portal hypertension is a rare event associated with poor prognosis. In our patient, severe presymptomatic sinusoidal portal hypertension was demonstrated by hepatic vein catheterization and coincided with abundant perisinusoidal amyloid infiltration. Despite these features and the absence of objective response to 20 courses of melphalan and prednisone, the patient was still in good clinical condition 4 years after initial diagnosis. This observation suggests that in primary amyloidosis, the incidence of sinusoidal portal hypertension might be underestimated and also that it may be associated with a relatively good prognosis.
Antineutrophil cytoplasmic autoantibodies in autoimmune liver and inflammatory bowel diseases
Authors: Claise C. , Johanet C. , Bouhnik Y. , Kapel N. , Homberg J C. , Poupon R.
Published: August 2010

Abstract: Perinuclear antineutrophil cytoplasmic autoantibodies have been described in inflammatory bowel diseases and in primary sclerosing cholangitis. Because the data concerning their occurrence are conflicting, we have used indirect immunofluorescence on ethanol‐fixed neutrophils to test the sera from a large population of 382 patients with various liver and digestive diseases: in particular, from 27 patients with primary sclerosing cholangitis, 105 patients with autoimmune chronic active hepatitis, 30 patients with primary biliary cirrhosis and 124 patients with inflammatory bowel disease. The prevalence of the perinuclear antineutrophil cytoplasmic autoantibodies was 37% in ulcerative colitis and 15% in Crohn's disease. They would not be helpful in the differential diagnosis between these two inflammatory bowel diseases. Within the group of autoimmune liver diseases, perinuclear antineutrophil cytoplasmic autoantibodies were detected in 44% of sera from patients with primary sclerosing cholangitis and in 36% of sera from patients with type I autoimmune active hepatitis, but not in primary biliary cirrhosis. When primary sclerosing cholangitis was associated with an inflammatory bowel disease, the prevalence of these autoantibodies was 60%. They were 88% specific for primary sclerosing cholangitis and 86% specific for type I autoimmune active hepatitis. Despite their moderate sensitivity and specificity in primary sclerosing cholangitis, they remain the only serologic marker of this autoimmune liver disease. Moreover, they turned out to be a more sensitive marker for inflammatory bowel disease with associated primary sclerosing cholangitis
Liver tumors and possible preneoplastic lesions, induced by a food‐derived heterocyclic amine in cynomolgus monkeys; a study of histology and cytokeratin expression
Authors: Thorgeirsson U. P. , Gomez D. E. , Lindsay C. K. , Sinha C. C. , Adamson R. H.
Published: August 2010

Abstract: A food‐derived mutagenic heterocyclic aromatic amine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline (IQ), is a potent hepatocarcinogen in cynomolgus monkeys. In an ongoing carcinogenesis study, 34 out of 40 monkeys dosed with IQ have developed malignant liver tumors. The histology and cytokeratin expression was examined in a total of 94 tumors and non‐neoplastic lesions obtained from 34 cases. The majority of the tumors were classified as hepatocellular carcinoma. In some cases, a striking difference in the histological features between individual tumor nodules was suggestive of a multicentric origin. Intrahepatic vascular invasion was seen in 14 (41.2%) and metastases in 6 (17.6%) of the hepatocellular carcinoma cases. There was no evidence of regenerative hyperplasia or fibrosis in the parenchyma of the tumor‐bearing livers. Clear‐cell foci composed of glycogen‐rich hepatocytes were the only macroscopic lesions detected prior to gross tumor development. Other liver lesions included dysplastic hepatocyte foci and areas of proliferating bile ductular like (oval) cells, located around the periportal areas and along the portal tracts. Expression of bile duct type cytokeratin 7 was observed in a few of the oval cells and non‐malignant hepatocytes, as well as in some of the hepatocellular carcinoma nodules. This aberrant cytokeratin expression raises questions concerning the histogenesis of the IQ‐induced hepatocellular carcinoma.
Expression of p53 in adenocarcinoma of the gallbladder and bile ducts
Authors: Washington Kay , Gottfried Marcia R.
Published: August 2010

Abstract: Point mutation of the p53 tumor suppressor gene appears to be an important event in tumor development and progression, and overexpression of the p53 gene product has been widely studied in a variety of neoplasms. Some point mutations of the p53 gene lead to an increase in half‐life in the gene product, which accumulates in the nucleus and can be detected by immunohistochemical means. We studied overexpression of p53 protein in specimens from 12 patients with adenocarcinoma of the gallbladder, two gallbladders with epithelial dysplasia without carcinoma, eight carcinomas of the common bile duct, 13 hilar cholangiocarcinomas, and six peripheral cholangiocarcinomas. The monoclonal antibody Ab‐2 (Oncogene Science) was used in conjunction with citrate microwave antigen retrieval. Nuclear staining was scored as positive (graded 1 to 3, depending on number of positive nuclei) or negative. Overexpression of p53 protein was present in 7/12 (58%) gallbladder carcinomas, and was seen more often in moderately or poorly differentiated tumors. Intramucosal carcinoma adjacent to invasive carcinoma was positive in three cases, although fewer cells stained than in the carcinoma. Two cases of low‐grade dysplasia not associated with carcinoma were negative. Expression of p53 was not an independent prognostic factor when survival was related to grade and stage of tumor. Three of eight (38%) common bile duct carcinomas and 5/13 (38%) hilar cholangiocarcinomas were positive for p53. Slightly fewer (2/6, 33%) peripheral cholangiocarcinomas were positive. No difference in survival relative to p53 expression was demonstrated.
Splenectomy‐reduced hepatic injury induced by ischemia/reperfusion in the rat
Authors: Okuaki Yasushi , Miyazaki Hiroshi , Zeniya Mikio , Ishikawa Tomohisa , Ohkawa Yasuhiko , Tsuno Shinichi , Sakaguchi Masami , Hara Masaki , Takahashi Hiroki , Toda Gotaro
Published: August 2010

Abstract: In the present study, we investigated the role of the spleen in experimental hepatic ischemia/reperfusion in the rat. After a 90‐min period of ischemia in the left and middle hepatic lobes, the ischemia was released and the liver was reperfused for up to 24 h. Plasma alanine aminotransferase reached a peak 3 h after the onset of reperfusion, and gradually decreased thereafter. A histological examination revealed evidence of hepatocellular necrosis and degeneration, especially 24 h after the onset of reperfusion. In addition, there was a noticeable accumulation of polymorphonuclear cells in the liver following ischemia/reperfusion. A splenectomy performed just prior to ischemia/reperfusion reduced both biochemical and histological hepatocellular injury. The number of polymorphonuclear cells in the liver following ischemia/reperfusion was significantly reduced in rats subjected to splenectomy, suggesting that the increase in polymorphonuclear cells may contribute to liver injury. The number of mononuclear cells also increased in the marginal zones of the spleen following ischemia/reperfusion, and appeared to be derived from the splenic monocyte/macrophage population, based on immunohistochemical studies. The spleen plays an important role in the pathogenesis of hepatic ischemia/reperfusion injury and the splenic monocyte/macrophage population contributes to liver damage.