Changes in the intermediate filament cytoskeleton of liver cells in alcoholic liver injury

Mallory bodies are a morphological key feature of severe alcoholic liver cell injury (alcoholic hepatitis) and the morphological expression of dysregulation and derangement of the intermediate filament cytoskeleton of the hepatocyte. Their pathogenesis is still unclear. Studies on Mallory body formation may not only help to elucidate the mechanisms of liver cell injury associated with alcoholic hepatitis, but may also contribute to our understanding of the regulation and function of the intermediate filament cytoskeleton.     

Th1/Th2 imbalance in HCV-related liver cirrhosis

The mechanism by which Hepatitis C virus(HCV) infection promotes the development of hepatocellular carcinoma(HCC) is not known exactly. HCV related HCC occurs frequency in the patients with cirrhosis. There have been reports indicating that Th2-type cytokines down-regulated antitumor immunity, and the activation of type 1 T cell responses produced antitumor immunity. We thought Th1/Th2 imbalance in HCV-related liver cirrhosis might be closely related to the development of HCC. In this study, therefore, we investigated the Th1/Th2 balance at the single lymphocyte level of the patients with HCV-related liver cirrhosis and compared with normal controls by using flow cytometry. Th1-type cytokines(IFN-gamma, IL-2) production was significantly decreased in patients with cirrhosis, whereas Th2-type cytokine production(IL-10) was increased. These suggest Th1/Th2 imbalance in HCV-related cirrhosis would decrease the antitumor immunity and its improvement might present the protective effect from HCC.     

Red blood cell status in alcoholic and non-alcoholic liver disease.

Macrocytosis is most commonly associated with vitamin B(12) and folic acid deficiency, followed by alcoholism, liver disease, and other pathologic conditions. We studied the red cell and vitamin status in 423 consecutive patients with various liver diseases, including 31 with acute viral hepatitis (AVH), 105 with chronic hepatitis (CH), and 134 with alcoholic liver disease (ALD), who consisted of 84 with non-cirrhotic alcoholic liver disease (NCALD) and 50 with alcoholic liver cirrhosis (ALC), 60 with non-alcoholic liver cirrhosis (NALC), and 93 with hepatocellular carcinoma (HCC). The mean corpuscular volume (MCV) and red cell distribution width (RDW) were significantly higher in patients with ALD and NALC, and among them macrocytosis occurred more frequently in patients with ALC. Macrocytic anemia was mostly found in cirrhotic patients, in which the Child-Pugh score was closely related to the development of macrocytic anemia. In ALD, the MCV was significantly correlated with the estimated alcohol consumption and inversely correlated with the serum folic acid level, which, however, was often maintained within the normal range in patients with macrocytic ALC. After abstinence from alcohol, the MCV and RDW were reduced significantly and were associated with an increasing serum folic acid level. This suggests that macrocytic anemia was a common feature of alcoholic and non-alcoholic liver cirrhosis and that alcohol abuse and folic acid deficiency play a secondary role in macrocytosis.     

Diagnostic significance of estimation of serum apolipoprotein A along with alpha-fetoprotein in alcoholic cirrhosis and hepatocellular carcinoma patients

The serum apolipoprotein A (Apo A) and alpha-fetoprotein (AFP) were evaluated in histologically verified 30 cases of alcoholic cirrhosis and 18 cases of hepatocellular carcinoma (HCC). The latter were also divided into subgroups depending on the presence or absence of associated cirrhosis. Serum Apo A levels were found to be significantly decreased in cirrhotics (p less than 0.001) compared to controls and non-cirrhotic HCC patients. In 22 cases of alcoholic cirrhosis (AFP less than 10 ng/ml) and 12 cases of HCC (AFP greater than 600 ng/ml), the AFP levels itself were diagnostic, but in the remaining cases, AFP levels (100-600 ng/ml) were not able to differentiate between cirrhosis and malignancy. In this later group of patients with low pathological range of AFP, serum Apo A levels found to be significantly decreased in alcoholic cirrhotic patients (p less than 0.001) compared to HCC patients. Thus, estimation of Apo A levels may be helpful to interpret the AFP values at lower pathological range due to suspected liver pathology.     

Laparoscopic findings in hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu disease)

The laparoscopic findings observed in eight patients with hereditary haemorrhagic telangiectasia are reported. Clinical signs or laboratory data suggestive of liver involvement were present in all cases and constituted the main indication for laparoscopic examination. Characteristic vascular lesions distributed at random were found in four cases. Numerous oval, round or polygonal areas of 0.5 to 1.5 cm in diameter were observed on the external surface of the liver. They were of a reddish or pink colour, flat or slightly raised, and made up of a dense vascular meshwork. In one patient macronodular cirrhosis was associated with the vascular lesions. In the remaining four cases laparoscopic examination did not show striking vascular changes, although the liver biopsy revealed a fatty liver in three cases and micronodular cirrhosis with intense inflammatory activity, steatosis and Mallory bodies in one case. In these cases the accompanying hepatic lesions could probably not be aetiopathogenically related to Osler's disease.     

Survival rates of early-stage HCV-related liver cirrhosis patients without hepatocellular carcinoma are decreased by alcohol

Although alcohol abuse is the most common cause of liver cirrhosis in the United States, the enhancing effects of alcohol on the long-term prognosis of hepatitis C virus (HCV) related liver cirrhosis has not been clarified. To investigate how alcohol abuse influences the prognosis of hepatitis virus related liver cirrhosis, we studied 716 Japanese patients. Cumulative survival and hepatocellular carcinoma (HCC) development rates were analyzed in alcohol abusive, cirrhotic patients with or without hepatitis virus infection. Patients who abused alcohol were younger (p<0.0001) than HCV infected, non-abusive patients. The overall survival rate among patients with alcoholic cirrhosis (Al group), HCV related cirrhosis (HCV group), and HCV infected + alcoholic cirrhosis (HCV + Al group), showed no significant differences, although the 10-year cumulative survival rate of Al group was the highest of the three groups. The HCC development rate of Al group was the lowest. In addition, alcohol abuse decreased the survival rates of HCV group in the early stage with no HCC (p = 0.0028). In conclusion, alcohol abuse might affect the progression of liver damage in HCV infected patients with liver cirrhosis in the early stage, although the influence of alcohol abuse on the long term prognosis seems to be rather small.     

Large liver cell dysplasia in hepatitis B virus x transgenic mouse liver and human chronic hepatitis B virus-infected liver

OBJECTIVES: Large liver cell dysplasia (LCD) is frequently associated with hepatitis B virus (HBV), but it remains uncertain whether it is reactive, senescent or preneoplastic. METHODS: The HBX transgenic mice and normal control mice were sacrificed at 1, 3, 5, 7, 9, 11, 13 and 15 months after birth. Twenty-three cases of human B viral chronic hepatitis/cirrhosis with prominent LCD were selected. The immunohistochemical stain of proliferating cell nuclear antigen (PCNA), transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and senescence-associated beta-galactosidase (SA-beta-Gal) were evaluated. RESULTS: In HBX transgenic mice, LCD was developed since 3 months and formed small nodules of hepatocellular adenoma, which progressed to hepatocellular carcinoma. The hepatocytes with LCD in HBX transgenic mice showed significantly higher PCNA-labeling index (LI) and lower TUNEL-LI than normal hepatocytes of control mice (p < 0.05). In the majority of human B viral chronic hepatitis/cirrhosis, the hepatocytes with LCD revealed higher PCNA-LI and lower TUNEL-LI than those without, when compared in each case using the same tissue block. SA-beta-Gal staining showed no difference between hepatocytes with and without LCD. CONCLUSION: It is suggested that LCD, related to HBV, might not be just an innocent bystander, but closely related to hepatocarcinogenesis.     

酒精性肝病与慢性病毒性肝炎的病理鉴别

本文对５４例单纯洒精性肝病（ＡＬＤ），６５例慢性乙型肝炎和１４例急慢性丙型肝炎的肝穿标本的病理变化进行了比较。在各型ＡＬＤ中常见的肝细胞变性，如肝脂变、小型肝细胞、巨大线粒体和麦氏小体，以及窦周纤维化，在病毒性肝炎中均少见，Ｐ值小于０．０５和０．０１。而病毒性肝炎中常见的汇管区及其周围炎、碎屑状坏死和桥接坏死以及肝窦内淋巴细胞渗出，在ＡＬＤ中少见，程度且轻。这对鉴别ＡＬＤ及病毒性肝炎有意义。     

腺苷蛋氨酸治疗酒精性肝硬化的临床效果分析

目的观察应用腺苷蛋氨酸治疗酒精性肝硬化的临床效果。方法抽取186例患有酒精性肝硬化的患者,将其分为对照组和治疗组,每组93例。对照组采用多烯磷脂酰胆治疗,治疗组采用腺苷蛋氨酸治疗,比较两组治疗疗效。结果治疗组患者酒精性肝硬化治疗效果明显优于对照组;治疗前后相关生化指标的改善幅度明显大于对照组;两组均未观察到任何药物原因导致的不良反应。结论应用腺苷蛋氨酸对患有酒精性肝硬化的患者实施治疗的临床效果非常明显。     

Tumor suppressor gene PTEN and non-alcoholic steatohepatitis (NASH)

Although hepatic steatosis had been considered to be a benign condition that does not deteriorate to either liver cirrhosis or hepatocellular carcinoma (HCC). Non-alcoholic steatohepatitis (NASH) is notable disease that has similar pathological features to alcoholic liver injury and progresses to liver cirrhosis and HCC. But the molecular mechanism for the onset of NASH, and for the transformation from steatosis to carcinogenesis are still unclear. Hepatocyte-specific PTEN deficient mice, we generated, have similar histological features to the patients of human NASH. These hepatocytes showed enhanced lipid accumulation, inflammatory change, and hyperoxidation. Moreover, they developed into HCC. Thus, impairment of PI3K/PTEN signaling may possibly be involved in a part of NASH/HCC cases in human.     

Detection of serum and intrahepatic human hepatocyte growth factor in patients with type C liver diseases

We determined hepatocyte growth factor (HGF) levels in the serum and liver of patients with hepatitis C and assessed the relationship to histological findings of the liver and hepatitis C virus-related markers in the serum in patients with type C liver diseases. The subjects were 108 patients with chronic hepatitis C (CH), 70 patients with liver cirrhosis C (LC), 38 patients with hepatocellular carcinoma (HCC) and 20 patients with acute hepatitis (AH). As normal controls 20 subjects were studied. The serum HGF levels were measured using an enzyme-linked immunosorbent assay kit. Intrahepatic HGF was investigated by immunoperoxidase staining using monoclonal HGF antibody. The serum HGF level was highest in patients with AH. The serum HGF levels tended to be higher in patients with LC and HCC than those with CH. Further, the serum HGF level was related to the degree of intrahepatic inflammatory cell infiltration and fibrosis, and intrahepatic HGF was noted primarily in the cell membrane of mesenchymal cells in focal necrosis. The degree of intrahepatic HGF expression tended to be higher in patients with high serum HGF levels. In patients with HCC, however, HGF showed little localization in cancer cells, but was noted in infiltrating mesenchymal cells in both cancerous and noncancerous regions. In conclusion, the measurement of serum HGF levels may be useful for estimating the degree of intrahepatic inflammatory reaction and fibrosis. Although further study is necessary, the high serum level of HGF revealed high carcinogenic states in chronic hepatitis and liver cirrhosis type C.     

Nonalcoholic steatohepatitis: a brief review on its concept

Since the first report by Ludwig, considerable progress has been made in the understanding of NASH and it is not currently considered as a merely benign clinical entity, but is rather thought as a common disease with a variety of clinical sequelae including liver cirrhosis and even hepatocellular carcinoma. Thus, NASH is considered as a type of a larger spectrum of nonalcoholic fatty liver disease (NAFLD) that is a consequence of insulin resistance and other underlining factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. In this brief review article, particular emphasis has been paid to the clinical entity, namely cryptogenic cirrhosis in relation to the pathogenesis of NASH.     

肝硬变的MRI诊断

笔者复习了我院９４年３～１１月经临床及ＭＲＩ诊断为肝硬变５０例，其中３７例伴有肝癌（７４％），提出肝硬变的ＭＲＩ特点：①肝内弥漫性结节，按结节大小分为小结节型．大结节型及大小结节混合型；②肝普遍增大；③肝表面凸凹不整．各叶比例失调；④肝内静脉细，稀少；⑤脾静脉扩张，胃底及脾门静脉曲张；⑥脾肿大；⑦腹水。文中着重分析肝内再生结节、脉瘤性增生结节及小肝癌三者的ＭＲＩ信号特点及其演变过程。提出ＭＲＩ诊断肝硬变的价值。     

Risk factors for long-term prognosis of hepatocellular carcinoma patients after anatomic hepatectomy

BACKGROUND The risk factors for patients with major postoperative complications immediately after liver resection have been identified;however,the intermediate and longterm prognoses for these patients have yet to be determined.AIM To evaluate the factors responsible for the long-term recurrence-free survival rate in patients with hepatocellular carcinoma(HCC)following anatomic hepatectomy.METHODS We performed a retrospective analysis of 74 patients with HCC who underwent precise anatomic hepatectomy at our institution from January 2013 to December 2015.The observational endpoints for this study were the tumor recurrence or death of the HCC patients.The overall follow-up duration was three years.The recurrence-free survival curves were plotted by the Kaplan-Meier method and were analyzed by the log-rank test.The value of each variable for predicting prognosis was assessed via multivariate Cox proportional hazards regression analysis.RESULTS The 1-year and 3-year recurrence-free survival rates of HCC patients were 68.92%and 55.41%,respectively,following anatomic liver resection.The results showed that the 3-year recurrence-free survival rate in HCC patients was closely related to preoperative cirrhosis,jaundice level,tumor stage,maximal tumor diameter,complications of diabetes mellitus,frequency of intraoperative hypotensive episodes,estimated blood loss(EBL),blood transfusion,fluid infusion,and postoperative infection(P<0.1).Based on multivariate analysis,preoperative cirrhosis,tumor stage,intraoperative hypotension,and EBL were identified to be predictors of 3-year recurrence-free survival in HCC patients undergoing anatomic hepatectomy(P<0.05).CONCLUSION Tumor stage and preoperative cirrhosis adversely affect the recurrence-free survival rate in HCC patients following anatomic hepatectomy.The long-term recurrence-free survival rate of patients with HCC is closely related to intraoperative hypotension and EBL.     

gamma-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.     

多药耐药基因相关蛋白在原发性肝癌中的表达及意义

目的探讨原发性肝细胞癌中耐药基因相关蛋白P-糖蛋白(P-gp)、DNA拓扑异构酶-Ⅱ(Topo-Ⅱ)、谷胱苷肽-S-转移酶(GST-π)的表达及其意义。方法应用免疫组织化学方法S-P法检测49例原发性肝癌组织、14例肝硬化组织及13例正常肝组织中P-gp、Topo-II、GST-π的表达。结果肝癌组三者表达均高于肝硬化组及正常组(P<0.05),肝硬化组与正常组之间两者表达差异无统计学意义。P-gp表达与肿瘤Edmondson分级呈负相关;Topo-II表达则与Edmondson分级和转移呈正相关。P-gp、Topo-II表达呈负相关。结论联合检测肝癌耐药基因相关蛋白P-gp、Topo-II、GST-π的表达有助于临床判断肝癌对化疗的敏感性及预后。     

Autoantibodies, sheep cell agglutinins and anti-albumin antibodies in alcoholic liver disease

The frequency of serum autoantibodies including anti-albumin antibodies was investigated for patients with various categories of alcoholic liver disease (ALD). The 95 patients were grouped into 3 categories: fatty liver (25 cases), alcoholic hepatitis (29 cases), and alcoholic cirrhosis (41 cases), and each group was matched with healthy controls by age, sex, ethnic origin and socio-economic status. For all patients with ALD, there was a 5-fold greater frequency over the controls of positive tests for antinuclear antibody (ANA), but titres were low; the pattern of ANA reactions was speckled in 50% of the cases. For patients with alcoholic cirrhosis, there was an 8-fold increase in frequency over the controls in anti-smooth muscle antibody (ASMA), but titres were low, pointing to a possibility that autoimmunity might be one of several determinants of progression of alcoholic hepatitis to cirrhosis. For none of the groups was there an increase over the controls in the mean titre of sheep red cell agglutinins, nor were there increased haemagglutinin titres of antibody to bovine serum albumin or to human albumin, arguing against a general increase in antibody production in ALD. Greater knowledge of the frequency, significance and pathogenicity of reactive autoantibodies which occur in response to various types of tissue damage is required for interpretation of the increase in ANA and ASMA in alcoholic liver disease.     

An Analysis of Lipoproteins, Bile Acids, and Red Cell Membranes Associated with Target Cells and Spur Cells in Patients with Liver Disease

Most patients with stable cirrhosis of the alcoholic have “target” red cells; however, a minority have “spur” cells and severe hemolytic anemia. These two syndromes were studied in 27 patients with target cells and 17 patients with spur cells, all of whom had advanced cirrhosis. The cholesterol and phospholipid content of red cell membranes effectively distinguished target cells from spur cells. Target cells alone were rich in lecithin, and both the cholesterol/phospholipid and cholesterol/lecithin mole ratios were greater in spur cells. The cholesterol/phospholipid mole ratio of both types of red cells correlated closely with the free cholesterol saturation of serum lipoproteins, as defined by the amount of free cholesterol relative to phospholipid and protein in these lipoproteins. Lecithin: cholesterol acyltransferase (LCAT) activity was decreased in most patients with target cells and spur cells; however, the relationship between this activity and the lipid abnormalities observed was weak. Serum bile acid levels also correlated poorly with serum and cell lipids. However, in patients with target cells the amount of cholic and deoxycholic acids in serum was approximately equal to the amount of chenodeoxycholic acid, whereas in patients with spur cells chenodeoxycholic acid (the precursor of lithocholic acid) predominated.     

肝癌肝硬化组织中铁铜的分布及其意义

为探讨铁、铜、乙肝病毒与肝癌的关系，利用组化染色及图像分析技术对贮存的７０例肝癌、肝硬化标本蜡块及１０例正常对照标本进行了观测分析．ＨＢｓＡｇ阳性组肝铁含量显著高于阴性组（Ｐ＜０．０５）．提示ＨＢＶ与铁关系密切．正常肝铁分布均匀；肝硬化铁分布参差不一，与肝细胞增生有关；肝癌细胞内无铁颗粒．与周围肝细胞形成了明显的界线．有铁聚集的肝再生巨结节（ＭＲＮ）中出现的“灶中灶”结构可能为肝硬化癌变的初始阶段表现，铁可能有促癌作用．铜颗粒的出现与炎性反应、纤维组织增生等有关，常出现于分化较好的肝癌细胞内，其作用不同于铁．     

肝细胞肝癌组织ICAM-1及血清sICAM-1水平变化的临床意义

目的：研究细胞间黏附分子-1（ICAM-1）在肝细胞肝癌（HCC）中表达的临床意义。方法：应用免疫组化方法结合全自动图像检测40例HCC组织及其癌旁组织和28例肝硬化组织中ICAM-1的表达，以酶联免疫吸附实验（ELISA）法测定42例HCC、26例肝硬化患者和22例正常健康者血清中可溶性细胞间黏附分子-1（sICAM-1）的水平，并与甲胎蛋白（AFP）进行同步分析。结果：40例HCC组织ICAM-1表达阳性率为80．0％，高于癌旁和肝硬化组织（P〈0．05），阳性率与组织学分类相关。HCC组织中ICAM-1含量高于癌旁及肝硬化组织（P〈0．05），转移组HCC中ICAM-1的含量也高于非转移组（P〈0．05），而癌旁及肝硬化组织中含量差异无显著性（P〉0．05）。HCC患者血清sICAM-1水平高于肝硬化及正常健康组（P〈0.05），HCC伴转移组患者血清中sICAM-1无转移组（P〈0.05），AFP阴性组与阳性组sICAM-1水平差异无显著性（P〉0.05）。结论：HCC组织中高度表达ICAM-1和血清中高水平的sICAM-1，在一定程度上可以反映HCC发展程度及转移状态，ICAM-1有可能作为HCC的一个新的诊断指标。