肝炎双语PPT演示课件

.,Viral hepatitis病毒性肝炎,.,General description,病毒性肝炎是由多种肝炎病毒引起的，以肝脏炎 症和坏死病变为主的，临床表现多变的一组传染病。 多种肝炎病毒 多种传播途径 发病机制复杂 病理改变多样 临床类型繁多 疾病转归不一,.,Viral hepatitis is defined as the hepatitis caused by hepatitis viruses that appear to target liver and produce liver disease as their major clinical manifestation. Other viruses such as EB virus and cytome-galovirus(巨细胞病毒), can also cause inflammation of the liver, but hepatitis is not the primary disease,.,The main clinical characteristics of hepatitis are :digestive tract symptoms: anorexia, nausea（恶心）, abdominal discomfort sign: enlargement and tenderness of liver Lab: elevated alanine aminotransferase (ALT),.,. Etiology,1. HAV（甲型肝炎）HAV is an unenveloped, single-stranded small RNA virus, and now is classified in a genus, hepatovirus. HAV has been successfully cultivated in cell cultures but growths poorly. HAV has only a single serotype. The resistance of the virus is strong, the virus is inactivated by boiling for 5 mins, chlorination, ultraviolet,.,电镜下可见空心和实心两种颗粒存在实心颗粒：成熟的病毒颗粒空心颗粒：不完整的病毒颗粒，仅含衣壳蛋白，无核酸。,HAV,.,2. HBVHBV is an enveloped DNA virus belongs to hepadnaviridae, other related agents have been identified :WHV（土拨鼠肝炎病毒 ）,GSHV（黄鼠肝炎病毒 ）, DHBV（鸭乙型肝炎病毒 ） The viral genome consists partially double-stranded DNA which comprises 3200 nucleotides.,.,乙型肝炎病人或携带者的血清中有种颗粒：小球形颗粒：直径1525nm管形颗粒：直径22nm、长50230nm大球形颗粒：直径42nm,大球形颗粒,管形颗粒,小球形颗粒,图 HBV三种颗粒，电镜，负染120000,.,大球形颗粒是完整的乙型肝炎病毒（HBV）颗粒，又称Dane颗，分为包膜与核心两部分。 包膜：含HBsAg、糖蛋白与细胞脂肪 核心：含环状双股DNA、DNAP、HBcAg 和HBeAg，是病毒复制的主体。,.,HBV is remarkably compact virus, with four ORFs that encode four major proteins: Surface gene core gene polymerase gene. X gene The four ORFs are overlapping, so more than half of the nt are used in different frame.,.,.,(1). Surface gene: There are three initiation codons（密码子） within the surface gene, so three related proteins are produced: LHBsAg: translated from pre-s1. MHBsAg: from pre-s2 SHBsAg or major HBsAg: from S, which is the main surface protein, accounts for 80% to 85% of total surface protein.,.,HBsAg： important serologic marker appears earliest strong antigenicity subtypes: adr, adw, ayr, ayw. anti-HBs : neutralizing antibodies appears in the convalescent period,.,(2) Core gene: two initiation codons within the core gene, so two proteins are produced Two kind of antibodies: anti-HBc-IgG, which existes very long time anti-HBc-IgM, which appears earlier, is the indication of new infection or relapse.,.,HBeAg: HBeAg is translated from genomic-length mRNA, so it is a marker of active viral replication. When HBeAg disappears and anti-HBe appears, the viral replication decreases. However, HBeAg is not necessary for viral replication. When Pre-C mutation（突变） appears, lack of HBeAg is associated with active viral replication and progressive liver disease.,.,(3) P geneP gene entirely overlaps（重叠） with S gene, and partially overlaps with C gene and X gene. P gene encodes（编码） a important enzyme which is special for HBV and functions as both a reverse transcriptase（逆转录酶） and endogenous polymerase,.,(4) X geneX gene encodes X protein. The function of X has not been fully elucidated, it appears to be essential for replication because viral genomes with mutations in the X gene fail to produce active infection in culture. X protein may be a transcriptional activator that influences the transcription of HBV gene.,.,3. HCVKnowledge of the structure and mechanism of replication of HCV is incomplete. HCV is a single-stranded positive-sense RNA virus that belongs to the the flaviviridae family（黄病毒科）. The genome of HCV is approximately 9400 nt and contains a single ORF capable of encoding a large viral polypeptide precursor of 3010 amino acids.,.,Like many RNA viruses, HCV has a very high mutational rate that results in considerable genomic heterogeneity（异质性）. There are at least six major genotype, theses genotypes have quite different geographic distributions and may be associated with different severities of disease as well as response to therapy.,.,HCV在血液中浓度极低，未能在电镜下直接观察到HCV病毒颗粒，但可观察到基本相似的HCV病毒样颗粒（virus-like particlesVLPs）。HCV VLPs：55nm直径的球形颗粒。 包膜和表面突起 核心部分：33nm直径， 核壳蛋白包被，内含 单股正链RNA基因组,图 HCV示意图,.,4. HDVThe delta agent was discovered by Rizzetto and associates in 1977, This new agent was designated HDV. HDV is a small animal virus that belongs to defective virus. This virus requires the presence of HBV to provide its protein shell and is thus found only in persons with HBV infection.,.,HDV是一种缺陷病毒：需有HBV或其他嗜肝DNA病毒（如WHV）的辅助才能复制、表达抗原及引起肝损害。在细胞核内HDV RNA无需HBV的辅助能自行复制，但HDV病毒颗粒的装配和释放需要HBV的辅助。,.,图 HDV示意图及电镜图,.,5. HEVHEV is most similar to viruses of the alpha-like supergroup of positive-strand RNA viruses, such as rubella virus. Despite the presence of genetically different isolates of HEV, there appears only one serotype.,.,HEV病毒颗粒呈球状，无包膜，表面不规则，直径2734nm，在胞浆中装配，呈晶格状排列，可形成包涵体。,图 HEV电镜图，球状无包膜，呈晶格状排列,HEV,.,6. Other hepatitis virusesHGV又称GBV-C，是1995年在国际上新发现的病毒，也是采用分子生物学技术发现的第二个病毒。HGV在人群中感染率较高，但迄今对其病毒学特性了解不多，特别是它与肝脏疾病的关系仍不明确，存在较大争议。 l997年NishiZdwd从一个输血后肝炎患者（TT）的血清中克隆出一个500bp的片段N22），并把该基因片段代表的病毒以患者名字命名为输血传播病毒（TTV）。,.,. Epidemilology,流行特点： 甲型肝炎多为散发性发病，也可因水和食物污染而暴发流行。秋冬季多见,全年可见散发病例. 易感和高发病率人群: 以6个月学龄期（10岁） 儿童多见。 戊型肝炎：我国部分地区因水污染造成流行,全国各地均有散发病例。 雨季,洪水后流行、全年可见散发病例; 儿童多为隐性感染; 成人多为临床性感染; 免疫力不持久,.,1. Hepatitis A,Source of infection: acute infected human being are the only natural reservoir of HA. HAV is secreted from the liver into bile（胆汁） and shed in high titer in the feces. The patient is maximally infectious from two weeks before the onset until one week after the onset.,.,Route of transmission: fecal/oral route Direct person-to-person spread is the most important means of transmssion.Transmission via fecally comtaminated food or water is well described and may be associated with outbreaks of HA. The most common vehicle for HA outbreak has been raw or partially cooked shellfish.,.,Susceptible personAll person who has not been infected are susceptible to HAV. Immunity after infection is lifelong. In our country most people acquired infection during children and adolescent stage. In recent years, because of better sanitation ,infection rates have been decreasing, but the mean ages of infected person are increased.,.,DistributionHA has a worldwide distribution, but the infection rates among different region and population are markedly different. The prevalence of infection is related to the age, quality of the water supply, level of sanitation. There is a marked epidemic peak in autumn and winter in our country,2. Hepatitis B:,source of infectionChronic carriers of HBV are the main reservoir of infection. In our country, 10% of all persons carry the virus, most of then are asymptomatic, but they are important source of infection.,.,Route of transmissionHBV is a parenterally transmitted virus acquired via blood or blood products. The modes of transmission include: Injection of Blood and blood products, using of inadequately sterilized(灭菌), blood-contaminated needles, injection drug use, tattooing(纹身法）, and so on.,.,Exposure by direct contact with blood or other body fluid, probably through small lesions. Mother-to-infant transmission: Infants born to HBeAg-positive mothers have a high risk of infection. In contrast, the risk of mother-to-infant transmission from HBeAg negative is substantially lower.,.,Sexual transmission: Sexual activity is a important mode of transmission in adults. Sexual partners of infected individuals are at risk for infection.,.,Susceptible person All persons without specific immunity are susceptible to HBV. The major determinant of chronicity of HBV infection is age at the time of exposure. Among infants born to HBeAg-positive mothers, the probability of developing a chronic infection is higher than 90%, the risk of chronicity among normal, healthy adults is less than 10%.,.,PrevalenceHepatitis B infection is very common all over the world, approximately 5% of the worlds population have chronic HBV infection. The prevalence of of HBV infection varies widely in different parts of the world. The world is divided into low (2%）， moderate and high（ 8%）prevalence area.,.,3. Hepatitis C,It is similar to HBV. The most important route or HCV transmission is blood transfusion. In our country more than 90% of patients have history of transfusion. Other routes include intravenous（静脉注射） drug use, sexual, tattooing, mother-to-infant transmission and so on.,.,4. Hepatitis D It is the same as hepatitis B 5. Hepatitis E It is similar to HAV. In outbreak setting, HEV transmission is most often associated with fecally contaminated drinking water.,.,. pathogenesis,Mechanisms of hepatocelllular injury are poorly understood. In general, viral infection can produce cellular injury by direct cytopathic effect and indirect immune-mediated injury.,.,Most evidence indicates that HAV and HEV do not have a cytopathic effect.There is some evidence that HDVAG and RNA may be directly cytotoxic to hepatocytes. Direct cytopathic effect may play some role in the HBV and HCV infection.,.,However, clinical observations suggest that the immune response of the host is more important than viral factor in viral hepatitis. It has been widely accepted that CTLs are responsible for destruction of virally infected hepatocytes and with viral clearance.Inflammatory cytokines, such as TNF, IL-1, IL-6 and so on may also be important in the liver cell injury.,.,HAV经口胃肠道血流（病毒血症）肝脏复制经胆汁排入肠道经粪便排出免疫介导肝损NK细胞CD8+T细胞HAV感染时肝细胞损伤也可能与凋亡有关,杀伤肝细胞,.,HBV经皮肤黏膜血流肝脏（及其他器官）复制血流免疫系统（T/B淋巴细胞）细胞/体液免疫病毒清除CD8+：识别肝细胞膜表达的HBcAg和MHC-肝细胞溶解CD4+：识别B细胞膜表达的HBsAg、HBcAg和MHC-B细胞释放抗-HBs清除病毒慢性化机制免疫耐受，病毒变异，细胞因子,.,急性HCV感染：可能是HCV直接致病作用 慢性HCV感染：病毒的细胞毒作用免疫介导肝内以CD8+浸润为主HCV感染者有许多自身免疫性疾病的表现，且短期激素治疗可以降低转氨酶水平免疫抑制病人并不导致肝病的加重,.,丁型肝炎CD8+ T细胞攻击宿主免疫在肝细胞损伤过程中起重要作用HDV复制过程及其表达产物对肝细胞有直接损伤作用，有待于进一步证实。,.,HEV在体内的定位以及感染过程尚未完全弄清HEV经口胃肠道血流(病毒血症)肝脏复制排入血液和胆汁经粪便排出细胞免疫反应细胞毒性T淋巴细胞（CTL）NK细胞,.,病理解剖,急性肝炎全小叶性病变肝细胞肿胀、水样变性及气球样变嗜酸性变、凋亡小体形成散在的点、灶状坏死窦库普弗细胞增生，窦内淋巴细胞、单核细胞增多汇管区呈轻至中度炎症反应,.,图1 汇管区炎细胞浸润，向肝实质溢出。无界面炎症。图2 肝细胞肿胀、气球样变，均匀分布。血窦细胞反应活跃。肝细胞、库普弗细胞胆色素沉积，毛细胆管淤胆。图3 腺泡带显著炎症坏死，腺泡内炎症活跃。图4 终末肝小静脉周围炎症坏死，网状纤维支架塌陷。,.,慢性肝炎炎症坏死 点、灶状坏死，融合坏死碎屑坏死（PN）：分为轻、中、重度 桥接坏死（BN）：分3类汇管区-汇管区（P-P）BN汇管区-小叶中央区（P-C）BN中央-中央（C-C）BN纤维化分为14期（S14）,.,图 慢性肝炎（大量炎症细胞浸润，如中性粒细胞，淋巴细胞及浆细胞）,.,重型肝炎(肝衰竭),急性重型肝炎一次性坏死，或亚大块性坏死，或桥接坏死存活肝细胞的重度变性亚急性重型肝炎肝细胞呈亚大块坏死，坏死面积小于1/2。肝小叶周边可见肝细胞再生，形成再生结节，周围被增生胶原纤维包绕。小胆管增生和淤胆慢性重型肝炎在慢性肝炎或肝硬化病变基础上出现亚大块或大块坏死，部分病例可见桥接及碎屑状坏死。,.,图 急性重型肝炎1.坏死带扩大，形成VP间的桥联坏死。2.终末肝静脉周围的肝细胞坏死后，残存网状纤维支架塌陷。汇管区有少量固有的纤维组织,.,肝硬化,活动性肝硬化：肝硬化伴明显炎症纤维间隔内炎症假小叶周围碎屑坏死再生结节内炎症病变静止性肝硬化假小叶周围边界清楚间隔内炎症细胞少结节内炎症轻,.,图 肝硬化（大体照片）,图 肝硬化（染色后低倍镜照片）,图 肝硬化（大体照片 小视野）,.,. clinical manifestation,The clinical manifestation of viral hepatitis is highly variable. The most important is : General symptoms: fatigue, malaise Digestive tract symptoms: loss of appetite, nausea, vomiting, abdominal discomfort Main sighs : jaundice（黄疸）, enlargement of liver and right upper abdominal pain.,.,1. acute hepatitis,Icteric and anicteric （黄疸和无黄疸）Common: HAV, HBV Onset: sudden(HAV), insidious (HBV) Fever: 85% (HAV), 20% (HBV)Very high ALT levelSevere digestive tract symptom: nausea, vomiting, diarrhea and abdominal pain,.,.,急性黄疸型肝炎：甲、戊型多见，总病程14个月黄疸前期（平均57d）：发热、疲乏、食欲下降、恶心、厌油、尿色加深，转氨酶水平升高黄疸期（26周）：皮肤巩膜黄染，肝脏肿大伴有压痛，浓茶样尿，转氨酶升高及血清胆红素升高。恢复期（12月）：黄疸渐退，症状消失，肝脾回缩，肝功能复常。,.,2.chronic hepatitis,Virus: HBV, HCV, HDV time: 6 months severity: mild (persistent) , moderate (active), severe (active) chronic mild hepatitis: no or mild symptoms,.,Chronic active hepatitis,Repeated attack of anorexia, jaundice, abdominal distention hepatomegaly, splenomegaly extrahepatic manifestations: hepatic face, capillary dilation （扩张）in the face, vascular spider, liver palms. Pathology: bridge and pieces necrosis,.,轻度慢性肝炎 常见于乙、丙、丁型肝炎 病情轻，可有疲乏、纳差、厌油、肝区不适、肝肿大、压痛、轻度脾肿大。肝功能指标仅1或2项轻度异常。中度慢性肝炎：居于轻度和重度之间 重度慢性肝炎有明显或持续的肝炎症状，伴肝病面容、肝掌、蜘蛛痣，进行性脾肿大，肝功能持续异常。具有早期肝硬化的肝活检病理改变与临床上代偿期肝硬化的表现。,.,3. hepatitis gravis（重型肝炎）,Acute liver failure (ALF,fulminant hepatitis) 10days subacute liver failure (SALF,subacute fulminant) 10days to months Acute on-chronic liver failure(ACLF): chronic liver failure(CLF): pre-existing chronic hepatic disease,.,Hepatitis gravis,Severe digestive tract symptoms progressively elevated jaundice obvious hemorrhagic tendency rapid development of ascites (腹水) rapid development of hepatorenal syndrome appearance of hepatic encephalopathy,.,病因及诱因复杂: 重叠感染、妊娠、HBV前C区突变、过度疲劳、饮酒、应用肝损药物、合并细菌感染等。表现一系列肝衰竭症候群：极度乏力，严重消化道症状，神经、精神症状;有明显出血现象，凝血酶原时间显著延长, PTA40;黄疸进行性加深，每天TB上升 17.1mol/L;可出现中毒性鼓肠，肝臭，肝肾综合征等;可见扑翼样震颤及病理反射，肝浊音界进行性缩小;胆酶分离，血氨升高。,.,4. Cholestatic hepatitis（淤胆型肝炎）,Prolong cholestasis, The duration of jaundice exceeds 3 weeks(usually 2 to 4 months) pruritus, clay-colored stool mild digestive tract symptoms and mild abnormal liver function apparently elevated AKP,GGT,.,亦称毛细胆管炎型肝炎。急性淤胆型肝炎起病类似急性黄疸型肝炎，但症状轻。慢性淤胆型肝炎是在慢性肝炎或肝硬化基础上发生。 有梗阻性黄疸临床表现：巩膜、皮肤黄染，消化道症状较轻，皮肤瘙痒，大便颜色变浅，肝大。肝功能检查血清总胆红素明显升高，以直接胆红素为主，-GT或GGT，ALP或AKP，TBA，CHO等升高。ALT,AST升高不明显，PT无明显延长，PTA60。 应与肝外梗阻性黄疸鉴别。,.,5. Cirrhosis（肝硬化）,Active cirrhosis: with symptoms and elevated ALT silent cirrhosis Compensatory（代偿性） cirrhosis (early cirrhosis) : no ascites, encephalopathy, hemorrhage decompensated cirrhosis: portal hypertention（门脉高压）,.,根据肝脏炎症情况分为两型活动性肝硬化：有慢性肝炎活动的表现，常有转氨酶升高、白蛋白下降。静止性肝硬化：无肝脏炎症活动的表现，症状轻或无特异性。,.,根据肝组织病理及临床表现分为两型,代偿性肝硬化无明显肝功能衰竭表现无腹水、肝性脑病或上消化道出血失代偿性肝硬化有明显肝功能异常及失代偿征象，如血清白蛋白35g/L，A/G1.0，胆红素35mol/L，凝血酶原活动度60%。有腹水、肝性脑病及上消化道出血,.,小儿病毒性肝炎多为隐性感染感染HBV后易成为HBsAg携带者小儿慢性肝炎以乙型和丙型多见，病情大多较轻。 老年病毒性肝炎老年急性病毒性肝炎以戊型肝炎较多见。 黄疸发生率高，黄疸程度较深，持续时间较长。淤胆型较多见，合并症较多。重型肝炎比例高，病死率较高,。,.,妊娠合并肝炎病情较重，尤其以妊娠后期为严重。消化道症状较明显，产后大出血多见。较易发展为肝衰竭，病死率较高，对胎儿有影响（早产、死胎、畸形）。,.,. laboratory examination,1. Biochemistry testMarkers for liver injury: ALT, AST, very sensitive, but not parallel to the severity markers for liver function: albumin, bilirubin（胆红素）, prothrombin time（凝血酶原时间） markers for differentiation: DBIL/TBIL, AKP, GGT, urine bilirubin, urobilinogen （尿胆原）,.,2. Special examination,HAV: Anti-HAV-IgM, early, 6 months, sensitive and specific HBV: serologic markers, detection of HBV DNA HCV: anti-HCV, detection of HCV RNA HDV: HDAg, HDAb HEV: anti-HEV,.,.,血清酶测定 ALT：反映肝细胞功能的最常用指标。AST：存在于线粒体中，意义与ALT相同。ALP：肝外梗阻性黄疸、淤胆型肝炎患者及儿童可明显升高。-GT：肝炎活动期时可升高，肝癌患者或胆管阻塞、药物性肝炎等患者中可显著升高。CHE：提示肝脏储备能力，肝功能有明显损害时可下降。,.,胆红素测定黄疸型肝炎患者血清胆红素升高重型肝炎患者血清总胆红素常超过171mol/L血清胆红素升高常与肝细胞坏死程度相关血清蛋白测定慢性肝炎中度以上、肝硬化、重型肝炎时血清白蛋白浓度下降血清球蛋白浓度上升白蛋白/球蛋白（A/G）比例下降甚至倒置,., . diagnosis and differential diagnosis,Diagnostic evidences:epidemiological data clinical features: anorexia, nausea, hepatomegaly laboratory finding: elevated ALT, eteologic findings,.,Basic requirements for writing format of diagnosis,Intact diagnosis of viral hepatitis includes clinical diagnosis and etiological diagnosis. Writing format example: 1. viral hepatitis acute icteric hepatitis anti-HAV-IgM(+),.,2. Viral hepatitis chronic moderate hepatitis HBsAg(+) 3. Viral hepatitis acute anicteric hepatitis unknown eteology,.,Differential diagnosis,Hemolytic（溶血性） jaundice Obstructive（梗阻性） jaundice Toxin-induced and drug-induced jaundice Other infectious hepatitis: EBV, CMV, typhoid fever, sepsis （败血症）, leptospirosis Hereditory jaundice（遗传性黄疸）: Gilbert syndrome, dubin-johnsin symdrome,.,. treatment,Fundamental principle:good rest sufficient nutrition properly using drugs for protecting liver avoiding drugs which injury liver,.,1.treatment for acute hepatitis,Bed rest Supportive treatment: give adequate nutrition, maintain the fluid, electrolyte and acid-base balance of the body, if necessary, give by intravenously. Liver-protective treatment,.,急性甲型、乙型和戊型肝炎：对症及支持治疗。孕妇和老年人患急性戊型肝炎，较易发展为重型肝炎，应按较重肝炎处理。急性丙型肝炎：尽早抗病毒治疗，早期应用干扰素可减少慢性化，加用利巴韦林口服，8001000mg/d，可增强疗效。,.,2. Treatment of Chronic hepatitis,Antiviral treatment (1) interferon alpha: two main actions inhibition of viral protein synthesis immunoregulatory effects（免疫调节因子） 3-5 million U, 3 times/week for 4-6 months,.,Side effects of interferon alphaFever, chill, myalgia, fatigue, arthralgia （关节痛） deterioration of liver function alopecia （脱发）impaired concentration, depression（抑郁）, suicide behavior should monitor closely the WBC, PLT,.,(2) Lamivudine:Nucleoside analogs, inhibit HBV DNA polymerase HBV DNA decreasing rapidly very safe rebound when treatment stopped long time treatment,.,一般治疗：合理休息、饮食、心理平衡对症治疗 非特异性护肝药：维生素、还原型谷胱甘肽、肝泰乐等降酶药：甘草甜素、联苯双酯、垂盆草、齐墩果酸等 退黄药：茵栀黄、苦黄、腺苷蛋氨酸、门冬氨酸钾镁等 抗病毒治疗 ：干扰素 、核苷类似物等免疫调节治疗：胸腺肽等抗肝纤维化治疗,.,治疗药物选择,A拉米夫定(lamivudine)：剂量为每日100mg。耐受性良好。随用药时间的延长患者发生病毒耐药变异的比例增高。阿德福韦酯 (adefovir dipivoxil)：剂量为每日10mg。在较大剂量时有一定肾毒性。应定期监测血清肌酐和血磷。其耐药发生率较低 。 恩替卡韦 (entecavir)：每日口服0.5 mg；对发生YMDD变异者剂量每日1mg 。对初治患者治疗1年时耐药发生率为0。 替比夫定(telbivudine) ：剂量为600 mg，每天一次口服，不受进食影响。具有良好的安全性和耐受性。美国FDA药物妊娠安全性分类的B级药物。,.,3. Treatment for gravis hepatitis,(1) Vigorous supportive treatment.Treatment is centered on intensive support of the failing organ to provide the optimal enviroment for liver regeneration. Bed rest, use of fresh-frozen plasma, maintaining of fluid and electrolye balance, acid base balance,.,(2) symptomatic treatment:Encephalopathy: a low protein diet, use of oral neomycin（新霉素） or lactulose（乳果糖）, administration of branched chain amino acid, early detection and treatment of cerebral edema. Bleeding: correction of prothrombin time with fresh frozen plasma, supplemant of vit K, use of H2 receptor blockage,.,Renal failure: including function renal failure and acute tubular necrosis. Use of albumin or plasma, low-dose dopamine （多巴胺）infusio