Đang tải... (xem toàn văn)
(BQ) Part 1 book Comprehensive textbook of hepatitis B has contents: Epidemiology of hepatitis B virus, transmission and prevention of hepatitis B, host immunity and clinical outcome in HBV-Infection,.... and other contents.
Comprehensive Textbook of Hepatitis B Comprehensive Textbook of Hepatitis B Editors Mamun-Al-Mahtab (Shwapnil) Assistant Professor Department of Hepatology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh Editor-in-Chief Jaypee’s World Clinics in Gastroenterology and Hepatology Editor LIVER: A Complete Book on Hepato-Pancreato-Biliary Diseases Deputy Editor-in-Chief International Journal of Hepatology SM Fazle Akbar Principal Investigator Department of Medical Sciences Toshiba General Hospital Tokyo, Japan Advisor Editor Jaypee’s World Clinics in Gastroenterology and Hepatology Editor Dentritic Cells in Clinics Salimur Rahman Professor Department of Hepatology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh Advisor Editor Jaypee’s World Clinics in Gastroenterology and Hepatology Editor-in-Chief International Journal of Hepatology ® JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD Kolkata • St Louis (USA) • Panama City (Panama) • London (UK) • New Delhi Ahmedabad • Bengaluru • Chennai • Hyderabad • Kochi • Lucknow • Mumbai • Nagpur Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd Corporate Office 4838/24 Ansari Road, Daryaganj, New Delhi - 110002, India Phone: +91-11-43574357, Fax: +91-11-43574314 Registered Office B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi - 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672 Rel: +91-11-32558559, Fax: +91-11-23276490, +91-11-23245683 e-mail: jaypee@jaypeebrothers.com, Website: www.jaypeebrothers.com Offices in India • Ahmedabad, Phone: Rel: +91-79-32988717, e-mail: ahmedabad@jaypeebrothers.com • Bengaluru, Phone: Rel: +91-80-32714073, e-mail: bangalore@jaypeebrothers.com • Chennai, Phone: Rel: +91-44-32972089, e-mail: chennai@jaypeebrothers.com • Hyderabad, Phone: Rel:+91-40-32940929, e-mail: hyderabad@jaypeebrothers.com • Kochi, Phone: +91-484-2395740, e-mail: kochi@jaypeebrothers.com • Kolkata, Phone: +91-33-22276415, e-mail: kolkata@jaypeebrothers.com • Lucknow, Phone: +91-522-3040554, e-mail: lucknow@jaypeebrothers.com • Mumbai, Phone: Rel: +91-22-32926896, e-mail: mumbai@jaypeebrothers.com • Nagpur, Phone: Rel: +91-712-3245220, e-mail: nagpur@jaypeebrothers.com Overseas Offices • • • North America Office, USA, Ph: 001-636-6279734 e-mail: jaypee@jaypeebrothers.com, anjulav@jaypeebrothers.com Central America Office, Panama City, Panama Ph: 001-507-317-0160, e-mail: cservice@jphmedical.com Website: www.jphmedical.com Europe Office, UK, Ph: +44 (0) 2031708910, e-mail: info@jpmedpub.com Comprehensive Textbook of Hepatitis B © 2011, Jaypee Brothers Medical Publishers All rights reserved No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editors and the publisher This book has been published in good faith that the material provided by contributors is original Every effort is made to ensure accuracy of material, but the publisher, printer and editors will not be held responsible for any inadvertent error(s) In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only First Edition : 2011 ISBN 978-93-5025-081-5 Typeset at JPBMP typesetting unit Printed at Ajanta Offset The publication of this work was possible with encouragement and support of our nearest and dearest parents, Mahtab Uddin Ahmed, Ayesha Mahtab, SK Muizuddin Ahmed, Syeda Ashrafun Nesa, Syeda Rowshanara Khatun; wives, Dr Nuzhat Choudhury Mahtab, Shamsunnehar Akbar, Sayeda Rahman; children, Musarrat Mahtab (Shukonnya), Mashrur Mahtab (Shurjo), Tasmin Akbar, Dr Shahrin Afroz (Rimi), Tahmidur Rahman and Obaidur Rahman; friends, Md Helal Uddin and others and also people with different opinions and beliefs The publication of this book was possible only due to immense help and cooperation from thousands of patients with HBV and other liver diseases; their entity and sufferings led us to adapt a path that should be followed, not one that is accepted by most in this field Contributors Ali Shorbagi Gastroenterology Clinic Department of Internal Medicine Hacettepe University Faculty of Medicine Ankara Turkey Amit Basnotra Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, India Anil Arora Hepatology Services Sir Ganga Ram Hospital New Delhi, India Ashish Kumar Institute of Liver and Biliary Sciences (ILBS), New Delhi, India Basher Atiquzzaman Department of Medicine St Cloud Regional Hospital Florida, USA Deirdre A Kelly Department of Paediatric Hepatology University of Birmingham Birmingham, UK Desmond Wai Asian Center for Liver Diseases and Transplantation, Gleneagles Hospital Singapore Fu-Sheng Wang Research Centre for Biological Therapy, Beijing 302 Hospital Beijing, China Gholam Ali Ghorbani Baqiyatallah University of Medical Sciences, Tehran, Iran Gokhan Kabacam Department of Gastroenterology Ankara University School of Medicine Ankara, Turkey Hamama-tul-Bushra Khaar Gastroenterology and Hepatology Division, Department of Medicine Holy Family Hospital Rawalpindi, Pakistan Hasan Ozkan Professor of Gastroenterology Ankara University School of Medicine, Ankara, Turkey Hyo-Suk Lee Liver Research Institute Seoul National University College of Medicine, Korea Jane R Campos Asian Hospital and Medical Centre Manila, The Philippines Jenny Heathcote Professor of Medicine Hepatology, Toronto Western Hospital, Toronto, Canada Jian Sun Hepatology Unit Department of Infectious Diseases Institute of Gastroenterology Nanfang Hospital Southern Medical University, China viii Comprehensive Textbook of Hepatitis B Jinlin Hou Hepatology Unit, Department of Infectious Diseases Institute of Gastroenterology Nanfang Hospital Southern Medical University, China Jose D Sollano Professor of Medicine University of Santo Tomas Hospital Manila, Philippines Kai-Chah Tan Asian Center for Liver Diseases and Transplantation, Gleneagles Hospital Singapore Kaushal Madan Department of Hepatology Institute of Liver and Biliary Sciences (ILBS), New Delhi, India Khalid Mumtaz Assistant Professor of Medicine Aga Khan University Hospital Karachi, Pakistan Koji Yano Chief, Gastroenterology and Hepatology National Nagasaki Medical Center Associate Professor Department of Hepatology Nagasaki University, Nagasaki, Japan Leung WD Department of Medicine University of Toronto Ontaria, Canada Mamun-Al-Mahtab Department of Hepatology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh Morikazu Onji Head, Department of Gastroenterology and Metabology Ehime University Graduate School of Medicine, Ehime, Japan Muhammad Umar Gastroenterology and Hepatology Division, Department of Medicine Holy Family Hospital Rawalpindi, Pakistan Nancy Leung The Chinese University of Hong Kong Hong Kong SAR, China Naresh Bansal Hepatology Services Sir Ganga Ram Hospital New Delhi, India Neeraj Saraf Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, India Pankaj Tyagi Department of Gastroenterology Ram Manohar Lohia Hospital New Delhi, India Peter Karayiannis Department of Medicine Imperial College London, UK Piyawat Komolmit Department of Medicine Chulalongkorn University Bangkok, Thailand Puja Sakhuja Department of Pathology GB Pant Hospital, New Delhi, India Contributors R Murali Department of Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Saeed S Hamid Professor of Medicine Faculty of Health Sciences The Aga Khan University Karachi, Pakistan Seyed-Moayed Alavian Baqiyatallah University of Medical Sciences, Tehran, Iran Shiv Kumar Sarin GB Pant Hospital Department of Molecular Medicine Jawaharlal Nehru University Institute of Liver and Biliary Sciences (ILBS), New Delhi, India SM Fazle Akbar Principal Investigator Department of Medical Sciences Toshiba General Hospital Tokyo, Japan ix Ulus Salih Akarca Professor of Medicine Ege University Medical Faculty Department of Gastroenterology Bornova, Izmir Turkey Vivek A Saraswat Professor of Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, India Yusuf Bayraktar Gastroenterology Clinic Department of Internal Medicine Hacettepe University Faculty of Medicine Ankara Turkey Zheng Zhang Research Centre for Biological Therapy, Beijing 302 Hospital Beijing, China 142 Comprehensive Textbook of Hepatitis B 15 Hepatitis B in Children Deirdre A Kelly INTRODUCTION Infection with viral hepatitis B leads to significant disease in children on a worldwide basis Acute infection is rare in childhood but chronic asymptomatic infection carries a risk of chronic liver disease and hepatocellular carcinoma Children with persistent viral hepatitis B should be seen annually in order to detect natural seroconversion, development of chronic liver disease or hepatocellular carcinoma and to consider antiviral therapy Children and families are encouraged to lead normal lives and should not be stigmatised by their disease PREVALENCE Hepatitis B infection is a major public health problem in children It is common in endemic areas of the world such as Africa and China, where 15 to 20% of the population are HBsAg carriers Perinatal transmission varies in different populations from 40% of infants in Taiwan, to only to 5% in sub-Saharan Africa The difference is in part explained by the higher prevalence of hepatitis B e-antigen (HBeAg) in Chinese (40%) than African (15%) mothers In Africa, the majority of infections are acquired between months and years of age, with other family members implicated as a source of infection In areas of intermediate endemicity such as Italy, Japan, Spain, Greece, Portugal, to 10% of the population are HBsAg carriers In Italy, the HBsAg carrier rate in pregnant women was 5% and the prevalence of hepatitis B markers in children was 1.7% before effective vaccination programs In areas of low endemicity (Northwest Europe, North America, United Kingdom, Australia), infection in infancy and childhood is uncommon and less than 1% of the population has chronic HBV-infection TRANSMISSION Infection in children is mainly by perinatal transmission although horizontal transmission still occurs Hepatitis B in Children 143 Perinatal Transmission Maternal-infant transmission remains an important infective mechanism as HBsAg can be detected in up to 5% of samples of cord blood taken at delivery from HBsAgpositive mothers, which is an indication of infection in utero The risk of perinatal transmission of hepatitis B is associated with the infectivity of the mother as demonstrated by circulating HBeAg and by direct measurement of HBV DNA Interventions such as amniocentesis and cesarean section not affect the transmission rate, although lower ‘microtransfusions of HBsAg’ occur during elective cesarean section Studies on placental tissue have demonstrated evidence of cell to cell transfer of hepatitis B antigen by immunohistochemistry staining and HBV DNA in situ hybridization showing a gradient of infection from the maternal to the fetal side There is also a direct association between transplacental HBV-infection and maternal HBeAg positivity (OR = 17.07, 95% CI 3.39–86.01): threatened preterm labor (OR = 5.44, 95% CI 1.15–25.67), higher levels of maternal HBsAg and HBV DNA, and active infection of the placenta particularly in layers close to the fetal side One important mode of infection is inoculation or ingestion by the newborn of infected maternal blood and vaginal secretions around the time of delivery The risk of infection is 15 to 40% if the mother is HBsAg- positive, but increases to 70 to 90% if the mother is HBeAg-positive Persistent infection in neonates of HBV HBeAg-positive mothers may be associated with the transfer of maternal HBeAg, a soluble antigen, across the placenta The HBeAg antigen shares epitopes with the virus core antigen and induces specific unresponsiveness of helper T cells to HBcAg in the neonates Cord blood mononuclear cells from neonates born to HBeAg-positive mothers not proliferate in response to HBcAg, suggesting that transplacental exposure to HBeAg induces nonresponsiveness in the developing fetal immune system HBeAg contains several sequence similarities with HBcAg, the principal target of cytotoxic T cells involved in hepatocellular damage leading to HBV clearance In the presence of maternal anti-HBe, the risk of viral transmission to the infant is only 10 to 20% Infants of HBe antigen negative mothers are at risk of developing fulminant liver failure either because they have partial immunity (from maternal ‘e’ antibody) or more commonly because they have a mutant virus 70% of mothers with acute hepatitis B during pregnancy may transmit the virus if infection occurs during the third trimester of pregnancy and 90% will so if it occurs within days of delivery There is no increased risk of abortion or malformation Breastfeeding does not affect the outcome in babies of HBV carrier mothers, especially in the post vaccination era Horizontal Transmission Horizontal transmission occurs through blood-borne contact or contaminated body fluids, such as blood transfusion or percutaneous exposure (e.g use of unsterilized instruments, tattooing, acupuncture, ear piercing) Inapparent 144 Comprehensive Textbook of Hepatitis B infection may also occur through intimate contact with body secretions and skin lesions and sharing of household utensils among family members as HBV is present in high concentrations in blood, serum and other serous exudates including saliva in infected individuals Up to 40% of children who are born to carrier mothers, but not infected at birth, acquire infection in the first years of life HBV is also found in low concentrations in feces and breast milk, but they are not associated with significant transmission Parenteral and sexual exposures are also effective routes of transmission Children at high risk include those requiring frequent transfusions (e.g with hemolytic anemia, thalassemia, hemophilia), those with high-risk sexual behavior, and intravenous drug users Environmental transmission in childhood may occur by exposure to infected body fluids through a broken skin surface, either directly by biting or by accidental contamination An increased risk of environmental transmission also occurs in residential institutions and hemodialysis centers A small proportion of those receiving an appropriate vaccination course (approximately 5%) will fail to achieve adequate protection and thus remain at risk Children who have received hospital care in countries with inadequate HBV prevention strategies are at risk of HBV acquisition In the UK, perinatal infection is still the most common route of infection in children either because of failed vaccination or in immigrants from endemic countries PREVENTION OF INFECTION Perinatal Infection The options for prevention of perinatal transmission of hepatitis B are as follows: a Passive: Hepatitis B immunoglobulin (HBIG) was shown to protect babies of HBeAg-positive mothers, but although some babies developed active immunity, postnatal infection lead to a persistent infection once passive protection waned b Active: Hepatitis B vaccine is effective in the prevention of perinatal transmission of hepatitis B in 95% babies of HBeAg-positive mothers The results are most striking in Taiwan The prevalence of HBsAg in children less than years old has decreased from 9.3% (31/332) in 1984 to 2% (9/457) in 1989 with an associated reduction in the incidence of hepatocellular carcinoma in children as a result of a mass hepatitis B immunization program Other studies have also shown that hepatitis B vaccine alone given for three or four doses during the first year of life is effective in preventing perinatal transmission In Gambia, where the majority of infections occurs after months of life, the prevalence of HBV-infection in 1- to 14-year-old children after mass immunization with vaccine alone has decreased from 60% (474 of 791) in 1984 to 9% (57 of 629) in 1993 Integrating the HBV vaccination into the routine childhood immunization program (i.e DPT), as occurs in Europe, may be the most cost effective means of preventing infection and has important Hepatitis B in Children 145 economic implications for countries unable to afford hepatitis B immunoglobulin c Combination of active and passive Many studies have shown that the administration of hepatitis B immunoglobulin and hepatitis B vaccine within 48 hours of birth, followed by further doses of vaccine in a variety of possible schedules (e.g 0,1,6; 0,1,2, and or 12 months) prevent perinatal transmission of HBV in up to 95% of infants of HBsAg carrier mothers Delaying the first dose of the vaccine beyond days increases the risk of infection and is a common cause of failed vaccination In areas of low endemicity, the current recommended policy is the screening of all pregnant women for HBsAg Newborns of HBsAg-positive mothers, whether or not HBeAg-positive, should be given specific immunoglobulin and HBV vaccine d Antiviral treatment during pregnancy Antiviral treatment during pregnancy effectively prevents mother to baby transmission of HIV and has prompted the investigation of the use of lamivudine in pregnancy in women with persistent hepatitis B A single case report in which complete viral suppression on lamivudine therapy failed to protect the baby from infection despite active and passive immunisation is not encouraging In contrast, lamivudine treatment during the last month of pregnancy in mothers with very high viremia (>109 genome equivalents /ml) reported that only one baby was not protected (12.5%), compared to a failure rate of 28% (7 out of 25) in historical controls Further evaluation of lamivudine in pregnancy requires larger controlled trials Antiviral treatment in pregnancy would reduce or eliminate the use of HBIG in newborns, thus limiting exposure of blood products to children and concentrate immune prophylaxisis on vaccine alone Universal Immunization Universal vaccination is the only effective measure to eradicate infection within populations In 1992 an assembly of the World Health Organization recommended that all countries should integrate hepatitis B vaccination into their national immunization programs by 1997 Economic and epidemiological evaluation suggested this to be cost effective even in countries of low HBV endemicity (i.e 90%) of children with acute hepatitis B infection recover completely within to 12 months Anti-HBs seroconversion occurrs after months in 77% and in 96% after 12 months Mild or asymptomatic acute infection is more likely to progress to chronicity Acute infection is rarely a severe illness, although in up to 1% of infected cases fulminant hepatic failure may occur It is uncommon to document HBVinfection in children with acute liver failure from Western Europe and the US, as demonstrated in the NIH Acute Liver Failure study, but it does occur in endemic areas or post bone marrow transplantation It is also described with coinfection or superinfection with the delta agent or in neonates born to mothers who are antiHBe-positive and carry viral mutations in the precore region of the HBV DNA The prognosis of HBV-related fulminant hepatic failure is generally worse than with other etiologies, with spontaneous recovery occurring in fewer than 20% of cases Patients with severe symptoms during acute infection are least likely to develop persistent infection, and those requiring liver transplantation for fulminant infection are less likely to have recurrence in the transplanted liver Diagnosis Acute hepatitis B is diagnosed serologically by the presence of HBsAg in serum along with IgM antibody to HBcAg Other markers which can be assayed to indicate progression of the acute infection are the transition from HBeAg to Anti-HBe and changes in the titre of HBsAg and HBV DNA Most acute HBV will resolve with clearance of HBsAg and development of anti-HBs and natural immunity Raised aminotransferase enzymes are detected in serum, and the typical serological markers of acute infection are present Liver biopsy is rarely required for diagnosis and may be contraindicated in children with abnormal coagulation CHRONIC HEPATITIS B Natural History Chronic hepatitis B (HBV) is defined as failure to clear HBsAg after months and is more likely if infection occurs early in life More than 80% of infants infected during the first year of life become chronic carriers as compared with a rate of 6% to 10% if infection occurs after the sixth year of life In perinatally infected children, HBeAg clearance is approximately 30% by the age of 10 years, but only few clear HBsAg The natural seroconversion rate is lower in boys than in girls In a prospective study of 420 HBsAg pediatric carriers in Taiwan, spontaneous loss of HBsAg occurred in only 10 patients (0.6% per year) Annual HBsAg clearance rate was significantly higher in those who were anti-HBe-positive than those with 148 Comprehensive Textbook of Hepatitis B HBeAg (1.7% vs 0.4%) Carrier children whose mothers were HBsAg-negative had a higher incidence of HBsAg clearance (5.6% vs 0.8%) Stage of HBV Chronic HBV-infection is characterized by three stages:- immune tolerance, immune clearance and residual inactive infection Immune Tolerance Initially in chronic infection, infected hepatocytes express viral proteins (HBcAg, HBeAg, HBsAg) and there is much viral replication of virus, with high levels of HBV DNA in the circulating blood The host T cell response is actively suppressed There is no immune-mediated destruction of infected hepatocytes and no elevation of hepatic transaminases or significant hepatic inflammation The child is usually asymptomatic This state may last for several decades, particularly after perinatal infection, before the immune response becomes activated and immune clearance begins Immune Clearance (HBeAg-positive chronic hepatitis) during this stage, there is a T cell mediated inflammatory response against infected hepatocytes, leading to cell necrosis and hepatic fibrosis This is accompanied by elevation in transaminases enzymes Continued viral replication and immune destruction lead to progressive liver damage and cirrhosis, the risk of liver failure and hepatocellular carcinoma Although the development of liver damage is slow, it has been reported in childhood Levels of circulating DNA fall with immune clearance of infected cells, eventually becoming undetectable (105); histological stage: hepatitis, not cirrhosis; likelihood of response (increased transaminases >2 × normal); tolerance of treatment associated side effects; previous treatment e.g resistance to previous therapy; coexisting disease, e.g HIV positivity Disease activity before and during treatment is assessed by markers of viral activity such as HBV DNA levels, seroconversion from HB eAg and markers of immune mediated inflammation, ALT and AST and histology In general response to treatment is higher in those children with active liver disease/immune response (ALT/AST > × Normal) Non responders tend to have low/normal ALT/AST; persistent viremia on treatment and insufficient reduction of HBV DNA which leads to increased viral resistance 152 Comprehensive Textbook of Hepatitis B Indications for Treatment Consensus guidelines for the treatment of chronic hepatitis B in children have not been established, although EMEA (European Medicines Agency) is currently developing them Indications for antiviral therapy in adults are not applicable for children It would be advisable to treat as early as possible to prevent viral replication and prevent liver damage However lack of effective therapy means that treatment is limited and should be confined to randomised clinical trials The indications for treatment are: Persistent infection HBe antigen positive > months, evidence of hepatic inflammation either by elevated aminotransferase enzymes or by liver biopsy Current treatment options include interferon, Lamivudine and Adefovir Dipivoxil, although a number of other drugs are undergoing evaluation Factors that are associated with a positive response to interferon or nucleoside analogues include high pretreatment levels of aminotransferase (>2 × ULN), low pretreatment HBV deoxyribonucleic acid (DNA) levels (