Hepatitis B
Hepatitis B
Gontar Alamsyah Siregar Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Sumatera Utara / RSUP H. Adam Malik Medan
Introduction Hepatitis B infection is caused by the hepatitis B virus (HBV), an enveloped DNA virus that infects the liver and causes hepatocellular necrosis and inflammation. HBV infection can be either acute or chronic, and may range from asymptomatic infection or mild disease to severe or rarely fulminant hepatitis. Acute hepatitis B is usually a self-limiting disease marked by acute inflammation and hepatocellular necrosis, with a case fatality rate of 0.5–1%. Chronic hepatitis B (CHB) infection encompasses a spectrum of disease, and is defined as persistent HBV infection (the presence of detectable hepatitis B surface antigen (HBsAg) in the blood or serum for longer than six months), with or without associated active viral replication and evidence of hepatocellular injury and inflammation. An estimated 2 billion people have been infected, and more than 350 million are chronic carriers of the virus. In the 2010 Global Burden of Disease study, HBV infection ranked in the top health priorities in the world, and was the tenth leading cause of death (786 000 deaths per year). These data have led WHO to include viral hepatitis in its major public health priorities. 1, 2
Epidemiology Roughly 30% of the world’s population shows serological evidence of current or past HBV infection. 3, 4 Age-specific HBsAg seroprevalence varies markedly by geographical region, with the highest prevalence (>5%) in sub-Saharan Africa, East Asia, some parts of the Balkan regions, the Pacific Islands and the Amazon Basin of South America. Prevalence below 2% is seen in regions such as Central Latin America, North America and Western Europe. The prevalence of HBeAg-negative disease has been increasing over the past decade as a result of ageing of the HBV-infected population, and accounts for the majority of cases in some regions, including Europe. 1 About half the total liver cancer mortality in 2010 was attributed to HBV infection, and from 1990 to 2010, the worldwide mortality associated with liver cancer increased by 62% and that associated with cirrhosis increased by 29%. 3
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Figure 1. Geographical distribution of major hepatitis B virus and worldwide frequency of CHB
2
Life Cycle and Natural History of HBV
HBV is a small, partially double-stranded DNA virus that belongs to the family Hepadnaviridae. The virion is comprised of a core particle containing the viral genome, nucleocapsid protein and polymerase, as well as a lipoprotein envelope composed of viral antigens. Broadly, HBV is classified into four serotypes (adr, adw, ayr and ayw) based on antigenic determinants of the hepatitis B surface antigen (HBsAg), and eight genotypes (A to H) based on its nucleotide sequence. The genotypes have distinct geographic distributions, and an increasing body of evidence suggests it may also influence disease severity and response to treatment. 5, 6
The replication cycle of HBV begins with viral entry into hepatocytes, mediated by the binding of the pre-S1 region on the virion envelope to the cellular sodium taurocholate cotransporting polypeptide. The virion is then uncoated, and transported into the nucleus. From a drug discovery point of view, two key events occur. One is the formation of covalently closed circular DNA (cccDNA) through covalent ligation. This DNA inter mediate is responsible for viral persistence, and is highly resistant to antiviral therapy. The second key event is viral genome replication by reverse transcription via pre-genomic RNA. The reverse transcriptase is inherently error prone, and is ultimately responsible for the emergence of nucleos(t)ide-resistant HBV quasispecies. The mature nucleocapsids may subsequently be recycled into the nucleus to
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mediate viral persistence, or secreted through exocytosis as Dane particles to infect other hepatocytes. A greater understanding of the viral cycle of HBV will enable new therapeutic strategies. 5
Figure 2. Hepatitis B viral replication cycle 5 The occurrence of symptoms during acute HBV infection and the outcome depend on age at infection. Infants and children are mostly asymptomatic, whereas roughly 70% of adults have subclinical or anicteric hepatitis and 30% have icteric hepatitis. Less than 1% of acute HBV infection in adults progresses to fulminant hepatitis, which has a mortality of around 80% without liver transplantation. HBsAg appears in the serum 2–10 weeks after exposure to HBV, before onset of symptoms and increases in aminotransferases, and it usually disappears in 4–6 months. Anti-HBs can appear several weeks before or after HBsAg seroclearance in people who recover. Persistence of HBsAg beyond 6 months is used to define progression to chronic infection. When HBV infection is acquired during infancy or early childhood, the initial phase of chronic infection is characterised by positive HBeAg, very high HBV DNA (>10⁷ IU/mL) and normal alanine aminotransferase concentrations, and minimum inflammation and fibrosis on histology. HBsAg concentrations are also high (>10⁵ IU/mL). 48 This phase can last for 20–40 years with minimum disease progression, and the rate of spontaneous HBeAg seroconversion is very low. An absence of liver disease despite high viraemia is because of immune tolerance, which is probably a result of clonal
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deletion of T cells against HBV in the fetus induced by in-utero exposure to HBeAg. Loss of immune tolerance triggers the second phase or immune clearance phase (HBeAg-positive chronic HBV infection), which is characterised by a decrease in HBV DNA and an increase in alanine aminotransferase concentrations. HBsAg concentrations are also lower (10³–10⁴ IU/mL). 48 Roughly 10–20% of patients will lose HBeAg and develop anti-HBe—ie, HBeAg seroconversion—in a year. Persistent or recurrent increases in alanine aminotransferase with unsuccessful immune clearance increase the risk of liver cirrhosis and hepatocellular carcinoma. Patients infected with genotype C HBV undergo HBeAg seroconversion at an older age than do patients infected with other HBV genotypes, which might account for the higher incidence of hepatocellular carcinoma in genotype-C-infected patients. Successful HBeAg seroconversion with suppression of HBV DNA and normalisation of alanine aminotransferase concentration marks transition to the inactive phase, during which serum HBV DNA concentration tends to be low (generally
Gontar Alamsyah Siregar Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Sumatera Utara / RSUP H. Adam Malik Medan
Introduction Hepatitis B infection is caused by the hepatitis B virus (HBV), an enveloped DNA virus that infects the liver and causes hepatocellular necrosis and inflammation. HBV infection can be either acute or chronic, and may range from asymptomatic infection or mild disease to severe or rarely fulminant hepatitis. Acute hepatitis B is usually a self-limiting disease marked by acute inflammation and hepatocellular necrosis, with a case fatality rate of 0.5–1%. Chronic hepatitis B (CHB) infection encompasses a spectrum of disease, and is defined as persistent HBV infection (the presence of detectable hepatitis B surface antigen (HBsAg) in the blood or serum for longer than six months), with or without associated active viral replication and evidence of hepatocellular injury and inflammation. An estimated 2 billion people have been infected, and more than 350 million are chronic carriers of the virus. In the 2010 Global Burden of Disease study, HBV infection ranked in the top health priorities in the world, and was the tenth leading cause of death (786 000 deaths per year). These data have led WHO to include viral hepatitis in its major public health priorities. 1, 2
Epidemiology Roughly 30% of the world’s population shows serological evidence of current or past HBV infection. 3, 4 Age-specific HBsAg seroprevalence varies markedly by geographical region, with the highest prevalence (>5%) in sub-Saharan Africa, East Asia, some parts of the Balkan regions, the Pacific Islands and the Amazon Basin of South America. Prevalence below 2% is seen in regions such as Central Latin America, North America and Western Europe. The prevalence of HBeAg-negative disease has been increasing over the past decade as a result of ageing of the HBV-infected population, and accounts for the majority of cases in some regions, including Europe. 1 About half the total liver cancer mortality in 2010 was attributed to HBV infection, and from 1990 to 2010, the worldwide mortality associated with liver cancer increased by 62% and that associated with cirrhosis increased by 29%. 3
Universitas Sumatera Utara
Figure 1. Geographical distribution of major hepatitis B virus and worldwide frequency of CHB
2
Life Cycle and Natural History of HBV
HBV is a small, partially double-stranded DNA virus that belongs to the family Hepadnaviridae. The virion is comprised of a core particle containing the viral genome, nucleocapsid protein and polymerase, as well as a lipoprotein envelope composed of viral antigens. Broadly, HBV is classified into four serotypes (adr, adw, ayr and ayw) based on antigenic determinants of the hepatitis B surface antigen (HBsAg), and eight genotypes (A to H) based on its nucleotide sequence. The genotypes have distinct geographic distributions, and an increasing body of evidence suggests it may also influence disease severity and response to treatment. 5, 6
The replication cycle of HBV begins with viral entry into hepatocytes, mediated by the binding of the pre-S1 region on the virion envelope to the cellular sodium taurocholate cotransporting polypeptide. The virion is then uncoated, and transported into the nucleus. From a drug discovery point of view, two key events occur. One is the formation of covalently closed circular DNA (cccDNA) through covalent ligation. This DNA inter mediate is responsible for viral persistence, and is highly resistant to antiviral therapy. The second key event is viral genome replication by reverse transcription via pre-genomic RNA. The reverse transcriptase is inherently error prone, and is ultimately responsible for the emergence of nucleos(t)ide-resistant HBV quasispecies. The mature nucleocapsids may subsequently be recycled into the nucleus to
Universitas Sumatera Utara
mediate viral persistence, or secreted through exocytosis as Dane particles to infect other hepatocytes. A greater understanding of the viral cycle of HBV will enable new therapeutic strategies. 5
Figure 2. Hepatitis B viral replication cycle 5 The occurrence of symptoms during acute HBV infection and the outcome depend on age at infection. Infants and children are mostly asymptomatic, whereas roughly 70% of adults have subclinical or anicteric hepatitis and 30% have icteric hepatitis. Less than 1% of acute HBV infection in adults progresses to fulminant hepatitis, which has a mortality of around 80% without liver transplantation. HBsAg appears in the serum 2–10 weeks after exposure to HBV, before onset of symptoms and increases in aminotransferases, and it usually disappears in 4–6 months. Anti-HBs can appear several weeks before or after HBsAg seroclearance in people who recover. Persistence of HBsAg beyond 6 months is used to define progression to chronic infection. When HBV infection is acquired during infancy or early childhood, the initial phase of chronic infection is characterised by positive HBeAg, very high HBV DNA (>10⁷ IU/mL) and normal alanine aminotransferase concentrations, and minimum inflammation and fibrosis on histology. HBsAg concentrations are also high (>10⁵ IU/mL). 48 This phase can last for 20–40 years with minimum disease progression, and the rate of spontaneous HBeAg seroconversion is very low. An absence of liver disease despite high viraemia is because of immune tolerance, which is probably a result of clonal
Universitas Sumatera Utara
deletion of T cells against HBV in the fetus induced by in-utero exposure to HBeAg. Loss of immune tolerance triggers the second phase or immune clearance phase (HBeAg-positive chronic HBV infection), which is characterised by a decrease in HBV DNA and an increase in alanine aminotransferase concentrations. HBsAg concentrations are also lower (10³–10⁴ IU/mL). 48 Roughly 10–20% of patients will lose HBeAg and develop anti-HBe—ie, HBeAg seroconversion—in a year. Persistent or recurrent increases in alanine aminotransferase with unsuccessful immune clearance increase the risk of liver cirrhosis and hepatocellular carcinoma. Patients infected with genotype C HBV undergo HBeAg seroconversion at an older age than do patients infected with other HBV genotypes, which might account for the higher incidence of hepatocellular carcinoma in genotype-C-infected patients. Successful HBeAg seroconversion with suppression of HBV DNA and normalisation of alanine aminotransferase concentration marks transition to the inactive phase, during which serum HBV DNA concentration tends to be low (generally