Clinical manifestations and natural history of hepatitis B virus infection

Anna SF Lok, MD

UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on March 29, 2006. The next version of UpToDate (14.3) will be released in October 2006. INTRODUCTION — The spectrum of clinical manifestations of hepatitis B virus (HBV) infection varies in both acute and chronic disease. During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis; during the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations also can occur with both acute and chronic infection. The clinical manifestations and natural history of HBV infection will be reviewed here. Issues related to epidemiology, transmission, and treatment are discussed separately. (See appropriate topic reviews.) Terms used to define different clinical states are summarized in Table 1 ( show table 1 ). These terms will be used throughout the discussion. This topic is also discussed in an official guideline issued by the American Association for the Study of Liver Diseases. ( See "AASLD guideline: Chronic hepatitis B" ). ACUTE HEPATITIS — Approximately 70 percent of patients with acute hepatitis B have subclinical or anicteric hepatitis, while 30 percent develop icteric hepatitis. The disease may be more severe in patients coinfected with other hepatitis viruses or with underlying liver disease [ 1 ] . Fulminant hepatic failure is unusual, occurring in approximately 0.1 to 0.5 percent of patients. Fulminant hepatitis B is believed to be due to massive immune-mediated lysis of infected hepatocytes. This explains why many patients with fulminant hepatitis B have no evidence of HBV replication at presentation [ 2 ] . The reasons that HBV has a fulminant course in some patients are not well-understood. A case-control trial evaluated risk factors for a fulminant course in an outbreak among injection drug users [ 3 ] . Compared with control patients, case patients were more likely to have used acetaminophen during their illness (p=.08) and had lost significantly more weight in the six months before illness, used more alcohol, and methamphetamine . Furthermore, all nine isolates were genotype D. Whether viral or environmental factors led to the fulminant course in this outbreak is unclear [ 4 ] . ( See "Clinical significance of hepatitis B virus genotypes" ). The method of acquiring HBV infection varies geographically. Perinatal transmission is most common in high prevalence areas such as southeast Asia and China, while sexual contact and percutaneous transmission (eg, intravenous drug use) are most common in the United States, Canada, and western Europe ( show table 1 ). ( See "Epidemiology, transmission and prevention of hepatitis B virus infection" ). The incubation period lasts one to four months. A serum sickness-like syndrome may develop during the prodromal period, followed by constitutional symptoms, anorexia, nausea, jaundice and right upper quadrant discomfort. The symptoms and jaundice generally disappear after one to three months, but some patients have prolonged fatigue even after normalization of serum aminotransferase concentrations. Laboratory testing during the acute phase reveals elevations in the concentration of alanine and aspartate aminotransferase levels (ALT and AST); values up to 1000 to 2000 IU/L are typically seen during the acute phase with ALT being higher than AST. The serum bilirubin concentration may be normal in patients with anicteric hepatitis. The prothrombin time is the best indicator of prognosis. In patients who recover, normalization of serum aminotransferases usually occurs within one to four months. Persistent elevation of serum ALT for more than six months indicates progression to chronic hepatitis. Outcome — Among patients who recover from acute hepatitis B, it has been thought that the virus is completely cleared by antiviral antibodies and specific cytotoxic T lymphocytes. However, traces of HBV are often detectable in the blood by PCR for many years after clinical recovery from acute hepatitis, despite the presence of serum antibodies and HBV-specific cytotoxic T cells, which can be present at high levels [ 5,6 ] . HBV-specific cytotoxic T cells may express activation markers, indicating recent contact with antigen, in patients studied up to 23 years after clinical and serologic recovery. One study found that HBV DNA was detected in the liver tissues in 13 of 14 healthy liver transplant donors who were positive for anti-HBc and anti-hepatitis B surface antibodies (anti-HBs) [ 7 ] . Persistent histologic abnormalities (including fibrosis and mild inflammation) were present as long as 10 years in another series focusing on nine patients who demonstrated complete serologic recovery after acute infection [ 8 ] . These observations suggest that complete eradication of HBV rarely occurs after recovery from acute HBV infection and that latent infection can maintain the T cell response for decades following clinical recovery, thereby keeping the virus under control [ 5 ] . Immunosuppression in such patients, as occurs after organ transplantation, can lead to reactivation of the virus [ 9 ] . Although some studies suggest that liver damage may be present in patients with latent infection, it is not clear how common this is since these studies were based on very few patients. The rate of progression from acute to chronic hepatitis B is primarily determined by the age at infection. The rate is approximately 90 percent for perinatally acquired infection [ 10 ] , 20 to 50 percent for infections between the age of one and five years [ 11,12 ] , and less than 5 percent for adult-acquired infection [ 13 ] . The factors responsible for the high rate of progression in neonates and children are discussed below ( see "Phases of chronic HBV infection" below ). CHRONIC HEPATITIS — A history of acute hepatitis is elicited in only a small percentage of patients with chronic HBV infection. In low or intermediate prevalence areas, approximately 30 to 50 percent of patients with chronic HBV infection have a past history of acute hepatitis; such a history is lacking in the remaining patients in these areas and in the majority of patients in high prevalence areas (predominantly perinatal infection). Many patients with chronic hepatitis B are asymptomatic (unless they progress to decompensated cirrhosis or have extrahepatic manifestations), while others have nonspecific symptoms such as fatigue. Some patients experience exacerbations of the infection which may be asymptomatic, mimic acute hepatitis, or manifest as hepatic failure. Physical examination may be normal or there may be stigmata of chronic liver disease. Jaundice, splenomegaly, ascites, peripheral edema, and encephalopathy may be present in patients with decompensated cirrhosis. Laboratory tests may be normal, but most patients have mild to moderate elevation in serum AST and ALT. During exacerbations, the serum ALT concentration may be as high as 50 times the upper limit of normal and alfa-fetoprotein (AFP) concentrations as high as 1000 ng/mL may be seen [ 14 ] . Progression to cirrhosis is suspected when there is evidence of hypersplenism (decreased white blood cell and platelet counts) or impaired hepatic synthetic function (hypoalbuminemia, prolonged prothrombin time, hyperbilirubinemia). Extrahepatic manifestations — Extrahepatic manifestations, which are thought to be mediated by circulating immune complexes, occur in 10 to 20 percent of patients with chronic HBV infection. As mentioned above, acute hepatitis may be heralded by a serum sickness-like syndrome manifested as fever, skin rashes, arthralgia and arthritis, which usually subside with the onset of jaundice. The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease.

• A variable proportion of patients with polyarteritis nodosa are HBsAg positive. The clinical manifestations are similar to those in patients with polyarteritis who are HBV-negative [ 15 ] . Patients with HBV-related polyarteritis may benefit from antiviral therapy. ( See "Clinical manifestations and diagnosis of polyarteritis nodosa" ).

• HBV can induce both membranous nephropathy and, less often, membranoproliferative glomerulonephritis. Most cases of HBV-related glomerulonephropathy occur in children [ 16-18 ] . The typical presentation is with nephrotic range proteinuria. Approximately 30 to 60 percent of children with HBV-related membranous nephropathy undergo spontaneous remission, usually in association with HBeAg to anti-HBe seroconversion. Progression to renal failure can occur, particularly in adults. The efficacy of antiviral therapy is uncertain. ( See "Renal disease associated with hepatitis B virus infection" ).

PHASES OF CHRONIC HBV INFECTION — The natural course of chronic hepatitis B virus (HBV) infection is determined by the interplay between virus replication and the host immune response. Other factors that may play a role in the progression of HBV-related liver disease include gender, alcohol consumption, and concomitant infection with other hepatitis virus(es). The outcome of chronic HBV infection depends upon the severity of liver disease at the time HBV replication is arrested. Chronic HBV infection generally consists of two phases: an early replicative phase with active liver disease; and a late or nonreplicative phase with remission of liver disease ( show figure 1 ) [ 19,20 ] . In patients with perinatally acquired HBV infection, there is an additional immune tolerance phase in which virus replication is not accompanied by active liver disease ( show figure 2 ) [ 21 ] . Replicative phase: Immune tolerance — In patients with perinatally acquired HBV infection, the initial phase is characterized by high levels of HBV replication — the presence of HBeAg (hepatitis B e antigen) and high levels of HBV DNA in serum — but no evidence of active liver disease as manifested by lack of symptoms, normal serum ALT concentrations and minimal changes on liver biopsy ( show figure 2 ) [ 22,23 ] . The lack of liver disease despite high levels of HBV replication is believed to be due to immune tolerance to HBV [ 24 ] . The exact mechanisms by which this occurs are unknown. Experiments in mice suggest that transplacental transfer of maternal HBeAg may induce specific unresponsiveness of T cells to HBeAg and to HBcAg, resulting in ineffective cytotoxic T cell lysis of infected hepatocytes [ 25 ] . Immune tolerance is believed to be the major reason for the poor response to interferon therapy in HBeAg-positive Asian patients who have normal serum ALT concentrations. The immune tolerance phase usually lasts 10 to 30 years, during which there is a very low rate of spontaneous HBeAg clearance [ 26,27 ] . Studies in Chinese children, for example, have found HBeAg in as many as 90 percent below the age of 5, and up to 80 percent below the age of 20 [ 23,26 ] . The cumulative rate of spontaneous HBeAg clearance is estimated to be approximately 2 percent during the first three years and only 15 percent after 20 years of infection [ 27,28 ] . The low rate of viral clearance in adolescence and early adulthood accounts for the high frequency of maternal-infant transmission in Asian countries. Replicative phase: Immune clearance — Transition from the immune tolerant to the immune clearance phase occurs during the second and third decades in patients with perinatally acquired HBV infection. During the immune clearance phase, spontaneous HBeAg clearance increases to an annual rate of 10 to 20 percent [ 26,27 ] . A seroconversion rate of 70 percent during 10 years of follow-up was described in a population-based study of 1536 Alaskan natives who acquired HBV as adults [ 29 ] . HBeAg seroconversion is frequently, but not always, accompanied by biochemical exacerbations (abrupt increases in serum ALT) ( show figure 2 ) [ 14,30,31 ] . Exacerbations are believed to be due to a sudden increase in immune-mediated lysis of infected hepatocytes. They are often preceded by an increase in serum HBV DNA [ 32 ] and a shift of HBcAg (hepatitis B core antigen) from nuclear to cytoplasmic sites within hepatocytes [ 33 ] , suggesting that immune clearance may be triggered by an increase in viral load or change in the presentation of viral antigens. How these changes occur is not known. Most exacerbations are asymptomatic and are discovered during routine follow-up. However, some are accompanied by symptoms of acute hepatitis and may lead to the incorrect diagnosis of acute hepatitis B in patients who are not previously known to have chronic HBV infection [ 34 ] . Exacerbations may be associated with an elevation in the IgM anti-HBc titer, which may lead to misdiagnosis of acute HBV infection, and an increase in the serum alpha-fetoprotein concentration, which may raise concerns about the diagnosis of HCC [ 14,35 ] . Exacerbations are more commonly observed in men than women [ 14 ] . The reason for the gender difference is not clear, but a higher frequency of exacerbations in men may at least in part account for a higher incidence of HBV-related cirrhosis and HCC among men. In a small percentage of patients, exacerbations result in hepatic decompensation and rarely death from hepatic failure [ 36 ] . Patients with severe exacerbations should be referred to specialized centers for liver transplantation or treatment with new antiviral agents such as lamivudine , adefovir , or entecavir . Interferon is not indicated in this setting since it can cause further exacerbation of the disease. ( See "Lamivudine monotherapy for chronic hepatitis B virus infection" and see "Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection" and see "Entecavir in the treatment of chronic hepatitis B virus infection" ). Not all exacerbations lead to HBeAg seroconversion and clearance of HBV DNA from the serum, a phenomenon termed abortive immune clearance [ 14,31 ] . These patients may develop recurrent exacerbations with intermittent disappearance of serum HBV DNA with or without transient loss of HBeAg ( show figure 2 ). Such repeated episodes of hepatitis may increase the risk of developing cirrhosis and hepatocellular carcinoma (HCC). As noted above, the initial phase in patients with childhood or adult-acquired chronic HBV infection consists of virus replication (presence of HBeAg and HBV DNA in serum) and active liver disease (elevated serum ALT and chronic hepatitis on liver biopsy) ( show figure 1 ). The prevalence of HBeAg among non-Asian adults with chronic HBV infection is usually in the range of 10 to 20 percent, lower than the 30 to 50 percent seen among Chinese adults with chronic HBV infection. The rate of spontaneous HBeAg clearance appears to be similar — 10 percent to 20 percent per year [ 19,20,27,37 ] . Exacerbations accompanying HBeAg seroconversion are less well described.
Low or nonreplication phase — Patients in the low or nonreplicating phase are HBeAg negative and anti-HBe positive. In some patients, virus replication has ceased although they remain HBsAg (hepatitis B surface antigen) positive. These patients have undetectable HBV DNA in serum, even when tested by polymerase chain reaction assays, and the liver disease is in remission as evidenced by normal serum ALT concentrations and resolution of necroinflammation in liver biopsies. Some patients with chronic HBV infection become HBsAg negative. The annual rate of delayed clearance of HBsAg has been estimated to be 0.5 to 2 percent in Western patients and much lower (0.1 to 0.8 percent) in Asian countries [ 37,38 ] . In most reports, noncirrhotic patients who cleared HBsAg appeared to have a good prognosis [ 39,40 ] . One of the largest series to address this issue focused on 218 such patients who were followed for a median of 62 months [ 40 ] . Of 189 patients who were not cirrhotic at the time of HBsAg clearance, three developed cirrhosis, two developed hepatocellular carcinoma, and one died of hepatocellular carcinoma. However, these complications developed only in patients who had concurrent HCV or HDV infection. Despite a generally favorable prognosis, clearance of HBsAg does not preclude development of cirrhosis or hepatocellular carcinoma [ 41,42 ] . In a series of 55 patients who spontaneously cleared HBsAg, complications developed in 33 percent (11 hepatocellular carcinoma, 6 cirrhosis, 1 subfulminant liver failure) during a mean follow-up of 23 months [ 42 ] . The ability of hepatitis B virus to cause complications despite clearance of HBsAg probably results from its integration into the genome, reflected by the persistence of HBV DNA when measured using sensitive polymerase chain reaction assays (see below). Although some patients who clear HBsAg remain at risk, this study probably overestimated the frequency with which this occurs. The study included 20 patients (36 percent) who had coinfection with either hepatitis C or hepatitis D, and it is unclear whether these patients were the ones who developed complications. Furthermore, some of the patients may have had undocumented cirrhosis or irreversible liver damage prior to seroconversion. Many patients (28 percent in one series) in the low replication phase have undetectable HBV DNA in serum when tested by hybridization assays but remain HBV DNA positive when tested by PCR assays [ 39 ] . ( See "Serologic diagnosis of hepatitis B virus infection" ). These patients may have low level HBV replication, but liver disease is usually inactive. A small proportion of patients with this profile (inactive carriers) may be infected with a mixture of the wild-type virus and HBV variants with a deletion in the pre-S1 region, which are associated with a reduction in HBsAg synthesis [ 43 ] . Reactivation of HBV replication with reappearance of HBeAg and HBV DNA (by hybridization assays) in serum and recrudescence of liver disease may occur when these patients are immunosuppressed [ 44 ] . The reactivation can vary in severity from mild and asymptomatic to severe with possible fulminant hepatic failure [ 45 ] . A small percentage of patients continue to have moderate levels of HBV replication (detection of HBV DNA in serum by hybridization assays) and active liver disease (elevated serum ALT and chronic inflammation on liver biopsies) [ 46,47 ] . These patients with HBeAg-negative chronic hepatitis may have residual wild type virus or HBV variants that cannot produce HBeAg due to precore or core promoter variants [ 48-51 ] .
SEQUELAE AND PROGNOSIS OF CHRONIC HBV INFECTION — The sequelae of chronic HBV infection vary from an inactive carrier state to the development of cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), extrahepatic manifestations, and death. The prognosis appears to vary with the clinical setting. Long-term follow-up studies of HBsAg positive blood donors have shown that the majority remain asymptomatic with a very low risk of cirrhosis or HCC [ 52-54 ] . In a 16-year follow-up study of 317 HBsAg positive blood donors from Montreal, for example, only three died from HBV-related cirrhosis and none developed HCC [ 52 ] . Another report included 296 potential blood donors who were excluded from donation after they were found to be HBsAg positive and were followed for 30 years [ 54 ] . The incidence of clinically significant liver disease, HCC, or other liver-related morbidity or mortality was not significantly greater than a control population of HBV negative blood donors. ( See "Epidemiology and etiologic associations of primary hepatocellular carcinoma" ). The prognosis is not so good in HBV-infected patients from endemic areas and in patients with chronic hepatitis B [ 55-58 ] . The estimated five-year rates of progression are:

• Chronic hepatitis to cirrhosis — 12 to 20 percent
• Compensated cirrhosis to hepatic decompensation — 20 to 23 percent ( show figure 3 )
• Compensated cirrhosis to HCC — 6 to 15 percent ( show figure 4 ) ( see "Surveillance for hepatocellular carcinoma" below )

The cumulative survival rate at each of these stages of progressive disease is [ 56,58-60 ] :

• Compensated cirrhosis — 85 percent at five years ( show figure 5 )
• Decompensated cirrhosis — 55 to 70 percent at one year and 14 to 35 percent at five years ( show figure 6 )

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