Clinical Manifestations and Natural History of Hepatitis B Virus Infection

Anna SF Lok, MD, Professor of Medicine, University of Michigan Medical School.

[UpToDate © 2000]

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.)

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] Mutant strains have been associated with fulminant disease, but it is not clear if they occur with a frequency greater than that seen in nonfulminant disease.^[3]

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 (table 1).

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.^{[4, 5]} 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).^[6]

These observations suggest that true cure of HBV frequently fails to occur after recovery from acute hepatitis and that latent infection can maintain the T cell response for decades following clinical recovery, thereby keeping the virus under control.^[4] Immunosuppression in such patients, as occurs after organ transplantation, can lead to reactivation of the virus.^[7]

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,^[8] 20 to 50 percent for infections between the age of one and five years,^{[9, 10]} and less than 5 percent for adult-acquired infection.^[11] The factors responsible for the high rate of progression in neonates and children are discussed 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.^[12] 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.^[13] Patients with HBV-related polyarteritis may benefit from antiviral therapy.

   

• HBV can induce both membranous nephropathy and, less often, membranoproliferative glomerulonephritis. Most cases of HBV-related glomerulonephropathy occur in children.^{[14, 15, 16]} 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.

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 nonreplicative phase with remission of liver disease (figure 1).^{[17, 18]} 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 (figure 2).^[19]

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 (figure 2).^{[20, 21]}

The lack of liver disease despite high levels of HBV replication is believed to be due to immune tolerance to HBV.^[22] 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.^[23] 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.^{[24, 25]} 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.^{[21, 24]} 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.^{[25, 26]} 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.^{[24, 25]} HBeAg seroconversion is frequently, but not always, accompanied by biochemical exacerbations (abrupt increases in serum ALT) (figure 2).^{[12, 27, 28]}

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^[29] and a shift of HBcAg (hepatitis B core antigen) from nuclear to cytoplasmic sites within hepatocytes,^[30] 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.^[31] 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.^{[32, 33]}

Exacerbations are more commonly observed in men than women.^[12] 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.^[34] Patients with severe exacerbations should be referred to specialized centers for liver transplantation or treatment with new antiviral agents such as lamivudine. Interferon is not indicated in this setting since it can cause further exacerbation of the disease.

Not all exacerbations lead to HBeAg seroconversion and clearance of HBV DNA from the serum, a phenomenon termed abortive immune clearance.^{[12, 28]} These patients may develop recurrent exacerbations with intermittent disappearance of serum HBV DNA with or without transient loss of HBeAg (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) (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.^{[17, 18, 25, 35]} Exacerbations accompanying HBeAg seroconversion are less well described.

Nonreplication Phase

Patients in the non- or low-replicating 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.^{[35, 36]} Patients who clear HBsAg appear to have a better outcome. In one series, for example, 83 percent who cleared HBsAg showed an improvement in liver function after HBsAg clearance and all were alive at follow-up (mean nine years).^[37] In comparison, among those with persistence of HBsAg, 27 percent had died and 29 percent showed a worsening in liver function. Patients who become HBsAg negative may be misdiagnosed as having cryptogenic cirrhosis or HCC if they were not previously known to have HBV-related liver disease.^[37]

However, clearance of HBsAg does not preclude development of cirrhosis or hepatocellular carcinoma. As an example, 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.^[38] 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.^[37] These patients may have low level HBV replication but liver disease is usually inactive. A small proportion of patients with this profile may be infected with a mixture of the wild-type virus and mutant virus with a deletion in the pre-S1 region, which is associated with a reduction in HBsAg synthesis.^[39] 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.^[40] The reactivation can vary in severity from mild and asymptomatic to severe with possible fulminant hepatic failure.^[41]

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).^{[42, 43]} These patients may have residual wild type virus or mutant HBV that cannot produce HBeAg due to precore or core promoter mutants.^{[44, 45, 46, 47]}

Sequelae and Prognosis of Chronic HBV Infection

The sequelae of chronic HBV infection vary from an asymptomatic "healthy" carrier state to the development of cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), the extrahepatic manifestations described above, 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.^{[48, 49]} 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.^[48]

The prognosis is not so good in HBV-infected patients from endemic areas and in patients with chronic hepatitis B.^{[50, 51, 52, 53]} 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 (figure 3)

   

  figure3

   

  Figure 3.

   

• Compensated cirrhosis to HCC — 6 to 15 percent (figure 4); the possible value of screening for HCC in chronic HBV infection is discussed elsewhere

  figure4

   

  Figure 4.

   

The cumulative survival rate at each of these stages of progressive disease is:^{[51, 53, 54, 55]}

• Compensated cirrhosis — 85 percent at five years (figure 5)

   

  figure5

   

  Figure 5.

   

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

  figure6

   

  Figure 6.

   

Among Chinese patients with chronic HBV infection, the life-time risk of a liver-related death has been estimated at 40 to 50 percent for men and 15 percent for women.^[56]

Factors Influencing Survival

A number of studies have evaluated factors influencing survival in patients with chronic HBV infection.^{[54, 55, 57]} Patients with a prolonged replication phase have a worse prognosis. This was illustrated in a study of 98 patients with HBsAg positive compensated cirrhosis.^[54] The five-year survival rate was significantly lower in patients who were HBeAg positive (72 versus 97 percent in those who were HBeAg negative). Clearance of HBeAg was associated with a 2.2-fold decrease in death rate.

Similar findings were noted in another series of 366 European patients with HBsAg positive compensated cirrhosis: the five-year survival rates were 77 and 88 percent in patients who were HBeAg positive and negative, respectively.^[55] Other independent factors associated with poor survival were older age, hypoalbuminemia, thrombocytopenia, splenomegaly, and hyperbilirubinemia. Biochemical remission and clearance of HBeAg or HBV DNA from the serum were significantly associated with a higher rate of survival.

The worse prognosis in patients with a prolonged replicative phase may be related to a longer duration of necroinflammation.^{[12, 58]} Recurrent episodes of hepatitis may, either directly or indirectly through immune-mediated injury, increase the risk of fibrosis, cirrhosis, and perhaps carcinogenesis. Even among patients with decompensated cirrhosis, suppression of HBV replication and delayed HBsAg clearance can result in improvement in liver disease.^{[37, 59]}

HBV and Chronic Alcohol Abuse

The prevalence of serum HBV markers among alcoholics has been estimated to be two to fourfold higher than a corresponding control population, suggesting an increased rate of HBV infection.^{[60, 61]} There is no clear evidence that alcoholics have an enhanced risk of chronic HBV infection. However, HBV DNA has been detected in the sera and liver tissues in some HBsAg negative alcoholics who present with liver disease, implying that occult HBV infection may have contributed to the liver disease in these patients.^{[62, 63]}

Alcoholics with HBV infection have also been reported to have accelerated liver injury, an elevated risk of developing cirrhosis and HCC, and reduced survival compared to alcoholics who are not HBV-infected.^{[64, 65, 66]} In a case-control study, for example, the relative risk of HBsAg positivity in patients with hepatocellular carcinoma was 11.4 compared to controls, while the relative risk of concurrent HBsAg and alcohol intake was 64.7.^[66]

Coinfection with HCV or HDV

Hepatitis B infected patients may also be infected with hepatitis C virus (HCV) or hepatitis D virus (HDV).

Hepatitis C Virus Infection

Acute coinfection with HBV and HCV may shorten the duration of HBs antigenemia and lower the peak serum aminotransferase concentration compared with acute HBV infection alone.^[67] These findings suggest that HCV coinfection may interfere with the replication of HBV, leading to attenuation of liver damage. However, acute coinfection of HCV and HBV has also been reported to increase the risk of fulminant hepatic failure.^[68]

Coexistent HCV infection has been estimated to be present in 10 to 15 percent of patients with HBV-associated chronic hepatitis, cirrhosis, or HCC.^[69] HCV superinfection in HBsAg carriers appears to reduce HBV DNA levels in serum and liver tissues and to increase the rate of HBsAg seroconversion.^{[70, 71, 72]} Most patients who have dual HCV and HBV infections have detectable serum HCV RNA but not HBV DNA, indicating that HCV is the predominant cause of liver disease in these patients. Nevertheless, the liver disease is usually more severe than in patients infected by HBV alone.^[73] Patients with dual HBV and HCV infection may also have a higher rate of HCC compared to patients infected by either virus alone.^{[74, 75]}

Hepatitis D Virus Infection

Although HDV can replicate autonomously, the simultaneous presence of HBV is required for complete virion assembly and secretion. As a result, individuals with hepatitis D are always dually infected with HDV and HBV.

Acute HBV and HDV coinfection tends to be more severe than acute HBV infection alone and is more likely to result in fulminant hepatitis.^[76] HDV superinfection in patients with chronic HBV infection is usually accompanied by suppression of HBV replication due to interference mechanisms that are not well understood.^[77] HDV superinfection in such patients has been associated with more severe liver disease and accelerated progression to cirrhosis in most studies,^{[78, 79, 80]} although discordant data have been reported.^[81]

Hepatitis A Virus Vaccination

The Advisory Committee on Immunization Practices (ACIP) recommended the immunization of all patients with chronic liver disease against hepatitis A virus (HAV) in December 1996.^[82] This recommendation was based upon theoretical grounds (that patients with chronic liver disease might have a worse prognosis if they developed superimposed acute hepatitis) rather than firm data, particularly with respect to HBV. In one study in which 163 patients with chronic hepatitis B were prospectively followed for seven years, hepatitis A superinfection occurred in 10.^[83] An uncomplicated course occurred in nine of these patients; one patient who also had preexisting cirrhosis developed marked cholestasis. The outcome was much worse in patients with chronic HCV: fulminant hepatic failure developed in 7 of the 17 patients who acquired hepatitis A; six of these patients died.

Despite the sparse data, we follow the ACIP guidelines and recommend immunization with HAV vaccine in patients with chronic HBV. However, countries with a high prevalence of HBV also have a high prevalence of HAV. Thus, testing for HAV antibody should be performed, with the vaccine being given only to patients who are HAV antibody-negative.

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