(See also Causes of Hepatitis Causes of Hepatitis Hepatitis is inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more , Overview of Chronic Hepatitis Overview of Chronic Hepatitis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more , and Acute Hepatitis B Hepatitis B, Acute Hepatitis B is caused by a DNA virus that is often parenterally transmitted. It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and... read more .)
Hepatitis lasting > 6 months is generally defined as chronic hepatitis, although this duration is arbitrary.
Acute hepatitis B Hepatitis B, Acute Hepatitis B is caused by a DNA virus that is often parenterally transmitted. It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and... read more becomes chronic in about 5 to 10% of immunocompetent patients overall. However, the younger the age that acute hepatitis B occurs, the higher the risk of developing chronic hepatitis B:
For infants: 90%
For children aged 1 to 5 years: 25 to 50%
For adults: About 5%
Acute hepatitis B becomes chronic in about 40% of adults receiving hemodialysis and in up to 20% of people who are immunocompromised.
The Centers for Disease Control and Prevention (CDC) estimates that 862,000 people in the US (1 General references Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more ), and the World Health Organization (WHO) estimates that about 257 million people worldwide, have chronic hepatitis B (2 General references Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more ).
Without treatment, chronic hepatitis B can resolve (uncommon), progress rapidly, or progress slowly to cirrhosis over decades. Resolution often begins with a transient increase in disease severity and results in seroconversion from hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe), followed by loss of hepatitis B surface antigen (HBsAg).
Chronic HBV infection even in the absence of cirrhosis increases the risk of hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more .
Coinfection with hepatitis D virus Hepatitis D Hepatitis D is caused by a defective RNA virus (delta agent) that can replicate only in the presence of hepatitis B virus. It occurs uncommonly as a coinfection with acute hepatitis B or as... read more (HDV) causes the most severe form of chronic HBV infection; without treatment, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more develops in up to 70% of patients.
Symptoms and Signs of Chronic Hepatitis B
Symptoms of chronic hepatitis B vary depending on the degree of underlying liver damage.
Many patients, particularly children, are asymptomatic. However, malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nonspecific upper abdominal discomfort. Jaundice is usually absent.
Often, the first findings are
Signs of chronic liver disease or cirrhosis (eg, splenomegaly, spider nevi, palmar erythema)
Complications of cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more (eg, portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in developed countries), schistosomiasis (in endemic areas), or hepatic vascular abnormalities... read more , ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more )
Extrahepatic manifestations may include polyarteritis nodosa Polyarteritis Nodosa (PAN) Polyarteritis nodosa is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries and occasionally affects small muscular arteries, resulting in secondary tissue... read more and glomerular disease Overview of Glomerular Disorders The hallmark of glomerular disorders is proteinuria, which is often in the nephrotic range (≥ 3 g/day). Glomerular disorders are classified based on urine changes as those that manifest predominantly... read more .
Diagnosis of Chronic Hepatitis B
The diagnosis Diagnosis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more of chronic hepatitis B is suspected in patients with any of the following:
Suggestive symptoms and signs
Incidentally noted elevations in aminotransferase levels
Previously diagnosed acute hepatitis
Diagnosis is confirmed by finding positive hepatitis B surface antigen (HBsAg) and IgG antibody to hepatitis B core (IgG anti-HBc) and negative IgM anti-HBc (see table Hepatitis B Serology Hepatitis B Serology* ) and by measuring hepatitis B virus DNA (quantitative HBV-DNA).
If chronic hepatitis B is confirmed, testing for hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) is usually done to help determine the prognosis and to guide antiviral therapy. If serologically confirmed HBV infection is severe or if patients belong to a known at-risk population (eg, those with HIV infection, injection drug users, men who have sex with men, or immigrants from areas of high endemicity, and possibly those who are HBsAg-positive with low HBV DNA but high ALT levels), antibody to hepatitis D virus (anti-HDV) is measured.
Quantitative HBV-DNA tests (viral load) are also used before and during treatment to assess response.
Noninvasive assessment of fibrosis is done to evaluate degree of fibrosis after chronic hepatitis B is diagnosed.
Biopsy is occasionally done to evaluate the extent of liver damage and to exclude other causes of liver disease. Liver biopsy is most useful in cases that do not meet clear-cut guidelines for treatment (see also the American Association for the Study of Liver Disease's practice guideline Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance).
Liver tests are needed if not previously done; they include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase.
Other tests should be done to evaluate liver function and disease severity; they include serum albumin, bilirubin, platelet count, and prothrombin time/international normalized ratio (PT/INR).
Patients should also be tested for HIV Diagnosis Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more and hepatitis C infection Diagnosis Hepatitis C is caused by an RNA virus that is often parenterally transmitted. It sometimes causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice but may be asymptomatic... read more because transmission of these infections is similar.
If symptoms or signs of cryoglobulinemia develop during chronic hepatitis, cryoglobulin levels and rheumatoid factor should be measured; high levels of rheumatoid factor and low levels of complement suggest cryoglobulinemia.
Screening for complications
Patients with chronic HBV infection should be screened every 6 months for hepatocellular carcinoma with ultrasonography and serum alpha-fetoprotein measurement, although the cost-effectiveness of this practice, particularly alpha-fetoprotein measurement, is debated. (See also the Cochrane review abstract on Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B.)
Treatment of Chronic Hepatitis B
Sometimes liver transplantation
(See also the American Association for the Study of Liver Disease (AASLD) guidelines Hepatitis B Guidance 2018 Update.)
Antiviral treatment is indicated for patients with chronic hepatitis B and one or more of the following:
Elevated aminotransferase levels
Elevated HBV viral load
Clinical or biopsy evidence of progressive disease
The goal is to eliminate HBV-DNA (1 Treatment reference Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more ). Treatment can occasionally cause loss of hepatitis B e antigen (HBeAg), or, even more rarely, loss of hepatitis B surface antigen (HBsAg). However, the majority of patients treated for chronic hepatitis B must be treated indefinitely. These drugs cannot cure the disease.
Stopping treatment prematurely can lead to relapse, which may be severe. However, treatment may be stopped if one of the following occurs:
HBeAg converts to antibody to HBeAg (anti-HBe).
Tests for HBsAg become negative.
Multiple antiviral drugs are active against hepatitis B, but only four are currently recommended: entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, and pegylated interferon-alfa (peginterferon alfa): Adefovir, interferon alfa, lamivudine, and telbivudine have been used but are no longer recommended as first-line treatment because of increased risk of adverse effects and development of drug resistance.
First-line treatment is usually with one of the following:
An oral antiviral drug, such as entecavir (a nucleoside analog) or tenofovir (a nucleotide analog)
Pegylated interferon alfa
Oral antiviral drugs have few adverse effects and can be given to patients with decompensated liver disease. Lactic acidosis is a potential side effect, and lactic acid levels should be checked if there is clinical concern. Combination therapy has not proved superior to monotherapy. Patients should be tested for HIV before treatment is initiated.
If HBsAg becomes undetectable and HBeAg seroconversion occurs in patients with HBeAg-positive chronic HBV infection, these patients may be able to stop antiviral drugs. Patients with HBeAg-negative chronic HBV infection almost always need to take antiviral drugs indefinitely to maintain viral suppression; they have already developed antibodies to HBeAg, and thus the only specific criterion for stopping HBV treatment would be HBsAg that becomes undetectable.
Entecavir has a high antiviral potency, and resistance to it is uncommon; it is considered a first-line treatment for HBV infection. Entecavir is effective against adefovir-resistant strains. Dosage is 0.5 mg orally once a day; however, patients who have previously taken a nucleoside analog should take 1 mg orally once a day. Dose reduction is required in patients with renal insufficiency. Serious adverse effects appear to be uncommon, although safety in pregnancy has not been established.
Tenofovir has replaced adefovir (an older nucleotide analog) as a first-line treatment. Tenofovir is the most potent oral antiviral for hepatitis B; resistance to it is minimal. It has few adverse effects. There are two forms of tenofovir:
Tenofovir disoproxil fumarate (TDF)
Tenofovir alafenamide (TAF), which is newer
Dosage for TDF is 300 mg orally once a day; dosing frequency may need to be reduced if creatinine clearance is reduced. Potential side effects include nephropathy, Fanconi syndrome, and osteomalacia. If patients are at risk of renal impairment, creatinine clearance, serum phosphate, and urine glucose and protein should be checked at least annually. Bone density studies at baseline and during treatment should be considered if patients have a history of fracture or risk factors for osteopenia.
Dosage for TAF is 25 mg orally once a day; no dose adjustments are necessary if creatinine clearance is reduced. TDF and TAF are similar in efficacy, but TAF is safer in patients when renal toxicity or bone density is a concern. Serum creatinine and phosphorus, creatinine clearance, and urine glucose and protein should be checked before initiating and during therapy.
Pegylated interferon alfa can be used instead of interferon alfa. Dosage for pegylated interferon alfa is usually 180 mcg by injection once a week for 48 weeks. Adverse effects are similar to those of interferon alfa but may be less severe. More than 40% of patients treated with pegylated interferon alfa report fatigue, fever, myalgia, and headache. Other potential side effects include mood disturbances, cytopenia, and autoimmune disorders.
Contraindications to pegylated interferon alfa include the following:
Decompensated liver disease
Solid organ transplantation
The following tests should be used to monitor patients treated with pegylated interferon alfa:
Complete blood count (monthly to every 3 months)
Thyroid-stimulating hormone (every 3 months)
Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications
Lactic acid levels if there is clinical concern
Test for HIV before initiating treatment
Nonpreferred antiviral therapies (adefovir, lamivudine, telbivudine, interferon alfa) may be considered if the above drugs are unavailable.
Adefovir is a nucleotide analog. Dosage is 10 mg orally once a day. It is not a preferred first-line treatment because renal failure and lactic acidosis are risks.
Lamivudine (a nucleoside analog) is no longer considered first-line treatment for HBV infection because risk of resistance is higher and efficacy is lower than those of newer antiviral drugs. Dosage is 100 mg orally once a day; it has few adverse effects.
Telbivudine is a nucleoside analog that has greater efficacy and potency than lamivudine but also has a high rate of resistance; it is not considered first-line treatment. Dosage is 600 mg orally once a day.
Interferon alfa can be used but is no longer considered first-line treatment and has generally been replaced by pegylated interferon alfa.
Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more should be considered for end-stage liver disease caused by HBV. In patients with HBV infection, the long-term use of first-line oral antivirals and peri-transplantation use of hepatitis B immune globulin (HBIG) has improved outcomes after liver transplantation. Survival is equal to or better than that after transplantation for other indications, and recurrences of hepatitis B are minimized.
1. American Association for the Study of Liver Diseases (AASLD) Hepatitis B Guidance 2018 Update: Update on prevention, diagnosis, and treatment of chronic hepatitis B Guidance. Hepatology 67(4), 2018. doi: 10.1002/hep.31060
Acute hepatitis B becomes chronic in about 5 to 10% of patients overall; risk is highest at a young age (90% for infants, 25 to 50% for children aged 1 to 5 years, and about 5% for adults).
The WHO estimates that about 257 million people worldwide have chronic hepatitis B infection.
Symptoms vary depending on the degree of underlying liver damage.
Antiviral drugs can improve liver test results and liver histology and delay progression to cirrhosis but may need to be taken indefinitely; drug resistance has become less of a concern with newer drugs.
Liver transplantation may be required in patients with decompensated cirrhosis due to hepatitis B.
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B: This study evaluates the beneficial and harmful effects of using alpha-fetoprotein, ultrasonography, or both to screen for hepatocellular carcinoma in patients with chronic hepatitis B. Accessed July 6, 2022.
American Association for the Study of Liver Disease Practice Guidelines (AASLD): A multidisciplinary panel of experts developed guidelines for diagnosing and managing various hepatic disorders using clinically relevant questions, which are answered by systematic reviews of the literature and followed by data-supported recommendations. The panel rates the quality (level) of the evidence and strength of each recommendation. Accessed July 6, 2022.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
tenofovir disoproxil fumarate
|No US brand name|