Viral hepatitis refers to an infectious liver disease caused by hepatotropic viruses, characterized pathologically by hepatocyte necrosis, degeneration, and inflammatory responses. The clinical manifestations vary widely, ranging from asymptomatic and subclinical forms (silent infections) to self-limited acute anicteric and icteric hepatitis, chronic hepatitis, and, in rare cases, severe hepatitis or liver failure. Other non-hepatotropic viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), can also cause liver function impairment following infection, but they are not included in this section.
Etiology and Pathogenesis
The causes of viral hepatitis include at least five types of viruses:
Hepatitis A Virus (HAV)
HAV is an RNA virus transmitted via the fecal-oral route, typically through contaminated food or water. The incubation period is 2–6 weeks, and it is most common in children and young adults. The disease course lasts 1–2 months and is typically acute and self-limiting.
Hepatitis B Virus (HBV)
HBV is a small DNA virus primarily transmitted through blood (e.g., unsafe injections), maternal-fetal transmission, and sexual contact. The incubation period ranges from 1–6 months. It can affect all population groups, with over 200 million people worldwide chronically infected with HBV. The current HBV carrier rate is approximately 6%, making it the most prevalent hepatitis virus. Based on genetic differences, HBV is classified into nine genotypes (A–I), with genotypes C and B being the most common.
Hepatitis C Virus (HCV)
HCV is an RNA virus primarily transmitted through blood, with sexual contact and maternal-fetal transmission posing a significant risk. The incubation period is 1–6 months. HCV is highly prone to mutation and has the highest chronicity rate among hepatitis viruses. The HCV infection rate is approximately 0.6%. Based on nucleotide sequence homology, HCV is classified into six genotypes (1–6), each further divided into subtypes (e.g., 1a, 1b, 2a, 2b, 3a, 3b). Genotype distribution shows clear regional variation.
Hepatitis D Virus (HDV)
HDV is a small, defective RNA virus that cannot independently cause infection. It requires the presence of HBV-DNA for replication and proliferation, meaning HDV infection occurs only in conjunction with or following HBV infection. HDV is primarily bloodborne, with an incubation period of 1–6 months, and can affect all population groups.
Hepatitis E Virus (HEV)
HEV is an RNA virus primarily transmitted via the fecal-oral route, often through contaminated food or water. The incubation period is 2–8 weeks. It is universally susceptible across populations, with the disease course typically being acute and self-limiting. However, chronic infection can occur in individuals with compromised immune function.
Hepatotropic viruses cause hepatocyte damage through mechanisms involving both immune responses of the host and viral factors. After invading the liver, hepatitis viruses activate the host immune response. Cytotoxic T lymphocytes (CTLs) directly target hepatocytes and secrete various cytokines, such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), leading to hepatocyte death. Additionally, local infiltration of inflammatory cells (e.g., neutrophils and macrophages) in liver tissue can cause further tissue damage. Liver injury caused by HAV and HBV is primarily immune-mediated. In other hepatotropic viruses, both immune responses and direct viral effects contribute to hepatocyte damage.
The chronicity of HBV and HCV infections is mainly attributed to weakened host immune responses, the development of immune tolerance, and viral molecular mutations or the secretion of related molecules that enable the virus to evade the host immune system.
Clinical Manifestations and Classification
Clinical Manifestations
Hepatitis A (HAV) and hepatitis E (HEV) typically have an acute onset. Early symptoms often include fever, chills, abdominal pain, and nausea, followed by pronounced anorexia, fatigue, dark urine resembling strong tea, and jaundice (yellowing of the skin and sclera). Symptoms usually begin to resolve 3–5 days after jaundice appears. Pregnant women and elderly individuals with HEV are more likely to progress to severe hepatitis or liver failure, characterized by extreme fatigue, loss of appetite, progressively worsening jaundice (with total bilirubin often exceeding 171 μmol/L), significantly prolonged prothrombin time, and complications such as hepatic encephalopathy, renal failure, and gastrointestinal bleeding.
HBV and HCV infections can lead to acute hepatitis, chronic hepatitis, or asymptomatic carrier states, with a small number developing severe hepatitis or liver failure. Acute-phase symptoms include fatigue, anorexia, dark urine, and pain in the liver region. Chronic hepatitis often presents with nonspecific symptoms such as fatigue, abdominal distension, dull pain in the right upper abdomen, and reduced concentration or work efficiency. Progressive chronic hepatitis may lead to liver cirrhosis, resulting in symptoms related to decreased liver reserve function and portal hypertension. Some HBV or HCV carriers show markers of viral infection but lack obvious clinical symptoms or abnormal biochemical indicators, referred to as asymptomatic carriers. HDV, which co-infects or superinfects HBV, can exacerbate or reactivate hepatitis in HBV patients.
Clinical Classification
Acute Phase:
- Acute icteric hepatitis
- Acute anicteric hepatitis
Severe Hepatitis:
- Acute liver failure: Liver failure occurring within 2 weeks of onset.
- Subacute liver failure: Liver failure developing 15 days to 26 weeks after onset.
- Acute-on-chronic liver failure (ACLF): Acute liver failure superimposed on chronic liver disease.
- Chronic liver failure: Gradual liver failure on the basis of cirrhosis.
Chronic Phase:
- Primarily observed in some HBV and HCV infections. HEV can also cause chronic infection in individuals with weakened immune systems (e.g., those on immunosuppressants). Clinical classifications include:
Chronic hepatitis
- Chronic hepatitis with cirrhosis
Laboratory and Auxiliary Examinations
Pathogen Serology
For HAV and HEV infections, a positive IgM antibody (anti-HAV IgM or anti-HEV IgM) indicates an active infection. If the initial test is negative, retesting after 1–2 weeks may be necessary. A positive IgG antibody indicates past infection or recovery from the current infection.
Serological markers of HBV infection include HBsAg, anti-HBs antibody, HBeAg, anti-HBe antibody, anti-HBc antibody, and anti-HBc IgM.
Positive HBsAg indicates HBV infection.
Anti-HBs antibody is a protective antibody, and its positivity indicates immunity to HBV, seen in individuals recovering from HBV or after vaccination.
Anti-HBc IgM is commonly seen in acute hepatitis B or acute exacerbations of chronic hepatitis B.
HBcAg is rarely detectable in serum, but anti-HBc antibody is usually positive in individuals who have been infected with HBV, regardless of whether the virus has been cleared.
For HCV, a positive anti-HCV antibody indicates HCV infection. HCV-RNA testing is required to confirm active infection. Higher anti-HCV antibody titers increase the likelihood of detecting HCV-RNA.
For HDV, HDAg or HDV-RNA, or anti-HD antibodies (including anti-HD IgM), can be detected in serum. HBV, HCV, and HDV infections can be confirmed by detecting viral replication levels (HBV-DNA, HCV-RNA, and HDV-RNA) in the blood.
Liver Function Biochemical Indicators
Common findings include significant elevations in ALT and AST, as well as increased total and conjugated bilirubin. In cases of cholestatic hepatitis, elevated total bile acids and alkaline phosphatase (ALP) may be observed.
Severe hepatitis or liver failure often presents with prolonged prothrombin time, reduced prothrombin activity, and decreased albumin levels.
Imaging Examinations
Ultrasound, CT, or MRI during the inflammatory phase may show homogeneous hepatomegaly and mild splenomegaly.
In the fibrosis or cirrhosis stage, the liver surface may appear inhomogeneous, wavy, or nodular, with moderate to severe splenomegaly and esophageal and/or gastric varices. Ascites may be present in decompensated cirrhosis.
Pathological Examination
The basic pathological changes of all types of viral hepatitis are similar and include:
- Hepatocyte degeneration and necrosis
- Inflammatory and exudative reactions
- Hepatocyte regeneration
- Varying degrees of liver fibrosis and even cirrhotic nodules in chronic cases
Mild infections may show ballooning degeneration of hepatocytes, focal necrosis, or confluent necrosis, with Kupffer cell proliferation and inflammatory cell infiltration in portal areas, sometimes accompanied by cholestasis. Severe cases may exhibit bridging necrosis between portal areas (zone 1), central veins (zone 3), or both (zone 2).
Chronic hepatitis may show piecemeal necrosis around hepatic lobules, lymphocyte and monocyte infiltration, ground-glass hepatocytes, and irregular swelling of bile duct epithelial cells. Chronic liver disease, such as chronic hepatitis B or C, commonly exhibits varying degrees of liver fibrosis and cirrhosis.
Diagnosis and Differential Diagnosis
The diagnosis of viral hepatitis requires a comprehensive analysis based on epidemiological history, symptoms, physical signs, liver biochemical tests, etiological and serological examinations, as well as the patient’s specific condition and dynamic changes. In certain cases, liver biopsy may be performed.
Acute viral hepatitis needs to be differentiated from drug-induced or toxic liver injury. This differentiation is primarily based on epidemiological history, history of medication or toxin exposure, and serological markers. Chronic hepatitis should be distinguished from autoimmune liver disease, Wilson’s disease, fatty liver disease, drug- or occupation-related toxic liver disease, and liver cancer.
Treatment
The treatment of viral hepatitis varies depending on the etiology, clinical manifestations, and disease stage. Management should be tailored to the specific type and phase of the disease.
General Treatment
In the early stage of acute hepatitis, hospitalization or home isolation with rest is recommended.
For chronic hepatitis, moderate rest is advised. As the condition improves, a balance between activity and rest is encouraged during recovery, but overexertion should still be avoided.
Patients with acute hepatitis who experience loss of appetite should consume a light diet that is easy to digest and rich in vitamins.
In cases of significant appetite loss accompanied by nausea and emesis, short-term intravenous infusion of 10–20% glucose solution, vitamins, and electrolytes may be required.
Alcohol consumption is strictly prohibited for all hepatitis patients.
Hepatoprotective Therapy
Patients with abnormal liver function may benefit from medications such as reduced glutathione, glycyrrhizic acid preparations, bicyclol, and vitamin E to reduce inflammation and oxidative damage. For patients with intrahepatic cholestasis, ursodeoxycholic acid or ademetionine may be used.
Antiviral Therapy
Hepatitis A (HAV) and Hepatitis E (HEV)
Antiviral therapy is not required.
Hepatitis D Virus (HDV)
In cases of acute hepatitis caused by HDV and HBV co-infection, antiviral therapy is generally unnecessary. However, in chronic hepatitis caused by HDV superinfection on HBV, interferon (IFN-α) may be considered.
Hepatitis B Virus (HBV)
Acute Hepatitis B
Antiviral treatment is generally not required for acute HBV infection. However, antiviral therapy may be initiated in the following cases to reduce the risk of chronic progression:
- HBV-DNA > 2,000 U/mL (equivalent to 104 copies/mL).
- Infection duration > 4 weeks with persistent positive HBV-DNA and HBsAg.
- For patients with genotype C or D (if genotyping is available).
Chronic Hepatitis B
Antiviral therapy is often required for chronic HBV infection. The indications include:
- HBeAg-positive patients: HBV-DNA ≥ 20,000 U/mL (equivalent to 105 copies/mL).
- HBeAg-negative patients: HBV-DNA ≥ 2,000 U/mL (equivalent to 104 copies/mL).
- ALT levels persistently elevated to ≥ 2 times the upper limit of normal (ULN).
- Patients with cirrhosis, regardless of viral replication status.
First-line antiviral drugs for HBV include nucleoside analogs (e.g., entecavir, tenofovir, telbivudine) and interferons (e.g., standard interferon-α or pegylated interferon-α [Peg IFN-α]). For treatment-naive HBV patients, entecavir, tenofovir, or long-acting interferons (Peg IFN-α) are recommended as first-line options.
Hepatitis C Virus (HCV)
All HCV-RNA-positive patients, whether acute or chronic, require antiviral therapy. Antiviral medications and regimens for HCV include:
- Direct-acting antiviral agents (DAAs): Examples include sofosbuvir/velpatasvir and glecaprevir/pibrentasvir.
- PR regimen: Pegylated interferon-α (Peg IFN-α) combined with ribavirin.
- DAA combined with PR regimen.
- Oral DAA regimens are the preferred treatment.
For both HBV and HCV, interferon-based antiviral therapy is contraindicated once the patient enters the cirrhosis stage.
Artificial Liver or Liver Transplantation
For patients with severe hepatitis of any type, artificial liver support systems or liver transplantation may be utilized as treatment options.
Prognosis and Prevention
Hepatitis A and Hepatitis E
These are mostly self-limiting diseases and rarely progress to chronic conditions, with generally favorable prognoses. However, hepatitis E in pregnant women and the elderly is more likely to develop into severe hepatitis, with a mortality rate of up to 20%.
Hepatitis B
The chronicity rate is approximately 10%, with over 200 million people worldwide living with chronic HBV infection. The annual incidence of liver cirrhosis among patients is 2%–10%, and the 5-year survival rate for decompensated cirrhosis ranges from 14% to 35%. The annual incidence of hepatocellular carcinoma (HCC) in cirrhotic patients is 3%–6%. Infection with HDV can exacerbate the severity of HBV-related disease.
Hepatitis C
The chronicity rate is 55%–85%. Factors such as being over 40 years old at the time of HCV infection, being male, heavy alcohol consumption (over 50 g/day), and co-infection with HIV leading to immunosuppression can accelerate disease progression. Once cirrhosis develops, the annual incidence of HCV-related liver cancer is 2%–4%. The clinical prognosis of chronic hepatitis C has significantly improved since the introduction of direct-acting antiviral (DAA) therapies.
Vaccines are available to prevent infections caused by HAV, HBV, and HEV. However, no vaccines are currently available for the prevention of HCV and HDV infections. Effective preventive measures include minimizing excessive contact with infected individuals, avoiding iatrogenic transmission (e.g., improper use of syringes or blood products), and reducing the risk of transmission through unsafe sexual practices.