bubble_chart Overview

Hepatitis B is a global disease caused by the hepatitis B virus. The incidence rate is high in developing countries. According to statistics, there are over 280 million asymptomatic carriers (HBsAg carriers) worldwide, with more than 100 million in China. Most cases are asymptomatic, but one-third exhibit clinical manifestations of liver damage. The disease is characterized by a relatively slow onset, with subclinical and chronic types being more common. HBsAg carriers without jaundice are more likely to develop chronic conditions. The disease is primarily transmitted through blood and close daily contact, with mother-to-child transmission being another route. The use of the hepatitis B vaccine is the fundamental measure for controlling and preventing hepatitis B.

bubble_chart Pathogen

Hepatitis B virus (HBV) is a hepatotropic virus. In recent years, with the advancement of nucleic acid molecular hybridization techniques, HBV-DNA has also been detected in extrahepatic organ cells. Experimental studies on duck hepatitis B virus in Beijing ducks have provided evidence of replication in extrahepatic cells. Human HBV may also replicate in extrahepatic cells, which requires further investigation. Electron microscopy of serum from HBV-infected individuals reveals three types of viral particles: ① Dane particles (HBV particles), with an outer envelope protein of HBsAg and a core containing HBV-DNA, HBV DNAp (DNA polymerase), HBcAg, and HBeAg; ② small spherical particles; ③ tubular particles. The latter two are excess viral envelopes (HBsAg) produced during HBV replication and do not contain nucleic acids.

The HBV genome (HBV-DNA) consists of a partially double-stranded circular DNA structure, comprising 3,200 nucleotides. Due to its narrow host range, successful isolation of the virus through in vitro cell culture has not yet been achieved. In recent years, with the application of molecular cloning techniques and successful transfection of in vitro cultured cell lines, further understanding of the HBV replication process has been gained. HBV-DNA is composed of a negative strand (long strand) and a positive strand (short strand). The negative strand contains four open reading frames (ORFs): ① the S gene region, consisting of the S gene, pre-S₂

(pre-S₂) gene, and pre-S₁ (pre-S₁) gene, encoding HBsAg, pre-S, pre-S₁, and the polyhuman serum albumin receptor (PHSA-R); ② the C gene region, consisting of the pre-C gene and C gene, encoding HBeAg and HBcAg, respectively; ③ the P gene region, encoding HBV-DNAp and possessing reverse transcriptase activity; ④ the X gene region, encoding HBxAg and having the function of activating the HBcAg gene.

HBV replication process: Although the HBV genome is a double-stranded circular DNA, its replication process shares characteristics with RNA retroviruses, requiring reverse transcriptase activity to generate RNA/DNA intermediates before continuing replication. The process is as follows: ① Under the action of viral and/or cellular DNA-p, the positive strand is first extended to form covalently closed circular DNA (cccDNA). ② This serves as a template, transcribed by host hepatocyte enzymes into replication intermediates. ③ Using these intermediates as templates, reverse transcriptase generates first- and second-generation DNA. This double-stranded DNA partially circularizes, completing the replication of HBV-DNA.

Research on HBV Mutant Strains Due to the unique replication mechanism of HBV, where reverse transcription occurs via an mRNA intermediate, the lack of proofreading enzymes makes HBV-DNA sequence mutations prone to occur. ① Mutations in the S gene region can lead to changes in HBsAg subtypes and result in HBsAg-negative, HBV-DNA-positive hepatitis, complicating clinical diagnosis. Some individuals, despite producing anti-HBs after vaccination, may still be infected by S gene mutant strains of HBV, evading the host's immune response. ② Mutations in the pre-C gene region are associated with post-HBV infection immunity and the onset of severe hepatitis. Generally, the seroconversion from HBeAg to anti-HBe in hepatitis B patients indicates reduced HBV replication activity and improved clinical symptoms. However, in some patients, despite HBeAg seroconversion, viral replication persists, and the disease progresses. In addition to HBsAg and anti-HBe, their serum may also test positive for HBV-DNA and anti-HBcIgM, with intrahepatic HBcAg positivity. After excluding other causes of liver damage, these findings suggest HBV-related disease progression. Such cases are characterized by a low likelihood of spontaneous remission, frequent progression to cirrhosis, and poor response to antiviral therapy. Studies indicate that these patients are infected with pre-C gene mutant HBV strains. ③ Mutations in the P gene region can weaken or halt HBV replication. ④ Mutations in the X gene region may impair the synthesis of HBxAg.

In recent years, it has been found that some HBV-infected individuals consistently test negative for anti-HBc; some patients in the stage of convalescence also test negative for anti-HBs, and even some patients show negative results for all HBV markers, yet HBV-DNA can be detected, with HBcAg and HBsAg present in hepatocytes and on the hepatocyte membrane. Infecting chimpanzees with serum from such patients can induce typical hepatitis manifestations. Some scholars have referred to this as HBV₂. Recent studies have shown that sequence analysis of HBV-DNA in the serum of these patients reveals multiple point mutations in the S, C, and X regions, suggesting that HBV₂ is a mutant strain of HBV.

The emergence of HBV mutant strains is a result of the virus adapting to the host cell environment and resisting immune responses. These mutations can occur during natural HBV infection, HBV vaccination, specific immunotherapy, or interferon treatment, or the initial HBV infection may already involve a mutant strain. The specific diagnostic indicators and their clinical significance are as follows:

1. HBsAg and anti-HBs

HBsAg: The presence of HBsAg in serum is a marker of HBV infection. It is antigenic but not pestilent. However, since HBsAg often coexists with HBV, it is considered one of the pestilence markers. It should be noted that HBV-DNA can integrate into hepatocytes starting from the terminus of the X gene region. The integrated S gene is strongly expressed, continuously producing HBsAg, while the integrated HBcAg genome is suppressed and does not express HBsAg or HBsAg. In such cases, even if HBV has been cleared from the body, HBsAg may remain positive. Theoretically, such HBsAg-positive blood is not pestilent. After acute HBV infection, HBsAg appears first in the serum and remains positive throughout the acute phase, with titers declining or turning negative during the stage of convalescence. If HBsAg remains positive for more than six months, the individual is termed a chronic HBsAg carrier (asymptomatic HBsAg carrier) and may remain positive for several years. Generally, the titer of HBsAg does not correlate with the severity of disease. Normal liver function with high HBsAg titers may still indicate significant liver pathology, whereas negative HBsAg and DNAp suggest no significant pestilence. Conversely, abnormal liver function with low HBsAg titers may still show significant liver pathology, as seen in some cirrhosis or liver cancer patients who test negative or have low HBsAg titers. Asymptomatic HBsAg carriers or chronic active hepatitis B can exhibit the same HBsAg titer changes, which do not reflect disease severity. Therefore, changes in HBsAg titers cannot be used as indicators of disease severity or treatment efficacy.

Immunoelectron microscopy and immunofluorescence have confirmed the presence of HBsAg in hepatocyte cytoplasm while serum HBsAg is negative, though the mechanism remains unclear. One known reason is that current RIA detection methods have a sensitivity of 10^-5_, which cannot detect the minimum infectious dose (10^-7), resulting in a 10% false-negative rate. Thus, a positive HBsAg result is diagnostically meaningful, but a negative result does not rule out HBV infection. Recent findings show that some patients test negative for all serum HBV markers but have HBV-DNA detected in leukocytes or hepatocytes, indicating that confirming or excluding HBV infection cannot rely solely on HBsAg positivity and should be combined with other markers.

HBsAg has 10 subtypes, with incomplete cross-immunity among them. Recent studies using subtype monoclonal antibodies have shown that the d and y, w and r determinants can coexist on the same viral antigen particle, forming composite subtypes such as adwr, aywr, adyw, and adyr. The mechanisms include: ① dual infection by different subtypes of the virus; ② point mutations in HBV-DNA after infection by a single subtype. Clinically, this manifests as recurrent illness and more severe liver damage, leading some HBV-infected individuals to test positive for both HBsAg and anti-HBs in their serum.

Anti-HBs is a protective antibody produced after HBV infection or hepatitis B vaccination. Anti-HBs appears 6-23 weeks after the initial HBV infection, with about 20% appearing in the early stage of infection. During the stage of convalescence, Anti-HBs appears several months to one year after the disappearance of HBsAg. A positive Anti-HBs indicates acquired immunity. Quantitative detection of Anti-HBs titer suggests that a titer ≥10 IU/ml is considered protective.

II. Pre-S1, Pre-S₂, and Pre-S

1. Pre-S₁, Pre-S₂

Both are indicators of HBV replication.

2. Anti-Pre-S

A positive Anti-Pre-S indicates that HBV is being or has been cleared.

III. HBcAg and Anti-HBc

HBcAg is an indicator of HBV replication. There is no free HBcAg in peripheral blood. When Dane particles are treated with detergents, HBcAg can be released, so it is generally undetectable in serum. It exists in the nuclei of infected hepatocytes and liver homogenates. Recent studies suggest that the presence of HBcAg in hepatocytes is a key target antigen that triggers immune responses leading to hepatocyte necrosis, and Anti-HBc has immunomodulatory effects.

Anti-HBc is a marker of HBV infection. A positive Anti-HBc IgM indicates acute or recent HBV infection, suggesting viral replication. A high titer represents the acute phase, while a low titer indicates chronic HBV infection or asymptomatic HBsAg carriers. A positive Anti-HBc IgG indicates past HBV infection.

Isolated Anti-HBc positivity may occur under the following circumstances: ① Early recovery phase (window period) after acute HBV infection, where HBsAg has disappeared but Anti-HBs has not yet appeared. ② Post-immunity loss of Anti-HBs or levels below detection. ③ HBsAg carriers with HBsAg levels below detection. ④ Passive transfer of Anti-HBc from mother to infant via the placenta.

IV. HBeAg is a key indicator of HBV replication. It is present in HBsAg-positive blood. When HBsAg is negative but HBeAg is positive, possible reasons include: ① Insensitive HBsAg detection methods; ② Interference from serum rheumatoid factor (RF); ③ Formation of immune complexes between HBsAg and Anti-HBs, rendering HBsAg undetectable; ④ Persistence of Dane particles in serum after HBsAg disappearance or Anti-HBs appearance, with the outer HBsAg shell masked by Anti-HBs, making HBsAg undetectable;

⑤ Reagent or operational factors leading to false-positive HBeAg results.

V. HBV-DNA and DNA-p

HBV-DNA positivity is the most reliable indicator of HBV replication. In recent years, the polymerase chain reaction (PCR) technique, an in vitro DNA amplification method, has improved sensitivity over 100-fold (10 fg/ml), enabling detection of extremely low viral loads. HBV-DNA-p is the DNA polymerase associated with the HBV core and acts as a reverse transcriptase during viral replication. DNA-p activity is a crucial indicator of HBV replication efficiency. Detection of HBV-DNA and DNA-p helps assess the degree of viral replication and infectivity in HBV carriers, providing a sensitive evaluation of antiviral drug efficacy.

In summary, the sequence of HBV markers is:

HBsAg, HBeAg, Anti-HBc (Anti-HBc IgM, Anti-HBc IgG), Anti-HBe, Anti-HBs. Simultaneous detection of these markers can clarify the stage of HBV infection.

bubble_chart Pathogenesis

The pathogenesis of hepatitis B is highly complex, with substantial research data available, yet it remains incompletely understood to date. Currently, it is believed that hepatocyte injury is not a direct result of HBV replication within liver cells but is mediated by T-cell cytotoxic responses. Following HBV infection, humans elicit both cellular and humoral immune responses, triggering autoimmune reactions and immune regulatory dysfunction. These immune responses play a crucial role in the clinical manifestations and outcomes of hepatitis B.

I. Acute Hepatitis

When individuals with normal immune function are infected with HBV, their cytotoxic T cells (Tc cells) attack the infected hepatocytes. The HBV released into the bloodstream from the damaged liver cells is neutralized by specific antibodies, and the production of interferon is sufficient, leading to HBV clearance, clinical improvement, and eventual recovery.

II. Chronic Active Hepatitis

This occurs in individuals with immune deficiencies or dysregulation. After HBV infection, due to abnormal Tc cell function or partial blockade of hepatocyte target antigens by specific antibodies, the T-cell cytotoxic response is constrained, resulting in partial hepatocyte damage. Interferon production is reduced, allowing persistent HBV replication. Insufficient formation of specific antibodies leads to repeated HBV invasion of hepatocytes, resulting in chronic infection. Additionally, hepatocyte membrane-specific lipoprotein (Lsp) becomes an autoantigen due to HBV infection, stimulating B cells to produce anti-Lsp (IgG type). Under conditions of reduced suppressor T cell (Ts cell) activity, the autoimmune ADCC effect causes progressive hepatocyte injury.

III. Chronic Persistent Hepatitis and Asymptomatic HBsAg Carriers

When the immune system is compromised, infection with HBV fails to elicit an effective immune response, resulting in minimal or no hepatocyte damage. Particularly in asymptomatic HBeAg carriers, the lack of interferon prevents viral clearance, leading to long-term HBV carriage.

IV. Fulminant Hepatitis

The occurrence of acute fulminant hepatitis is attributed to an excessive immune response, where Tc cells rapidly destroy a large number of HBV-infected hepatocytes in a short period. Alternatively, the rapid formation of abundant antigen-antibody complexes activates complement, inducing localized hypersensitivity (Arthus reaction) and causing massive hepatocyte necrosis. The absorption of gut-derived internal toxins may trigger Schwartzman reactions, leading to ischemic necrosis of hepatocytes. Additionally, cytokines such as α-tumor necrosis factor (TNF-α), IL-1, and leukotrienes released by mononuclear macrophages exacerbate hepatocyte injury. The pathogenesis of subacute fulminant hepatitis is similar to that of acute fulminant hepatitis but progresses more slowly. The mechanism of chronic fulminant hepatitis is more complex and requires further investigation.

bubble_chart Pathological Changes

Liver lesions are most prominent, diffusely distributed throughout the liver. The basic pathological changes include hepatocyte degeneration, necrosis, inflammatory cell infiltration, hepatocyte regeneration, and fibrous tissue proliferation.

I. Acute Hepatitis

① Hepatocytes exhibit diffuse degeneration, with fine swelling forming spherical shapes (ballooning degeneration), eosinophilic changes of hepatocytes, and eosinophilic bodies; ② Spotty or focal necrosis of hepatocytes; ③ Hepatocyte regeneration and inflammatory cell infiltration in the portal area (grade I).

The liver lesions in jaundice-type and non-jaundice-type hepatitis differ only in severity, with the former potentially showing intrahepatic cholestasis.

II. Chronic Hepatitis

① Chronic persistent hepatitis resembles acute hepatitis but is milder, with intact lobular limiting plates. ② Chronic active hepatitis is more severe than acute hepatitis, often featuring piecemeal necrosis, destruction of the limiting plates, or bridging necrosis. In severe cases, liver lobules are destroyed, hepatocytes show irregular nodular hyperplasia, and collagen and fibrous tissue proliferate in the lobules and portal areas.

III. Severe Hepatitis

1. Acute severe hepatitis can be divided into two types:

（1）Necrotic type: Characterized by massive hepatocyte necrosis. The liver shrinks, hepatocytes dissolve and disappear, with only a few residual hepatocytes at the periphery of the lobules. Generally, there is no hepatocyte regeneration or fibrous tissue proliferation, but cholestasis is present in the remaining hepatocytes and small bile ducts.

（2）Edema type: The prominent feature is widespread, significant ballooning degeneration of hepatocytes, which compress each other, forming a "plant cell"-like appearance, along with focal hepatocyte necrosis.

2. Subacute severe hepatitis: Shows varying degrees of sub-massive or massive liver necrosis of different ages coexisting with nodular hepatocyte hyperplasia, along with connective tissue proliferation in the portal areas.

3. Chronic severe hepatitis: Occurs secondary to sub-massive or massive liver necrosis on the basis of chronic active hepatitis or post-hepatitis cirrhosis. It affects multiple liver lobules, with pseudolobule formation and severe distortion of liver tissue architecture.

bubble_chart Clinical Manifestations

The characteristics of HBV infection include diverse clinical manifestations and a long incubation period (approximately 45 to 160 days, with an average of 60 to 90 days).

1. Acute Hepatitis B The onset is slower than that of Hepatitis A.

(1) Jaundice Type Clinically, it can be divided into the pre-jaundice phase, jaundice phase, and convalescence stage, with the entire course lasting 2 to 4 months. Most patients experience gastrointestinal symptoms during the pre-jaundice phase, such as aversion to oily food, loss of appetite, nausea, vomiting, abdominal distension and fullness, and lack of strength. Some patients may have low-grade fever or serum sickness-like symptoms, such as arthralgia, urticaria, angioneurotic edema, and rash, which are more common than in Hepatitis A. The disease progression and outcome are similar to those of Hepatitis A, but a few patients may develop chronic hepatitis due to prolonged illness.

(2) Non-jaundice Type The clinical symptoms are mild or asymptomatic. Most cases are discovered during physical examinations or tests for other conditions, with only elevated ALT levels, and are prone to becoming chronic.

2. Cholestatic Type

Similar to Hepatitis A. It manifests as prolonged intrahepatic obstructive jaundice with mild gastrointestinal symptoms, hepatomegaly, and findings of intrahepatic obstructive jaundice, lasting for several months.

3. Chronic Hepatitis B The course of the disease exceeds 6 months.

(1) Chronic Persistent Hepatitis (CPH) Clinical symptoms are mild, with no jaundice or grade I jaundice, grade I hepatomegaly, and the spleen is generally not palpable. Liver function impairment is mild, often presenting as fluctuating ALT levels, while thymol turbidity and plasma protein levels show no significant abnormalities. There are usually no extrahepatic manifestations.

(2) Chronic Active Hepatitis (CAH) Clinical symptoms are severe, persistent, or recurrent, with obvious signs such as a liver disease facial appearance, spider angiomas, and palmar erythema. There may be varying degrees of jaundice. The liver is enlarged and moderately firm, and the spleen is often enlarged. Liver function impairment is significant, with persistently or recurrently elevated ALT levels, markedly abnormal thymol turbidity, elevated plasma globulin, and decreased or inverted A/G ratio. Some patients may have extrahepatic manifestations, such as arthritis, nephritis, Sjögren's syndrome, and nodular polyarteritis. Autoantibody tests, such as antinuclear antibodies, anti-smooth muscle antibodies, and anti-mitochondrial antibodies, may be positive. Some patients may present without jaundice or atypically, with a short medical history and mild symptoms but showing signs of chronic liver disease and liver function impairment. Others may resemble chronic persistent hepatitis but are confirmed as chronic active hepatitis through liver biopsy.

In recent years, with advances in research on HBV-DNA precore gene mutations, some scholars advocate classifying chronic hepatitis B into two types based on HBeAg and anti-HBe status: ① HBeAg-positive chronic hepatitis (typical chronic hepatitis B) caused by infection with wild-type HBV strains. The course includes both HBeAg-positive and anti-HBe-positive phases. Consistent with previous views, HBeAg positivity indicates active HBV replication in the body, positive serum HBV-DNA, liver function impairment, and pathological changes in liver tissue. When HBeAg turns negative and anti-HBe turns positive, it signifies weakened or halted HBV replication, negative serum HBV-DNA, restored liver function, and improved liver tissue lesions. ② Anti-HBe-positive chronic hepatitis (atypical chronic hepatitis B) is believed to be caused by infection with HBV precore gene mutant strains. The serum is HBeAg-negative and anti-HBe-positive, with ongoing HBV replication in the body. The liver shows progressive and severe lesions, prone to developing into severe hepatitis, cirrhosis, and hepatocellular carcinoma.

4. Severe Hepatitis B

(1) Acute severe hepatitis (fulminant hepatitis) has an onset similar to acute jaundice hepatitis, but with extreme lack of strength and prominent gastrointestinal symptoms such as severe anorexia, frequent nausea, vomiting, abdominal distension and fullness. Hepatic encephalopathy develops within 10 days of onset. Most patients first exhibit excitement, euphoria, talkativeness, and abnormal personality behaviors 3-5 days after illness onset, along with daytime drowsiness and nighttime insomnia, reversed day-night cycles, blurred vision, and unsteady gait. Disorientation and impaired calculation ability appear, progressing further to excitement, mania, and high-pitched screaming. In severe cases, symptoms may manifest as cerebral edema leading to increased intracranial pressure, such as elevated blood pressure, bulbar conjunctival edema, or even unequal pupil size and cerebral herniation. Therefore, preventing and actively treating cerebral edema to avoid cerebral herniation is crucial for patient rescue. Jaundice deepens rapidly after appearance, accompanied by shrinking hepatic dullness area and obvious bleeding tendency. Generally, there is no ascites or advanced stage development; patients often die within 3 weeks from complications like cerebral herniation or hemorrhage.

(2) Subacute Severe Hepatitis The onset is similar to that of general acute jaundice hepatitis, but the condition worsens more than 10 days after onset, characterized by extreme lack of strength, abdominal distension and fullness, loss of appetite, and progressively deepening jaundice, with a marked tendency to bleed. In the late stage [third stage], hepatorenal syndrome and hepatic encephalopathy may occur. The course of the disease lasts from several weeks to months. This type is prone to progress to post-necrotic cirrhosis. In some cases, hepatic encephalopathy may be the first symptom after onset, but the history exceeds 10 days, with other features resembling acute severe hepatitis.

(4) Asymptomatic HBsAg Carriers Most are asymptomatic and are found to be HBsAg-positive during physical examinations, with normal liver function or isolated ALT elevation in some cases. Signs are minimal.

The clinical characteristics of viral hepatitis in the elderly include a relatively slow onset, mild subjective symptoms that do not match the severity of the condition, and a slow recovery with a tendency to become chronic. The incidence of severe hepatitis and chronic active hepatitis is higher, with subacute and chronic severe hepatitis being more common.

bubble_chart Auxiliary Examination

1. Liver function tests

include bilirubin, thymol turbidity test, AST, ALT, A/G, prothrombin time, serum protein electrophoresis, etc.

2. Specific serological pathogen tests

include HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, anti-HBcIgM. If conditions permit, HBV-DNA can be detected,

DNA-p, Pre-S₁, Pre-S₂, etc. In situ hybridization is used to detect intrahepatic HBV-DNA.

bubble_chart Diagnosis

Based on clinical characteristics, referring to epidemiological data, and excluding other related diseases, the diagnosis is confirmed by serological pathogen testing. For cases with atypical clinical manifestations, liver biopsy pathological examination should be performed.

I. Etiological Diagnosis

Due to the high number of asymptomatic HBsAg carriers, when these individuals are infected with hepatitis A, C, D, or E viruses or other hepatitis viruses, they may be misdiagnosed as having acute hepatitis B because of HBsAg positivity. Therefore, caution should be exercised when making a definitive diagnosis.

II. Diagnostic Criteria for Acute Hepatitis B

①HBsAg positive; ②HBeAg positive; ③Anti-HBcIgM positive, with high titer (≥1:1000); ④HBV-DNA positive.

bubble_chart Treatment Measures

Different treatment measures should be adopted according to the clinical type and different types of pathogens. The general principle is: appropriate rest and reasonable nutrition should be the main focus, supplemented by selective use of drugs. Alcohol should be avoided, overwork should be prevented, and hepatotoxic drugs should be avoided. Medication should be kept simple rather than complicated.

I. Treatment of Acute Hepatitis

Early and strict bed rest is the most important. When symptoms significantly improve, activity can be gradually increased, with the principle of not feeling fatigued. Treatment continues until symptoms disappear, the isolation period ends, and liver function returns to normal before discharge. After 1–3 months of rest, work can be gradually resumed.

The diet should be tailored to the patient's taste, consisting of easily digestible and light foods. It should contain various vitamins, sufficient calories, and an appropriate amount of protein, with fat not overly restricted. For those with reduced food intake or vomiting, intravenous drip of 10% glucose solution (1000–1500ml) with 3g of vitamin C, 400mg of glucurolactone, and 8–16U of regular insulin can be administered once daily. Energy mixture and 10% potassium chloride may also be added. For those with severe heat, modified *Yin Chen Stomach Poria Decoction* can be used; for those with both dampness and heat, modified *Yin Chen Hao Decoction* combined with *Wei Ling Decoction*; for liver qi depression, *Peripatetic Powder*; and for spleen deficiency with dampness retention, *Stomach-Calming Powder*. Some advocate the use of a high dose of *Red Peony Root* for deep jaundice, which can be effective. Generally, acute hepatitis can be cured.

II. Treatment of Chronic Hepatitis

This mainly includes inhibiting viral replication, improving immune function, protecting liver cells, and promoting liver cell regeneration. Due to the tendency for relapse and persistent positivity of HBV replication markers, the following methods can be selected based on the situation:

1. Antiviral Therapy

For chronic HBV infection with persistently positive viral replication markers, antiviral therapy is an important measure. Currently, the efficacy of antiviral drugs is not entirely satisfactory. They can temporarily suppress HBV replication, but this suppression disappears after discontinuation, causing the previously suppressed markers to return to their original levels. Some drugs act slowly and require a longer time to observe effects. Given the limited efficacy of antiviral drugs and their effectiveness only when viral replication is active, recent treatment for chronic hepatitis B tends to favor combination therapy to improve efficacy.

(1) Interferons (IFN) are currently recognized as drugs with some effect on HBV replication. Their mechanisms include: ① Blocking viral reproduction and replication, mainly through antiviral proteins (AVP), leading to mRNA cleavage and inhibiting HBV replication; ② Inducing the expression of class I MHC antigens on infected liver cell membranes, promoting Tc cell recognition and killing effects. Currently, genetically engineered interferons are mainly used clinically, including IFN-α-1b, IFN-α-2a, and IFN-α-2b. ① Recombinant IFN-α-2b (Intron A): 3 million U per dose, intramuscular injection, once daily for the first week, then every other day, for a course of 3–6 months. The HBeAg and HBV-DNA seroconversion rate can reach 30–70%, with definite effects on suppressing HBV replication. However, the majority still remain HBeAg-positive, possibly due to HBV-DNA integration. ② α₁ genetically engineered interferon (Interferon Ling): 2–6 million U per dose, intramuscular injection, once daily for a course of 2 months, with a recent HBeAg seroconversion rate of 55%.

The efficacy of interferon varies among reports, with an HBeAg seroconversion rate generally around 40–50%. To improve efficacy, some use corticosteroids followed by interferon, but caution is needed as it is contraindicated in severe chronic active hepatitis, as it may worsen the condition. For HBV infections believed to involve precore gene mutations (i.e., anti-HBe-positive, HBV-DNA-positive chronic hepatitis), high-dose interferon therapy is not ideal. The efficacy of β- and γ-interferon on HBV replication is inferior to that of α-IFN.

Factors affecting the efficacy of interferon therapy: ① Chronic active hepatitis is better than chronic persistent hepatitis; ② Females respond better than males; ③ Patients with elevated ALT show better efficacy than those with normal ALT; ④ Lower titers of HBsAg, HBeAg, and HBV-DNA correlate with better outcomes; ⑤ Patients who have not previously used antiviral drugs or immunosuppressants respond better than those who have used them without effect; ⑥ Dose and treatment duration, higher doses and longer courses appear more effective.

Side effects are related to the duration of treatment and the size of the dose. The most common is "flu-like syndrome," manifested as fear of cold, fever, headache, general soreness, lack of strength, etc. However, these symptoms often gradually lessen with continued use or dose reduction. Most cases involve transient fever, commonly seen with the first dose, with no observed correlation to efficacy. It may also cause leukopenia, thrombocytopenia, etc., which usually resolve naturally after discontinuation and do not affect treatment. Currently, it is widely believed that combining it with other antiviral or immunomodulatory drugs may enhance efficacy.

(2) Acyclovir (ACV, domestic name Apulowei): This drug is a nucleoside analog that inhibits various DNA viruses. In the body, Neijing thymidine kinase (TK) activates its conversion into the antiviral-active acyclovir triphosphate, which inhibits DNA polymerase (DNAp) and terminates viral DNA chain elongation. Therefore, it is more effective against viruses with TK, such as herpes viruses. HBV lacks TK, so its effect is generally modest, and it is often considered more effective when combined with interferon. The dosage is 15 mg/kg daily, diluted and administered intravenously over 2 hours, once daily for 30 days, followed by a 15-day break and another 15-day course, totaling 60 days. Domestic reports vary on efficacy, with results generally inferior to α-interferon.

(3) Vidarabine (Ara-A) and its monophosphate (Ara-AMP): Both are purine analogs that selectively inhibit viral DNA polymerase and nucleotide reductase activity, preventing DNA virus replication. Due to their significant side effects, Ara-A and Ara-AMP are rarely used in recent years.

(4) Polyinosinic-polycytidylic acid (PolyI:C): A synthetic interferon inducer used domestically for a long time, though its efficacy remains uncertain. It shows no significant effect on chronic hepatitis B. The dosage is 4 mg intramuscularly twice weekly for 3–6 months.

2. Immunomodulatory drugs: Aimed at enhancing antiviral immunity.

(1) Thymosin: Enhances T-cell activity by influencing cAMP. The dosage is 10–20 mg daily, intramuscularly or intravenously, for 2–3 months.

(2) Interleukin-2 (IL-2): Stimulates immune effector cell proliferation and induces γ-interferon. The dosage is 1000–2000 U daily, intramuscularly, once daily for 28–56 days. Some patients show HBeAg seroconversion.

(3) Lymphokine-activated killer cells (LAK cells): Derived by stimulating precursor cells with lymphokines (e.g., IL-2 and γ-IFN). Domestic reports indicate partial HBeAg and HBV-DNA seroconversion in some patients.

3. Hepatoprotective drugs

(1) Legalon: Contains silymarin extracted from water-ground milk thistle seeds, which stabilizes hepatocyte membranes and promotes liver cell regeneration. The dosage is 2 tablets three times daily for 3 months.

(2) Stronger Neo-Minophagen C (SNMC): Contains glycyrrhizin extracted from liquorice root, effective against carbon tetrachloride-induced liver damage. For hepatitis, it primarily reduces enzyme levels, though rebound may occur after discontinuation. A similar product, Glycyrrhizin injection, has been shown to outperform SNMC in enzyme reduction. The dosage is 150 mg in 10% glucose solution intravenously once daily for 1–2 months. Contraindicated in cases of heart or kidney failure, severe hypokalemia, or hypernatremia. Not suitable for pregnant women or infants.

(3) Oleanolic acid tablets: The dosage is 80 mg three times daily for 3 months. Bifendate: 15–25 mg three times daily, with dose reduction after normalizing transaminase levels, for 6 months. Both have enzyme-lowering effects.

III. Treatment of Severe Hepatitis

Refer to the section on fulminant hepatic failure treatment.

IV. Treatment of Asymptomatic HBsAg Carriers

For those with positive HBV replication markers, antiviral drug therapy is applicable, with α-IFN being the first choice.

In summary, research on drugs for hepatitis B antiviral treatment indicates that the key lies in whether the drugs can inhibit HBV's supercoiled covalently closed circular DNA (cccDNA). However, current antiviral Yaodui drugs have no effect on the viral cccDNA in hepatocyte nuclei. Therefore, after discontinuation of the drugs, cccDNA resumes its role as the template for viral replication transcription, leading to viral replication. Recent reports on biological targeted therapy for hepatitis suggest that antisense ribonucleic acid can block key coding genes essential for viral replication. This gene-level targeted therapy may bring new hope for hepatitis B treatment. Therefore, hepatitis B treatment should also focus on symptomatic supportive therapy and comprehensive treatment combining Chinese and Western medicines.

bubble_chart Prevention

Comprehensive measures should be taken, focusing on vaccination and cutting off transmission routes.

I. Application of Hepatitis B Vaccine and Hepatitis B Immune Globulin (HBIG)

Given the widespread presence of HBsAg carriers and the difficulty in managing epidemic sources, the key measure for controlling and preventing hepatitis B is vaccination. China has incorporated hepatitis B vaccination into its immunization program. Additionally, the following groups are also eligible for vaccination: ① Newborns of HBsAg-positive mothers, especially those who are also HBeAg-positive; ② Children under 3 years old in high-prevalence areas; ③ Medical personnel and individuals exposed to blood; ④ Patients who frequently receive blood transfusions or blood products; ⑤ Family members of HBsAg-positive individuals, especially spouses. Vaccination is contraindicated for those with acute or chronic illnesses or allergies to formaldehyde or the preservative thimerosal.

1. Hepatitis B vaccination varies by individual. The immunization doses and schedules used in China are as follows: ① Newborns of HBsAg-positive mothers receive three doses of 30μg each; ② Newborns of HBsAg-negative mothers receive a first dose of 30μg, followed by two doses of 10μg each; ③ High-risk groups, such as renal dialysis patients and those with occupational exposure to hepatitis B, receive three doses of 20μg each; ④ Other susceptible populations (including children and adults) receive three doses of 10μg each. All follow the 0, 1, and 6-month schedule, but the first dose for newborns should be administered within 24 hours of birth for better efficacy. Some also use a 0, 1, and 2-month schedule.

Currently, it is widely recommended that high-risk groups (especially newborns of HBsAg- and HBeAg-positive mothers; individuals accidentally exposed to HBV, such as needle-stick injuries with HBsAg-positive blood, splashes of HBsAg-positive blood into the conjunctiva or oral mucosa, transfusions of HBsAg-positive blood, or scalpel injuries to the skin, etc.) should receive an intramuscular injection of HBIG immediately (within 24 hours). If the HBIG contains ≥200 IU of anti-HBs per milliliter, the dose is 0.5–0.7 ml/kg. Domestically produced HBIG in China contains 60–160 IU (mostly 100 IU) of anti-HBs per milliliter, so the dose is 0.075–0.2 ml/kg (depending on the concentration). The goal is to achieve an anti-HBs level of ≥100 mIU/ml in the body (protective effect). After HBIG administration, three doses of hepatitis B vaccine should be given: the first dose at 30μg and the second and third doses at 10μg each, following the 0, 1, and 6-month schedule. The deltoid muscle is the preferred injection site. Side effects of the vaccine are mild, mostly local pain, occasional redness or induration, and rarely fever or fatigue (>38℃ in 1.8% of cases). Guillain-Barré syndrome is extremely rare (0.5/100,000). Opinions on booster doses vary. Since antibodies persist for 3–5 years after three doses, a booster (10 or 20μg) is recommended if anti-HBs levels are ≤10 mIU/ml. Booster immunization is also advised for high-risk groups, including medical personnel (especially hemodialysis workers), frequent recipients of blood products, and spouses of HBeAg-positive individuals (including the vaccinated partner).

2. Hepatitis B vaccine can be administered simultaneously with other vaccines, such as DPT, BCG, measles vaccine, or polio vaccine, without significant interference.

After hepatitis B vaccination, 5-15% of recipients show no response and fail to produce anti-HBs. This is currently a hot research topic. Immune non-response mainly occurs in newborns of HBsAg-positive pregnant women. High levels of HBV-DNA in maternal serum are the primary cause of immunization failure. Some also believe that non-responders may already have HBV infection. Whether this is related to HBV mutant strains remains to be studied.

II. Cutting Off Transmission Routes

The focus is on preventing transmission through blood and body fluids. Measures include: ① Needles, syringes, acupuncture needles, and blood collection needles should be sterilized by high-pressure steam or boiled for 20 minutes; ② For vaccinations or injections, use one needle and one syringe per person, and employ disposable syringes; ③ Strictly screen and manage blood donors, using sensitive detection methods; ④ Strictly control indications for blood transfusions and blood products; ⑤ Use dedicated tableware and personal grooming items; ⑥ Wash hands with soap and river water after contact with patients; ⑦ HBsAg carriers should not work in the catering industry, food processing, water supply management, or childcare facilities.

bubble_chart Complications

1. Hepatogenous diabetes

The clinical manifestations are similar to those of type II diabetes, with the difference being that hepatogenous diabetes shows significantly elevated fasting insulin levels while C-peptide remains normal. After glucose intake, insulin levels rise markedly, but the peak C-peptide level remains slightly lower than normal. This is due to the liver's reduced ability to inactivate insulin, leading to increased insulin levels. Additionally, decreased inactivation of glucagon by the liver, combined with a reduction in insulin receptors on hepatocytes, results in insulin resistance. Thus, despite elevated insulin levels, blood glucose remains high. Meanwhile, C-peptide is less affected by the liver, so it does not increase, indicating no significant abnormality in β-cell secretory function. To differentiate from type II diabetes, insulin release tests and C-peptide release tests can be used.

2. Fatty liver

The mechanism remains unclear. Its characteristics include generally good overall condition, mild and isolated ALT elevation (grade II), increased blood lipids, and fatty liver waveforms observed on B-mode ultrasound. Definitive diagnosis relies on liver biopsy and pathological examination.

3. Liver cirrhosis

The progression of chronic hepatitis to liver cirrhosis is the result of liver fibrosis. The underlying mechanism is not yet fully understood. It is also observed in subacute and chronic severe hepatitis, as well as asymptomatic HBsAg carriers with an insidious onset.

4. Liver cancer

HBV and HCV infections are closely associated with its pathogenesis. It is commonly seen in cases of chronic active hepatitis and liver cirrhosis progressing to liver cancer. It can also occur in chronic HBV infections that develop into liver cancer without passing through the cirrhosis stage. The current understanding of its mechanism involves HBV-DNA integration, particularly the integration of the X gene. HBxAg's transactivation of proto-oncogenes plays a significant role. Additionally, carcinogens such as aflatoxin have a certain synergistic effect.

bubble_chart Differentiation

1. Drug-induced hepatitis

is characterized by: ① A history of medication use, with many known drugs capable of causing varying degrees of liver damage. For example, isoniazid and rifampin can lead to clinical manifestations similar to viral hepatitis; long-term use of diethylstilbestrol, methyldopa, etc., can result in chronic active hepatitis; chlorpromazine, methyltestosterone, arsenic, antimony agents, ketoconazole, etc., can cause cholestatic hepatitis. ② Mild clinical symptoms, isolated ALT elevation, and increased eosinophils. ③ Symptoms gradually improve and ALT returns to normal after discontinuation of the drug.

2. Cholelithiasis

A history of biliary colic, high fever, chills, right upper abdominal pain, positive Murphy's sign, elevated white blood cell count, and increased neutrophils.

3. Primary biliary cirrhosis

is characterized by: ① More common in middle-aged women; ② Persistent and significant jaundice, cutaneous pruritus, often with xanthomas, marked hepatosplenomegaly, significantly elevated ALP, and positive anti-mitochondrial antibodies in most cases; ③ Mild liver function impairment; ④ Negative hepatitis B markers.

4. Hepatolenticular degeneration (Wilson's disease)

Often has a family history, typically presenting with coarse limb tremors, increased muscle tone, a brownish-green pigmented ring (K-F ring) at the edge of the cornea, reduced blood copper and ceruloplasmin levels, and increased urinary copper. In contrast, chronic active liver disease shows significantly elevated blood copper and ceruloplasmin.

5. Acute fatty liver of pregnancy

Mostly occurs in the late stage of pregnancy (third trimester). Clinical features include: ① Initial stage (first stage) presents with acute severe upper abdominal pain and elevated amylase, resembling acute pancreatitis; ② Despite severe jaundice and elevated serum direct bilirubin, urinary bilirubin is often negative. Domestic reports suggest this phenomenon may also occur in acute severe hepatitis for reference; ③ Severe bleeding and renal impairment often appear before liver failure, with elevated ALT but normal thymol turbidity; ④ B-ultrasound shows a fatty liver pattern, aiding early diagnosis, with confirmation relying on pathological examination. Pathological features include enlarged hepatocytes in the central zone of the liver lobule, cytoplasm filled with fat vacuoles, and absence of massive hepatocyte necrosis.

6. Extrahepatic obstructive jaundice

Conditions such as pancreatic cancer, common bile duct cancer, and chronic pancreatitis require differentiation.