How to manage chronic hepatitis B whose liver function indicators continue to be normal?

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Based on the 2019 China Guidelines for the Prevention and Treatment of Chronic Hepatitis B, this consensus supplements the latest developments in chronic hepatitis B (CHB) in which alanine aminotransferase (ALT) continues to be normal, and aims to help clinicians maintain normal ALT.

The results of the national epidemiological survey in 2014 showed that the positive rate of hepatitis B surface antigen (HBsAg) in the Chinese population was 5.

ALT upper limit of normal

ALT is the most direct indicator of liver inflammation

The American Society of Liver Diseases (AASLD) recommends adjusting the ULN of ALT to 30 U/L for men and 19 U/L for women; South Korea recommends adjusting to 34 U/L for men and 24 U/L for women; Japan recommends adjusting it to 29 U/L for men , Female 23 U/L; China’s latest research suggests adjusting it to 35 U/L for males and 23 U/L for females

Recommendation: The ULN standard for ALT varies from country to country or region, and it is recommended that the respective recommendations prevail

The pathological changes of liver tissue of CHB with persistently normal ALT

A large number of studies have confirmed that CHB patients with persistently normal ALT have liver biopsy histopathology, and most of them have chronic inflammation or fibrosis.

Influence of baseline ALT levels in CHB patients with persistently normal ALT on antiviral efficacy

Some scholars have studied patients with normal or mildly elevated ALT.

Recommendation: Because ALT levels are not always parallel to the degree of liver inflammation and fibrosis; therefore, relying solely on ALT levels to determine whether treatment is necessary has great limitations

Clinical evaluation

Assess whether it is in clinical CHB and decide whether treatment before, to the exclusion of fatty liver disease, their immune liver disease, other diseases and so on

HBV DNA is mainly used to assess the level of virus replication in HBV infected persons, and is an important indicator for the selection of indications and efficacy of antiviral therapy

age

Age> 30 years old, no family history of liver cirrhosis or liver cancer, non-invasive evaluation of liver fibrosis or liver histological examination, there is obvious liver inflammation or fibrosis, antiviral therapy is recommended

Family history

With a family history of liver cirrhosis or liver cancer, and the age is more than 30 years old, antiviral therapy is recommended

Laboratory examination

1.

2.

3.

4.

5.
Others: The ratio of serum cytokeratin 18-M30 and M65 fragments (M30/M65) has a good diagnostic value for CHB and is expected to become a new diagnostic marker for chronic hepatitis B.
>120 U/L is active hepatitis B
.
(Level C evidence, Level 2 recommendation)

Image diagnosis

1.
Transient elastography (TE): In a multi-center study in China, the diagnostic cut-off value for hepatitis B cirrhosis is recommended to be the measured value of liver stiffness (LSM) 160.
0 mm Hg (1kPa=7.
5 mm Hg), advanced liver fibrosis LSM > 93.
0 mm Hg, significant liver fibrosis LSM> 68.
2 mm Hg; if the diagnostic criteria for liver fibrosis is not met, and the combination of viral and serological indicators still cannot determine whether treatment should be performed, liver biopsy should be considered
.
(Level B evidence, Level 2 recommendation)

2.
Abdominal ultrasound: the liver surface is not smooth and the boundary is not clear; CT indicates that the liver is reduced in size, the edges of the liver are not smooth, and multiple regenerative nodules; MRI indicates that there are multiple cirrhosis and atypical regenerative nodules in the liver parenchyma.
The basis should be active antiviral treatment
.
(Level A evidence, Level 1 recommendation)

3.
Magnetic Resonance Elastography (MRE): The evaluation of liver fibrosis has high reliability, and the diagnostic accuracy is not affected by the patient's age, gender, obesity and liver inflammation; the acoustic pulse radiation force is still in the clinical research stage (ARFI) Elastography and Two-dimensional Shear Wave Elastography (2D-SWE) have initially shown a certain diagnostic value
.

Pathology

Liver histology shows obvious inflammation grade (Grade ≥ G2) and/or fibrosis stage (State ≥ S2), and antiviral therapy is recommended
.
(Level A evidence, Level 1 recommendation)

Hepatic Venous Pressure Gradient (HVPG)

When HVPG> 5 mmHg, it indicates the presence of portal hypertension in liver cirrhosis, and antiviral therapy is recommended
.
HVPG has important significance in the risk stratification of portal hypertension in liver cirrhosis, but it is not used as a routine method to predict the degree of liver cirrhosis
.
(Level B evidence, Level 2 recommendation)

treatment

The overall goal of CHB treatment with continuous normal ALT is: to maximize long-term inhibition or elimination of HBV, alleviate liver cell inflammation and necrosis and liver fibrosis, and prevent the disease from progressing to liver cirrhosis and liver cancer
.
The main treatment methods include antiviral, anti-inflammatory and liver protection and symptomatic treatment.
Among them, antiviral treatment is the key.
As long as there are indications and conditions permit, standard antiviral treatment should be carried out
.

The more limited clinical stage treatment for CHB patients with persistently normal transaminases, including interferons, nucleotide analogues, hepatoprotective drugs and the like
.

Interferon

China has approved peginterferon (Peg-IFN-α) and common interferon-α for the treatment of CHB patients with persistently normal transaminase
.
The usage, dosage, and course of interferon can be recommended by referring to the 2019 Chronic Hepatitis B Guidelines
.
(Level B evidence, level 1 recommendation)

Nucleotide analogs

Entecavir: level B evidence, level 1 recommendation;

Tenofovir: Level B evidence, Level 1 recommendation;

Lamivudine: Level C evidence, level 1 recommendation
.

Chinese medicine liver protection drugs

Traditional Chinese medicine treatment of chronic liver disease is to strengthen the body and eliminate the evil.
Common treatment methods include clearing away heat and detoxification, removing phlegm and dredging collaterals, soothing the liver and regulating qi, promoting blood circulation and removing blood stasis, softening and dispelling masses, replenishing qi and nourishing yin, invigorating the spleen and removing dampness, invigorating the kidney, softening the liver, and clearing away heat.
detoxification, dampness detoxification, blood detoxification, righting detoxification
.
Yinchenhao Decoction, Biejia Decoction Pills, Chaihu Shugan Powder and other traditional Chinese medicine prescriptions are widely used in the clinical treatment of liver disease
.
(Level C evidence, level 1 recommendation)
.

Other treatments

Recombinant highly effective antitumor and antiviral protein injection (level B evidence, level 1 recommendation)
.

In addition to the above-mentioned antiviral treatments, for CHB patients with persistently normal ALT, anti-inflammatory and hepatoprotective drugs can also be used to relieve inflammation in the liver, such as reduced glutathione, etc.
, to promote liver cell regeneration
.
(Level B evidence, level 1 recommendation)

Treatment prospects

The treatment of chronic hepatitis B is a long-term process.
It is necessary to correctly evaluate the relationship between normal ALT level and liver inflammation, and the timing of CHB antiviral treatment with normal ALT level should be considered in many factors
.
Existing antiviral treatments are difficult to clear HBV infection and achieve a complete cure.
Many patients need to receive nucleotide analog antiviral therapy for a long time.
The root cause is the presence of transcriptionally active covalently closed circular DNA in the liver cell nucleus.
(CccDNA)
.
Therefore, the direct use of cccDNA targeting agents combined with immunotherapy can be used as a new and effective means to cure chronic hepatitis B, and has far-reaching clinical treatment prospects
.

Reference materials:

Chen Yongping,Yang Yongping,Ding Huiguo,Lin Minghua,Zhang Mingxiang,Chen Liang,Deng Cunliang,Wu Xiaoping,Li Yongguo,Lin Feng.
Expert consensus on diagnosis and treatment of chronic hepatitis B with persistent normal alanine aminotransferase[J].
Chinese Research Hospital,2021, 8(04):1-6.