Professor Li Jie: When chronic HBV infection encounters hepatic steatories

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Professor Li Jie

• Doctor of Medicine, Chief Physician, Researcher

• Professor of Nanjing University, doctoral supervisor, Jiangsu distinguished medical expert

• Administrative Director of the Department of Infectious Diseases, Drum Tower Hospital, Nanjing University School of Medicine

• Visiting scholar at Stanford University and the University of Hong Kong

• Vice President of Infectious Physician Branch of Jiangsu Medical Association

• Member of the Standing Committee of the Hepatology Professional Committee of the Chinese Association of Research Hospitals, Deputy Head of the Fatty Liver and Alcoholic Hepatology Group

• Youth Committee Member of Hepatology Branch of Chinese Medical Association, Member of Fatty Liver and Alcoholic Hepatology Group

• The First "Qilu Health and Health Outstanding Young Talents" in Shandong Province

• His main research interests are the pathogenesis and clinical diagnosis and treatment
  of fatty liver disease and viral hepatitis.
  First author/corresponding author in Lancet Gastroenterology & Hepatology, American Journal of Gastroenterology, Clinical Gastroenterology Hepatology, Alimentary Pharmacology & Therapeutics and other SCI journals have published more than 30 papers, of which 3 have been selected as ESI highly cited
  .
  

• He has undertaken 3 projects of the National Natural Science Foundation of China, as well as 17 projects such as the Ministry of Education Fund, the "13th Five-Year Plan" major special sub-projects, the China Postdoctoral Fund, the Natural Science Foundation of Shandong Province (general and key), and the key research and development plan of Shandong Province
  .
  He has won one Shandong Provincial Science and Technology Progress Award, one Shandong Provincial Medical Science and Technology Award, one Shandong Province University Science and Technology Progress Award, and one Huaxia Medical Science and Technology Award
  .
  

In 2021, a meta-analysis published by Professor Zheng Qi's team from the First Affiliated Hospital of Fujian Medical University included 28,648 CHB patients from 54 studies and found that the rate of CHB combined with hepatic steatosis was as high as 32.
8%, with risk factors including advanced age, male sex, and metabolic factors, whereas hepatitis B e antigen (HBeAg) and HBV DNA levels were negatively correlated with hepatitis steeatosis (Table 1).

Table 1 Influencing factors of CHB combined with hepatic steatosis

Several studies have explored the interaction between CHB and NAFLD:

• A 2019 retrospective study in Israel enrolled 524 patients with treatment-naïve CHB with an average follow-up of 6 years, and both ultrasound and liver puncture diagnosis showed that HBV DNA load was inversely correlated
  with the degree of fatty liver change.
  

• However, the interaction between HBV and hepatic steatosis is still controversial
  .
  Several studies have shown that HBV infection is inversely associated with the risk of hepatic steatosis(Table 2).
  
  

Table 2 Risk of hepatic steatosis in patients with HBV infection

1.
Effect of hepatic steatosis on HBsAg serological conversion rate in CHB patients

In 2020, a retrospective cohort study published by Professor Li Jie's team included 6786 CHB patients with an average follow-up of 131.
88 ±77.
28 months, 564 patients developed cirrhosis, 281 patients developed hepatocellular carcinoma (HCC), and 478 patients obtained HBsAg seroclearance
.
Studies have found that hepatic steatosis can increase the seroconversion rate of HBsAg in CHB patients, but does not increase the incidence of cirrhosis and HCC (Figure 1).

Fig.
1 Comparison of HBsAg seroconversion rate and incidence of liver cirrhosis and HCC in patients with CHB alone with hepatic stestosis

Prospective cohort studies from Taiwan and retrospective studies from Hong Kong also found that comitant fatty liver increased HBsAg serological conversion in CHB patients
.

2.
Effect of hepatic steatosis on CHB inflammation/fibrosis

In 2021, a meta-analysis published by Professor Zheng Qi's team included 28,648 CHB patients from 54 studies, and the results showed that there was no significant correlation between hepatic steeatosis and fibrosis progression in CHB patients (Figure 2).

Fig.
2 Relationship between hepatic steatosis and fibrosis progression in CHB patients

3.
Effect of hepatic steatosis on HCC in CHB patients

In 2021, a retrospective study from Hong Kong, China, enrolled 2403 CHB patients with an average follow-up of 46.
4 months, and 48 patients developed HCC
.
Age (HR 1.
063), male (HR 2.
032), and albumin-bilirubin ratio (HR 2.
393) were positively correlated with HCC occurrence.
Liver CAP (HR 0.
993) was negatively correlated
with HCC development.
Every 10 dB/m reduction in CAP increases the risk
of HCC by 6%.
Conversely, patients with CHB with severe hepatic steosis have a lower incidence of HCC (Figure 3).

In addition, the study found no serious hepatic steatosis, but the incidence of HCC was highest
in CHB patients with F3/F4.

Fig.
3 HCC-free cumulative survival stratified by severity of hepatic steteaosis

4.
Effect of non-alcoholic steatohepatitis (NASH) on liver fibrosis in CHB patients

A 2021 North American study of 420 HBsAg-positive liver biopsy patients from the Hepatitis B Research Network (North American Cohort) included 31.
4% of patients with FLD, of which 18.
3% had isolated steatosis and 13.
1% had NASH
.
Studies have found that the combination of NASH rather than hepatic steatosis increases the risk of
liver fibrosis in patients with CHB.

Table 3 Relationship between FLD status and liver fibrosis in patients with chronic HBV infection

Similarly, a 2022 prospective and cross-sectional study from Shanghai Ruijin Hospital enrolled 1081 patients with liver biopsy with CHB to evaluate liver inflammation and fibrosis showed that NASH instead of NAFLD increased the risk of
liver fibrosis in CHB patients.

5.
Effects of combined NASH on hepatic-related events of CHB

A 2020 hepatic puncture cohort from Canada enrolled 1089 CHB patients between 1985 and 2016 with an average follow-up of 10.
0 years found that comorbid NASH increased the risk of liver-related events (decompensated cirrhosis, liver cancer) and death in CHB patients (Figure 4).

Fig.
4 Combined NASH increases the risk of liver-related events and death in CHB patients

The effect of combined NAFLD on the antiviral response to CHB is inconsistent
.
In 2020, a retrospective single-center cohort study published by Professor Li Jie's team included 555 CHB patients with a median follow-up of 42 months, and found that NAFLD did not affect the antiviral response virology and biochemical response of CHB patients (Figure 5).

Concomitant NAFLD or metabolic syndrome is not
associated with response to antiviral therapy in CHB patients.

Fig.
5 Effect of NAFLD on response to antiviral therapy in CHB patients

A 2016 retrospective multicenter cohort study in Turkey enrolled 145 patients with chronic HBV infection found that NAFLD did not affect the virologic response
to entecavir or tenofovir dip at six and twelve months.

However, another study published in 2017 included 153 patients with treatment-naïve CHB, defined CAP ≥224 dB/m as elevated CAP values, and divided patients into two groups based on CAP values at baseline, showing that patients with normal CAP values had significantly higher rates of alanine aminotransferase (ALT) recursion, HBV DNA clearance, and HBeAg serological conversion than patients with increased CAP
。

A study published in 2012 in 213 CHB patients receiving entecavir as initial antiviral therapy showed that hepatic steeatosis was an independent predictor
of entecavir treatment failure.

Several studies have shown that liver inflammation and fibrosis rather than hepatic steatrosis are the main causes of
disease progression in CHB patients.
At present, the prognosis of clinical outcomes in CHB patients with hepatic steatories is inconsistent, which is related to the diagnostic methods and ethnic differences of patients with hepatic steeatosis in different cohorts, especially the results obtained by the "hepatic penetration cohort" need to be interpreted
with caution.

Metabolic disorders themselves can increase cirrhosis, HCC, and all-cause mortality
in CHB patients.
This suggests that screening and managing metabolic abnormalities in patients with CHB and NAFLD is important
to prevent CHB disease progression in addition to aggressive antiviral therapy.
In the future, it is still necessary to conduct large-sample, multi-center long-term follow-up studies
in CHB patients with NAFLD in terms of disease history, clinical prognosis, and response to antiviral therapy.