Title: Prognostic Value of Plasma Level of Superoxide Dismutase in HBV-related Acute-on-
chronic Liver Failure
Version: 2 Date: 02 May 2022
Reviewer's report:
Dear Editor,
This is a really interesting paper, recommending a novel prognostic marker in the era of acute-
on-chronic liver failure in HBV patients. However, there are significant limitations.
Major comments:
1) The manuscript needs editing for grammar and syntax errors.
2) Lines 58-61. Authors stated that “while in American and European countries, alcoholic liver
disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the major causes of ACLF” and
“In China, more than 80% ACLF cases are caused by chronic HBV infection, as almost 7.18%
adults are positive for HBV surface antigen”. This is not actually true. ACLF is not “caused”
by the underlying chronic liver disease. According to both EASL and APASL guidelines, the
cause of ACLF refers to the precipitating event-acute insult. For example, alcoholic liver disease
and non-alcoholic fatty liver disease are the main causes of chronic liver disease/cirrhosis in
Europe. However, the most common precipitating events of ACLF, regardless of the chronic
liver disease, are infections and alcoholic hepatitis. [Bajaj JS. Defining acute-on-chronic liver
failure: will East and West ever meet? Gastroenterology. 2013;144:1337–1339, Sharin SK et
al, Hepatol Int. 2019 Jul; 13(4): 353–390]. Hepatitis B is a cause of ACLF in case either of
reactivation in patients with chronic hepatitis B or new infection in patients with preexisting
liver disease whatever the cause of the chronic condition.
3) Authors should clarify the cause of the chronic liver disease in cirrhotic patients studied as
controls.
4) The manuscript is entitled “Prognostic Value of Plasma level of SOD in HBV-related Acute-
on-Chronic Liver Failure caused by Discontinuation of Entecavir”
- Group of Discontinuation of ETV includes only 47 from 200 HBV-ACLF patients. ROC curve
as well as multivariate analysis were performed for the total cohort of HBV-ACLF patients. In
my opinion, the content of the manuscript cannot justify the choice of the title. Authors could
provide a sub-analysis only for these specific group of patients.
-Authors should provide information about the acute insult that led to ACLF in HBV patients
that were under treatment with ETV. Based on the statistical analysis provided, it seems that
SOD is an accurate marker of adverse events in HBV-ACLF in general and not only in the
subgroup that discontinued ETV.
5) Multivariate analysis.
- Authors should clarify which variables they included in multivariate analysis.
- It seems authors included both MELD score and its component, INR. Inclusion of highly related
variables leads to collinearity problems making analysis unreliable.
Minor Comments:
1) Line 25. Please add “is” after “whether plasma level of SOD…”
2) Please expand the abbreviation “SOD” both in the title as well as the first time mentioned
in the abstract
3) Lines 53-54. Please rephrase “and high short-time mortality in patients based on chronic liver
diseases”
4) Lines 79-80. Please rephrase “score can be used assessing disease severity and outcomes of
HBV-ACLF patients”
5) Lines 95-96: Please rephrase “especially patients caused by ETV withdrawal”.
6) Line 113: “Plasma” levels instead of “Plasm”
7) Line 123: Please expand the abbreviation “HIV”
8) Line 150: Authors could write “in the present” instead of “in this present study”
9) Line 152: Please rephrase “Withdrawal of ETV improved mortality rate in HBV-ACLF
patients”
10) Lines 156-157:  Please rephrase “We collected another 16 HBV-ACLF patients didn’t take
any NAs or treat with interferon, and found 8 patients died at 90 days (Figue1A)”
11) Lines 159-160:  Please rephrase “To our knowledge, withdrawal of NAs leads to reactivation
of HBV, we then compared Log10(HBV-DNA among different groups”
12) Line 170: Authors could add “mortality” after “HBV-ACLF”
13) Line 219-220: Please rephrase “mortality rates compared to ETV treated patients, we then
wonder what causes this difference”
14) Line 229: Please rephrase “Oxidative stress has been shown participated”
Title: Prognostic Value of Plasma Level of Superoxide Dismutase in HBV-related Acute-on-
chronic Liver Failure
Version: 2 Date: 02 May 2022
Reviewer's report:
Dear Editor,
This is a really interesting paper, recommending a novel prognostic marker in the era of acute-
on-chronic liver failure in HBV patients. However, there are significant limitations.
Major comments:
1) The manuscript needs editing for grammar and syntax errors.
2) Lines 58-61. Authors stated that “while in American and European countries, alcoholic liver
disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the major causes of ACLF” and
“In China, more than 80% ACLF cases are caused by chronic HBV infection, as almost 7.18%
adults are positive for HBV surface antigen”. This is not actually true. ACLF is not “caused”
by the underlying chronic liver disease. According to both EASL and APASL guidelines, the
cause of ACLF refers to the precipitating event-acute insult. For example, alcoholic liver disease
and non-alcoholic fatty liver disease are the main causes of chronic liver disease/cirrhosis in
Europe. However, the most common precipitating events of ACLF, regardless of the chronic
liver disease, are infections and alcoholic hepatitis. [Bajaj JS. Defining acute-on-chronic liver
failure: will East and West ever meet? Gastroenterology. 2013;144:1337–1339, Sharin SK et
al, Hepatol Int. 2019 Jul; 13(4): 353–390]. Hepatitis B is a cause of ACLF in case either of
reactivation in patients with chronic hepatitis B or new infection in patients with preexisting
liver disease whatever the cause of the chronic condition.
3) Authors should clarify the cause of the chronic liver disease in cirrhotic patients studied as
controls.
4) The manuscript is entitled “Prognostic Value of Plasma level of SOD in HBV-related Acute-
on-Chronic Liver Failure caused by Discontinuation of Entecavir”
- Group of Discontinuation of ETV includes only 47 from 200 HBV-ACLF patients. ROC curve
as well as multivariate analysis were performed for the total cohort of HBV-ACLF patients. In
my opinion, the content of the manuscript cannot justify the choice of the title. Authors could
provide a sub-analysis only for these specific group of patients.
-Authors should provide information about the acute insult that led to ACLF in HBV patients
that were under treatment with ETV. Based on the statistical analysis provided, it seems that
SOD is an accurate marker of adverse events in HBV-ACLF in general and not only in the
subgroup that discontinued ETV.
5) Multivariate analysis.
- Authors should clarify which variables they included in multivariate analysis.
- It seems authors included both MELD score and its component, INR. Inclusion of highly related
variables leads to collinearity problems making analysis unreliable.
Minor Comments:
1) Line 25. Please add “is” after “whether plasma level of SOD…”
2) Please expand the abbreviation “SOD” both in the title as well as the first time mentioned
in the abstract
3) Lines 53-54. Please rephrase “and high short-time mortality in patients based on chronic liver
diseases”
4) Lines 79-80. Please rephrase “score can be used assessing disease severity and outcomes of
HBV-ACLF patients”
5) Lines 95-96: Please rephrase “especially patients caused by ETV withdrawal”.
6) Line 113: “Plasma” levels instead of “Plasm”
7) Line 123: Please expand the abbreviation “HIV”
8) Line 150: Authors could write “in the present” instead of “in this present study”
9) Line 152: Please rephrase “Withdrawal of ETV improved mortality rate in HBV-ACLF
patients”
10) Lines 156-157:  Please rephrase “We collected another 16 HBV-ACLF patients didn’t take
any NAs or treat with interferon, and found 8 patients died at 90 days (Figue1A)”
11) Lines 159-160:  Please rephrase “To our knowledge, withdrawal of NAs leads to reactivation
of HBV, we then compared Log10(HBV-DNA among different groups”
12) Line 170: Authors could add “mortality” after “HBV-ACLF”
13) Line 219-220: Please rephrase “mortality rates compared to ETV treated patients, we then
wonder what causes this difference”
14) Line 229: Please rephrase “Oxidative stress has been shown participated”
Please review this paper.
user
Title: Prognostic Value of Plasma Level of Superoxide Dismutase in HBV-related Acute-on-
chronic Liver Failure
Version: 2 Date: 02 May 2022
Reviewer's report:
Dear Editor,
This is a really interesting paper, recommending a novel prognostic marker in the era of acute-
on-chronic liver failure in HBV patients. However, there are significant limitations.
Major comments:
1) The manuscript needs editing for grammar and syntax errors.
2) Lines 58-61. Authors stated that “while in American and European countries, alcoholic liver
disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the major causes of ACLF” and
“In China, more than 80% ACLF cases are caused by chronic HBV infection, as almost 7.18%
adults are positive for HBV surface antigen”. This is not actually true. ACLF is not “caused”
by the underlying chronic liver disease. According to both EASL and APASL guidelines, the
cause of ACLF refers to the precipitating event-acute insult. For example, alcoholic liver disease
and non-alcoholic fatty liver disease are the main causes of chronic liver disease/cirrhosis in
Europe. However, the most common precipitating events of ACLF, regardless of the chronic
liver disease, are infections and alcoholic hepatitis. [Bajaj JS. Defining acute-on-chronic liver
failure: will East and West ever meet? Gastroenterology. 2013;144:1337–1339, Sharin SK et
al, Hepatol Int. 2019 Jul; 13(4): 353–390]. Hepatitis B is a cause of ACLF in case either of
reactivation in patients with chronic hepatitis B or new infection in patients with preexisting
liver disease whatever the cause of the chronic condition.
3) Authors should clarify the cause of the chronic liver disease in cirrhotic patients studied as
controls.
4) The manuscript is entitled “Prognostic Value of Plasma level of SOD in HBV-related Acute-
on-Chronic Liver Failure caused by Discontinuation of Entecavir”
- Group of Discontinuation of ETV includes only 47 from 200 HBV-ACLF patients. ROC curve
as well as multivariate analysis were performed for the total cohort of HBV-ACLF patients. In
my opinion, the content of the manuscript cannot justify the choice of the title. Authors could
provide a sub-analysis only for these specific group of patients.
-Authors should provide information about the acute insult that led to ACLF in HBV patients
that were under treatment with ETV. Based on the statistical analysis provided, it seems that
SOD is an accurate marker of adverse events in HBV-ACLF in general and not only in the
subgroup that discontinued ETV.
5) Multivariate analysis.
- Authors should clarify which variables they included in multivariate analysis.
- It seems authors included both MELD score and its component, INR. Inclusion of highly related
variables leads to collinearity problems making analysis unreliable.
Minor Comments:
1) Line 25. Please add “is” after “whether plasma level of SOD…”
2) Please expand the abbreviation “SOD” both in the title as well as the first time mentioned
in the abstract
3) Lines 53-54. Please rephrase “and high short-time mortality in patients based on chronic liver
diseases”
4) Lines 79-80. Please rephrase “score can be used assessing disease severity and outcomes of
HBV-ACLF patients”
5) Lines 95-96: Please rephrase “especially patients caused by ETV withdrawal”.
6) Line 113: “Plasma” levels instead of “Plasm”
7) Line 123: Please expand the abbreviation “HIV”
8) Line 150: Authors could write “in the present” instead of “in this present study”
9) Line 152: Please rephrase “Withdrawal of ETV improved mortality rate in HBV-ACLF
patients”
10) Lines 156-157:  Please rephrase “We collected another 16 HBV-ACLF patients didn’t take
any NAs or treat with interferon, and found 8 patients died at 90 days (Figue1A)”
11) Lines 159-160:  Please rephrase “To our knowledge, withdrawal of NAs leads to reactivation
of HBV, we then compared Log10(HBV-DNA among different groups”
12) Line 170: Authors could add “mortality” after “HBV-ACLF”
13) Line 219-220: Please rephrase “mortality rates compared to ETV treated patients, we then
wonder what causes this difference”
14) Line 229: Please rephrase “Oxidative stress has been shown participated”
assistant