Title: Liver histology pattern of young patients with inactive chronic hepatitis B virus infection
from a Hospital in South West Nigeria
Version: 4 Date: 27 Aug 2024
Reviewer's report:
Abstract:
Okay
Background:
Could be more focused. The infectiousness and mode of transmission of hepatitis B are not
really relevant to the issue being studied. There is also a lot of focus on HCC throughout, which
is also not directly relevant. In addition there is also a lot of repetition with the same concepts
being stated in different ways.
The upper limit of normal of ALT should be explicitly indicated.
Methods:
The authors need to state which hospital the study was done.
The upper limit of normal of ALT as per SOGHIN should be explicitly indicated.
The authors should indicate in the article the reason they gave in the point to point response
for using HBsAg prevalence (which is not related to the outcome of interest) to calculate the
sample size.
Which hospital is “our hospital”? The 6 authors are from 4 different hospitals.
Results
Is there any expected association of occupation, religion and tribe with the results?
Instead of presenting bilirubin results as normal (up to 20 µmol/L) and high (greater than 20
µmol/L), it may be more informative to have them in ranges e.g.  <34.2 µmol/L, 34.2-51.3 µmol/
L, > 51.3 µmol/L (as per the Child Pugh Scoring system). This would allow a better definition
of the degree of bilirubin elevation seen. It would also eliminate the issue of reference intervals
(are the intervals the authors used specific to the Nigerian population?). A study from Kenya
obtained a reference intervals of total bilirubin of 6–43 µmol/L for males and 5–27 µmol/L for
females, which are higher than those from outside Africa. (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC7347104/#pone.0235234.s006)
The more interesting results is necro-inflammation rather than fibrosis. Fibrosis is expected in
this population due to transition through immune active phases in the past. The focus of the
results therefore should be on the presence of inflammation in the biopsy results without lumping
it together with fibrosis. These can be presented separately.
The difference in the presence of inflammation and fibrosis according to age group (25-29 vs
<25) was not statistically significant. The statement needs to be rephrased to make it clear.
Discussion:
The methodology of the study does not allow an inference of the age of acquisition of hepatitis B.
To my knowledge, binding of hormones and calcium to albumin does not affect albumin levels.
See point on bilirubin under results. The reference ranges used may explain why bilirubin was
elevated without any correlation to necroinflammation and fibrosis.
As noted above, presence of fibrosis should not be unexpected given that the patients have
transitioned from an immune active phase previously. There are other non-invasive ways to
assess for fibrosis like liver elastography. This should be factored into the discussion given
the limitations noted with APRI score. The focus of the discussion therefore should be on
presence of necroinflammation. There should be a balanced discussion on the reasons of ongoing
necroinflammation despite an inactive state of hepatitis B infection. This should be based on
the limitations of the study i.e. evaluating for presence of HDV, metabolic, toxic among other
causes of ongoing liver inflammation vs the role of hepatitis B. The way this is presented in
the manuscript is leaning heavily towards implicating hepatitis B with the other causes coming
as an afterthought.
Could the presence of necroinflammation in the patients with a family history of liver disease/
death from liver disease be due to a heritable condition like hemochromatosis?
Limitations and Strengths:
Two pathologists reviewing the histology should appear under methodology as well.
Conclusions:
Given the limitations of the methodology, are the authors certain that the liver histology findings
are solely attributable to hepatitis B?
Title: Liver histology pattern of young patients with inactive chronic hepatitis B virus infection
from a Hospital in South West Nigeria
Version: 4 Date: 27 Aug 2024
Reviewer's report:
Abstract:
Okay
Background:
Could be more focused. The infectiousness and mode of transmission of hepatitis B are not
really relevant to the issue being studied. There is also a lot of focus on HCC throughout, which
is also not directly relevant. In addition there is also a lot of repetition with the same concepts
being stated in different ways.
The upper limit of normal of ALT should be explicitly indicated.
Methods:
The authors need to state which hospital the study was done.
The upper limit of normal of ALT as per SOGHIN should be explicitly indicated.
The authors should indicate in the article the reason they gave in the point to point response
for using HBsAg prevalence (which is not related to the outcome of interest) to calculate the
sample size.
Which hospital is “our hospital”? The 6 authors are from 4 different hospitals.
Results
Is there any expected association of occupation, religion and tribe with the results?
Instead of presenting bilirubin results as normal (up to 20 µmol/L) and high (greater than 20
µmol/L), it may be more informative to have them in ranges e.g.  <34.2 µmol/L, 34.2-51.3 µmol/
L, > 51.3 µmol/L (as per the Child Pugh Scoring system). This would allow a better definition
of the degree of bilirubin elevation seen. It would also eliminate the issue of reference intervals
(are the intervals the authors used specific to the Nigerian population?). A study from Kenya
obtained a reference intervals of total bilirubin of 6–43 µmol/L for males and 5–27 µmol/L for
females, which are higher than those from outside Africa. (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC7347104/#pone.0235234.s006)
The more interesting results is necro-inflammation rather than fibrosis. Fibrosis is expected in
this population due to transition through immune active phases in the past. The focus of the
results therefore should be on the presence of inflammation in the biopsy results without lumping
it together with fibrosis. These can be presented separately.
The difference in the presence of inflammation and fibrosis according to age group (25-29 vs
<25) was not statistically significant. The statement needs to be rephrased to make it clear.
Discussion:
The methodology of the study does not allow an inference of the age of acquisition of hepatitis B.
To my knowledge, binding of hormones and calcium to albumin does not affect albumin levels.
See point on bilirubin under results. The reference ranges used may explain why bilirubin was
elevated without any correlation to necroinflammation and fibrosis.
As noted above, presence of fibrosis should not be unexpected given that the patients have
transitioned from an immune active phase previously. There are other non-invasive ways to
assess for fibrosis like liver elastography. This should be factored into the discussion given
the limitations noted with APRI score. The focus of the discussion therefore should be on
presence of necroinflammation. There should be a balanced discussion on the reasons of ongoing
necroinflammation despite an inactive state of hepatitis B infection. This should be based on
the limitations of the study i.e. evaluating for presence of HDV, metabolic, toxic among other
causes of ongoing liver inflammation vs the role of hepatitis B. The way this is presented in
the manuscript is leaning heavily towards implicating hepatitis B with the other causes coming
as an afterthought.
Could the presence of necroinflammation in the patients with a family history of liver disease/
death from liver disease be due to a heritable condition like hemochromatosis?
Limitations and Strengths:
Two pathologists reviewing the histology should appear under methodology as well.
Conclusions:
Given the limitations of the methodology, are the authors certain that the liver histology findings
are solely attributable to hepatitis B?
Please review this paper.
user
Title: Liver histology pattern of young patients with inactive chronic hepatitis B virus infection
from a Hospital in South West Nigeria
Version: 4 Date: 27 Aug 2024
Reviewer's report:
Abstract:
Okay
Background:
Could be more focused. The infectiousness and mode of transmission of hepatitis B are not
really relevant to the issue being studied. There is also a lot of focus on HCC throughout, which
is also not directly relevant. In addition there is also a lot of repetition with the same concepts
being stated in different ways.
The upper limit of normal of ALT should be explicitly indicated.
Methods:
The authors need to state which hospital the study was done.
The upper limit of normal of ALT as per SOGHIN should be explicitly indicated.
The authors should indicate in the article the reason they gave in the point to point response
for using HBsAg prevalence (which is not related to the outcome of interest) to calculate the
sample size.
Which hospital is “our hospital”? The 6 authors are from 4 different hospitals.
Results
Is there any expected association of occupation, religion and tribe with the results?
Instead of presenting bilirubin results as normal (up to 20 µmol/L) and high (greater than 20
µmol/L), it may be more informative to have them in ranges e.g.  <34.2 µmol/L, 34.2-51.3 µmol/
L, > 51.3 µmol/L (as per the Child Pugh Scoring system). This would allow a better definition
of the degree of bilirubin elevation seen. It would also eliminate the issue of reference intervals
(are the intervals the authors used specific to the Nigerian population?). A study from Kenya
obtained a reference intervals of total bilirubin of 6–43 µmol/L for males and 5–27 µmol/L for
females, which are higher than those from outside Africa. (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC7347104/#pone.0235234.s006)
The more interesting results is necro-inflammation rather than fibrosis. Fibrosis is expected in
this population due to transition through immune active phases in the past. The focus of the
results therefore should be on the presence of inflammation in the biopsy results without lumping
it together with fibrosis. These can be presented separately.
The difference in the presence of inflammation and fibrosis according to age group (25-29 vs
<25) was not statistically significant. The statement needs to be rephrased to make it clear.
Discussion:
The methodology of the study does not allow an inference of the age of acquisition of hepatitis B.
To my knowledge, binding of hormones and calcium to albumin does not affect albumin levels.
See point on bilirubin under results. The reference ranges used may explain why bilirubin was
elevated without any correlation to necroinflammation and fibrosis.
As noted above, presence of fibrosis should not be unexpected given that the patients have
transitioned from an immune active phase previously. There are other non-invasive ways to
assess for fibrosis like liver elastography. This should be factored into the discussion given
the limitations noted with APRI score. The focus of the discussion therefore should be on
presence of necroinflammation. There should be a balanced discussion on the reasons of ongoing
necroinflammation despite an inactive state of hepatitis B infection. This should be based on
the limitations of the study i.e. evaluating for presence of HDV, metabolic, toxic among other
causes of ongoing liver inflammation vs the role of hepatitis B. The way this is presented in
the manuscript is leaning heavily towards implicating hepatitis B with the other causes coming
as an afterthought.
Could the presence of necroinflammation in the patients with a family history of liver disease/
death from liver disease be due to a heritable condition like hemochromatosis?
Limitations and Strengths:
Two pathologists reviewing the histology should appear under methodology as well.
Conclusions:
Given the limitations of the methodology, are the authors certain that the liver histology findings
are solely attributable to hepatitis B?
assistant