Title: Liver histology pattern of young patients with inactive chronic hepatitis B virus infection
from a Hospital in South West Nigeria
Version: 3 Date: 21 Jul 2024
Reviewer's report:
This was an interesting study that sought to evaluate the histologic findings of patients under 30
years old with inactive chronic hepatitis B.
There were some important methodologic limitations in the study:
1. How did you ascertain that the selected patients indeed had inactive chronic hepatitis B?  Liver
enzymes and DNA levels fluctuate and a single ALT level and HBV DNA level is insufficient
to assign a phase of infection. Longitudinal follow up of these markers +/- histology is needed
to ascertain the phase of infection. In your inclusion criteria, you did not specify how long
and frequently the patients were followed up before being assigned as having inactive chronic
hepatitis B.
2. You have indicated that all patients in the study had normal ALT levels but did not define
what you considered normal. The upper limit of normal are lower than the lab defined ranges
and are 35 for males and 25 for females as per the AASLD. Did you use these ranges or the
laboratory defined ranges which you seemed to have used in table 2 for AST?
3. Nigeria has a high prevalence of chronic hepatitis D/ hepatitis B infection. Patients with
chronic HBV/HDV infection generally have low HBV DNA levels and are frequently HBeAg
negative  and hepatitis B e antibody (anti-Hbe) positive. This is the exact population you
were analyzing. Did you check for presence of anti-HDV antibody in these population? The
presence of concomitant HDV infection would be the driver of inflammation and fibrosis seen
on histology,
4. You calculated the sample size based on the prevalence of HBsAg in the town where the study
was conducted. I do not see how the prevalence of HBsAg factors into sample size calculation
in this study where you are looking at the presence of inflammation and fibrosis in patients with
inactive chronic hepatitis B.
Conclusions:
A lot of the conclusions are not appropriate and relevant to the study.
You cannot conclude that the ability to recruit 88 patients under 30 years makes early acquisition
common  in your region. This is not what the study was geared towards and should be removed
from the manuscript.
Patients with inactive chronic hepatitis B phase have variable amounts of fibrosis depending
on how long they spent in the immune active phase. This is a well known phenomenon. What
is more important is the finding of necroinflammation in these patients as this would not be
expected given the low ALT levels (which is another limitation as what was considered low
was not defined). Your discussion should have centered around why there could be ongoing
necroinflammation in these patients. I have highlighted some possible causes including in my
earlier points including inappropriate participant selection (point 1) and patients with chronic
HBV/HDV coinfection (point 3).
Title: Liver histology pattern of young patients with inactive chronic hepatitis B virus infection
from a Hospital in South West Nigeria
Version: 3 Date: 21 Jul 2024
Reviewer's report:
This was an interesting study that sought to evaluate the histologic findings of patients under 30
years old with inactive chronic hepatitis B.
There were some important methodologic limitations in the study:
1. How did you ascertain that the selected patients indeed had inactive chronic hepatitis B?  Liver
enzymes and DNA levels fluctuate and a single ALT level and HBV DNA level is insufficient
to assign a phase of infection. Longitudinal follow up of these markers +/- histology is needed
to ascertain the phase of infection. In your inclusion criteria, you did not specify how long
and frequently the patients were followed up before being assigned as having inactive chronic
hepatitis B.
2. You have indicated that all patients in the study had normal ALT levels but did not define
what you considered normal. The upper limit of normal are lower than the lab defined ranges
and are 35 for males and 25 for females as per the AASLD. Did you use these ranges or the
laboratory defined ranges which you seemed to have used in table 2 for AST?
3. Nigeria has a high prevalence of chronic hepatitis D/ hepatitis B infection. Patients with
chronic HBV/HDV infection generally have low HBV DNA levels and are frequently HBeAg
negative  and hepatitis B e antibody (anti-Hbe) positive. This is the exact population you
were analyzing. Did you check for presence of anti-HDV antibody in these population? The
presence of concomitant HDV infection would be the driver of inflammation and fibrosis seen
on histology,
4. You calculated the sample size based on the prevalence of HBsAg in the town where the study
was conducted. I do not see how the prevalence of HBsAg factors into sample size calculation
in this study where you are looking at the presence of inflammation and fibrosis in patients with
inactive chronic hepatitis B.
Conclusions:
A lot of the conclusions are not appropriate and relevant to the study.
You cannot conclude that the ability to recruit 88 patients under 30 years makes early acquisition
common  in your region. This is not what the study was geared towards and should be removed
from the manuscript.
Patients with inactive chronic hepatitis B phase have variable amounts of fibrosis depending
on how long they spent in the immune active phase. This is a well known phenomenon. What
is more important is the finding of necroinflammation in these patients as this would not be
expected given the low ALT levels (which is another limitation as what was considered low
was not defined). Your discussion should have centered around why there could be ongoing
necroinflammation in these patients. I have highlighted some possible causes including in my
earlier points including inappropriate participant selection (point 1) and patients with chronic
HBV/HDV coinfection (point 3).
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: 3 Date: 21 Jul 2024
Reviewer's report:
This was an interesting study that sought to evaluate the histologic findings of patients under 30
years old with inactive chronic hepatitis B.
There were some important methodologic limitations in the study:
1. How did you ascertain that the selected patients indeed had inactive chronic hepatitis B?  Liver
enzymes and DNA levels fluctuate and a single ALT level and HBV DNA level is insufficient
to assign a phase of infection. Longitudinal follow up of these markers +/- histology is needed
to ascertain the phase of infection. In your inclusion criteria, you did not specify how long
and frequently the patients were followed up before being assigned as having inactive chronic
hepatitis B.
2. You have indicated that all patients in the study had normal ALT levels but did not define
what you considered normal. The upper limit of normal are lower than the lab defined ranges
and are 35 for males and 25 for females as per the AASLD. Did you use these ranges or the
laboratory defined ranges which you seemed to have used in table 2 for AST?
3. Nigeria has a high prevalence of chronic hepatitis D/ hepatitis B infection. Patients with
chronic HBV/HDV infection generally have low HBV DNA levels and are frequently HBeAg
negative  and hepatitis B e antibody (anti-Hbe) positive. This is the exact population you
were analyzing. Did you check for presence of anti-HDV antibody in these population? The
presence of concomitant HDV infection would be the driver of inflammation and fibrosis seen
on histology,
4. You calculated the sample size based on the prevalence of HBsAg in the town where the study
was conducted. I do not see how the prevalence of HBsAg factors into sample size calculation
in this study where you are looking at the presence of inflammation and fibrosis in patients with
inactive chronic hepatitis B.
Conclusions:
A lot of the conclusions are not appropriate and relevant to the study.
You cannot conclude that the ability to recruit 88 patients under 30 years makes early acquisition
common  in your region. This is not what the study was geared towards and should be removed
from the manuscript.
Patients with inactive chronic hepatitis B phase have variable amounts of fibrosis depending
on how long they spent in the immune active phase. This is a well known phenomenon. What
is more important is the finding of necroinflammation in these patients as this would not be
expected given the low ALT levels (which is another limitation as what was considered low
was not defined). Your discussion should have centered around why there could be ongoing
necroinflammation in these patients. I have highlighted some possible causes including in my
earlier points including inappropriate participant selection (point 1) and patients with chronic
HBV/HDV coinfection (point 3).
assistant