Title: Hepatocellular carcinoma in nonalcoholic fatty liver disease with or without cirrhosis: a
population-based study
Version: 1 Date: 05 May 2021
Reviewer's report:
This is an interesting and important study.  However there are some limitations with the dataset.
If these cannot be rectified, they should be acknowledged more specifically in the discussion.
1. Only patients with an established diagnosis of cirrhosis are classified as such.  It is likely that
within the group classed as non-cirrhotic, there are patients with cirrhosis which has not been
reported or detected. This is a limitation, when considering the prevalence of HCC within the
groups.  It may be helpful to include platelet count as a surrogate marker of portal hypertension,
or at least have it shown in the Tables, with the range.  It wasn't clear how the diagnosis of HCC
was made.  Biopsy is required for a diagnosis of HCC in non-cirrhotic patients and may also
provide an opportunity to detect 'asymptomatic' cirrhosis.
2. The alcohol history was not included.  To be more confidant these are NAFLD cases, it may
be relevant to have included searches that would detect alcohol use - either as an exclusion or
as a co-factor.
3. Age analyses are restricted to >65 years for both categories.  What was the age of non-cirrhotic
HCC versus cirrhotic HCC?  I would have liked to see a Table (similar to Table 1) comparing
the characteristics of cirrhotic versus non-cirrhotic HCC cases.
4. This is a comment, rather than something that needs to be further discussed. Obesity was not
an independent risk factor for patients with HCC in patients with NAFLD.  This has also been
seen in genetic studies assessing the risks of HCC in NAFLD.  It is possible that if weight is taken
only at the time of HCC diagnosis, it is lower as a consequence of the cancer and therefore simply
a confounder.  But a lower BMI in NAFLD HCC patients versus NAFLD no HCC patients has
been reported for all stages of cancers.  It may be age related - as older patients get cancers
and weight reduces with age. It is also possible, that fatter NAFLD patients get cirrhosis (plus
cancers)  and thinner ones are less likely to get cirrhosis, but still have a cancer risk with different
biological mechanisms at play. Distinct from the things that promote progression to cirrhosis.
And it takes longer - they are probably older in your cohort.
Title: Hepatocellular carcinoma in nonalcoholic fatty liver disease with or without cirrhosis: a
population-based study
Version: 1 Date: 05 May 2021
Reviewer's report:
This is an interesting and important study.  However there are some limitations with the dataset.
If these cannot be rectified, they should be acknowledged more specifically in the discussion.
1. Only patients with an established diagnosis of cirrhosis are classified as such.  It is likely that
within the group classed as non-cirrhotic, there are patients with cirrhosis which has not been
reported or detected. This is a limitation, when considering the prevalence of HCC within the
groups.  It may be helpful to include platelet count as a surrogate marker of portal hypertension,
or at least have it shown in the Tables, with the range.  It wasn't clear how the diagnosis of HCC
was made.  Biopsy is required for a diagnosis of HCC in non-cirrhotic patients and may also
provide an opportunity to detect 'asymptomatic' cirrhosis.
2. The alcohol history was not included.  To be more confidant these are NAFLD cases, it may
be relevant to have included searches that would detect alcohol use - either as an exclusion or
as a co-factor.
3. Age analyses are restricted to >65 years for both categories.  What was the age of non-cirrhotic
HCC versus cirrhotic HCC?  I would have liked to see a Table (similar to Table 1) comparing
the characteristics of cirrhotic versus non-cirrhotic HCC cases.
4. This is a comment, rather than something that needs to be further discussed. Obesity was not
an independent risk factor for patients with HCC in patients with NAFLD.  This has also been
seen in genetic studies assessing the risks of HCC in NAFLD.  It is possible that if weight is taken
only at the time of HCC diagnosis, it is lower as a consequence of the cancer and therefore simply
a confounder.  But a lower BMI in NAFLD HCC patients versus NAFLD no HCC patients has
been reported for all stages of cancers.  It may be age related - as older patients get cancers
and weight reduces with age. It is also possible, that fatter NAFLD patients get cirrhosis (plus
cancers)  and thinner ones are less likely to get cirrhosis, but still have a cancer risk with different
biological mechanisms at play. Distinct from the things that promote progression to cirrhosis.
And it takes longer - they are probably older in your cohort.
Please review this paper.
user
Title: Hepatocellular carcinoma in nonalcoholic fatty liver disease with or without cirrhosis: a
population-based study
Version: 1 Date: 05 May 2021
Reviewer's report:
This is an interesting and important study.  However there are some limitations with the dataset.
If these cannot be rectified, they should be acknowledged more specifically in the discussion.
1. Only patients with an established diagnosis of cirrhosis are classified as such.  It is likely that
within the group classed as non-cirrhotic, there are patients with cirrhosis which has not been
reported or detected. This is a limitation, when considering the prevalence of HCC within the
groups.  It may be helpful to include platelet count as a surrogate marker of portal hypertension,
or at least have it shown in the Tables, with the range.  It wasn't clear how the diagnosis of HCC
was made.  Biopsy is required for a diagnosis of HCC in non-cirrhotic patients and may also
provide an opportunity to detect 'asymptomatic' cirrhosis.
2. The alcohol history was not included.  To be more confidant these are NAFLD cases, it may
be relevant to have included searches that would detect alcohol use - either as an exclusion or
as a co-factor.
3. Age analyses are restricted to >65 years for both categories.  What was the age of non-cirrhotic
HCC versus cirrhotic HCC?  I would have liked to see a Table (similar to Table 1) comparing
the characteristics of cirrhotic versus non-cirrhotic HCC cases.
4. This is a comment, rather than something that needs to be further discussed. Obesity was not
an independent risk factor for patients with HCC in patients with NAFLD.  This has also been
seen in genetic studies assessing the risks of HCC in NAFLD.  It is possible that if weight is taken
only at the time of HCC diagnosis, it is lower as a consequence of the cancer and therefore simply
a confounder.  But a lower BMI in NAFLD HCC patients versus NAFLD no HCC patients has
been reported for all stages of cancers.  It may be age related - as older patients get cancers
and weight reduces with age. It is also possible, that fatter NAFLD patients get cirrhosis (plus
cancers)  and thinner ones are less likely to get cirrhosis, but still have a cancer risk with different
biological mechanisms at play. Distinct from the things that promote progression to cirrhosis.
And it takes longer - they are probably older in your cohort.
assistant