Title: Low thyroid function is associated with an increased risk of advanced fibrosis in patients
with metabolic dysfunction-associated fatty liver disease
Version: 1 Date: 29 Sep 2022
Reviewer's report:
Major
1. Table 1 legend definition of Type II diabetes is inconsistent with the definition mentioned
in the method section. Please check carefully which definition is used for analysis and update
table/methods accordingly. This may also affect the NFS score itself!
2. There are several non-invasive tests available that aid clinicians in selecting patients at
risk of hepatic fibrosis. However, it should be noted that these scores have low PPV and the
established associations may actually be driven by something else than fibrosis. The fact that
two independent non invasive tests yielded similar results is reassuring, but these findings need
to be validated using more sophisticated techniques like transient elastography, MRE or even
liver biopsies. I realise that this data may not be available, but this should be mentioned as a
limitation. Another option would be to check the associations of the individual components of
the non-invasive scores to investigate what contributed most. If that would be age (although this
was already adjusted for) the association might be primarily driven by age, rather than actual
fibrosis.
3. Somehow I get the feeling that two manuscripts have been combined into one reading this
paper. The first key message is the changes over time in FLD and lean FLD prevalence and the
other key message focusses on thyroid function and (advanced) liver disease. Given the title I
would recommend the authors to solely focus on thyroid function then the paper will be more
concise and easier to read for the readership. In another paper the authors may focus on changes
in FLD prevalence overtime in China.
4. Although the authors stated clearly why to choose for the entire FLD spectrum instead of
NAFLD or MAFLD, I think this may have potentially contributed in not finding an association
between FLD and thyroid function. Patients that have FLD (and fibrosis) due to alcohol
consumption may express different thyroid function than patients with metabolic dysfunction
associated fatty liver disease. I recommend the authors to do a (supplementary) sensitivity
analysis with NAFLD or MAFLD as exposure, since the potential mechanism of thyroid function
being a risk factor is due to increased metabolic dysfunction.
Minor
1. Please show the middle group as well in figure 2
2. Line 257: “It is worth noting that, in addition to hypothyroidism, SCH, which had a higher
prevalence, was also associated with FLD risk” The reviewer does not see any evidence in this
study that hypothyroidism is associated with increased FLD risk. If this is based on previous
studies please mention that explicitly.
3. Line 270: Please check whether incidence is the right term, or whether this should actually
be prevalence.
4. Line 265: “our findings indicate that patients with FLD should maintain their TSH levels
at a strict-normal level to reduce the risk of hepatic fibrosis.” This is a rather bold statement
especially since this is a cross-sectional study which could not provide information on causality.
I would state that the finding requires validation in longitudinal studies whether indeed
maintaining TSH levels results in reduced rates of fibrosis progression in FLD patients.
5. Please include in table 3 the covariates that were adjusted for in the table legend.
Title: Low thyroid function is associated with an increased risk of advanced fibrosis in patients
with metabolic dysfunction-associated fatty liver disease
Version: 1 Date: 29 Sep 2022
Reviewer's report:
Major
1. Table 1 legend definition of Type II diabetes is inconsistent with the definition mentioned
in the method section. Please check carefully which definition is used for analysis and update
table/methods accordingly. This may also affect the NFS score itself!
2. There are several non-invasive tests available that aid clinicians in selecting patients at
risk of hepatic fibrosis. However, it should be noted that these scores have low PPV and the
established associations may actually be driven by something else than fibrosis. The fact that
two independent non invasive tests yielded similar results is reassuring, but these findings need
to be validated using more sophisticated techniques like transient elastography, MRE or even
liver biopsies. I realise that this data may not be available, but this should be mentioned as a
limitation. Another option would be to check the associations of the individual components of
the non-invasive scores to investigate what contributed most. If that would be age (although this
was already adjusted for) the association might be primarily driven by age, rather than actual
fibrosis.
3. Somehow I get the feeling that two manuscripts have been combined into one reading this
paper. The first key message is the changes over time in FLD and lean FLD prevalence and the
other key message focusses on thyroid function and (advanced) liver disease. Given the title I
would recommend the authors to solely focus on thyroid function then the paper will be more
concise and easier to read for the readership. In another paper the authors may focus on changes
in FLD prevalence overtime in China.
4. Although the authors stated clearly why to choose for the entire FLD spectrum instead of
NAFLD or MAFLD, I think this may have potentially contributed in not finding an association
between FLD and thyroid function. Patients that have FLD (and fibrosis) due to alcohol
consumption may express different thyroid function than patients with metabolic dysfunction
associated fatty liver disease. I recommend the authors to do a (supplementary) sensitivity
analysis with NAFLD or MAFLD as exposure, since the potential mechanism of thyroid function
being a risk factor is due to increased metabolic dysfunction.
Minor
1. Please show the middle group as well in figure 2
2. Line 257: “It is worth noting that, in addition to hypothyroidism, SCH, which had a higher
prevalence, was also associated with FLD risk” The reviewer does not see any evidence in this
study that hypothyroidism is associated with increased FLD risk. If this is based on previous
studies please mention that explicitly.
3. Line 270: Please check whether incidence is the right term, or whether this should actually
be prevalence.
4. Line 265: “our findings indicate that patients with FLD should maintain their TSH levels
at a strict-normal level to reduce the risk of hepatic fibrosis.” This is a rather bold statement
especially since this is a cross-sectional study which could not provide information on causality.
I would state that the finding requires validation in longitudinal studies whether indeed
maintaining TSH levels results in reduced rates of fibrosis progression in FLD patients.
5. Please include in table 3 the covariates that were adjusted for in the table legend.
Please review this paper.
user
Title: Low thyroid function is associated with an increased risk of advanced fibrosis in patients
with metabolic dysfunction-associated fatty liver disease
Version: 1 Date: 29 Sep 2022
Reviewer's report:
Major
1. Table 1 legend definition of Type II diabetes is inconsistent with the definition mentioned
in the method section. Please check carefully which definition is used for analysis and update
table/methods accordingly. This may also affect the NFS score itself!
2. There are several non-invasive tests available that aid clinicians in selecting patients at
risk of hepatic fibrosis. However, it should be noted that these scores have low PPV and the
established associations may actually be driven by something else than fibrosis. The fact that
two independent non invasive tests yielded similar results is reassuring, but these findings need
to be validated using more sophisticated techniques like transient elastography, MRE or even
liver biopsies. I realise that this data may not be available, but this should be mentioned as a
limitation. Another option would be to check the associations of the individual components of
the non-invasive scores to investigate what contributed most. If that would be age (although this
was already adjusted for) the association might be primarily driven by age, rather than actual
fibrosis.
3. Somehow I get the feeling that two manuscripts have been combined into one reading this
paper. The first key message is the changes over time in FLD and lean FLD prevalence and the
other key message focusses on thyroid function and (advanced) liver disease. Given the title I
would recommend the authors to solely focus on thyroid function then the paper will be more
concise and easier to read for the readership. In another paper the authors may focus on changes
in FLD prevalence overtime in China.
4. Although the authors stated clearly why to choose for the entire FLD spectrum instead of
NAFLD or MAFLD, I think this may have potentially contributed in not finding an association
between FLD and thyroid function. Patients that have FLD (and fibrosis) due to alcohol
consumption may express different thyroid function than patients with metabolic dysfunction
associated fatty liver disease. I recommend the authors to do a (supplementary) sensitivity
analysis with NAFLD or MAFLD as exposure, since the potential mechanism of thyroid function
being a risk factor is due to increased metabolic dysfunction.
Minor
1. Please show the middle group as well in figure 2
2. Line 257: “It is worth noting that, in addition to hypothyroidism, SCH, which had a higher
prevalence, was also associated with FLD risk” The reviewer does not see any evidence in this
study that hypothyroidism is associated with increased FLD risk. If this is based on previous
studies please mention that explicitly.
3. Line 270: Please check whether incidence is the right term, or whether this should actually
be prevalence.
4. Line 265: “our findings indicate that patients with FLD should maintain their TSH levels
at a strict-normal level to reduce the risk of hepatic fibrosis.” This is a rather bold statement
especially since this is a cross-sectional study which could not provide information on causality.
I would state that the finding requires validation in longitudinal studies whether indeed
maintaining TSH levels results in reduced rates of fibrosis progression in FLD patients.
5. Please include in table 3 the covariates that were adjusted for in the table legend.
assistant