Title: A clinical predictive score of high liver iron content in metabolic hyperferritinemia; a
retrospective cohort pilot study
Version: 2 Date: 06 Mar 2025
Reviewer:  Tomas Koller
Reviewer's report:
Dear editor, I read with interest the manuscript entitled "A clinical predictive score of high liver
iron content in metabolic hyperferritinemia; a retrospective cohort pilot study "
The topic is up-to-date, and the study is nicely presented with a sound introduction, methods,
and results. The clinical application of the results is somewhat limited, but since very few studies
have addressed the prediction of liver iron overload in DIOS, it is certainly of value to clinicians,
particularly hepatologists. I have no major comments or issues, but I have a few questions.
1. The threshold for DIOS has been set at 74 umol/g (citation 20). What percentage of the cohort
had grade 3 DIOS according to this cut-off? The authors do not explain in detail what was the
rationale for this value. Was there any evidence that iron overload beyond this value is toxic
for the liver?  If so, it would be clinically useful to identify all patients with DIOS, not only
those with severe iron overload beyond 100umol/g. Were the authors considering the predictive
model for this DIOS threshold?
2. The predictive score is not very granular as seen in the ROC curve, so my question is did the
authors consider a more granular means of creating the predictive score (values for ferritin and
transferrin saturation are numerical), for example, a logit equation with probability?
3. Did the authors have a chance to add some fibroscan parameters (stiffness, CAP) to the
predictive model, I imagine that these patients had these exams done at some point.
4. I do not see any liver tests or GGT in the Tables, those should have been available since they
are listed in the data collection, were they tested as predictors of DIOS?
5. It is interesting to see some difference in dyslipidemia between the groups, but not in the
actual triglycerides or HDL. How do the authors explain this finding? Did they consider therapy
for dyslipidemia as a possible cause?
6. From the studied cohort with a follow-up of over  6 years, did the authors have a chance to
look at outcomes in terms of morbidity and mortality according to iron overload?
Title: A clinical predictive score of high liver iron content in metabolic hyperferritinemia; a
retrospective cohort pilot study
Version: 2 Date: 06 Mar 2025
Reviewer:  Tomas Koller
Reviewer's report:
Dear editor, I read with interest the manuscript entitled "A clinical predictive score of high liver
iron content in metabolic hyperferritinemia; a retrospective cohort pilot study "
The topic is up-to-date, and the study is nicely presented with a sound introduction, methods,
and results. The clinical application of the results is somewhat limited, but since very few studies
have addressed the prediction of liver iron overload in DIOS, it is certainly of value to clinicians,
particularly hepatologists. I have no major comments or issues, but I have a few questions.
1. The threshold for DIOS has been set at 74 umol/g (citation 20). What percentage of the cohort
had grade 3 DIOS according to this cut-off? The authors do not explain in detail what was the
rationale for this value. Was there any evidence that iron overload beyond this value is toxic
for the liver?  If so, it would be clinically useful to identify all patients with DIOS, not only
those with severe iron overload beyond 100umol/g. Were the authors considering the predictive
model for this DIOS threshold?
2. The predictive score is not very granular as seen in the ROC curve, so my question is did the
authors consider a more granular means of creating the predictive score (values for ferritin and
transferrin saturation are numerical), for example, a logit equation with probability?
3. Did the authors have a chance to add some fibroscan parameters (stiffness, CAP) to the
predictive model, I imagine that these patients had these exams done at some point.
4. I do not see any liver tests or GGT in the Tables, those should have been available since they
are listed in the data collection, were they tested as predictors of DIOS?
5. It is interesting to see some difference in dyslipidemia between the groups, but not in the
actual triglycerides or HDL. How do the authors explain this finding? Did they consider therapy
for dyslipidemia as a possible cause?
6. From the studied cohort with a follow-up of over  6 years, did the authors have a chance to
look at outcomes in terms of morbidity and mortality according to iron overload?
Please review this paper.
user
Title: A clinical predictive score of high liver iron content in metabolic hyperferritinemia; a
retrospective cohort pilot study
Version: 2 Date: 06 Mar 2025
Reviewer:  Tomas Koller
Reviewer's report:
Dear editor, I read with interest the manuscript entitled "A clinical predictive score of high liver
iron content in metabolic hyperferritinemia; a retrospective cohort pilot study "
The topic is up-to-date, and the study is nicely presented with a sound introduction, methods,
and results. The clinical application of the results is somewhat limited, but since very few studies
have addressed the prediction of liver iron overload in DIOS, it is certainly of value to clinicians,
particularly hepatologists. I have no major comments or issues, but I have a few questions.
1. The threshold for DIOS has been set at 74 umol/g (citation 20). What percentage of the cohort
had grade 3 DIOS according to this cut-off? The authors do not explain in detail what was the
rationale for this value. Was there any evidence that iron overload beyond this value is toxic
for the liver?  If so, it would be clinically useful to identify all patients with DIOS, not only
those with severe iron overload beyond 100umol/g. Were the authors considering the predictive
model for this DIOS threshold?
2. The predictive score is not very granular as seen in the ROC curve, so my question is did the
authors consider a more granular means of creating the predictive score (values for ferritin and
transferrin saturation are numerical), for example, a logit equation with probability?
3. Did the authors have a chance to add some fibroscan parameters (stiffness, CAP) to the
predictive model, I imagine that these patients had these exams done at some point.
4. I do not see any liver tests or GGT in the Tables, those should have been available since they
are listed in the data collection, were they tested as predictors of DIOS?
5. It is interesting to see some difference in dyslipidemia between the groups, but not in the
actual triglycerides or HDL. How do the authors explain this finding? Did they consider therapy
for dyslipidemia as a possible cause?
6. From the studied cohort with a follow-up of over  6 years, did the authors have a chance to
look at outcomes in terms of morbidity and mortality according to iron overload?
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