Title: A clinical predictive score of high liver iron content in metabolic hyperferritinemia; a
retrospective cohort pilot study
Version: 2 Date: 28 Feb 2025
Reviewer's report:
HEPEDIOS manuscript
Overall an interesting article that is useful for guiding decision making in the selection on
individuals with elevated serum transferrin saturation and ferritin levels. The emphasis needs to
be taken off the “guiding who to find for treatment with phlebotomy” as there is no evidence that
phlebotomy in the DIOS is of any benefit and it could easily result in inappropriate introduction
of this practice.
The aim is simple – find a predictive algorithm for those likely to have LIC > 100. Simply align
the introduction with that aim.
Comments
Introduction
Page 6 – whilst ferritin levels reflect body iron stores in iron overload syndromes and low levels
indicate iron deficiency, there is no evidence that increasing serum ferritin levels accurately
reflect increasing body iron stores outside of the setting Haemochromatosis or secondary iron
overload disorders (eg Olynyk et al Clin Gastroenterol Hepatol 2009 Mar;7(3):359-62.doi:
10.1016/j.cgh.2008.11.010.). Please modify the statement “….whose serum concentration
reflects the patient’s iron stores” to de-emphasise this statement.
Page 7, second paragraph – the authors should also include coverage of the MR methodologies
that are licensed by regulatory bodies – FerriScan, FerriSmart. Many other methods have not
been licensed and are simply delivered locally (St Pierre et al Blood 2005 Jan 15;105(2):855-61.
doi: 10.1182/blood-2004-01-0177).
There is a large heterogeneity in the effects of iron in the liver. Just because iron is elevated above
36 umol/g there is no consensus as to whether that is clinically relevant or should be treated in
anyway. Thus, the last line of the paragraph should state “Currently, there is no indication for
recommending iron depletion therapy in this condition”.
In paragraph 3, the first line should remove the statement “.. and who may therefore benefit
from bloodletting” as it implies a benefit when none has been shown to exists (eg Adams LA et
al Hepatology 2015; Laien et al Hepatology 2017). Furthermore, any discussion about defining
a threshold for treatment of DIOS with phlebotomy has no support in the literature and the
remainder of the introduction in this last paragraph should be removed and replaced with a
statement that the study was designed to validate a model for prediction of LIC greater than 100
umol/g without any reference to a therapeutic application.
There are a number of grammatical errors related to English – please check this out eg
‘differentiale’ instead of ‘differential’.
Methods
Exclusion criteria – whilst p.Cys282Tyr homozygosity is an exclusion, the authors if possible
should document the presence of the compound heterozygous genotype as that may increase
serum iron biochemistry and HIC to some extent and compare this with individuals who possess
neither variant.
Given that at least 25% of the population in most western countries consume more alcohol than
recommended, it would be interesting to see if evaluating the performance of the model whilst
not excluding high alcohol would change the results?
The Gandon method – Was there a quality control system in place for use of the Gandon method
to ensure reproducibility and accuracy of measurement? Were all scans at a single centre or
multiple centres. The method is valid but as with all methods there is the potential for variability
unless stringent quality controls are in place especially if performed at multiple centres.
Results
On page 13, what do the authors mean “No significant difference was found in ferritin level
(960 [Q1Q3: 751-1200] µg/L in patients with LIC # 100 µmol/g vs 827 [Q1Q3: 624-1125] µg/
L, p = 0.08).” Compared with what?
The mutations in HFE as described in the text and table 2 need to be specified as per my earlier
comment related to compound heterozygosity. Many constituencies still regard C282Y/H63D
compound heterozygosity as a type of HFE haemochromatosis requiring treatment and that
may be why the family history of phlebotomy is being revealed. The study may be showing
that individuals with compound heterozygosity and metabolic syndrome (both very common)
are reported to have phlebotomy treatment – this would not be novel. If individuals are being
subjects to phlebotomy outside a diagnosis of iorn overload that would be inappropriate. Please
resolve.
The recommendation that persistent elevation of ferritin above a cut off over 600 and TRS >
45% fits with recent recommendations in other countries and seems logical – the only way to
know how much iron you have is to measure it and the best validated methods for this are MR
methods (eg Zhang et al Med J Aust. 2025 Feb 27.
doi: 10.5694/mja2.52618).
Title: A clinical predictive score of high liver iron content in metabolic hyperferritinemia; a
retrospective cohort pilot study
Version: 2 Date: 28 Feb 2025
Reviewer's report:
HEPEDIOS manuscript
Overall an interesting article that is useful for guiding decision making in the selection on
individuals with elevated serum transferrin saturation and ferritin levels. The emphasis needs to
be taken off the “guiding who to find for treatment with phlebotomy” as there is no evidence that
phlebotomy in the DIOS is of any benefit and it could easily result in inappropriate introduction
of this practice.
The aim is simple – find a predictive algorithm for those likely to have LIC > 100. Simply align
the introduction with that aim.
Comments
Introduction
Page 6 – whilst ferritin levels reflect body iron stores in iron overload syndromes and low levels
indicate iron deficiency, there is no evidence that increasing serum ferritin levels accurately
reflect increasing body iron stores outside of the setting Haemochromatosis or secondary iron
overload disorders (eg Olynyk et al Clin Gastroenterol Hepatol 2009 Mar;7(3):359-62.doi:
10.1016/j.cgh.2008.11.010.). Please modify the statement “….whose serum concentration
reflects the patient’s iron stores” to de-emphasise this statement.
Page 7, second paragraph – the authors should also include coverage of the MR methodologies
that are licensed by regulatory bodies – FerriScan, FerriSmart. Many other methods have not
been licensed and are simply delivered locally (St Pierre et al Blood 2005 Jan 15;105(2):855-61.
doi: 10.1182/blood-2004-01-0177).
There is a large heterogeneity in the effects of iron in the liver. Just because iron is elevated above
36 umol/g there is no consensus as to whether that is clinically relevant or should be treated in
anyway. Thus, the last line of the paragraph should state “Currently, there is no indication for
recommending iron depletion therapy in this condition”.
In paragraph 3, the first line should remove the statement “.. and who may therefore benefit
from bloodletting” as it implies a benefit when none has been shown to exists (eg Adams LA et
al Hepatology 2015; Laien et al Hepatology 2017). Furthermore, any discussion about defining
a threshold for treatment of DIOS with phlebotomy has no support in the literature and the
remainder of the introduction in this last paragraph should be removed and replaced with a
statement that the study was designed to validate a model for prediction of LIC greater than 100
umol/g without any reference to a therapeutic application.
There are a number of grammatical errors related to English – please check this out eg
‘differentiale’ instead of ‘differential’.
Methods
Exclusion criteria – whilst p.Cys282Tyr homozygosity is an exclusion, the authors if possible
should document the presence of the compound heterozygous genotype as that may increase
serum iron biochemistry and HIC to some extent and compare this with individuals who possess
neither variant.
Given that at least 25% of the population in most western countries consume more alcohol than
recommended, it would be interesting to see if evaluating the performance of the model whilst
not excluding high alcohol would change the results?
The Gandon method – Was there a quality control system in place for use of the Gandon method
to ensure reproducibility and accuracy of measurement? Were all scans at a single centre or
multiple centres. The method is valid but as with all methods there is the potential for variability
unless stringent quality controls are in place especially if performed at multiple centres.
Results
On page 13, what do the authors mean “No significant difference was found in ferritin level
(960 [Q1Q3: 751-1200] µg/L in patients with LIC # 100 µmol/g vs 827 [Q1Q3: 624-1125] µg/
L, p = 0.08).” Compared with what?
The mutations in HFE as described in the text and table 2 need to be specified as per my earlier
comment related to compound heterozygosity. Many constituencies still regard C282Y/H63D
compound heterozygosity as a type of HFE haemochromatosis requiring treatment and that
may be why the family history of phlebotomy is being revealed. The study may be showing
that individuals with compound heterozygosity and metabolic syndrome (both very common)
are reported to have phlebotomy treatment – this would not be novel. If individuals are being
subjects to phlebotomy outside a diagnosis of iorn overload that would be inappropriate. Please
resolve.
The recommendation that persistent elevation of ferritin above a cut off over 600 and TRS >
45% fits with recent recommendations in other countries and seems logical – the only way to
know how much iron you have is to measure it and the best validated methods for this are MR
methods (eg Zhang et al Med J Aust. 2025 Feb 27.
doi: 10.5694/mja2.52618).
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: 28 Feb 2025
Reviewer's report:
HEPEDIOS manuscript
Overall an interesting article that is useful for guiding decision making in the selection on
individuals with elevated serum transferrin saturation and ferritin levels. The emphasis needs to
be taken off the “guiding who to find for treatment with phlebotomy” as there is no evidence that
phlebotomy in the DIOS is of any benefit and it could easily result in inappropriate introduction
of this practice.
The aim is simple – find a predictive algorithm for those likely to have LIC > 100. Simply align
the introduction with that aim.
Comments
Introduction
Page 6 – whilst ferritin levels reflect body iron stores in iron overload syndromes and low levels
indicate iron deficiency, there is no evidence that increasing serum ferritin levels accurately
reflect increasing body iron stores outside of the setting Haemochromatosis or secondary iron
overload disorders (eg Olynyk et al Clin Gastroenterol Hepatol 2009 Mar;7(3):359-62.doi:
10.1016/j.cgh.2008.11.010.). Please modify the statement “….whose serum concentration
reflects the patient’s iron stores” to de-emphasise this statement.
Page 7, second paragraph – the authors should also include coverage of the MR methodologies
that are licensed by regulatory bodies – FerriScan, FerriSmart. Many other methods have not
been licensed and are simply delivered locally (St Pierre et al Blood 2005 Jan 15;105(2):855-61.
doi: 10.1182/blood-2004-01-0177).
There is a large heterogeneity in the effects of iron in the liver. Just because iron is elevated above
36 umol/g there is no consensus as to whether that is clinically relevant or should be treated in
anyway. Thus, the last line of the paragraph should state “Currently, there is no indication for
recommending iron depletion therapy in this condition”.
In paragraph 3, the first line should remove the statement “.. and who may therefore benefit
from bloodletting” as it implies a benefit when none has been shown to exists (eg Adams LA et
al Hepatology 2015; Laien et al Hepatology 2017). Furthermore, any discussion about defining
a threshold for treatment of DIOS with phlebotomy has no support in the literature and the
remainder of the introduction in this last paragraph should be removed and replaced with a
statement that the study was designed to validate a model for prediction of LIC greater than 100
umol/g without any reference to a therapeutic application.
There are a number of grammatical errors related to English – please check this out eg
‘differentiale’ instead of ‘differential’.
Methods
Exclusion criteria – whilst p.Cys282Tyr homozygosity is an exclusion, the authors if possible
should document the presence of the compound heterozygous genotype as that may increase
serum iron biochemistry and HIC to some extent and compare this with individuals who possess
neither variant.
Given that at least 25% of the population in most western countries consume more alcohol than
recommended, it would be interesting to see if evaluating the performance of the model whilst
not excluding high alcohol would change the results?
The Gandon method – Was there a quality control system in place for use of the Gandon method
to ensure reproducibility and accuracy of measurement? Were all scans at a single centre or
multiple centres. The method is valid but as with all methods there is the potential for variability
unless stringent quality controls are in place especially if performed at multiple centres.
Results
On page 13, what do the authors mean “No significant difference was found in ferritin level
(960 [Q1Q3: 751-1200] µg/L in patients with LIC # 100 µmol/g vs 827 [Q1Q3: 624-1125] µg/
L, p = 0.08).” Compared with what?
The mutations in HFE as described in the text and table 2 need to be specified as per my earlier
comment related to compound heterozygosity. Many constituencies still regard C282Y/H63D
compound heterozygosity as a type of HFE haemochromatosis requiring treatment and that
may be why the family history of phlebotomy is being revealed. The study may be showing
that individuals with compound heterozygosity and metabolic syndrome (both very common)
are reported to have phlebotomy treatment – this would not be novel. If individuals are being
subjects to phlebotomy outside a diagnosis of iorn overload that would be inappropriate. Please
resolve.
The recommendation that persistent elevation of ferritin above a cut off over 600 and TRS >
45% fits with recent recommendations in other countries and seems logical – the only way to
know how much iron you have is to measure it and the best validated methods for this are MR
methods (eg Zhang et al Med J Aust. 2025 Feb 27.
doi: 10.5694/mja2.52618).
assistant