Reviewer ’s report  
 
Title: Anemia following zinc treatment for  Wilson's disease:a case report and literature review  
 
Version: 0 Date: 10 Feb 2019  
 
Reviewer: Michael Schilsky  
 
Reviewer's report:  
 
The manuscript by Cai et al "Anemia following zinc treatment for Wilson's disease: a case report 
and literature review" presents a case of  a 12-year old with Wilson disease who developed a 
relative copper deficiency and neurologic symptoms and anemia due to excessive zinc treatment. 
The anemia and symptoms improved with withholding of treatment for Wilson disease. Other 
cases of anemia on zi nc therapy were reviewed.  
 
1. It is unclear why the patient was ever treated with a dosage of daily elemental zinc of 
greater than 50 mg three times daily.  No data was presented showing poor zinc absorption or of 
a lack of response to the zinc therapy to  justify the increase above this daily value.  In the 
original registration studies of zinc acetate for Wilson disease by Brewer to the FDA, there were 
some non -responders to zinc therapy. In these cases, this review would not recommend 
increasing zinc adm inistration but rather changing the type of treatment for the Wilson disease. 
This was not considered or discussed in this manuscript and is a serious omission.  
2. In Discussion, the authors talk about gait disturbance.  Excess zinc treatment leading to 
copper deficiency has been associated with myelopathy and gait disturbances. No discussion of 
this or details of examination for posterior column changes clinically or by imaging are presented 
for this patient. Again, another omission given the known relati onship of zinc induced copper 
deficiency and clinical neurologic symptoms.  
 
 
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in t he manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of wr itten English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content o f the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any  non-financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on  the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license  (http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Anemia following zinc treatment for  Wilson's disease:a case report and literature review  
 
Version: 0 Date: 10 Feb 2019  
 
Reviewer: Michael Schilsky  
 
Reviewer's report:  
 
The manuscript by Cai et al "Anemia following zinc treatment for Wilson's disease: a case report 
and literature review" presents a case of  a 12-year old with Wilson disease who developed a 
relative copper deficiency and neurologic symptoms and anemia due to excessive zinc treatment. 
The anemia and symptoms improved with withholding of treatment for Wilson disease. Other 
cases of anemia on zi nc therapy were reviewed.  
 
1. It is unclear why the patient was ever treated with a dosage of daily elemental zinc of 
greater than 50 mg three times daily.  No data was presented showing poor zinc absorption or of 
a lack of response to the zinc therapy to  justify the increase above this daily value.  In the 
original registration studies of zinc acetate for Wilson disease by Brewer to the FDA, there were 
some non -responders to zinc therapy. In these cases, this review would not recommend 
increasing zinc adm inistration but rather changing the type of treatment for the Wilson disease. 
This was not considered or discussed in this manuscript and is a serious omission.  
2. In Discussion, the authors talk about gait disturbance.  Excess zinc treatment leading to 
copper deficiency has been associated with myelopathy and gait disturbances. No discussion of 
this or details of examination for posterior column changes clinically or by imaging are presented 
for this patient. Again, another omission given the known relati onship of zinc induced copper 
deficiency and clinical neurologic symptoms.  
 
 
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in t he manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of wr itten English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content o f the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any  non-financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on  the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license  (http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Anemia following zinc treatment for  Wilson's disease:a case report and literature review  
 
Version: 0 Date: 10 Feb 2019  
 
Reviewer: Michael Schilsky  
 
Reviewer's report:  
 
The manuscript by Cai et al "Anemia following zinc treatment for Wilson's disease: a case report 
and literature review" presents a case of  a 12-year old with Wilson disease who developed a 
relative copper deficiency and neurologic symptoms and anemia due to excessive zinc treatment. 
The anemia and symptoms improved with withholding of treatment for Wilson disease. Other 
cases of anemia on zi nc therapy were reviewed.  
 
1. It is unclear why the patient was ever treated with a dosage of daily elemental zinc of 
greater than 50 mg three times daily.  No data was presented showing poor zinc absorption or of 
a lack of response to the zinc therapy to  justify the increase above this daily value.  In the 
original registration studies of zinc acetate for Wilson disease by Brewer to the FDA, there were 
some non -responders to zinc therapy. In these cases, this review would not recommend 
increasing zinc adm inistration but rather changing the type of treatment for the Wilson disease. 
This was not considered or discussed in this manuscript and is a serious omission.  
2. In Discussion, the authors talk about gait disturbance.  Excess zinc treatment leading to 
copper deficiency has been associated with myelopathy and gait disturbances. No discussion of 
this or details of examination for posterior column changes clinically or by imaging are presented 
for this patient. Again, another omission given the known relati onship of zinc induced copper 
deficiency and clinical neurologic symptoms.  
 
 
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in t he manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of wr itten English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content o f the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any  non-financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on  the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license  (http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant