Reviewer’s report
Title:  Extracorporeal liver support: trending epidemiology and mortality - A nationwide database  
analysis 2007-2015
Version: 0 Date: 25 May 2019
Reviewer: Fuat Saner
Reviewer's report:
Title: Extracorporeal liver support: trending epidemiology and mortality
-A nationwide database analysis 2007-2015
BMGE: -D-19-00070
Wiesmann et al conducted a retrospective study about using rate of liver support systems in Germany  
between 2007 and 2015.
The aim of the study was to recruit epidemiologic data about about frequency use of liver assist device  
and crude mortality and morbidity for this patient cohort.
They found that between 2007 and 2015 a total of 2886 patients were treated within this time frame.  
Overall mortality was 51.49%, whereas male population suffered from a higher mortality. While in the  
first 7 years main indication was liver dysfunction, since 2012 liver support system was more used in  
cardiac surgery due to ischemic liver injury.
The conclusion of the authors was that since 2007 the using rate of liver support systems remains  
stable, while since 2012 the indication moved from hepatologic patients more to cardiac surgery  
patients. 
There are some major concerns, which should be addressed.
First of all the authors should be define, what kind of liver assist devices they aimed to evaluate.
There are biological and non-biological systems. Within the non-biological systems the most used in  
the recent 20 years was MARS, Prometheus (FPSA) and plasmapheresis. This is not clear in the text  
and should be figured out.
You should compare each by each and do not put all devices together and talk about liver support. 
Introduction:
First sentence:
"Acute liver failure (ALF) might occur in patients with preexisting (acute- on-chronic,
3 ACLF [1]) or non-preexisting (ALF) liver disease."
Well ALF is clear defined as acute onset of liver dysfunction (transaminases at least 3 times above  
baseline),  coagulopathy  (INR  >  1.5),  jaundice  and  hepatic  encephalopathy  (see  O'Grady,  
Gastroenterology 1989 and Lancet 1993). The EASL (European Society of study of the Liver) stratified  
patients in acute liver injury, which means acute hepatitis without encephalopathy and acute liver  
failure, which includes hepatic encephalopathy. 
ACLF is a distinct liver failure which is first figured out in 2013 (Moreau et al m Gastroenterology  
2013).
Your statement that liver assist devices are poorly evaluated is not correct. Only for MARS you will  
find more than 500 pubmed citation. Please remove this statement. 
Line 10:
"detoxification functions (e.g. hyper-ammonemia and other protein-bound molecules)
10 to improve morbidity and mortality."
Ammonia is not protein bound, It is a very small molecule, can easily diffuse between different cells.  
Ammonia can also easily removed with hemodialysis.
Your statement that Liver assist devices is an established treatment option is also not correct. It is a  
possible treatment, but till today, beside the high-volume plasmapheresis (Larsen, J Hepatol 2016) no  
device had shown any benefit on survival.
Discussion p. 12, line 21. It is the FUMAR and not FULMAR study. Moreover you cannot compare  
blind your patient population (by the way you did not mentioned, what kind of patients they are) with  
the FUMAR study, where all patients were listed high-urgency and transplanted within 16 h.
Moreover, the use of any kind of liver support in cardiac failure does not make any sense. The cited  
studies in your manuscript provides a limited number of patients (13 against 14 and 14 against 14). In  
the study of 2004 there was no benefit, just bilirubin improvement and the other in MARS group there  
was a decreased 30 day mortality. I suppose that in 90 days almost 90% of the patients will pass
However, the main issue in these patients is the recovery of the heart, which seems to be successful  
particular in survivors of the second study.
The whole manuscript has some potential for improvement. My suggestion are stratifying the patients  
device depending and according the diagnosis. It is impossible to put all patient and liver assist devices  
together and try to get a conclusion.
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.
No
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 the 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.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
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 of 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 have no competeing 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:  Extracorporeal liver support: trending epidemiology and mortality - A nationwide database  
analysis 2007-2015
Version: 0 Date: 25 May 2019
Reviewer: Fuat Saner
Reviewer's report:
Title: Extracorporeal liver support: trending epidemiology and mortality
-A nationwide database analysis 2007-2015
BMGE: -D-19-00070
Wiesmann et al conducted a retrospective study about using rate of liver support systems in Germany  
between 2007 and 2015.
The aim of the study was to recruit epidemiologic data about about frequency use of liver assist device  
and crude mortality and morbidity for this patient cohort.
They found that between 2007 and 2015 a total of 2886 patients were treated within this time frame.  
Overall mortality was 51.49%, whereas male population suffered from a higher mortality. While in the  
first 7 years main indication was liver dysfunction, since 2012 liver support system was more used in  
cardiac surgery due to ischemic liver injury.
The conclusion of the authors was that since 2007 the using rate of liver support systems remains  
stable, while since 2012 the indication moved from hepatologic patients more to cardiac surgery  
patients. 
There are some major concerns, which should be addressed.
First of all the authors should be define, what kind of liver assist devices they aimed to evaluate.
There are biological and non-biological systems. Within the non-biological systems the most used in  
the recent 20 years was MARS, Prometheus (FPSA) and plasmapheresis. This is not clear in the text  
and should be figured out.
You should compare each by each and do not put all devices together and talk about liver support. 
Introduction:
First sentence:
"Acute liver failure (ALF) might occur in patients with preexisting (acute- on-chronic,
3 ACLF [1]) or non-preexisting (ALF) liver disease."
Well ALF is clear defined as acute onset of liver dysfunction (transaminases at least 3 times above  
baseline),  coagulopathy  (INR  >  1.5),  jaundice  and  hepatic  encephalopathy  (see  O'Grady,  
Gastroenterology 1989 and Lancet 1993). The EASL (European Society of study of the Liver) stratified  
patients in acute liver injury, which means acute hepatitis without encephalopathy and acute liver  
failure, which includes hepatic encephalopathy. 
ACLF is a distinct liver failure which is first figured out in 2013 (Moreau et al m Gastroenterology  
2013).
Your statement that liver assist devices are poorly evaluated is not correct. Only for MARS you will  
find more than 500 pubmed citation. Please remove this statement. 
Line 10:
"detoxification functions (e.g. hyper-ammonemia and other protein-bound molecules)
10 to improve morbidity and mortality."
Ammonia is not protein bound, It is a very small molecule, can easily diffuse between different cells.  
Ammonia can also easily removed with hemodialysis.
Your statement that Liver assist devices is an established treatment option is also not correct. It is a  
possible treatment, but till today, beside the high-volume plasmapheresis (Larsen, J Hepatol 2016) no  
device had shown any benefit on survival.
Discussion p. 12, line 21. It is the FUMAR and not FULMAR study. Moreover you cannot compare  
blind your patient population (by the way you did not mentioned, what kind of patients they are) with  
the FUMAR study, where all patients were listed high-urgency and transplanted within 16 h.
Moreover, the use of any kind of liver support in cardiac failure does not make any sense. The cited  
studies in your manuscript provides a limited number of patients (13 against 14 and 14 against 14). In  
the study of 2004 there was no benefit, just bilirubin improvement and the other in MARS group there  
was a decreased 30 day mortality. I suppose that in 90 days almost 90% of the patients will pass
However, the main issue in these patients is the recovery of the heart, which seems to be successful  
particular in survivors of the second study.
The whole manuscript has some potential for improvement. My suggestion are stratifying the patients  
device depending and according the diagnosis. It is impossible to put all patient and liver assist devices  
together and try to get a conclusion.
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.
No
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 the 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.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
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 of 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 have no competeing 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:  Extracorporeal liver support: trending epidemiology and mortality - A nationwide database  
analysis 2007-2015
Version: 0 Date: 25 May 2019
Reviewer: Fuat Saner
Reviewer's report:
Title: Extracorporeal liver support: trending epidemiology and mortality
-A nationwide database analysis 2007-2015
BMGE: -D-19-00070
Wiesmann et al conducted a retrospective study about using rate of liver support systems in Germany  
between 2007 and 2015.
The aim of the study was to recruit epidemiologic data about about frequency use of liver assist device  
and crude mortality and morbidity for this patient cohort.
They found that between 2007 and 2015 a total of 2886 patients were treated within this time frame.  
Overall mortality was 51.49%, whereas male population suffered from a higher mortality. While in the  
first 7 years main indication was liver dysfunction, since 2012 liver support system was more used in  
cardiac surgery due to ischemic liver injury.
The conclusion of the authors was that since 2007 the using rate of liver support systems remains  
stable, while since 2012 the indication moved from hepatologic patients more to cardiac surgery  
patients. 
There are some major concerns, which should be addressed.
First of all the authors should be define, what kind of liver assist devices they aimed to evaluate.
There are biological and non-biological systems. Within the non-biological systems the most used in  
the recent 20 years was MARS, Prometheus (FPSA) and plasmapheresis. This is not clear in the text  
and should be figured out.
You should compare each by each and do not put all devices together and talk about liver support. 
Introduction:
First sentence:
"Acute liver failure (ALF) might occur in patients with preexisting (acute- on-chronic,
3 ACLF [1]) or non-preexisting (ALF) liver disease."
Well ALF is clear defined as acute onset of liver dysfunction (transaminases at least 3 times above  
baseline),  coagulopathy  (INR  >  1.5),  jaundice  and  hepatic  encephalopathy  (see  O'Grady,  
Gastroenterology 1989 and Lancet 1993). The EASL (European Society of study of the Liver) stratified  
patients in acute liver injury, which means acute hepatitis without encephalopathy and acute liver  
failure, which includes hepatic encephalopathy. 
ACLF is a distinct liver failure which is first figured out in 2013 (Moreau et al m Gastroenterology  
2013).
Your statement that liver assist devices are poorly evaluated is not correct. Only for MARS you will  
find more than 500 pubmed citation. Please remove this statement. 
Line 10:
"detoxification functions (e.g. hyper-ammonemia and other protein-bound molecules)
10 to improve morbidity and mortality."
Ammonia is not protein bound, It is a very small molecule, can easily diffuse between different cells.  
Ammonia can also easily removed with hemodialysis.
Your statement that Liver assist devices is an established treatment option is also not correct. It is a  
possible treatment, but till today, beside the high-volume plasmapheresis (Larsen, J Hepatol 2016) no  
device had shown any benefit on survival.
Discussion p. 12, line 21. It is the FUMAR and not FULMAR study. Moreover you cannot compare  
blind your patient population (by the way you did not mentioned, what kind of patients they are) with  
the FUMAR study, where all patients were listed high-urgency and transplanted within 16 h.
Moreover, the use of any kind of liver support in cardiac failure does not make any sense. The cited  
studies in your manuscript provides a limited number of patients (13 against 14 and 14 against 14). In  
the study of 2004 there was no benefit, just bilirubin improvement and the other in MARS group there  
was a decreased 30 day mortality. I suppose that in 90 days almost 90% of the patients will pass
However, the main issue in these patients is the recovery of the heart, which seems to be successful  
particular in survivors of the second study.
The whole manuscript has some potential for improvement. My suggestion are stratifying the patients  
device depending and according the diagnosis. It is impossible to put all patient and liver assist devices  
together and try to get a conclusion.
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.
No
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 the 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.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
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 of 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 have no competeing 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