Reviewer ’s report  
 
Title:  Unexplained chronic liver disease in Ethiopia: a cross -sectional study  
 
Version: 0 Date: 21 Dec 2017 
 
Reviewer:  Monica  Robotin  
 
Reviewer’s report:  
 
This is a well written paper, describing a carefully conducted study into the aetiology of chronic 
liver disease in Ethiopia.  
 
The fact that no aetiological factor for CLD could be established for over half of the study 
participants is disappointing, but not entirely surprising.  
 
Could the authors comment of the implications of using HBsAg as a biomarker for HBV 
infection rather than HBV DNA to estimate chronic HBV infection?  
 
In patients with HCC (rather than chronic liver disease), a review by Bosch et al  mentions that 
HBV DNA in the serum was detectable in the serum of 25.1 % of pat ients without any HBV 
markers (Bosch et al, 2004).  This is in line with earlier reports using samples from three 
geographical world regions (South Africa, Europe and Japan), prompting the authors to conclude 
that in countries with low levels of exposure t o HBV, between a third and a half of the HBsAg -
negative liver cancer cases may be related to HBV (Paterlini et al, 1990). Similar results were 
observed for HCV infection, as close to 15% of HCC cases were negative for all three viral 
markers of HCV infecti on (Brechot et al, 2004).  
 
 
REFERENCES:  
 
Bosch, F.X., et al., Primary liver cancer: worldwide incidence and trends. Gastroenterology, 
2004. 127(5 Suppl 1): p. S5 -S16. 
 
Brechot, C., Pathogenesis of hepatitis B virus -related hepatocellular carcinoma: old and ne w 
paradigms. Gastroenterology, 2004. 127(5 Suppl 1): p. S56 -61. 
 
Paterlini, P., et al., Polymerase chain reaction to detect hepatitis B virus DNA and RNA 
sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl 
J Med , 1990. 323(2): p. 80 -5 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
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.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend a n 
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:  
 
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 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 de clare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that 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 websi te 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:  Unexplained chronic liver disease in Ethiopia: a cross -sectional study  
 
Version: 0 Date: 21 Dec 2017 
 
Reviewer:  Monica  Robotin  
 
Reviewer’s report:  
 
This is a well written paper, describing a carefully conducted study into the aetiology of chronic 
liver disease in Ethiopia.  
 
The fact that no aetiological factor for CLD could be established for over half of the study 
participants is disappointing, but not entirely surprising.  
 
Could the authors comment of the implications of using HBsAg as a biomarker for HBV 
infection rather than HBV DNA to estimate chronic HBV infection?  
 
In patients with HCC (rather than chronic liver disease), a review by Bosch et al  mentions that 
HBV DNA in the serum was detectable in the serum of 25.1 % of pat ients without any HBV 
markers (Bosch et al, 2004).  This is in line with earlier reports using samples from three 
geographical world regions (South Africa, Europe and Japan), prompting the authors to conclude 
that in countries with low levels of exposure t o HBV, between a third and a half of the HBsAg -
negative liver cancer cases may be related to HBV (Paterlini et al, 1990). Similar results were 
observed for HCV infection, as close to 15% of HCC cases were negative for all three viral 
markers of HCV infecti on (Brechot et al, 2004).  
 
 
REFERENCES:  
 
Bosch, F.X., et al., Primary liver cancer: worldwide incidence and trends. Gastroenterology, 
2004. 127(5 Suppl 1): p. S5 -S16. 
 
Brechot, C., Pathogenesis of hepatitis B virus -related hepatocellular carcinoma: old and ne w 
paradigms. Gastroenterology, 2004. 127(5 Suppl 1): p. S56 -61. 
 
Paterlini, P., et al., Polymerase chain reaction to detect hepatitis B virus DNA and RNA 
sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl 
J Med , 1990. 323(2): p. 80 -5 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
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.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend a n 
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:  
 
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 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 de clare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that 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 websi te 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:  Unexplained chronic liver disease in Ethiopia: a cross -sectional study  
 
Version: 0 Date: 21 Dec 2017 
 
Reviewer:  Monica  Robotin  
 
Reviewer’s report:  
 
This is a well written paper, describing a carefully conducted study into the aetiology of chronic 
liver disease in Ethiopia.  
 
The fact that no aetiological factor for CLD could be established for over half of the study 
participants is disappointing, but not entirely surprising.  
 
Could the authors comment of the implications of using HBsAg as a biomarker for HBV 
infection rather than HBV DNA to estimate chronic HBV infection?  
 
In patients with HCC (rather than chronic liver disease), a review by Bosch et al  mentions that 
HBV DNA in the serum was detectable in the serum of 25.1 % of pat ients without any HBV 
markers (Bosch et al, 2004).  This is in line with earlier reports using samples from three 
geographical world regions (South Africa, Europe and Japan), prompting the authors to conclude 
that in countries with low levels of exposure t o HBV, between a third and a half of the HBsAg -
negative liver cancer cases may be related to HBV (Paterlini et al, 1990). Similar results were 
observed for HCV infection, as close to 15% of HCC cases were negative for all three viral 
markers of HCV infecti on (Brechot et al, 2004).  
 
 
REFERENCES:  
 
Bosch, F.X., et al., Primary liver cancer: worldwide incidence and trends. Gastroenterology, 
2004. 127(5 Suppl 1): p. S5 -S16. 
 
Brechot, C., Pathogenesis of hepatitis B virus -related hepatocellular carcinoma: old and ne w 
paradigms. Gastroenterology, 2004. 127(5 Suppl 1): p. S56 -61. 
 
Paterlini, P., et al., Polymerase chain reaction to detect hepatitis B virus DNA and RNA 
sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl 
J Med , 1990. 323(2): p. 80 -5 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
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.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend a n 
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:  
 
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 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 de clare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that 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 websi te 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