Reviewer’s report
Title: Hepatobiliary and Pancreatic Manifestations in Inflammatory Bowel Diseases: A Referral Center  
Study
Version: 0 Date: 15 Jun 2018
Reviewer: Armand Abergel
Reviewer's report:
The study of Fousekis et al. evaluates the frequency of liver, biliary and pancreatic diseases in patients  
with IBD.
This is a retrospective study conducted in a tertiary center from Greece
Major comments:
This is a retrospective study from a tertiary center and has the drawbacks of this kind of study:  
selection bias (tertiary center) and classification bias (quality of the data in a retrospective data)
There is no new information but there are interesting results about the epidemiology of drug induced  
liver  and pancreatic  injuries  (DILI  and  DIPI). I think, you  should give more details  on these 2  
populations and less on biliary diseases (see below)
To improve the quality of the manuscript, we need more information on the way the diagnosis was  
affirmed as drug induced injury is an exclusion diagnosis.
It is necessary to use standardized definitions. For example use the criteria of Aithal et al. (Clinical  
pharmacology & Therapeutics 2011) for DILI and Badalov et al. for DIPI (Clin Gastroenterol Hepatol  
2007)
How did you evaluate the causality? Roussel Uclaf Causality Assessment Method for DILI?
Can you give a clear message to the readers: when do they have to stop for example azathioprine when  
ALT is increased ? ALT > 3N or 5N?
Some studies have shown that DILI with azathioprine is cytolytic in roughly in one third of the  
patients, cholestatic 1/3, mixte 1/3. Did you observe a cholestatic injury?
DILI by AZA can be dose dependent or dose independent, did you observe the 2 types?
For  steatosis,  do  you  have  information  on  BMI  and  the  metabolic  syndrome  (waist  size,  lipids,  
glycemia, hypertension). Is steatosis nowadays associated with the activity of the disease or denutrition  
or metabolic syndrome? 
How many patients had excessive consumption of alcohol?
Use also standardized epidemiological words as person-years when you give results of incidence 
How do you explain the low number of PSC? When did your center started to use biliary MRI?
Minor comments:
Page 5, lane 23; several patients underwent imaging evaluation: how many? This is a selection bias.  
Then the frequency of biliary lithiasis has a very limited interest.
Page 6
lane 10: I think Table 1 does not add information
lane 16: The most    "a word is missing"  were males
lane 26: did you look for thrombophilia?
Page 7
Lane 8: this message is confusing as amylase should not be tested if the patient has no abdominal pain
Lane 18: what was the interval for sulfasalazine
Lane 21: You use ALT > 2 ULN, what are the percentage of patients with ALT > 3 ULN, 5 ULN and  
Hy's Law?
Lane 27: please say clearly that the patient received both drugs for 2 months and that azathioprine was  
started 6 months before methylprednisolone
Page 8
Lane 2: What was the value of HBVDNA and ALT in the second patient with reactivation?
Lane 24: associated instead of correlated
Page 9
Lane 3: in patients with PSC
Lane 8: did you observe common bile duct lithiasis?
Lane 15: can you comment on differential diagnosis of DIPI as autoimmune pancreatitis (IgG4) and  
familial pancreatitis? Other causes like duodenal inflammation……
Lane 18: viral hepatitis should move to lane 9
Lane 21: use the definitions of the EASL (2017 recommendations)
Page 10
Lane 18: same comments as page 7, lane 21
Page 13
Complete the last reference please
Page 16
The table does not add information
Pages 17 and 18
The title is too long
Page 21
% with ALT > 3N, ALT > 5N
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.
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.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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.
No conflict of interest
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: Hepatobiliary and Pancreatic Manifestations in Inflammatory Bowel Diseases: A Referral Center  
Study
Version: 0 Date: 15 Jun 2018
Reviewer: Armand Abergel
Reviewer's report:
The study of Fousekis et al. evaluates the frequency of liver, biliary and pancreatic diseases in patients  
with IBD.
This is a retrospective study conducted in a tertiary center from Greece
Major comments:
This is a retrospective study from a tertiary center and has the drawbacks of this kind of study:  
selection bias (tertiary center) and classification bias (quality of the data in a retrospective data)
There is no new information but there are interesting results about the epidemiology of drug induced  
liver  and pancreatic  injuries  (DILI  and  DIPI). I think, you  should give more details  on these 2  
populations and less on biliary diseases (see below)
To improve the quality of the manuscript, we need more information on the way the diagnosis was  
affirmed as drug induced injury is an exclusion diagnosis.
It is necessary to use standardized definitions. For example use the criteria of Aithal et al. (Clinical  
pharmacology & Therapeutics 2011) for DILI and Badalov et al. for DIPI (Clin Gastroenterol Hepatol  
2007)
How did you evaluate the causality? Roussel Uclaf Causality Assessment Method for DILI?
Can you give a clear message to the readers: when do they have to stop for example azathioprine when  
ALT is increased ? ALT > 3N or 5N?
Some studies have shown that DILI with azathioprine is cytolytic in roughly in one third of the  
patients, cholestatic 1/3, mixte 1/3. Did you observe a cholestatic injury?
DILI by AZA can be dose dependent or dose independent, did you observe the 2 types?
For  steatosis,  do  you  have  information  on  BMI  and  the  metabolic  syndrome  (waist  size,  lipids,  
glycemia, hypertension). Is steatosis nowadays associated with the activity of the disease or denutrition  
or metabolic syndrome? 
How many patients had excessive consumption of alcohol?
Use also standardized epidemiological words as person-years when you give results of incidence 
How do you explain the low number of PSC? When did your center started to use biliary MRI?
Minor comments:
Page 5, lane 23; several patients underwent imaging evaluation: how many? This is a selection bias.  
Then the frequency of biliary lithiasis has a very limited interest.
Page 6
lane 10: I think Table 1 does not add information
lane 16: The most    "a word is missing"  were males
lane 26: did you look for thrombophilia?
Page 7
Lane 8: this message is confusing as amylase should not be tested if the patient has no abdominal pain
Lane 18: what was the interval for sulfasalazine
Lane 21: You use ALT > 2 ULN, what are the percentage of patients with ALT > 3 ULN, 5 ULN and  
Hy's Law?
Lane 27: please say clearly that the patient received both drugs for 2 months and that azathioprine was  
started 6 months before methylprednisolone
Page 8
Lane 2: What was the value of HBVDNA and ALT in the second patient with reactivation?
Lane 24: associated instead of correlated
Page 9
Lane 3: in patients with PSC
Lane 8: did you observe common bile duct lithiasis?
Lane 15: can you comment on differential diagnosis of DIPI as autoimmune pancreatitis (IgG4) and  
familial pancreatitis? Other causes like duodenal inflammation……
Lane 18: viral hepatitis should move to lane 9
Lane 21: use the definitions of the EASL (2017 recommendations)
Page 10
Lane 18: same comments as page 7, lane 21
Page 13
Complete the last reference please
Page 16
The table does not add information
Pages 17 and 18
The title is too long
Page 21
% with ALT > 3N, ALT > 5N
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.
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.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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.
No conflict of interest
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: Hepatobiliary and Pancreatic Manifestations in Inflammatory Bowel Diseases: A Referral Center  
Study
Version: 0 Date: 15 Jun 2018
Reviewer: Armand Abergel
Reviewer's report:
The study of Fousekis et al. evaluates the frequency of liver, biliary and pancreatic diseases in patients  
with IBD.
This is a retrospective study conducted in a tertiary center from Greece
Major comments:
This is a retrospective study from a tertiary center and has the drawbacks of this kind of study:  
selection bias (tertiary center) and classification bias (quality of the data in a retrospective data)
There is no new information but there are interesting results about the epidemiology of drug induced  
liver  and pancreatic  injuries  (DILI  and  DIPI). I think, you  should give more details  on these 2  
populations and less on biliary diseases (see below)
To improve the quality of the manuscript, we need more information on the way the diagnosis was  
affirmed as drug induced injury is an exclusion diagnosis.
It is necessary to use standardized definitions. For example use the criteria of Aithal et al. (Clinical  
pharmacology & Therapeutics 2011) for DILI and Badalov et al. for DIPI (Clin Gastroenterol Hepatol  
2007)
How did you evaluate the causality? Roussel Uclaf Causality Assessment Method for DILI?
Can you give a clear message to the readers: when do they have to stop for example azathioprine when  
ALT is increased ? ALT > 3N or 5N?
Some studies have shown that DILI with azathioprine is cytolytic in roughly in one third of the  
patients, cholestatic 1/3, mixte 1/3. Did you observe a cholestatic injury?
DILI by AZA can be dose dependent or dose independent, did you observe the 2 types?
For  steatosis,  do  you  have  information  on  BMI  and  the  metabolic  syndrome  (waist  size,  lipids,  
glycemia, hypertension). Is steatosis nowadays associated with the activity of the disease or denutrition  
or metabolic syndrome? 
How many patients had excessive consumption of alcohol?
Use also standardized epidemiological words as person-years when you give results of incidence 
How do you explain the low number of PSC? When did your center started to use biliary MRI?
Minor comments:
Page 5, lane 23; several patients underwent imaging evaluation: how many? This is a selection bias.  
Then the frequency of biliary lithiasis has a very limited interest.
Page 6
lane 10: I think Table 1 does not add information
lane 16: The most    "a word is missing"  were males
lane 26: did you look for thrombophilia?
Page 7
Lane 8: this message is confusing as amylase should not be tested if the patient has no abdominal pain
Lane 18: what was the interval for sulfasalazine
Lane 21: You use ALT > 2 ULN, what are the percentage of patients with ALT > 3 ULN, 5 ULN and  
Hy's Law?
Lane 27: please say clearly that the patient received both drugs for 2 months and that azathioprine was  
started 6 months before methylprednisolone
Page 8
Lane 2: What was the value of HBVDNA and ALT in the second patient with reactivation?
Lane 24: associated instead of correlated
Page 9
Lane 3: in patients with PSC
Lane 8: did you observe common bile duct lithiasis?
Lane 15: can you comment on differential diagnosis of DIPI as autoimmune pancreatitis (IgG4) and  
familial pancreatitis? Other causes like duodenal inflammation……
Lane 18: viral hepatitis should move to lane 9
Lane 21: use the definitions of the EASL (2017 recommendations)
Page 10
Lane 18: same comments as page 7, lane 21
Page 13
Complete the last reference please
Page 16
The table does not add information
Pages 17 and 18
The title is too long
Page 21
% with ALT > 3N, ALT > 5N
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.
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.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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.
No conflict of interest
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