Reviewer's report 
 The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and Title: 
primary sclerosing cholangitis 
 1  20 October 2004 Version: Date: 
 Daniel Forton Reviewer: 
Reviewer's report: 
General 
There are 2 main aspects to this study: 1. A comparison of plasma concentrations of amino acids (aa) in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), chronic hepatitis C infections (HCV) and 
controls. Statistically significant increases were found in tyrosine (PBC,HCV) and phenylalanine 
(PBC) and significant reductions were found in tryptophan (PBC,HCV) and the branch-chained 
amino acids (PBC,PSC)compared to 73 healthy controls. These findings parallel previous published 
findings. The authors state that these changes are not completely explained by decreased liver 
function, although in the PBC group there were significant associations between the presence of 
cirrhosis and the aa concentrations that were elevated i.e. tyrosine and phenylalanine. Furthermore, there were significant associations between abnormal levels of aa and markers of liver disease (bilirubin and albumin). There is therefore no evidence to suggest that the abnormal aa 
concentrations are unrelated to liver function. 
2. The authors attempted to find associations between aa concentrations and fatigue/QOL scores. 
The only significant association was counter-intuitive, given the above findings. There was an 
INVERSE association between tyrosine levels and fatigue/QOL. The authors' presention of these 
data and the discussion is confusing since they refer to LOW tyrosine levels, when they have already 
stated that the PBC group had elevated levels of tyrosine. The finding of an association between 
normal levels of tyrosine and fatigue / QOL suggests to me that this aa is irrelevant in this regard. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
See 1. and 2. above. I am not sure how these can be addressed adequately 
3. In the introduction, it is stated that aa abnormalities have been detected in non-hepatological conditions and are related to fatigue - references 7-13 are given but none of these are relevant to this statement 
4. Indeed, there are several unreferenced statements eg effect of diet on aa 
5. The authors do not state how cirrhosis was diagnosed clinically or the proportion of HCV patients 
with cirrhosis - clearly important if the argument is that the aa abnormalities are unrelated to cirrhosis 
6. The results are somewhat selectively reported. The fatigue/QOL data for the positive control 
group (HCV)are not given and associations betwwen aa and liver indices are only partially reported eg branch-chained aa and albumin? 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
With regard to para 3 of the discussion, there are data from our group suggesting that brain 
manganese concentrations may be related to fatigue in PBC 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of limited interest Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
None 
Reviewer's report 
 The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and Title: 
primary sclerosing cholangitis 
 1  20 October 2004 Version: Date: 
 Daniel Forton Reviewer: 
Reviewer's report: 
General 
There are 2 main aspects to this study: 1. A comparison of plasma concentrations of amino acids (aa) in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), chronic hepatitis C infections (HCV) and 
controls. Statistically significant increases were found in tyrosine (PBC,HCV) and phenylalanine 
(PBC) and significant reductions were found in tryptophan (PBC,HCV) and the branch-chained 
amino acids (PBC,PSC)compared to 73 healthy controls. These findings parallel previous published 
findings. The authors state that these changes are not completely explained by decreased liver 
function, although in the PBC group there were significant associations between the presence of 
cirrhosis and the aa concentrations that were elevated i.e. tyrosine and phenylalanine. Furthermore, there were significant associations between abnormal levels of aa and markers of liver disease (bilirubin and albumin). There is therefore no evidence to suggest that the abnormal aa 
concentrations are unrelated to liver function. 
2. The authors attempted to find associations between aa concentrations and fatigue/QOL scores. 
The only significant association was counter-intuitive, given the above findings. There was an 
INVERSE association between tyrosine levels and fatigue/QOL. The authors' presention of these 
data and the discussion is confusing since they refer to LOW tyrosine levels, when they have already 
stated that the PBC group had elevated levels of tyrosine. The finding of an association between 
normal levels of tyrosine and fatigue / QOL suggests to me that this aa is irrelevant in this regard. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
See 1. and 2. above. I am not sure how these can be addressed adequately 
3. In the introduction, it is stated that aa abnormalities have been detected in non-hepatological conditions and are related to fatigue - references 7-13 are given but none of these are relevant to this statement 
4. Indeed, there are several unreferenced statements eg effect of diet on aa 
5. The authors do not state how cirrhosis was diagnosed clinically or the proportion of HCV patients 
with cirrhosis - clearly important if the argument is that the aa abnormalities are unrelated to cirrhosis 
6. The results are somewhat selectively reported. The fatigue/QOL data for the positive control 
group (HCV)are not given and associations betwwen aa and liver indices are only partially reported eg branch-chained aa and albumin? 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
With regard to para 3 of the discussion, there are data from our group suggesting that brain 
manganese concentrations may be related to fatigue in PBC 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of limited interest Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
None 
Please review this paper.
user
Reviewer's report 
 The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and Title: 
primary sclerosing cholangitis 
 1  20 October 2004 Version: Date: 
 Daniel Forton Reviewer: 
Reviewer's report: 
General 
There are 2 main aspects to this study: 1. A comparison of plasma concentrations of amino acids (aa) in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), chronic hepatitis C infections (HCV) and 
controls. Statistically significant increases were found in tyrosine (PBC,HCV) and phenylalanine 
(PBC) and significant reductions were found in tryptophan (PBC,HCV) and the branch-chained 
amino acids (PBC,PSC)compared to 73 healthy controls. These findings parallel previous published 
findings. The authors state that these changes are not completely explained by decreased liver 
function, although in the PBC group there were significant associations between the presence of 
cirrhosis and the aa concentrations that were elevated i.e. tyrosine and phenylalanine. Furthermore, there were significant associations between abnormal levels of aa and markers of liver disease (bilirubin and albumin). There is therefore no evidence to suggest that the abnormal aa 
concentrations are unrelated to liver function. 
2. The authors attempted to find associations between aa concentrations and fatigue/QOL scores. 
The only significant association was counter-intuitive, given the above findings. There was an 
INVERSE association between tyrosine levels and fatigue/QOL. The authors' presention of these 
data and the discussion is confusing since they refer to LOW tyrosine levels, when they have already 
stated that the PBC group had elevated levels of tyrosine. The finding of an association between 
normal levels of tyrosine and fatigue / QOL suggests to me that this aa is irrelevant in this regard. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
See 1. and 2. above. I am not sure how these can be addressed adequately 
3. In the introduction, it is stated that aa abnormalities have been detected in non-hepatological conditions and are related to fatigue - references 7-13 are given but none of these are relevant to this statement 
4. Indeed, there are several unreferenced statements eg effect of diet on aa 
5. The authors do not state how cirrhosis was diagnosed clinically or the proportion of HCV patients 
with cirrhosis - clearly important if the argument is that the aa abnormalities are unrelated to cirrhosis 
6. The results are somewhat selectively reported. The fatigue/QOL data for the positive control 
group (HCV)are not given and associations betwwen aa and liver indices are only partially reported eg branch-chained aa and albumin? 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
With regard to para 3 of the discussion, there are data from our group suggesting that brain 
manganese concentrations may be related to fatigue in PBC 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article of limited interest Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
None 
assistant