Title: Serum ferritin levels are associated with advanced liver fibrosis in treatment-naive
autoimmune hepatitis
Version: 0 Date: 21 Nov 2021
Reviewer's report:
Chen et al investigated the association between variables related to iron metabolism and liver
fibrosis in untreated patients with autoimmune hepatitis.
The investigation could be of interest however there are several major limitations:
1. Introduction: Liver biopsy in AIH is essential not only for fibrosis estimation but also for
establishment of diagnosis. So, the aim of the study to potentially associate iron metabolism
variables with fibrosis stage in patients with AIH at diagnosis (before treatment) is weak and
ambiguous, since liver biopsy for diagnosis is absolutely necessary. In addition, at diagnosis
there is usually increased inflammation in the liver with acute phase reaction, so ferritin can
not be a reliable marker for fibrosis since it could reflect inflammation. On the contrary, if the
same study was contacted in treated patients after remission it could make sense for estimate
disease progression.
Minor: ref 1 is old, could be replaced with newer
2. Study population: the diagnosis of AIH is also ambiguous. For research purposes the diagnosis
of AIH should be based on the IAIHG criteria 1999 and/or 2008 but not only to histology as the
text implies (…..and/or (3) histological features indicative of AIH). It is well known that there
are no pathognomonic histological features for AIH and the diagnosis should combine exclusion
of other causes, IgG levels and autoantibodies.
3. General characteristics and lab tests: the autoantibodies starting dilution should be mentioned.
In addition, the cut off values for IgG, AST, ALT and ALP should be included.
4. Statistics: AOC for ferritin should be included as well the DeLong test for best cut off ferritin
level predicting advanced fibrosis stage. Sensitivity and specificity should also be calculated
5. Results: Table 1 should include the percentages of the patients according to the detected
autoantibodies (ANA, SMA, LKM, anti-SLA/LP). In addition, the IAIHG score of 1999 and the
simplified score 2008 should be included in the Table. According to the results 14.4% of the
patients did not have any autoantibody detectable. How the diagnosis was established in these
patients, given that liver biopsies were not stained for hemosiderin deposits and there was no
genetic testing for hemochromatosis? Furthermore, according to Table 1, TSI in some patients
was >45%. These patients should had been tested for hemochromatosis.
In addition, Table 1 should include mHAI activity score.
Finally, after AOC analysis and finding the best cut off point, a Table based to this cut off level
of ferritin should be presented with patients characteristics according to this cut off, in order
to prove that the patients with higher histological activity scores, ALT and IgG did not have
increased inflammatory activity. In addition, if histological activity score enters the multivariate
analysis, it is not sure that fibrosis will remain in the model.
Title: Serum ferritin levels are associated with advanced liver fibrosis in treatment-naive
autoimmune hepatitis
Version: 0 Date: 21 Nov 2021
Reviewer's report:
Chen et al investigated the association between variables related to iron metabolism and liver
fibrosis in untreated patients with autoimmune hepatitis.
The investigation could be of interest however there are several major limitations:
1. Introduction: Liver biopsy in AIH is essential not only for fibrosis estimation but also for
establishment of diagnosis. So, the aim of the study to potentially associate iron metabolism
variables with fibrosis stage in patients with AIH at diagnosis (before treatment) is weak and
ambiguous, since liver biopsy for diagnosis is absolutely necessary. In addition, at diagnosis
there is usually increased inflammation in the liver with acute phase reaction, so ferritin can
not be a reliable marker for fibrosis since it could reflect inflammation. On the contrary, if the
same study was contacted in treated patients after remission it could make sense for estimate
disease progression.
Minor: ref 1 is old, could be replaced with newer
2. Study population: the diagnosis of AIH is also ambiguous. For research purposes the diagnosis
of AIH should be based on the IAIHG criteria 1999 and/or 2008 but not only to histology as the
text implies (…..and/or (3) histological features indicative of AIH). It is well known that there
are no pathognomonic histological features for AIH and the diagnosis should combine exclusion
of other causes, IgG levels and autoantibodies.
3. General characteristics and lab tests: the autoantibodies starting dilution should be mentioned.
In addition, the cut off values for IgG, AST, ALT and ALP should be included.
4. Statistics: AOC for ferritin should be included as well the DeLong test for best cut off ferritin
level predicting advanced fibrosis stage. Sensitivity and specificity should also be calculated
5. Results: Table 1 should include the percentages of the patients according to the detected
autoantibodies (ANA, SMA, LKM, anti-SLA/LP). In addition, the IAIHG score of 1999 and the
simplified score 2008 should be included in the Table. According to the results 14.4% of the
patients did not have any autoantibody detectable. How the diagnosis was established in these
patients, given that liver biopsies were not stained for hemosiderin deposits and there was no
genetic testing for hemochromatosis? Furthermore, according to Table 1, TSI in some patients
was >45%. These patients should had been tested for hemochromatosis.
In addition, Table 1 should include mHAI activity score.
Finally, after AOC analysis and finding the best cut off point, a Table based to this cut off level
of ferritin should be presented with patients characteristics according to this cut off, in order
to prove that the patients with higher histological activity scores, ALT and IgG did not have
increased inflammatory activity. In addition, if histological activity score enters the multivariate
analysis, it is not sure that fibrosis will remain in the model.
Please review this paper.
user
Title: Serum ferritin levels are associated with advanced liver fibrosis in treatment-naive
autoimmune hepatitis
Version: 0 Date: 21 Nov 2021
Reviewer's report:
Chen et al investigated the association between variables related to iron metabolism and liver
fibrosis in untreated patients with autoimmune hepatitis.
The investigation could be of interest however there are several major limitations:
1. Introduction: Liver biopsy in AIH is essential not only for fibrosis estimation but also for
establishment of diagnosis. So, the aim of the study to potentially associate iron metabolism
variables with fibrosis stage in patients with AIH at diagnosis (before treatment) is weak and
ambiguous, since liver biopsy for diagnosis is absolutely necessary. In addition, at diagnosis
there is usually increased inflammation in the liver with acute phase reaction, so ferritin can
not be a reliable marker for fibrosis since it could reflect inflammation. On the contrary, if the
same study was contacted in treated patients after remission it could make sense for estimate
disease progression.
Minor: ref 1 is old, could be replaced with newer
2. Study population: the diagnosis of AIH is also ambiguous. For research purposes the diagnosis
of AIH should be based on the IAIHG criteria 1999 and/or 2008 but not only to histology as the
text implies (…..and/or (3) histological features indicative of AIH). It is well known that there
are no pathognomonic histological features for AIH and the diagnosis should combine exclusion
of other causes, IgG levels and autoantibodies.
3. General characteristics and lab tests: the autoantibodies starting dilution should be mentioned.
In addition, the cut off values for IgG, AST, ALT and ALP should be included.
4. Statistics: AOC for ferritin should be included as well the DeLong test for best cut off ferritin
level predicting advanced fibrosis stage. Sensitivity and specificity should also be calculated
5. Results: Table 1 should include the percentages of the patients according to the detected
autoantibodies (ANA, SMA, LKM, anti-SLA/LP). In addition, the IAIHG score of 1999 and the
simplified score 2008 should be included in the Table. According to the results 14.4% of the
patients did not have any autoantibody detectable. How the diagnosis was established in these
patients, given that liver biopsies were not stained for hemosiderin deposits and there was no
genetic testing for hemochromatosis? Furthermore, according to Table 1, TSI in some patients
was >45%. These patients should had been tested for hemochromatosis.
In addition, Table 1 should include mHAI activity score.
Finally, after AOC analysis and finding the best cut off point, a Table based to this cut off level
of ferritin should be presented with patients characteristics according to this cut off, in order
to prove that the patients with higher histological activity scores, ALT and IgG did not have
increased inflammatory activity. In addition, if histological activity score enters the multivariate
analysis, it is not sure that fibrosis will remain in the model.
assistant