Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 3 Date: 27 May 2021
Reviewer's report:
The paper, aimed to evaluate the prevalence and the possible causes of hypercortisolism in
patients with cholestasis, after a first revision has been modified adequately and the required
elements have been added.
However, there is one point I would like to focus on, already underlined in the previous revision:
an unknown hypercortisolism with endocrine basis has never really been excluded: in addition
to have examined only the absence of adrenal or pituitary diseases in the anamnesis without
having investigated the finding of increased basal cortisol, no further assessments were carried
out at the end of the acute event to verify that the basal hypercortisolism was really related to
the cholestatic pathology. I agree to cite the Endocrine Society Guidelines for the diagnosis of
Cushing's syndrome and I understand that none of the patients had any characteristics that could
suggest true overt endocrine hypercortisolism, but these guidelines are used in clinical practice,
in patients without already reported increased cortisol levels. Being in this case a clinical study
aimed at evaluating the presence of hypercortisolism related to cholestasis, and having been
found an increase in basal cortisol, I believe it was of primary importance to exclude other
causes of hypercortisolism, not only based on the anamnestic absence of adrenal and/or pituitary
diseases, but also by performing targeted imaging and, possibly, suppression test or urinary free
cortisol. Not having done so, I think it is important to add it within the limits of the study.
Also considering that often the features of hypercortisolism can be very nuanced (subclinical
hypercortisolism) and have not yet caused consequences in terms of physiognomy and/or long-
term complications, making it difficult to apply Endocrine Society Guidelines.
Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 3 Date: 27 May 2021
Reviewer's report:
The paper, aimed to evaluate the prevalence and the possible causes of hypercortisolism in
patients with cholestasis, after a first revision has been modified adequately and the required
elements have been added.
However, there is one point I would like to focus on, already underlined in the previous revision:
an unknown hypercortisolism with endocrine basis has never really been excluded: in addition
to have examined only the absence of adrenal or pituitary diseases in the anamnesis without
having investigated the finding of increased basal cortisol, no further assessments were carried
out at the end of the acute event to verify that the basal hypercortisolism was really related to
the cholestatic pathology. I agree to cite the Endocrine Society Guidelines for the diagnosis of
Cushing's syndrome and I understand that none of the patients had any characteristics that could
suggest true overt endocrine hypercortisolism, but these guidelines are used in clinical practice,
in patients without already reported increased cortisol levels. Being in this case a clinical study
aimed at evaluating the presence of hypercortisolism related to cholestasis, and having been
found an increase in basal cortisol, I believe it was of primary importance to exclude other
causes of hypercortisolism, not only based on the anamnestic absence of adrenal and/or pituitary
diseases, but also by performing targeted imaging and, possibly, suppression test or urinary free
cortisol. Not having done so, I think it is important to add it within the limits of the study.
Also considering that often the features of hypercortisolism can be very nuanced (subclinical
hypercortisolism) and have not yet caused consequences in terms of physiognomy and/or long-
term complications, making it difficult to apply Endocrine Society Guidelines.
Please review this paper.
user
Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 3 Date: 27 May 2021
Reviewer's report:
The paper, aimed to evaluate the prevalence and the possible causes of hypercortisolism in
patients with cholestasis, after a first revision has been modified adequately and the required
elements have been added.
However, there is one point I would like to focus on, already underlined in the previous revision:
an unknown hypercortisolism with endocrine basis has never really been excluded: in addition
to have examined only the absence of adrenal or pituitary diseases in the anamnesis without
having investigated the finding of increased basal cortisol, no further assessments were carried
out at the end of the acute event to verify that the basal hypercortisolism was really related to
the cholestatic pathology. I agree to cite the Endocrine Society Guidelines for the diagnosis of
Cushing's syndrome and I understand that none of the patients had any characteristics that could
suggest true overt endocrine hypercortisolism, but these guidelines are used in clinical practice,
in patients without already reported increased cortisol levels. Being in this case a clinical study
aimed at evaluating the presence of hypercortisolism related to cholestasis, and having been
found an increase in basal cortisol, I believe it was of primary importance to exclude other
causes of hypercortisolism, not only based on the anamnestic absence of adrenal and/or pituitary
diseases, but also by performing targeted imaging and, possibly, suppression test or urinary free
cortisol. Not having done so, I think it is important to add it within the limits of the study.
Also considering that often the features of hypercortisolism can be very nuanced (subclinical
hypercortisolism) and have not yet caused consequences in terms of physiognomy and/or long-
term complications, making it difficult to apply Endocrine Society Guidelines.
assistant