Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 2 Date: 20 Mar 2021
Reviewer's report:
The study is aimed to evaluate the prevalence and the possible causes of hypercortisolism in
patients with cholestasis. Though the sample size is small and the topic has already been studied
in other papers, the presence of a control group of patients without cholestasis is a strength point.
Moreover the paper is well written and clear.
Anyway, I have several comments:
1) In the introduction I suggest to deepen, with a brief explanation, how FXR and, above all,
TGR5 have an action both in enterohepatic circulation and in glucocorticoid metabolism (the last
receptor is just mentioned).  I think it would be more clear for the reader in order to understand
one of the main known mechanisms of cross-talk between cortisol metabolism and cholestasis.
2) Among the exclusion criteria, there are pituitary or adrenal diseases or tumours: how have
you excluded them? Pituitary and adrenal imaging has been performed in all patients?
3) How have you excluded hypercortisolism due to endocrine causes in patients with higher
basal cortisol levels? It would have been correct to evaluate cortisol secretion also at the end of
the acute disease event, for example with the 1 mg dexamethasone suppression test,  in order to
verify that higher levels of cortisol were caused actually by cholestasis and not by other diseases,
at least in few patients.
4) “ (…) patients with cholestasis showed hypercortisolism associated with disease severity as
mirrored by levels of bilirubin. A short duration of disease seems to have more pronounced
effects on cortisol metabolism than long-standing disease”. Regardless of the effects that
levels of bilirubin may have on cortisol metabolism, what could be the clinical implications
of hypercortisolism in these patients? It would have been interesting to evaluate the possible
correlation beetween levels of cortisol and (for example) prognosis, incidence of infections,
duration of hospitalization...
Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 2 Date: 20 Mar 2021
Reviewer's report:
The study is aimed to evaluate the prevalence and the possible causes of hypercortisolism in
patients with cholestasis. Though the sample size is small and the topic has already been studied
in other papers, the presence of a control group of patients without cholestasis is a strength point.
Moreover the paper is well written and clear.
Anyway, I have several comments:
1) In the introduction I suggest to deepen, with a brief explanation, how FXR and, above all,
TGR5 have an action both in enterohepatic circulation and in glucocorticoid metabolism (the last
receptor is just mentioned).  I think it would be more clear for the reader in order to understand
one of the main known mechanisms of cross-talk between cortisol metabolism and cholestasis.
2) Among the exclusion criteria, there are pituitary or adrenal diseases or tumours: how have
you excluded them? Pituitary and adrenal imaging has been performed in all patients?
3) How have you excluded hypercortisolism due to endocrine causes in patients with higher
basal cortisol levels? It would have been correct to evaluate cortisol secretion also at the end of
the acute disease event, for example with the 1 mg dexamethasone suppression test,  in order to
verify that higher levels of cortisol were caused actually by cholestasis and not by other diseases,
at least in few patients.
4) “ (…) patients with cholestasis showed hypercortisolism associated with disease severity as
mirrored by levels of bilirubin. A short duration of disease seems to have more pronounced
effects on cortisol metabolism than long-standing disease”. Regardless of the effects that
levels of bilirubin may have on cortisol metabolism, what could be the clinical implications
of hypercortisolism in these patients? It would have been interesting to evaluate the possible
correlation beetween levels of cortisol and (for example) prognosis, incidence of infections,
duration of hospitalization...
Please review this paper.
user
Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 2 Date: 20 Mar 2021
Reviewer's report:
The study is aimed to evaluate the prevalence and the possible causes of hypercortisolism in
patients with cholestasis. Though the sample size is small and the topic has already been studied
in other papers, the presence of a control group of patients without cholestasis is a strength point.
Moreover the paper is well written and clear.
Anyway, I have several comments:
1) In the introduction I suggest to deepen, with a brief explanation, how FXR and, above all,
TGR5 have an action both in enterohepatic circulation and in glucocorticoid metabolism (the last
receptor is just mentioned).  I think it would be more clear for the reader in order to understand
one of the main known mechanisms of cross-talk between cortisol metabolism and cholestasis.
2) Among the exclusion criteria, there are pituitary or adrenal diseases or tumours: how have
you excluded them? Pituitary and adrenal imaging has been performed in all patients?
3) How have you excluded hypercortisolism due to endocrine causes in patients with higher
basal cortisol levels? It would have been correct to evaluate cortisol secretion also at the end of
the acute disease event, for example with the 1 mg dexamethasone suppression test,  in order to
verify that higher levels of cortisol were caused actually by cholestasis and not by other diseases,
at least in few patients.
4) “ (…) patients with cholestasis showed hypercortisolism associated with disease severity as
mirrored by levels of bilirubin. A short duration of disease seems to have more pronounced
effects on cortisol metabolism than long-standing disease”. Regardless of the effects that
levels of bilirubin may have on cortisol metabolism, what could be the clinical implications
of hypercortisolism in these patients? It would have been interesting to evaluate the possible
correlation beetween levels of cortisol and (for example) prognosis, incidence of infections,
duration of hospitalization...
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