Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 2 Date: 06 Apr 2021
Reviewer's report:
The authors examined if cholestatic liver disease changed glucocorticoid metabolism.  They
included 36 patients with cholestasis of different etiologies and 32 patient from the same hospital
without cholestasis.
Baseline Se-cortisol was higher in the cholestatic group than in controls, while ACTH levels
were similar. The responses to a 1µg  ATCH test were similar in the two groups. They conclude
that the effect of cholestasis was not mediated via the pituitary gland but  rather from increased
adrenal synthesis of glucocorticoids or reduced hepatic or renal elimination.
The paper is well written, experimental procedures easy to understand and well chosen for
the purpose. The finding of hypercortisolism in these patients will surprise many. I have some
concerns that I think should be addressed.
Major concerns
1. Based on previous findings in their own lab and reports from others, where supranormal
concentrations of bile acids stimulated adrenal cortisole production,  they expected that baseline
cortisol would correlate to bile acid concentrations. That was however not the case. Nevertheless
they use most of the discussion to infer that their findings actually supported their prior
hypothesis.  That conclusion is not supported by the data, and I think they should rewrite their
discussion accordingly.
2. Bilirubin concentrations did in fact correlate with cortisol concentrations. They could
speculate whether that could be a direct effect. However since we are dealing with a cross
sectional study,  they cannot explore cause-and-effect questions.
Minors
Abstract. Don’t use the term “delta cortisol” in the abstract, it is not explained until later in the
paper. Rewording or explanation needed.
Page 4. The publications suggesting a “hepato-adrenal syndrome” were based on patients with
cirrhosis. They may still be valid, since the patients in this study  did not yet have cirrhosis (at
least most of them did not). If the authors think the old hypothesis is refuted by their data they
should explain why.
Page 5. Important to mention if the cholestatic patients were hospitalized (like the
control group).
Page 14 . UCDA was clearly elevated in the Cholestatic group. How many were treated with
UDCA and could that affect the findings ?
Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 2 Date: 06 Apr 2021
Reviewer's report:
The authors examined if cholestatic liver disease changed glucocorticoid metabolism.  They
included 36 patients with cholestasis of different etiologies and 32 patient from the same hospital
without cholestasis.
Baseline Se-cortisol was higher in the cholestatic group than in controls, while ACTH levels
were similar. The responses to a 1µg  ATCH test were similar in the two groups. They conclude
that the effect of cholestasis was not mediated via the pituitary gland but  rather from increased
adrenal synthesis of glucocorticoids or reduced hepatic or renal elimination.
The paper is well written, experimental procedures easy to understand and well chosen for
the purpose. The finding of hypercortisolism in these patients will surprise many. I have some
concerns that I think should be addressed.
Major concerns
1. Based on previous findings in their own lab and reports from others, where supranormal
concentrations of bile acids stimulated adrenal cortisole production,  they expected that baseline
cortisol would correlate to bile acid concentrations. That was however not the case. Nevertheless
they use most of the discussion to infer that their findings actually supported their prior
hypothesis.  That conclusion is not supported by the data, and I think they should rewrite their
discussion accordingly.
2. Bilirubin concentrations did in fact correlate with cortisol concentrations. They could
speculate whether that could be a direct effect. However since we are dealing with a cross
sectional study,  they cannot explore cause-and-effect questions.
Minors
Abstract. Don’t use the term “delta cortisol” in the abstract, it is not explained until later in the
paper. Rewording or explanation needed.
Page 4. The publications suggesting a “hepato-adrenal syndrome” were based on patients with
cirrhosis. They may still be valid, since the patients in this study  did not yet have cirrhosis (at
least most of them did not). If the authors think the old hypothesis is refuted by their data they
should explain why.
Page 5. Important to mention if the cholestatic patients were hospitalized (like the
control group).
Page 14 . UCDA was clearly elevated in the Cholestatic group. How many were treated with
UDCA and could that affect the findings ?
Please review this paper.
user
Title: Hypercortisolism in Patients with Cholestasis is Associated with Disease Severity
Version: 2 Date: 06 Apr 2021
Reviewer's report:
The authors examined if cholestatic liver disease changed glucocorticoid metabolism.  They
included 36 patients with cholestasis of different etiologies and 32 patient from the same hospital
without cholestasis.
Baseline Se-cortisol was higher in the cholestatic group than in controls, while ACTH levels
were similar. The responses to a 1µg  ATCH test were similar in the two groups. They conclude
that the effect of cholestasis was not mediated via the pituitary gland but  rather from increased
adrenal synthesis of glucocorticoids or reduced hepatic or renal elimination.
The paper is well written, experimental procedures easy to understand and well chosen for
the purpose. The finding of hypercortisolism in these patients will surprise many. I have some
concerns that I think should be addressed.
Major concerns
1. Based on previous findings in their own lab and reports from others, where supranormal
concentrations of bile acids stimulated adrenal cortisole production,  they expected that baseline
cortisol would correlate to bile acid concentrations. That was however not the case. Nevertheless
they use most of the discussion to infer that their findings actually supported their prior
hypothesis.  That conclusion is not supported by the data, and I think they should rewrite their
discussion accordingly.
2. Bilirubin concentrations did in fact correlate with cortisol concentrations. They could
speculate whether that could be a direct effect. However since we are dealing with a cross
sectional study,  they cannot explore cause-and-effect questions.
Minors
Abstract. Don’t use the term “delta cortisol” in the abstract, it is not explained until later in the
paper. Rewording or explanation needed.
Page 4. The publications suggesting a “hepato-adrenal syndrome” were based on patients with
cirrhosis. They may still be valid, since the patients in this study  did not yet have cirrhosis (at
least most of them did not). If the authors think the old hypothesis is refuted by their data they
should explain why.
Page 5. Important to mention if the cholestatic patients were hospitalized (like the
control group).
Page 14 . UCDA was clearly elevated in the Cholestatic group. How many were treated with
UDCA and could that affect the findings ?
assistant