Benign Recurrent Intrahepatic Cholestasis: Where Are We Now?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this review article, Geladari et al. provided an update of our current knowledge of the genetics, pathophysiology, clinical presentation, diagnosis, and treatment of benign recurrent intrahepatic cholestasis (BRIC). Overall, it is a well-written review providing information that is helpful for both researchers and clinicians. I have a few comments/suggestions:

 

1.     In the abstract, the authors stated that “Unlike PFIC, BRIC does not progress to chronic liver disease or cirrhosis”. However, there are reports showing that BRIC may develop a continuous and progressive form of cholestasis (Van Ooteghem et al., J Hepatol. 2002, 36:439-443; Van Mil et al.,Semin. Liver Dis. 2001, 21:535-44).

2.     BRIC has been traditionally thought to be autosomal recessive. Yet, several recent studies indicate that heterozygous variants in ATP8B1 or ABCB11 are sufficient to cause BRIC, raising the possibility of haploinsufficiency (Kato et al., J Clin Med 2023 12(18):5979; Bing et al., Front Med. 2022 9:897108; Suzuki et al., Front Med. 2022 9:891659; Piazzolla et al., World J Hepatol 2020 12(2):64-71). 

3.     The review focuses on BRIC1 and BRIC2. It has been shown that mutations in other genes can cause BRIC. In addition to USP53 that is described in the article, mutations in MTM1, PKLR, UGT1A, and TJP2 have also been associated with BRIC (Karolczak et al., J Clin Invest 2023, 133(18):e166275; Kornitzer and Alvarez, JPGN Rep. 2021, 2(3):e087; Wu et al., Front Genet. 2023. 14:1229271). It will be worthwhile discussing these new discoveries as they demonstrated the importance of genetic testing in BRIC diagnosis and treatment. 

4.     For BRIC treatment, surgical strategies, such as biliary diversion, should also be discussed.

 

Minor points:

1.     Line 119 contains typo: “in in aforementioned genes”.

2.     Page 3 – although ICP is mentioned in the subtitle and summary paragraph, it was barely described in this part of the review.

3.     Fig 1: suggest to change the color of “PC” and “AMP”. The white color is very difficult to see.

4.     MDR3 is a floppase, not a flippase. 

Author Response

Dear Reviewer,

We would like to thank you for giving us the opportunity to submit a revised version of our manuscript. We appreciate the time and effort that you dedicated to providing feedback on our manuscript and are grateful for the insightful comments and valuable improvements to our paper. We believe that after completion of the suggested edits, the revised manuscript was improved in overall presentation and clarity. We have incorporated your suggestions to the best extent possible. In our revised manuscript, all revisions have been highlighted in yellow. Below you will find a point-by-point response to the comments, which appear in italics.

Reviewer 1

In this review article, Geladari et al. provided an update of our current knowledge of the genetics, pathophysiology, clinical presentation, diagnosis, and treatment of benign recurrent intrahepatic cholestasis (BRIC). Overall, it is a well-written review providing information that is helpful for both researchers and clinicians. I have a few comments/suggestions:

RE: In the abstract, the authors stated that “Unlike PFIC, BRIC does not progress to chronic liver disease or cirrhosis”. However, there are reports showing that BRIC may develop a continuous and progressive form of cholestasis (Van Ooteghem et al., J Hepatol. 2002, 36:439-443; Van Mil et al.,Semin. Liver Dis. 2001, 21:535-44)

AU: The phrase has changed according to the suggestions. Moreover, the Introduction section was modified(, and the two articles have been added in the text and References section [10,11].

RE: 2.BRIC has been traditionally thought to be autosomal recessive. Yet, several recent studies indicate that heterozygous variants in ATP8B1 or ABCB11 are sufficient to cause BRIC, raising the possibility of haploinsufficiency (Kato et al., J Clin Med 2023 12(18):5979; Bing et al., Front Med. 2022 9:897108; Suzuki et al., Front Med. 2022 9:891659; Piazzolla et al., World J Hepatol 2020 12(2):64-71). 

AU: The information was added in Section 4 “Genetic aspects etc”, Page 3-4, lines 94-96. Moreover, the articles reported have been added in the References section [17-20].

RE: 3.The review focuses on BRIC1 and BRIC2. It has been shown that mutations in other genes can cause BRIC. In addition to USP53 that is described in the article, mutations in MTM1, PKLR, UGT1A, and TJP2 have also been associated with BRIC (Karolczak et al., J Clin Invest 2023, 133(18):e166275; Kornitzer and Alvarez, JPGN Rep. 2021, 2(3):e087; Wu et al., Front Genet. 2023. 14:1229271). It will be worthwhile discussing these new discoveries as they demonstrated the importance of genetic testing in BRIC diagnosis and treatment. 

AU: The information was added in Section 4 “Genetic aspects etc”, Page 4, lines 119-120. Moreover, the articles reported have been added in the References section [21-23].

RE: 4.For BRIC treatment, surgical strategies, such as biliary diversion, should also be discussed.

AU: The information was added in Section 9 “treatment options,,,”, lines 294-302.

Minor points:

RE:1.  Line 119 contains typo: “in in aforementioned genes”.

AU: It was corrected.

RE: 2. Page 3 – although ICP is mentioned in the subtitle and summary paragraph, it was barely described in this part of the review.

AU: It was corrected.

RE: 3. Fig 1: suggest to change the color of “PC” and “AMP”. The white color is very difficult to see.

AU: It was corrected.

RE: 4.MDR3 is a floppase, not a flippase. 

AU: It was corrected.

 

Yours sincerely

Alexandra Alexopoulou

Professor of Medicine

Reviewer 2 Report

Comments and Suggestions for Authors

Line 162: bile acids accumulate in hepatocytes as well as canaliculi

Line 293: I disagree with this statement. Obeticholic acid's main side effect is pruritus, It is not as stated, significantly more promising.

Author Response

Dear Reviewer,

We would like to thank you for giving us the opportunity to submit a revised version of our manuscript. We appreciate the time and effort that you dedicated to providing feedback on our manuscript and are grateful for the insightful comments and valuable improvements to our paper. We believe that after completion of the suggested edits, the revised manuscript was improved in overall presentation and clarity. We have incorporated your suggestions to the best extent possible. In our revised manuscript, all revisions have been highlighted in yellow. Below you will find a point-by-point response to the reviewers’ comments, which appear in italics.

Reviewer 2

RE: Line 162: bile acids accumulate in hepatocytes as well as canaliculi

AU: It was corrected, line 169.

 

RE: Line 293: I disagree with this statement. Obeticholic acid's main side effect is pruritus, It is not as stated, significantly more promising.

AU: It was corrected, lines 306-311.

 

Thank you for your consideration. 

Yours sincerely

Alexandra Alexopoulou

Professor of Medicine

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Changes accepy

Author Response

Dear Reviewer,

We would like to thank you for giving us the opportunity to submit a revised version of our manuscript.