Congenital Hepatic Fibrosis as a Cause of Recurrent Cholangitis: A Case Report and Review of the Literature

Round 1

Reviewer 1 Report

This manuscript is a case report outlining a patient with recurrent cholangitis and ultimately diagnosed with congenital hepatic fibrosis which is coupled to a literature review on the same topic. Congenital hepatic fibrosis and related diseases/syndromes are relatively rare, so patients presenting with cholangitis may not be identified as concomitantly having a disease associated with ductal plate malformation. Thus, this case study and literature review would be valuable for clinicians who have patients with recurrent cholangitis episodes to potentially expedite appropriate therapy and limit disease exacerbation or progression and associated morbidity/mortality. I have a few suggestions:

1. I recommend expanding on the liver diseases which are associated with ductal plate malformation. In other words, how are congenital hepatic fibrosis, Caroli syndrome and polycystic liver disease different from one another? For example, congenital hepatic fibrosis is associated with autosomal recessive polycystic liver disease and genetic mutations in the PKHD1 gene leading to dysfunctional fibrocystin found in cholangiocyte primary cilia is involved in disease pathogenesis and progression.
2. I recommend describing how cholangitis is diagnosed in the clinic to improve readability by non-clinicians and/or trainees in medicine or basic research.
3. The discussion could be improved by expanding what is presented. For example, the authors should consider discussing from where are the bacteria coming (the gut?) and the implication of this. In other words, is ductal plate malformation associated with gut dysbiosis, bacterial overgrowth, and increased gut permeability? Could any of this information inform potential therapies prior to liver transplantation? Or, is antibiotic treatment the only effective therapy for recurrent cholangitis? Given the clear importance of the gut-liver axis to homeostasis, it seems as though there is a missed opportunity to think more deeply about how to handle cholangitis in this patient population which could have positive impacts on the liver (does limiting cholangitis episodes delay CHF progression?) and the gut (could pro-biotics reduce episodes of recurrent cholangitis?).

Minor comments

1. Line 60: cytokeratin is misspelled.
2. Be sure genus and species of bacteria described are italicized
3. Please spell out ‘FPD’ in Table 1’s title
4. The manuscript could benefit from a (slight) revision of English grammar and usage.

Author Response

Reviewer 1:

This manuscript is a case report outlining a patient with recurrent cholangitis and ultimately diagnosed with congenital hepatic fibrosis which is coupled to a literature review on the same topic. Congenital hepatic fibrosis and related diseases/syndromes are relatively rare, so patients presenting with cholangitis may not be identified as concomitantly having a disease associated with ductal plate malformation. Thus, this case study and literature review would be valuable for clinicians who have patients with recurrent cholangitis episodes to potentially expedite appropriate therapy and limit disease exacerbation or progression and associated morbidity/mortality. I have a few suggestions:

1. I recommend expanding on the liver diseases which are associated with ductal plate malformation. In other words, how are congenital hepatic fibrosis, Caroli syndrome and polycystic liver disease different from one another? For example, congenital hepatic fibrosis is associated with autosomal recessive polycystic liver disease and genetic mutations in the PKHD1 gene leading to dysfunctional fibrocystin found in cholangiocyte primary cilia is involved in disease pathogenesis and progression.

As suggested, we have added a brief overview of these diseases (see lines 35-43).

2. I recommend describing how cholangitis is diagnosed in the clinic to improve readability by non-clinicians and/or trainees in medicine or basic research.

We have added a paragraph describing the clinical highlights of cholangitis (see lines 48-52).

3. The discussion could be improved by expanding what is presented. For example, the authors should consider discussing from where are the bacteria coming (the gut?) and the implication of this. In other words, is ductal plate malformation associated with gut dysbiosis, bacterial overgrowth, and increased gut permeability? Could any of this information inform potential therapies prior to liver transplantation? Or, is antibiotic treatment the only effective therapy for recurrent cholangitis? Given the clear importance of the gut-liver axis to homeostasis, it seems as though there is a missed opportunity to think more deeply about how to handle cholangitis in this patient population which could have positive impacts on the liver (does limiting cholangitis episodes delay CHF progression?) and the gut (could pro-biotics reduce episodes of recurrent cholangitis?).

We rewrote part of the discussion according to the reviewer’s suggestions (see lines     162-182).

Minor comments

Line 60: cytokeratin is misspelled.

Agreed and so modified (line 75).

Be sure genus and species of bacteria described are italicized

We rechecked the manuscript and corrected the mistypes. Kingdom, phylum, class, order (such as Enterobacterales), and suborder begin with a capital letter but should not be italicized.

Please spell out ‘FPD’ in Table 1’s title

Corrected.

The manuscript could benefit from a (slight) revision of English grammar and usage.

We thoroughly reviewed the entire manuscript with the support of an English native speaker.

We appreciate the insightful revisions and hope that our manuscript can now be considered for publication in the Livers.

Author Response File: Author Response.doc

Reviewer 2 Report

This paper described on the congenital hepatic fibrosis as a cause of recurrent cholangitis: using a 2 case report and review of the literature. Authors also reviewed the literature collecting cases of recurrent infections occurring in 26 patients with ductal plate malformation.

• In Table 1, authors added the gender of patients in the table 1.
• Authors also clearly described the conclusion of this case-report in this paper.

Author Response

Reviewer 2:

This paper described on the congenital hepatic fibrosis as a cause of recurrent cholangitis: using a 2 case report and review of the literature. Authors also reviewed the literature collecting cases of recurrent infections occurring in 26 patients with ductal plate malformation.

In Table 1, authors added the gender of patients in the table 1.

Authors also clearly described the conclusion of this case-report in this paper.

We thank the reviewer for the comment. Gender of patients was not specified in most of the work cited.

We appreciate the insightful revisions and hope that our manuscript can now be considered for publication in the Livers.

Author Response File: Author Response.doc