Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms
Round 1
Reviewer 1 Report
Dear Author,
It is a very interesting review on the mechanisms, benefits and side effects of glucocorticoid therapy in severe alcoholic hepatitis (sAH).
Major:
- rows 159-163: It is not clear who conducted the study: the author of this article or another group? The figure is presenting the results from which study? .....To elucidate the exact role of GC/GR in sAH, it is very important to understand changes of hepatic GR signaling in sAH. Thus, we conducted data mining of a hepatic transcriptome analysis of livers from patients with sAH (MDF score >32) and normal livers (GSE28619) [72]. Compared to normal livers, livers from sAH patients had moderate decreases of GR and the GR-target BA transporter NTCP [45] (Fig. 1). The same (It is not clear who conducted the study) for rows 204-210, 244-248, 347-350.
- Fig 1, Fig 2 legend: N=7-15 - what is the meaning? Is is 7 patients or 15?
For Fig 1 is corresponding reference 45: Eloranta, J.J.; Jung, D.; and Kullak-Ublick, G.A. The human Na+-taurocholate cotransporting polypeptide gene is acti- 525 vated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed 526 by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol, 2006, 20: 65-79.
For fig 2 is corresponding reference 72: Affo, S.; Dominguez, M.; Lozano, J.J.; Sancho-Bru, P.; Rodrigo-Torres, D.; Morales-Ibanez, O.; Moreno, M.; Millan, C.; Loaeza-del-Castillo, A.; Altamirano, J.; Garcia-Pagan, J.C.; Arroyo, V.; Gines, P.; Caballeria, J.; Schwabe, R.F.; and Bataller, R. Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis. Gut, 2013, 62: 452-60
Minor:
- row 60: ... odd ratio of 0.72 0.72 .....
- row 82: ... in in non-epithelial ...
- HSD11β2 or HSD11B2?
Author Response
Dear Author,
It is a very interesting review on the mechanisms, benefits and side effects of glucocorticoid therapy in severe alcoholic hepatitis (sAH).
Major:
- rows 159-163: It is not clear who conducted the study: the author of this article or another group? The figure is presenting the results from which study? .....To elucidate the exact role of GC/GR in sAH, it is very important to understand changes of hepatic GR signaling in sAH. Thus, we conducted data mining of a hepatic transcriptome analysis of livers from patients with sAH (MDF score >32) and normal livers (GSE28619) [72]. Compared to normal livers, livers from sAH patients had moderate decreases of GR and the GR-target BA transporter NTCP [45] (Fig. 1). The same (It is not clear who conducted the study) for rows 204-210, 244-248, 347-350.
Answer: We conducted data mining of hepatic transcriptome in patients with alcoholic hepatitis and normal livers (GSE28619) deposited in GEO DataSets by Dr. Bataller’s group (PMID: 22637703). The microarray data were generated by Dr. Bataller’s group and reanalyzed by the author. Additionally, we have conducted data mining of another data set of RNA-sequencing analysis of hepatic transcriptome (GSE142530) in patients with alcoholic hepatitis and alcoholic cirrhosis. We have modified the text and the figure legends to make it clear the authorship as follows: “To elucidate the exact role of GC/GR in sAH, it is very important to understand changes of hepatic GR signaling in sAH. Thus, we reanalyzed the microarray data of hepatic transcriptome (generated by Dr. Bataller’s group) in patients with sAH (MDF score >32) and normal livers (GSE28619) [85]”. “Additionally, we also reanalyzed the data of RNA-sequencing analysis of hepatic transcriptome in patients with AH (N=10) and alcoholic cirrhosis (AC, N=6) (GSE142530, generated by Dr. Bataller’s group) [46]”.
- Fig 1, Fig 2 legend: N=7-15 - what is the meaning? Is is 7 patients or 15?
Answer: There were 7 normal livers and 15 AH livers in this study. The legend has been rewritten as follows: N=7 normal human livers and 15 AH human livers.
For Fig 1 is corresponding reference 45: Eloranta, J.J.; Jung, D.; and Kullak-Ublick, G.A. The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed 526 by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol, 2006, 20: 65-79.
For fig 2 is corresponding reference 72: Affo, S.; Dominguez, M.; Lozano, J.J.; Sancho-Bru, P.; Rodrigo-Torres, D.; Morales-Ibanez, O.; Moreno, M.; Millan, C.; Loaeza-del-Castillo, A.; Altamirano, J.; Garcia-Pagan, J.C.; Arroyo, V.; Gines, P.; Caballeria, J.; Schwabe, R.F.; and Bataller, R. Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis. Gut, 2013, 62: 452-60
Answer: The author apologizes for the confusion. Both Figures 1 and 2 are corresponding to the same reference by Affo et al. The papers that report the given gene as a GR-target gene are cited for these so-called GR-target genes. The paper by Eloranta et al. was cited for reporting NTCP as a GR-target gene.
Minor:
- row 60: ... odd ratio of 0.72 0.72 .....
Answer: the redundant 0.72 has been removed.
- row 82: ... in in non-epithelial ...
Answer: the redundant “in” has been removed.
- HSD11β2 or HSD11B2?
Answer: the term “HSD11β2” has been kept consistent in the revised article.
Reviewer 2 Report
Reviewer Report
Manuscript ID # Mini-Review
Mini-Review article entitled” Glucocorticoids in alcoholic hepatitis: benefits, side effects, and mechanisms written by Author Hong Lu submitted in Journal of Xenobiotics for publication is reviewed.
The purpose of writing this mini- review is with an objective to improve Glucocorticoids therapy of severe alcoholic hepatitis and author has suggested that effort should be focused on developing biomarker(s) for glucocorticoid responsiveness, liver-targeting glucocorticoid receptor agonists, and strategies to overcome glucocorticoid non-responsiveness and prevent alcohol relapse in severe alcoholic hepatitis.
Therefore, a deep understanding of the interactions of GCs and PKC delta with GR and MR in severe alcoholic hepatitis will not only markedly improve the GC therapy of severe alcoholic hepatitis but also help attenuate compulsive alcohol use and key determinant of the long-term outcome of glucocorticoid therapy of severe alcoholic hepatitis.
This mini-review is well written and most of the statements are well supported by published literatures.
Some minor corrections are needed at certain places such as on Line # 145 ’sick cell disease’ should corrected to sickle cell disease.
On line #181 and 182 statement mentioned as “Metallothionein protects against non-alcoholic fatty liver and ALD by inhibiting oxidative stress (98,99)”. This sentence should be revised for clarity and better understanding.
In my opinion, this mini-review may be accepted for publication after suggested correction done by author.
Author Response
Mini-Review article entitled” Glucocorticoids in alcoholic hepatitis: benefits, side effects, and mechanisms written by Author Hong Lu submitted in Journal of Xenobiotics for publication is reviewed.
The purpose of writing this mini- review is with an objective to improve Glucocorticoids therapy of severe alcoholic hepatitis and author has suggested that effort should be focused on developing biomarker(s) for glucocorticoid responsiveness, liver-targeting glucocorticoid receptor agonists, and strategies to overcome glucocorticoid non-responsiveness and prevent alcohol relapse in severe alcoholic hepatitis.
Therefore, a deep understanding of the interactions of GCs and PKC delta with GR and MR in severe alcoholic hepatitis will not only markedly improve the GC therapy of severe alcoholic hepatitis but also help attenuate compulsive alcohol use and key determinant of the long-term outcome of glucocorticoid therapy of severe alcoholic hepatitis.
This mini-review is well written and most of the statements are well supported by published literatures.
Some minor corrections are needed at certain places such as on Line # 145 ’sick cell disease’ should corrected to sickle cell disease.
Answer: ’sick cell disease’ has been corrected to “sickle cell disease”.
On line #181 and 182 statement mentioned as “Metallothionein protects against non-alcoholic fatty liver and ALD by inhibiting oxidative stress (98,99)”. This sentence should be revised for clarity and better understanding.
Answer: this sentence has been revised to “Metallothionein protects against non-alcoholic fatty liver and ALD by inhibiting oxidative stress and leptin resistance [111, 112]. MT1X is a major member of metallothionein 1 family that acts as a tumor suppressor in hepatoma cells by inactivating NF-kB signaling [113]”.
Reviewer 3 Report
Dr. Lu describes the role of glucocorticoids in alcoholic hepatitis in the presented review paper. Since the discussed area has very impressive heritage since 1978 and the true impact of GC on sAH remains elusive, this paper is very welcome to the field. I found the paper nicely written, however, some editorial minors (like double spaces and unnecessary highlighting) should be fixed.
I would like to see the introduction (or substantial expansion of paragraph starting in line 55) of the more critical paragraph that will take into account published within the last 5 years analysis that stands in the oppose to current semi-paradigm of the curative role of GC towards sAH.
Please also describe some pharmaco-economic impact of the usage of GC in managing sAH as well as any kind of information regarding the possibilities of differentiation of the GC action based on pharmacogenomic would be highly appreciated.
Moving further, there is a very limited amount of information given regarding the following PRISMA guidelines and description of the searching strategy, which is so crucial for review papers. The Author should include at least: Data sources and searches, Study eligibility criteria, Study selection process, Data extraction, and study quality assessment (assessing the risk of bias (ROB) for each included study), Data synthesis. MeSH terms (in addition/replacement of keywords) are necessary to be included. For each step, it is necessary to explain to the reader with pictures or tables. It is necessary to explain what was drawn at each step to lead to the result. Moreover, a figure showing the PRISMA-based workflow must be drawn accordingly to the Prisma schema. After that, a discussion is valuable even for narrative papers. Description of Data Mining strategy should also be included.
Figure 3 should have a legend that is readable when standing alone. In other words, please expand the figure description to make it more clear for the Readers.
Please indicate the type of paper above the title.
There is no need to put figure legends description in lines 406 - 413
Line 5: please delete "From the"
Author Response
Dr. Lu describes the role of glucocorticoids in alcoholic hepatitis in the presented review paper. Since the discussed area has very impressive heritage since 1978 and the true impact of GC on sAH remains elusive, this paper is very welcome to the field. I found the paper nicely written, however, some editorial minors (like double spaces and unnecessary highlighting) should be fixed.
I would like to see the introduction (or substantial expansion of paragraph starting in line 55) of the more critical paragraph that will take into account published within the last 5 years analysis that stands in the oppose to current semi-paradigm of the curative role of GC towards sAH.
Answer: Based on extensive analysis of research published in the last 5 years, GCs have significant beneficial therapeutic effects in only select patients with moderately severe alcoholic hepatitis. The summary of the largely expanded Section 8 regarding the GC responsiveness/non-responsiveness of sAH patients clearly indicates that good GC responsiveness in sAH patients correlates with moderate disease severity (MELD score <51), less liver fibrosis/cirrhosis, and moderately severe inflammation (5 <NLR < 8) and apoptosis (high keratin-18 fragments).
Please also describe some pharmaco-economic impact of the usage of GC in managing sAH as well as any kind of information regarding the possibilities of differentiation of the GC action based on pharmacogenomic would be highly appreciated.
Answer: Information on some pharmaco-economic impact of AH treatment has been added as follows: “An analysis of 2007-2014 national inpatient sample shows that among 159,973 ALD hospitalizations in the USA, 83.7% and 18.4% have a primary diagnosis of alcohol-associated cirrhosis and AH, respectively [8]. Native Americans (OR=1.88) and Asian/Pacific Islanders (OR=2.02) with AH have significantly higher in-hospital mortality compared with non-Hispanic whites [8]. In a health care claims analysis of over 15,000 commercially insured adults hospitalized with AH between 2006 and 2013 in the USA, the total costs are nearly $145,000 per patient, and about two-thirds of hospitalized sAH patients die within 5 years after the initial hospitalization [9]. In 2016, AH-related and alcoholic cirrhosis-related hospitalizations account for $1.15 billion and $7.67 billion in the USA, respectively [10]. Therefore, ALD, and sAH in particular, is a major health and economic burden worldwide [1].”
Regarding the possibilities of differentiation of the GC action based on pharmacogenomic, there were pharmacogenomic studies of GC responses in other diseases, but not in AH treatment. The following information has been added in Section 9: “There are many (more than 100) GR mutations in the general population that may contribute to the intrinsic GCR [152]. The common GR 9β SNP rs6198, which causes stabilization and increased translation of the GRβ mRNA to decrease GC response, is associated with poor efficacy of GC therapy in patients with childhood acute lymphoblastic leukemia [153]. Additionally, the common GR polymorphism rs41423247 (BclI) located in the intron2-3 with GC hypersensitivity is associated with better responses to GC’s protective effects on postoperative posttraumatic stress disorder symptoms in cardiac surgery patients and inflammatory bowel disease [154, 155]. So far, there is no published pharmacogenetic studies on the effects of various mutations/SNPs of GR on the GC responsiveness in sAH patients.”
Moving further, there is a very limited amount of information given regarding the following PRISMA guidelines and description of the searching strategy, which is so crucial for review papers. The Author should include at least: Data sources and searches, Study eligibility criteria, Study selection process, Data extraction, and study quality assessment (assessing the risk of bias (ROB) for each included study), Data synthesis. MeSH terms (in addition/replacement of keywords) are necessary to be included. For each step, it is necessary to explain to the reader with pictures or tables. It is necessary to explain what was drawn at each step to lead to the result. Moreover, a figure showing the PRISMA-based workflow must be drawn accordingly to the Prisma schema. After that, a discussion is valuable even for narrative papers. Description of Data Mining strategy should also be included.
Answer: This review article was written as a narrative review rather than a systemic review, to address multiple questions regarding the efficacy, side effects, and underlying mechanisms of GC therapy of severe AH, with a much broader scope than a systemic review. The title of this review article has been changed to “Narrative review: Glucocorticoids in alcoholic hepatitis - benefits, side effects, and mechanisms”. Currently, there is no strict protocol to be followed for narrative review. Nevertheless, we have added the information regarding the searching strategy, Data sources, and searches as follows: “PubMed and Scopus databases were searched using search syntaxes of: 1) "alcoholic hepatitis"[Title/Abstract] AND (glucocorticoid*[Title/Abstract] OR corticosteroid*[Title/Abstract]); 2) “Glucocorticoid resistance”[Title/Abstract] AND liver[Title/Abstract]; and 3) “Glucocorticoid response”[Title/Abstract] AND liver[Title/Abstract]. Additional search syntaxes include “mineralocorticoid receptor”[Title/Abstract] AND (liver[Title/Abstract] or alcohol[Title/Abstract]), (chemokine*[Title/Abstract] OR neutrophil*[Title/Abstract]) AND “alcoholic hepatitis”[Title/Abstract], as well as PKCD*[Title/Abstract] AND liver[Title/Abstract], etc. The last search was conducted on August 29, 2022.”
Additionally, description of Data Mining strategy has been added as follows: “Data mining was conducted in GEO DataSets using the search syntaxes of "alcoholic hepatitis" AND human AND (microarray or RNA-sequencing). The mRNA expression of microarray (GSE28619) and RNA-sequencing (GSE142530) data were retrieved from GEO DataSets and normalized to β-actin, with values of normal human livers set as 1.0. Statistical difference between the AH group and the normal group in the microarray dataset was determined by Student’s t-test, with significance set at P < 0.05. Statistical differences between the AH group and the normal group as well as the alcoholic cirrhosis (AC) group and the normal group in the RNA-sequencing dataset were determined by Two-way ANOVA followed by Dunnett's multiple comparisons test, with significance set at P < 0.05.”
Figure 3 should have a legend that is readable when standing alone. In other words, please expand the figure description to make it more clear for the Readers.
Answer: Detailed legend for Fig. 3 with figure description has been added.
Please indicate the type of paper above the title.
Answer: The title of this review article has been changed to “Narrative review: Glucocorticoids in alcoholic hepatitis - benefits, side effects, and mechanisms”.
There is no need to put figure legends description in lines 406 – 413
Answer: Figure legends description has been removed in the text.
Line 5: please delete "From the"
Answer: "From the" has been deleted.
Round 2
Reviewer 1 Report
Dear Author,
The manuscript is improved and it is clear the review on the mechanisms, benefits and side effects of glucocorticoid therapy in severe alcoholic hepatitis (sAH).
Minor:
- the references have numbers twice... e.g. 1. 1. Singal, A.K.; and Mathurin, P. Diagnosis and Treatment of Alcohol-Associated Liver Disease: A Review. JAMA, 2021, 566 326: 165-176. 567
2. 2. Termeie, O.; Fiedler, L.; Martinez, L.; Foster, J.; Perumareddi, P.; Levine, R.S.; and Hennekens, C.H. Alarming Trends: 568 Mortality from Alcoholic Cirrhosis in the United States. Am J Med, 2022. 569
Author Response
The formatting issue of double numbers in the references has been fixed.
Reviewer 3 Report
The Author fixed the draft in an appropriate way - all my majors and minors were correctly addressed. The presented manuscript is suitable for acceptance in JoX now.
Author Response
Thank you for your positive comments and approval for acceptance!
