Review for 10.1186/s12876-025-03966-0 (2025)

Title: Nonlinear Association between AST/ALT Ratio and 28-Day All-Cause Mortality
Following ICU Admission in Critically Ill Cirrhotic Patients: A Retrospective Cohort Study
Version: 1 Date: 01 Apr 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While the MIMIC-IV database is valuable, it only represents patients admitted to a single
medical center (Beth Israel Deaconess Medical Center), which might limit the generalizability
of the findings to other institutions or populations. Factors like geographic location, healthcare
system differences, and population demographics could all influence the results.
-The exclusion of patients with liver cancer or other malignancies limits the applicability of the
findings to this group. While it is necessary to exclude certain conditions for clarity, cirrhotic
patients with malignancies may have different prognostic profiles, which means the findings
may not fully represent all cirrhotic ICU patients.
-Excluding ICU stays under 24 hours could also exclude some patients who were critically ill
but did not survive the first day of admission, potentially underestimating the severity of illness
in some cases.
-While the study includes a comprehensive set of covariates, the complex, multifactorial nature
of cirrhosis in the ICU means there could be unmeasured confounders that influence outcomes.
Factors like comorbidities, previous liver disease treatments, or acute decompensation events
are important but not always captured in database studies.
-Some covariates, like comorbidity data (e.g., heart failure, diabetes), may not be fully captured
or available in the MIMIC-IV database, potentially impacting the robustness of the multivariable
models.
-While the nonlinear analysis through two-piecewise regression is an important methodological
step, determining the optimal inflection point for the AST/ALT ratio could be prone to
overfitting. The selection of the inflection point is based on exploratory analysis, which could
introduce some bias if not carefully handled.
-Additionally, testing for multiple inflection points could increase the risk of false positives, and
it’s essential to justify the choice of these points rigorously.
-The AST/ALT ratio is based on blood tests taken within 24 hours of ICU admission. Given
the dynamic nature of critical illness, it's possible that these initial measurements may not fully
represent the patient's liver function throughout their ICU stay.
Additionally, variations in the timing of laboratory tests and patient management could introduce
some bias in the AST/ALT measurements.
-While the statistical findings are essential, the discussion could place more emphasis on the
clinical implications of these results. For example, while the study identifies the critical threshold
of 3.6 for the AST/ALT ratio, it could further explore how this information could be used in
clinical practice to aid decision-making or triage in ICU settings. The clinical relevance of such a
threshold could be emphasized more, particularly in guiding early intervention and personalized
care.
-Although the nonlinear relationship between the AST/ALT ratio and mortality is an important
finding, the discussion could be clearer about the reasons why this threshold (3.6) is significant
and how it could be practically applied in different clinical contexts. For instance, is this
threshold consistent across various liver diseases or other patient characteristics, or is it specific
to critically ill cirrhotic patients?
-The study does well to explain the attenuation effect above the threshold, but it might benefit
from further discussion on why this occurs. Are there other factors that become more important
than the AST/ALT ratio in severe liver disease? What other biomarkers could be more relevant
in this range?
-While the study adjusts for a broad range of covariates, the discussion acknowledges that
unmeasured confounders may still play a significant role in the results. It would be helpful to
explore specific potential confounders that could not be captured in the study, such as genetic
factors, prior liver function, or other comorbidities (e.g., sepsis, infections). This could lead to
more nuanced recommendations for future research on unmeasured variables.
-While the study offers potential mechanisms linking the AST/ALT ratio to mortality risk,
further mechanistic insights would strengthen the discussion. For example, how might the
specific role of AST vs. ALT in liver injury contribute to the observed patterns? What cellular
or molecular processes could explain the saturation effect seen in the nonlinear relationship?