Title: Fibrosis status, extrahepatic multimorbidity and all-cause mortality in 53093 women
and 74377 men with metabolic dysfunction associated steatotic liver disease (MASLD) in UK
Biobank
Version: 1 Date: 24 May 2025
Reviewer:  Xianhua Mao
Reviewer's report:
This is a large cohort study to explore the association of liver fibrosis with multimorbidity
and all-cause mortality in 127479 patients with MASLD using data from the UK biobank.
The authors reported that high FIB4 was associated with a 41% and 94% higher risk of
multimorbidity and all-cause mortality than low FIB4. Although these results are meaningful
for the preventive strategies in individuals with MASLD, some limitation should be note.
Introduction
Paragraph 1: In addition to CVD and extrahepatic cancers, please include chronic kidney disease
as a primary extrahepatic disease in relation to MASLD.
Paragraph 2: Move the sentence “Among these, fibrosis-4 score…” to the Method section.
Method
Page 4, Paragraph 1: In the sentence “…obesity (BMI #25 kg/m² AND/OR waist circumference
> 94/80 cm (male/female)), diabetes…”, change “obesity” to “overweight/obesity” and
“diabetes” to “prediabetes/diabetes” based on the standard criteria.
Page 4, Paragraph 2: The authors excluded patients with ALD, MetALD and other chronic liver
disease to exclude the influence of these liver diseases. It is a good and commonly used method
but why are patients with liver fibrosis and cirrhosis also excluded? FIB4 score is used to assess
the fibrosis status, and how the association between fibrosis and outcomes is examined if fibrosis
has been excluded at baseline? Please clarify it.
Page 4, Paragraph 4: Can the author provide a detailed list of 47 LTCs for the clear format?
Page 5, Paragraph 2: How about the end of follow-up when multimorbidity is considered as a
study outcome? Occurrence of the study outcome?
Page 6, Paragraph 1: Can the authors examine the association between FIB4 and LTCs using an
RR or HR rather than an OR because they can present a causal relationship? Also, please provide
a subgroup analysis for HbA1c since it is closely related to fibrosis progression in previous
clinical studies.
Page 6, Paragraph 2: How about specific-cause mortality in relation to FIB4 such as CVD-
related?
Page 6, Paragraph 3: Similarly, please provide a subgroup analysis for HbA1c for the association
between FIB4 and mortality.
Results
Page 7, Paragraph 3: How about the OR when adjusted for lifestyle factors including alcohol
use and smoking?
Page 7, Paragraph 3: Any correlation for FIB4 and No. of multimorbidity?
Table 4: How about HR after adjusting for all conditions (i.e. heart failure and stroke etc) because
they are all linked to mortality?
Discussion
How about FIB4 change over time which is a key factor for mortality? If unavailable, can the
authors provide FIB4 change between 2 time points instead?
How about medication use in the cohort? Such as aspirin, statin, and metformin which are in
related to fibrosis progression etc.
Title: Fibrosis status, extrahepatic multimorbidity and all-cause mortality in 53093 women
and 74377 men with metabolic dysfunction associated steatotic liver disease (MASLD) in UK
Biobank
Version: 1 Date: 24 May 2025
Reviewer:  Xianhua Mao
Reviewer's report:
This is a large cohort study to explore the association of liver fibrosis with multimorbidity
and all-cause mortality in 127479 patients with MASLD using data from the UK biobank.
The authors reported that high FIB4 was associated with a 41% and 94% higher risk of
multimorbidity and all-cause mortality than low FIB4. Although these results are meaningful
for the preventive strategies in individuals with MASLD, some limitation should be note.
Introduction
Paragraph 1: In addition to CVD and extrahepatic cancers, please include chronic kidney disease
as a primary extrahepatic disease in relation to MASLD.
Paragraph 2: Move the sentence “Among these, fibrosis-4 score…” to the Method section.
Method
Page 4, Paragraph 1: In the sentence “…obesity (BMI #25 kg/m² AND/OR waist circumference
> 94/80 cm (male/female)), diabetes…”, change “obesity” to “overweight/obesity” and
“diabetes” to “prediabetes/diabetes” based on the standard criteria.
Page 4, Paragraph 2: The authors excluded patients with ALD, MetALD and other chronic liver
disease to exclude the influence of these liver diseases. It is a good and commonly used method
but why are patients with liver fibrosis and cirrhosis also excluded? FIB4 score is used to assess
the fibrosis status, and how the association between fibrosis and outcomes is examined if fibrosis
has been excluded at baseline? Please clarify it.
Page 4, Paragraph 4: Can the author provide a detailed list of 47 LTCs for the clear format?
Page 5, Paragraph 2: How about the end of follow-up when multimorbidity is considered as a
study outcome? Occurrence of the study outcome?
Page 6, Paragraph 1: Can the authors examine the association between FIB4 and LTCs using an
RR or HR rather than an OR because they can present a causal relationship? Also, please provide
a subgroup analysis for HbA1c since it is closely related to fibrosis progression in previous
clinical studies.
Page 6, Paragraph 2: How about specific-cause mortality in relation to FIB4 such as CVD-
related?
Page 6, Paragraph 3: Similarly, please provide a subgroup analysis for HbA1c for the association
between FIB4 and mortality.
Results
Page 7, Paragraph 3: How about the OR when adjusted for lifestyle factors including alcohol
use and smoking?
Page 7, Paragraph 3: Any correlation for FIB4 and No. of multimorbidity?
Table 4: How about HR after adjusting for all conditions (i.e. heart failure and stroke etc) because
they are all linked to mortality?
Discussion
How about FIB4 change over time which is a key factor for mortality? If unavailable, can the
authors provide FIB4 change between 2 time points instead?
How about medication use in the cohort? Such as aspirin, statin, and metformin which are in
related to fibrosis progression etc.
Please review this paper.
user
Title: Fibrosis status, extrahepatic multimorbidity and all-cause mortality in 53093 women
and 74377 men with metabolic dysfunction associated steatotic liver disease (MASLD) in UK
Biobank
Version: 1 Date: 24 May 2025
Reviewer:  Xianhua Mao
Reviewer's report:
This is a large cohort study to explore the association of liver fibrosis with multimorbidity
and all-cause mortality in 127479 patients with MASLD using data from the UK biobank.
The authors reported that high FIB4 was associated with a 41% and 94% higher risk of
multimorbidity and all-cause mortality than low FIB4. Although these results are meaningful
for the preventive strategies in individuals with MASLD, some limitation should be note.
Introduction
Paragraph 1: In addition to CVD and extrahepatic cancers, please include chronic kidney disease
as a primary extrahepatic disease in relation to MASLD.
Paragraph 2: Move the sentence “Among these, fibrosis-4 score…” to the Method section.
Method
Page 4, Paragraph 1: In the sentence “…obesity (BMI #25 kg/m² AND/OR waist circumference
> 94/80 cm (male/female)), diabetes…”, change “obesity” to “overweight/obesity” and
“diabetes” to “prediabetes/diabetes” based on the standard criteria.
Page 4, Paragraph 2: The authors excluded patients with ALD, MetALD and other chronic liver
disease to exclude the influence of these liver diseases. It is a good and commonly used method
but why are patients with liver fibrosis and cirrhosis also excluded? FIB4 score is used to assess
the fibrosis status, and how the association between fibrosis and outcomes is examined if fibrosis
has been excluded at baseline? Please clarify it.
Page 4, Paragraph 4: Can the author provide a detailed list of 47 LTCs for the clear format?
Page 5, Paragraph 2: How about the end of follow-up when multimorbidity is considered as a
study outcome? Occurrence of the study outcome?
Page 6, Paragraph 1: Can the authors examine the association between FIB4 and LTCs using an
RR or HR rather than an OR because they can present a causal relationship? Also, please provide
a subgroup analysis for HbA1c since it is closely related to fibrosis progression in previous
clinical studies.
Page 6, Paragraph 2: How about specific-cause mortality in relation to FIB4 such as CVD-
related?
Page 6, Paragraph 3: Similarly, please provide a subgroup analysis for HbA1c for the association
between FIB4 and mortality.
Results
Page 7, Paragraph 3: How about the OR when adjusted for lifestyle factors including alcohol
use and smoking?
Page 7, Paragraph 3: Any correlation for FIB4 and No. of multimorbidity?
Table 4: How about HR after adjusting for all conditions (i.e. heart failure and stroke etc) because
they are all linked to mortality?
Discussion
How about FIB4 change over time which is a key factor for mortality? If unavailable, can the
authors provide FIB4 change between 2 time points instead?
How about medication use in the cohort? Such as aspirin, statin, and metformin which are in
related to fibrosis progression etc.
assistant