Title: Prevalence of advanced liver fibrosis in the general population of the Paris region
according to FIB-4 score and Liver Risk Score
Version: 1 Date: 21 Mar 2025
Reviewer's report:
Tran et al., have conducted a cross-sectional study of 179,865 individuals representing the
general population from Paris, who undergo blood sampling from the primary care sector. They
report the estimated prevalence of significant and advanced liver fibrosis according to FIB-4
and LRS, evaluate the concordance between the two tests, and estimate the costs associated
with FIB-4 as first line screening test versus LRS. The study is relevant and timely and the
high numbers of individuals provides an important strength. However, no data exists on the risk
profiles or existing diagnoses of liver diseases, and individuals did not undergo LSM, biopsies,
fibrosis markers (e.g., ELF) or outcome data evaluation. It is therefore not possible to assess
the true diagnostic accuracy of FIB-4, LRS or true prevalence of significant or advanced liver
disease.
The findings are relevant and interesting, but there is room for improvement of the manuscript
and presentation of results. Importantly, “Development of a pragmatic screening algorithm”
should be deleted, as the study does not hold any reference data (i.e., LSM, biopsies or outcomes)
to support this. Similarly, should the discussion not favorite LRS over FIB-4. This especially
important given the novelty (and rather few) studies on LRS. Of note, it has been reported that
LRS underestimate LSM and is less accurate for predicting outcomes in patients from secondary
care (doi 10.1016/j.jhepr.2024.101169). Moreover, I am questioning whether the population
truly represented the general population escpecally given the lack of information on risk profiles,
diagnoses, medicine usages etc. Was it known that blood tests were done due to routine health
care check-ups and not due to symptoms, follow-up for chronic diseases etc? Otherwise this
should be clearly stated in the methods and included in the discussion.
Besides the need of proof-reading, I have following comments presented in a chronological
order:
Abstract:
• The aim should be presented.
• The conclusion should be revised. The data cannot support LRS being better than FIB-4 or
vice versa. Should only conclude on the reported estimates, concordance and costs.
Introduction:
• The introduction should more accurately introduce steatotic liver disease (SLD) and the major
subclasses including MASLD, MetALD and ALD. As this study includes the general population,
ALD is most likely also highly represented. Especially L9-13 should be revised.
• P4 L 18-19: Unclear
• P5 L3-4: FIB-4 is an algorithm, not a single test
• The presented aim is unclear and not fully covering
Methods:
• P7 L 17-18: The listed cut-offs for AST (34 U/L) and ALT (55 U/L) differs from the ones in
table 1 (> 40 U/L). Which cut-offs were used? I would encourage to use the sex-specified cut-
offs according to doi 10.1080/00365510410006324
• Important to note that cut-offs for FIB-4 are >=1.3 and >=2.67 and not >1.3 and >2.67, unclear
which was used – given the sample size this is very important.
• Was glucose fasting-glucose? This is required by LRS. If not, this is important to include in
the methods and discussion.
• Please state how the costs where calculated – what are the estimated costs based on, as this
differs between countries.
• Was is possible to exclude patients with an existing diagnosis of liver disease as both FIB-4
and LRS are suggested for screening?
Results:
• P8 L8-15: results could be more clearly presented. Unknown how many had a high LRS >=15
• P8 L23-24: does “fibrosis scores” refer to FIB>=2.67 and LRS>=10? And is “older” referring
to > 40 years? Usually, 65 years is used.  Should be rephrased and more clearly presented as
it is an important finding.
• P8 L30: Unclear formulation.
• P8 L32: Please stick to the surrogate markers – here LRS >=10 and not LSM/TE
• P9 L4-6: What is a “normal liver tests”? Different cut-offs for ALT and AST are listed in
methods vs. table 1. Also GGT would be relevant to consider.
• P9 L7-13: data are not presented. Does it mean that 84-85% had FIB-4 < 1.3 at all measurements
or did 84-85% of all participants have low FIB-4 at each time point? Was inconsistent scores
defined as just two measurements variating from each other or more? How many measurements
did the 4,720 have? It could be suspected that these patients were monitored due to ex. severe
infection hereby affecting results.
• P9 L14-18 “Development of a pragmatic screening algorithm”: Out of line with this study. This
study explores the prevalence of elevated FIB-4, LRS and the concordance between the two. It
does not compare to LSM, biopsies or ex. ELF and can therefore not compare the accuracy of
the tests and hereby suggest new screening pathways. Should be deleted.
• P9 L19 “cost comparisons”: Only at risk individuals are suggested to undergo screening.
Should be revised to only include (estimated) at risk individuals (e.g., alcohol overuse, diabetes
type 2, overweight) rather than all adults. Please also elaborate on the costs of each step in the
pathway, as a hepatologist consultation might provide more benefit than just an elastography.
Finally, figure 3 can be used in this context (and not as a suggestion for a new screening pathway
given my comment above), but should also illustrate the alternative pathway including FIB-4.
Discussion:
• P10 L3: 30.8% or 33?
• P10 L12-13: Unclear statement.
• P11 L8-9: Identifying a lower number does not make LRS more accurate per se, should be
deleted.
• P11 L17-30 + P12 L6-7, L17-20: Should be revised and statements about LRS being superior
to FIB-4 should be deleted, as this study does not provide data supporting this statement. It
demonstrates a lower positive rate and costs of LRS, which is relevant to discuss without
favorising one of the two. It is also relevant to discuss the findings of the low concordance.
• Moreoever, it is relevant to discuss the population truly represents a general population, as
these individuals all undergo blood sampling. Is it routine in Paris to perform health check ups
without futher indication in 18-80years old? Or could it be assumed that these patients represents
patients going to their GP due to chronic diseases, symptoms etc?
Figures and tables:
• Figure 1: Healthy population should be deleted – unknown if they are healthy… General
population instead?
• Figure 2: Important figure. However, it currently looks like each FIB-4 group have the same
sample size. Should be changed so it illustrates the true proportions i.e., the green box covers
69% of the total ex. Should also be named “FIB < 1.3” rather than “no fibrosis” as the true
degree of fibrosis is unknown.
• Figure 3: see comments above. Should include the FIB- pathway and only be used to illustrate
the two approaches used for cost calculations. Moreover, ALD should also be included and
“alcoholic” changed to “alcohol-related” due to stigma.
• Table 1: See comment above regarding cut-offs. Moreover, it reports that in total 25,573 had
elevated transaminases, but 17,667 men and 21,328 women (= 38,995). Should be revised. Also
levels of ex. GGT, FIB-4 and LRS are important to include. Possibly also INR, CRP, leucocytes,
albumine, bilirubine etc. if available. Finally, I would prefer the table to list men and women in
a coloumn next to total (horizontally) instead of below, for better overview.
• Table 2: Should also include LRS >= 15. Unsure what the P-value < 0.001 refers to? For LRS
it should be >= and not >
• Table 3: Should be revised for better readability, ex unclear what the blue boxes refer.
Title: Prevalence of advanced liver fibrosis in the general population of the Paris region
according to FIB-4 score and Liver Risk Score
Version: 1 Date: 21 Mar 2025
Reviewer's report:
Tran et al., have conducted a cross-sectional study of 179,865 individuals representing the
general population from Paris, who undergo blood sampling from the primary care sector. They
report the estimated prevalence of significant and advanced liver fibrosis according to FIB-4
and LRS, evaluate the concordance between the two tests, and estimate the costs associated
with FIB-4 as first line screening test versus LRS. The study is relevant and timely and the
high numbers of individuals provides an important strength. However, no data exists on the risk
profiles or existing diagnoses of liver diseases, and individuals did not undergo LSM, biopsies,
fibrosis markers (e.g., ELF) or outcome data evaluation. It is therefore not possible to assess
the true diagnostic accuracy of FIB-4, LRS or true prevalence of significant or advanced liver
disease.
The findings are relevant and interesting, but there is room for improvement of the manuscript
and presentation of results. Importantly, “Development of a pragmatic screening algorithm”
should be deleted, as the study does not hold any reference data (i.e., LSM, biopsies or outcomes)
to support this. Similarly, should the discussion not favorite LRS over FIB-4. This especially
important given the novelty (and rather few) studies on LRS. Of note, it has been reported that
LRS underestimate LSM and is less accurate for predicting outcomes in patients from secondary
care (doi 10.1016/j.jhepr.2024.101169). Moreover, I am questioning whether the population
truly represented the general population escpecally given the lack of information on risk profiles,
diagnoses, medicine usages etc. Was it known that blood tests were done due to routine health
care check-ups and not due to symptoms, follow-up for chronic diseases etc? Otherwise this
should be clearly stated in the methods and included in the discussion.
Besides the need of proof-reading, I have following comments presented in a chronological
order:
Abstract:
• The aim should be presented.
• The conclusion should be revised. The data cannot support LRS being better than FIB-4 or
vice versa. Should only conclude on the reported estimates, concordance and costs.
Introduction:
• The introduction should more accurately introduce steatotic liver disease (SLD) and the major
subclasses including MASLD, MetALD and ALD. As this study includes the general population,
ALD is most likely also highly represented. Especially L9-13 should be revised.
• P4 L 18-19: Unclear
• P5 L3-4: FIB-4 is an algorithm, not a single test
• The presented aim is unclear and not fully covering
Methods:
• P7 L 17-18: The listed cut-offs for AST (34 U/L) and ALT (55 U/L) differs from the ones in
table 1 (> 40 U/L). Which cut-offs were used? I would encourage to use the sex-specified cut-
offs according to doi 10.1080/00365510410006324
• Important to note that cut-offs for FIB-4 are >=1.3 and >=2.67 and not >1.3 and >2.67, unclear
which was used – given the sample size this is very important.
• Was glucose fasting-glucose? This is required by LRS. If not, this is important to include in
the methods and discussion.
• Please state how the costs where calculated – what are the estimated costs based on, as this
differs between countries.
• Was is possible to exclude patients with an existing diagnosis of liver disease as both FIB-4
and LRS are suggested for screening?
Results:
• P8 L8-15: results could be more clearly presented. Unknown how many had a high LRS >=15
• P8 L23-24: does “fibrosis scores” refer to FIB>=2.67 and LRS>=10? And is “older” referring
to > 40 years? Usually, 65 years is used.  Should be rephrased and more clearly presented as
it is an important finding.
• P8 L30: Unclear formulation.
• P8 L32: Please stick to the surrogate markers – here LRS >=10 and not LSM/TE
• P9 L4-6: What is a “normal liver tests”? Different cut-offs for ALT and AST are listed in
methods vs. table 1. Also GGT would be relevant to consider.
• P9 L7-13: data are not presented. Does it mean that 84-85% had FIB-4 < 1.3 at all measurements
or did 84-85% of all participants have low FIB-4 at each time point? Was inconsistent scores
defined as just two measurements variating from each other or more? How many measurements
did the 4,720 have? It could be suspected that these patients were monitored due to ex. severe
infection hereby affecting results.
• P9 L14-18 “Development of a pragmatic screening algorithm”: Out of line with this study. This
study explores the prevalence of elevated FIB-4, LRS and the concordance between the two. It
does not compare to LSM, biopsies or ex. ELF and can therefore not compare the accuracy of
the tests and hereby suggest new screening pathways. Should be deleted.
• P9 L19 “cost comparisons”: Only at risk individuals are suggested to undergo screening.
Should be revised to only include (estimated) at risk individuals (e.g., alcohol overuse, diabetes
type 2, overweight) rather than all adults. Please also elaborate on the costs of each step in the
pathway, as a hepatologist consultation might provide more benefit than just an elastography.
Finally, figure 3 can be used in this context (and not as a suggestion for a new screening pathway
given my comment above), but should also illustrate the alternative pathway including FIB-4.
Discussion:
• P10 L3: 30.8% or 33?
• P10 L12-13: Unclear statement.
• P11 L8-9: Identifying a lower number does not make LRS more accurate per se, should be
deleted.
• P11 L17-30 + P12 L6-7, L17-20: Should be revised and statements about LRS being superior
to FIB-4 should be deleted, as this study does not provide data supporting this statement. It
demonstrates a lower positive rate and costs of LRS, which is relevant to discuss without
favorising one of the two. It is also relevant to discuss the findings of the low concordance.
• Moreoever, it is relevant to discuss the population truly represents a general population, as
these individuals all undergo blood sampling. Is it routine in Paris to perform health check ups
without futher indication in 18-80years old? Or could it be assumed that these patients represents
patients going to their GP due to chronic diseases, symptoms etc?
Figures and tables:
• Figure 1: Healthy population should be deleted – unknown if they are healthy… General
population instead?
• Figure 2: Important figure. However, it currently looks like each FIB-4 group have the same
sample size. Should be changed so it illustrates the true proportions i.e., the green box covers
69% of the total ex. Should also be named “FIB < 1.3” rather than “no fibrosis” as the true
degree of fibrosis is unknown.
• Figure 3: see comments above. Should include the FIB- pathway and only be used to illustrate
the two approaches used for cost calculations. Moreover, ALD should also be included and
“alcoholic” changed to “alcohol-related” due to stigma.
• Table 1: See comment above regarding cut-offs. Moreover, it reports that in total 25,573 had
elevated transaminases, but 17,667 men and 21,328 women (= 38,995). Should be revised. Also
levels of ex. GGT, FIB-4 and LRS are important to include. Possibly also INR, CRP, leucocytes,
albumine, bilirubine etc. if available. Finally, I would prefer the table to list men and women in
a coloumn next to total (horizontally) instead of below, for better overview.
• Table 2: Should also include LRS >= 15. Unsure what the P-value < 0.001 refers to? For LRS
it should be >= and not >
• Table 3: Should be revised for better readability, ex unclear what the blue boxes refer.
Please review this paper.
user
Title: Prevalence of advanced liver fibrosis in the general population of the Paris region
according to FIB-4 score and Liver Risk Score
Version: 1 Date: 21 Mar 2025
Reviewer's report:
Tran et al., have conducted a cross-sectional study of 179,865 individuals representing the
general population from Paris, who undergo blood sampling from the primary care sector. They
report the estimated prevalence of significant and advanced liver fibrosis according to FIB-4
and LRS, evaluate the concordance between the two tests, and estimate the costs associated
with FIB-4 as first line screening test versus LRS. The study is relevant and timely and the
high numbers of individuals provides an important strength. However, no data exists on the risk
profiles or existing diagnoses of liver diseases, and individuals did not undergo LSM, biopsies,
fibrosis markers (e.g., ELF) or outcome data evaluation. It is therefore not possible to assess
the true diagnostic accuracy of FIB-4, LRS or true prevalence of significant or advanced liver
disease.
The findings are relevant and interesting, but there is room for improvement of the manuscript
and presentation of results. Importantly, “Development of a pragmatic screening algorithm”
should be deleted, as the study does not hold any reference data (i.e., LSM, biopsies or outcomes)
to support this. Similarly, should the discussion not favorite LRS over FIB-4. This especially
important given the novelty (and rather few) studies on LRS. Of note, it has been reported that
LRS underestimate LSM and is less accurate for predicting outcomes in patients from secondary
care (doi 10.1016/j.jhepr.2024.101169). Moreover, I am questioning whether the population
truly represented the general population escpecally given the lack of information on risk profiles,
diagnoses, medicine usages etc. Was it known that blood tests were done due to routine health
care check-ups and not due to symptoms, follow-up for chronic diseases etc? Otherwise this
should be clearly stated in the methods and included in the discussion.
Besides the need of proof-reading, I have following comments presented in a chronological
order:
Abstract:
• The aim should be presented.
• The conclusion should be revised. The data cannot support LRS being better than FIB-4 or
vice versa. Should only conclude on the reported estimates, concordance and costs.
Introduction:
• The introduction should more accurately introduce steatotic liver disease (SLD) and the major
subclasses including MASLD, MetALD and ALD. As this study includes the general population,
ALD is most likely also highly represented. Especially L9-13 should be revised.
• P4 L 18-19: Unclear
• P5 L3-4: FIB-4 is an algorithm, not a single test
• The presented aim is unclear and not fully covering
Methods:
• P7 L 17-18: The listed cut-offs for AST (34 U/L) and ALT (55 U/L) differs from the ones in
table 1 (> 40 U/L). Which cut-offs were used? I would encourage to use the sex-specified cut-
offs according to doi 10.1080/00365510410006324
• Important to note that cut-offs for FIB-4 are >=1.3 and >=2.67 and not >1.3 and >2.67, unclear
which was used – given the sample size this is very important.
• Was glucose fasting-glucose? This is required by LRS. If not, this is important to include in
the methods and discussion.
• Please state how the costs where calculated – what are the estimated costs based on, as this
differs between countries.
• Was is possible to exclude patients with an existing diagnosis of liver disease as both FIB-4
and LRS are suggested for screening?
Results:
• P8 L8-15: results could be more clearly presented. Unknown how many had a high LRS >=15
• P8 L23-24: does “fibrosis scores” refer to FIB>=2.67 and LRS>=10? And is “older” referring
to > 40 years? Usually, 65 years is used.  Should be rephrased and more clearly presented as
it is an important finding.
• P8 L30: Unclear formulation.
• P8 L32: Please stick to the surrogate markers – here LRS >=10 and not LSM/TE
• P9 L4-6: What is a “normal liver tests”? Different cut-offs for ALT and AST are listed in
methods vs. table 1. Also GGT would be relevant to consider.
• P9 L7-13: data are not presented. Does it mean that 84-85% had FIB-4 < 1.3 at all measurements
or did 84-85% of all participants have low FIB-4 at each time point? Was inconsistent scores
defined as just two measurements variating from each other or more? How many measurements
did the 4,720 have? It could be suspected that these patients were monitored due to ex. severe
infection hereby affecting results.
• P9 L14-18 “Development of a pragmatic screening algorithm”: Out of line with this study. This
study explores the prevalence of elevated FIB-4, LRS and the concordance between the two. It
does not compare to LSM, biopsies or ex. ELF and can therefore not compare the accuracy of
the tests and hereby suggest new screening pathways. Should be deleted.
• P9 L19 “cost comparisons”: Only at risk individuals are suggested to undergo screening.
Should be revised to only include (estimated) at risk individuals (e.g., alcohol overuse, diabetes
type 2, overweight) rather than all adults. Please also elaborate on the costs of each step in the
pathway, as a hepatologist consultation might provide more benefit than just an elastography.
Finally, figure 3 can be used in this context (and not as a suggestion for a new screening pathway
given my comment above), but should also illustrate the alternative pathway including FIB-4.
Discussion:
• P10 L3: 30.8% or 33?
• P10 L12-13: Unclear statement.
• P11 L8-9: Identifying a lower number does not make LRS more accurate per se, should be
deleted.
• P11 L17-30 + P12 L6-7, L17-20: Should be revised and statements about LRS being superior
to FIB-4 should be deleted, as this study does not provide data supporting this statement. It
demonstrates a lower positive rate and costs of LRS, which is relevant to discuss without
favorising one of the two. It is also relevant to discuss the findings of the low concordance.
• Moreoever, it is relevant to discuss the population truly represents a general population, as
these individuals all undergo blood sampling. Is it routine in Paris to perform health check ups
without futher indication in 18-80years old? Or could it be assumed that these patients represents
patients going to their GP due to chronic diseases, symptoms etc?
Figures and tables:
• Figure 1: Healthy population should be deleted – unknown if they are healthy… General
population instead?
• Figure 2: Important figure. However, it currently looks like each FIB-4 group have the same
sample size. Should be changed so it illustrates the true proportions i.e., the green box covers
69% of the total ex. Should also be named “FIB < 1.3” rather than “no fibrosis” as the true
degree of fibrosis is unknown.
• Figure 3: see comments above. Should include the FIB- pathway and only be used to illustrate
the two approaches used for cost calculations. Moreover, ALD should also be included and
“alcoholic” changed to “alcohol-related” due to stigma.
• Table 1: See comment above regarding cut-offs. Moreover, it reports that in total 25,573 had
elevated transaminases, but 17,667 men and 21,328 women (= 38,995). Should be revised. Also
levels of ex. GGT, FIB-4 and LRS are important to include. Possibly also INR, CRP, leucocytes,
albumine, bilirubine etc. if available. Finally, I would prefer the table to list men and women in
a coloumn next to total (horizontally) instead of below, for better overview.
• Table 2: Should also include LRS >= 15. Unsure what the P-value < 0.001 refers to? For LRS
it should be >= and not >
• Table 3: Should be revised for better readability, ex unclear what the blue boxes refer.
assistant