Gastroenterology Today December 2025

Volume 34 No. 12 Winter 2025

Read more on page 6

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CONTENTS

CONTENTS

Gastroenterology Today

4 EDITOR’S COMMENT

9 FEATURE Aggregate index of systemic inflammation tied to

increased fatty liver disease risk: insights from

NHANES data

21 FEATURE Timing of endoscopy in patients with acute variceal

bleeding in cirrhosis: an updated systematic review

and meta-analysis

This issue edited by:

Dr George Lennox

c/o Media Publishing Company

Greenoaks, Lockhill

Upper Sapey, Worcester, WR6 6XR

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EDITOR’S COMMENT

EDITOR’S COMMENT

“At the quiet end

of the spectrum:

could something

as routine as a

full blood count

help us get

ahead of the fatty

liver epidemic?”

Gastroenterology is increasingly a specialty of timing. We are asked to spot trouble years before the first

abnormal LFT, guide a capsule camera through the gut before its battery dies, and decide whether “urgent”

really means “right now” when a cirrhotic patient starts bleeding. The three papers in this issue each sit on

different parts of that timeline, but all ask the same question: not just what we do, but when we do it.

At the quiet end of the spectrum: could something as routine as a full blood count help us get ahead of the

fatty liver epidemic? By combining neutrophils, platelets, monocytes and lymphocytes into an “aggregate

index of systemic inflammation” and linking it to liver stiffness, the authors explore whether low-grade

inflammation can flag those at highest risk long before clinics are overwhelmed. It’s an appealing idea: better

targeting of screening and lifestyle interventions using tests we already order every day.

Further along the patient journey comes capsule endoscopy. From prokinetics to magnetic steering, the

review compares strategies to nudge the capsule along and improve completion rates. The question is

whether we can be more deliberate, and more personalised, about how we prepare different patients for

capsule studies.

At the sharp end, another meta-analysis challenges the assumption that earlier is always better in acute

variceal bleeding. The authors find no survival benefit to the very earliest endoscopy and even a suggestion

of higher mortality when scoping within six hours compared with a steadier 6–24-hour window. It’s a

provocative finding that asks us to rethink what “urgent” should mean in real-world on-call decisions.

Collectively, these papers show that timing shapes care as much as any tool we use. A blood test, a capsule

protocol, an endoscopy slot: small decisions that set the tempo. As you read on, it’s worth thinking not only

about what you might do differently, but when you would choose to do it.

Dr George Lennox


Publishers Comment

On behalf of everyone involved with the publishing of Gastroenterology Today I would like to say a big

thank you to our contributors for their input and a special thank you to our advertisers as without their

ongoing support we would not be able to print and despatch copies of this very unique publication to all

Gastroenterology Departments and Endoscopy Units.

Terry Gardner

Publisher

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SEEING THE UNSEEN: ADVANCING

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Missed lesions in gastrointestinal (GI) endoscopy pose serious

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be overlooked, which leads to delays in diagnosis and disease

progression. This often results in more invasive treatments, higher

healthcare costs, and an increased need for repeated procedures,

affecting both patients’ quality of life and healthcare systems 1 .

For clinicians, each missed lesion is a lost opportunity for early

intervention and disease prevention. Studies show a wide variation

in adenoma detection rates (ADR) among practitioners, with missed

lesions frequently contributing to interval cancers. A 1% increase in

ADR is linked to a 3% reduction in colorectal cancer risk 2 . Notably,

more than half of interval colorectal cancers are associated with

lesions missing during colonoscopy 3 .

Limitations of Standard Imaging and

Clinical Gaps

As Dr. Rajaratnam Rameshshankar, Consultant Gastroenterologist

at Hillingdon Hospitals NHS Foundation Trust and The London

Clinic, notes, “Enhanced visualization tools are essential to reduce

detection variability and enable earlier, more consistent diagnosis of

GI pathology.”

Elevating Detection: The Role of the PENTAX

Medical INSPIRA Video Processor

The PENTAX Medical INSPIRA video processor was developed to

address these challenges. It integrates ultra-high-definition 4K imaging

with technologies such as i-scan and Auto HDR to improve mucosal

and vascular visualization. These technologies have been shown to

significantly improve detection rates: using i-scan 1, when paired with

HD+ endoscopes, increased neoplastic lesion detection from 13% to

38% 4 , and the i-scan 1 raised adenoma detection by 10% compared to

white-light imaging 5 .

Conventional white-light endoscopy has limited ability to highlight

subtle or early-stage abnormalities. Its broad-spectrum illumination can

offer minimal contrast and fails to enhance microvascular or mucosal

details, causing small, flat lesions to blend indistinguishably with

healthy tissue.

“Advanced imaging tools like INSPIRA are becoming integral part of

reducing variability in lesion detection,” shares Dr. Rameshshanker.

“With features like i-scan and Optical Enhancement, clinicians can

differentiate benign from malignant lesions in real time, optimizing

patient management.”


Even with advanced endoscopic tools, certain GI tract configurations

remain difficult to visualize, increasing the risk of missed lesions. These

challenges stem from blind spots, poor bowel preparation, human

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In the lower GI tract, lesions are often missed in the right colon,

particularly sessile serrated lesions (SSLs), due to their flat morphology

and mucous cap. Folds, flexures, the rectum, and cecum create

additional visual obstacles, often worsened by limited retroflexion. In

the upper GI tract, missed lesions commonly occur in the cardia and

fundus for similar retroflexion-related reasons. At the gastroesophageal

junction (GEJ), peristalsis and subtle mucosal shifts further

reduce visibility.

Imaging Clarity: A Clinical Priority for Safer,

More Effective Outcomes

Missed lesions reflect more than a technological gap, they represent

a substantial clinical risk, with serious implications for patient safety,

quality of life, and healthcare costs. Enhanced visualization, thanks to

the technology in the PENTAX Medical INSPIRA, directly supports

earlier diagnosis and improved patient care.

As GI endoscopy technology evolves, systems like INSPIRA combine

ultra-high-definition 4K imaging, advanced digital and optical i-scan 1

modalities, and a broader spectrum of light through 5-LED technology.

These features improve visualization and lay the foundation for further

innovations that support clinicians in delivering optimal patient care.

1

Bessone V; Roppenecker DB; Adamsen S. Work-related musculoskeletal injury rates, risk factors, and ergonomics in different endoscopic

specialties: A review. Healthcare. 2024 Apr 24;12(9):885. https://doi.org/10.3390/healthcare12090885

2

Pilonis ND, Spychalski P, Kalager M, et al. Adenoma Detection Rates by Physicians and Subsequent Colorectal Cancer Risk. JAMA.

2025;333(5):400–407. doi:10.1001/jama.2024.22975

3

Pilonis ND, Spychalski P, Kalager M, et al. Adenoma Detection Rates by Physicians and Subsequent Colorectal Cancer Risk. JAMA.

2025;333(5):400–407. doi:10.1001/jama.2024.22975

4

Hoffman, A.; Sar, F.; Goetz, M.; Tresch, A.; Mudter, J.; Biesterfeld, S.; Galle, P. R.; Neurath, M. F.; Kiesslich, R. High definition colonoscopy

combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized

controlled trial. Endoscopy 2010; 42(10): 827-833 DOI: 10.1055/s-0030-1255713 https://www.thieme-connect.com/products/ejournals/

abstract/10.1055/s-0030-1255713

5

Kidambi, Trilokesh D.; Terdiman, Jonathan P.; El-Nachef, Najwa; Singh, Aparajita; Kattah, Michael G. Lee, Jeffrey K.. Effect of I-scan Electronic

Chromoendoscopy on Detection of Adenomas During Colonoscopy. Clinical Gastroenterology and Hepatology. Volume 17, Issue 4p701-708.

e1March 2019 DOI: 10.1016/j.cgh.2018.06.024. https://doi.org/10.1016/j.cgh.2018.06.024

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FEATURE


8

AGGREGATE INDEX OF SYSTEMIC

INFLAMMATION TIED TO INCREASED

FATTY LIVER DISEASE RISK: INSIGHTS

FROM NHANES DATA

Meng Zhang 1† , Yuan Yuan 2† , Chenglong Wang 1 , You Huang 3 , Mingli Fan 3 , Xiangling Li 3* and Zujie Qin 1*

Zhang et al. BMC Gastroenterology (2025) 25:399 https://doi.org/10.1186/s12876-025-03998-6

FEATURE

RESEARCH

Abstract

Background Fatty liver disease (FLD), characterized by hepatic lipid

accumulation, impairs quality of life and can progress to cirrhosis and

hepatocellular carcinoma, imposing a healthcare burden. This study

investigates the association between the aggregate index of systemic

inflammation (AISI) and FLD prevalence, evaluating AISI’s potential as

an early biomarker for risk assessment.

Methods Data were obtained from the National Health and Nutrition

Examination Survey (NHANES) database, which encompasses the years

2017 through 2020. Participants were chosen based on the availability

of controlled attenuation parameter (CAP) scores derived from transient

elastography (TE), a technique utilized for assessing liver steatosis. The

formula employed to compute the AISI is as follows: AISI = N × P × M /

L, where N, P, M, and L refer to neutrophils, platelets, monocytes, and

lymphocytes, respectively. Additionally, demographic, socioeconomic,

dietary, and health-related information was gathered. Logistic regression

models were utilized to pinpoint risk factors associated with FLD, and a

nomogram was created to forecast FLD risk.

Keywords Aggregate index of systemic inflammation, Fatty liver

disease, NHANES, Inflammation, Complete blood cell count-derived

inflammatory indicator

Introduction

Fatty liver disease (FLD) has emerged as a major global public health

challenge. Over the past three decades, its prevalence has significantly

increased from 25.3 to 38.2%, closely linked to the epidemics of

obesity and metabolic syndrome [1]. As the global obesity problem

intensifies, the clinical and economic burdens associated with FLD

are expected to rise further, placing immense pressure on healthcare

systems. Moreover, the risk of disease progression cannot be

overlooked, as approximately 7% of patients develop cirrhosis or

hepatocellular carcinoma, significantly increasing liver-related mortality

(0.77 per 1000 person-years) [2]. Significant bottlenecks currently

exist in FLD screening: conventional ultrasound has a high miss rate

and is operator-dependent, the cost of MRI limits its application, and

the invasiveness and sampling variability of liver biopsy preclude its

widespread use for early screening. Therefore, there is a pressing

requirement to create more efficient and economically viable

approaches for screening and assessing risk levels [3].

Results Of the 3,961 participants, 2,377 (60.0%) were diagnosed with

FLD based on a CAP score ≥ 248 dB/m. Elevated AISI was significantly

associated with FLD (P = 0.021). Other significant risk factors included

sex, age, BMI, race, marital status, hypertension, and diabetes. The

nomogram demonstrated excellent discriminatory performance with an

AUC of 0.814 (95% CI: 0.800, 0.827) and good calibration.

Conclusion This study reveals a significant, independent association

between elevated AISI and increased FLD risk in the U.S. population,

even after adjusting for confounders. AISI demonstrated good

discriminative performance for FLD, but its effect size suggests it

should supplement, not replace, existing clinical risk assessment tools.

AISI, a cost-effective biomarker, holds potential for enhancing FLD

screening, particularly in resource-limited settings.

†

Meng Zhang and Yuan Yuan contributed equally to this work.

*Correspondence:

Xiangling Li

haoyunlinglong@163.com

Zujie Qin

109741754@qq.com

Chronic low-grade inflammation is considered a key driver of metabolic

dysfunction. By activating immune cells and releasing pro-inflammatory

factors, it triggers insulin resistance, lipid metabolism disorders, and

adipose tissue dysfunction, ultimately promoting the development

and progression of FLD [4, 5]. In obesity, for example, activation of the

TLR4/NF-κB pathway can induce the polarization of adipose tissue

macrophages towards the M1 phenotype. These macrophages then

release pro-inflammatory factors such as tumor necrosis factor-α

(TNF-α), which intensifies the inflammatory response and contributes

to the dysregulation of hepatic lipid metabolism [6]. This vicious

cycle between inflammation and metabolism is highly associated

with the development and progression of FLD [7, 8]. In recent years,

Complete blood cell count-derived inflammatory markers, such as the

neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammatory


9

FEATURE


index (SII), and aggregate index of systemic inflammation (AISI),

have provided new avenues for assessing systemic inflammation.

These indices are widely used for diagnosis, prognostic assessment,

and monitoring treatment efficacy in various chronic inflammatory

diseases. Research indicates that both NLR and SII are significantly

linked to the likelihood of developing FLD. Furthermore, elevated NLR

is positively correlated with the severity of liver fibrosis, indicating its

potential utility in predicting FLD risk and its progression [9–11]. AISI,

by integrating additional cellular parameters, holds promise for more

comprehensively reflecting the systemic inflammatory state and has

demonstrated good predictive power in research on various chronic

diseases [12, 13]. While AISI has been associated with FLD among

hypertensive individuals [14], large population-based evidence is still

lacking. Our study addresses this gap with the general U.S. population.

Therefore, based on the National Health and Nutrition Examination

Survey (NHANES) database, this study employed multivariable logistic

regression to systematically analyze the association between AISI and

FLD, and developed a risk prediction model for FLD. The objective

was to evaluate the potential utility of AISI in FLD screening and risk

assessment, thereby providing new evidence and theoretical support

for the clinical application of inflammatory markers.

Methods

Data sources and population selection

The information utilized in this research was exclusively derived

from the NHANES. NHANES is an ongoing health and nutrition

assessment program for U.S. adults and children, conducting surveys

on demographics, socioeconomic status, dietary habits, and health

issues. NHANES has received approval from the National Center for

Health Statistics Ethics Review Board (https://www.cdc.gov/nchs/

nhanes/about/erb.html). All participants provided informed consent

prior to their involvement in the study.

This analysis utilized information from the NHANES cycles spanning

March 2017 to March 2020, focusing on data from 2017 to 2018 and

March 2019 to March 2020. The COVID-19 pandemic limited data

collection in 2020, necessitating the combination of these cycles for

robust analysis.

This study utilized liver transient elastography (TE). Participants were

divided into FLD and non-FLD groups using a controlled attenuation

parameter (CAP) criterion of ≥ 248 dB/m. We selected participants

from the initial 24,814 individuals in the NHANES database (2017–

2020). The screening process involved excluding individuals for the

following reasons: missing the CAP data (n = 9,168); being under 18

years old (n = 2,210); missing education status (n = 664); missing

marital status (n = 7); missing economic status (n = 1,696); missing

height and weight data (n = 95); missing smoking and drinking

information (n = 1,444); missing hypertension and diabetes history

(n = 303); and missing blood cell count data (n = 5,266). Due to the

NHANES protocol, not all participants underwent CAP scoring or blood

cell count testing each year, leading to significant data gaps for these

measures [15]. Ultimately, our analysis included 3,961 participants

(Fig. 1).

Outcome variable: FLD

TE of the liver is widely used for the screening of FLD due to its high

accuracy and non-invasive nature. In the NHANES program, CAP data

were obtained using a FibroScan ® 502 V2 Touch device by health

technicians who were uniformly trained and certified. In this study, a

CAP value of ≥ 248 dB/m was used as the threshold to differentiate

between FLD and non-FLD groups. This threshold has been widely

validated for effectively identifying hepatic steatosis at stage S1 or

above [16, 17], making it suitable for large-scale epidemiological

screening and reducing the risk of missed diagnoses of early-stage

FLD.

Exposure variable: AISI

Following an overnight fasting period, venous blood specimens were

obtained in the morning at the mobile examination center of NHANES.

AISI is clinically important as it indicates the body’s inflammatory status

and helps in diagnosing diseases, assessing conditions, monitoring

treatments, and evaluating prognosis. AISI is defined as AISI = N ×

P × M / L, where L, M, N, and P denote lymphocytes, monocytes,

neutrophils, and platelets, respectively.

Covariates

To control for potential confounding biases in this study, we selected

covariates from the NHANES database based on clinical practice and

previous literature: sex, age, weight, height, body mass index (BMI),

race, poverty income ratio (PIR), education level, marital status, alcohol

consumption, smoking status, and histories of hypertension and

diabetes.

Age was stratified into < 60 years and ≥ 60 years. BMI categories were

defined as normal (< 25 kg/m²), overweight (25–30 kg/m²), or obese (≥

30 kg/m²). The racial categories encompassed individuals identifying

as Mexican American, members of other Hispanic groups, non-

Hispanic Whites, non-Hispanic Blacks, as well as those belonging to

other races or having a mixed-race background. PIR was categorized

as < 1.5, 1.5–3.5, or ≥ 3.5. Education levels were grouped into less

than high school, high school/GED, and some college/AA degree or

higher. Marital status was dichotomized as married/living with a partner

or living alone. A questionnaire was used to collect data on alcohol

consumption, smoking, and histories of hypertension and diabetes.

“Drinkers” were defined as individuals who consumed at least 12

drinks annually or drank more than twice in the past 12 months,

whereas “non-drinkers” were those who drank fewer than 12 times

annually or less than twice in the past 12 months. Individuals classified

as “smokers” were those who had consumed over 100 cigarettes in

their lifetime. Histories of hypertension and diabetes were based on

diagnoses by physicians or healthcare professionals.

Statistics analysis

Statistical analyses were performed using R version 4.3.2.

Continuous variables are presented as mean ± standard deviation,

and categorical variables as frequencies (percentages). Betweengroup

comparisons were conducted using independent samples

t-tests or chi-square tests. Univariate logistic regression was used

for preliminary screening of variables associated with FLD; variables

with P < 0.05 were included in the multivariate model to assess the

independent association between AISI and FLD risk. To improve the

predictive model, a backward stepwise regression was employed

10

Zhang et al. BMC Gastroenterology (2025) 25:399

Page 3 of 12

FEATURE

Fig. 1 Participant selection flowchart

who were uniformly trained and certified. In this study,

a CAP value of ≥ 248 dB/m was used as the threshold to

to derive differentiate the final model between and construct FLD and a nomogram. non-FLD Given groups. the This

skewed threshold distribution has of been raw widely AISI data, validated log2 transformation effectively was identifying

to hepatic enhance steatosis statistical power at stage while S1 preserving or above [16, interpretability 17], mak-

applied

ing it suitable for large-scale epidemiological screening

of the original AISI values. Results were reported as odds ratios

and reducing the risk of missed diagnoses of early-stage

(OR) FLD. with their 95% confidence intervals (CI). The area under the

curve (AUC) of the receiver operating characteristic (ROC) was

Exposure variable: AISI

used to evaluate the model discrimination performance. Calibration

Following an overnight fasting period, venous blood

of the nomogram was validated by calibration curves using 1,000

specimens were obtained in the morning at the mobile

bootstrap resamples. Decision curve analysis (DCA) was conducted

to quantify the clinical net benefit of the model across different

threshold probabilities. All statistical tests were two-sided, and a

P value < 0.05 was considered statistically significant.

examination center of NHANES. AISI is clinically important

as it indicates the body’s inflammatory status and

Results helps in diagnosing diseases, assessing conditions, monitoring

treatments, and evaluating prognosis. AISI is

Fundamental defined as AISI characteristics = N × P × M / L, where L, M, N, and P

Table denote 1 outlines lymphocytes, the core attributes monocytes, of NHANES neutrophils, carried out and between platelets,

and respectively. 2020. There were 3,961 participants, among whom 2017 2,377

were diagnosed with FLD. This group comprised 1,313 males (55.24%)

Covariates

and 1,064 females (44.76%). The mean age was 47.11 ± 18.46 years

To control for potential confounding biases in this study,

for the non-FLD group, and 53.21 ± 16.03 years for the FLD group.

we selected covariates from the NHANES database based

The non-FLD group had a mean BMI of 25.90 ± 5.24, as opposed to

on clinical practice and previous literature: sex, age,

32.66 ± 7.31 for the FLD group. In contrast to individuals without FLD,

those diagnosed with FLD tended to be older and exhibited elevated

weight and BMI. Additionally, the two groups showed significant

differences in height, race, marital status, education, smoking status,

and medical histories of hypertension and diabetes (P < 0.05). The


11

FEATURE

two groups showed no significant differences in family PIR, or alcohol

consumption. Patients with FLD showed significantly higher average

values for both the AISI and log2-AISI. This disparity was notable when

compared to the non-FLD population.

Univariate logistic regression examination

Table 2 showed that the univariate logistic regression analysis identified

several factors significantly associated with FLD incidence. The AISI

and log2-AISI were significantly correlated with an increased risk of

developing FLD. Moreover, factors such as sex, age, weight, height, BMI,

ethnic background, education, marital situation, smoking, hypertension,

and diabetes were associated with the development of FLD.

Multiple Zhang logistic et al. BMC regression Gastroenterology models (2025) 25:399

Figure 2 showed a multiple logistic regression model. In this model, the

primary variable was log2-AISI, with sex, age, BMI, race, education,

marital status, alcohol use, hypertension, and diabetes serving as

covariates. After accounting for the multiple logistic regression model,

the AISI score was still an important marker of FLD risk. Individuals

with higher log2-AISI values had an increased likelihood of developing

FLD (OR = 1.08, 95% CI: 1.01, 1.16, P = 0.021). Age (OR = 1.02, 95%

CI: 1.02, 1.03, P < 0.001) and BMI (OR = 1.23, 95% CI: 1.21, 1.25, P <

0.001) were positively correlated with increased FLD risk. Women had

a lower FLD risk than men (OR = 0.64, 95% CI: 0.54, 0.74, P < 0.001).

Compared to Mexican American, FLD risk was significantly lower in

Other Hispanic (OR = 0.63, 95% CI: 0.45, 0.88, P = 0.006), Non-

Hispanic White (OR = 0.52, 95% CI: 0.40, 0.69, P < 0.001), and Non-

Hispanic Black (OR = 0.27, 95% CI: 0.20, 0.36, P < 0.001). Unmarried

individuals exhibited a notably reduced FLD risk compared Page to 5 those of 12

who were married or living with partner (OR = 0.83, 95% CI: 0.71, 0.98,


Table 1 Baseline characteristics

Variables Overall (n = 3,961) Non-FLD group (n = 1,584) FLD group (n = 2,377) P-value

Sex, n (%) < 0.001

Male 2,058 (51.96%) 745 (47.03%) 1,313 (55.24%)

Female 1,903 (48.04%) 839 (52.97%) 1,064 (44.76%)

Age, years, mean(SD) 50.77 ± 17.30 47.11 ± 18.46 53.21 ± 16.03 < 0.001

< 60years 2,512 (63.42%) 1,105 (69.76%) 1,407 (59.19%) < 0.001

≥ 60years 1,449 (36.58%) 479 (30.24%) 970 (40.81%)

Weight, kg, mean(SD) 84.05 ± 22.53 72.03 ± 16.04 92.07 ± 22.68 < 0.001

Height, cm, mean(SD) 167.28 ± 9.75 166.64 ± 9.54 167.71 ± 9.86 < 0.001

BMI, kg/m 2 , mean(SD) 29.95 ± 7.34 25.90 ± 5.24 32.66 ± 7.31 < 0.001

Race, n (%) < 0.001

Mexican American 513 (12.95%) 139 (8.78%) 374 (15.73%)

Other Hispanic 359 (9.06%) 132 (8.33%) 227 (9.55%)

Non-Hispanic White 1,563 (39.46%) 610 (38.51%) 953 (40.09%)

Non-Hispanic Black 864 (21.81%) 423 (26.70%) 441 (18.55%)

Other race (including multi-racial) 662 (16.71%) 280 (17.68%) 382 (16.07%)

Family PIR 0.511

< 1.5 1,300 (32.82%) 531 (33.52%) 769 (32.35%)

1.5–3.5 1,415 (35.72%) 549 (34.66%) 866 (36.43%)

≥ 3.5 1,246 (31.46%) 504 (31.82%) 742 (31.22%)

Education, n (%) 0.029

Less than high school 673 (16.99%) 240 (15.15%) 433 (18.22%)

High school or GED 972 (24.54%) 386 (24.37%) 586 (24.65%)

Some college or AA degree above 2,316 (58.47%) 958 (60.48%) 1,358 (57.13%)

Marital status, n (%) < 0.001

Married/Living with partner 2,350 (59.33%) 868 (54.80%) 1,482 (62.35%)

Living alone 1,611 (40.67%) 716 (45.20%) 895 (37.65%)

Alcohol user, n (%) 0.099

Yes 2,642 (66.70%) 1,081 (68.24%) 1,561 (65.67%)

No 1,319 (33.30%) 503 (31.76%) 816 (34.33%)

Smoking status, n (%) 0.002

Yes 1,857 (46.88%) 694 (43.81%) 1,163 (48.93%)

No 2,104 (53.12%) 890 (56.19%) 1,214 (51.07%)

Hypertension, n (%) < 0.001

Yes 1,499 (37.84%) 417 (26.33%) 1,082 (45.52%)

No 2,462 (62.16%) 1,167 (73.67%) 1,295 (54.48%)

Diabetes, n (%) < 0.001

Yes 632 (15.96%) 116 (7.32%) 516 (21.71%)

No 3,329 (84.04%) 1,468 (92.68%) 1,861 (78.29%)

AISI 392.15 ± 383.54 346.37 ± 331.30 422.65 ± 411.97 < 0.001

log2-AISI 8.16 ± 1.13 8.00 ± 1.12 8.27 ± 1.12 < 0.001

12

(OR = 1.22, 95% CI: 1.02, 1.47, P = 0.030) or diabetes

(OR = 1.79, 95% CI: 1.39, 2.31, P < 0.001) were at increased

risk of FLD.

age, obesity, Mexican American, married/living with

partner, hypertension, and diabetes were risk factors for

FLD. Clinicians could obtain corresponding scores from

FEATURE

P = 0.024). Patients with a history of hypertension (OR = 1.22, 95% CI:

1.02, 1.47, P = 0.030) or diabetes (OR = 1.79, 95% CI: 1.39, 2.31, P <

0.001) were at increased risk of FLD.

could be used to estimate the risk of developing FLD. A higher total

score indicated a greater risk, which can aid in implementing stratified

management and personalized interventions.

Nomogram to predict FLD

Based on significant risk factors identified through multivariate logistic

regression analysis, we developed a nomogram (Fig. 3) to predict FLD

risk. The model demonstrated a C-index of 0.814 and an AIC value of

4015.7, with no multicollinearity among the variables (Supplementary

Table 1) nor interaction effects (Supplementary Table 2). The results

showed that higher AISI, male, older age, obesity, Mexican American,

married/living with partner, hypertension, and diabetes were risk

factors for FLD. Clinicians could obtain corresponding scores from

the Zhang nomogram et al. BMC based Gastroenterology on the patient’s specific (2025) 25:399 characteristics. By

summing these scores, the probability associated with the total score

Table 2 Univariate logistic regression examination of FLD

Variables OR(95%CI) P-value

Sex, n (%)

Male

Reference

Female 0.72 (0.63, 0.82) < 0.001

Age, years, mean(SD) 1.02 (1.02, 1.02) < 0.001

< 60years Reference

≥ 60years 1.59 (1.39, 1.82) < 0.001

Weight, kg, mean(SD) 1.06 (1.06, 1.06) < 0.001

Height, cm, mean(SD) 1.01 (1.00, 1.02) < 0.001

BMI, kg/m 2 , mean(SD) 1.22 (1.20, 1.24) < 0.001

Race, n (%)

Mexican American

Reference

Other Hispanic 0.64 (0.48, 0.85) 0.003

Non-Hispanic White 0.58 (0.47, 0.72) < 0.001

Non-Hispanic Black 0.39 (0.31, 0.49) < 0.001

Other race (including multi-racial) 0.51 (0.40, 0.65) < 0.001

Family PIR

< 1.5 Reference

1.5–3.5 1.09 (0.93, 1.27) 0.277

≥ 3.5 1.02 (0.87, 1.19) 0.839

Education, n (%)

Less than high school

Reference

High school or GED 0.84 (0.69, 1.03) 0.096

Some college or AA degree above 0.79 (0.66, 0.94) 0.008

Marital status, n (%)

Married/Living with Partner

Reference

Living alone 0.73 (0.64, 0.83) < 0.001

Alcohol user, n (%)

No

Reference

Yes 0.89 (0.78, 1.02) 0.092

Smoking status, n (%)

No

Reference

Yes 1.23 (1.08, 1.40) 0.002

Hypertension, n (%)

No

Reference

Yes 2.34 (2.04, 2.68) < 0.001

Diabetes, n (%)

No

Reference

Yes 3.50 (2.84, 4.35) < 0.001

AISI 1.00 (1.00, 1.00) < 0.001

log2-AISI 1.20 (1.13, 1.27) < 0.001

(AUC = 0.807, 95% CI: 0.794, 0.821), the inclusion of

log2-AISI provided a statistically meaningful improvement

in predictive accuracy. The optimal cutoff value was

Nomogram demonstrated good discriminatory performance, with

an AUC of 0.814 (95% CI: 0.800, 0.827) (Fig. 4). Compared to the

model excluding log2-AISI (AUC = 0.807, 95% CI: 0.794, 0.821), the

inclusion of log2-AISI provided a statistically meaningful improvement

in predictive accuracy. The optimal cutoff value was 0.082, with the

maximum Youden index of 0.459, yielding a sensitivity of 74.9% and

a specificity of 71.0% for prediction. The calibration curve results (Fig.

5) showed a high level of agreement between the model’s predicted

probabilities and the actual observed probabilities, with a mean

absolute error of only 0.021, indicating that the model was wellcalibrated.

DCA (Fig. 6) demonstrated that the nomogram offered

Page 6 of 12

a

greater net benefit compared to both the “treat-all” and “treat-none”

approaches over a threshold probability range from 10 to 95%,

confirming its clinical utility in routine practice.

threshold probability range from 10 to 95%, confirming

its Correlation clinical utility between in routine AISI and practice. CAP

To clarify the correlation between AISI and the severity of hepatic

Correlation steatosis, between this study employed AISI and CAP Spearman’s rho analysis to assess the

To association clarify the between correlation AISI and between CAP. The AISI findings and indicated the severity a significant

of hepatic positive correlation steatosis, between this study AISI employed and FLD (R = Spearman’s 0.13, P < 0.001) rho (Fig. 7).

analysis to assess the association between AISI and CAP.

The Relationship findings indicated between AISI a significant and FLD positive correlation

between In the overall AISI and population, FLD (R univariate = 0.13, P logistic < 0.001) regression (Fig. 7). results showed

a positive association between AISI and FLD (OR: 1.24, 95% CI: 1.17,

Relationship 1.32, P < 0.001). between This association AISI and FLD persisted after adjusting for age, sex,

In and the race overall (Model population, 2: OR 1.23, 95% univariate CI: 1.16, logistic 1.31, P < regression 0.001) and after full

results covariate showed adjustment a positive (Model association 3: OR 1.09, 95% between CI: 1.01, AISI 1.16, and P = 0.021).

FLD When (OR: log2-AISI 1.24, 95% was divided CI: 1.17, into 1.32, quartiles P < (Q1–Q4), 0.001). This the Q1 association

the reference persisted in logistic after regression. adjusting In for Model age, 1, sex, the Q4 and group race had

group was

(Model a significantly 2: OR 1.23, higher 95% OR CI: than 1.16, Q1 (OR: 1.31, 1.82, P < 95% 0.001) CI: 1.51, and 2.18, after P <

full 0.001). covariate In Model adjustment 3, patients in (Model the highest 3: OR log2-AISI 1.09, quartile 95% had CI: a 26%

1.01, higher 1.16, disease P = 0.021). odds than When the reference log2-AISI group was (OR: divided 1.26, 95% into CI: 1.01,

quartiles 1.57, P = (Q1–Q4), 0.044). Complete the Q1 results group are provided was the in reference Table 3. in

logistic regression. In Model 1, the Q4 group had a significantly

higher OR than Q1 (OR: 1.82, 95% CI: 1.51, 2.18,

Restricted cubic spline (RCS) analysis revealed a significant linear

P < 0.001). In Model 3, patients in the highest log2-AISI

association between AISI and FLD risk (Fig. 8). Threshold analysis after

quartile had a 26% higher disease odds than the reference

full adjustment in Model 3 identified an AISI inflection point at 8.12. FLD

group (OR: 1.26, 95% CI: 1.01, 1.57, P = 0.044). Complete

risk remained low below this threshold but increased significantly when

results are provided in Table 3.

AISI exceeded 8.12.

Restricted cubic spline (RCS) analysis revealed a significant

linear association between AISI and FLD risk

(Fig. Discussion

8). Threshold analysis after full adjustment in Model

3 identified an AISI inflection point at 8.12. FLD risk

remained FLD has low emerged below as this a major threshold global public but health increased burden significantly

high when prevalence, AISI insidious exceeded symptoms, 8.12. and close associations with

due to its

chronic conditions such as cardiovascular diseases and diabetes [18].

Discussion

Based on the large-scale NHANES cohort, this study is the first to

FLD systematically has emerged identify as a a major significant global independent public health association burden between

due AISI to and its high FLD risk prevalence, (per one-unit insidious increase symptoms, in log2-AISI was and associated close

associations with an 8% elevated with chronic FLD risk; conditions OR = 1.08, such 95% CI: as 1.01, cardiovascular

0.021). diseases Furthermore, and diabetes after incorporating [18]. Based AISI on into the the large-scale multivariate risk

1.16, P =

NHANES model, its cohort, discriminative this study ability is reached the first an AUC to systematically

of 0.814 (95% CI:

identify 0.800, a 0.827). significant Fatty Liver independent Index (FLI) and association Hepatic Steatosis between Index (HSI)

AISI are and two widely FLD risk used (per serum-based one-unit non-invasive increase methods in log2-AISI for predicting

was FLD. associated External validation with an studies 8% elevated have shown FLD that risk; the OR AUCs = 1.08, of FLI

95% CI: 1.01, 1.16, P = 0.021). Furthermore, after incorporating

AISI into the multivariate risk model, its discriminative

ability reached an AUC of 0.814 (95% CI:

0.800, 0.827). Fatty Liver Index (FLI) and Hepatic Steato-


13

FEATURE


Page 7 of 12

Fig. 2 Multiple logistic regression analysis of FLD


Fig. 3 Nomogram of FLD

Chronic inflammation plays a pivotal role in FLD; however,

HSI in not different all populations clinical inflammatory often range from biomarkers 0.69 to 0.86 [19, exhibit

and

20]. pathophysiological In comparison, the diagnostic relevance efficacy to of the this prediction condition. model in In

this FLD—a study falls disease within a similar characterized range, suggesting by complex its potential inflammatory clinical

predictive mechanisms—the value and providing utility a new of reference traditional dimension single for inflammatory

assessment markers of FLD. remains contentious. While white blood

clinical

risk

Chronic inflammation plays a pivotal role in FLD; however, not all

clinical inflammatory biomarkers exhibit pathophysiological relevance

to this condition. In FLD—a disease characterized by complex

inflammatory mechanisms—the utility of traditional single inflammatory

cell count (WBC) has been inconsistently associated

markers with FLD remains across contentious. diverse populations, While white blood C-reactive cell count protein (WBC) has

been (CRP) inconsistently demonstrates associated limited with diagnostic FLD across efficacy diverse populations, for distinguishing

protein disease (CRP) severity demonstrates [21–23]. limited Furthermore, diagnostic efficacy CRP for

C-reactive

distinguishing suffers from disease low specificity severity [21–23]. due Furthermore, to interference CRP suffers from from

low other specificity inflammatory due interference states and from incurs other higher inflammatory testing states costs and

incurs higher testing costs compared to routine blood tests [24]. By

contrast, AISI possesses a theoretical basis to more comprehensively

reflect the body’s complex chronic inflammatory process because it

integrates information from multiple types of immune cells. A recent

cohort study involving 34,303 Chinese adults with hypertension further

14


Page 8 of 12

FEATURE

Fig. 4 AUC value of multiple logistic regression model

Fig. 5 Calibration profile of multiple logistic regression model

compared to routine blood tests [24]. By contrast, AISI

possesses a theoretical basis to more comprehensively

validated the value of AISI in FLD risk assessment. Results showed

reflect the body’s complex chronic inflammatory process

that each standard deviation increase in AISI was associated with a

because it integrates information from multiple types of

74% higher FLD risk (OR = 1.74, 95% CI: 1.69, 1.80), with the highest

immune cells. A recent cohort study involving 34,303

quartile group having three times the risk of lowest quartile. AISI

Chinese adults with hypertension further validated the

demonstrated the highest diagnostic performance (AUC = 0.659,

value of AISI in FLD risk assessment. Results showed

95%

that

CI:

each

0.654,

standard

0.665) among

deviation

multiple

increase

inflammatory

in AISI

indices,

was

indicating

associated

superior with predictive a 74% higher advantage FLD for risk FLD (OR risk [14]. = 1.74, It is 95% important CI: 1.69, to

its

note 1.80), that a with study the has highest demonstrated quartile a negative group correlation having three between times

AISI the and risk the risk of the of liver lowest fibrosis quartile. in patients AISI with psoriasis. demonstrated This the

finding may indicate pathophysiological differences between early

steatosis and advanced fibrosis [25]. Specifically, while a high AISI

value indicates heightened systemic inflammation and an increased

FLD risk, progression to significant fibrosis may involve depletion or

exhaustion of immune and inflammatory cells, resulting in a decrease

highest in measurable diagnostic AISI values. performance Therefore, the (AUC clinical = 0.659, utility of 95% AISI may CI:

0.654, vary depending 0.665) among the multiple stage of liver inflammatory disease, underscoring indices, the indicating

for longitudinal its superior studies predictive to elucidate advantage its dynamic for role FLD throughout risk [14]. the

need

It disease important course. This to note study, that based a study on the NHANES has demonstrated database, is a the

negative first to assess correlation the association between between AISI AISI and and the FLD risk of in the liver U.S.

fibrosis population. in patients The findings with revealed psoriasis. a statistically This finding significant may association indicate

between pathophysiological AISI and FLD. While differences the effect size between was relatively early steatosis

AISI—a and simple advanced and readily fibrosis accessible [25]. Specifically, marker from while routine a blood high

modest,

AISI tests—still value holds indicates potential heightened as a supplementary systemic tool inflammation

for early screening.

and an increased FLD risk, progression to significant

fibrosis Multivariate may regression involve analysis depletion showed or exhaustion that male, older of immune age,

and higher inflammatory BMI, Mexican cells, American, resulting hypertension, in a decrease and diabetes in measurable

all independent AISI values. risk factors Therefore, FLD, the consistent clinical with utility previous of AISI

are

may epidemiological vary depending evidence on [26–30]. the stage The of reduced liver disease, risk observed underscoring

women could the need be linked for longitudinal to the protective studies properties to elucidate of estrogen its

in

dynamic and the lower role occurrence throughout of detrimental the disease lifestyle course. choices, This such study, as

based tobacco on use the and NHANES alcohol consumption database, is [26]. the Mexican first to Americans assess the

association have a significantly between higher AISI FLD and risk FLD compared risk to in other U.S. ethnic population.

and potential The mechanisms findings revealed include visceral a statistically fat distribution, significant specific

groups,

association genetic polymorphisms between AISI (such and as PNPLA3 FLD. While and TM6SF2), the effect and size

was sociodemographic relatively modest, factors AISI—a (such as simple diet and and access readily to healthcare) accessible

It should marker be from noted routine that these blood risk factors tests—still are not holds entirely potential independent

[29].

as but a supplementary act synergistically tool promote for early the screening.

onset and progression of FLD

through Multivariate complex regression interactions. For analysis example, showed aging not that only directly male,

older leads to age, metabolic higher disorders BMI, Mexican and systemic American, inflammation, hypertension,

significantly and diabetes increases are the risk all of independent hypertension and risk diabetes factors [27]. for BMI

but also

FLD, is a key consistent predictor of with FLD, previous with an incidence epidemiological as high as 42% evidence among

[26–30]. individuals The with reduced a high BMI risk (BMI observed ≥ 25 kg/m²), in significantly women could higher be

linked than the to 26% the observed protective in people properties of normal of weight estrogen [28]. Obesity, and the

lower diabetes, occurrence and FLD share of detrimental chronic inflammation lifestyle and choices, insulin resistance such

as as tobacco a common use pathological and alcohol basis. consumption Chronic, low-grade [26]. inflammation Mexican

Americans have a significantly higher FLD risk compared

to other ethnic groups, and potential mecha-

associated with obesity can enhance hepatic insulin resistance and

lipid accumulation through increased macrophage infiltration and the

nisms include visceral fat distribution, specific genetic

release of inflammatory mediators, including TNF-α and Interleukin-6

polymorphisms (such as PNPLA3 and TM6SF2), and

(IL-6), thus accelerating the progression of the disease [31].

sociodemographic factors (such as diet and access to

healthcare) [29]. It should be noted that these risk factors

The mechanisms by which elevated AISI increases FLD risk remain

are not entirely independent but act synergistically to

under investigation. Studies suggest that neutrophils worsen liver

promote the onset and progression of FLD through complex

interactions. For example, aging not only directly

inflammation and hasten the progression from simple steatosis

to steatohepatitis via releasing reactive oxygen species and proinflammatory

factors like TNF-α and IL-6 [32, 33]. In lymphocytes, the

leads to metabolic disorders and systemic inflammation,

but also significantly increases the risk of hypertension

infiltration of CD8 + T cells and their secretion of interferon-γ (IFN-γ) and

and diabetes [27]. BMI is a key predictor of FLD, with an

TNF-α intensify hepatic inflammation and fibrosis [34, 35]. Activated

incidence as high as 42% among individuals with a high

B cells, stimulated by oxidative stress and activating factors, produce

BMI (BMI ≥ 25 kg/m²), significantly higher than the 26%

antibodies and pro-inflammatory mediators that drive liver fibrosis

observed in people of normal weight [28]. Obesity, diabetes,

and FLD share chronic inflammation and insulin

[36]. Monocytes infiltrate the liver and differentiate into macrophages,

which further induce hepatic lipid accumulation and tissue damage

resistance as a common pathological basis. Chronic, lowgrade

inflammation associated with obesity can enhance

by secreting inflammatory mediators like interleukin-1β (IL-1β) and

hepatic TNF-α, while insulin modulating resistance lipid and metabolism-related lipid accumulation signaling through pathways

increased [37, 38]. Beyond macrophage their traditional infiltration pro-coagulant and role, the platelets release amplify of

inflammatory immune signaling mediators, and promote including hepatic inflammatory TNF-α and cascades Interleukin-6

releasing (IL-6), mediators thus accelerating such as platelet the factor progression 4 (PF4) and of transforming the dis-

by

ease growth [31]. factor β (TGF-β), as well as forming heterotypic aggregates with

leukocytes [39]. It should be noted that most of these mechanisms are

derived from animal or in vitro studies, with limited clinical evidence in

human populations.

This study isn’t without several limitations. First, the cross-sectional


15

FEATURE


Page 9 of 12

Fig. 6 Decision graph of multiple logistic regression model

Fig. 7 Scatter plot of Log2-AISI and CAP


Table 3 Relationship between AISI and FLD risk was examined using logistic regression analyses

Model 1 Model 2 Model 3

OR(95% CI) P OR(95% CI) P OR(95% CI) P

log2-AISI 1.24 (1.17, 1.32) < 0.001 1.23 (1.16, 1.31) < 0.001 1.09 (1.01, 1.16) 0.021

log2-AISI(quartile)

Q1(< 7.39) Reference Reference Reference

Q2(7.39 ~ 8.12) 1.17 (0.98, 1.40) 0.083 1.15 (0.95, 1.38) 0.147 0.96 (0.7, 1.19) 0.723

Q3(8.12 ~ 8.92) 1.49 (1.24, 1.78) < 0.001 1.44 (1.19, 1.74) < 0.001 1.05 (0.84, 1.30) 0.688

Q4(> 8.92) 1.82 (1.51, 2.18) < 0.001 1.78 (1.48, 2.16) < 0.001 1.26 (1.01, 1.57) 0.044

P for trend < 0.001 < 0.001 0.033

OR, odds ratio; CI, Confidence interval

Model 1: No covariates were included in the adjustment

Model 2: Adjusted for age, sex, and race

Model 3: Adjusted for age, sex, race, BMI, family PIR, education, marital status, alcohol user, smoking status, hypertension, and diabetes

16


Page 10 of 12

FEATURE

Fig. 8 Decision graph of multiple logistic regression model (A) Pre-adjustment RCS prediction chart; (B) Adjusted RCS prediction chart

The mechanisms by which elevated AISI increases FLD

nature risk of the remain study limits under it to investigation. demonstrating the Studies correlation suggest between that

AISI neutrophils and FLD, rather worsen than establishing liver inflammation a definitive causal and relationship, hasten the

and progression lacks long-term from follow-up simple to observe steatosis the progression to steatohepatitis of the via

disease. releasing Second, reactive the diagnostic oxygen criteria species did not and incorporate pro-inflammatory clinical

diagnosis, factors liver like function TNF-α indicators, and IL-6 or pathological [32, 33]. staging In lymphocytes,

information,

which the may infiltration affect the accuracy of CD8 of + disease T cells classification. and their Third, secretion due to of

considerations interferon-γ such (IFN-γ) as cost-effectiveness and TNF-α intensify and participant hepatic compliance, inflammation

study had and a relatively fibrosis high [34, sample 35]. Activated exclusion rate, B cells, leading stimulated to a

this

higher by prevalence oxidative of stress FLD in and the sample activating and resulting factors, in produce some selection antibodies

Fourth, and the study pro-inflammatory data were derived mediators from a U.S. that population, drive liver

bias.

without fibrosis accounting [36]. Monocytes for differences infiltrate laboratory the standards liver or differentiate

into macrophages, across regions, which limits further generalizability induce hepatic of the lipid

genetic

backgrounds

findings. accumulation Fifth, although and various tissue confounding damage factors by secreting were adjusted inflammatory

statistical mediators analysis, the like absence interleukin-1β of data on important (IL-1β) and variables TNF-

for

in the

such α, as while diet, physical modulating activity, lipid and medication metabolism-related history could still signaling lead to

residual pathways confounding. [37, 38]. Sixth, Beyond the effect their size traditional of AISI as an pro-coagulant

independent

risk role, factor is platelets relatively amplify limited, and immune its actual signaling value and feasibility and promote for

clinical hepatic application inflammatory require further cascades supporting by evidence. releasing mediators

such as platelet factor 4 (PF4) and transforming growth

Based factor on the β above (TGF-β), limitations, as well future as research forming can heterotypic be pursued aggregates

areas. with First, leukocytes large-sample [39]. prospective It should cohort be noted studies that should most

in the

following

be conducted of these to mechanisms clarify the temporal are relationship derived from between animal AISI and or the in

onset vitro and progression studies, with of FLD. limited Second, clinical the predictive evidence capacity in human of AISI

for FLD populations. should be further validated in multi-center studies and diverse

ethnic This populations, study with isn’t exploration without of several appropriate limitations. reference First, intervals. the

Third, cross-sectional combining more nature accurate of diagnostic the study tools limits for FLD it can to improve demonstrating

and the credibility correlation of research between findings. AISI At and the same FLD, time, rather it

the precision

is necessary than establishing to analyze in depth a definitive the specific causal roles of relationship, each component and

of AISI lacks in the long-term staging and follow-up pathogenesis to of observe fatty liver. Furthermore, progression

exploring of the risk disease. models that Second, combine the AISI diagnostic with other biomarkers criteria did or not

imaging incorporate characteristics clinical may help diagnosis, enhance the liver accuracy function of FLD indicators,

or Finally, pathological it is also important staging to information, evaluate the actual which effects may

risk

assessment.

of AISI-targeted affect the novel accuracy anti-inflammatory of disease intervention classification. strategies Third, in the due

prevention to considerations and treatment such of fatty as liver. cost-effectiveness and participant

compliance, this study had a relatively high sample

Conclusion

This study establishes a significant independent association between

elevated AISI and increased FLD risk in the U.S. population, even

exclusion rate, leading to a higher prevalence of FLD in

after the sample adjusting and for demographic, resulting in metabolic, some selection and lifestyle bias. confounders. Fourth,

Incorporating the study data AISI were into the derived prediction from model a U.S. demonstrated population, good without

accounting performance differences (AUC = 0.814). in laboratory While its effect standards size is limited

discriminative

when or genetic predicting backgrounds FLD risk alone, across it is not regions, yet sufficient which to completely limits the

replace generalizability existing clinical of the risk assessment findings. Fifth, tools. Nevertheless, although various our

findings confounding suggest factors that AISI, were as a cost-effective adjusted for and in readily the statistical accessible

biomarker, analysis, the has the absence potential of to data supplement on important existing variables screening such systems,

particularly as diet, physical in primary activity, care settings and or medication resource-limited history scenarios could

where still lead rapid to initial residual screening confounding. is needed. Sixth, the effect size of

AISI as an independent risk factor is relatively limited,

and its actual value and feasibility for clinical application

Abbreviations

require further supporting evidence.

FLD Fatty liver disease

Based on the above limitations, future research can be

TNF-α Tumor necrosis factor-α

pursued in the following areas. First, large-sample prospective

cohort studies should be conducted to clarify

NLR Neutrophil-to-lymphocyte ratio

SII Immune-inflammatory index

the temporal relationship between AISI and the onset

AISI Aggregate index of systemic inflammation

and progression of FLD. Second, the predictive capacity

NHANES National Health and Nutrition Examination Survey

of AISI for FLD should be further validated in multi-center

studies Transient and diverse elastography ethnic populations, with explora-

TE

CAP tion of appropriate Controlled attenuation reference parameter intervals. Third, combining

BMI more accurate Body mass diagnostic index tools for FLD can improve the

PIR precision and Poverty credibility income ratio of research findings. At the same

AUC time, it is Area necessary under the to analyze curve in depth the specific roles

ROC of each component Receiver operating of AISI characteristic in the staging and pathogenesis

of fatty Decision liver. Furthermore, curve analysis exploring risk models that

DCA

RCS combine AISI Restricted with cubic other spline biomarkers or imaging characteristics

Fatty may liver help index enhance the accuracy of FLD risk

FLI

HSI assessment. Hepatic Finally, steatosis it index also important to evaluate the

WBC actual effects White of blood AISI-targeted cell count novel anti-inflammatory

CRP intervention C-reactive strategies protein

the prevention and treatment of

IL-6 fatty liver. Interleukin-6

IFN-γ Interferon-γ

IL-1β Interleukin-1β

PF4 Platelet factor 4

TGF-β Transforming growth factorβ

Supplementary Information

The online version contains supplementary material available at

https://doi.org/10.1186/s12876-025-03998-6.


17

FEATURE


Supplementary Material 1

Supplementary Material 2

Acknowledgements

The author expresses gratitude for the significant contributions made

by the staff and participants involved in the NHANES study.

Author contributions

MZ and YY contributed to the study design, manuscript drafting, and

critical revision. CW participated in data visualization. YH and MF were

responsible for data curation, software implementation. XL contributed

to methodology development and manuscript review. ZQ oversaw

project administration, funding acquisition, and final manuscript

approval. All authors contributed to the article and approved the

submitted version.

Funding

This research received funding from the NATCM’s Project for Highlevel

Construction of Key TCM Disciplines in Minority Pharmacy

(Zhuang Pharmacy) (No. zyyzdxk-2023165), the Guangxi Natural

Science Foundation (No. 2023GXNSFBA026188), and the Guangxi Key

Discipline of TCM (Zhuang medicine) (No. GZXK-Z-20-60).

Data availability

The data used in this study were obtained from the NHANES, which

is provided by the Centers for Disease Control and Prevention (CDC).

NHANES data can be accessed publicly through the CDC website

(https://wwwn.cdc.gov/nchs/nhanes/Default.aspx).

Declarations

Ethics approval and consent to participate

The NCHS research ethics review board approved the NHANES study

involving human subjects, and participants provided written informed

consent upon enrollment. The studies were carried out in compliance

with local regulations and institutional guidelines.Participants gave

written informed consent before joining the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Received: 26 February 2025 / Accepted: 15 May 2025

Published online: 23 May 2025

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FEATURE

TIMING OF ENDOSCOPY IN PATIENTS WITH

ACUTE VARICEAL BLEEDING IN CIRRHOSIS:

AN UPDATED SYSTEMATIC REVIEW AND

META-ANALYSIS

Shicheng Luo 1† , Kaini Wu 1† and Xiaodong Zhou 1*

Luo et al. BMC Gastroenterology (2025) 25:488 https://doi.org/10.1186/s12876-025-04088-3

SYSTEMATIC REVIEW

Abstract

Mortality, Rebleeding, Systematic review, Meta-analysis

Introduction

Background Endoscopy is a critical tool in the management of

acute variceal bleeding (AVB). However, the optimal timing for its

implementation remains controversial, with varying recommendations

across different clinical guidelines. This study aims to evaluating the

impact of endoscopy timing on patient outcomes.

Methods PubMed, the Cochrane Library, and Embase were searched

from the earliest available publication to January 31, 2024. Both fixedeffect

and random-effect models were employed to calculate the odds

ratio (OR) and 95% confidence intervals (CIs), based on the levels of

heterogeneity. Newcastle-Ottawa Scale was used to assess the quality

of each included studies. The mortality, incidence of rebleeding and

other secondary outcomes were compared between urgent and early

endoscopy groups. Subgroup analysis was performed based on the

endoscopy time defined in each included studies and the reporting

time of primary outcomes. The publication bias was examined through

Egger’s test and Begg’s test.

Results Our analysis showed no significant difference in overall

mortality (OR = 0.99, 95% CI, 0.60–1.62, P = 0.96) and rebleeding (OR

= 1.06, 95% CI, 0.77–1.47, P = 0.71) as well as secondary outcomes

between the two groups. Subgroup analysis indicated that the

mortality in the 6–24 h endoscopy group was significantly lower than in

the < 6 h endoscopy group (OR = 2.05, 95% CI, 1.29–3.26, P = 0.002).

However, no statistical difference between the other groups.

Conclusion Endoscopy performed within 6 h might be associated

with higher mortality. Furthermore, urgent and early endoscopy did

not significantly affect other outcomes in AVB patients. Therefore,

the timing for endoscopy would be more appropriate based on each

patient’s condition within 24 h.

Keywords Timing of endoscopy, Acute variceal bleeding, Cirrhosis,

†Shicheng Luo and Kaini Wu contributed equally to this work.

Acute variceal bleeding (AVB) is one of the most common and severe

complications of cirrhosis and portal hypertension, accounting for

approximately 70% of upper gastrointestinal bleeding in cirrhosis, with

an incidence rate of 10–15% [1]. Despite significant advancements

in the diagnosis, hemostasis and supportive treatment for AVB in

recent decades, its 6-week mortality remains at 10–15% [2]. Current

clinical guidelines for the management of AVB primarily include blood

transfusion, antibiotic prophylaxis, vasoactive drugs, endoscopy,

transjugular intrahepatic portosystemic shunt (TIPS), and balloon

tamponade [3–5]. Endoscopic treatment, including endoscopic

variceal ligation (EVL), endoscopic injection sclerotherapy (EIS), and

endoscopic injection of tissue adhesives (cyanoacrylate) (Fig. 1),

can not only identify the bleeding site and source for emergency

hemostasis but also prevent rebleeding [6].

Although endoscopy is widely recommended as the first-line therapy

for AVB, the optimal timing of endoscopy remains controversial in

current guidelines. The American Association for the Study of Liver

Diseases (AASLD) practice guidelines recommend that endoscopy

should be performed within 12 h after presentation [2]. The Baveno

VII consensus, the European Society of Gastrointestinal Endoscopy

(ESGE) guidelines, and the Austrian consensus recommend

that endoscopy should be performed as soon as possible after

hemodynamic stabilization. The Austrian consensus further suggests

that if patients are hemodynamically unstable, endoscopy should

be performed as soon as it is deemed safe [7–9]. The UK guidelines

recommend that endoscopy of all AVB patients should be performed

within 24 h, and for patients with persistent hemodynamic instability,

endoscopy should be performed more urgently following fluid

resuscitation [10]. The Chinese guidelines suggest that for AVB

patients with stable or recovered hemodynamics, endoscopy should

be performed within 12–24 h [11]. However, these recommendations

are primarily based on “expert opinion” and lack conclusive evidence,

*Correspondence:

Xiaodong Zhou

ndyfy02046@ncu.edu.cn

1

Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology,

Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China


21

Gastrointestinal Endoscopy (ESGE) guidelines, and the

Austrian consensus recommend that endoscopy should

be performed as soon as possible after hemodynamic

stabilization.The Austrian consensus further suggests

that if patients are hemodynamically unstable, endoscopy

should be performed as soon as it is deemed safe

FEATURE

Fig. 1 Endoscopic treatment in patients with acute variceal bleeding. A

and B Endoscopic variceal ligation in the treatment of acute esophageal

variceal bleeding. C and D Endoscopic injection sclerotherapy and tissue

adhesives in the treatment of acute gastric variceal bleeding

leaving the optimal timing for endoscopic treatment a subject of

ongoing debate. Despite numerous retrospective cohort studies on the

timing of endoscopy in AVB patients, the results remain inconsistent.

A recent study suggests that performing endoscopy after adequate

pharmacological treatment may be more effective than urgent

endoscopy [12]. Some studies indicate that the timing of endoscopy

is not associated with mortality or rebleeding in AVB patients [13–15].

It remains unclear whether urgent endoscopy can improve the overall

prognosis of AVB patients.

Therefore, we performed a systematic review and meta-analysis

of all studies meeting the inclusion criteria to assess the impact of

endoscopy timing on patient outcomes.

Methods

Methods

Registration

This study was developed according to the Preferred

Reporting Items for Systematic Reviews and Meta-Analyses

Protocol (PRISMA) checklist [16]. The study protocol

has been registered with PROSPERO (registration

number: CRD42024597970). As this study is a systematic

further review, review. ethical After approval reviewing all and titles patient and abstracts, consent 2234 are irrelevant not

required. articles were excluded, and the full texts of the remaining 36 articles

were assessed. Case reports, abstracts, editorials, reviews, letters,

Search meta-analyses, strategy and guidelines, inclusion conference criteriaproceedings, and clinical trials

We were searched excluded. for Studies articles were related also excluded to the if timing they did of not endoscopy

following variceal criteria: bleeding (1) non-cirrhotic from the populations; earliest available (2) upper gastrointestinal

publi-

meet the

cation bleeding to January unrelated 31, to 2024, cirrhosis; in (3) PubMed, studies not Cochrane focused Library, on the timing

and of endoscopy; Embase. The (4) studies search that strategy did not report was developed data on mortality using or

a combination rebleeding AVB of patients. keywords The complete and MeSH search terms, strategy including

in Table “esophageal S1. and gastric varices[Mesh]”, keywords

is provided

included “bleeding” and “timing of treatment”. The study

population Definitions was and outcomes restricted to humans, with no limitations

Definition on language, of urgent and publication early endoscopy: date, or In each publication included study, status,

resulting in 2681 articles being identified. Duplicates

the

group that underwent endoscopy earlier was defined as the urgent

were removed using EndNote, leaving 2270 articles for

endoscopy group, while the group that underwent endoscopy later

further review. After reviewing all titles and abstracts,

was defined as the early endoscopy group. The definition of time

2234 irrelevant articles were excluded, and the full texts

to endoscopy was consistent with the definitions provided in each

of the remaining 36 articles were assessed. Case reports,

included study. Salvage treatment was defined as balloon tamponade,

abstracts, editorials, reviews, letters, meta-analyses,

additional endoscopic therapy, and TIPS.

guidelines, conference proceedings, and clinical trials

were excluded. Studies were also excluded if they did not

Data extraction

meet the following criteria: (1) non-cirrhotic populations;

References were managed using Endnote 20.4 (USA, 2020, Thomson

Corp), and two researchers (S.L. and K.W.) independently extracted the

following information from each included study: first author, publication

year, country, study design, number of AVB patients, number of

patients who underwent urgent endoscopy, and number of patients

who underwent early endoscopy. Disagreements were resolved by

discussion or re-review of studies between S.L. and K.W.; If it is difficult

to reach an agreement, a third author (X.Z.) reviewed and decided.

According to the Baveno VII consensus on endpoint management

for AVB patients, rebleeding and mortality were extracted as primary

outcomes, while length of hospital stay, need for salvage treatment,

and units of transfusion were extracted as secondary outcomes. To

compare the baseline characteristics of AVB patients in the urgent and

early endoscopy groups, the following data were further extracted:

Child-Pugh score, Model for End-Stage Liver Disease (MELD) score

and Glasgow-Blatchford score. For studies that divided endoscopy

timing into multiple groups, the group closest to 12 h was selected for

the endpoint data. The remaining endoscopy timing groups followed

the original classifications in each included study.


Registration

This study was developed according to the Preferred Reporting

Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA)

checklist [16]. The study protocol has been registered with PROSPERO

(registration number: CRD42024597970). As this study is a systematic

review, ethical approval and patient consent are not required.

Search strategy and inclusion criteria

We searched for articles related to the timing of endoscopy in variceal

bleeding from the earliest available publication to January 31, 2024,

in PubMed, Cochrane Library, and Embase. The search strategy

was developed using a combination of keywords and MeSH terms,

including “esophageal and gastric varices[Mesh]”, keywords included

“bleeding” and “timing of treatment”. The study population was

restricted to humans, with no limitations on language, publication

date, or publication status, resulting in 2681 articles being identified.

Duplicates were removed using EndNote, leaving 2270 articles for

Quality assessment

Quality assessment of the included cohort studies was performed

using the Newcastle-Ottawa Scale (NOS). Two researchers (S.L. and

K.W.) independently graded each study based on factors such as the

representativeness and comparability of the exposed groups. The risk

of bias was assessed within each major category. A semi-quantitative

scoring system was employed, consisting of three components:

selection, comparability, and outcomes, with a total of 8 indicators.

One star was awarded for each criterion met. The maximum possible

NOS score is 8 stars: studies scoring above 6 stars were considered

high quality, 4–6 stars as moderate quality, and below 4 stars as

low quality.

Statistical analysis

This meta-analysis was performed using Review Manager software

(Version 5.3, Copenhagen: The Nordic Cochrane Centre, The

Cochrane Collaboration, 2014) and R Studio (Version 4.3.2). A P value

22

FEATURE

of < 0.05 was considered statistically significant. The odds ratio

(OR) and 95% confidence interval (CI) were calculated. Dichotomous

outcomes were expressed as ORs with 95% CIs, while continuous

outcomes were expressed as mean differences (MDs) with 95% CIs.

Statistical heterogeneity was assessed using I² and the Cochrane

Q test. I² > 50% or a P value < 0.1 from the Cochrane Q test were

considered indicative of significant heterogeneity, in which case a

random-effects model was used. I² ≤ 50% and a P value ≥ 0.1 from

the Cochrane Q test were considered to indicate no significant

heterogeneity, in which case a fixed-effects model was used.

Publication bias was assessed using the Egger and Begg tests,

with a P value > 0.05 indicating no potential publication bias. For the

primary outcomes, subgroup analysis was performed based on the

endoscopy timing defined in each included studies, using 6 h and 12

h as the cutoff points, and the reporting time of primary outcomes.

Furthermore, severity of liver disease and hemodynamic in the urgent

and early endoscopy groups were also evaluated by subgroup

analysis. For primary outcomes, sensitivity analysis was performed by

using a leave-one-out approach, whereby each study was sequentially

excluded and the resulting changes in pooled effect estimates

were systematically evaluated. In addition, a random-effects metaregression

was conducted to identify baseline Child-Pugh and MELD

scores associated with the incidence of rebleeding and mortality used

the Luo metafor al. BMC package Gastroenterology in R Studio. (2025) 25:488

Results

Study selection

A total of 2,681 studies were identified from the PubMed, Embase, and

Cochrane Library databases. After removing duplicates, 2,270 studies

remained. After screening titles and abstracts, 2,234 studies unrelated

to the topic were excluded, leaving 36 articles for further assessment.

12 studies were excluded due to the inability to extract relevant data,

6 studies for not meeting the target population criteria, 2 studies for

having ineligible study designs, and 4 studies due to small sample

sizes or low positive rates. Ultimately, 12 eligible studies were included

in the analysis (Fig. 2) [12–15, 17–24].

Study characteristics

The eligible studies, published between 2009 and 2023, had sample

sizes ranging from 101 to 3,319 participants. All studies were

retrospective cohort studies. 7 studies were from China, 2 were from

South Korea, and 1 each from the United States, Canada, and Egypt.

A total of 6,541 participants were included in the analysis, with 4,072

patients in the urgent endoscopy group and 2,469 patients in the early

endoscopy group (Table 1). The prognostic scores of the original data

were summarized in Table 2. 8 studies classified endoscopy timing

into less than 12 h and more than 12 h, while 2 studies used less than

6 h and 6–24 h. Additionally, 2 studies categorized endoscopy timing

into less than 15 h and more than 15 h, or 12–24 h and more than

24 h, respectively. All studies defined the time to endoscopy as the

interval between hospital admission and the initiation Page of endoscopy.

4 of 13


Fig. 2 Flow-diagram of study selection

All studies were retrospective cohort studies. 7 studies

were from China, 2 were from South Korea, and 1 each

from the United States, Canada, and Egypt. A total of

More than 5 studies pointed to the severity of liver disease

(as measured by MELD or Child-Pugh score) at

admission as independent risk factors for the primary

23

FEATURE

All studies reported mortality as the primary outcome, with 6 studies

reporting 6-week mortality and 6 reporting in-hospital mortality. 10

studies reported rebleeding as the primary outcome, with 6 reporting

6-week rebleeding and 3 reporting in-hospital rebleeding (Table S2).

8 studies reported length of hospital stay, 4 reported the need for

salvage treatment, and 4 reported units of transfusion (Table S3). 6

studies found a statistically significant difference in primary outcomes

related to endoscopy timing, while the results of most studies did

not show significant changes after propensity score matching (PSM)

analysis. More than 5 studies pointed to the severity of liver disease (as

measured by MELD or Child-Pugh score) at admission as independent

risk factors for the primary outcomes, while 3 studies identified the

indicators related to hemodynamics as an independent risk factor.

Most studies used antibiotics and vasoactive drugs after the admission

of AVB patients (Table S4). According to the NOS, 9 studies were rated

as high quality and 3 as moderate quality (Table S5). Publication bias

of each groups are listed in Table S9. If PSM analysis was performed in

the original study, the data before PSM were used.

(365/6,541) of patients died, with 5.7% (231/4,072) in the urgent

endoscopy group and 5.4% (134/2,469) in the early endoscopy group.

There was no significant difference in overall mortality between the

urgent and early endoscopy groups (OR = 0.99, 95% CI, 0.60–1.62, P

= 0.96). Significant heterogeneity was observed (I² = 69%, P = 0.0002)

(Fig. 3a), and publication bias was not statistically significant (Egger

test, P = 0.41; Begg test, P = 0.34).

Overall rebleeding in the urgent and early endoscopy groups

Ten studies involving a total of 6,032 patients explored rebleeding

following urgent and early endoscopy (Table S2). Overall, 8.6%

(517/6,032) of patients experienced rebleeding, with 8.8% (328/3,738)

in the urgent endoscopy group and 8.2% (189/2,294) in the early

endoscopy group. There was no significant difference in the overall

rebleeding between the urgent and early endoscopy groups (OR

= 1.06, 95% CI, 0.77–1.47, P = 0.71). Significant heterogeneity was

observed (I² = 51%, P = 0.03) (Fig. 3b), and publication bias was not

statistically significant (Egger test, P = 0.4; Begg test, P = 0.1).

Meta-analysis of primary outcomes

Overall mortality in the urgent and early endoscopy groups

Luo et al. BMC Gastroenterology (2025) 25:488

Twelve studies involving a total of 6,541 patients explored mortality

following urgent and early endoscopy (Table S2). Overall, 5.6%

Meta-analysis of secondary outcomes

Length of hospital stay in the urgent and early endoscopy groups

Page 5 of 13

Eight studies involving a total of 5,403 patients explored the length of

hospital stay following urgent and early endoscopy (Table S3). There


Table 1 Main characteristics and of the included studies

First

Author(year)

Country Study design Sample size Age(years) Sex (male%)

Cheung (2009) [17] Canada Retrospective 210 Mean ± SD:

55 ± 12

Hsu (2009) [18]

Chen (2012) [19]

China

(Taiwan)

China

(Taiwan)

Retrospective 311 Median:

55 (48–64)

Retrospective 101 Median:

57(49–75)

Tapper (2018) [20] USA Retrospective 239 Mean ± SD:

57.5 ± 11.2

Yoo (2018) [13] Republic of Korea Retrospective 274 Mean ± SD:

overall: 58.05 ± 12.10

urgent: 57.62 ± 12.09

early: 58.77 ± 12.22

Wang (2018) [21] China Retrospective 124 Mean ± SD:

urgent: 56 ± 8.9

early: 59.6 ± 9.6

Huh (2019) [12] Republic of Korea Retrospective 411 Mean ± SD:

overall: 53.6 ± 11.3

urgent: 53.9 ± 11.6

early: 52.6 ± 10.6

Mousa (2021) [22] Egypt Retrospective 297 Mean ± SD:

urgent: 61.3 ± 8.6

early: 59.6 ± 5.3

Wu (2022) [23] China Retrospective 456 Mean ± SD:

urgent: 53.0 ± 12.8

early: 53.1 ± 11.4

Yan (2022) [15] China Retrospective 312 Mean ± SD:

overall: 62.98 ± 12.2

urgent: 61.78 ± 13.74

early: 64.42 ± 9.93

Peng (2023) [14] China Retrospective 534 Mean ± SD:

55.78 ± 11.61

Zhang (2023) [24] China Retrospective 3319 Mean ± SD:

overall: 54.33 ± 11.41

urgent: 54.04 ± 11.40

early: 55.07 ± 11.42

71%

73.31%

84%

66.1%

overall: 75.5%

urgent: 74.0%

early: 78.2%

urgent: 73.8%

early: 82.5%

overall: 70.8%

urgent: 71.3%

early: 69.1%

urgent: 62.2%

early: 59.0%

urgent: 74.9%

early: 71.7%

overall: 62.5%

urgent: 58.2%

early: 67.6%

70.4%

overall: 70.99%

urgent: 71.3%

early: 70.3%

24

Overall rebleeding in the urgent and early endoscopy

groups

Ten studies involving a total of 6,032 patients explored

endoscopy (Table S3). There was no significant difference

in the length of hospital stay between the urgent

and early endoscopy groups (MD = −0.41, 95% CI, −2.36

FEATURE

was no significant difference in the length of hospital stay between the

urgent and early endoscopy groups (MD = −0.41, 95% CI, −2.36 to

1.55, P = 0.68). Significant heterogeneity was observed (I² = 98%, P <

0.00001) (Fig. 4a), and publication bias was not statistically significant

(Egger test, P = 0.06; Begg test, P = 0.05).

Need for salvage treatment in the urgent and early

endoscopy groups

Four studies involving a total of 4,498 patients explored the need for

salvage treatment following urgent and early endoscopy (Table S3).

A total of 18.9% (848/4,498) of patients needed salvage treatment,

with 20% (612/3,061) in the urgent endoscopy group and 16.4%

(236/1,437) in the early endoscopy group. There was no significant


difference in the need for salvage treatment between the urgent and

early endoscopy groups (OR = 1.13, 95% CI, 0.95–1.34, P = 0.16). The

heterogeneity was not significant (I² = 24%, P = 0.27) (Fig. 4b), and

publication bias showed statistical significance (Egger test, P = 0.04;

Begg test, P = 0.5).

Units of transfusion in the urgent and early endoscopy groups

Four studies involving a total of 1,389 patients explored the units of

transfusion following urgent and early endoscopy (Table S3). There

was no significant difference in the units of transfusion between the

urgent and early endoscopy groups (MD = 0.36, 95% CI, −0.53 to

1.26, P = 0.42). Significant heterogeneity was observed (I² = 87%, P <

0.0001) (Fig. 4c), and publication bias was not statistically significant

Page 6 of 13

(Egger test, P = 0.7; Begg test, P = 1).

Table 2 Prognostic score of the included studies. MELD, model for end-stage liver disease; NA, not available in the original studies

First

Author(year)

Child-Pugh score MELD score Glasgow-Blatchford score

Cheung (2009) [17]

Mean ± SD:

8.5 ± 2.0

Mean ± SD:

14.3 ± 5.3

Hsu (2009) [18] NA Median:

11.6 (8.5–14.8)

Chen (2012) [19]

Median:

overall: 9 (7.5–11)

urgent: 9 (8–11)

early: 9 (8–11)

Median:

overall: 13 (10–20)

urgent: 13 (9.5–18)

early: 16 (11–22)

Tapper (2018) [20] NA Median:

14 (11–21)

Yoo (2018) [13] NA Mean ± SD:

overall: 15.9 ± 7.8

urgent: 15.4 ± 6.9

early: 16.9 ± 9.2

Wang (2018) [21] > 9 urgent: 75.4%

early: 82.5%

Huh (2019) [12]

Mean ± SD:

overall: 8.3 ± 2.4

urgent: 8.2 ± 2.4

early: 8.5 ± 2.4

Mousa (2021) [22] ≤ 6 urgent: 6.67%

early: 10.26%

> 6 ≤9 urgent: 25.56%

early: 15.38%

> 9 urgent: 67.78%

early: 74.36%

Wu (2022) [23]

Mean ± SD:

urgent: 7.8 ± 1.8

early: 7.2 ± 1.6

Yan (2022) [15]

Mean ± SD:

overall: 8.05 ± 1.69

urgent: 8.19 ± 1.83

early: 7.89 ± 1.48

Peng (2023) [14]

Mean ± SD:

7.47 ± 1.82

Zhang (2023) [24] ≤ 6 overall: 25.82%

urgent: 22.3%

early: 34.7%

> 6 ≤ 9 overall: 55.56%

urgent: 57.3%

early: 51.1%

> 9 overall: 18.62%

urgent: 20.4%

early: 14.2%

> 17 urgent: 73.8%

early: 84.1%

Mean ± SD:

overall: 12.1 ± 6.9

urgent: 12.3 ± 7.1

early: 11.5 ± 6.4

NA

Mean ± SD:

urgent: 10.6 ± 4.0

early: 9.3 ± 4.1

Mean ± SD:

overall: 14.21 ± 4.99

urgent: 14.04 ± 4.92

early: 14.42 ± 5.09

Mean ± SD:

11.92 ± 4.61

NA

NA

NA

NA

NA

Mean ± SD:

overall: 9.1 ± 3.5

urgent: 9.2 ± 3.3

early: 9.1 ± 3.9

≥ 6 urgent: 70.5%

early: 79.4%

NA

NA

Mean ± SD:

urgent: 12.4 ± 3.2

early: 11.5 ± 3.5

Mean ± SD:

overall: 11.22 ± 3.07

urgent: 11.2 ± 3.02

early: 11.24 ± 3.13

NA

NA


significant (I² = 24%, P = 0.27) (Fig. 4b), and publication

bias showed statistical significance (Egger test, P = 0.04;

Begg test, P = 0.5).

P < 0.0001) (Fig. 4c), and publication bias was not statistically

significant (Egger test, P = 0.7; Begg test, P = 1).

25

FEATURE

Subgroup analysis

Mortality under different definitions of endoscopy timing

Two studies involving a total of 3631 patients divided the endoscopy

timing into < 6 h and 6–24 h (Table S2). The mortality in the < 6 h

group was significantly higher than in the 6–24 h group (OR = 2.05,

95% CI, 1.29–3.26, P = 0.002). No heterogeneity was observed (I² =

0; P = 0.44) (Fig. S1a). However, There was no significant difference in

8 studies involving a total of 2475 patients that divided the endoscopy

timing into ≤ 12 h and > 12 h groups (OR = 1.04, 95% CI, 0.62–1.76,

P = 0.87). Significant heterogeneity was observed (I² = 54%; P = 0.04)

(Fig. S1b).

Rebleeding under different definitions of endoscopy timing

Two studies involving a total of 3631 patients divided the endoscopy

timing into < 6 h and 6–24 h (Table S2). No significant difference in

rebleeding between the two groups (OR = 0.96, 95% CI, 0.49–1.90,

P = 0.91). Significant heterogeneity was observed (I² = 67%; P = 0.08)

(Fig. S1c). Additionally, there was no significant difference in 7 studies

involving a total of 2277 patients that divided the endoscopy timing

into ≤ 12 h and > 12 h groups (OR = 1.10, 95% CI, 0.69–1.77, P = 0.68).


Significant heterogeneity was observed (I² = 59%; P = 0.02) (Fig. S1d).

Reporting time of mortality

Six studies involving a total of 1465 patients reported the 6-week

mortality for the urgent and early endoscopy groups (Table S2). No

significant difference in the 6-week mortality between the two groups

(OR = 0.8, 95% CI, 0.46–1.40, P = 0.44). Significant heterogeneity

was observed (I² = 55%; P = 0.44) (Fig. S2a). Additionally, 6 studies

involving a total of 5053 patients reported the in-hospital mortality for

the urgent and early endoscopy groups. No significant difference in

the in-hospital mortality between the two groups (OR = 1.35, 95% CI,

0.67–2.72, P = 0.40). Significant heterogeneity was observed (I² = 72%;

P = 0.003) (Fig. S2b).

Reporting time of rebleeding

Six studies involving a total of 1678 patients reported the 6-week

rebleeding for the urgent and early endoscopy groups (Table S2). No

significant difference in the 6-week rebleeding between the two groups

(OR = 1.06, 95% CI, 0.61–1.84, P = 0.84). Significant heterogeneity was

observed (I² = 69%; P = 0.006) (Fig. S2c). Additionally, 3 studies involving

a total of 4057 patients reported the in-hospital rebleeding for the urgent

and early endoscopy groups. No significant difference in the in-hospital

rebleeding between the two groups (OR = 1.35, 95% CI, 0.94–1.92, P =

Page 7 of 13

0.10). No heterogeneity was observed (I² = 0; P = 0.97) (Fig. S2d).


Fig. 3 Forrest plot of the primary outcomes between the urgent and early endoscopy groups. a Overall mortality; b Overall rebleeding

26

that divided the endoscopy timing into ≤ 12 h and > 12 h

groups (OR = 1.04, 95% CI, 0.62–1.76, P = 0.87). Significant

heterogeneity was observed (I² = 54%; P = 0.04) (Fig.

S1b).

6-week mortality between the two groups (OR = 0.8,

95% CI, 0.46–1.40, P = 0.44). Significant heterogeneity

was observed (I² = 55%; P = 0.44) (Fig. S2a). Additionally,

6 studies involving a total of 5053 patients reported the

FEATURE

Hemodynamics in the urgent and early endoscopy groups

The hemodynamics of the urgent and early endoscopy groups were

estimated by systolic blood pressure (SBP), heart rate, hemoglobin

and Glasgow-Blatchford score (GBS) (Table S6). The pooled effect

sizes are presented as follows: No significant difference in the SBP

between the two groups (MD = −0.29, 95% CI, −1.43–0.86, P = 0.62).

No heterogeneity was observed (I² = 0%; P = 0.59) (Fig. S3a). The heart

rate in the urgent group was significantly higher than in the early group

(MD = 3.96, 95% CI, 0.12–7.79, P = 0.04). Significant heterogeneity was

observed (I² = 88%; P < 0.00001) (Fig. S3b). The hemoglobin in the

urgent group was significantly lower than in the early group (MD = −2.26,

95% CI, −3.94–−0.57, P = 0.009). No heterogeneity was observed (I² =

0%; P = 0.49) (Fig. S3c). No significant difference in the GBS between

the two groups (MD = 0.36, 95% CI, −0.27–0.99, P = 0.27). Significant

heterogeneity was observed (I² = 56%; P = 0.11) (Fig. S3d).

Severity of liver disease in the urgent and early endoscopy groups

The Child-Pugh and MELD scores were compared between the urgent

and early endoscopy groups (Table S7). No significant difference in

the Child-Pugh score between the two groups (MD = 0.22, 95% CI,

−0.17–0.62, P = 0.27). Significant heterogeneity was observed (I² =


64%; P = 0.04) (Fig. S4a). No significant difference in the MELD score

between the two groups (MD = −0.14, 95% CI, −1.39–1.12, P = 0.83).

Significant heterogeneity was observed (I² = 74%; P = 0.004) (Fig. S4b).

Sensitivity analysis for the primary outcomes in the urgent and

early endoscopy groups

Sensitivity analyses of the primary outcomes revealed that the overall

mortality were not affected by the sensitivity analysis (worst-bestcase

analysis OR = 1.15, 95% CI, 0.72–1.83; best-worst-case analysis

OR = 0.89, 95% CI, 0.54–1.47). Similarly, the overall rebleeding also

showed consistent stability (worst-best-case analysis OR = 1.15, 95%

CI, 0.85–1.57; best-worst-case analysis analysis OR = 0.98, 95% CI,

0.71–1.35).

The association between the severity of liver disease and the

incidence of rebleeding and mortality

Meta-regression of study-level data showed that Child-Pugh score was

significantly associated with the risk of overall mortality (OR = 0.36,

95% CI, 0.17–0.76, P = 0.007), no significant association was observed

for rebleeding (OR = 0.44, 95% CI, 0.15–1.29, P = 0.134). MELD

score showed no significant associations with either bleeding (OR =

0.80, 95% CI, 0.62–1.04, P = 0.096) or mortality (OR = 0.85, 95% CI,

Page 8 of 13

0.59–1.23, P = 0.394) (Table S8, Fig. S5).


Fig. 4 Forrest plot of the secondary outcomes between the urgent and early endoscopy groups. a Length of hospital stay; b Need for salvage treatment;

c Units of transfusion

0.94–1.92, P = 0.10). No heterogeneity was observed (I² =

0; P = 0.97) (Fig. S2d).

P = 0.27). Significant heterogeneity was observed (I² =

56%; P = 0.11) (Fig. S3d).

27

FEATURE


Discussion

This study systematically reviewed and meta-analyzed 12 retrospective

cohort studies to compare the effects of different endoscopy timing on

the prognosis and adverse events of patients with AVB. Our analysis

found that the timing of endoscopy was not significantly associated

with mortality, rebleeding, length of hospital stay, need for salvage

treatment, or units of transfusion. Subgroup analysis indicated that

endoscopy within 6 h may be significantly associated with higher

mortality but not with rebleeding. However, it is important to note that

the studies showed considerable heterogeneity. To explore this further,

we performed additional subgroup analysis to assess the impact of

endoscopy timing defined in each included studies and the reporting

time of primary outcomes, which may be the primary source of this

variability.

Two previous meta-analyses have examined the timing of endoscopy

in patients with AVB. The meta-analysis by Jung et al. published in

2020, found no significant effect of endoscopy timing on mortality or

rebleeding in AVB patients [25]. In contrast, a 2021 meta-analysis by

Bai et al. suggested that endoscopy timing might influence mortality

in AVB patients [26]. Concurrently, considering that hemodynamic

and severity of liver disease may impact the endoscopy timing, we

conducted subgroup analysis pooling effect sizes across studies

reporting these variables. Our results show that endoscopy within

6 h may be associated with higher mortality, and no significant

difference in overall mortality between the urgent and early endoscopy

groups. Although only two studies were included, our outcome still

has reasonable reference significance. We further reviewed the

baseline of the studies included in the analysis and found that the

hemodynamic were not significantly different between the urgent and

early endoscopy groups, and none of them reached a state of shock.

Although urgent endoscopy can help identify the site and extent of

bleeding, premature endoscopy may hinder the restoration of tissue

and organ perfusion and oxygenation, unclear visualization due to

insufficient time for medication administration, as well as increased

risk of complications (perforation, aspiration pneumonia). Patients with

poor liver function classification have limited hemostasis effect under

endoscopy due to coagulation dysfunction, which may aggravate the

condition. Such patients require comprehensive treatment (such as

TIPS and hemostasis under vascular intervention), rather than simply

pursuing the speed of endoscopy.

Recent years, additional research has been conducted, with 5 original

studies published after Bai et al.‘s analysis [14, 15, 22–24], including

a notable study by Zhang et al., which involved 3,319 patients across

34 centers [24]. The increase in sample size in these studies could

influence the results of the meta-analysis. Our study updates Bai et

al.‘s work, expanding the sample size to 6,541 cases, compared to the

2,824 cases in Bai et al.‘s study. Furthermore, our study extends Bai et

al.‘s analysis of mortality, rebleeding, length of hospital stay, need for

salvage treatment and units of transfusion, providing a comprehensive

assessment of the impact of endoscopy timing on various prognostic

outcomes. However, we did not perform subgroup analyses for

secondary outcomes due to the limited number of original studies and

high heterogeneity, which could make the results unreliable. In contrast

to Bai et al., our subgroup analysis decreased the heterogeneity,

with some outcomes showing minimal or even no heterogeneity.

Our study also offers a more detailed examination of post-admission

management strategies, data analysis methods, independent risk

factors, the potential factors influencing endoscopy timing and the

risk factors for the primary outcomes of AVB prognosis in the included

studies. Additionally, the studies by Badave and Anghelici included

in Bai et al.‘s analysis were abstracts and lacked comprehensive

information on baseline characteristics, definitions, statistical methods,

post-admission management strategies and outcomes [27, 28]. The

absence of such critical data may have contributed to lower quality

in the original studies, potentially introducing bias into the statistical

results. Furthermore, Our study utilized data prior to PSM, as these

data more accurately reflect the real-world clinical scenarios. We also

conducted an analysis of the primary outcomes after PSM and found

that most of the results remained consistent with those before PSM.

The Child-Pugh score and MELD score are widely used to assess the

prognosis of patients with cirrhosis. Among the studies included in our

analysis, 3 performed risk stratification based on the severity of liver

disease (as measured by MELD or Child-Pugh score) at admission [12,

14, 24]. Huh et al. found that in patients with a MELD score ≤ 17, urgent

endoscopy was associated with higher mortality and rebleeding [12].

Zhang et al. reported that in Child-Pugh B patients, urgent endoscopy

could lead to a higher incidence of rebleeding [24]. However, the study

by Peng et al., which defined endoscopy timing as the interval between

admission and endoscopy, found no significant correlation between

endoscopy timing and mortality or rebleeding at different Child-Pugh

scores [14]. We extracted Child-Pugh and MELD scores for the urgent

and early endoscopy groups from the included studies. Subgroup

analyses combined all studies reporting these risk factors and revealed

no significant correlation between the time to endoscopy and the

severity of liver disease. As more than 5 studies identified the severity

of liver disease at admission as an independent risk factor for the

primary outcomes, we performed meta-regression analysis on studies

reporting Child-Pugh scores or MELD scores for the urgent and early

endoscopy groups with their mortality and rebleeding. These analyses

suggested that only Child-Pugh scores was significantly associated

with the risk of overall mortality. We synthesized the available data, but

due to the limited number of studies providing this specific information

and inconsistencies in data reporting formats, these conclusions

should be interpreted with caution.

Hemodynamics play a critical role in assessing the vital signs of

patients with upper gastrointestinal bleeding and the Glasgow-

Blatchford score (GBS), which has been shown to be associated

with mortality [29]. Several studies have demonstrated that

emergency endoscopy yields an excellent prognosis for patients with

hemodynamic instability due to non-variceal upper gastrointestinal

bleeding [30, 31]. The American Gastroenterology Association

(AGA) clinical practice guidelines recommend that emergency

endoscopy should be performed for patients with non-variceal upper

gastrointestinal bleeding who experience persistent hemodynamic

instability after initial resuscitation [32]. However, no studies have yet

explored the relationship between the prognosis of hemodynamically

instable AVB patients and the timing of endoscopy. Among the

studies included in our review, Cheung et al. explicitly excluded

hemodynamically instable patients prior to endoscopy [17], Chen et al.

and Hsu et al. performed endoscopy after hemodynamic stabilization

[18, 19], while the remaining studies either left the decision to the

28

FEATURE

endoscopist’s discretion or did not specify the timing. To evaluate

whether hemodynamics at admission affects endoscopy time, we

extracted hemodynamic-related characteristics such as systolic

blood pressure (SBP), heart rate, hemoglobin, and GBS scores from

the urgent and early endoscopy groups in the included studies.

Subgroup analyses combined all studies reporting these risk factors,

and revealed that the urgent group had significantly higher heart

rates and lower hemoglobin levels compared to the early group.

Although GBS scores did not differ statistically, a trend toward

higher scores was observed in the urgent endoscopy group. These

findings suggest that urgent endoscopy cohorts may have included

patients with greater hemodynamic instability at baseline, potentially

confounding the observed association between urgent endoscopy

and higher mortality. However, due to the limited number of studies

reporting comprehensive hemodynamic parameters and uniformity

of the hemodynamic indices provided, meta-regression analyses

lacked sufficient statistical power to establish definitive interactions

between hemodynamics and primary outcomes. Future studies with

standardized data collection and larger sample sizes are warranted to

validate these associations.

Another strength of our study is its detailed presentation of medication

use in AVB patients from admission to endoscopic treatment,

particularly the use of vasoactive drugs and prophylactic antibiotics.

Most existing guidelines recommend the early administration of

vasoactive drugs and prophylactic antibiotics upon admission for

AVB patients. A meta-analysis by Rahman et al., which included

8 randomized controlled trials (RCTs) involving 598 patients,

demonstrated that the infusion of erythromycin prior to endoscopy

improved visualization, reduced the need for a second endoscopy, and

shortened hospital stay [34]. Additionally, 3 RCTs showed that the use

of vasoactive drugs significantly improved the management of active

bleeding in patients [35–37]. Therefore, pharmacological treatment

plays a crucial role in the outcomes of AVB patients. Fortunately, twothirds

of the studies included in our analysis provided comprehensive

coverage of vasoactive drugs and antibiotics for all AVB patients.

Proton pump inhibitors (PPIs) are essential for hemostasis in nonvariceal

bleeding; however, for variceal bleeding patients, it is

recommended to discontinue their use after endoscopy. Unfortunately,

relevant data regarding the use of proton pump inhibitors could not be

extracted from several studies.

Currently, the main treatment of variceal bleeding include endoscopic

variceal ligation (EVL), sclerotherapy, and tissue adhesive injection.

However, differences exists among various studies regarding the

choice of primary hemostatic technique. This variation is likely

attributable to temporal differences in study conduct, regional

disparities in healthcare resources, and the predominant reliance

on endoscopist discretion in clinical practice. Recently, hemostatic

powders have emerged as a promising adjunct for upper

gastrointestinal bleeding. A meta-analysis by Facciorusso et al. which

included 24 studies involving 1063 patients demonstrated the efficacy

and safety of hemostatic powders in upper Gastrointestinal bleeding

(UGIB) [33]. Two cohort studies and one randomized controlled trial

(RCT) confirmed the efficacy and safety of immediate endoscopic

application of hemostatic powder before secondary endoscopy in

variceal bleeding. Unfortunately, none of the studies we included

mentioned the efficacy of applying hemostatic powder during

endoscopic treatment for acute variceal bleeding, which may be due

to the fact that acute variceal bleeding is mainly due to high pressures

in the portal vein and collateral circulation, and the priority is to reduce

portal pressure and embolize the variceal veins; therefore, hemostatic

powder has not been widely popularized.

In all the studies included in our analysis, the time to endoscopy was

defined as the interval between hospital admission and the initiation of

endoscopy. Currently, the Baveno VI consensus, AASLD guidelines,

UK guidelines, and Austrian consensus define the time to endoscopy

as the interval from the occurrence of bleeding to the performance of

endoscopy [2, 7, 9, 10]. In contrast, the ESGE and Chinese guidelines

define it as the interval from hospital admission to endoscopy [8, 11].

Peng et al. investigated the results of these two definitions and found

that they led to differing outcomes [14]. Defining the time to endoscopy

as the interval from bleeding onset to the procedure can help eliminate

inconsistencies related to patients’ arrival times at the hospital;

however, the interval from bleeding to admission is often reliant on the

patient’s subjective report, which may introduce information bias.

Our meta-analysis has several limitations. First, all included studies

were retrospective and not randomized, which may introduce selection

bias. Second, there was variability in the decisions regarding the

timing of endoscopy, the reporting time of primary outcomes, and

the management protocols across different studies, which may have

affected the quality of the data. Although we attempted to reduce bias

through subgroup analyses and comparisons of study characteristics,

it could not be fully eliminated. Third, inferring the optimal timing

of endoscopy solely based on the outcomes of AVB patients is

challenging. Factors such as the use of non-selective β-blockers

(NSBBs) after endoscopy when hemodynamic stability was achieved,

the patient’s nutritional status, lifestyle, and regular endoscopic

variceal ligation (often recommended 2–4 weeks after the first

endoscopic variceal therapy) may all influence prognosis. Notably, only

the study by Chen et al. provided prophylactic protocols subsequent

to initial endoscopic hemostasis. Consequently, future studies should

emphasize standardized prophylactic protocols after hemodynamic

stability was achieved. Finally, most of the samples in this study were

drawn from the Asia-Pacific region, where the majority of patients have

hepatitis B virus-related cirrhosis, which may limit the generalizability

of the results to patients with cirrhosis caused by hepatitis C, alcoholic

liver disease (ALD), or non-alcoholic fatty liver disease (NAFLD).

Conclusions

This meta-analysis found that endoscopy performed within 6 h might

be associated with higher mortality, but it did not show a significant

impact on rebleeding. Furthermore, urgent and early endoscopy

did not significantly affect other outcomes in AVB patients. While

RCTs offer the potential to minimize bias and provide high-quality,

comparable data, their implementation is challenging due to ethical

considerations. Therefore, crafted and large-scale prospective studies

are needed to further validate the impact of endoscopy timing on

the prognosis of AVB patients. In the interim, we recommend that

the timing for endoscopy would be more appropriate based on each

patient’s condition within 24 h.


29

FEATURE


Abbreviations

AVB Acute variceal bleeding

OR Odds ratio

CI Confidence interval

TIPS Transjugular intrahepatic portosystemic shunt

EVL Endoscopic variceal ligation

EIS Endoscopic injection sclerotherapy

AASLD American association for the study of liver diseases

ESGE European society of gastrointestinal endoscopy

MELD Model for end-stage liver disease

NOS Newcastle-Ottawa scale

MDs Mean differences

PSM Propensity score matching

NA Not available

IPW Inverse probability weighting

HCC Hepatocellular carcinoma

EGD Esophagogastroduodenoscopy

GBS Glasgow-blatchford score

AGA American gastroenterology association

RCTs Randomized controlled trials

PPIs Proton pump inhibitors

NSBBs Non-selective β-blockers

ALD Alcoholic liver disease

NAFLD Non-alcoholic fatty liver disease

SBP Systolic blood pressure

UGIB Upper Gastrointestinal bleeding

Supplementary Information

The online version contains supplementary material available at

https://doi.org/10.1186/s12876-025-04088-3.

Supplementary Material 1.

Acknowledgements

This work was supported by the Key Laboratory Project of Digestive

Diseases in Jiangxi Province (2024SSY06101), and Jiangxi Clinical

Research Center for Gastroenterology (20223BCG74011).

Authors’ contributions

Shicheng Luo and Kaini Wu concepted and designed the review;

Shicheng Luo acquisited the data and negotiated with Kaini Wu

together; Shicheng Luo and Kaini Wu performed the statistical

analysis; Shicheng Luo drafted the initial manuscript; Xiaodong Zhou

projected administration and supervision; All authors reviewed and

approved the final manuscript as submitted.

Funding

National Natural Science Foundation of China, Grant/Award Numbers:

81760524, 82260599;

Data availability

All data generated or analysed during this study are included in this

published article [and its supplementary information files].

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Received: 6 April 2025 / Accepted: 13 June 2025

Published online: 01 July 2025

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