Development of a Hepato-Splenic Microcirculatory Perfusion Model Using IVIM MRI to Rule Out High-Risk Varices in Patients With Compensated Hepatitis B-Related Cirrhosis
Conditions: Hepatitis B Virus Related Cirrhosis, Portal Hypertension Related to Cirrhosis, Esophagogastric Varices
Sponsor: Beijing Friendship Hospital

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Application of Hepatic and Splenic IVIM Quantitative Parameters in the Noninvasive
Prediction of High-Risk Esophagogastric Varices
Clinical Research Protocol
Sponsor
Beijing Friendship Hospital, Capital Medical University
Principal Investigator
Hong You
Version No.
V1.0
Version Date
2025.11

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Investigator Clinical Protocol Agreement Page
Principal Investigator：
I agree to conduct this clinical study in accordance with the design and requirements of this
protocol. I acknowledge that I am responsible for the implementation of this trial and agree to
personally participate in or supervise the entire conduct of the clinical study.
I agree to ensure that all personnel involved in this study clearly understand their respective
responsibilities and that the study staff at the trial site have access to appropriate information
throughout the course of the study.
I will accept monitoring, auditing, and inspections by monitors, auditors, and the Ministry of
Science and Technology of the People’s Republic of China, the National Health Commission of
the People’s Republic of China, and the Health Department of the General Logistics Department
of the Chinese People’s Liberation Army, in order to ensure the quality of the study.

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Abstract
Study Title
Application of Hepatic and Splenic IVIM Quantitative Parameters in the
Noninvasive Prediction of High-Risk Esophagogastric Varices
Study
Objectives
Primary Objective:
To evaluate the diagnostic performance of hepatic and splenic IVIM
parameters in identifying high-risk esophagogastric varices.
Secondary Objectives:
1. To compare the diagnostic efficacy of IVIM parameters with noninvasive
indices, including Baveno VI criteria, FIB-4, and APRI, in assessing
esophagogastric varices.
2. To assess the reproducibility of IVIM parameters.
Study Design
Retrospective cohort study.
Study
Population
Patients aged over 18 years with chronic hepatitis B–related cirrhosis.
Study Grouping
According to endoscopic findings, patients will be categorized into:
1. High-risk esophagogastric varices group
2. Non–high-risk group
High-risk esophagogastric varices are defined as:
1.Medium to large varices (≥F2 or diameter ≥5 mm)
2.Presence of red wale signs
Inclusion
Criteria
1. Age ≥18 years.
2. Clinical diagnosis of chronic hepatitis B–related cirrhosis, defined as
HBsAg positivity for ≥6 months, and meeting one of the following
criteria:

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
Liver biopsy confirming cirrhosis (F4 according to the METAVIR
scoring system).

Meeting at least one of the following two conditions:
①Endoscopic evidence of esophageal and/or gastric varices, with non-
cirrhotic portal hypertension excluded;
②In the absence of endoscopy, meeting at least two of the following four
criteria:Imaging findings (ultrasound, CT, etc.) suggestive of cirrhosis,
including irregular liver surface and granular or nodular parenchymal
changes; Liver stiffness measurement (LSM) > 12.4 kPa;

Serum albumin < 35 g/L or prolonged prothrombin time > 3 seconds
(after discontinuation of thrombolytic or anticoagulant drugs for ≥7
days) or decreased cholinesterase;

Platelet count < 100 × 10⁹/L, with no other identifiable cause.
3. Underwent upper gastrointestinal endoscopy for screening or evaluation.
4. Underwent abdominal MRI including IVIM sequences within 6 months
of the endoscopic examination.
Exclusion
Criteria
1. Coexisting other chronic liver diseases.
2. Previous portosystemic shunt procedures or splenectomy.
3. History of upper gastrointestinal variceal treatment that may affect
evaluation.
4. Severe iron deposition in the liver or spleen.
5. Patients with decompensated cirrhosis.

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6. Presence of malignant tumors.
Primary
Outcome
Measure
The diagnostic performance of IVIM parameters in predicting high-risk
esophagogastric varices.
Secondary
Outcome
Measures
1. Comparison of the diagnostic efficacy of IVIM parameters with
noninvasive indices, including Baveno VI criteria, FIB-4, and APRI, in
assessing esophagogastric varices.
2. Reproducibility of IVIM parameters.
Planned Sample
Size
150 patients.
Statistical
Methods
Continuous variables will be expressed as mean ± standard deviation or
median (interquartile range), as appropriate. Between-group comparisons
will be performed using the Student’s t-test or the Mann–Whitney U test.
Categorical variables will be presented as frequency (percentage) and
compared using the chi-square test or Fisher’s exact test.
The presence of high-risk esophagogastric varices will be defined as
the primary outcome. The predictive performance of hepatic and splenic
IVIM parameters will be evaluated by constructing receiver operating
characteristic (ROC) curves. The DeLong test will be used to compare their
performance with noninvasive indices, including Baveno VI criteria, FIB-4,
and APRI.
Multivariable logistic regression analysis will be conducted to develop
a combined prediction model and to assess its discriminative ability. Under
a predefined sensitivity threshold of ≥95%, the proportion of avoided
endoscopies and the rate of missed high-risk esophagogastric varices will
be calculated.

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All statistical tests will be two-sided, and a P value < 0.05 will be
considered statistically significant.
Expected
Timeline
From Feburary 2026 to October 2026.
Main Text
Ⅰ. Research Background
High-risk esophageal varices represent a major complication of portal hypertension in
patients with cirrhosis. Once acute variceal bleeding occurs, the mortality rate may reach
approximately 35%[1]. Currently, upper gastrointestinal endoscopy is the gold standard for
diagnosing high-risk esophagogastric varices. However, as an invasive procedure, it is
associated with patient discomfort, relatively high cost, and considerable time consumption,
which limit its use in large-scale screening.
To reduce unnecessary endoscopic examinations, several noninvasive assessment methods
have been proposed in clinical practice, including maximal spleen diameter, platelet count,
platelet-to-spleen diameter ratio, aspartate aminotransferase-to-platelet ratio index (APRI),
FIB-4, and the Baveno criteria[2-5].
The latest Baveno VII consensus states that if platelet count (PLT) > 150 × 10⁹/L, liver
stiffness measured by transient elastography (TE) < 20 kPa, and spleen stiffness ≤40 kPa, the
proportion of patients who can safely avoid endoscopy can be further increased while
maintaining a low rate of missed high-risk varices. In addition, magnetic resonance
elastography (MRE) has been reported to be more accurate than TE in measuring liver stiffness.
However, these elastography-based techniques require specialized equipment, which limits
their widespread implementation[6].
In contrast, intravoxel incoherent motion (IVIM) imaging does not require contrast agents
and can separate true molecular diffusion from microcirculatory perfusion using a multi–b-
value biexponential model. It provides quantitative parameters including D (related to tissue

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cellular density), f (microvascular volume fraction), and D* (associated with microcirculatory
perfusion), thereby reflecting local microcirculatory and hemodynamic alterations at both
hepatic and splenic levels. The development of portal hypertension is not only associated with
intrahepatic fibrosis and regenerative nodules leading to microvascular remodeling, but also
influenced by intrahepatic vasoconstriction. Moreover, increased portal vascular resistance may
further induce splenic hemodynamic and structural changes, including fibrosis and
angiogenesis[7]. Therefore, IVIM theoretically holds significant potential for assessing high-risk
esophagogastric varices.
Existing studies have demonstrated correlations between hepatic IVIM parameters and
portal hypertension or esophageal varices. However, its ability to exclude high-risk
esophagogastric varices remains unclear. IVIM parameters reflecting splenic microcirculatory
changes have been even less systematically investigated. To date, no study has applied IVIM
techniques to develop an exclusion strategy for high-risk esophagogastric varices[8]。
Based on the above background, this study aims to explore the value of hepatic and splenic
IVIM imaging parameters in excluding high-risk esophagogastric varices in patients with
cirrhosis, thereby providing novel imaging-based evidence for the noninvasive identification of
high-risk varices.

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References
[1]Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and
outcomes. Gastroenterology. 2002;122(6):1620-1630. doi:10.1053/gast.2002.33419
[2]Takuma Y, Nouso K, Morimoto Y, et al. Measurement of spleen stiffness by acoustic
radiation force impulse imaging identifies cirrhotic patients with esophageal varices.
Gastroenterology. 2013;144(1):92-101.e2. doi:10.1053/j.gastro.2012.09.049
[3]Gaspar R, Silva M, Cardoso P, et al. Spleen stiffness: a new tool to predict high-risk varices in
cirrhotic patients. J Gastroenterol Hepatol. 2023;38(11):1840-1846. doi:10.1111/jgh.16344
[4]Shin SU, Lee JM, Yu MH, et al. Prediction of esophageal varices in patients with cirrhosis:
usefulness of three-dimensional MR elastography with echo-planar imaging technique.
Radiology. 2014;272(1):143-153. doi:10.1148/radiol.14130916
[5]Reverter E, Tandon P, Augustin S, et al. A MELD-based model to determine risk of mortality
among patients with acute variceal bleeding. Gastroenterology. 2014;146(2):412-419.e3.
doi:10.1053/j.gastro.2013.10.018
[6]Zhang X, Song J, Zhang Y, et al. Baveno VII algorithm outperformed other models in ruling
out high-risk varices in individuals with HBV-related cirrhosis. J Hepatol. 2023;78(3):574-583.
doi:10.1016/j.jhep.2022.10.030
[7]Mejias M, Garcia-Pras E, Gallego J, et al. Relevance of the mTOR signaling pathway in the
pathophysiology of splenomegaly in rats with chronic portal hypertension. J Hepatol.
2010;52(4):529-539. doi:10.1016/j.jhep.2010.01.004
[8]Chen F, Chen YL, Chen TW, et al. Liver lobe-based intravoxel incoherent motion diffusion-
weighted imaging in hepatitis B-related cirrhosis: association with Child-Pugh class and
esophageal and gastric fundic varices. Medicine (Baltimore). 2020;99(4):e18671.
doi:10.1097/MD.0000000000018671

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II. Study Objectives
1. Primary Objective
To evaluate the ability of hepatic and splenic IVIM parameters to identify high-risk
esophagogastric varices.
2. Secondary Objectives

To compare the diagnostic performance of IVIM with noninvasive indices, including
Baveno VI criteria, FIB-4, and APRI, in assessing esophagogastric varices

To assess the reproducibility of IVIM parameters.
III. Study Content
This retrospective study will include patients with cirrhosis or advanced chronic liver
disease who have completed both upper gastrointestinal endoscopy and abdominal MRI
(including IVIM sequences). According to endoscopic findings, subjects will be classified into a
high-risk esophagogastric varices group and a non–high-risk group.
Hepatic and splenic IVIM parameters (D, D*, f, and ADC) will be extracted and compared
between the two groups to evaluate their predictive performance for high-risk varices.
Furthermore, comparisons will be conducted with commonly used noninvasive methods,
including Baveno VI criteria, FIB-4, and APRI.
In addition, correlations between IVIM parameters and the severity of varices as well as
clinical indicators will be explored. Subgroup analyses will also be performed to assess the
diagnostic performance of IVIM under different clinical characteristics.

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Ⅳ. Study Protocol
1. Study Design
Retrospective cohort study
2. Study Population
2.1 Source of Subjects
Patients identified from the Beijing Friendship Hospital All-Disease Platform, with visits up to
October 31, 2025
2.2 Inclusion Criteria
（1）Age ≥18 years.
（2）Clinical diagnosis of chronic hepatitis B–related cirrhosis, defined as HBsAg positivity for
≥6 months, and meeting the following criteria:

Liver biopsy confirming cirrhosis, defined as F4 according to the METAVIR scoring system

Meeting at least one of the following two conditions：①Endoscopic evidence of esophageal
and/or gastric varices, with non-cirrhotic portal hypertension excluded；②In the absence of
endoscopy, meeting at least two of the following four criteria：Imaging findings (ultrasound,
CT, etc.) suggestive of cirrhosis, including irregular liver surface and granular or nodular
parenchymal changes; Liver stiffness measurement (LSM) > 12.4 kPa; Serum albumin < 35
g/L, or prolonged prothrombin time > 3 seconds (after discontinuation of thrombolytic or
anticoagulant drugs for ≥7 days), or decreased cholinesterase; Platelet count < 100 × 10⁹/L,
without other identifiable causes.
（3）Underwent upper gastrointestinal endoscopy for screening or evaluation.

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（4）Underwent abdominal MRI including IVIM sequences within 6 months of the endoscopic
examination.
2.3 Exclusion Criteria
（1）Coexisting other chronic liver diseases.
（2）Previous portosystemic shunt procedures or splenectomy.
（3）History of upper gastrointestinal variceal treatment that may affect evaluation.
（4）Severe iron deposition in the liver or spleen.
（5）Decompensated cirrhosis.
（6）Presence of malignant tumors.
3. Study Procedures
3.1 Assessments
（1）Demographic data: sex and age.
（2）Hematological parameters: complete blood count, coagulation function, and liver function
tests.
（3）Imaging examinations: liver stiffness measurement (LSM), MRI sequences, and upper
gastrointestinal endoscopy
4. Study Endpoints
4.1 Primary Endpoint：
The primary study endpoint is the presence of high-risk esophagogastric varices
4.2 Secondary Endpoints：

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（1）Correlation between IVIM parameters and the severity of varices.
（2）Correlation between IVIM parameters and commonly used noninvasive indices.
（3）Reproducibility analysis of IVIM parametersIVIM
5. Study Assessments and Definitions
5.1 High-Risk Esophagogastric Varices
High-risk esophagogastric varices will be determined based on endoscopic findings and defined
as meeting any of the following criteria:
（1）Medium or large varices (≥F2 or diameter ≥5 mm) ；
（2）Presence of red wale signs
6、Sample Size Determination
Using endoscopic findings as the gold standard, this study aims to evaluate the
noninvasive predictive value of hepatic and splenic IVIM imaging parameters for high-risk
esophagogastric varices. Based on previous literature, hepatic and splenic IVIM parameters have
demonstrated a moderate to high effect size (approximately 0.8) in distinguishing patients with
and without high-risk varices.
Referring to similar imaging studies, assuming a significance level of α = 0.05 and
statistical power of 1 −β = 0.9, the required total sample size is estimated to be approximately
120–140 patients.
Considering that this is a retrospective study and that some cases may have suboptimal
image quality or incomplete data, a total of 150 patients will ultimately be included to ensure
adequate statistical power and model stability. This sample size is sufficient to meet the statistical
requirements of the primary study objective.

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Ⅴ. Statistical Analysis
Continuous variables will be expressed as mean ± standard deviation or median
(interquartile range) after testing for normality. Categorical variables will be presented as
frequencies and percentages. Between-group comparisons will be performed using the
independent sample t-test or Mann-Whitney U test, depending on data distribution, and chi-
square or Fisher’s exact test will be used for categorical variables.
The primary outcome variable is the presence of high-risk esophagogastric varices.
Receiver operating characteristic (ROC) curves will be calculated for hepatic and splenic IVIM
parameters to assess their diagnostic performance. Additionally, comparisons with commonly
used noninvasive indices will be made.
A multivariable logistic regression model will be used to construct a combined IVIM
prediction model. Under the condition of sensitivity ≥95%, the proportion of avoided
endoscopies and the rate of missed high-risk esophagogastric varices will be calculated for
different models. The stability of the model will be internally validated through bootstrap
resampling (B=1000 times), and the bias-corrected AUC will be obtained.
Correlation analysis will also be conducted to explore the relationships between IVIM
parameters and the grading of varices, platelet count, liver stiffness, FIB-4, APRI, and other
noninvasive indices. All tests will be two-sided, and a P value < 0.05 will be considered
statistically significant.
Ⅵ. Ethical Considerations
Ethical review: This study must comply with the Declaration of Helsinki and relevant
clinical research regulations in China. The clinical research protocol must be reviewed and
approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University,
before the study begins.
Ⅶ. Informed Consent and Confidentiality of Study Information

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The clinical information of patients in this study will be collected through the Beijing
Friendship Hospital All-Disease Platform, and de-identified (anonymized) data will be exported
from the clinical big data platform. The information obtained will not include identifiable subject
information such as names, phone numbers, ID numbers, or registration numbers. As the
information cannot be used to identify or contact the subjects, a waiver of informed consent is
requested.
Ⅷ. Protocol Amendments
Once this protocol has been approved by the Ethics Committee, any major modifications
during the study's implementation will be documented in an "Amendment to the Protocol"
written by the principal investigator. The amendment will be signed and submitted to the Ethics
Committee for approval before it can be implemented