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Bibliometric-analysis visualization and review of non-invasive methods for monitoring and managing the portal hypertension

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Background Portal hypertension monitoring is important throughout the natural course of cirrhosis. Hepatic venous pressure gradient (HVPG), regarded as the golden standard, is limited by invasiveness and technical difficulties. Portal hypertension is increasingly being assessed non-invasively, and hematological indices, imaging data, and statistical or computational models are studied to surrogate HVPG. This paper discusses the existing non-invasive methods based on measurement principles and reviews the methodological developments in the last 20 years. Methods First, we used VOSviewer to learn the architecture of this field. The publications about the non-invasive assessment of portal hypertension were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer 1.6.17.0 was used to analyze and visualize these publications, including the annual trend, the study hotspots, the significant articles, authors, journals, and organizations in this field. Next, according to the cluster analysis result of the keywords, we further retrieved and classified the related studies to discuss. Results A total of 1,088 articles or review articles about our topic were retrieved from WoSCC. From 2000 to 2022, the number of publications is generally growing. “World Journal of Gastroenterology” published the most articles ( n = 43), while “Journal of Hepatology” had the highest citations. “Liver fibrosis” published in 2005 was the most influential manuscript. Among the 20,558 cited references of 1,088 retrieved manuscripts, the most cited was a study on liver stiffness measurement from 2007. The highest-yielding country was the United States, followed by China and Italy. “Berzigotti, Annalisa” was the most prolific author and had the most cooperation partners. Four study directions emerged from the keyword clustering: (1) the evaluation based on fibrosis; (2) the evaluation based on hemodynamic factors; (3) the evaluation through elastography; and (4) the evaluation of variceal bleeding. Conclusion The non-invasive assessment of portal hypertension is mainly based on two principles: fibrosis and hemodynamics. Liver fibrosis is the major initiator of cirrhotic PH, while hemodynamic factors reflect secondary alteration of splanchnic blood flow. Blood tests, US (including DUS and CEUS), CT, and magnetic resonance imaging (MRI) support the non-invasive assessment of PH by providing both hemodynamic and fibrotic information. Elastography, mainly USE, is the most important method of PH monitoring.
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fmed-09-960316 September 10, 2022 Time: 16:6 # 1
TYPE Review
PUBLISHED 15 September 2022
DOI 10.3389/fmed.2022.960316
OPEN ACCESS
EDITED BY
Lorenzo Ridola,
Sapienza University of Rome, Italy
REVIEWED BY
Ciro Celsa,
University of Palermo, Italy
Elton Dajti,
University of Bologna, Italy
*CORRESPONDENCE
Xiao Li
simonlixiao@gmail.com
Meng Niu
13998217255@163.com
These authors have contributed
equally to this work and share first
authorship
SPECIALTY SECTION
This article was submitted to
Hepatology,
a section of the journal
Frontiers in Medicine
RECEIVED 02 June 2022
ACCEPTED 22 August 2022
PUBLISHED 15 September 2022
CITATION
Sun X, Ni HB, Xue J, Wang S, Aljbri A,
Wang L, Ren TH, Li X and Niu M (2022)
Bibliometric-analysis visualization and
review of non-invasive methods for
monitoring and managing the portal
hypertension.
Front. Med. 9:960316.
doi: 10.3389/fmed.2022.960316
COPYRIGHT
© 2022 Sun, Ni, Xue, Wang, Aljbri,
Wang, Ren, Li and Niu. This is an
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the terms of the Creative Commons
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or reproduction is permitted which
does not comply with these terms.
Bibliometric-analysis
visualization and review of
non-invasive methods for
monitoring and managing the
portal hypertension
XiaoHan Sun1, Hong Bo Ni1, Jian Xue1, Shuai Wang1,
Afaf Aljbri1, Liuchun Wang1, Tian Hang Ren1, Xiao Li2*and
Meng Niu1*
1Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang,
China, 2Department of Interventional Therapy, National Cancer Center/National Clinical Research
Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, China
Background: Portal hypertension monitoring is important throughout the
natural course of cirrhosis. Hepatic venous pressure gradient (HVPG),
regarded as the golden standard, is limited by invasiveness and technical
difficulties. Portal hypertension is increasingly being assessed non-invasively,
and hematological indices, imaging data, and statistical or computational
models are studied to surrogate HVPG. This paper discusses the existing
non-invasive methods based on measurement principles and reviews the
methodological developments in the last 20 years.
Methods: First, we used VOSviewer to learn the architecture of this field.
The publications about the non-invasive assessment of portal hypertension
were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer
1.6.17.0 was used to analyze and visualize these publications, including the
annual trend, the study hotspots, the significant articles, authors, journals, and
organizations in this field. Next, according to the cluster analysis result of the
keywords, we further retrieved and classified the related studies to discuss.
Results: A total of 1,088 articles or review articles about our topic were
retrieved from WoSCC. From 2000 to 2022, the number of publications is
generally growing. “World Journal of Gastroenterology” published the most
articles (n= 43), while “Journal of Hepatology” had the highest citations. “Liver
fibrosis” published in 2005 was the most influential manuscript. Among the
20,558 cited references of 1,088 retrieved manuscripts, the most cited was a
study on liver stiffness measurement from 2007. The highest-yielding country
was the United States, followed by China and Italy. “Berzigotti, Annalisa” was
the most prolific author and had the most cooperation partners. Four study
directions emerged from the keyword clustering: (1) the evaluation based on
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fibrosis; (2) the evaluation based on hemodynamic factors; (3) the evaluation
through elastography; and (4) the evaluation of variceal bleeding.
Conclusion: The non-invasive assessment of portal hypertension is mainly
based on two principles: fibrosis and hemodynamics. Liver fibrosis is the
major initiator of cirrhotic PH, while hemodynamic factors reflect secondary
alteration of splanchnic blood flow. Blood tests, US (including DUS and
CEUS), CT, and magnetic resonance imaging (MRI) support the non-invasive
assessment of PH by providing both hemodynamic and fibrotic information.
Elastography, mainly USE, is the most important method of PH monitoring.
KEYWORDS
portal hypertention, bibliometric, elastography, non-invasive, VOSviewer
Introduction
Portal hypertension (PH), defined as portal pressure
gradient (PPG) or hepatic venous pressure gradient (HVPG)
> 5 mmHg, nearly 90% is cirrhotic PH, which belongs to
intrahepatic PH (1). Cirrhotic PH is the result of the growing
hepatic sinusoidal resistance and splanchnic blood flow.
Cirrhosis can be caused by various factors like viruses, alcohol,
drug, and fat, which lead to inflammatory necrosis and fibrosis
of hepatocytes. The nodular regeneration surrounded by a
dense fibrous septum and the dedifferentiation of capillary-like
hepatic sinusoids induced by chronic inflammation led to the
distortion and the high resistance of intrahepatic vessels (2,
3). In addition to the structural changes, chronic hepatitis
increases the intrahepatic vascular tone by reducing the
activity of vasodilative factors like NO (4). When portal
vein blood could not flow smoothly through the liver
to the inferior vena cava, the portal pressure rises and
stimulates the secretion of vasodilator in the splanchnic
blood vessels and the formation of collateral circulation,
neovascularization, and hyperdynamic state. In turn, it
exacerbates the hyperemia of splanchnic circulation and
portal hypertension (5). Overall, the intrahepatic factors
included collage deposition and the imbalance of vasodilation
and vasoconstriction, while the extrahepatic factor was
hyperdynamic circulation.
HVPG, the golden criterion to assess the presence and
severity of portal hypertension, is the difference between
wedge-shaped hepatic venous pressure (WHVP) and free
hepatic venous pressure (FHVP) (6). Grading of portal
hypertension in cirrhosis helps to stratify patients with a
poorer clinical course: HVPG >5 mmHg is associated
with chronic hepatitis progression and hepatitis recurrence
after liver transplantation (7,8); HPVG >10 mmHg
represents clinically significant portal hypertension (CSPH),
predicts the development of varices and ascites, and high
risk of decompensation and recurrence of liver cancer after
hepatectomy (913); HPVG >12 mmHg significantly increases
the risk of variceal bleeding (14); when HPVG >16 mmHg,
the risk of death was significantly increased (15). For cirrhotic
patients awaiting liver transplantation, for every 1 mmHg
increase in HVPG, the risk of death is increased by 3% (16).
Therefore, as outlined in the major clinical practice guidelines
(1720), the routine measurement of portal vein pressure
is of great significance for the management of the whole
course of liver cirrhosis, not only as an index to evaluate the
prognosis but also as an important basis to determine the
direction of treatment.
The high technical difficulty, high cost, invasiveness,
and low feasibility of multiple measurements restrict the
widespread clinic application of HVPG (21). Otherwise,
one study (22) in cirrhotic patients with non-alcoholic
steatohepatitis (NASH) shows that the consistency between
WHVP and portal pressure (PP) is poorer than in cirrhotic
patients with alcohol- or virus-related hepatitis, and HVPG
may underrate the level of PH in the NASH-related
cirrhosis. Although the studies (23,24) about endoscopic
ultrasound (EUS)-guided PPG measurement have proven its
accuracy compared to HVPG, which could directly obtain
PP with fewer injuries, EUS-guided PPG measurement
is still a high-risk operation with a great requirement
of equipment and technology. Hence, the non-invasive
detection of portal hypertension is necessary and urgent.
Based on the developing mechanisms of portal hypertension,
the indices of liver fibrosis, liver function, intrahepatic
endothelial dysfunction, inflammation, and intra- or extra-
hepatic hemodynamics have been assessed to substitute
HVPG. Moreover, the rapid rise of radiomics and artificial
intelligence (AI) revolutionarily changes the diagnosis and
management of liver disease, which can fully exploit the uses
of the information from routine imaging and serological
examinations. The increasing studies successfully estimate
the portal pressure by constructing a computer model with
superior performance.
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This article reviews the development of non-invasive
detection of portal pressure with the assistance of bibliometric-
analysis visualization and analyzes the current shortcomings and
future expectations, in hopes of the routine monitoring of PH
being a reality in the clinic.
Methods
On 8 April 2022, we retrieved a total of 1,209 records
(publication time from 2000 to 2022) on the Web of Science
Core Collection (WoSCC) by searching the term Topic (“portal
hypertension” or “Hypertension, Portal” or “portal pressure” or
“portal vein pressure” or “portal venous pressure”) AND Topic
(“non-invasive” or “non-invasive or “non-invasive”). A total of
121 meeting abstracts, editorial materials, letters, corrections,
and reprints were excluded. Approximately, 1,088 articles or
review articles were included in this study. The full record and
cited references of the 1,088 articles were exported in the format
of a plain text file. Figure 1 shows the process of data collection.
Next, the bibliographic data were imported to VOSviewer
1.6.17.0 to create analytic maps. VOSviewer was a feature-
rich bibliometric analysis tool, and the abundant bibliometric
information in WOS data made it play completely. The analytic
results were saved in the format of a figure and were exported to
Microsoft Office Excel 2021. The analysis of the trend of annual
publications and the rank of authors, regions, organizations,
journals, literature, and keywords were finished in Excel.
Based on keyword clustering, the four clusters inspired further
discussion of non-invasive methods for PH detection.
Results
Annual publication
Figure 2 shows that the number of published related articles
is increasing year by year. It started to rise rapidly in 2007,
and, since 2012, the number of published related articles has
stabilized at more than 60. At present, 2020 is the year with the
most published articles, with 99 articles in total.
Top 10 high-yielding journals
There were in total 306 journals of 1,088 searched pieces
of literature, and the top 10 high-yielding journals are listed in
Table 1, the 10 journals published the 25% retrieved literature,
of which, “Journal of Hepatology” and “Hepatology” were
the top 2 high-cited journals with citations of 4,920 and
2,663, respectively, while “World Journal of Gastroenterology”
published the most articles.
Top 10 high-cited documents
There were in total retrieved 1,088 documents, and the 10
documents in Table 2 were the highest cited. Among them,
the 4th and 7th were practice guidelines about the application
of ultrasound elastography and the non-invasive measurements
of liver disease; the 1st, 2nd, 3rd, 6th, and 9th were reviews
about liver disease and non-invasive measurements of liver
disease; the 5th, 8th, and 10th were articles about liver
stiffness measured by transient elastography (TE) and magnetic
resonance elastography (MRE), and platelet count/spleen
diameter in screening esophageal varices, respectively. Of the 10
publications, 3 were published by “Journal of Hepatology.”
Co-authorship of countries and
regions/organizations
Totally, of the 68 countries/regions of the 1,088 documents,
34 countries/regions met the requirement of 5 publications.
Of the 34 countries/regions, 32 countries/regions had
connections with others and constructed the network as
Figure 3A. The 32 countries/regions were divided into 5
clusters in different colors, the size of circles reflected the
publications of each region, and the size of lines reflected the
link strength between the two regions. The top 10 high-yield
regions are listed in Table 3. USA accounted for the most
publications, followed by China, which might enter the field
of PH non-invasive assessment relatively late but rapidly
developed. Moreover, according to the results of co-authorship,
the red cluster with the center of Italy (publications of 119),
France (publications of 113), and England (publications of 72)
was the largest (items of 11). The United States and France had
the most cooperation partners of 26.
Totally, of the 1,400 organizations, 100 organizations met
the restriction condition of publishing over 5 pieces of literature,
of which 91 organizations had connections and consisted of
the co-authorship network (Figure 3B). The 91 organizations
were grouped into 10 clusters, the size of circles reflected the
publications of each organization, and the size of lines reflected
the link strength between the two organizations. The red cluster,
which was made up of 21 organizations, was the largest one,
and “Mayo Clinic” is in the center. “University of Bologna (in
yellow Cluster 4) and “University of Bern” (in blue Cluster 3)
have the most cooperative organizations (n= 26). The top 10
high-production organizations are shown in Table 3.
Co-authorship of authors
In total, there were 5,779 authors of 1,088 pieces of literature;
130 authors met the threshold of over 5 publications, of which,
100 authors have a connection and composed the co-authorship
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FIGURE 1
Shows the main processes of data collection and screening and analysis.
FIGURE 2
Shows the number of articles published in different years in the field of non-invasive prediction of portal hypertension over a period of 22 years.
network as Figure 3C. The 100 authors were grouped into 10
clusters, the size of circles reflected the publications of each
author, and the size of lines reflects the cooperation strength
between the two authors. The red Cluster 1 with the center of
“berzigotti, annalisa” included 17 authors and was the largest
cluster; “berzigotti, annalisa” was also the highest-yield author
with 40 publications, had the most cooperation authors (n= 42),
and had a connection with other 7 clusters (except for yellow
Cluster 4 and pink Cluster 10). The top 10 high-yield authors
are listed in Table 4, and the highest-yield author of each cluster
is also listed in Table 5.
Co-citation of documents
In total, there were 20,558 references of 1,088 retrieved
pieces of literature, from 2,908 journals, having 13,108 first
authors. Of the 20,558 references, there were 309 references
cited over 20 times by the 1,088 retrieved literature. The
top 10 high-cited references are listed in Table 6. The 10
documents were all articles (no review) and are all cited
over 100 times. “Liver stiffness measurement predicts severe
portal hypertension in patients with HCV-related cirrhosis
published in 2007 was the highest cited (n= 254) and
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TABLE 1 Top 10 high-yielding journals.
Rank Journal Documents Account for Citations IF
1 World Journal of Gastroenterology 43 4% 811 5.742
2 Journal of Hepatology 39 4% 4,920 25.083
3 Liver International 31 3% 814 5.828
4 Hepatology 28 3% 2,663 17.425
5 European Journal of Gastroenterology and Hepatology 25 2% 363 2.566
6 Digestive and Liver Disease 23 2% 611 4.088
7 Ultrasound in Medicine and Biology 22 2% 763 2.998
8 Hepatology Research 21 2% 203 4.288
9 Journal of Ultrasound in Medicine 21 2% 315 2.153
10 Journal of Gastroenterology and Hepatology 20 2% 484 4.029
25%
TABLE 2 Top 10 high-cited documents.
Rank Title Journal Citations Pub. year References
1 Liver fibrosis Journal of clinical
investigation
3,605 2005 (135)
2 Liver cirrhosis Lancet 1,286 2008 (2)
3 Non-invasive evaluation of liver fibrosis using transient
elastography
Journal of Hepatology 939 2008 (136)
4 EASL-ALEH clinical practice guidelines: non-invasive
tests for evaluation of liver disease severity and
prognosis
Journal of Hepatology 861 2015 (137)
5 Liver stiffness measurement predicts severe portal
hypertension in patients with HCV-related cirrhosis
Hepatology 495 2007 (103)
6 Non-invasive methods to assess liver disease in patients
with hepatitis b or c
Gastroenterology 419 2012 (138)
7 WFUMB guidelines and recommendations for clinical
use of ultrasound elastography: part 3: liver
Ultrasound in medicine and
biology
393 2015 (139)
8 Magnetic resonance imaging more accurately classifies
steatosis and fibrosis in patients with non-alcoholic
fatty liver disease than transient elastography
Gastroenterology 381 2016 (140)
9 Complications of cirrhosis. I. Portal hypertension Journal of Hepatology 373 2000 (141)
10 Platelet count/spleen diameter ratio: proposal and
validation of a non-invasive parameter to predict the
presence of esophageal varices in patients with liver
cirrhosis
Gut 313 2003 (128)
was often co-cited with “Transient elastography accurately
predicts the presence of significant portal hypertension in
patients with chronic liver disease” (rank 8th) published
in 2008, “Liver stiffness measurement selects patients with
cirrhosis at risk of bearing large esophageal varices” (rank 7th)
published in 2006, and “Transient elastography for diagnosis
of advanced fibrosis and portal hypertension in patients
with hepatitis C recurrence after liver transplantation”
(rank 14th) published in 2006. Moreover, “Expanding
consensus in portal hypertension: Report of the Baveno VI
Consensus Workshop: Stratifying risk and individualizing
care for portal hypertension” (rank 2nd) was more
recent.
Co-occurrence of all keywords
There was a total of 2,806 keywords retrieved from 1,088
publications. Among them, 102 keywords occurred over 20
times and formed the network as Figure 4A. The keywords
density visualization map is shown in Figure 4B. The top 25
high-occurrence keywords are listed in Table 7. The order
of clusters depended on the number of keywords in each
cluster. The 102 keywords were divided into 4 clusters; the
most frequent keywords in Clusters 1, 2, 3, and 4 were “portal
hypertension, “esophageal varices, “fibrosis, and “transient
elastography fibroscan, respectively. According to the result
of the analysis, elastography based on ultrasound or magnetic
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FIGURE 3
Shows the research level and connections of different countries and regions, institutions, and researchers. (A) Shows the number of relevant
articles published in different countries and regions and the cooperation relationship. The size of the circle represents the number of articles
published, the number of lines represents the number of cooperation, and the thickness of the lines represents the closeness of cooperation.
(B) Shows the number of published articles and the cooperative relationship between different research institutions, and (C) shows the number
of published articles and the cooperative relationship between different researchers.
resonance accounted for the most important role in predicting
portal hypertension.
Co-occurrence overlayed with time
Figure 4C shows the development trend of keywords in
recent years. The timeline in the lower right corner of the picture
showed the years represented by different colors. As technology
advances, the research hotspots of researchers and research
institutions also change over time. It could be clearly seen from
the figure that the hotspots of the current research were transient
elastography fibroscan, liver and stiffness hardness, and stiffness
measurement, while Doppler ultrasonography was a relatively
old topic. This indicated that elastography still attracted the
major attention of researchers in this field today.
Discussion
Blue cluster 3: The evaluation of portal
hypertension based on fibrosis
Blue Cluster 3 consisted of 26 keywords shown in Figure 5A,
mainly about “the evaluation of portal hypertension based
on fibrosis.” In this cluster, the highest-occurrence word was
“fibrosis, and the studied populations included the patients
with “HCV” (occurrence of 275), “HBV” (occurrence of 57),
and “non-alcoholic fatty liver disease” (occurrence of 23).
The keywords “liver stiffness measurement” and “stiffness
measurement” worked as biomechanical indexes of fibrosis
to evaluate portal hypertension and would be addressed in
more detail in Cluster 4, while the keywords “biomarker,
“serum markers, “platelet ratio index, and “fibrotest” reflected
the application of biochemical markers to assess liver fibrosis
and portal hypertension, which is described in detail in
this part. Around this theme, we also further retrieved and
supplemented the information of other detecting methods based
on fibrosis.
Portal hypertension-related fibrosis included liver fibrosis
and spleen fibrosis, the former was the leading component
of PH, and the latter reflected the extrahepatic secondary
alterations caused by PH. This part mainly depicted
the PH evaluation based on liver fibrosis. Liver fibrosis
was characterized by the chronic inflammatory insult of
liver parenchyma and excessive collagen deposition and
was also accompanied by the occurrence of endothelial
dysfunction (25). Cirrhotic PH was determined by intrahepatic
collagen deposition, increased intrahepatic vascular tone,
and extrahepatic hyperdynamic circulation. Excessive
collagen accumulation was the major component of
portal hypertension (PH), accounting for 70–80% (26).
Therefore, evaluating PH based on the level of fibrosis was
rational and reliable.
Blood test
The indicators of liver function
The injury of liver parenchyma was the feature of
liver fibrosis, related liver function indices including single
platelet count (PLT), aspartate aminotransferase to alanine
aminotransferase (AAR) ratio, aspartate aminotransferase to
platelet count ratio index (APRI), fibrosis index based on 4
factors (FIB-4 consists of PLT, AST, ALT, and age), glutamyl
transpeptidase to platelet (GPR), King’s score (consists of
Age, AST, INR, and PLT), Lok score (consists of PLT, AST,
ALT, and INR), and the CSPH risk score (consists of ALB,
INR, and ALT) have been validated to evaluate PH. Using
HVPG 10 mmHg as the golden standard, the area under the
receiver operating characteristic curve (AUROC) of the above
indices to diagnose CSPH was 0.6–0.8 and hardly exceeds 0.8
(2729).
The indicators of collagen deposition
In addition to the above conventional biomarkers, the
more proprietary markers like increased osteopontin (OPN)
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TABLE 3 Top 10 high-yield countries and regions/top 10 high-production organizations.
Rank Countries/Regions Documents Citations Avg. Pub. Year Organization Documents Citations Avg. Pub. year
1 United States 169 10,561 2014.567 University of Barcelona 31 2,298 2012.83
2 China 144 2,284 2017.31 Hospital Clinic de Barcelona 29 2,922 2013.69
3 Italy 119 6,815 2013.303 University of Bologna 28 1,308 2014.25
4 France 113 6,807 2013.441 Mayo Clinic 27 1,333 2014.37
5 Japan 93 2,613 2013.835 Yonsei University 27 883 2013.577
6 Spain 90 8689 2013.966 Medical University of Vienna 26 801 2017.24
7 Germany 82 2747 2014.45 University of Bern 22 818 2018
8 England 72 2128 2015.268 University of Milan 19 909 2012.79
9 South Korea 60 2247 2015.068 Hopital Universitaire Beaujon 18 742 2015.529
10 Switzerland 40 1150 2017.8 University College London 18 410 2016.5
accompanying liver fibrosis have also been discussed (30).
Plasma OPN>80 ng/ml could detect CSPH with a sensitivity
of 75% and specificity of 63%, and plasma OPN>90 ng/ml
could detect HVPG 12 mmHg with a sensitivity of 71% and
specificity of 62%. Similarly, apelin secreted by activated hepatic
stellate cells showed the potency to predict CSPH with AUROC
of 0.962 (31).
A recent study (32) of NASH cirrhosis has shown that
the enhanced liver fibrosis (ELF) score correlates with HVPG
at values<20 mmHg. The ELF score includes three indices:
tissue inhibitor of matrix metalloproteinases (TIMP1), the
aminoterminal peptide of procollagen type III (PIIINP), and
hyaluronic acid (HA), which mainly reflects the stroma
deposition during liver fibrosis. ELF identified patients with
a high probability of CSPH with AUROC of 0.833; however,
the performance of ELF to detect HVPG > 20 mmHg is
unsatisfactory with AUROC of 0.677. Moreover, ELF could
also detect CSPH with AUROC of 0.884 in the patients
with recovered HCV after 12 months of sustained virological
response (33).
The indicators of endothelial dysfunction
An important determinant of increased intrahepatic
vascular resistance was endothelial dysfunction (34).
Asymmetric dimethylarginine (ADMA) is an endogenous
nitric oxide synthase inhibitor and a recognized mediator and
marker of endothelial dysfunction. A statistically significant
positive correlation was found between ADMA and portal
hypertension (R= 0.77, p<0.0001) in 2007, but missed
further study (35). One study (36) published in 2012 supported
that von Willebrand factor antigen (vWF-AG) released by
activated endothelial cells (ECs) had the potential to be a novel
biomarker to monitor PH. This study in 286 patients showed
that vWF-Ag was correlated with HVPG (R= 0.69, p0.0001)
and was independent of the Child-Pugh score prediction.
When the taken cut-off value of vWF-AG was 241%, the
positive predictive value of detecting CSPH was 87%, and the
negative predictive value was 80% (AUROC, 0.85). Another
study (37) combining vWF-AG and PLT (VITRO) reported
better detection of CSPH with AUROC of 0.86. Ding et al.
(38) conducted a meta-analysis on the relationship between
the vWF and portal hypertension. The results showed that the
serum vWF in the cirrhosis group with portal hypertension was
significantly higher than that in the non-portal hypertension
group, with a comprehensive sensitivity of 0.823 (95% CI:0.788,
0.855) and a binding specificity of 0.782 (95% CI:0.708, 0.845).
The diagnostic odds ratio was 18.347 (95% CI: 11.725, 28.708),
and the AUROC was 0.8896. Others, the meta-analysis by Zou
et al. (39) also proved that vWF was moderately correlated
with HVPG and performed well in the diagnosis of CSPH
and SPH in patients with cirrhosis. But EASL Clinical Practice
Guidelines considered that the validation studies of vWF were
still insufficient (40).
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TABLE 4 Top 10 high-yield authors.
Rank Author Documents Citations Avg. citations Avg. Pub. year
1 Berzigotti, Annalisa 40 2,172 54.3 2015.5
2 Castera, Laurent 23 3,690 160.4348 2013.739
3 Reiberger, Thomas 21 596 28.381 2018.1
4 Pinzani, Massimo 19 1,963 103.3158 2014.5
5 Bosch, Jaime 17 1,509 88.7647 2013.118
6 Abraldes, Juan G. 16 1,140 71.25 2013.313
7 Festi, Davide 16 727 45.4375 2017.188
8 Mandorfer, Mattias 15 365 24.3333 2019
9 Ehman, Richard L. 14 1,025 73.2143 2014.357
10 Procopet, Bogdan 14 902 64.4286 2015.429
TABLE 5 The highest-yield author of each cluster.
Cluster Author Documents Citations Avg. citations Avg. Pub. year
1 Berzigotti, Annalisa 40 2,172 54.3 2015.5
2 Reiberger, Thomas 21 596 28.381 2018.1
3 Pinzani, Massimo 19 1,963 103.3158 2014.5
4 Ehman, Richard L. 14 1,025 73.2143 2014.357
5 Castera, Laurent 23 3,690 160.4348 2013.739
6 Sporea, Ioan 11 634 57.6364 2015.182
7 Han, Joon Koo 9 383 42.5556 2016.111
8 Qi, Xiaolong 7 87 12.4286 2019.333
9 Procopet, Bogdan 14 902 64.4286 2015.429
10 Kleiner, David E. 7 171 24.4286 2016.571
The indicators of inflammation
Inflammation was an initiating and accompanying factor of
liver fibrosis, and the study (41) in 90 cirrhotic patients proved
the significant correlation between PH and inflammatory
biomarkers, including IL-1b, IL-1Ra, Fas-R, and VCAM-1, and
construct a paradigm based on TNFb, HSP-70, alcohol use, and
Child-Pugh Class B, which could screen HVPG <12 mmHg
with the accuracy of 86%, however, performed poorly in
diagnosing HVPG 12 mmHg with AUROC of 0.767.
Under the stimulation of long-term inflammation, liver
macrophages would be activated to varying degrees (42).
CD163, a scavenger receptor expressed only in monocytes
and macrophages, was upregulated and entered the blood
circulation as soluble CD163 (sCD163) under macrophage
proliferation and activation conditions (43). During cirrhosis,
Kupffer cells were also activated in patients with cirrhosis and
portal hypertension. They showed more than three times the
concentration of sCD163 in patients compared with the control
group (median, 5.22 mg/L vs. 1.45 mg/L, p0.001) (44). On this
basis, Grønbaek et al. (45) measured sCD163 concentrations,
HVPG values, cardiac output (CO), cardiac index, and systemic
vascular resistance (SVR) in 81 cirrhotic patients (26 Child
A patients, 29 B patients, and 26 C patients) and 22 healthy
subjects. When the concentration of sCD163 reached 5 mg/L,
HVPG increased sharply, with an asymptote of 22 mmHg.
When the concentration of sCD163 increased further, HVPG
did not increase. The results suggested that sCD163 was an
independent predictor of HVPG. Sandahl et al. (46) predicted
portal hypertension by combining sCD163 values with the ELF
score. The AUROC of HVPG >10 mmHg predicted by a single
indicator was about 0.80, and the combined score optimized
by logistic regression analysis improved the AUROC to 0.91
in the test cohort and 0.90 in the validation cohort. These
results indicated that the combination of macrophage activation
marker sCD163 and collagen accumulation markers could
predict significant portal hypertension with higher accuracy.
The changes and shifts of intestinal flora caused by
cirrhosis and portal hypertension had always been a research
hotspot, but this phenomenon had not been thoroughly
analyzed in PH. A recent study from 2022 (47) has shown
that the circulating plasma microbiota profile of cirrhotic
patients was significantly different from that of the control
group, characterized by rich Comamonas,Cnuella, Dialister,
Escherichia/Shigella, and Prevotella, but poor Bradyrhizobium,
Curvibacter,Diaphorobacter,Pseudarcicella, and Pseudomonas.
There was no significant difference in peripheral and hepatic
venous blood in patients with cirrhosis. Concentrations of
Bacteroides,Escherichia/Shigella, and Prevotella were found
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TABLE 6 The top 10 high-cited references.
Rank First author Title Journal Year Citations
1 Vizzutti, Francesco Liver stiffness measurement predicts severe portal
hypertension in patients with HCV-related
cirrhosis
Hepatology 2007 254
2 de Franchis, Roberto Expanding consensus in portal hypertension:
Report of the Baveno VI Consensus Workshop:
Stratifying risk and individualizing care for portal
hypertension
Journal of Hepatology 2015 209
3 Wai, Chun Tao A simple non-invasive index can predict both
significant fibrosis and cirrhosis in patients with
chronic hepatitis C
Hepatology 2003 190
4 Sandrin, Laurent Transient elastography: a new non-invasive
method for assessment of hepatic fibrosis
Ultrasound in Medicine and
Biology
2003 179
5 Colecchia, Antonio Measurement of spleen stiffness to evaluate portal
hypertension and the presence of esophageal
varices in patients with HCV-related cirrhosis
Gastroenterology 2012 167
6 Castera, Laurent Prospective comparison of transient elastography,
Fibrotest, APRI, and liver biopsy for the
assessment of fibrosis in chronic hepatitis C
Gastroenterology 2005 164
7 Kazemi, Farhad Liver stiffness measurement selects patients with
cirrhosis at risk of bearing large esophageal varices
Journal of Hepatology 2006 157
8 Bureau, Christophe Transient elastography accurately predicts
presence of significant portal hypertension in
patients with chronic liver disease
Alimentary Pharmacology
and Therapeutics
2008 151
9 Giannini, Edoardo Giovanni Platelet count/spleen diameter ratio: proposal and
validation of a non-invasive parameter to predict
the presence of esophageal varices in patients with
liver cirrhosis
Gut 2003 144
10 Ziol, Marianne Non-invasive assessment of liver fibrosis by
measurement of stiffness in patients with chronic
hepatitis C
Hepatology 2005 144
FIGURE 4
The co-occurrence analysis of keywords occurred over 20 times. (A) Shows the number of times the keywords appear and how they relate to
one another. The size of the circles indicates how often they appear, the lines between the circles indicate how connected they are, and the
thickness of the lines indicates how close the relationship is. (B) Shows the current research hotspots in keywords, and the red circles represent
the research hotspots. (C) The color of the timeline in the lower right corner represents the year in which the keywords appeared.
in patients with severe portal hypertension (SPH). Another
study (48) had shown that short-chain fatty acids (SCFAs), a
derivative of intestinal microorganisms involved in maintaining
the integrity of the intestinal barrier and the host immune
response, had a negative correlation with HVPG values. The
blood level of SCFA in patients with cirrhosis showed an
overall trend of decline. Although the composition of circulating
microorganisms could not predict the severity of PH at present,
it might be studied as a future direction of research.
In general, routine blood tests were minimally invasive,
convenient, and reproducible; however, the PH predictive
accuracy of these biomarkers did not meet the clinical need, and
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TABLE 7 Top 25 high-occurrence keywords.
Rank Label Cluster Occurrences Avg. Pub. year
1 Portal hypertension 1 744 2014.951
2 Cirrhosis 1 557 2014.846
3 Transient elastography fibroscan 4 461 2015.653
4 Fibrosis 3 400 2015.463
5 Non-invasive 4 389 2015.479
6 Esophageal varices 2 298 2015.449
7 HCV 3 275 2014.434
8 Diagnosis 2 246 2014.284
9 Liver stiffness 4 138 2016.587
10 Disease 3 132 2014.385
11 Spleen stiffness 4 131 2017.177
12 Ultrasound 1 131 2013.74
13 Elastography 4 130 2017.242
14 Risk 2 119 2016.931
15 Stiffness measurement 3 119 2015.496
16 Liver cancer 3 113 2015.67
17 MRE 4 111 2016.418
18 Venous-pressure gradient 4 110 2015.43
19 Management 2 104 2015.748
20 Predict 2 97 2014.691
21 Shear wave elastography 4 95 2018.297
22 Liver 1 91 2015.067
23 Liver stiffness measurement 3 87 2015.279
24 Biopsy 3 83 2013.317
25 Gastroesophageal varices 2 74 2016.493
they were easy to be affected by the various systemic disease. As
suggested by EASL Clinical Practice Guidelines and Baveno VII
(17,40), serum markers solely were insufficient to detect PH but
could work as a complement.
Computed-tomography: Liver surface nodularity
In addition to the biochemical markers, CT and magnetic
resonance imaging (MRI) could also assess the level of fibrosis
through related morphological features, and then evaluate PH.
Liver surface nodularity (LSN) has been proven to differentiate
cirrhotic from non-cirrhotic livers with AUROC = 0.929 (49).
Based on the high correlation between liver fibrosis and
PH, Sartoris et al. (50) showed the probability to evaluate
PH by quantifying LSN in CT images. According to the
CT images on the portal venous phase, the LSN score
was calculated by measuring the roughness of the real liver
margin using a smooth polynomial line that delineated the
normally assumed surface margin of the left liver. The LSN
scores of patients with CSPH were higher than that of non-
CSPH patients (3.2 ±0.6 vs. 2.4 ±0.3; p<0.001) and
correlated with HVPG (r= 0.75, p<0.001). When the
LSN scores cutoff value of 2.8 was used to detect CSPH,
the positive predictive value was 88%. The AUROC of LSN
scores was 0.88 ±0.03, which was higher than most blood
tests. LSN scores could also be obtained from MRI, and
the result was similar (51). But the sample size of the two
studies was small.
Magnetic resonance imaging-mapping
In 2014, MR T1 mapping of the liver was firstly reported to
provide high diagnostic accuracy in the non-invasive assessment
of liver fibrosis (52). Extracellular volume fraction (ECV)
was a measure of the extracellular space and represented the
percentage of the volume of non-cellular tissue. T1 values
could be measured before and after the extracellular contrast
agent was given to calculate the extra computed extracellular
volume (ECV) (53). In 2018, Luetkens et al. (54) designed
animal studies to validate the non-invasive assessment of liver
fibrosis and portal hypertension by evaluating MRI T1 and T2
positioning techniques. Results showed that T1 and T2 values
were significantly higher in the bile duct ligation (BDL) model
and carbon tetrachloride (CCl4) intoxication than in the control
group (p<0.001). ECV values showed the same trend. The
results showed a high correlation between ECV and portal
hypertension (BDL: r= 0.54, p= 0.003; CCl4: r= 0.39, p= 0.043).
Subsequently, clinical data by Mesropyan et al. (55) showed that
splenic ECV correlated with portal pressure (r= 0.72; p<0.001)
and directly with HVPG (r= 0.50; p= 0.003), and had a good
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FIGURE 5
The four clusters of the 102 keywords occurred over 20 times. The size of frames represented the occurrence times of the keywords, and the
line thickness indicated the link strength between the keywords at either end. Panel (A) is Cluster 3 about the evaluation of portal hypertension
based on fibrosis. This cluster included 26 keywords, and “fibrosis” was the highest frequency. The keywords relating to the method of PH
evaluation were “liver stiffness measurement,” “fibrotest,” “stiffness measurement,” “biomarker,” “serum markers,” and “platelet ratio index.” Panel
(B) was Cluster 1 about the evaluation of portal hypertension based on hemodynamic factors. There were 30 keywords, and “portal
hypertension” was the highest frequency. The referred indices included “blood-flow,” “hemodynamics” and “ascites,” and referred methods were
“ultrasound,” “Doppler ultrasonography,” “contrast-enhanced ultrasound,” “computed-tomography” (CT), and “MRI.” Panel (C) was Cluster 4
about the evaluation of portal hypertension through elastography. There were 20 keywords and “transient elastography fibroscan” was the
highest frequency. Elastography could be divided into “ultrasound elastography” and “MRE,” and “transient elastography fibroscan” was the most
commonly used method of “ultrasound elastography.” Panel (D) Was Cluster 2 about the evaluation of portal hypertension-induced variceal
bleeding. There were 26 keywords and “esophageal varices” was the highest frequency. This cluster is also referred to “platelet count” and
“count/spleen diameter.”
diagnostic effect for CSPH (AUC = 1.000). In the validation
cohort, the diagnostic performance of mapping parameters was
comparable. Splenic ECV has a good predictive value for portal
hypertension in patients with advanced liver disease.
Artificial intelligence/computational model
Artificial intelligence and machine learning, which seem
to have nothing to do with medicine, have been gradually
changing clinical diagnosis and treatment by fully utilizing
the information from routine imaging, serological, and other
examinations. Bosch et al. (56) conducted a study to
measure portal pressure in patients with NASH cirrhosis
using machine learning (ML). The results showed that the
identification ability of the model was higher than that
of liver collagen (AUROCs in the test set:0.76 vs. 0.65)
and similar to the ELF score (AUROC, 0.78) when used
alone. The ML model could identify fibrous matrix features
associated with increased portal pressure. Furthermore, the
complete model combining the ML model with the conventional
clinical parameters (ELF, platelet, AST, bilirubin, APRI,
and FIB-4) improved the performance of the ML HVPG
score in detecting CSPH (AUROC of the test set ranging
from 0.81 to 0.85). However, in the case of higher portal
pressure, the correlation between the algorithm and HVPG
was weak. The ML HVPG score did not predict clinical
events at the baseline, possibly due to the ML algorithm’s
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inability to distinguish between portal pressure levels above
the CSPH threshold.
In summary, the ML algorithm could identify fibrous
matrix features and correlate with HVPG measurements. In
addition to morphology-based features, texture features and
deep convolutional neural network-based imaging analysis also
showed a potential performance in assessing PH (28,57).
However, due to the end-to-end nature of the model, specific
features that helped improve diagnostic performance could
not be elucidated.
Red cluster 1: The evaluation of portal
hypertension based on hemodynamic
factors
Red Cluster 1 includes 30 keywords shown in Figure 5B
mainly about “the evaluation of portal hypertension based
on hemodynamic factors, the mentioned methods included
“ultrasound, “Doppler ultrasonography” (DUS), “MRI,
“computed-tomography” (CT), and “contrast-enhanced
ultrasound” (CEUS), which could monitor the blood flow of
portal system directly or through the phase change of contrast.
CEUS was relatively recent, and its average publication year was
2016.
The PH assessment methods based on fibrosis and
hemodynamics were not completely separate, as hemodynamic
indices like hepatic perfusion could also be used to evaluate the
level of liver fibrosis. PH-related hemodynamic factors include
intrahepatic and extrahepatic blood flow, the former mainly
included portal vein, hepatic vein, and hepatic artery; while
the latter included splenic vein, renal artery, and collateral
circulations. US, CT, and MRI could provide static indices
as vessel diameter and dynamic indices as flow velocity to
reflect portal pressure. Moreover, ascites, spleen sclerosis,
and splenomegaly could also be regarded as extrahepatic
hemodynamic factors.
Blood test
Although imaging was the most common method of
estimating blood flow, blood tests like the filtration test of
indocyanine green (ICG) and cholate could also reflect the status
of hepatic blood flow, which worked as the contrast in imaging.
The ICG retention test was first used to evaluate the residual
liver function before hepatectomy and was determined by the
liver secretory function and liver blood flow (58). In 2014, one
study (59) suggested the indocyanine green 15-min retention
(ICG-r15) test as a non-invasive method of monitoring PH. To
exclude the effect of impaired liver function, all 96 participants
were in the child grade A (74 with clinically significant CSPH
and 59 with SPH); ICG-r15 values 16.7% and 18.4% could
detect CSPH and SPH, respectively, with the high specificity
of 90.9 and 91.9% but with relatively low sensitivity of 60.8
and 62.7% (AUROC, 0.808 and 0.821). The same authors
also conducted prospective studies to demonstrate that ICG-
r15 was significantly related to PH and could predict the
occurrence of hepatic decompensation (60). Another research
(61) further studied the application of ICG-r15 in patients
with different child grades and found that the child grade did
impact the diagnostic power of ICG-r15. In Child A, ICG-r15
was more correlated with CSPH than in Children B and C
(AUROC, 0.832 vs. 0.7448 vs. 0.7392). Moreover, the previous
research had found that the PH of alcohol-related cirrhosis was
higher than that of virus-related cirrhosis with similar residual
liver function. A recent study (62) in the cirrhotic patients
of Children A and B has shown that the ICG-r15 level was
correlated with portal pressure in both non-viral cirrhosis and
viral cirrhosis, which could detect HVPG 12 mmHg with the
specificity of 79.0% and sensitivity of 72.3% (AUROC, 0.780).
Cholate, similar to ICG, was high hepatic extraction, and
its extraction was determined by hepatic blood flow instead
of hepatic metabolism (63). The more recent HepQuant
SHUNT trial has used double clearance of cholates after oral
and intravenous administration to quantify hepatic perfusion
without the effects of total plasma volume. A study (29) of
early clinical compensatory chronic liver disease in 42 patients
found that patients with portal hypertension had lower portal
hepatic filtration rates and higher portal-systemic spillover of
oral d4-cholate percentage (SHUNT%), which presented the
increasing portal-systemic flow and the decreasing intrahepatic
flow. When evaluated CSPH, using HVPG >10 mmHg or
direct portal pressure (dPP) >22 mmHg as gold standards,
the sensitivity and specificity of SHUNT% >0.35 was 76.9 and
89.6%, respectively. Another key finding was that SHUNT% was
able to detect portal hypertension early in the course of disease
in patients without cirrhosis, as SHUNT% >0.295 could detect
HVPG >5/dPP >17 mmHg, with the sensitivity of 85.7% and
specificity of 80.9%. This indicated that HepQuant SHUNT trial
results were significantly positive at portal pressure 5 mmHg.
The non-invasive Hepquant SHUNT assay, either alone or
in combination with other non-invasive tests, could be an
alternative to existing invasive methods for assessing portal vein
pressure and hypertension.
Although the principle was similar to ICG, there was
no comparison between the HepQuant SHUNT test and
ICG-R15 in predicting portal pressure. Additionally, the
relatively complicated and costed blood tests, such as ICG-
r15 and HepQuant SHUNT tests, required larger confirmatory
studies to check the cut-offs and the feasibility in different
clinical scenarios.
Doppler ultrasonography and
contrast-enhanced ultrasound
The introduction of Doppler ultrasound (DUS) was an
important breakthrough in evaluating organ hemodynamics
(64). DUS was used early as a non-invasive tool to predict portal
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hypertension, which could provide real-time hemodynamic
information, like (i) the velocity of the portal vein (), splenic
vein (), and azygos vein (), (ii) resistive or pulsatility indices
of the hepatic artery (), splenic artery (), and renal artery (),
and (iii) hepatic vein waveform/hepatic vein waveform damping
index (65). As early as 1997, researchers found that the hepatic
vascular index (portal vein velocity/hepatic arterial pulsatility
indices) was a highly sensitive and specific DUS parameter for
diagnosing liver cirrhosis and portal hypertension, and liver
cirrhosis and portal hypertension could be identified when the
hepatic vascular index was less than 12 cm/s (66). Berzigotti
et al. (67) examined the correlation between renal vascular
impedance measured by pulsed DUS and portal pressure
measured by HVPG in patients with cirrhosis and found that, in
cirrhotic patients with normal renal function, high impedance
of renal vasoconstriction could be considered an indication
of HVPG 16 mmHg, although CSPH might have normal
renal atrial resistance. Routine examination of renal vascular
impedance in patients with cirrhosis might help non-invasively
identify a group of patients with portal hypertension at high
risk for complications. Berzigotti et al. also found that the
emergency abdominal collaterals examined by DUS could detect
HVPG 16 mmHg with a sensitivity of 57% and a specificity of
87%. They also evaluated the prognostic value of a single HVPG
measurement and DUS in patients with cirrhosis and CSPH.
Although HVPG had a strong and independent predictive value
for mortality and first decompensation in patients with cirrhosis
and CSPH, DUS to examine abdominal vessels still had a high
positive predictive value (68). Another hepatic vein waveform,
reflecting the change of central venous pressure during the
cardiac cycle, should be a normal triphasic waveform. The
portal-hepatic vein shunts accompanying portal hypertension
could cause the flattening of the hepatic vein waveform. A study
(69) found a correlation between the abnormal hepatic venous
waveform and HVPG in patients with liver cirrhosis. There
were 44 cases (56%) having biphasic waveforms, 28 (36%)
having monophasic waveforms, and 6 (8%) having triphasic
waveforms. The monophasic waveform was associated with
HVPG >15 mmHg, with a sensitivity of 74% and a specificity of
95%. Furthermore, the damping index (DI), equaling minimum
velocity divided by the maximum velocity of the hepatic
vein waveform, was a quantitative index of the hepatic vein
waveform. DI >0.6 could detect HVPG >12 mmHg, with a
sensitivity of 75.9% and a specificity of 81.8% (70).
Contrast-enhanced ultrasound (CEUS) with microbubbles
improved the imaging quality of the US with a higher
signal-to-noise ratio. When the ultrasound pulse reached
the microbubbles, the microbubbles resonated and scattered
the fundamental wave, subharmonics, second harmonics, and
superharmonics, and the harmonics created contrast imaging
with tissue echoes. Among these harmonics, the second
harmonic was the strongest signal (71). The hemodynamic
indices of CEUS could be divided into two types: (i) the
transit time of microbubbles and (ii) the size change of
the microbubbles. Berzigotti et al. (72) validated the inverse
correlation of regional hepatic perfusion (RHP, as microbubbles
velocity ×microbubble concentration) and effective perfusion
of the liver, which proved that RHP increased primarily through
intrahepatic shunts caused by PH. Studies using CEUS to
assess portal pressure have been carried out on this basis.
Kim et al. (73) explored the correlation of HVPG and hepatic
vein arrival time (HVAT, transit time from venous injection
to arriving hepatic vein) in 71 consecutive patients with
compensated cirrhosis (derivation set) and validated it in 35
patients of another medical center (validation set). For CSPH,
the sensitivity and the specificity of HVAT <14 s were,
respectively 92.7 and 86.7%. In the validation set, HVAT was
still highly correlated with HVPG; the AUROC of detecting
CSPH was 0.953. The study by Jeong et al. (74) showed
that intrahepatic transit time was significantly reduced in the
SPH group (HVPG 12 mmHg) compared to the non-SPH
group. ITT 6 s could indicate HVPG 12 mmHg with
a sensitivity of 92% and a specificity of 89%. Moreover, the
CEUS parameter about splenic circulation was also evaluated to
assess PH based on the increasing resistance of splenic vessels
following PH. A study (75) in 62 patients with liver cirrhosis and
29 patients in the control group found that peak enhancement
time (PET, transit time from onsetting in splenic artery to
reaching maximum intensity in splenic vein) could also identify
HVPG 10 mmHg and 12 mmHg with AUROC of both 0.76.
The received intensity of the ultrasound signal was
determined by transmitting pulses and microbubble scatter
areas. Due to the compressibility of a microbubble, ambient
pressure could change its size and scatter area. Hence, the
change of harmonic amplitude could reflect ambient pressure,
and the subharmonic was the most sensitive harmonic (76).
Based on the above, subharmonic-aided pressure estimation
(SHAPE, the mean subharmonic signal in the hepatic vein
minus that in the portal vein) was used to evaluate PH. In
2013, Eisenbrey et al. (77) conducted a pilot study of SHAPE
in 33 patients with chronic hepatitis. They validated the good
correlation of SHAPE and HVPG (r= 0.82), and the correlation
was greater (r= 0.97) when HVPG 12 mmHg (n= 6). In
2021, a larger-scale clinical study in 125 patients with chronic
hepatitis of various etiologies was carried out by Gupta et al.
(78). Compared to the pilot study, the correlation decreased
(r= 0.68), and the correlation was lower (r= 0.41) when the
HVPG 12 mmHg (n= 14), which was contradictory and
possibly because of the low sample size or the changed transmit
pulses. Nonetheless, SHAPE 0.11 dB could discriminate
HVPG 10 mmHg with sensitivity of 91% and specificity of
82% and discriminate HVPG 12 mmHg with sensitivity of
90% and specificity of 80%.
Generally, although DUS was easy to use and could acquire
data in real-time with non-invasiveness, it was not easy to
measure due to the influence of fat, ascites, and the depth of
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targeted vessels. Low accuracy, large variability, and a certain
failure rate of DUS limited the prediction of PH. Hence, the
study of single parameters of DUS has been less and less in
recent years, while CEUS emerged as the updated way, which
could provide clearer and more accurate signals. SHAPE was
a special and novel application of CEUS and was suggested to
do further validation by the Baveno VII. But CEUS was limited
by the availability of contrast agents and is still not available in
some countries. The dynamics and metabolism of microbubbles
in vivo had not been fully studied, and the interpretation of
the contrasting results also required further study (79). Besides,
CEUS still has the inherent disadvantages of the US and needs
more validation research.
Computed-tomography
Recently, an increasing number of studies have explored,
applying CT or MRI to assess PH. CT or MRI could provide
both the hemodynamic and morphological information, which
was more stable and consistent than that provided by the
US. Moreover, compared with the point information measured
by the US, CT, and MRI could provide the hemodynamic
information of the total portal system.
In 2014, Iranmanesh et al. conducted a study (80) on
65 patients with hepatocellular carcinoma (HCC) and showed
that the liver/spleen volume ratio and peri-hepatic ascites in
contrast-enhanced multi-detector CT were good predictors for
PH. The statistical models based on these two indices, HVPG
score = 17.37–4.91 ×ln (Live/Spleen volume ratio) + 3.8 (if with
peri-hepatic ascites), were proved to predict HVPG >10 mmHg
with a sensitivity of 92% and specificity of 79% (AUROC, 0.911),
when the cut-off was 11.606. Furthermore, in the validation set
of 70 patients (the number of HCC patients was 24), the HVPG
score could still assess PH with an AUROC of 0.820. Afterward,
there were other studies about non-invasive methods of PH
monitoring using this model as the control, and the AUROC of
the HVPG score in these studies was <0.8 (50,81). Qi et al. (82)
validated this model in 131 patients with HBV-related cirrhosis
and concluded that the HVPG score was not enough to diagnose
CSPH with AUROC of only 0.568. Iranmanesh explained that
the difference in AUROC might be caused by the higher HVPG
in Qi’s study (HVPG: 16.58 ±5.84 mmHg vs. 11 ±6 mmHg),
and their model was more accurate when HVPG was around
10 mmHg (83). Overall, the HVPG score based on CT was
unsatisfactory in the external validation and was not widely
applicable to patients with varying degrees of PH.
Magnetic resonance imaging
In 2003, flow parameters measured by MRI had been
studied to evaluate portal hypertension and were compared
with DUS (84). Due to the inherent advantages of lower intra-
and inter-observer variability, an increasing number of studies
have focused on evaluating PH by using blood flow parameters
measured by MRI instead of DUS in the recent past.
A study (85) in 30 patients with mean HVPG = 9.8 mmHg
constructed a PH prediction model, combining hemodynamic
information with liver fibrotic information measured by MRI.
Based on the prior validation of the correlation between
liver T1 relaxation time and liver fibrosis, this study found a
good correlation between splenic artery velocity and HVPG
and concluded that the best predictive model for HVPG was
28 + 0.04(liver spin-echo echo-planar imaging T1) + 0.27
(splenic artery velocity). The calculated HVPG value based
on this model kept a significant correlation with real HVPG
(R= 0.85), and in the validation set with 10 patients still
kept a high correlation. More recently, Hectors et al. (86) have
collected information on 35 patients with cirrhosis measured
by HVPG and examined using gadoxetate dynamic contrast-
enhanced (DCE) MRI imaging of the liver and the spleen
to investigate its potential for diagnosing portal hypertension.
Liver ki (the intracellular uptake rate) showed the best diagnostic
performance, with AUC, sensitivity, and specificity of 0.74,
71.4, and 78.6%, respectively. The combination of liver ki and
spleen ve (Interstitial volume fraction) was the best method for
diagnosing CSPH with an AUC of 0.87.
Besides, the velocity of azygos, hepatic arterial fraction
of total liver blood flow, and portal vein hyperintensity on
20-min delayed T1 contrast-enhanced MRI observed by two-
dimensional (2D) or three-dimensional (3D) MRI have also
proved the correlation with HVPG (8789), and azygos blood
flow could detect HVPG 16 mmHg with AUROC of 0.96,
while other indices lacked the further tests to validate their
diagnostic performance.
Time-resolved 3D PC MRI with 3D flow velocity encoding
referred to as 4D flow MRI allowed for the comprehensive
in vivo measurement of 3D blood flow dynamics in the
heart and the large vessels (90). Bane et al. (91) assessed 4D
flow parameters for predicting the presence of cirrhosis/PH
and the severity of the liver disease. The Spiral 4D flow
provides a comprehensive assessment of the abdominal
blood vessels in a single breath-holding activity and has
considerable interobserver repeatability, but variability tests
retest repeatability. Motosugi et al. (92) showed that azygos
flowing greater than 0.1 L/min and portal vein flowing less than
the sum of the splenic vein and superior mesenteric vein flow
were useful markers of gastroesophageal variceal bleeding risk
in patients with cirrhosis. Although 4D flow MRI has unique
advantages, it still faces some problems in clinical applications.
The first problem is that detection takes too long, such as
10–20 min for respiratory and cardiac Cartesian acquisition,
which is the main reason preventing its clinical application
(93). The second technical limitation of 4D flow is its need
for a preset VENC parameter for measurements in all vessels
captured within the acquisition volume. The VENC for 4D flow
collection must be set according to the clinical problem being
investigated, and multiple collections of different VENCs are
required (94).
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Artificial intelligence/computational model
In 2015, Amat-Roldan et al. (95) constructed a
computational graph model of hepatic vascular network
connectivity based on the imaging of CEUS in the right liver
lobe. Due to the good capability of CEUS in microvessel
imaging, this graph model could detect PH by reflecting the
difference in the intrahepatic vascular network between normal
and PH participants. In a healthy set (n= 4) with strong
vascular network connectivity, the clustering coefficient was
0.4447; while, in the set with HVPG 10 mmHg (n= 11), the
clustering coefficient was 0.0237. The correlation coefficient
between the predicted HVPG of this model and measured
HVPG was greater than 0.8. Xiao Long Qi and his team
proposed an interesting idea (81), that was, to establish and
validate a computed model of the HVPG based on CT vascular
images, namely, virtual HVPG (v-HVPG), to achieve a non-
invasive diagnosis of portal hypertension in liver cirrhosis. In
brief, DUS and CT angiography were used to create a virtual
HVPG based on a 3D reconstruction model and computational
fluid dynamics. Using the original CT angiography images, a
3D model of the liver portal system was reconstructed from the
2D composite image and surrounding tissues, analyzed using
the computational fluid dynamics solver ANSYS 13.0 (Ansys,
Canonsburg, Pa), and meshed with inner tetrahedra. Portal
venous velocity was measured by DUS, with portal venous
velocity as the boundary condition. After that, finite element
analysis and computational fluid dynamics analysis were used
to calculate the pressure distribution of the 3D model. The
average time to calculate the virtual HVPG was about 2.5 h,
of which 1.5 h was spent on human processing and 1 h was
spent on machine calculations. Results showed that, in the
training cohort (n= 29), the AUROC of v-HVPG in predicting
CSPH was 0.83. In the validation cohort (n= 73), diagnostic
performance was prospectively confirmed with an AUROC of
0.89. The inter- and intra-observer agreement was 0.88 and
0.96, respectively, indicating good reproducibility of virtual
HVPG measurements.
Yellow cluster 4: The evaluation of
portal hypertension through
elastography
Yellow Cluster 4 consists of 20 keywords shown
in Figure 5C, mainly about “the evaluation of portal
hypertension through elastography.” Elastography was
also based on fibrosis, so the locations of items in Cluster
4 and Cluster 3 were interleaved. Due to the great role
in predicting portal hypertension and the large body
of the related studies, elastography became a separate
cluster. Elastography could be divided into “ultrasound
elastography” (USE) and “MRE, whose measure targets
included “liver stiffness” and “spleen stiffness.” In USE, the
“transient elastography fibroscan” was the most commonly
used method, and “acoustic radiation force impulse (arfi),
including pSWE and 2D-SWE, was more recent than transient
elastography.
Ultrasound elastography
Similarly, based on the relationship between liver fibrosis
and PH, liver stiffness measurement (LSM) was the best
recognized and the most widely used method to surrogate
HVPG. The past study (96) had supposed to apply liver
stiffness measured by transient elastography (TE) to evaluate
PH more than a decade ago. After that, a series of studies
focused on validating the feasibility and accuracy of LSM in
different clinical settings, and a meta-analysis in 2017 showed
that LSM with TE could detect CSPH with AUROC >0.9
(97). Moreover, with the advancement of technology, point
shear wave (pSWE) and two-dimensional real-time shear wave
elastography (2D-SWE) emerged as a novel USE and were
also validated to predict PH. Compared to TE, pSWE and
2D-SWE allowed flexibility in selecting the measured position
and depth, and the region of interest (ROIs) of 2D-SWE was
larger than that of TE and pSWE. However, in terms of the
performance to discriminate liver fibrosis and PH, pSWE and
2D-SWE did not generally unfold the superiority (98). Due
to the LSM of TE having the most studied data, the Baveno
VI consensus firstly suggested that, in patients with virus-
infected compensated advanced chronic liver disease (cACLD),
LSM 20–25 kPa in TE could be regarded as CSPH. In
contrast, patients with cACLD with other etiologies of PH
required additional explanation (99). In addition, in the latest
Baveno VII, LSM 25 kPa in TE of patients cACLD with virus
hepatitis, alcohol-hepatitis, and NASH with BMI <30 kg/m2
could be diagnosed as CSPH (17). Under the condition of the
same LSM level, patients with NASH with BMI 30 kg/m2
showed a higher false-positive rate with a positive predictive
value (PPV) of only 62.8%, which might derive from the
technical accuracy influenced by the fat thickness and probe
size (M or XL), or from the physical increased stiffness of
fat accumulation, which lowers the correlation between liver
stiffness and cirrhosis (100). Notably, this study also used
HVPG as a golden standard to discuss the PH diagnostic
ability of LSM. However, a recent study has supposed that
HVPG may underestimate the real portal pressure of patients
with NASH (22,101), so the relationship between LSM and
PPG in the patients with NASH should be further tested. As
suggested by Baveno VII, the combination of LSM, platelet
count, and BMI might be useful in the patients with NASH, but
required further validation about proper technology, standards,
and cut-offs. Otherwise, due to the relatively smaller body of
studies and the variability of cut-offs among the various studies,
LSM of pSWE and 2D-SWE was not recommended by the
main guidelines of liver disease (17,40). However, the Society
of Radiologists in Ultrasound suggested that LSM>17 kPa
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FIGURE 6
Shows the occurrence time of different non-invasive detection of portal pressure.
(2.4 m/s) in pSWE and 2D-SWE could be used to screen
CSPH (102).
Although LSM has gained widespread acknowledgment in
assessing PH, the past study proved that the relationship
between LSM and PH was blunted with increasing
pressure when HVPG 10–12 mmHg, which might
be from the stronger involvement of extrahepatic
factors like collateral circulation (103). Moreover, after
NSBB treatment, LSM had no significant decrease
in the HVPG-down patients (104). Conversely, after
etiological treatment, LSM might immediately decrease
due to the regression of inflammation, while PH is
still maintained (105). Hence, HVPG was still the only
metric recommended by the clinical guidelines to evaluate
the changed portal pressure after various treatments
(17,19).
Spleen stiffness measurement (SSM) holds the potential to
address the above issues with the ability to reflect extrahepatic
hemodynamic changes. In 2012, a study (106) in 100 patients
with HCV with a median HVPG of 12 mmHg firstly validated
the close relationship between SSM of TE and HVPG, and,
compared to LSM, SSM owed a similar diagnostic capability
to detect HVPG 10 mmHg, HVPG 12 mmHg with
AUROC of 0.966 and 0.959, respectively. Moreover, SSM of
TE had a similar effect to HVPG on predicting EV. One
recent meta-analysis study has also shown the potential capacity
of SSM in assessing CSPH, and the pool sensitivity and the
specificity of SSM in 7 studies were 0.85 and 0.86, respectively
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(107). In the latest Baveno VII, SSM >50 kPa of TE was
regarded as a cut-off to identify CSPH. In assessing the
changed portal pressure, SSM exhibited good values. In 2019,
a prospective study (108) of 106 cirrhotic patients (mean
HVPG = 19.6 ±5.8 mmHg) in the derivation set and 63
patients (mean HVPG = 19.2 ±4.9 mmHg) in the external
validation set firstly validated that the difference of pre- and
post-treatment spleen stiffness (1SS) measured by pSWE could
be used to predict the hemodynamic change after NSBB
therapy. Moreover, this study also constructed a model 1SS
(0.04902.8345 ×1SS), which could screen the deceased
HVPG 20% or the post-NSBB HVPG <12 mmHg with
AUC of 0.801 and 0.848 in the derivation set and the external
validation set, respectively. Another study (104) in 20 patients
with high-risk EV also proved that the cutoff 10.5% of the
changed SSM of TE could screen the deceased HVPG 10%
with a sensitivity of 100% and specificity of 60% (AUROC.973),
while the changed LSM do especially poorly (AUROC.587).
Otherwise, there were also studies (109,110) that showed that
SSM was better than LSM in reflecting the changed portal
pressure after TIPS and etiological treatments, but the data were
relatively scarce.
In summary, USE was the most significant hot spot
in predicting PH, which is comprehensively proper in
terms of technical difficulty and risk, consumption of time
and money, feasibility, and accuracy. The studies about
USE in assessing PH could be mainly grouped into three
directions:
1. The technical questions, including operation protocols
(fast for 4 h, location, breath, probe size, measurement
systems, etc.), the influence of subcutaneous fat
thickness, spleen size, the alanine aminotransferase
level, and other diseases.
2. The comparison of LSM and SSM
3. The combination of USE with other markers
For the first direction, there had been specialized
recommendations (102,111,112) to standard operation
for achieving the best reproducibility and consistency in
the different studies. Furthermore, a new dedicated system
for SSM was also studied (113), as the spleen was stiffer
than the liver, and the upper limit of common TE may not
cover the whole SSM. As supported by Baveno VII, the
best cut-off of SSM by using a 100-Hz-specific TE-probe,
pSWE, and 2D-SWE needed further validation. As for the
second direction, in assessing untreated PH by LSM or
SSM, neither was universally better than the other. Although
SSM had superior performance in screening high-risk EVs
than LSM, the successful measurement rate was lower than
LSM, and the recognized cut-off SSM was still lacking (114,
115). There were also two studies (114,116) discussing the
sequential application of LSM and SSM, but the diagnostic
TABLE 8 Different lesions correspond to the examination.
Feature Methods
Liver fibrosis USE
Spleen fibrosis MRE
Liver surface nodules
MRI-mapping
Radiomics
Blood flow of portal system ICG
Cholate
DUS
CEUS
MRI with contrast
CT with contrast
Computational model
Hepatic function AST
ALT
ALB
INR
ALB
Fibrogenesis related molecular mechanism OPN
TIMP1
PIIINP
HA
ADMA
VWF-AG
CD163
SCFAs
accuracy has large gaps in these two studies. Additionally,
in the case of reflecting the changed portal pressure after
various treatments, SSM might be more potential than LSM.
In the third direction, the combinations of (1) LSM of TE,
spleen size of US, and PLT (LSPS) in untreated cirrhotic
patients, (2) LSM of TE, sex, spleen size of US, and PLT
(the PH risk score) in untreated cirrhotic patients, (3) LSM
and VITRO in the patients after IFN-free therapy, (4) LSM
and FIB-4 (PLT, AST, ALT, and age) in patients with chronic
liver disease, all had been reported to diagnose CSPH with
AUROC >0.8, but also need large validation studies (27,
117,118).
Magnetic resonance elastography
In addition to ultrasound elastography, MRE could also
measure tissue stiffness in clinical MRI examinations by
encoding shear wave propagation into magnetic resonance
phase signals. MRE showed an excellent ability to detect
liver fibrosis and cirrhosis with a low failure rate (119).
The EASL Clinical Practice Guidelines mentioned MRE as
the most accurate non-invasive approach to liver fibrosis
staging (40). In a large animal model of cholestatic liver
disease in 2013, Yin et al. (120) compared the association
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TABLE 9 Screening criteria and prediction models for different types of diseases.
Diseases Applicable methods Criteria for prediction
Cirrhosis caused by HCV virus SSM and LSM by US elastography HVPG = 4.44 + 0.241LS + 0.226SS (R2= 0.85,
p<0.00001).
After the TIPS SSM by US elastography SSM was significantly reduced after TIPS surgery.
Hepatitis B cirrhosis von Willebrand Factor vWF (1510.5 mU/mL and 1701 ’/mL) had higher positive
predictive values for clinically significant and severe portal
hypertension (PPV, 90.2 and 87.5%).
Alcoholic cirrhosis LSM by US elastography 32.2 kPa, for diagnosing HVPG 10 mmHg (94.5% PPV)
and 36.6 kPa, for diagnosing HVPG 12 mmHg (91.0%
PPV).
Alcoholic liver disease, chronic hepatitis B,
chronic hepatitis C, and non-obese
non-alcoholic steatohepatitis (NASH)
LSM by US elastography LSM 25 kpa is considered to be the optimal threshold for
determining CSPH.
NASH Body mass index, LSM, and platelet count LSM 15 kPa plus platelets 150109/L could rule out
CSPH caused by most causes.
NCPH SSM and LSM by MRE and MRI LSM of NCPH was significantly lower than that of CPH,
SSM/LSM ratio was significantly higher than that of CPH,
and LSM <4.7 kPa could effectively exclude CPH.
LSM, liver stiffness measurement; US, ultrasonic; MRE, Magnetic resonance enhancement; SSM, spleen stiffness measurement; HVAT, hepatic vein arrival time; CEUS, contrast-
enhanced ultrasonography; MRI, Magnetic resonance imaging; CT, computerized tomography; MDCT,multi-detector row computed tomography; ICG, Indocyanine green; RHP, regional
hepatic perfusion; sCD163, soluble CD163; ADMA, Asymmetric dimethylarginine; HCV, Hepatitis C virus; HVPG, Hepatic Venous Pressure Gradient; Tips, transjugular intrahepatic
portosystemic stent-shunt; NCPH, Non-cirrhotic portal hypertension.
of MRE with direct portal vein pressure gradient (D-HVPG).
The results showed that F1 fibrosis appeared in the liver
of animals after 4 weeks, and the portal pressure reached
11. ±5.1 mmHg; after 8 weeks, it became F3 fibrosis, and
the portal pressure increased to 11.3 ±3.2 mmHg. At the
same time, the mean stiffness of the spleen increased from
1.72 ±0.33 kPa to 3.54 ±0.31 kPa after 4 weeks, while it
stabilized at 3.38 ±0.06 kPa at week 8, consistent with the
pattern of changes in portal pressure. In a study on patients
with HBV and HCV (121), researchers divided participants
into:
Liver biopsy with no evidence of portal hypertension
(Group1, n= 155)
Patients with portal hypertension who were tested for
HVPG (Group 2, n= 85)
Healthy subjects (Group 3, n= 60)
Among multiple viscoelastic parameters, the liver damping
ratio and splenic shear stiffness measured in 60-Hz 3D
MRE were correlated with HVPG. Danielsen et al. (122)
assessed whether MRE of the liver or spleen reflected the
severity of PH in cirrhotic patients and whether the effect
of NSBB on liver and spleen stiffness could be a reflection
of its efficacy on portal pressure. The results suggest that
liver or spleen stiffness estimated by 2D MRE could reflect
the degree of portal hypertension in patients with cirrhosis,
but changes in stiffness after NSBB could not predict the
effect on HVPG. Besides, Wagner et al. (123) carried out
the combination of DCE-MRI and MRE to determine portal
hypertension. The results showed that the combination of
liver stiffness and perfusion indicators had good accuracy in
diagnosing CSPH.
Overall, the measured area of MRE was larger than
USE, and MRE could even simultaneously acquire liver
stiffness and spleen stiffness (112). However, compared to
USE, the research data in MRE were relatively insufficient,
and it was not feasible in many countries and regions
due to its complicated, time-consuming, and expensive
operation. Therefore, this kind of detection may be more
suitable for scientific research than clinical practice at
the present stage.
Green cluster 2: The evaluation of
portal hypertension-induced variceal
bleeding
Green Cluster 2 includes 26 keywords shown in Figure 5D,
mainly about “the evaluation of portal hypertension-induced
variceal bleeding.” In this situation, the platelet count
was important in the risk stratification of PH and the
prediction of variceal hemorrhage, and the combination
of the platelet count and the spleen diameter was also
mentioned.
Esophagogastric variceal bleeding is a common and
severe decompensation event of portal hypertension.
Esophagogastroduodenoscopy was the gold reference to
evaluate varices, and its application was limited by invasiveness
and low tolerance of patients. As the hemorrhage risk of
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varices significantly decreased when HVPG <12 mmHg,
some studies used esophagogastric variceal bleeding as
the observation endpoint or standard to evaluate the PH
prediction capability of non-invasive methods. In turn, the
performance of detecting HVPG 12 mmHg could also
be regarded as predicting variceal bleeding. Hence, most
of the non-invasive predictors described above were also
studied in evaluating esophagogastric varices, like ICG-r15
could identify patients at high risk for esophageal varices
and have similar performance with HVPG (AUROC, 0.859
vs. 0.816) (59); SHAPE could screen high-risk variceal
bleeding with AUROC of 0.95 (78); other indices as PLT,
AST, ALT, VWF-AG, LSM, and SSM were also discussed
(124127). Among these, the combination of LSM by
TE <20 kPa and the platelet count >150 G/L was the
most recognized surrogate of endoscopic screening, which
just missed 0–2% of high-risk varicose veins (40); the
platelet count/spleen diameter ratio also received much
attention, and the platelet count/spleen diameter ratio >909
would not miss any esophagogastric varices (128). In the
renewing BavenoVII, the patients with LSM of TE 20 kPa
or platelet count 150 L ×109L needed an endoscopic
screen, but the endoscopy could be avoided when SSM of
TE 40 kPa.
Limitation
This review was based on bibliometric analysis and
reviewed the non-invasive methods of PH monitoring
according to the keywords clustering results of VOSviewer.
The limitations included that the search strategy could
not cover all the literature about non-invasive tools on
PH. Besides, inequality in the quality of the retrieved
literature might influence the credibility of the analysis
results. However, the retrieved literature was enough to show
the basic architecture of this field and supported further
system retrieval.
Conclusion
The portal vein was away from the surface of the body,
making direct puncture a high-risk operation. WHVP was first
proposed as an indirect method to measure portal pressure
in the 1950s (129), from the 1970s to the 1980s, a large
body of studies focused on validating the correlation between
WVHP and portal pressure (130). Now, HVPG has been
the golden standard to evaluate PH (17). In 2004 (131), a
EUS-guided portal vein puncture and pressure measurement
succeed in pigs and then succeeded in patients in 2017 (132).
EUS-guided pressure measurement of the portal vein and the
hepatic vein (or inferior vena cava) obtained a real PPG,
which might be useful in diagnosing other types of PH than
cirrhosis. However, EUS was still invasive and risky, not
suitable to monitor PH continuously throughout the natural
course of chronic liver disease. Hence, monitoring PH non-
invasively was an inevitable development, and the time axis of
the emergence of various non-invasive methods is shown in
Figure 6.
As listed in Tables 8,9, blood tests, US, CT, and MRI
provided various features and were studied in different clinical
settings. Serum markers often worked as a complement to
the LSM, and the new serum markers were continuously
appearing with the deepening of the pathophysiological studies
of liver fibrosis and portal hypertension. The application
of DUS to predict PH was early described in the 1990s,
which provided real-time hemodynamic information but was
limited by a high-failure rate and inter- or intra-observer
variance. The appearance of CEUS in this field was in the
2010s, and SHAPE exploited new ideas on portal hypertension
assessment but was still limited by the intrinsic defect of
the US. CT and MRI could provide both fibrotic and
hemodynamic information about portal hypertension, and
MRI has been studied more in this area. The studies
focusing on the diagnostic performance of USE on PH were
started in the 2000s. LSM of TE was supported by the
largest body of literature, and LSM 25 kPa was widely
recognized to diagnose CSPH. The rising of quantitative
imaging techniques opened the door to a brand-new world of
portal hypertension prediction. The abundant possibilities of
imaging analysis were appealing, but the results need rational
interpretations.
As far as detecting changes in portal pressure after various
therapies, LSM was unreliable in evaluating the effect of
NSBB, and NSBB could not significantly change the stiffness
of the liver (122). While hemodynamic factors such as SSM
and the portal vein diameter showed a correlation with the
changed PH (104,108,133). In the situation of antiviral
therapy, SSM could also reflect changes in portal hypertension
(134). However, as a result of insufficient data, Baveno VII
did not recommend using SSM or other non-invasive indices
to assess changes in PH (17). Although there is still a gap
between all the current non-invasive testing methods and
HVPG, we believe that, with further research, non-invasive
prediction of portal hypertension will replace or even surpass
invasive testing.
Author contributions
MN and XL contributed to the conception, design, and
final approval of the manuscript. JX, SW, AA, LW, and TR
contributed to sequencing data. XS and HN wrote the final
manuscript. All authors have read and approved the final
version of the manuscript.
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Funding
This work was funded by the National Key Scientific
Instrument and Equipment Development Projects of China
Award (Award No. 2019YFC0118100, Recipient: MN);
PLiao Ning Revitalization Talents Program (Award No.
XLYC2007029, Recipient: MN).
Acknowledgments
We thank the Department of Interventional Radiology,
The First Hospital of China Medical University, and the
Department of Interventional Therapy, National Cancer
Center/National Clinical Research Center for Cancer/Cancer
Hospital, Chinese Academy of Medical Sciences, and Peking
Union Medical College.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
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