
==== Front
J Cardiothorac Surg
J Cardiothorac Surg
Journal of Cardiothoracic Surgery
1749-8090
BioMed Central London

3047
10.1186/s13019-024-03047-5
Research
Assessing the predictive efficacy of noninvasive liver fibrosis indices and portal vein diameter in predicting esophageal variceal bleeding in patients with cirrhosis
Lin Xiaoxiao 1
Lan Qiaoli 1
Liu Ya 1
Dong Xiuli 2
Wu Lecan wuyuecanwycn9@126.com

1
1 grid.268099.c 0000 0001 0348 3990 Department of Gastroenterology, The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People’s Hospital, No.57 Canghou Street, Wenzhou, Zhejiang 325000 China
2 https://ror.org/03cyvdv85 grid.414906.e 0000 0004 1808 0918 Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000 China
18 9 2024
18 9 2024
2024
19 53227 5 2024
9 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

The objective of this study is to evaluate the diagnostic accuracy of noninvasive serum liver fibrosis markers and portal vein diameter (PVD) in predicting the occurrence of esophageal variceal bleeding (EVB) in patients with cirrhosis.

Methods

A cohort comprising 102 individuals diagnosed with cirrhosis was divided into two groups: the P group (without EVB) and the PE group (with EVB). We conducted a comprehensive analysis comparing various noninvasive serum liver fibrosis indices, the Child-Pugh classification, ratios of aspartate aminotransferase to alanine aminotransferase, aspartate aminotransferase to platelet ratio index, fibrosis index based on four factors (FIB-4), PVD, and spleen thickness (SPT) between these groups. Receiver operating characteristic (ROC) curves were constructed for variables showing significant differences between the two groups, with subsequent calculation of the area under the ROC curve (AUROC) for each variable.

Results

Significant distinctions were noted in the serum liver fibrosis markers between the P and PE groups, encompassing hyaluronic acid (HA), type III procollagen (PC-III), type IV collagen (IV-C), PVD, SPT, and FIB-4 (p < 0.05), as evidenced by univariate analysis findings. The respective AUROC values for these markers were 0.653, 0.706, 0.710, 0.730, 0.660, and 0.633. Additionally, upon integration with PVD, SPT, and FIB4, the AUROC values for liver fibrosis markers surged to 0.793, 0.763, and 0.706 correspondingly, highlighting the enhanced diagnostic potential.

Conclusion

The integration of noninvasive liver fibrosis indices and PVD showcased remarkable diagnostic potential in EVB, underscoring its clinical relevance in predicting hemorrhagic events.

Keywords

Esophageal varices bleeding
Liver fibrosis
Liver fibrosis indexes
Portal vein diameter
Liver cirrhosis
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Esophageal variceal bleeding (EVB) is the most prevalent and hazardous complication associated with liver cirrhosis, affecting between 30 and 70% of individuals with this condition and posing a significant risk of mortality [1]. EVB serves as a critical indicator of the severity of liver cirrhosis, often accompanied by high rates of mortality and rebleeding. The 2016 consensus guidelines from the Asian Pacific Association for the Study of the Liver (APASL) highlighted the pivotal role of liver fibrosis in diagnosing and prognosticating liver cirrhosis, owing to its accuracy in gauging the extent of portal hypertension and the development of esophageal varices [2–4].

Recent studies and guidelines emphasize the importance of assessing portal hypertension (PH) through the measurement of hepatic venous pressure gradient, a valuable predictor of PH-related complications in cirrhotic patients [5]. However, due to its invasive nature, this technique is not routinely employed in clinical settings. Noninvasive methods for assessing liver fibrosis, such as measuring indices like hyaluronic acid (HA), type III procollagen (PC-III), and type IV collagen (IV-C), have gained prominence in clinical practice [6]. Although these indices have been shown to correlate with cirrhosis prognosis, their utility in predicting EVB is still not fully understood.

In another study, various markers including aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST to platelet ratio index (APRI), platelet count to spleen diameter (PC/SD), fibrosis-4-index (FIB-4), fibrosis index (FI), and King’s Score were evaluated for their predictive efficacy in esophageal variceal bleeding among Albanian patients diagnosed with liver cirrhosis. The findings indicated that FIB-4 emerged as the most effective noninvasive liver fibrosis marker, offering promise as an initial screening tool for cirrhotic patients [7].

In this study, we sought to investigate the potential and effectiveness of liver fibrosis markers in predicting EVB, thereby laying a groundwork for the prevention, management, and prognosis of EVB in individuals with cirrhosis.

Materials and methods

Materials

A retrospective analysis was conducted on 102 cirrhotic patients with esophageal varices who were consecutively admitted to our hospital between January 2011 and January 2022. This cohort consisted of 66 males and 36 females, with ages ranging from 28 to 82 years. Liver cirrhosis was attributed to various causes: hepatitis (n = 64), alcohol consumption (n = 20), cholestatic disorders (n = 2), and unknown etiology (n = 16). The diagnosis of liver cirrhosis was based on a comprehensive assessment that included patient history, physical examination, laboratory tests, ultrasound, abdominal computed tomography (CT) imaging, and liver biopsy [8]. Liver puncture was not the only criterion. Gastroscopy was employed to ascertain the presence and characteristics of esophageal varices, which were categorized based on size (small, medium, or large) and location, as per the Sarin classification (GOV: gastroesophageal varices; IGV: isolated gastric varices) [9]. All included patients underwent gastroscopy within one week of admission for definitive diagnosis.

The primary concern associated with esophageal varices is the risk of bleeding. Indications of bleeding esophageal varices encompass vomiting substantial amounts of blood, experiencing black, tarry, or bloody stools, feeling lightheaded due to blood loss, and in severe cases, losing consciousness. Exclusion criteria for this study encompassed patients with hepatocellular carcinoma, those who underwent endoscopic esophageal varix ligation, or individuals with severe organ dysfunction. The Ethics Committee of the Wenzhou People’s Hospital approved the study protocol.

Methods

The study encompassed 102 patients with cirrhosis who were categorized into two groups: the P group (without EVB), and the PE group (with EVB). Various serum markers and other scores of liver fibrosis, such as HA, PC-III, IV-C, Child-Pugh stage, AAR, APRI, FIB-4, portal vein diameter (PVD), and spleen thickness (SPT), were retrospectively examined. Blood samples were taken within 24 h after admission. Serum levels of HA, PC-III, IV-C, Child-Pugh stage, AAR, APRI, FIB-4 were measured by commercially available kits purchased from Shenzhen Yahui Long Biotechnology Co., Ltd. (China) using chemiluminescence assay. PVD and SPT were measured using ultrasound. The patient was positioned in supine position, and the internal diameter of the main portal vein was measured from the body surface using an ultrasound probe. In the right lateral position, the probe was placed between the anterior and posterior axillary lines to obtain the thickness of the spleen. The examination was completed during the patient’s hospitalization.

Through univariate analysis, variables exhibiting significant differences between the two groups were identified. Subsequently, the receiver operating characteristic (ROC) curve and area under the ROC (AUROC) values were computed to assess the diagnostic efficacy of these variables in predicting esophageal variceal bleeding. Significant variables were further analyzed using binary logistic regression to establish their combined predictive value. Adherence to the Declaration of Helsinki principles was ensured throughout the study, and the Ethics Committee of Wenzhou People’s Hospital approved the research protocol (KY02022-027).

Statistical analysis

SPSS 22.0 software was utilized for statistical analysis. For normally distributed measurement data, mean ± standard deviation (SD) were presented and compared using the t-test. Skewed variables were expressed as median and interquartile range (IQR), with differences assessed via nonparametric tests. Enumeration data were compared using the chi-squared (χ2) test, while grade data were analyzed using the rank-sum test. Significance was set at p < 0.05. Variables exhibiting significant differences between groups were identified. To evaluate diagnostic performance, ROC analysis was employed for these variables, with each AUROC value calculated. Binary logistic regression was then applied to amalgamate these variables. Subsequently, the ROC curve was constructed, and AUROC was computed based on the amalgamated variables.

Results

Univariate analysis between the two groups.

Univariate analysis revealed notable differences in noninvasive serum liver fibrosis markers, such as HA, PC-III, IV-C, PVD, SPT, and FIB-4, between the P and PE groups (p < 0.05) (Table 1).

Table 1 Univariate analysis of patient characteristics and factors associated with EVB between the two groups

Variables	PE group (n = 42)	P group (n = 60)	P value	
Gender (M/F)	28/14	38/22	0.729	
Age(year), mean ± SD	55.93 ± 10.98	58.33 ± 11.96	0.304	
HA (µg), median (IQR)	537.05(628.67)	316.51(375.21)	0.009	
PC-III(µg), median (IQR)	133.45(124.85)	62.30(76.98)	0.000	
IV-C(µg), median (IQR)	103.39(64.07)	61.30(52.55)	0.006	
ALT(U/L), median (IQR)	32(13.75)	31(22.5)	0.496	
AST(U/L), median (IQR)	40(15.5)	46(28.25)	0.051	
PLT count (109/L), median (IQR)	53.5(55.25)	88.5(77)	0.000	
AAR, median (IQR)	1.38(0.82)	1.52(0.82)	0.671	
APRI, median (IQR)	1.79(1.55)	1.39(1.71)	0.242	
FIB4,median (IQR)	4.05(3.91)	3.43(3.99)	0.023	
Child-Puge classification, n(%)			0.213	
A	12(28.6%)	27(45%)		
B	22(52.4%)	26(43.3%)		
C	8(19%)	7(11.7)		
PVD(mm), median (IQR)	12(2.25)	11(2)	0.000	
SPT(mm), median (IQR)	48(11)	42(8)	0.006	

ROC curves of the factors with significant differences associated with EVB between the two groups.

The ROC curves were generated for several liver fibrosis indices including HA, PC-III, IV-C, PVD, SPT, and FIB-4, demonstrating their corresponding AUROC values of 0.653, 0.706, 0.710, 0.730, 0.660, and 0.633. Notably, these results underscore the robust diagnostic capabilities of these indices, particularly highlighting the efficacy of PVD in conjunction with other liver fibrosis markers (Fig. 1; Table 2).

Fig. 1 Performance of serum liver fibrosis indexes, PVD, SPT, and FIB-4 in the detection of EVB. ROC curves demonstrate the diagnostic accuracy of HA, PC-III, IV-C, PVD, SPT, and FIB-4 in predicting the presence of EVB in patients with liver cirrhosis

Table 2 The ROC curve values of the factors with significant differences associated with EVB between the two groups

	95% CI	Sensitivity	Specificity	
HA	0.545–0.761	0.643	0.600	
PC-III	0.599–0.813	0.714	0.667	
IV-C	0.606–0.814	0.714	0.683	
PVD	0.629–0.831	0.548	0.833	
SPT	0.551–0.768	0.405	0.783	
FIB-4	0.525–0.741	0.619	0.617	
CI, confidence interval of AUC values

Diagnostic performance of combined indicators.

We incorporated liver fibrosis markers (HA, PC-III, and IV-C) in conjunction with PVD into a binary logistic regression model to estimate prediction probability (PRE_1). Subsequently, the ROC curve was generated, yielding an AUROC of 0.793. Following this, PRE_2 was calculated by incorporating liver fibrosis markers and SPT using binary logistic regression, with resulting ROC curves and an AUROC of 0.763. Lastly, the diagnostic accuracy of liver fibrosis markers in conjunction with FIB-4 was evaluated, revealing an AUROC of 0.706 (refer to Fig. 2; Table 3). Consequently, the diagnostic efficacy of liver fibrosis markers combined with PVD surpasses that of their combination with SPT or FIB-4, and outperforms individual variables in EVB among cirrhotic patients.

Fig. 2 Performance of combined variables in the detection of EVB. ROC curves demonstrate that a combination of serum liver fibrosis indices and PVD result in higher diagnostic accuracy in predicting the presence of EVB in patients with liver cirrhosis

Table 3 Diagnostic performances of combined indicators

	95% CI	Sensitivity	Specificity	
Liver fibrosis indexes combined with PVD	0.699–0.888	0.683	0.786	
Liver fibrosis indexes combined with SPT	0.666–0.860	0.667	0.738	
Liver fibrosis indexes combined with FIB-4	0.599–0.813	0.633	0.714	
CI, confidence interval of AUC values

Discussion

EVB constitutes a common and severe complication often encountered in patients with liver cirrhosis. EVB manifests with sudden onset, rapid deterioration, and a significantly heightened fatality rate. Despite its gravity, there exists a conspicuous absence of effective predictive models or systems for assessing EVB risk in clinical settings. In recent years, there has been a surge of interest in noninvasive index prediction of EVB within academic circles [10]. In this study, we conducted a comparison among various noninvasive serum liver fibrosis indicators, including but not limited to HA, PC-III, IV-C, Child-Pugh stage, AAR, APRI, FIB-4, PVD, and SPT.

Patients diagnosed with cirrhosis were categorized into two groups, namely the P group (without EVB) and the PE group (with EVB). Presently, a variety of methods are employed to assess the risk and prognosis of EVB, with noninvasive markers being particularly emphasized [11, 12]. In this study, a univariate analysis was undertaken, revealing notable differences in HA, PC-III, IV-C, PVD, SPT, and FIB-4 between the aforementioned groups. Recent studies have demonstrated that the stage of liver cirrhosis, when combined with hepatic venous pressure gradient, may predict the likelihood of EVB [13]. Nonetheless, invasive procedures are often poorly tolerated by patients and are not universally applicable. Employing binary logistic regression, we integrated these variables, constructed the ROC curves, and computed the AUROC. Our findings indicate that a composite of liver fibrosis indicators, comprising HA, PC-III, IV-C, and PVD, exhibits the highest diagnostic efficacy for EVB.

Liver fibrosis, a pathological state, manifests through an abnormal accumulation of extracellular matrix elements within the liver, potentially progressing into decompensated cirrhosis if left unaddressed, leading to severe health ramifications. In contemporary medical practice, indicators like HA, PC-III, and IV-C are routinely utilized to gauge cirrhosis severity.

Extensive research highlights the exceptional effectiveness of HA in precisely determining the extent of liver cirrhosis [14, 15]. Elevated concentrations of HA are consistently observed during both the active and advanced stages of liver disease, highlighting its potential close association with the progression of liver fibrosis. This is evidenced by the positive correlation between HA levels and the severity of fibrosis [16].

PC-III, derived from both hepatocytes and interstitial cells, is present in the bloodstream. Evaluating serum PC-III levels provides insight on the synthesis of collagen by hepatocytes. As an amino-terminal polypeptide, PC-III acts as a precursor to type III collagen, which is prevalent in the early phases of liver fibrosis. Thus, monitoring PC-III provides critical insights into the metabolism of type III collagen during these early fibrotic processes. Research findings indicate that PC-III is a promising metric for the assessment of liver fibrosis [17, 18].

IV-C, a key component of the hepatic basement membrane, exhibits escalated synthesis subsequent to liver injury, potentially functioning as a marker for the severity of liver fibrosis. Previous studies have revealed a significant positive correlation between serum levels of HA and IV-C among patients, along with the extent of esophageal varices [19]. Prior investigations have demonstrated a direct correlation between HA levels and the severity of esophageal varices [20, 21].

Hence, the elevation in serum levels of these markers likely mirrors the advancement of liver cirrhosis and the extent of esophageal varices, indicative of a heightened risk of bleeding commensurate with the severity of the varices. Moreover, in this study, no significant variances in age or Child-Pugh classification were discerned between the two groups.

Prior studies have scrutinized the risk factors for EVB in cirrhotic patients. Findings suggest that factors such as gender and age exhibit minimal correlation with EVB, while a higher Child-Pugh score demonstrates a notable association with its incidence. However, it is important to note that, despite its correlation with the incidence of EVB in cirrhosis, the Child-Pugh classification does not constitute an independent risk factor and possesses limited clinical significance in the prognostic assessment of EVB [22].

PH is a prominent clinical manifestation of liver cirrhosis, significantly impacting mortality rates among afflicted individuals [23]. PVD acts as an indirect gauge of PH severity, with higher PVD levels correlating with more pronounced EV and heightened susceptibility to EVB. Measurements obtained through real-time shear wave elastography in patients with cirrhosis have shown a direct relationship between PVD and the severity of EV, indicating that an increase in PVD is associated with more severe cases of EV. Enhanced MRI has demonstrated potential in predicting PH and identifying high-risk EV in patients with cirrhosis due to hepatitis B, highlighting the association between PV characteristics and EVB risk. Integrating MRI with PVD measurement, as evidenced in studies conducted in China, offers a comprehensive approach for assessing severe EV, demonstrating high diagnostic efficacy. Numerous studies have independently verified PVD as a significant risk factor for EVB and subsequent rebleeding events.

Conclusion

Compared with the individual predictive risk, the integration of serum liver fibrosis markers and PVD enhances the effectiveness of predicting the onset of EVB and plays a substantial role in markedly improving the disease prognosis in clinical settings. In addition, the laboratory indicators and imaging examinations involved in this study are based on the premise of non-invasive examination. Compared with invasive examination, they are more acceptable to patients and can be widely used in clinical practice in the future.

Limitations

The aim of this study was to explore the efficacy of combined indicators in a non-invasive approach for predicting EVB occurrences in clinical settings. It is crucial to acknowledge that this study was carried out in a single center with a restricted sample size. Consequently, it is imperative for forthcoming studies to prioritize multi-center trials to bolster the applicability of the results. Particularly, there is a need for further scrutiny into the training and validation sets.

Acknowledgements

We would like to acknowledge the hard and dedicated work of all the staff who implemented the intervention and evaluation components of the study.

Author contributions

Conception and design of the research: Xiaoxiao Lin, Lecan Wu. Acquisition of data: Xiaoxiao Lin, Xiuli Dong. Analysis and interpretation of the data: Qiaoli Lan, Ya Liu. Statistical analysis: Qiaoli Lan, Xiuli Dong. Obtaining financing: None. Writing of the manuscript: Xiaoxiao Li, Lecan Wu. Critical revision of the manuscript for intellectual content: Ya Liu, Lecan Wu. All authors read and approved the final draft.

Funding

No external funding received to conduct this study.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Wenzhou People’s Hospital (No: KY02022-027). This study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all the participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

EVB Esophageal varices bleeding

PVD Portal vein width

EV Esophogeal varices

AST Aspartate aminotransferase

ALT Alanine aminotransferase

AAR AST-to-ALT

APRI AST-to-platelet ratio index

FIB-4 Fibrosis index based on the four factors

PVD Portal vein width

SPT Spleen thickness

ROC curve Receiver Operating Characteristic curve

AUROC Area under the ROC curve

HA Hyaluronic acid

PC-III Type III procollagen

IV-C Type IV collagen

APASL Asian- Pacific Association for the Study of the Liver

HVPG Hepatic venous pressure gradient

PH Portal hypertension

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Pallio S Melita G Shahini E Vitello A Sinagra E Lattanzi B Facciorusso A Ramai D Maida M Diagnosis and management of Esophagogastric Varices Diagnostics (Basel) 2023 13 6 1031 10.3390/diagnostics13061031 36980343
Pallio S, Melita G, Shahini E, Vitello A, Sinagra E, Lattanzi B, Facciorusso A, Ramai D, Maida M. Diagnosis and management of Esophagogastric Varices. Diagnostics (Basel). 2023;13(6):1031.36980343
2. Sun X Ni HB Xue J Wang S Aljbri A Wang L Ren TH Li X Niu M Bibliometric-analysis visualization and review of non-invasive methods for monitoring and managing the portal hypertension Front Med (Lausanne) 2022 9 960316 10.3389/fmed.2022.960316 36186776
Sun X, Ni HB, Xue J, Wang S, Aljbri A, Wang L, Ren TH, Li X, Niu M. Bibliometric-analysis visualization and review of non-invasive methods for monitoring and managing the portal hypertension. Front Med (Lausanne). 2022;9:960316.36186776
3. Deng H Qi XS Peng Y At El. Diagnostic accuracy of APRI,AAR,FIB-4,FI,and King scores for diagnosis of esophageal varices in liver cirrhosis: a retrospective study Med Sci Monit 2015 21 3961 77 10.12659/MSM.895005 26687574
Deng H, Qi XS, Peng Y. At El. Diagnostic accuracy of APRI,AAR,FIB-4,FI,and King scores for diagnosis of esophageal varices in liver cirrhosis: a retrospective study. Med Sci Monit. 2015;21:3961–77.26687574
4. Procopet B Cristea VM Robic MA Erum tests,liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension Dig Liver Dis 2015 47 411 6 10.1016/j.dld.2015.02.001 25732434
Procopet B, Cristea VM, Robic MA, et al. Erum tests,liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension. Dig Liver Dis. 2015;47:411–6.25732434
5. Roccarina D Rosselli M Genesca J Tsochatzis EA Elastography methods for the non-invasive assessment of portal hypertension Expert Rev Gastroenterol Hepatol 2018 12 155 64 10.1080/17474124.2017.1374852 28856972
Roccarina D, Rosselli M, Genesca J, Tsochatzis EA. Elastography methods for the non-invasive assessment of portal hypertension. Expert Rev Gastroenterol Hepatol. 2018;12:155–64.28856972
6. Wang L Feng Y Ma X Diagnostic efficacy of noninvasive liver fibrosis indexes in predicting portal hypertension in patients with cirrhosis PLoS ONE 2017 12 8 e0182969 10.1371/journal.pone.0182969 28820885
Wang L, Feng Y, Ma X, et al. Diagnostic efficacy of noninvasive liver fibrosis indexes in predicting portal hypertension in patients with cirrhosis. PLoS ONE. 2017;12(8):e0182969. 10.1371/journal.pone.0182969. Published 2017 Aug 18.28820885
7. Kraja B Mone I Akshija I Koçollari A Prifti S Burazeri G Predictors of esophageal varices and first variceal bleeding in liver cirrhosis patients World J Gastroenterol 2017 23 26 4806 14 10.3748/wjg.v23.i26.4806 28765702
Kraja B, Mone I, Akshija I, Koçollari A, Prifti S, Burazeri G. Predictors of esophageal varices and first variceal bleeding in liver cirrhosis patients. World J Gastroenterol. 2017;23(26):4806–14. 10.3748/wjg.v23.i26.4806. PMID: 28765702; PMCID: PMC5514646.28765702
8. Smith A Baumgartner K Bositis C Cirrhosis Diagnosis and management Am Fam Physician 2019 100 12 759 70 31845776
Smith A, Baumgartner K, Bositis C, Cirrhosis. Diagnosis and management. Am Fam Physician. 2019;100(12):759–70. PMID: 31845776.31845776
9. Wani ZA Bhat RA Bhadoria AS Maiwall R Choudhury A Gastric varices: classification, endoscopic and ultrasonographic management J Res Med Sci 2015 20 12 1200 7 10.4103/1735-1995.172990 26958057
Wani ZA, Bhat RA, Bhadoria AS, Maiwall R, Choudhury A. Gastric varices: classification, endoscopic and ultrasonographic management. J Res Med Sci. 2015;20(12):1200–7.26958057
10. Abd-Elsalam SM Ezz MM Gamalel-Din S Esmat G Elakel W ElHefnawi M Derivation of Egyptian varices prediction (EVP) index: a novel noninvasive index for diagnosing esophageal varices in HCV patients J Adv Res 2021 35 87 97 10.1016/j.jare.2021.02.005 35024195
Abd-Elsalam SM, Ezz MM, Gamalel-Din S, Esmat G, Elakel W, ElHefnawi M. Derivation of Egyptian varices prediction (EVP) index: a novel noninvasive index for diagnosing esophageal varices in HCV patients. J Adv Res. 2021;35:87–97.35024195
11. Afsar A Nadeem M Shah SAA Hussain H Rani A Ghaffar S Platelet count can predict the grade of esophageal varices in cirrhotic patients: a cross-sectional study F1000Res 2021 10 101 10.12688/f1000research.28005.2 35035881
Afsar A, Nadeem M, Shah SAA, Hussain H, Rani A, Ghaffar S. Platelet count can predict the grade of esophageal varices in cirrhotic patients: a cross-sectional study. F1000Res. 2021;10:101.35035881
12. Guinazu C Fernández Muñoz A Maldonado MD De La Cruz JA Herrera D Arruarana VS Calderon Martinez E. assessing the predictive factors for bleeding in esophageal Variceal Disease: a systematic review Cureus 2023 15 11 e48954 38106778
Guinazu C, Fernández Muñoz A, Maldonado MD, De La Cruz JA, Herrera D, Arruarana VS. Calderon Martinez E. assessing the predictive factors for bleeding in esophageal Variceal Disease: a systematic review. Cureus. 2023;15(11):e48954.38106778
13. Kumar A, Sharma P. Arora A. A new prognostic algorithm based on stage of cirrhosis and HVPG to improve risk-stratification after variceal bleeding.Hepatology. 2020 Apr 410.1002/hep.31254
14. Younesi S Parsian H Diagnostic accuracy of glycoproteins in the assessment of liver fibrosis: a comparison between laminin, fibronectin, and hyaluronic acid Turk J Gastroenterol 2019 30 6 524 31 10.5152/tjg.2019.17339 31144658
Younesi S, Parsian H. Diagnostic accuracy of glycoproteins in the assessment of liver fibrosis: a comparison between laminin, fibronectin, and hyaluronic acid. Turk J Gastroenterol. 2019;30(6):524–31.31144658
15. Aleknavičiūtė-Valienė G Banys V Clinical importance of laboratory biomarkers in liver fibrosis Biochem Med (Zagreb) 2022 32 3 030501 36277426
Aleknavičiūtė-Valienė G, Banys V. Clinical importance of laboratory biomarkers in liver fibrosis. Biochem Med (Zagreb). 2022;32(3):030501.36277426
16. Grecian SM McLachlan S Fallowfield JA Hayes PC Guha IN Morling JR Glancy S Williamson RM Reynolds RM Frier BM Zammitt NN Price JF Strachan MWJ Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: the Edinburgh type 2 diabetes study Obes Sci Pract 2021 7 5 497 508 10.1002/osp4.484 34631129
Grecian SM, McLachlan S, Fallowfield JA, Hayes PC, Guha IN, Morling JR, Glancy S, Williamson RM, Reynolds RM, Frier BM, Zammitt NN, Price JF, Strachan MWJ. Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: the Edinburgh type 2 diabetes study. Obes Sci Pract. 2021;7(5):497–508.34631129
17. Bril F Leeming DJ Karsdal MA,Kalavalapalli S Barb D,Lai J Rabe M1,Cusi K.Use of plasma fragments of Propeptides of Type III, V, and VI Procollagen for the detection of liver fibrosis in type 2 diabetes Diabetes Care 2019 42 7 1348 51 10.2337/dc18-2578 31221701
Bril F, Leeming DJ, Karsdal MA,Kalavalapalli S, Barb D,Lai J. Rabe M1,Cusi K.Use of plasma fragments of Propeptides of Type III, V, and VI Procollagen for the detection of liver fibrosis in type 2 diabetes. Diabetes Care. 2019;42(7):1348–51.31221701
18. Mosca A Comparcola D,Romito I,Mantovani A,Nobili V,Byrne CD,Alisi A Targher G Plasma N-terminal propeptide of type III procollagen accurately predicts liver fibrosis severity in children with non-alcoholic fatty liver disease Liver Int 2019 39 12 2317 29 10.1111/liv.14225 31436362
Mosca A, Comparcola D,Romito I,Mantovani A,Nobili V,Byrne CD,Alisi A, Targher G. Plasma N-terminal propeptide of type III procollagen accurately predicts liver fibrosis severity in children with non-alcoholic fatty liver disease. Liver Int. 2019;39(12):2317–29.31436362
19. Wang J Yu G Xu H Ding Y Ding R Zu H Correlation studies between real-time shear wave elastography measuring liver stiffness and the degree of esophageal varices Zhonghua Gan Zang Bing Za Zhi 2015 23 7 502 6 26398840
Wang J, Yu G, Xu H, Ding Y, Ding R, Zu H. Correlation studies between real-time shear wave elastography measuring liver stiffness and the degree of esophageal varices. Zhonghua Gan Zang Bing Za Zhi. 2015;23(7):502–6.26398840
20. Kropf J Gressner AM Tittor W Logistic-regression model for assessing portal hypertension by measuring hyaluronic acid (hyaluronan) and laminin in serum Clin Chem 1991 37 1 30 5 10.1093/clinchem/37.1.30 1988206
Kropf J, Gressner AM, Tittor W. Logistic-regression model for assessing portal hypertension by measuring hyaluronic acid (hyaluronan) and laminin in serum. Clin Chem. 1991;37(1):30–5.1988206
21. Sebastiani G Tempesta D Fattovich G Et a1. Prediction of esophageal varices in hepatic cirrhosis by simple serum non-invasive markers: results of a multicenter, large-scale study J Hepatol 2010 53 4 630 8 10.1016/j.jhep.2010.04.019 20615567
Sebastiani G, Tempesta D, Fattovich G. Et a1. Prediction of esophageal varices in hepatic cirrhosis by simple serum non-invasive markers: results of a multicenter, large-scale study. J Hepatol. 2010;53(4):630–8.20615567
22. Kothari HG Gupta SJ Gaikwad NR Sankalecha TH Samarth AR Role of non-invasive markers in prediction of esophageal varices and variceal bleeding in patients of alcoholic liver cirrhosis from central India Turk J Gastroenterol 2019 30 12 1036 43 10.5152/tjg.2019.18334 31854309
Kothari HG, Gupta SJ, Gaikwad NR, Sankalecha TH, Samarth AR. Role of non-invasive markers in prediction of esophageal varices and variceal bleeding in patients of alcoholic liver cirrhosis from central India. Turk J Gastroenterol. 2019;30(12):1036–43.31854309
23. Hu X Huang X Hou J Ding L Su C Meng F Diagnostic accuracy of spleen stiffness to evaluate portal hypertension and esophageal varices in chronic liver disease: a systematic review and meta-analysis Eur Radiol 2021 31 4 2392 404 10.1007/s00330-020-07223-8 32974686
Hu X, Huang X, Hou J, Ding L, Su C, Meng F. Diagnostic accuracy of spleen stiffness to evaluate portal hypertension and esophageal varices in chronic liver disease: a systematic review and meta-analysis. Eur Radiol. 2021;31(4):2392–404.32974686
