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Matthieu FARON

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Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness

Introduction The development of portal hypertension is a common consequence of chronic liver diseases and

leads to the major complications of liver cirrhosis, such as ascites, hepatic encephalopathy, variceal

bleeding, and decompensation. Furthermore, decompensation is the most important predictor of

prognosis and mortality in patients with liver cirrhosis (1). Thus, early diagnosis of portal

hypertension is essential for adequate treatment to reduce the mortality rate of portal

hypertension–related complications (2).

Measurement of the hepatic venous pressure gradient (HVPG) has been accepted as the reference

standard for portal hypertension assessment in patients with cirrhosis. Patients with clinically

important portal hypertension (HVPG ≥ 10 mm Hg) are at increased risk of developing varices, while

patients with severe portal hypertension (HVPG ≥ 12 mm Hg) are at risk for variceal bleeding, with

mortality rates ranging from 20% to 35% (3).

However, measurement of HVPG is an invasive procedure associated with complications and is costly.

Thus, there is a need for accurate and noninvasive methods of assessing the progression of portal

hypertension.

Liver stiffness (LS) measured by using transient elastography is a rapid and noninvasive method for

the diagnosis of portal hypertension in patients with liver cirrhosis (4–6). However, Vizzutti et al (4)

confirmed a poor correlation between the HVPG and LS when the HVPG is greater than 12 mm Hg,

and LS measurements obtained by using transient elastography have been considered a useful but

not a suitable method for identifying esophageal varices (EVs) (7). Colecchia et al (8) have reported

that measuring spleen stiffness (SS) by using transient elastography was another feasible method for

identifying portal hypertension in patients with hepatitis C virus–induced cirrhosis. However,

transient elastography has some limitations. Measuring LS with transient elastography is difficult in

patients who are obese or who have narrow intercostal spaces and is impossible in patients with

ascites (9).

Acoustic radiation force impulse (ARFI) imaging can be performed with clear observation of the

actual measuring site with B-mode imaging and can be used even in obese patients and in patients

with ascites (10–14). In our recent study (11), SS evaluated by using ARFI imaging was shown to be

closely correlated with the presence of EVs; however, that study did not have the reference standard

of HVPG.

The aim of our current study was to evaluate the accuracy of SS and LS measured by using ARFI

imaging in the diagnosis of portal hypertension in patients with liver cirrhosis, with HVPG as a

reference standard.

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Material and methods

Patients This study was performed in accordance with the guidelines of and was approved by our institutional

review board. Written informed consent was obtained.

Eighty patients with liver cirrhosis underwent assessment of portal pressure and endoscopic findings

before starting prophylactic treatment with a β-blocker or endoscopic treatment; these patients

were considered for inclusion in the study between February 2012 and August 2013 on being

referred to the Kurashiki Central Hospital.

Of these 80 patients, 18 were excluded for the following reasons: episodes of recent (<6 months)

gastrointestinal bleeding (n = 8), a history of splenectomy (n = 2), a history of partial splenic

embolization (n = 2), a history of β-blocker therapy (n = 4), and the presence of portal thrombosis (n

= 2) (Fig 1).

Figure 1: Flowchart of study participants.

A diagnosis of cirrhosis was determined as described previously (12,13) on the basis of the results of

histologic examination of liver tissue or combined physical, laboratory, and radiologic findings.

ARFI measurements in each patient were obtained by using an ultrasonography (US) system (Acuson

S2000; Siemens, Erlangen, Germany) by one of two sonographers (J.T. and A.S., with 10 and 15 years

of experience, respectively) who were blinded to the clinical data. After an overnight fast, each

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patient was placed in the supine position and underwent ARFI imaging with B-mode imaging. A

region of interest (a fixed-dimension 1 × 0.5-cm box; maximum evaluable depth, 5.5 cm) in the liver

and spleen parenchyma that was free of large blood vessels was selected. LS was measured in the

right lobe of the liver, 1 cm below the liver capsule, by using the intercostal approach. SS was

measured 1 cm below the spleen capsule by using the intercostal approach. ARFI shear-wave velocity

was measured in meters per second. According to previous reports (10,14,15), more than five

successful measurements should be performed for each patient. Thus, five valid measurements were

performed in the liver and in the spleen of each patient, and median values were calculated. LS or SS

measurement failure was defined as when there were zero valid shots, and unreliable measurements

were defined as when the ratio of the interquartile range to the median value was greater than 30%

or when the success rate was less than 60% (9,16). The maximum spleen bipolar diameter was

estimated by using US and was expressed in millimeters. Platelet count to spleen diameter ratio

(PSR) (17) was calculated for all patients. Clinical and laboratory parameters were measured in each

patient on the day of US, which included ARFI imaging.

Within 1 week (mean, 2.3 days; range, 1–6 days) after the measurement of LS and SS, HVPG

measurements were performed in patients who had fasted overnight by a hepatologist (Y.T., with 18

years of experience with HVPG measurement) who was blinded to the US data. The right hepatic vein

was catheterized percutaneously through the femoral vein, and pressure was recorded in both the

wedged position and the free position with a 5- or 6-F balloon-tipped catheter (Terumo, Tokyo,

Japan). HVPG was determined by subtracting the free hepatic vein pressure from the wedged hepatic

vein pressure, and all measurements were performed in triplicate. Clinically important portal

hypertension was defined as an HVPG of 10 mm Hg or greater, and severe portal hypertension was

defined as an HVPG of 12 mm Hg or greater, according to the Baveno V criteria (18).

After the US examinations, all patients also underwent screening upper gastrointestinal endoscopy,

and the presence of EVs was determined by one of six endoscopists (each with more than 7 years of

experience), who were blinded to the US data and HVPG. EVs were classified on the basis of the

criteria for describing endoscopic findings of esophagogastric varices in Japan (19). The severity of

EVs was classified as follows: A score of F1 indicated straight and small-caliber varices; a score of F2,

beady varices; and a score of F3, tumor-shaped varices. Presence of a red color indicated a high risk

of variceal bleeding. EVs in danger of rupture (high-risk EVs) were defined as F2 or F3 EVs or as F1 EVs

with red color signs or Child-Pugh class C disease according to the Baveno V criteria (18). Low-risk EVs

were defined as F1 EVs without red color signs or Child-Pugh class C disease. If the patients had high-

risk EVs or clinically important portal hypertension, administration of a β-blocker or endoscopic

treatment was considered.

Complete evaluation for each patient (US and endoscopic measurements) was performed within 3

months (mean, 1.4 months; range, 1 day to 2.90 months).

Statistical Analysis After we analyzed the normal or nonnormal distribution of the continuous variables with the

Kolmogorov-Smirnov test, we examined differences between continuous and categoric variables

using the Student t test (for normally distributed variables), the Mann-Whitney test (for non-

normally distributed variables), and the χ2 test. Variables found to be associated with the presence

of clinically important portal hypertension and severe portal hypertension at univariate analysis (P

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< .05) were entered into multivariate backward stepwise logistic regression analysis. SS and LS were

separately entered into each multivariate analysis because of the strong correlation between SS and

LS (r = 0.689), which might cause errors in multivariate analysis.

Linear correlations between noninvasive parameters of portal hypertension and HVPG were assessed

by using the Spearman rank-order correlation coefficient (r). To compare the performance of two

correlation coefficients, we performed the Steiger Z test for correlated correlations within a

population (20). By convention, values greater than |1.96| are considered significant if a two-tailed

test is performed.

Receiver operating characteristic curve analysis of the parameters was used to assess their diagnostic

value for identifying clinically important portal hypertension, severe portal hypertension, EVs, and

high-risk EVs. The method suggested by DeLong et al (21) was used to compare the areas under the

receiver operating characteristic curve (AUCs) of various parameters of portal hypertension such as

SS, LS, spleen diameter, platelet count, and PSR. The overall performance of the models was

evaluated with the Nagelkerke R2 and the Brier score. A higher R2 and a lower Brier score indicate

better discriminative performance (Brier scores range from 0 [perfect] to 0.25 [worthless]) (22).

Diagnostic value was calculated by using sensitivity, specificity, positive predictive value (PPV),

negative predictive value (NPV), accuracy, positive likelihood ratio (PLR), and negative likelihood ratio

(NLR). Cutoff values were chosen according to the aim of the screening test (to rule out the presence

of any condition), choosing the lowest NLR. Data are given as means or as values with 95%

confidence intervals (CIs). For all analyses, P < .05 was considered to indicate a statistically significant

difference. Data were analyzed by using SPSS 16.0 J for Windows (SPSS, Chicago, Ill), MedCalc

(MedCalc Software, Broekstraat, Mariakerke, Belgium), and R software, version 3.0.1.

Results

Baseline Characteristics of Patients with Liver Cirrhosis Among the 62 patients who satisfied the inclusion criteria, two had an inconclusive SS measurement

because the spleen was poorly visualized secondary to obesity or gastrointestinal gas. In total, there

were 60 patients in the final analysis group.

Table 1 shows the clinical, biochemical, endoscopic, and US characteristics of the 60 patients. The

mean age was 70.8 years, 34 patients (56.7%) were male, and 36 patients (60.0%) had histologically

proven cirrhosis. A total of 34 patients (56.7%) had clinically important portal hypertension, 29

(48.3%) had severe portal hypertension, 24 (40.0%) had EVs, and 16 (26.7%) had high-risk EVs.

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Table 1 Baseline Patient Characteristics

Note.—Data are means 6 standard deviations or numbers of patients, with percentages in parentheses. AST = aspartate aminotransferase. * P = .99.

Clinical Parameters for Identifying Clinically Important Portal

Hypertension and Severe Portal Hypertension Platelet count, prothrombin time, albumin level, ALT level, Child-Pugh classification, LS, SS, and PSR

were associated with the presence of clinically important portal hypertension according to univariate

logistic regression analysis (P = .009, P = .012, P = .043, P = .005, P = .023, P < .001, P < .001, and P

= .008, respectively) (Table 2). SS was selected as an independent parameter associated with the

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presence of clinically important portal hypertension after adjustment for platelet count in

multivariate logistic regression analysis (P < .001) (Table 2). Furthermore, LS was also selected as an

independent parameter associated with the presence of clinically important portal hypertension

after adjustment for ALT level in multivariate logistic regression analysis (P = .001).

Platelet count, prothrombin time, albumin, ALT level, Child-Pugh classification, LS, SS, spleen

diameter, and PSR were significant parameters associated with the presence of severe portal

hypertension in univariate logistic regression analysis (P = .007, P = .003, P = .022, P = .006, P = .002, P

< .001, P < .001, P = .010, and P = .001, respectively) (Table E1 [online]). SS was selected as an

independent parameter associated with the presence of severe portal hypertension after adjustment

for platelet count in multivariate logistic regression analysis (P < .001). Furthermore, LS was also

selected as an independent parameter associated with the presence of severe portal hypertension

after adjustment for ALT level and spleen diameter in multivariate logistic regression analysis (P

= .001).

Table 2 Univariate and Multivariate Analysis of Clinical Parameters for Patients with HVPG Greater

than 10 mm Hg

Note.—Data in parentheses are 95% CIs. AST = aspartate aminotransferase.

Correlations of SS, LS, and HVPG Both SS and LS were strongly linearly correlated with HVPG (SS: r = 0.876; LS: r = 0.609) (Fig 2). The

correlation coefficient between SS and HVPG was significantly higher than that between LS and HVPG

(P < .0001). In patients with an HVPG of 10 mm Hg or greater (n = 34), both SS and LS were

significantly correlated with HVPG (SS: r = 0.764; LS: r = 0.426) (Fig 3). The correlation coefficient

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between SS and HVPG was significantly higher than that between LS and HVPG (P = .017). In patients

with an HVPG of less than 10 mm Hg (n = 26), there was a significant correlation between HVPG and

SS (r = 0.451), while no correlation was observed between HVPG and LS (r = 0.034) (Fig 3).

Figure 2: Scatterplots show correlations between HVPG and, A, SS and, B, LS.

Figure 3: A, B, Scatterplots show correlations between HVPG and, A, SS and, B, LS in patients with an HVPG of 10 mm Hg or greater (n =

34). C, D, Scatterplots show correlations between HVPG and, C, SS and, D, LS in patients with an HVPG of less than 10 mm Hg (n = 26).

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AUCs of SS and Other Noninvasive Parameters for Identifying Clinically

Important Portal Hypertension and Severe Portal Hypertension Among these parameters, SS was the most accurate diagnostic factor for clinically important portal

hypertension (AUC, 0.943; 95% CI: 0.852, 0.987) and severe portal hypertension (AUC, 0.963; 95% CI:

0.880, 0.995), and both AUCs of SS were significantly higher than those of LS, spleen diameter,

platelet count, and PSR (P < .05 for all) (Table 3). Indicating its overall diagnostic performance for

clinically important portal hypertension and severe portal hypertension, SS had high Nagelkerke R2

values (0.710 for clinically important portal hypertension and 0.770 for severe portal hypertension)

and low Brier scores (0.100 for clinically important portal hypertension and 0.080 for severe portal

hypertension) (Table 3).

Thus, SS had the best overall performance for the diagnosis of clinically important and severe portal

hypertension.

Table 3 Performance of Clinical Parameters for Association with Portal Hypertension

Note.—Data in parentheses are 95% CIs.

AUCs of SS and Other Noninvasive Parameters for Identifying EVs and High-

Risk EVs SS was the most accurate diagnostic factor for EVs (AUC, 0.937; 95% CI: 0.844, 0.984) and high-risk

EVs (AUC, 0.955; 95% CI: 0.867, 0.992) and both AUCs for association with EVs and high-risk EVs of SS

were significantly higher than those of LS, spleen diameter, platelet count, and PSR (P < .05 for all for

both parameters) (Table E2 [online]).SS had high Nagelkerke R2 values (0.684 for EVs and 0.717 for

high-risk EVs), low Brier scores (0.099 for EVs and 0.081 for high-risk EVs) (Table E2 [online]).

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Diagnostic Ability of SS for Identifying Clinically Important Portal

Hypertension, Severe Portal Hypertension, EVs, and High-Risk EVs The SS cutoff values of 3.10, 3.15, 3.36, and 3.51 m/sec were selected to rule out the presence of

clinically important portal hypertension, severe portal hypertension, EVs, and high-risk EVs

(sensitivity, 97.1%, 96.6%, 95.8%, and 93.8%, respectively; NLR, 0.051, 0.056, 0.054, and 0.074,

respectively) (Table 4).

Table 4 Cutoff Values and Diagnostic Accuracies of SS for Association with Portal Hypertension and

EVs

Note.—Data in parentheses are percentages, with 95% CIs in square brackets.

Among 24 patients with EVs, 23 (95.8%) had high SS values (≥3.36 m/sec) (Fig 4), while one patient

had a low SS value (3.18 m/sec) and had small EVs without the red color sign. No high-risk EV was

misdiagnosed with the SS cutoff value at 3.36 m/sec, which was proposed to rule out EVs. Moreover,

no EVs were observed when the SS cutoff value was set at 3.10 m/sec, which was proposed to rule

out clinically important portal hypertension.

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Figure 4: Dot diagrams show findings of SS in the absence and presence of, A, clinically important portal hypertension, B, severe portal

hypertension, C, EVs, and, D, high-risk EVs in patients with cirrhosis. Solid line = optimal cutoff value. Dot = a patient.

Discussion We found that the AUCs of SS for identifying clinically important portal hypertension, severe portal

hypertension, EVs, and high-risk EVs were excellent (0.943, 0.963, 0.937, and 0.955, respectively).

Similar to results of previous studies (23,24), our results showed that the AUC for identifying EVs with

LS measured at ARFI imaging was 0.789, and LS was therefore considered useful, but not excellent.

Thus, these results suggest that, in most patients evaluated by using SS, SS could be used to diagnose

clinically important portal hypertension and severe portal hypertension associated with EVs and

high-risk EVs. Thus, if our results are corroborated by future prospective studies, SS could potentially

be used as an indication for screening endoscopy and prophylactic treatments such as β-blocker

therapy or endoscopic variceal ligation. Moreover, the SS cutoff value of 3.51 m/sec proposed to rule

out high-risk EVs was able to exclude the EVs in danger of rupture with a sensitivity of 93.8% and an

NLR of 0.074.

Furthermore, no high-risk EVs were misdiagnosed with the SS cutoff value of 3.36 m/sec proposed to

rule out EVs, and no EV was observed when the SS cutoff value was less than the 3.10 m/sec

proposed to rule out clinically important portal hypertension.

In this study, we clearly demonstrated that the correlation coefficient between SS and HVPG was

significantly higher than that between LS and HVPG (r = 0.876 vs r = 0.609, P < .0001). Furthermore,

the correlation coefficient between SS and HVPG was significantly higher than that between LS and

HVPG (r = 0.764 vs r = 0.426, P = .017) in patients with an HVPG of 10 mm Hg or greater.

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A few investigators have assessed the correlation coefficient between SS and HVPG. Hirooka et al

(27) reported that although both SS and LS values obtained by using real-time tissue elastography

were linearly correlated with HVPG, the r value was higher for SS than for LS (r = 0.854 and r = 0.510,

respectively). Colecchia et al (8) concluded that both SS and LS values obtained by using transient

elastography were strongly correlated with HVPG (r = 0.885 and r = 0.836, respectively). However,

these previous studies did not provide the statistical comparison of the strength of the two

correlation coefficients (SS and HVPG vs LS and HVPG). Talwalkar et al (28) suggested that SS values

greater than 10.5 kPa measured at magnetic resonance elastography in compensated cirrhosis were

associated with EVs in all patients. These results indicate that additional assessment of SS may be

better than measuring LS for identifying portal hypertension and EVs.

In a systematic review (29) of 12 studies of the diagnostic accuracy of transient elastography–based

LS measurements, the diagnostic odds ratios for detecting the presence of any EV and large EVs were

7.5 (95% CI: 4.5, 12.7) and 8.8 (95% CI: 5.9, 13.2), respectively. Comparable diagnostic odds ratios for

SS were 19.3 and 12.6, respectively, and the diagnostic performance of SS was significantly better

than that of LS. SS is potentially characterized by a wider range of applications than is LS, because SS

directly reflects the hemodynamic changes of extrahepatic factors caused by increases in portal

pressure such as hyperdynamic splanchnic circulation and portosystemic collateral vessels (4,8,29).

An elevated SS value may be caused not only by congestion of the red pulp and tissue hyperplasia

but also by diffuse fibrosis of spleen trabeculae (30,31).

Vizzutti et al (4) reported that strong correlation between HVPG and LS was observed in patients with

an HVPG of less than 10 mm Hg and in those with an HVPG of less than 12 mm Hg (r = 0.81, P < .0001

and r = 0.91, P < .0001, respectively). In contrast, in our study, there was poor correlation between

HVPG and LS in patients with an HVPG of less than 10 mm Hg (r = 0.034, P = .869).

An important clinical advantage of the ARFI device is that the success rate of ARFI measurements is

higher than that of transient elastography measurements (33,34). In fact, the rates of unsuccessful

measurements of LS and SS at ARFI imaging in our study were 0% and 3.2%, respectively. In contrast,

rates of unsuccessful measurements of LS and SS at transient elastography have been reported to be

18.9% (9) and 14.6% (23), respectively. Furthermore, in a prior study (11), we showed that LS and SS

measurements consistently had excellent reproducibility, with intraobserver and interobserver

agreement intraclass correlation coefficients of ARFI measurements of 0.97 and 0.97 for LS and 0.98

and 0.98 for SS, respectively.

We found that SS measurement at ARFI imaging had a high diagnostic performance for defining the

degree of portal hypertension (HVPG ≥ 10 or ≥ 12 mm Hg). However, our study was a cross-sectional

study. More recently, Colecchia et al (35) reported that SS value obtained by using transient

elastography represented an accurate predictor of clinical decompensation, with accuracy at least

equivalent to that of HVPG, in patients with compensated cirrhosis in a longitudinal cohort study.

Therefore, a longitudinal cohort study needs to be performed of the prediction of complications of

cirrhosis with ARFI imaging.

The limitations of this study included the facts that the sample size of 60 participants was relatively

small, the timing of SS measurements was not fixed, and this was a single-center study without

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external validation. We used the current population to set our thresholds for analysis, which can lead

to an overestimation of results.

In conclusion, SS measured by using ARFI imaging provides excellent diagnostic performance for

identifying portal hypertension in liver cirrhosis. Our findings are complementary to those of

previous studies that suggest a role for SS measurements in the treatment of patients with liver

cirrhosis. The measurement of SS could help select suitable patients for procedures such as screening

endoscopy or prophylactic treatment for decompensation.

References 1. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of

survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44(1):217–

231.

2. Bosch J, Garcia-Pagán JC, Berzigotti A, Abraldes JG. Measurement of portal

pressure and its role in the management of chronic liver disease. Semin Liver Dis

2006;26(4):348–362.

3. Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications,

and outcomes. Gastroenterology 2002;122(6):1620–1630.

4. Vizzutti F, Arena U, Romanelli RG, et al. Liver stiffness measurement predicts

severe portal hypertension in patients with HCV-related cirrhosis. Hepatology

2007;45(5):1290–1297.

5. Bureau C, Metivier S, Peron JM, et al. Transient elastography accurately

predicts presence of significant portal hypertension in patients with chronic liver

disease. Aliment Pharmacol Ther 2008;27(12):1261–1268.

6. Lemoine M, Katsahian S, Ziol M, et al. Liver stiffness measurement as a

predictive tool of clinically significant portal hypertension in patients with

compensated hepatitis C virus or alcohol-related cirrhosis. Aliment Pharmacol

Ther 2008;28(9):1102–1110.

7. Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension

using transient elastography. J Hepatol 2012;56(3):696–703.

8. Colecchia A, Montrone L, Scaioli E, et al. Measurement of spleen stiffness to

evaluate portal hypertension and the presence of esophageal varices in patients

with HCV-related cirrhosis. Gastroenterology 2012;143(3):646–654.

9. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement:

a 5-year prospective study of 13,369 examinations. Hepatology 2010;51(3):828–

835. Medline

10. Friedrich-Rust M, Nierhoff J, Lupsor M, et al. Performance of

Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a

pooled meta-analysis. J Viral Hepat 2012;19(2):e212–e219.

11. Takuma Y, Nouso K, Morimoto Y, et al. Measurement of spleen

stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients

with esophageal varices. Gastroenterology 2013;144(1):92–101.e2.

12. Di Lelio A, Cestari C, Lomazzi A, Beretta L. Cirrhosis: diagnosis with

sonographic study of the liver surface. Radiology 1989;172(2):389–392. Abstract,

Medline

13. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet

2008;371(9615):838–851.

14. Takahashi H, Ono N, Eguchi Y, et al. Evaluation of acoustic

radiation force impulse elastography for fibrosis staging of chronic liver disease:

a pilot study. Liver Int 2010;30(4):538–545.

15. Yoneda M, Suzuki K, Kato S, et al. Nonalcoholic fatty liver disease:

US-based acoustic radiation force impulse elastography. Radiology

2010;256(2):640–647. Abstract, Medline

16. Friedrich-Rust M, Wunder K, Kriener S, et al. Liver fibrosis in viral

hepatitis: noninvasive assessment with acoustic radiation force impulse imaging

versus transient elastography. Radiology 2009;252(2):595–604. Abstract,

Medline

17. Giannini E, Botta F, Borro P, et al. Platelet count/spleen diameter

ratio: proposal and validation of a non-invasive parameter to predict the

presence of oesophageal varices in patients with liver cirrhosis. Gut

2003;52(8):1200–1205.

18. de Franchis R; Baveno V Faculty. Revising consensus in portal

hypertension: report of the Baveno V consensus workshop on methodology of

diagnosis and therapy in portal hypertension. J Hepatol 2010;53(4):762–768.

19. Idezuki Y. General rules for recording endoscopic findings of

esophagogastric varices (1991). Japanese Society for Portal Hypertension. World

J Surg 1995;19(3):420–422; discussion 423.

20. Steiger JH. Tests for comparing elements of a correlation matrix.

Psychol Bull 1980;87(2):245–251. CrossRef

21. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas

under two or more correlated receiver operating characteristic curves: a

nonparametric approach. Biometrics 1988;44(3):837–845.

22. Gerds TA, Andersen PK, Kattan MW. Calibration plots for risk

prediction models in the presence of competing risks. Stat Med

2014;33(18):3191–3203.

23. Stefanescu H, Grigorescu M, Lupsor M, Procopet B, Maniu A,

Badea R. Spleen stiffness measurement using Fibroscan for the noninvasive

assessment of esophageal varices in liver cirrhosis patients. J Gastroenterol

Hepatol 2011;26(1):164–170.

24. Foucher J, Chanteloup E, Vergniol J, et al. Diagnosis of cirrhosis by

transient elastography (FibroScan): a prospective study. Gut 2006;55(3):403–408.

25. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE,

Glickman M. Portal pressure, presence of gastroesophageal varices and variceal

bleeding. Hepatology 1985;5(3):419–424.

26. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous

pressure gradient predicts clinical decompensation in patients with

compensated cirrhosis. Gastroenterology 2007;133(2):481–488.

27. Hirooka M, Ochi H, Koizumi Y, et al. Splenic elasticity measured

with real-time tissue elastography is a marker of portal hypertension. Radiology

2011;261(3):960–968. Abstract, Medline

28. Talwalkar JA, Yin M, Venkatesh S, et al. Feasibility of in vivo MR

elastographic splenic stiffness measurements in the assessment of portal

hypertension. AJR Am J Roentgenol 2009;193(1):122–127.

29. Singh S, Eaton JE, Murad MH, Tanaka H, Iijima H, Talwalkar JA.

Accuracy of spleen stiffness measurement in detection of esophageal varices in

patients with chronic liver disease: systematic review and meta-analysis. Clin

Gastroenterol Hepatol 2014;12(6):935–45.e4.

30. Manenti A, Botticelli A, Gibertini G, Botticelli L. Experimental

congestive splenomegaly: histological observations in the rat. Pathologica

1993;85(1100):721–724. Medline

31. Terayama N, Makimoto KP, Kobayashi S, et al. Pathology of the

spleen in primary biliary cirrhosis: an autopsy study. Pathol Int 1994;44(10-

11):753–758.

32. Elkrief L, Rautou PE, Ronot M, et al. Prospective comparison of

spleen and liver stiffness by using shear-wave and transient elastography for

detection of portal hypertension in cirrhosis. Radiology 2015;275(2):589–598.

Abstract, Medline

33. Rifai K, Cornberg J, Mederacke I, et al. Clinical feasibility of liver

elastography by acoustic radiation force impulse imaging (ARFI). Dig Liver Dis

2011;43(6):491–497.

34. Rizzo L, Calvaruso V, Cacopardo B, et al. Comparison of transient

elastography and acoustic radiation force impulse for non-invasive staging of

liver fibrosis in patients with chronic hepatitis C. Am J Gastroenterol

2011;106(12):2112–2120.

35. Colecchia A, Colli A, Casazza G, et al. Spleen stiffness

measurement can predict clinical complications in compensated HCV-related

cirrhosis: a prospective study. J Hepatol 2014;60(6):1158–1