Fifty-nine consecutive patients with cirrhosis (48 men and 11 women, mean age 49.5±8.9; age range 29-69 years) underwent HVPG measurement between February 1, 2009 and February 1, 2010 upon referral to the hemodynamic laboratory of our institution. All patients had previous histopathological confirmation of cirrhosis (METAVIR F4)16 or a diagnosis of cirrhosis suspected on the basis of standard clinical, ultrasonographic, and biochemical parameters. Exclusion criteria were an age younger than 19 or older than 75 years, shock status requiring a vasopressor, active infection (e.g., spontaneous bacterial peritonitis), acute renal failure of any cause, hepatocellular carcinoma or a history of another primary malignancy within 3 years, clinically relevant coronary artery disease (NYHA functional angina classification III/IV), congestive heart failure NYHA III/IV, clinically relevant cardiomyopathy, history of myocardial infarction in the past 1 year, poorly controlled hypertension (blood pressure >150/100) mmHg, transaminases above tenfold the upper limit of normal, ongoing antiviral therapy, the use of vasoactive drugs, including beta-blockers, diuretics, and anti-inflammatory drugs, pregnancy or lactation, involvement in another study within 90 days, and medical or psychological conditions that would not permit the subject to complete the study or sign informed consent. The study protocol was approved by the Institutional Review Board for Human Research at the Yonsei University Wonju Severance Christian Hospital (Wonju, Republic of Korea). The nature of the study was explained to all patients, each of whom provided written informed consent before the beginning of the study, in accordance with the principles of the Declaration of Helsinki (revision of Edinburgh, 2000).

After an overnight fasting, all patients underwent a complete abdominal ultrasonography examination in the morning. Immediately following the examination, TE was performed by two experienced operators. The Fibroscan device (Fibroscan®, Echosens, France) consists of a 3.5 MHz ultrasound transducer M probe mounted on the axis of a vibrator. Mild amplitude and low-frequency vibrations (50 Hz) are transmitted to the liver tissue, inducing an elastic shear wave that propagates through the underlying liver tissue. TE was performed as previously described on the right lobe of the liver; in the intercostal space with the patient lying in dorsal decubitus with the right arm at maximal abduction.17-18 The operator, assisted by an ultrasonic time-motion image, located a liver portion at least 6 cm thick and free of large vascular structures and the gallbladder. Ten successful measurements were performed on each patient. The success rate was calculated as the ratio of the number of successful measurements over the total number of acquisitions. Only LSM with an interquartile range ≤30% of the median value and a success rate of at least 60% were considered reliable. Results are expressed in kilopascals (kPa) and the median value was used a representative of LSM.

After an overnight fast, the HVPG was measured. The right hepatic vein was catheterized percutaneously through the femoral vein, and the pressures in both the wedged and the free positions were recorded with a 7-F balloon-tipped catheter (Arrow Deutschland, PostfachErding, Germany). In case that shunt was observed in right hepatic vein, HVPG was measured in middle hepatic vein. All measurements were performed at least in triplicate, and permanent tracings were obtained on a multichannel recorder.19,20 HVPG was determined by subtracting the free hepatic venous pressure from the wedged hepatic venous pressure.3 An examiner (Y.J.K.) with 12 years of experience with HVPG measurement performed all HVPG procedures. Clinically significant portal hypertension (CSPH) was defined as an HVPG ≥10 mmHg according a consensus definition.21 Severe portal hypertension was defined as an HVPG ≥12 mmHg.

Laboratory Parameters were obtained in all patients on the day of HVPG measurement and included serum albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase, platelet count, hemoglobin, hematocrit, white blood cell, International Normalized Ratio (INR), blood urea nitrogen, creatinine, electrolyte, and C-reactive protein. The model for end-stage liver disease (MELD) and the Child-Pugh score were calculated.

Statistical analyses performed using SPSS 18.0 for Windows. All results are expressed as mean±standard deviation (SD). Linear regression analyses were calculated according to the least squares methods. P-values less than 0.05 were considered statistically significant. The statistical significance of inter-group differences was evaluated by the means of the spearman rank correlation coefficient. The relationship between sensitivity and specificity of LSM at different cutoff points; as a predictor of patients with HVPG ≥10 mmHg or patients with HVPG ≥12 mmHg was evaluated by receiver operating characteristic (ROC) curves. Optimal liver stiffness cutoff values were selected on the basis of sensitivity, specificity, and positive and negative predictive values.

The characteristics of the patients are summarized in Table 1. The etiology of cirrhosis was classified as alcohol (36, 61.0%), hepatitis B virus (13, 22.0%), alcohol with hepatitis B virus (5, 8.5%), alcohol with hepatitis C virus (2, 3.4%), and cryptogenic cirrhosis (3, 5.1%). The mean Child-Pugh and MELD scores were 6.5±1.8 and 9.6±3.7 (range 6-21), respectively. Mean HVPG and LSM were 13.1±5.2 mmHg (range 5-24) and 36.5±23.6 kPa (range 5.4-75.0), respectively.

Considering the whole patient population, a statistically significant positive correlation between HVPG and LSM was found (Fig. 1). Figure 1A demonstrates significant linear correlation between HVPG and LSM (r²=0.496, P< 0.05). In patients with HVPG ≥10 mmHg or ≥12 mmHg, there was a statistically significant correlation with LSM (r²=0.297, P<0.05 and r²=0.192, P=0.05, respectively) (Fig. 1B and 1C). However, in case of HVPG ≥12 mmHg, the correlation was relatively weak compared with that of the HVPG ≥10 mmHg group.

Figure 2 presents the ROC curve of LSM for the prediction of CSPH. In case of HVPG ≥10 mmHg, the area under the ROC curves (AUROC) was 0.851 (95% confidence index 0.752-0.949). In cases of HVPG ≥12 mmHg, the AUROC was 0.877 (95% confidence index 0.792-0.962). Based on the ROC curves, different cutoff values for LSM were determined. An LSM ≥21.95 kPa exhibited a positive predictive value (PPV) of 86.8% and a negative predictive value (NPV) of 66.7% with a sensitivity of 82.5% and a specificity 73.7% for the prediction of patients with HVPG ≥10 mmHg. An LSM ≥24.25 kPa exhibited a PPV of 80.6% and an NPV of 73.9% with a sensitivity of 82.9% and a specificity of 70.8% for the prediction of patients with HVPG ≥12 mmHg.