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Point Shear Wave Elastography for Non-invasive Assessment of Liver Fibrosis in Patients with Viral Hepatitis
ARTICLE IN PRESS Ultrasound in Med. & Biol., Vol. 00, No. 00, pp. 19, 2018 Copyright © 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Printed in the USA. All rights reserved. 0301-5629/$ - see front matter
https://doi.org/10.1016/j.ultrasmedbio.2018.07.031
Original Contribution POINT SHEAR WAVE ELASTOGRAPHY FOR NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS IN PATIENTS WITH VIRAL HEPATITIS TAGEDPTHERESA BUCSICS,*,y BENJAMIN GRASL,*,y ARNULF FERLITSCH,*,y,1 PHILIPP SCHWABL,*,y MATTIAS MANDORFER,*,y KERSTIN ZINOBER,*,y RAFAEL STERN,*,2 DAVID CHROMY,*,y BERNHARD SCHEINER,*,y WOLFGANG SIEGHART,*,y MARKUS PECK-RADOSAVLJEVIC,*,y,3 MICHAEL TRAUNER,* and THOMAS REIBERGER*,yAGEDNTE * Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and y Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria (Received 3 May 2018; revised 19 July 2018; in final from 28 July 2018)
Abstract—Elastography point quantification (ElastPQ) is a new ultrasound-based shear wave elastography method for non-invasive assessment of liver fibrosis. We evaluated the diagnostic accuracy of ElastPQ in patients with chronic viral hepatitis. Fibrosis stage (F) was determined by transient elastography (F0/F1: <7.1 kPa, F2: 7.19.4 kPa, F3: 9.512.4 kPa, F4: 12.5 kPa). Area under the receiver operator characteristics curve (AUROC) analysis was performed to assess ElastPQ cutoffs for significant fibrosis (F2) and cirrhosis (F4). Paired transient elastography and ElastPQ measurements were obtained from 217 patients (mean age § SEM: 49 § 0.79 years, 68.2% male, F0/F1: n = 98 [45.0%], F2: 47 [21.6%], F3: 22 [10.1%], F4: 50 [22.9%]). AUROC for F2 was 0.843 (95% confidence interval: 0.7910.895), and for F4, 0.933 (95% confidence interval: 0.8940.972). The optimal ElastPQ cutoff for F2 was 6.68 kPa (sensitivity: 80.7%, specificity: 70.4%, positive predictive value: 78.5%, negative predictive value: 72.3%), and for F4 11.28 kPa (sensitivity: 86.0%, specificity: 85.6%, positive predictive value: 60.52%, negative predictive value: 97.16%). In conclusion, ElastPQ represents an accurate tool for non-invasive staging of liver fibrosis in patients with viral hepatitis. (E-mail: [email protected]) © 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Liver fibrosis, Viral hepatitis, Transient elastography, Shear wave elastography.
biopsy. However, even if liver biopsy is considered the ‘imperfect gold standard’ for fibrosis assessment (European Association for the Study of the Liver [EASL] Asociacion Latinoamericana para el Estudio del Higado [ALEH] 2015; Bravo et al. 2001) as it can assess both fibrosis stage and necro-inflammation (Bedossa and Poynard 1996), it may cause severe complications requiring hospitalization in about 1%3% of cases. Moreover, histologic assessment by liver biopsy is associated with considerable sample error and interobserver variability (Regev et al. 2002). More recently, non-invasive methods including elastography (EASL 2014) and blood-based fibrosis scores (Castera et al. 2005; Maieron et al. 2013; Poynard et al. 2011; Voican et al. 2017) have increasingly been used for screening for liver fibrosis in clinical practice. Non-invasive liver elastography can be performed either via magnetic resonance imaging (MRI elastography) or using ultrasound-based techniques
INTRODUCTION Chronic liver diseases represent a major global contributor to morbidity and mortality, with hepatitis B virus (HBV) and hepatitis C virus (HCV) among the most common etiologies (Blachier et al. 2013; Hatzakis et al. 2011; Ott et al. 2012; Rehm et al. 2013; Stanaway et al. 2016). Liver fibrosis, and ultimately cirrhosis, results from repetitive or ongoing liver injury (Tsochatzis et al. 2014) and has traditionally been assessed by liver Address correspondence to: Thomas Reiberger, Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: [email protected] 1 Present address: Department of Internal Medicine, Krankenhaus der Barmherzigen Br€uder Wien, Vienna, Austria. 2 Present address: Department of Internal Medicine, Krankenhaus Oberpullendorf, Oberpullendorf, Austria. 3 Present adress: Department of Gastroenterology, Hepatology, Endocrinology, and Nephrology, Klinikum Klagenfurt am Woerthersee, Klagenfurt, Austria
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(Barr et al. 2016). Currently, two types of ultrasound-based elastography modalities are commercially available: strain or transient elastography (TE) and shear wave elastography (SWE) (Barr 2018). Although results are commonly expressed in kilopascals (kPa) or as shear wave propagation velocity (m/s) when using SWE, cutoff values for fibrosis staging cannot be readily compared across different elastography techniques. At the moment, TE is the most widely used and best validated method for assessing liver fibrosis (Castera et al. 2008). TE is performed using a self-standing system equipped with specific probes according to a standardized procedure and interpreted using previously published quality criteria (Schwabl et al. 2015). Point SWE is used in the acoustic radiation force impulse (ARFI) imaging system and the elastography point quantification (ElastPQ) system (Ferraioli et al. 2014; Lee et al. 2017), both implemented into conventional ultrasound devices using modified ultrasound probes. Thus, SWE can be used to assess the severity of liver fibrosis in patients with chronic viral hepatitis while performing a standard abdominal sonography examination. However, whereas ARFI has been thoroughly compared with TE in previous studies and meta-analyses (Berzigotti et al. 2011; Bota et al. 2013; Rizzo et al. 2011), data on cross-validation of the ElastPQ method to TE are limited (Ferraioli et al. 2016; Fraquelli et al. 2016; Lee et al. 2017; Mare et al. 2017). METHODS Study design This was a prospective single-center cross-sectional study to evaluate a novel point SWE method (Affiniti70, Philips Medical Systems, Bothell, WA, USA) for liver stiffness measurement in comparison to a well-validated TE system (FibroScan 502 Touch, Echosens, Paris, France) (Reiberger et al. 2012a). We aimed to establish optimal ElastPQ cutoff values for non-invasive diagnosis of significant fibrosis (F2) and cirrhosis (F4) in patients with chronic viral hepatitis to facilitate individualized therapy. Patients Consecutive patients with chronic viral hepatitis seen at the outpatient clinic at the Division of Gastroenterology and Hepatology of the Medical University of Vienna from April 2016 until September 2016 were screened. Patients on beta blocker therapy were not considered as beta blockers are known to affect liver stiffness measurements (Reiberger et al. 2012b). Patients with failure of TE or ElastPQ measurement
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or non-viral etiology of liver disease were excluded from this study. This study was approved by the local ethics committee of the Medical University of Vienna (EK No. 1667/2016) and has been performed in accordance with the Declaration of Helsinki. All patients provided written informed consent before participating in this study. Diagnostic devices and examination procedure All included patients underwent sequential noninvasive assessment of liver fibrosis using both quantitative ElastPQ (Affiniti 70) and TE (FibroScan 502 Touch). Measurements were performed only by trained medical personnel. Patients were examined in supine position with the right arm in maximal abduction. The probes were placed into an intercostal space above the right lobe of the liver. During examination, patients were asked to hold their breath in the mid-position of the respiratory circle, avoiding both Valsalva and deep inspiration maneuvers. In general, M probes were used for TE examinations but examiners were allowed to use XL probes when recommended by the system (skinliver capsule distance >2.5 cm). We aimed at 5 measurements per examination with the ElastPQ method, as 5 measurements have previously been reported to be sufficient (Ferraioli et al. 2016), and 10 valid measurements using TE. Clinical parameters Age, sex, etiology of liver disease, height, weight, body mass index and date of examination/study inclusion were documented for each patient. ElastPQ and TE examinations (including measurements of liver stiffness and controlled attenuation parameter [CAP], a marker indicative of steatosis) were performed in each patient as described above. The cutoff values from Castera et al. (2005) were used for non-invasive diagnosis of liver fibrosis (stratified by fibrosis stage [F]) in TE examination: F0/F1: <7.1 kPa, F2: 7.19.4 kPa, F3: 9.512.4 kPa, F4: 12.5 kPa. The following cutoff values were used for determining the grade of hepatic steatosis in TE examination according to CAP values (Karlas et al. 2017): S0: <248 dB/m, S1: 248-267 dB/m, S2/S3: 268 dB/m. Laboratory data necessary for calculating blood fibrosis scores and the model for end-stage liver disease (MELD; i.e., platelets (Plt), aspartate transaminase [AST], alanine transaminase [ALT], bilirubin, creatinine, international normalized ratio [INR], von Willebrand factor antigen [vWF]) were recorded from the most recent laboratory report (maximum of 30 d before study inclusion). Blood fibrosis scores for predicting liver fibrosis were computed as follows (Hametner et al. 2016; Maieron et al. 2013; Sterling et al. 2006; Wai et al. 2003):
ARTICLE IN PRESS Point Shear Wave Elastography for Non-invasive Assessment of Liver T. BUCSICS et al.
for the AST-to-platelet ratio index (APRI), AST½U=L AST½U=LULN1 Plt ½g=L1 for the fibrosis 4 score (FIB-4), 1 ðage½y AST½U=LÞ Plt½g=L ALT½U=L1=2 and for the von Willebrand factor antigen-to-thrombocyte ratio (VITRO), vWFð%Þ Pltðg=LÞ1 The upper limit of normal (ULN) of AST equals 50 IU/L according to our local laboratory. The MELD score was calculated as previously reported (Boursier et al. 2009; Kamath et al. 2001). Statistical analysis Quantitative variables are expressed as the mean (standard error of the mean [SEM]) unless otherwise noted. Categorical variables are presented as the absolute number (relative numbers, %). Comparisons between groups were calculated using Student’s t-test or the WilcoxonMannWhitney U-test when appropriate for quantitative variables, and the x2-test or Fisher’s exact test for qualitative variables where applicable. Correlations between variables were computed using Pearson’s or Spearman’s coefficient when appropriate. To assess the performance of liver fibrosis staging by point SWE (ElastPQ) in patients with chronic liver diseases, the sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values and area under the receiver operating characteristic curve (AUROC) were calculated for diagnosis of significant fibrosis (F2) or cirrhosis (F4) using TE as the reference standard for significant fibrosis (F2 7.1 kPa) and cirrhosis (F4 12.5 kPa). The respective ElastPQ cutoff values were identified using Youden’s index. The a error was set at 0.05. All p values are two-sided. Statistical analysis was performed using SPSS software (Version 24.0 for Windows, IBM, Armonk, NY, USA) and GraphPad Prism (Version 7.3 for Windows, GraphPad Software, La Jolla, CA, USA). RESULTS Patient characteristics During the study period, 222 individual patients with viral hepatitis presented at our outpatient clinics and signed written informed consent forms. After excluding n = 4 patients with invalid TE measurements and n = 1 patient with missing data, a final n = 217 patients were considered for the final analysis (Table 1). The mean age was 49 y, and about two-thirds of the study population were men (68.7%). HCV mono-infection
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Table 1. Patient characteristics* No. of patients
217
Sex Age Etiology HCV mono-infection HBV mono-infection HIV co-infection HBV/HCV co-infection Body mass index Liver stiffness (TE) XL probe used Controlled attenuation parameter (available in 211 patients) S0 S1 S2/S3 Liver stiffness (ElastPQ) IQR/median <30% Fibrosis stage (as determined by TE) F0/F1 F2 F3 F4 APRI score FIB-4 score VITRO score MELD score Laboratory data Aspartate transaminase Alanine transaminase g-Glutamyl transferase Platelets White blood cells Bilirubin Albumin Von Willebrand factor antigen
148/69 (68.2% male) 48.7 (0.79) y 139 (64.1%) 14 (6.5%) 57 (26.3%) 7 (3.2%) 25.2 (0.33) kg/m2 11.8 (0.8) kPa 30 (13.8%) 233.4 (4.37) dB/m 128 (60.7%) 20 (9.5%) 63 (29.9%) 10.6 (0.58) kPa 128 (59.0%) 98 (45.0%) 47 (21.6%) 22 (10.1%) 50 (22.9%) 0.35 [0.230.65] 1.45 [0.992.39] 1.06 [0.711.77] 8.0 (0.2) 34 [2651] U/L 33 [2057] U/L 34 [2167] U/L 202 [160248] g/L 6.40 (0.16) g/L 0.49 [0.360.72] mg/dL 44.1 (0.29) g/L 188% [148%246%]
APRI = aspartate transaminase-to-platelet ratio index; ElastPQ = elastography point quantification; FIB-4 = fibrosis 4 score; = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IQR = interquartile range; MELD = model for end-stage liver disease; HBV TE = transient elastography; VITRO = Von Willebrand factor antigen-to-thrombocyte ratio. * Data are expressed as the number (%), mean (standard error of the mean) or mean [interquartile range].
was the predominant etiology in 64.1% of patients, followed by viral co-infections (HBV/HCV or co-infection with HIV) in 29.5% of cases and HBV mono-infection in 6.5%. The median body mass index was 24.7 kg/m2 (SEM: 0.33 kg/m2). The CAP was available for n = 211 patients (97.2%) and was on average 233.4 (4.37) dB/m. Although 43.6% were diagnosed with S1 steatosis, significant steatosis was detected in 17.1% of patients (n = 36). The median APRI score was 0.35 (interquartile range [IQR]: 0.230.65), the median FIB-4 score was 1.45 (IQR: 0.992.39) and the median VITRO score was 1.06 (IQR: 0.711.77). Liver stiffness as evaluated by TE and ElastPQ The median liver stiffness measured by TE was 7.5 (IQR: 5.611.8) kPa. Overall, 98 patients (45.0%) presented without significant liver fibrosis in
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TE examination (F0/F1, <7.2 kPa), 47 (21.6%) patients were diagnosed with significant F2 fibrosis (7.29.5 kPa), 22 (10.1%) with F3 fibrosis (9.612.4 kPa) and 50 (22.9%) with F4/cirrhosis (12.5 kPa) (Table 2). Median liver stiffness as assessed using ElastPQ was 7.7 kPa. Liver stiffness values correlated well between ElastPQ and TE (r = 0.7025, p < 0.001) (Fig. 1A). Mean liver stiffness values as measured by ElastPQ were 6.21 kPa for F0/F1, 8.51 kPa for F2, 10.66 kPa for F3 and 21.16 kPa for F4 fibrosis using TE as reference. ElastPQ increased steadily between fibrosis stages and was able to distinguish no/minimal from significant fibrosis (F0/F1: 6.2 [0.25] kPa vs. F2: 8.5 [0.51] kPa, p < 0.0001) and advanced fibrosis from cirrhosis (F3: 10.7 [1.00] kPa vs. F4: 18.1 (1.65) kPa, p = 0.0007) but did not discriminate well between intermediate fibrosis stages (F2 vs. F3, p = 0.0667). Cutoff values for liver fibrosis staging using ElastPQ We computed an AUROC analysis and calculated Youden’s index to assess the optimal cutoff value for detecting F2 and F4 fibrosis using the ElastPQ method. A cutoff value of 6.68 kPa detected F2 fibrosis with a sensitivity of 80.7%, specificity of 70.4%, PPV of 78.45% and NPV of 72.28% (AUROC: 0.843, 95% CI: 0.7910.895). For determining F4 fibrosis (i.e., cirrhosis), we determined a cutoff value of 11.28 kPa (AUROC: 0.933, 95% confidence interval [CI]: 0.8940.972; sensitivity: 86%, specificity: 85.6%, PPV: 60.52%, NPV: 97.16%) (Fig. 1C, D). Table 2. Fibrosis scores by fibrosis stage, as stratified by TE and Elast-PQ* Fibrosis grade by transient elastography F0F1 F2 F3 F4 Stiffness (Elast-PQ, kPa) APRI FIB-4 VITRO MELD
6.21 (0.25) 8.51 (0.51) 10.66 (1.00) 21.16 (1.65) 0.52 (0.12) 1.72 (0.32) 1.46 (0.66) 7.21 (0.20)
0.57 (0.13) 1.60 (0.11) 1.06 (0.12) 7.79 (0.52)
Fibrosis grade (Elast-PQ) F0-F1 Stiffness (TE, kPa) APRI FIB-4 VITRO MELD
6.20 (0.23) 0.41 (0.07) 1.29 (0.07) 0.79 (0.10) 7.31 (0.30)
0.77 (0.15) 2.15 (0.24) 1.28 (0.17) 7.98 (0.44)
0.91 (0.13) 3.99 (0.42) 2.43 (0.38) 9.62 (0.45)
F2-F3
F4
9.61 (1.08) 0.90 (0.21) 2.62 (0.56) 2.07 (0.57) 7.66 (0.23)
21.46 (1.91) 0.76 (0.08) 3.31 (0.31) 2.03 (0.31) 9.23 (0.41)
APRI = aspartate transaminase-to-platelet ratio index; ElastPQ = elastography point quantification; FIB-4 = fibrosis 4 score; MELD = model for end-stage liver disease; TE = transient elastography; VITRO = Von Willebrand factor antigen-to-thrombocyte ratio. * Data are expressed as the mean (standard of the mean).
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Correlation of liver ElastPQ values with blood-based fibrosis scores and MELD score Parameters for calculating the APRI and FIB-4 scores were available in n = 213 (98.2%) patients, the MELD score was available for 199 patients (91.7%) and the VITRO score was calculated for only 90 patients (41.5%), because von Willebrand factor antigen was available for only a fraction of the patients. All fibrosis scores that were assessed correlated significantly with ElastPQ values, though there were several outliers in all scores. The best correlation was achieved with the FIB-4 score (Fig. 2B) (r = 0.5002 [95% CI: 0.38880.5973], p < 0.001), followed by APRI (r = 0.3991 [95% CI: 0.27600.5094], p < 0.001), while the correlation with ElastPQ values was just modest with VITRO (r = 0.3210 [95% CI: 0.1220-0.4951], p = 0.020). The MELD score, although not a marker for liver fibrosis but for liver function, also significantly correlated with ElastPQ values (r = 0.3901 [95% CI: 0.2616-0.5051], p < 0.001) (Figs. 2 and 3, Table 2). After determining the cutoff values for diagnosing liver fibrosis using ElastPQ by AUROC analysis (Fig. 1C, D), we consecutively stratified patients into F0/ F1 fibrosis (ElastPQ <6.68 kPa), F2/F3 fibrosis (ElastPQ 6.6811.27 kPa) and F4 fibrosis (ElastPQ 11.28 kPa). We then evaluated the association of ElastPQ fibrosis stages with serum fibrosis markers. Both APRI and VITRO differentiated well between patients with and without significant fibrosis (APRI: F0/F1 vs. F2/F3: mean = 0.41 (SEM = 0.67) vs. 0.90 (0.21), p = 0.0002; VITRO: F0/F1 vs. F2/F3: 0.79 (0.10) vs. 2.07 (0.57), p = 0.0014), but not between significant fibrosis and cirrhosis (APRI: F2/F3 vs. F4: 0.90 (0.21) vs. 0.76 (0.62), p = 0.1181; VITRO: F2/F3 vs. F4: 2.07 vs. 2.03, p = 0.6772). FIB-4, on the other hand, distinguished well between the different fibrosis stages (F0/F1 vs. F2/F3: 1.29 [0.07] vs. 2.62 [0.56], p = 0.0077; F2/F3 vs. F4: 2.62 [0.56] vs. 3.31 [0.31], p < 0.0001). Also, MELD increased significantly with each fibrosis stage (F0/F1: 7.31 vs. F2/F3: 7.66, p = 0.0241; F2/F3: 7.66 vs F4: 9.23, p = 0.0023). DISCUSSION Non-invasive assessment of liver fibrosis is increasingly used for monitoring liver disease progression or regression in order to guide antiviral therapy and to individualize clinical follow-up. Transient elastography (TE) is a well-validated method for estimating liver fibrosis and has drastically reduced the need for liver biopsy in recent years. SWE is an alternative, non-invasive method for assessing liver fibrosis, but data on the accuracy of the ElastPQ method for staging liver fibrosis is limited. Cutoff values for determining fibrosis stages
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Fig. 1. Liver stiffness measurement by TE versus ElastPQ and fibrosis staging. (A) Correlation of liver stiffness measurements by TE with measurements by ElastPQ. (B) ElastPQ values across the different fibrosis stages as determined by TE. (C) AUROC analysis for assessing the optimal single cutoff value for ElastPQ to detect significant fibrosis (F2). The cutoff value selected was >6.68 kPa. (D) AUROC analysis for assessing the optimal single cutoff value for ElastPQ to detect cirrhosis (F4). The cutoff value selected was >11.28 kPa. *p < 0.05. **p < 0.01. ***p < 0.001. Boxes depict median plus interquartile range; whiskers depict 5th and 95th percentiles. AUROC (AUC) = area under the receiver operating characteristic curve; ElastPQ = elastography point quantification; F = fibrosis stage, TE = transient elastography.
have been proposed (Ferraoli et al. 2016; Ma et al. 2014), but not yet validated in large patient cohorts. Thus, in this prospective study, we evaluated ElastPQ for non-invasive liver fibrosis stagin in 217 patients with chronic viral hepatitis. We demonstrared that liver stiffness measured by ElastPQ correlated well with the reference standard TE. An ElastPQ cutoff of 6.68 kPa detected significant fibrosis (F2) with an AUROC of 0.843, a sensitivity of 80.7% and a PPV of 78.45%. For diagnosis of F4/cirrhosis, we determined an ElastPQ cutoff at >11.28 kPa with an AUROC of 0.933 (95% CI: 0.8940.972) and a sensitivity and specificity of 86% and 85.6%, respectively. Of note, the ElastPQ cutoff
value of 11.28 kPa had excellent performance in ruling out cirrhosis with a NPV of 97.16%. Importantly, patients with chronic viral hepatitis with ElastPQ11.28kPa have a very low likelihood of developing complications related to cirrhosis or portal hypertension. On the other hand, patients with ElastPQ values >11.28 kPa should undergo regular screening for hepatocellular carcinoma, as well as endoscopy for evaluation of varices. Interestingly, ElastPQ results also correlated well with MELD, a score that reflects liver function and prognosis in patients with liver cirrhosis and is used for liver transplant allocation. This implicates that liver ElastPQ also reflects liver function and prognosis in patients with
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Fig. 2. Correlation of liver ElastPQ with liver fibrosis scores and MELD. (A) Correlation of liver ElastPQ with APRI. (B) Correlation of liver ElastPQ with the FIB-4 score. (C) Correlation of liver ElastPQ with VITRO score. (D) Correlation of liver ElastPQ with MELD score. APRI = aspartate-to-platelet ratio index; ElastPQ = elastography point quantification; MELD = model for end-stage liver disease; VITRO = von Willebrand antigen/thrombocyte ratio.
chronic viral hepatitis. Thus, liver ElastPQ may also assist in stratifying patients at risk who may require further evaluation and/or treatment. However, prospective studies are required to adequately ascertain the prognostic value of ElastPQ in patients with advanced liver disease. This is not the first study to evaluate the ElastPQ method in patients with viral hepatitis. Ferraioli et al. (2016) published a study on the diagnostic accuracy of ElastPQ in patients with chronic hepatitis C and also used TE as a reference standard. They found comparable accuracy of 10 versus 5 measurements when using the ElastPQ method, which is why we decided to use at least 5 ElastPQ measurements for our study design. The authors disregarded ElastPQ results when the individual standard deviation/mean ratio exceeded 30%. Although the authors applied different TE reference values for staging fibrosis (7.0 kPa for F2 fibrosis, 9.5 kPa for F3 fibrosis and 12.0 kPa for F4 fibrosis), the resulting cutoff values recommended for ElastPQ were comparable to
ours, with 6.43 kPa for F2 and 11.34 kPa for F4 (Ferraioli et al. 2016) (vs. F2: 6.68 kPa and F4: 11.28 kPa in our study). The diagnostic accuracy of ElastPQ in our study was also similar to a recent study by Lee et al. (2017) in which the diagnostic capability of ElastPQ was compared to TE and APRI. However, they used a different ultrasound unit for measuring ElastPQ (iU-22, Philips Medical Systems), which yielded lower stiffness results. This may explain their lower cutoff values with narrow ranges for determining significant fibrosis (F2: 4.26 kPa, AUROC: 0.929) and cirrhosis (F4: 4.86 kPa, AUROC: 0.834). In Lee et al. (2017), liver biopsy was used as the reference standard, and ElastPQ measurements were as accurate for predicting fibrosis stages as TE and superior to APRI. Next, we assessed the association of ElastPQ with non-invasive blood-based fibrosis tests. A previous study by Xiao et al. (2017) reported that SWE has excellent predictive value for estimating fibrosis
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Fig. 3. Liver fibrosis scores according to fibrosis stage assessed using ElastPQ. (A) APRI. F0/1 versus F2/3: p = 0.0002; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p = 0.1181. (B) FIB-4. F0/1 versus F2/3: p = 0.0077; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p < 0.0001. (C) VITRO. F0/1 versus F2/3: p = 0.0014; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p = 0.6772. (D) MELD. F0/1 versus F2/3: p = 0.0241; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p = 0.0023. Boxes depict median plus interquartile range; whiskers depict 5th and 95th percentiles. APRI = aspartate-to-platelet ratio index; ElastPQ = elastography point quantification; FIB-4 = fibrosis 4 score; MELD = model for end-stage liver disease; VITRO = von Willebrand antigen/thrombocyte ratio.
in patients with non-alcoholic fatty liver disease, equal to magnetic resonance imaging and superior to blood fibrosis tests and TE. However, the correlations of ElastPQ with FIB-4 and APRI were, although significant, rather weak, with a r coefficient of only 0.500 for FIB-4 and 0.3991 for APRI. This phenomenon may be explained by the inclusion of patients with HIV co-infection, which may have a distinct pattern of necro-inflammation (Mandorfer et al. 2015; Scheiner et al. 2015), thus, often entailing a different clinical course of chronic viral hepatitis (Reiberger et al. 2010). Similarly, in a previous study from our group, the FIB-4 test was poorly correlated with TE in HIV/HCV co-infection (Chromy et al. 2017). In several studies, TE has been reported to increase with the presence of histologic necro-inflammation (Knop
et al. 2016; Schwabl et al. 2015, 2017). Intriguingly, we did not find a significant association of ElastPQ values with elevated AST/ALT levels (data not shown). Still, we suggest interpreting ElastPQ results with caution in patients with significant elevations of transaminases. In general, we recommend using non-invasive fibrosis tests complementary to elastography for assessment of liver fibrosis (EASLALEH 2015). It has also been found that in patients infected with HIV, both coinfections with HCV or HBV and long-term administration of anti-retroviral drugs are associated with increased risk of hepatic fibrosis (Anadol et al. 2018; Mohr et al. 2015). Thus, we recommend monitoring hepatic fibrosis closely in patients with viral co-infections, regardless of treatment status.
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One limitation of this study is the lack of liver biopsy results as a reference standard for fibrosis evaluation. Being an invasive method, liver biopsy bears the risk of complications and is also vulnerable to sample bias. Thus, we decided against performing diagnostic biopsies for this study. As a result, we were not able to determine inferiority or superiority of ElastPQ as compared to TE for fibrosis assessment. CONCLUSIONS Point shear wave elastography assessed by ElastPQ is a useful and accurate non-invasive method for evaluation of liver fibrosis in patients with viral hepatitis. ElastPQ results correlated with TE, and a cutoff value of 6.68 kPa performed well in detecting significant liver fibrosis (F2). An ElastPQ cutoff value at 11.28 kPa is reliable to rule out liver cirrhosis with a NPV of 97.2%. Acknowledgments—We thank Philips Healthcare (Bothell, WA, USA), who provided the ultrasound unit (Affiniti70) and financial support for this study.
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ARTICLE IN PRESS Point Shear Wave Elastography for Non-invasive Assessment of Liver T. BUCSICS et al. Mare R, Sporea I, Lupu¸s oru R, S¸ irli R, Popescu A, Danila M, Pienar C. The value of ElastPQ for the evaluation of liver stiffness in patients with B and C chronic hepatopathies. Ultrasonics 2017;77:114–151. Mohr R, Schierwagen R, Schwarze-Zander C, Boesecke C, Wasmuth JC, Trebicka J, Rockstroh JK. Liver fibrosis in HIV patients receiving a modern cART. Medicine (Baltimore) 2015;94:e2127. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012;30:2212–2219. Poynard T, Ngo Y, Perazzo H, Munteanu M, Lebray P, Moussalli J, Thabut D, Benhamou Y, Ratziu V. Prognostic value of liver fibrosis biomarkers: A meta-analysis. Gastroenterol Hepatol 2011;7:445–454. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, Feng ZZ, Reddy KR, Schiff ER. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 97, 2002, 26142618. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013;59:160–168. Reiberger T, Ferlitsch A, Sieghart W, Kreil A, Breitenecker F, Rieger A, Schmied B, Gangl A. HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. J Viral Hepat 2010;17:400–409. Reiberger T, Ferlitsch A, Payer BA, Pinter M, Schwabl P, Stift J, Trauner M, Peck-Radosavljevic M. Noninvasive screening for liver fibrosis and portal hypertension by transient elastography—A large single center experience. Wien Klin Wochenschr 2012;124: 340–395. Reiberger T, Ferlitsch A, Payer BA, Pinter M, Homoncik M, Peck-Radosavljevic M. Vienna Hepatic Hemodynamic Lab. Non-selective betablockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis. J Gastroenterol 2012;47:561–568. Rizzo L, Calvaruso V, Cacopardo B, Alessi N, Attanasio M, Petta S, Fatuzzo F, Montineri A, Mazzola A, L’abbate L, Nunnari G, Bronte F, Di Marco V, Craxı A, Camma C. 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;106:2112–2120. Scheiner B, Mandorfer M, Schwabl P, Payer BA, Bucsics T, Bota S, Aichelburg MC, Grabmeier-Pfistershammer K, St€attermayer A, Ferenci P, Trauner M, Peck-Radosavljevic M, Reiberger T. The impact of PNPLA3 rs738409 SNP on liver fibrosis progression, portal hypertension and hepatic steatosis in HIV/HCV coinfection. PLoS One 2015;10:1–14.
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Schwabl P, Bota S, Salzl P, Mandorfer M, Payer BA, Ferlitsch A, Stift J, Wrba F, Trauner M, Peck-Radosavljevic M, Reiberger T. New reliability criteria for transient elastography increase the number of accurate measurements for screening of cirrhosis and portal hypertension. Liver Int 2015;35:381–390. Schwabl P, Mandorfer M, Steiner S, Scheiner B, Chromy D, Herac M, Bucsics T, Hayden H, Grabmeier-Pfistershammer K, Ferlitsch A, Oberhuber G, Trauner M, Peck-Radosavljevic M, Reiberger T. Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease. Aliment Pharmacol Ther 2017;45:139–149. Stanaway JD, Flaxman AD, Naghavi M, Fitzmaurice C, Vos T, Abubakar I, Abu-Raddad LJ, Assadi R, Bhala N, Cowie B, Forouzanfour MH, Groeger J, Hanafiah KM, Jacobsen KH, James SL, MacLachlan J, Malekzadeh R, Martin NK, Mokdad AA, Mokdad AH, Murray CJL, Plass D, Rana S, Rein DB, Richardus JH, Sanabria J, Saylan M, Shahraz S, So S, Vlassov VV, Weiderpass E, Wiersma ST, Younis M, Yu C, El Sayed Zaki M, Cooke GS. The global burden of viral hepatitis from 1990 to 2013: Findings from the Global Burden of Disease Study 2013. Lancet 2016;388: 1081–1088. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M. APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–1325. Tsochatzis EA, Bosch J, Borroughs AK. Liver cirrhosis. Lancet 2014;383:1749–1761. Voican CS, Louvet A, Trabut JB, Njike-Nakseu M, Dharancy S, Sanchez A, Corouge M, Lamouri K, Lebrun A, Balian A, Prevot S, Lachgar M, Maitre S, Agostini H, Mathurin P, Perlemuter G, Naveau S. Transient elastography alone and in combination with FibroTestÒ for the diagnosis of hepatic fibrosis in alcoholic liver disease. Liver Int 2017;37:1697–1705. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518–526. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or MRE to detect fibrosis in patients with non-alcoholic fatty liver disease: A meta-analysis. Hepatology 2017;66:1486–1501.
https://doi.org/10.1016/j.ultrasmedbio.2018.07.031
Original Contribution POINT SHEAR WAVE ELASTOGRAPHY FOR NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS IN PATIENTS WITH VIRAL HEPATITIS TAGEDPTHERESA BUCSICS,*,y BENJAMIN GRASL,*,y ARNULF FERLITSCH,*,y,1 PHILIPP SCHWABL,*,y MATTIAS MANDORFER,*,y KERSTIN ZINOBER,*,y RAFAEL STERN,*,2 DAVID CHROMY,*,y BERNHARD SCHEINER,*,y WOLFGANG SIEGHART,*,y MARKUS PECK-RADOSAVLJEVIC,*,y,3 MICHAEL TRAUNER,* and THOMAS REIBERGER*,yAGEDNTE * Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and y Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria (Received 3 May 2018; revised 19 July 2018; in final from 28 July 2018)
Abstract—Elastography point quantification (ElastPQ) is a new ultrasound-based shear wave elastography method for non-invasive assessment of liver fibrosis. We evaluated the diagnostic accuracy of ElastPQ in patients with chronic viral hepatitis. Fibrosis stage (F) was determined by transient elastography (F0/F1: <7.1 kPa, F2: 7.19.4 kPa, F3: 9.512.4 kPa, F4: 12.5 kPa). Area under the receiver operator characteristics curve (AUROC) analysis was performed to assess ElastPQ cutoffs for significant fibrosis (F2) and cirrhosis (F4). Paired transient elastography and ElastPQ measurements were obtained from 217 patients (mean age § SEM: 49 § 0.79 years, 68.2% male, F0/F1: n = 98 [45.0%], F2: 47 [21.6%], F3: 22 [10.1%], F4: 50 [22.9%]). AUROC for F2 was 0.843 (95% confidence interval: 0.7910.895), and for F4, 0.933 (95% confidence interval: 0.8940.972). The optimal ElastPQ cutoff for F2 was 6.68 kPa (sensitivity: 80.7%, specificity: 70.4%, positive predictive value: 78.5%, negative predictive value: 72.3%), and for F4 11.28 kPa (sensitivity: 86.0%, specificity: 85.6%, positive predictive value: 60.52%, negative predictive value: 97.16%). In conclusion, ElastPQ represents an accurate tool for non-invasive staging of liver fibrosis in patients with viral hepatitis. (E-mail: [email protected]) © 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Liver fibrosis, Viral hepatitis, Transient elastography, Shear wave elastography.
biopsy. However, even if liver biopsy is considered the ‘imperfect gold standard’ for fibrosis assessment (European Association for the Study of the Liver [EASL] Asociacion Latinoamericana para el Estudio del Higado [ALEH] 2015; Bravo et al. 2001) as it can assess both fibrosis stage and necro-inflammation (Bedossa and Poynard 1996), it may cause severe complications requiring hospitalization in about 1%3% of cases. Moreover, histologic assessment by liver biopsy is associated with considerable sample error and interobserver variability (Regev et al. 2002). More recently, non-invasive methods including elastography (EASL 2014) and blood-based fibrosis scores (Castera et al. 2005; Maieron et al. 2013; Poynard et al. 2011; Voican et al. 2017) have increasingly been used for screening for liver fibrosis in clinical practice. Non-invasive liver elastography can be performed either via magnetic resonance imaging (MRI elastography) or using ultrasound-based techniques
INTRODUCTION Chronic liver diseases represent a major global contributor to morbidity and mortality, with hepatitis B virus (HBV) and hepatitis C virus (HCV) among the most common etiologies (Blachier et al. 2013; Hatzakis et al. 2011; Ott et al. 2012; Rehm et al. 2013; Stanaway et al. 2016). Liver fibrosis, and ultimately cirrhosis, results from repetitive or ongoing liver injury (Tsochatzis et al. 2014) and has traditionally been assessed by liver Address correspondence to: Thomas Reiberger, Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: [email protected] 1 Present address: Department of Internal Medicine, Krankenhaus der Barmherzigen Br€uder Wien, Vienna, Austria. 2 Present address: Department of Internal Medicine, Krankenhaus Oberpullendorf, Oberpullendorf, Austria. 3 Present adress: Department of Gastroenterology, Hepatology, Endocrinology, and Nephrology, Klinikum Klagenfurt am Woerthersee, Klagenfurt, Austria
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(Barr et al. 2016). Currently, two types of ultrasound-based elastography modalities are commercially available: strain or transient elastography (TE) and shear wave elastography (SWE) (Barr 2018). Although results are commonly expressed in kilopascals (kPa) or as shear wave propagation velocity (m/s) when using SWE, cutoff values for fibrosis staging cannot be readily compared across different elastography techniques. At the moment, TE is the most widely used and best validated method for assessing liver fibrosis (Castera et al. 2008). TE is performed using a self-standing system equipped with specific probes according to a standardized procedure and interpreted using previously published quality criteria (Schwabl et al. 2015). Point SWE is used in the acoustic radiation force impulse (ARFI) imaging system and the elastography point quantification (ElastPQ) system (Ferraioli et al. 2014; Lee et al. 2017), both implemented into conventional ultrasound devices using modified ultrasound probes. Thus, SWE can be used to assess the severity of liver fibrosis in patients with chronic viral hepatitis while performing a standard abdominal sonography examination. However, whereas ARFI has been thoroughly compared with TE in previous studies and meta-analyses (Berzigotti et al. 2011; Bota et al. 2013; Rizzo et al. 2011), data on cross-validation of the ElastPQ method to TE are limited (Ferraioli et al. 2016; Fraquelli et al. 2016; Lee et al. 2017; Mare et al. 2017). METHODS Study design This was a prospective single-center cross-sectional study to evaluate a novel point SWE method (Affiniti70, Philips Medical Systems, Bothell, WA, USA) for liver stiffness measurement in comparison to a well-validated TE system (FibroScan 502 Touch, Echosens, Paris, France) (Reiberger et al. 2012a). We aimed to establish optimal ElastPQ cutoff values for non-invasive diagnosis of significant fibrosis (F2) and cirrhosis (F4) in patients with chronic viral hepatitis to facilitate individualized therapy. Patients Consecutive patients with chronic viral hepatitis seen at the outpatient clinic at the Division of Gastroenterology and Hepatology of the Medical University of Vienna from April 2016 until September 2016 were screened. Patients on beta blocker therapy were not considered as beta blockers are known to affect liver stiffness measurements (Reiberger et al. 2012b). Patients with failure of TE or ElastPQ measurement
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or non-viral etiology of liver disease were excluded from this study. This study was approved by the local ethics committee of the Medical University of Vienna (EK No. 1667/2016) and has been performed in accordance with the Declaration of Helsinki. All patients provided written informed consent before participating in this study. Diagnostic devices and examination procedure All included patients underwent sequential noninvasive assessment of liver fibrosis using both quantitative ElastPQ (Affiniti 70) and TE (FibroScan 502 Touch). Measurements were performed only by trained medical personnel. Patients were examined in supine position with the right arm in maximal abduction. The probes were placed into an intercostal space above the right lobe of the liver. During examination, patients were asked to hold their breath in the mid-position of the respiratory circle, avoiding both Valsalva and deep inspiration maneuvers. In general, M probes were used for TE examinations but examiners were allowed to use XL probes when recommended by the system (skinliver capsule distance >2.5 cm). We aimed at 5 measurements per examination with the ElastPQ method, as 5 measurements have previously been reported to be sufficient (Ferraioli et al. 2016), and 10 valid measurements using TE. Clinical parameters Age, sex, etiology of liver disease, height, weight, body mass index and date of examination/study inclusion were documented for each patient. ElastPQ and TE examinations (including measurements of liver stiffness and controlled attenuation parameter [CAP], a marker indicative of steatosis) were performed in each patient as described above. The cutoff values from Castera et al. (2005) were used for non-invasive diagnosis of liver fibrosis (stratified by fibrosis stage [F]) in TE examination: F0/F1: <7.1 kPa, F2: 7.19.4 kPa, F3: 9.512.4 kPa, F4: 12.5 kPa. The following cutoff values were used for determining the grade of hepatic steatosis in TE examination according to CAP values (Karlas et al. 2017): S0: <248 dB/m, S1: 248-267 dB/m, S2/S3: 268 dB/m. Laboratory data necessary for calculating blood fibrosis scores and the model for end-stage liver disease (MELD; i.e., platelets (Plt), aspartate transaminase [AST], alanine transaminase [ALT], bilirubin, creatinine, international normalized ratio [INR], von Willebrand factor antigen [vWF]) were recorded from the most recent laboratory report (maximum of 30 d before study inclusion). Blood fibrosis scores for predicting liver fibrosis were computed as follows (Hametner et al. 2016; Maieron et al. 2013; Sterling et al. 2006; Wai et al. 2003):
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for the AST-to-platelet ratio index (APRI), AST½U=L AST½U=LULN1 Plt ½g=L1 for the fibrosis 4 score (FIB-4), 1 ðage½y AST½U=LÞ Plt½g=L ALT½U=L1=2 and for the von Willebrand factor antigen-to-thrombocyte ratio (VITRO), vWFð%Þ Pltðg=LÞ1 The upper limit of normal (ULN) of AST equals 50 IU/L according to our local laboratory. The MELD score was calculated as previously reported (Boursier et al. 2009; Kamath et al. 2001). Statistical analysis Quantitative variables are expressed as the mean (standard error of the mean [SEM]) unless otherwise noted. Categorical variables are presented as the absolute number (relative numbers, %). Comparisons between groups were calculated using Student’s t-test or the WilcoxonMannWhitney U-test when appropriate for quantitative variables, and the x2-test or Fisher’s exact test for qualitative variables where applicable. Correlations between variables were computed using Pearson’s or Spearman’s coefficient when appropriate. To assess the performance of liver fibrosis staging by point SWE (ElastPQ) in patients with chronic liver diseases, the sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values and area under the receiver operating characteristic curve (AUROC) were calculated for diagnosis of significant fibrosis (F2) or cirrhosis (F4) using TE as the reference standard for significant fibrosis (F2 7.1 kPa) and cirrhosis (F4 12.5 kPa). The respective ElastPQ cutoff values were identified using Youden’s index. The a error was set at 0.05. All p values are two-sided. Statistical analysis was performed using SPSS software (Version 24.0 for Windows, IBM, Armonk, NY, USA) and GraphPad Prism (Version 7.3 for Windows, GraphPad Software, La Jolla, CA, USA). RESULTS Patient characteristics During the study period, 222 individual patients with viral hepatitis presented at our outpatient clinics and signed written informed consent forms. After excluding n = 4 patients with invalid TE measurements and n = 1 patient with missing data, a final n = 217 patients were considered for the final analysis (Table 1). The mean age was 49 y, and about two-thirds of the study population were men (68.7%). HCV mono-infection
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Table 1. Patient characteristics* No. of patients
217
Sex Age Etiology HCV mono-infection HBV mono-infection HIV co-infection HBV/HCV co-infection Body mass index Liver stiffness (TE) XL probe used Controlled attenuation parameter (available in 211 patients) S0 S1 S2/S3 Liver stiffness (ElastPQ) IQR/median <30% Fibrosis stage (as determined by TE) F0/F1 F2 F3 F4 APRI score FIB-4 score VITRO score MELD score Laboratory data Aspartate transaminase Alanine transaminase g-Glutamyl transferase Platelets White blood cells Bilirubin Albumin Von Willebrand factor antigen
148/69 (68.2% male) 48.7 (0.79) y 139 (64.1%) 14 (6.5%) 57 (26.3%) 7 (3.2%) 25.2 (0.33) kg/m2 11.8 (0.8) kPa 30 (13.8%) 233.4 (4.37) dB/m 128 (60.7%) 20 (9.5%) 63 (29.9%) 10.6 (0.58) kPa 128 (59.0%) 98 (45.0%) 47 (21.6%) 22 (10.1%) 50 (22.9%) 0.35 [0.230.65] 1.45 [0.992.39] 1.06 [0.711.77] 8.0 (0.2) 34 [2651] U/L 33 [2057] U/L 34 [2167] U/L 202 [160248] g/L 6.40 (0.16) g/L 0.49 [0.360.72] mg/dL 44.1 (0.29) g/L 188% [148%246%]
APRI = aspartate transaminase-to-platelet ratio index; ElastPQ = elastography point quantification; FIB-4 = fibrosis 4 score; = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IQR = interquartile range; MELD = model for end-stage liver disease; HBV TE = transient elastography; VITRO = Von Willebrand factor antigen-to-thrombocyte ratio. * Data are expressed as the number (%), mean (standard error of the mean) or mean [interquartile range].
was the predominant etiology in 64.1% of patients, followed by viral co-infections (HBV/HCV or co-infection with HIV) in 29.5% of cases and HBV mono-infection in 6.5%. The median body mass index was 24.7 kg/m2 (SEM: 0.33 kg/m2). The CAP was available for n = 211 patients (97.2%) and was on average 233.4 (4.37) dB/m. Although 43.6% were diagnosed with S1 steatosis, significant steatosis was detected in 17.1% of patients (n = 36). The median APRI score was 0.35 (interquartile range [IQR]: 0.230.65), the median FIB-4 score was 1.45 (IQR: 0.992.39) and the median VITRO score was 1.06 (IQR: 0.711.77). Liver stiffness as evaluated by TE and ElastPQ The median liver stiffness measured by TE was 7.5 (IQR: 5.611.8) kPa. Overall, 98 patients (45.0%) presented without significant liver fibrosis in
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TE examination (F0/F1, <7.2 kPa), 47 (21.6%) patients were diagnosed with significant F2 fibrosis (7.29.5 kPa), 22 (10.1%) with F3 fibrosis (9.612.4 kPa) and 50 (22.9%) with F4/cirrhosis (12.5 kPa) (Table 2). Median liver stiffness as assessed using ElastPQ was 7.7 kPa. Liver stiffness values correlated well between ElastPQ and TE (r = 0.7025, p < 0.001) (Fig. 1A). Mean liver stiffness values as measured by ElastPQ were 6.21 kPa for F0/F1, 8.51 kPa for F2, 10.66 kPa for F3 and 21.16 kPa for F4 fibrosis using TE as reference. ElastPQ increased steadily between fibrosis stages and was able to distinguish no/minimal from significant fibrosis (F0/F1: 6.2 [0.25] kPa vs. F2: 8.5 [0.51] kPa, p < 0.0001) and advanced fibrosis from cirrhosis (F3: 10.7 [1.00] kPa vs. F4: 18.1 (1.65) kPa, p = 0.0007) but did not discriminate well between intermediate fibrosis stages (F2 vs. F3, p = 0.0667). Cutoff values for liver fibrosis staging using ElastPQ We computed an AUROC analysis and calculated Youden’s index to assess the optimal cutoff value for detecting F2 and F4 fibrosis using the ElastPQ method. A cutoff value of 6.68 kPa detected F2 fibrosis with a sensitivity of 80.7%, specificity of 70.4%, PPV of 78.45% and NPV of 72.28% (AUROC: 0.843, 95% CI: 0.7910.895). For determining F4 fibrosis (i.e., cirrhosis), we determined a cutoff value of 11.28 kPa (AUROC: 0.933, 95% confidence interval [CI]: 0.8940.972; sensitivity: 86%, specificity: 85.6%, PPV: 60.52%, NPV: 97.16%) (Fig. 1C, D). Table 2. Fibrosis scores by fibrosis stage, as stratified by TE and Elast-PQ* Fibrosis grade by transient elastography F0F1 F2 F3 F4 Stiffness (Elast-PQ, kPa) APRI FIB-4 VITRO MELD
6.21 (0.25) 8.51 (0.51) 10.66 (1.00) 21.16 (1.65) 0.52 (0.12) 1.72 (0.32) 1.46 (0.66) 7.21 (0.20)
0.57 (0.13) 1.60 (0.11) 1.06 (0.12) 7.79 (0.52)
Fibrosis grade (Elast-PQ) F0-F1 Stiffness (TE, kPa) APRI FIB-4 VITRO MELD
6.20 (0.23) 0.41 (0.07) 1.29 (0.07) 0.79 (0.10) 7.31 (0.30)
0.77 (0.15) 2.15 (0.24) 1.28 (0.17) 7.98 (0.44)
0.91 (0.13) 3.99 (0.42) 2.43 (0.38) 9.62 (0.45)
F2-F3
F4
9.61 (1.08) 0.90 (0.21) 2.62 (0.56) 2.07 (0.57) 7.66 (0.23)
21.46 (1.91) 0.76 (0.08) 3.31 (0.31) 2.03 (0.31) 9.23 (0.41)
APRI = aspartate transaminase-to-platelet ratio index; ElastPQ = elastography point quantification; FIB-4 = fibrosis 4 score; MELD = model for end-stage liver disease; TE = transient elastography; VITRO = Von Willebrand factor antigen-to-thrombocyte ratio. * Data are expressed as the mean (standard of the mean).
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Correlation of liver ElastPQ values with blood-based fibrosis scores and MELD score Parameters for calculating the APRI and FIB-4 scores were available in n = 213 (98.2%) patients, the MELD score was available for 199 patients (91.7%) and the VITRO score was calculated for only 90 patients (41.5%), because von Willebrand factor antigen was available for only a fraction of the patients. All fibrosis scores that were assessed correlated significantly with ElastPQ values, though there were several outliers in all scores. The best correlation was achieved with the FIB-4 score (Fig. 2B) (r = 0.5002 [95% CI: 0.38880.5973], p < 0.001), followed by APRI (r = 0.3991 [95% CI: 0.27600.5094], p < 0.001), while the correlation with ElastPQ values was just modest with VITRO (r = 0.3210 [95% CI: 0.1220-0.4951], p = 0.020). The MELD score, although not a marker for liver fibrosis but for liver function, also significantly correlated with ElastPQ values (r = 0.3901 [95% CI: 0.2616-0.5051], p < 0.001) (Figs. 2 and 3, Table 2). After determining the cutoff values for diagnosing liver fibrosis using ElastPQ by AUROC analysis (Fig. 1C, D), we consecutively stratified patients into F0/ F1 fibrosis (ElastPQ <6.68 kPa), F2/F3 fibrosis (ElastPQ 6.6811.27 kPa) and F4 fibrosis (ElastPQ 11.28 kPa). We then evaluated the association of ElastPQ fibrosis stages with serum fibrosis markers. Both APRI and VITRO differentiated well between patients with and without significant fibrosis (APRI: F0/F1 vs. F2/F3: mean = 0.41 (SEM = 0.67) vs. 0.90 (0.21), p = 0.0002; VITRO: F0/F1 vs. F2/F3: 0.79 (0.10) vs. 2.07 (0.57), p = 0.0014), but not between significant fibrosis and cirrhosis (APRI: F2/F3 vs. F4: 0.90 (0.21) vs. 0.76 (0.62), p = 0.1181; VITRO: F2/F3 vs. F4: 2.07 vs. 2.03, p = 0.6772). FIB-4, on the other hand, distinguished well between the different fibrosis stages (F0/F1 vs. F2/F3: 1.29 [0.07] vs. 2.62 [0.56], p = 0.0077; F2/F3 vs. F4: 2.62 [0.56] vs. 3.31 [0.31], p < 0.0001). Also, MELD increased significantly with each fibrosis stage (F0/F1: 7.31 vs. F2/F3: 7.66, p = 0.0241; F2/F3: 7.66 vs F4: 9.23, p = 0.0023). DISCUSSION Non-invasive assessment of liver fibrosis is increasingly used for monitoring liver disease progression or regression in order to guide antiviral therapy and to individualize clinical follow-up. Transient elastography (TE) is a well-validated method for estimating liver fibrosis and has drastically reduced the need for liver biopsy in recent years. SWE is an alternative, non-invasive method for assessing liver fibrosis, but data on the accuracy of the ElastPQ method for staging liver fibrosis is limited. Cutoff values for determining fibrosis stages
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Fig. 1. Liver stiffness measurement by TE versus ElastPQ and fibrosis staging. (A) Correlation of liver stiffness measurements by TE with measurements by ElastPQ. (B) ElastPQ values across the different fibrosis stages as determined by TE. (C) AUROC analysis for assessing the optimal single cutoff value for ElastPQ to detect significant fibrosis (F2). The cutoff value selected was >6.68 kPa. (D) AUROC analysis for assessing the optimal single cutoff value for ElastPQ to detect cirrhosis (F4). The cutoff value selected was >11.28 kPa. *p < 0.05. **p < 0.01. ***p < 0.001. Boxes depict median plus interquartile range; whiskers depict 5th and 95th percentiles. AUROC (AUC) = area under the receiver operating characteristic curve; ElastPQ = elastography point quantification; F = fibrosis stage, TE = transient elastography.
have been proposed (Ferraoli et al. 2016; Ma et al. 2014), but not yet validated in large patient cohorts. Thus, in this prospective study, we evaluated ElastPQ for non-invasive liver fibrosis stagin in 217 patients with chronic viral hepatitis. We demonstrared that liver stiffness measured by ElastPQ correlated well with the reference standard TE. An ElastPQ cutoff of 6.68 kPa detected significant fibrosis (F2) with an AUROC of 0.843, a sensitivity of 80.7% and a PPV of 78.45%. For diagnosis of F4/cirrhosis, we determined an ElastPQ cutoff at >11.28 kPa with an AUROC of 0.933 (95% CI: 0.8940.972) and a sensitivity and specificity of 86% and 85.6%, respectively. Of note, the ElastPQ cutoff
value of 11.28 kPa had excellent performance in ruling out cirrhosis with a NPV of 97.16%. Importantly, patients with chronic viral hepatitis with ElastPQ11.28kPa have a very low likelihood of developing complications related to cirrhosis or portal hypertension. On the other hand, patients with ElastPQ values >11.28 kPa should undergo regular screening for hepatocellular carcinoma, as well as endoscopy for evaluation of varices. Interestingly, ElastPQ results also correlated well with MELD, a score that reflects liver function and prognosis in patients with liver cirrhosis and is used for liver transplant allocation. This implicates that liver ElastPQ also reflects liver function and prognosis in patients with
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Fig. 2. Correlation of liver ElastPQ with liver fibrosis scores and MELD. (A) Correlation of liver ElastPQ with APRI. (B) Correlation of liver ElastPQ with the FIB-4 score. (C) Correlation of liver ElastPQ with VITRO score. (D) Correlation of liver ElastPQ with MELD score. APRI = aspartate-to-platelet ratio index; ElastPQ = elastography point quantification; MELD = model for end-stage liver disease; VITRO = von Willebrand antigen/thrombocyte ratio.
chronic viral hepatitis. Thus, liver ElastPQ may also assist in stratifying patients at risk who may require further evaluation and/or treatment. However, prospective studies are required to adequately ascertain the prognostic value of ElastPQ in patients with advanced liver disease. This is not the first study to evaluate the ElastPQ method in patients with viral hepatitis. Ferraioli et al. (2016) published a study on the diagnostic accuracy of ElastPQ in patients with chronic hepatitis C and also used TE as a reference standard. They found comparable accuracy of 10 versus 5 measurements when using the ElastPQ method, which is why we decided to use at least 5 ElastPQ measurements for our study design. The authors disregarded ElastPQ results when the individual standard deviation/mean ratio exceeded 30%. Although the authors applied different TE reference values for staging fibrosis (7.0 kPa for F2 fibrosis, 9.5 kPa for F3 fibrosis and 12.0 kPa for F4 fibrosis), the resulting cutoff values recommended for ElastPQ were comparable to
ours, with 6.43 kPa for F2 and 11.34 kPa for F4 (Ferraioli et al. 2016) (vs. F2: 6.68 kPa and F4: 11.28 kPa in our study). The diagnostic accuracy of ElastPQ in our study was also similar to a recent study by Lee et al. (2017) in which the diagnostic capability of ElastPQ was compared to TE and APRI. However, they used a different ultrasound unit for measuring ElastPQ (iU-22, Philips Medical Systems), which yielded lower stiffness results. This may explain their lower cutoff values with narrow ranges for determining significant fibrosis (F2: 4.26 kPa, AUROC: 0.929) and cirrhosis (F4: 4.86 kPa, AUROC: 0.834). In Lee et al. (2017), liver biopsy was used as the reference standard, and ElastPQ measurements were as accurate for predicting fibrosis stages as TE and superior to APRI. Next, we assessed the association of ElastPQ with non-invasive blood-based fibrosis tests. A previous study by Xiao et al. (2017) reported that SWE has excellent predictive value for estimating fibrosis
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Fig. 3. Liver fibrosis scores according to fibrosis stage assessed using ElastPQ. (A) APRI. F0/1 versus F2/3: p = 0.0002; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p = 0.1181. (B) FIB-4. F0/1 versus F2/3: p = 0.0077; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p < 0.0001. (C) VITRO. F0/1 versus F2/3: p = 0.0014; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p = 0.6772. (D) MELD. F0/1 versus F2/3: p = 0.0241; F0/1 versus F4: p < 0.0001; F2/3 versus F4: p = 0.0023. Boxes depict median plus interquartile range; whiskers depict 5th and 95th percentiles. APRI = aspartate-to-platelet ratio index; ElastPQ = elastography point quantification; FIB-4 = fibrosis 4 score; MELD = model for end-stage liver disease; VITRO = von Willebrand antigen/thrombocyte ratio.
in patients with non-alcoholic fatty liver disease, equal to magnetic resonance imaging and superior to blood fibrosis tests and TE. However, the correlations of ElastPQ with FIB-4 and APRI were, although significant, rather weak, with a r coefficient of only 0.500 for FIB-4 and 0.3991 for APRI. This phenomenon may be explained by the inclusion of patients with HIV co-infection, which may have a distinct pattern of necro-inflammation (Mandorfer et al. 2015; Scheiner et al. 2015), thus, often entailing a different clinical course of chronic viral hepatitis (Reiberger et al. 2010). Similarly, in a previous study from our group, the FIB-4 test was poorly correlated with TE in HIV/HCV co-infection (Chromy et al. 2017). In several studies, TE has been reported to increase with the presence of histologic necro-inflammation (Knop
et al. 2016; Schwabl et al. 2015, 2017). Intriguingly, we did not find a significant association of ElastPQ values with elevated AST/ALT levels (data not shown). Still, we suggest interpreting ElastPQ results with caution in patients with significant elevations of transaminases. In general, we recommend using non-invasive fibrosis tests complementary to elastography for assessment of liver fibrosis (EASLALEH 2015). It has also been found that in patients infected with HIV, both coinfections with HCV or HBV and long-term administration of anti-retroviral drugs are associated with increased risk of hepatic fibrosis (Anadol et al. 2018; Mohr et al. 2015). Thus, we recommend monitoring hepatic fibrosis closely in patients with viral co-infections, regardless of treatment status.
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One limitation of this study is the lack of liver biopsy results as a reference standard for fibrosis evaluation. Being an invasive method, liver biopsy bears the risk of complications and is also vulnerable to sample bias. Thus, we decided against performing diagnostic biopsies for this study. As a result, we were not able to determine inferiority or superiority of ElastPQ as compared to TE for fibrosis assessment. CONCLUSIONS Point shear wave elastography assessed by ElastPQ is a useful and accurate non-invasive method for evaluation of liver fibrosis in patients with viral hepatitis. ElastPQ results correlated with TE, and a cutoff value of 6.68 kPa performed well in detecting significant liver fibrosis (F2). An ElastPQ cutoff value at 11.28 kPa is reliable to rule out liver cirrhosis with a NPV of 97.2%. Acknowledgments—We thank Philips Healthcare (Bothell, WA, USA), who provided the ultrasound unit (Affiniti70) and financial support for this study.
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