Comparison of transient elastography to Doppler indices in prediction of hepatitis C induced liver fibrosis and cirrhosis

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1 The Egyptian Journal of Radiology and Nuclear Medicine (2011) 42, Egyptian Society of Radiology and Nuclear Medicine The Egyptian Journal of Radiology and Nuclear Medicine Comparison of transient elastography to Doppler indices in prediction of hepatitis C induced liver fibrosis and cirrhosis Marwa I. Fahmy a, *, Hanaa M. Badran b a Diagnostic Radiology, Ain Shams Faculty of Medicine, Egypt b Tropical Medicine, Hepatology, National Liver Institute, Menofeya University, Egypt Received 26 April 2011; accepted 10 May 2011 Available online 12 July 2011 KEYWORDS Hepatic fibrosis; Transient elastography; Doppler indices Abstract Objectives: The aim of our study was to examine the efficiency of transient elastography (TE) and Doppler indices, namely hepatic vein damping index (DI) and splenic artery pulsatility index (SAPI) for evaluating the degree of hepatic fibrosis in chronic hepatitis C (CHC) patients. Patients and methods: One hundred and ten CHC patients were enrolled. Hepatic vein DI, SAPI, and TE were performed to all patients before liver biopsy. Fibrosis was assessed on semi quantitative scoring system (METAVIR score). We examine the efficiency of each test in differentiating different stages of hepatic fibrosis and their diagnostic accuracy in predicting significant fibrosis F P 2 and cirrhosis. Results: TE showed the best results in differentiating different stages of fibrosis (p < 0.001), TE had the best diagnostic accuracy for prediction of significant fibrosis and cirrhosis (AUROCs: for F P 2 TE 0.92 vs. SAPI 0.74, DI 0.75; for cirrhosis TE 0.95 vs. DI 0.80, SAPI 0. 79). At a * Corresponding author. Address: 6 Elbagoury Street, Heliopolis, Cairo, Egypt. Tel.: address: marwafahmy888@hotmail.com (M.I. Fahmy) X Ó 2011 Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. Open access under CC BY-NC-ND license. Peer review under responsibility of Egyptian Society of Radiology and Nuclear Medicine. doi: /j.ejrnm Production and hosting by Elsevier

2 112 M.I. Fahmy, H.M. Badran cut-off of 7 kpa, TE predicted significant fibrosis with 87% sensitivity and 86% specificity, it correctly classified 87% of patients vs. 71% for DI and 68% for SAPI. For prediction of cirrhosis, TE at 16.5 kpa had 87% sensitivity and 91% specificity it correctly classified 90% of patients vs. 70% for DI and 68% for SAPI. Conclusion: TE is a non-invasive technique to accurately detect the presence of significant fibrosis and cirrhosis in patients with CHC. While the ability of Doppler tests was limited. Ó 2011 Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. All rights reserved. 1. Introduction Hepatitis C virus infection, with an estimated prevalence of more than 170 millions worldwide, is a major public health care problem (1). The prognosis and treatment of chronic liver disease depend on the stage of liver fibrosis (2). In chronic viral hepatitis, the presence of significant fibrosis (F P 2) indicates the necessity of antiviral therapies (3). Beyond being marker of injury, liver fibrosis appears to play a direct role in the pathogenesis of hepatocellular dysfunction and portal hypertension (4). Furthermore, reduced treatment response and tolerability to antiviral may be encountered in cirrhotic patients (5). An accurate assessment of the severity of hepatic fibrosis is therefore important for both diagnostic and therapeutic purposes (6). Staging fibrosis is an assessment of the combination of the amount of fibrosis and architecture disorganization (7). Liver biopsy is the gold standard for assessment of the degree of fibrosis in chronic liver disease. However, liver biopsy is invasive and costly and its interpretation requires an experienced hepatopathologist. Although with precaution liver biopsy is rather a safe procedure, between 0.6% and 5% of biopsy patients have had some complications. Since liver biopsy represent only about 1/50,000 of the liver tissue, inadequate sample size and sampling error may lead to erroneous estimation of the degree of fibrosis. For these reasons, non-invasive assessment of liver fibrosis is a major objective that has encouraged many new approaches (8). Several Doppler indices have been proposed for patients with chronic hepatitis C (CHC). It is known that the normal triphasic hepatic vein (HV) Doppler waveform is transformed into a biphasic or monophasic waveform in cirrhosis and portal hypertension (9 14). However, the evaluation of HV waveform with a lack of quantitative value reduces its clinical value. Assessment of damping index (DI) allows the quantification of the extent of the abnormal HV waveform (14). Splenic impedance indices including splenic artery pulsatility index (SAPI) were associated with portal vein resistance, significant hepatic fibrosis, and grade of esophageal varices (15 17). The latest technological advance in the setting of noninvasive diagnosis is the measurement of liver stiffness (LS) by mean of transient elastography (TE) (18), which is an ultrasound technique that uses pulse-echo ultrasound acquisitions to measure liver stiffness in a volume of the liver that is approximately 100 times bigger than liver biopsy, and thus might be less prone than biopsy to sampling error. LS measurement is a good method for the diagnosis of fibrosis and cirrhosis irrespective of the cause of liver disease (19). LS measured by a fibroscan has been reported to correlate with stage of liver fibrosis in various liver disease (18 29). The aim of this work is to examine the efficiency of TE and Doppler indices, namely (DI) and (SAPI) for evaluating the degree of hepatic fibrosis in CHC patients. 2. Patients and methods The study was conducted at the Italian Hospital in Cairo and a fibroscan center in the period from March 2010 to February It included 110 newly diagnosed patients, who were positive for HCVAb and HCV-RNA by polymerase chain reaction and who did not start interferon treatment. Patients with other causes of chronic liver disease, bleeding tendency, cardiac disease, and decompensate liver disease were not included in our study group. The patient s characteristics are summarized in Table 1. All patients were subjected to the following Color Doppler sonography of the middle hepatic vein and splenic artery Which was performed by one radiologist (to avoid interobserver variability) using Toshiba Xario with convex probe 3.5 MHz. Doppler HV waveforms were recorded from the mean of three repeated measurements. The maximum velocity and minimum velocity of downward HV flow were measured and DI was calculated by the minimum velocity/maximum velocity (30). The SAPI was measured automatically by the machine by placing the sampling cursor in the branches of the intrasplenic artery near the splenic hilum. Table 1 Characteristics of the study group. Characteristics Study group (n = 110) Age, (y) 41 ± 9 Male sex, n (%) 84 (76%) Body mass index ±.37 Histological activity index <10/> ± /15 Steatosis ve/+ve 92/18 Alanine aminotransferase ± 4.24 Albumin, (gm/l) ± 0.03 Bilirubin, (mg/dl) ± Hemoglobin, (g/dl) ± White blood cell counts, ( 10 3 /ml) ± Platelets, ( 10 3 /ml) 195 ± Viral load, log 10, (IU/ml) 785 ± 259 Fibrosis score (METAVIR), n (%) F (39%) F2 27 (25%) F3 F4 18 (16%) 22 (20%)

3 Comparison of transient elastography to Doppler indices in prediction of hepatitis C induced liver fibrosis and cirrhosis Transient elastography Liver stiffness measurement was performed with the fibroscan apparatus (Echosens, Paris, France) within a week of liver biopsy, according to the classical methodology (18). The measurements were made on patients lying in dorsal decubitus with the right arm in maximal abduction. The tip of the probe transducer was covered with coupling gel and placed on the skin, between the ribs at the level of the right lobe of the liver. The operator, assisted by ultrasound time-motion and A-mode images, located a portion of the liver free of large vascular structures that was at least 6 cm thick. Once the measurement area was located, the operator pressed the probe button to begin an acquisition. Ten validated measurements were made on each patient. The results were expressed in kilopascals (kpa). Only procedures with 10 validated measurements and a success rate of at least 60% (ratio of the number of successful acquisitions over the total number of acquisitions) were considered reliable. The median value was considered representative of the liver elastic modulus Liver biopsy Liver biopsy specimens composed of core >15 mm were assessed according to METAVIR scoring system (31). Fibrosis was staged on a 0 4 scale: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis and few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis Statistical analysis Data was analyzed with SPSS version 13. Data was summarized using mean and standard deviation (SD) for quantitative variables and percent for qualitative variables. Comparisons between quantitative variables were carried out using independent-sample T-test. One-way ANOVA (analysis of variable) test with post hoc analysis were used in cases of more than two quantitative variables. Receiver operator characteristic (ROC) curves were constructed to evaluate the diagnostic accuracy in predicting significant fibrosis and cirrhosis, areas under ROC curves (AUROCs) of individual tests with 95% confidence intervals were calculated and compared (32). Kappa test was used to test the agreement between different predictors and METAVIR score of fibrosis. The results were considered statistically significant when p < Results Patient s characteristics are listed in Table 1. Our results showed that TE, DI, and SAPI increase with advances of hepatic fibrosis, TE showed a statistically significant difference between different subgroups (p < 0.001), on the other hand, DI showed no significant difference between (F0 1/F2) and (F3/F4). Regarding SAPI there was no significant difference between (F0 1/F2), (F2/F3), and (F3/ F4) (Table 2), (Figs. 1 4). TE had a significantly higher (AUROC) in predicting significant fibrosis and cirrhosis than the Doppler indices (p < 0.001), with no significant difference found between DI and SAPI (p > 0.05) (Fig. 5). TE also showed the highest degree of agreement with the stage of hepatic fibrosis according to METAVIR score (k = 0.7). At a cut-off point of P7 kpa, significant fibrosis could be predicted with 91% certainty and excluded with 80% certainty with a total validity of 87%. At a cut off point of P16.5 kpa, hepatic cirrhosis could be predicted with 71% certainty and excluded with 96% certainty with a total validity of 90%, Doppler parameters showed low negative and positive predictive values and low overall validity in predicting significant Table 2 Mean ± SD of the non-invasive tests in different fibrosis stages. F0 1 F2 F3 F4 TE (kpa) 5.8 ± 1.5 b,c 8.9 ± 3.4 a,c 15.5 ± 4.6 a,b 23.1 ± 9.2 a,b,c DI 0.50 ±.22 c 0.52 ±.21 c 0.74 ±.21 a,b 0.81 ±.1 a,b SAPI 0.91 ± ± ±.24 a 1.3 ±.21 a,b TE, transient elastography; DI, damping index; SAPI, splenic artery pulsatility index. a p < 0.05 vs. F0 1. b p < 0.05 vs. F2. c p < 0.05 vs. F3. Figure 1 CHC patient with grade 1 fibrosis: (A) TE was 4.4 kpa, (B) HV showed a biphasic waveform with a mean DI 0.37, and (C) SAPI was 0.85.

4 114 M.I. Fahmy, H.M. Badran Figure 2 was CHC patient with grade 2 fibrosis: (A) TE was 7.6 kpa, (B) HV showed a triphasic waveform with a mean DI 0.5, and (C) SAPI Figure 3 CHC patient with grade 3 fibrosis: (A) TE was 11.1 kpa, (B) HV showed a monophasic waveform pattern with a mean DI 0.64, and (C) SAPI was Figure 4 CHC patient with cirrhosis: (A) TE was 21.3 kpa, (B) HV wave form showed monophasic waveform with a mean DI 0.77, and (C) SAPI was fibrosis. Using a cut off value of for SAPI and 60.7 for DI, each test excluded cirrhosis with a NPV of 91% and 95%, respectively. Conversely, prediction of cirrhosis was much less reliable with a PPV of 37% and 40%, respectively (Tables 3 and 4). 4. Discussion The presence of significant fibrosis is considered a hallmark of a progressive liver disease. Therefore, in clinical practice, the differentiation between mild and no fibrosis (F0 1) versus significant fibrosis (F P 2) is of great importance. The results of the present study showed that TE is the most accurate method for predicting significant fibrosis and cirrhosis, with AUROCs of 0.92 and 0.95, respectively. Furthermore, TE showed the highest degree of agreement with METAVIR score (k = 0.7), a finding in keeping with other studies, where AUROC ranged from 0.79 to 0.91 for prediction of significant fibrosis (26,29,33 36), and ranged from 0.94 to 0.98 in prediction of cirrhosis (19,33,34,37,38). This comes in partial agreement with results of Degos et al. (39), who found that the diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. But it stated among non-invasive tests, fibroscan ranks first in diagnostic accuracy especially when compared to biochemical tests, the diagnostic accuracy of fibroscan is not 100% as tissue abnormalities independent of fibrosis, such as edema and inflammation, cholestasis and congestion, may impact fibroscan. The risk of overestimating liver stiffness values has been reported in the case of alanine amniotransferse flares in patients with acute viral hepatitis or chronic hepatitis B as well as in cases of extrahepatic cholestasis (34,40 42). In our series, by inclusion criteria none of the patients had hepatic congestion or extra hepatic cholestasis. The diagnostic accuracy of TE for prediction of significant fibrosis and cirrhosis were significantly higher than SAPI and

5 Comparison of transient elastography to Doppler indices in prediction of hepatitis C induced liver fibrosis and cirrhosis 115 Figure 5 ROC curves of TE (fibroscan), DI and SAPI in predicting patients with significant hepatic fibrosis (F P 2) (A) and cirrhosis (B), TE showed a significantly higher AUROC than DI and SAPI, while AUROC of DI and SAPI were comparable. DI (p < 0.001), which show no significant different in between them (p > 0.05). For predicting significant hepatic fibrosis, TE set at 7 kpa resulted in 86% correctly classified cases, while for cirrhosis, TE set at 16 kpa resulted in 90% correctly classified cases. Similar cut-off level for predicting significant fibrosis was reported in other studies (21,36), while other studies reported cut off level ranging from 5 to 9.1 (22,27,29,34,43). Different cut off level for cirrhosis were reported in other studies ranging from 11.6 to 26 kpa (19,21,22,24,27,29,34,36). With the advance of hepatic fibrosis, the portal resistance increases, causing the increased outflow resistance of the splenic artery. The decreased diastolic velocity of the splenic artery results in increased splenic impedance indices (splenic artery resistive index (SARI) and SAPI). The later which uses the mean arterial velocity instead of the peak arterial velocity, makes it more sensitive than SARI in detecting the waveform changes on increased portal resistance (15). Previous studies have shown that hepatic impedance indices (hepatic artery resistive and pulsaitility indices) were correlated with the severity of hepatic fibrosis, based on the assumption of distortion of hepatic architecture and reduction of intrahepatic vascular space (44,45). In the current study SAPI as well as DI gave good result in excluding cirrhosis, being suboptimal to modest in predicting significant fibrosis and cirrhosis. Liu et al. (6) found a high PPV for SAPI in predicating significant fibrosis (98%) but a modest NPV (76%), both values were high in predicting cirrhosis (90%) and (97%), respectively. The suboptimal diagnostic power of SAPI in excluding the presence of significant fibrosis could be explained by the subtle change of portal resistance in mild to moderate hepatic fibrosis. Kim et al. (28) found a significant positive correlation between hepatic veins DI and the grade of hepatic venous pressure gradient. To our knowledge, this is the first study to examine a possible correlation between hepatic veins DI and the severity of hepatic fibrosis. In the current study DI shows comparable results to SAPI, its low prediction power could be attributed to hepatic fatty changes and the increase of hepatic indices with age in healthy subjects (46), making the indices less reliable in detecting the severity of hepatic fibrosis. In case of SAPI <1 and DI <0.64, another complimentary test, such as fibroscan should be performed to increase diagnostic accuracy. However, we found that each of Table 3 Comparative performance of the noninvasive tests for prediction of significant hepatic fibrosis F P 2. Cut-off point Sn Sp PPV NPV Correctly classified AUROC Kappa TE (kpa) 7 87% 86% 91% 80% 87% DI % 74% 81% 60% 71% SAPI 1 66% 72% 79% 57% 68% Sn, sensitivity; sp, specificity; PPV, positive predictive value; NPV, negative predictive value; AUROC, area under receiver operating characteristic curve. Table 4 Comparative performance of the non invasive tests for prediction of cirrhosis. Cut-off point Sn Sp PPV NPV Correctly classified AUROC Kappa TE (kpa) % 91% 71% 96% 90% DI % 65% 40% 95% 70% SAPI % 67% 37% 91% 68%

6 116 M.I. Fahmy, H.M. Badran these tests was more suited for exclusion of cirrhosis than for its prediction. TE has certain advantages over Doppler indices, for it measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma (7), and it provides more direct measurement of fibrosis, being highly reproducible and operator-independent technique (29,33). Because TE can be performed rapidly, painlessly and has high patient acceptance, it might become a common way of assessing fibrosis in routine practice (47). 5. Conclusions An accurate and objective quantification of hepatic fibrosis is essential to provide clinically useful information for the monitoring of CHC progression and therapy. The performance of Doppler indices was limited. The value of TE and the relation to tissue diagnosis in patients with CHC is promising and needs further assessment. 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