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BJR Received: 16 May 2016

© 2016 The Authors. Published by the British Institute of Radiology Revised: 27 July 2016

Accepted: 15 August 2016

http://dx.doi.org/10.1259/bjr.20160423

Cite this article as: ´ ska K, Inglot M, Patyk M, et al. Shear wave elastography (SWE) of the spleen in patients with Pawlu´s A, Inglot M, Chabowski M, Szyman hepatitis B and C but without significant liver fibrosis. Br J Radiol 2016; 89: 20160423.

FULL PAPER

Shear wave elastography (SWE) of the spleen in patients with hepatitis B and C but without significant liver fibrosis ´ MD, 1MARCIN INGLOT, MD, 2MARIUSZ CHABOWSKI, MD, PhD, 1KINGA SZYMANSKA, ´ ALEKSANDER PAWLUS, MD, MAŁGORZATA INGLOT, MD, PhD, 1MATEUSZ PATYK, MD, 1JOANNA SŁONINA, MD, PhD, 3FILIPE CASEIRO-ALVES, MD, PhD, 2 DARIUSZ JANCZAK, MD, PhD and 1URSZULA ZALESKA-DOROBISZ, MD, PhD 1

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Department of General and Pediatric Radiology, Wroclaw Medical University, 68 Marii Curie-Skłodowskiej street, 50-369 Wroclaw Division of Surgical Specialties, Department of Clinical Nursing, Faculty of Health Science, Wroclaw Medical University, Wroclaw, Poland Department of Radiology, Coimbra Medical University, Coimbra, Portugal 4 Department of Infectious Diseases, Hepatology and Acquired Immune Deficiencies, Wroclaw Medical University, 5 Koszarowa street, 51-149 Wroclaw 2

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Address correspondence to: Mr Mariusz Chabowski E-mail: [email protected]

Objective: The aim of the study was to compare the elasticity of the spleen in patients with hepatitis B and C but without liver fibrosis with that of healthy subjects using a shear wave elastography (SWE) examination. Methods: Between December 2014 and December 2015, 35 patients with hepatitis B virus (HBV) infections and 45 patients with (hepatitis C virus) HCV infections and liver stiffness below 7.1 kPa were included in the study. The control group was composed of 53 healthy volunteers without any chronic liver disease, with no abnormal findings in their ultrasound examinations and with an SWE of the liver below 6.5 kPa. The SWE measurements were a part of routine ultrasound abdominal examinations. The examinations were performed using an Aixplorer device by two radiologists with at least 6 years’ experience. To compare spleen stiffness between the groups, the Mann–Whitney U-test was applied. To analyze the dependency between liver and spleen elasticity, Spearman’s rank correlation coefficient was calculated.

Results: A total of 133 SWE findings were analyzed. Stiffness of the spleen was significantly higher in patients with HBV and HCV but without significant liver fibrosis than it was in the healthy controls (p 5 0.0018 and 0.0000, respectively). This correlation was also present in patients with liver stiffness below 6.5 kPa (p 5 0.0041 and 0.0000, respectively). Analysis revealed no significant correlation between liver and spleen stiffness in patients with hepatitis B and C and without significant fibrosis (p 5 0.3216 and 0.0626, respectively). Conclusion: Patients with hepatitis B and C but without significant liver fibrosis have stiffer spleens than healthy controls. There is no dependency between liver and spleen elasticity in patients without significant fibrosis. Advances in knowledge: The SWE examination might be an important tool and could be used in addition to conventional imaging. Our study may become a starting point in further investigations into the role of the spleen in HCV and HBV infections and perhaps into introducing spleen elastography into diagnostic and follow-up procedures.

INTRODUCTION Shear wave elastography (SWE) is a relatively new imaging technique that allows an estimation of the stiffness of the tissues in a quantitative way. Its usefulness is based on the assumption that pathological changes tend to be harder and less elastic than the surrounding healthy tissue. The SWE technique is based on creating shear waves in the tissue, which interfere with themselves and create a new, transversal cone-shaped wave. Estimation of the stiffness is based on the fact that the propagation of mechanical waves is greater in less elastic materials. The very quick data acquisition enables the assessment of tissue elasticity in real time as a colour map of stiffness superimposed over a grey-scaled B-mode. Putting a

region of interest (ROI) in the area being investigated provides quantitative information about tissue elasticity in kilopascals or metre per second.1 The usefulness of SWE has been established, i.e. in the assessment of liver fibrosis or in the differentiation of breast or thyroid lesions, but only a few studies concerning SWE of the spleen have been published.1,2 The spleen is considered an important part of the immune system. In patients with chronic hepatitis, SWE may help to assess the condition of not only the liver, which is at increased risk of cirrhosis, but also the spleen, which is an extrahepatic site of hepatitis B virus (HBV) replication and a reservoir of the hepatitis C virus (HCV).3–5 Although Leung et al6 reported

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a strong positive correlation between spleen stiffness and the severity of liver fibrosis, this association was less accurate for lower stages of fibrosis because of the overlapping of SWE between study groups and healthy controls. The authors of the present study wanted to shed more light on the accuracy of SWE of the spleen in patients with hepatitis who had not developed liver fibrosis. Therefore, the aim of the study was to evaluate stiffness of the spleen as measured by SWE in patients with HBV and HCV infections but without liver fibrosis and to compare the stiffness of the spleen between patients with hepatitis and healthy controls. METHODS AND MATERIALS The study was approved by the ethics committee of the Wroclaw Medical University (KB-636/2014). All patients gave their informed consent to participate in the study. Patients There were 35 patients with HBV, 45 patients with HCV and 53 healthy volunteers enrolled in the study. All the participants were adults and none of them were receiving any antiviral or antifibrotic therapy. None of the patients had coinfections of another hepatotropic virus or human immunodeficiency virus. All the patients underwent an ultrasound abdominal examination, SWE of the liver and SWE of the spleen. Only patients with normal liver echogenicity (e.g. without signs of steatosis), with normal portal vein diameter, a normal-sized spleen and without other signs of portal hypertension were included in the study. The healthy volunteers had no history of chronic liver disease and had liver stiffness below 6.5 kPa in the SWE examination. Patients with HBV and HCV who had liver stiffness higher than 7.1 kPa were not included in the study.6,7 An unsatisfactory spleen elastography was performed on 37 subjects, who were therefore not included in the study, giving successful spleen

measurements in about 72% of patients with non-enlarged spleens. Liver elastography was successful in all subjects. Examination The examination was performed using an Aixplorer device (Aixplorer Ultrasound System; SuperSonic Imagine SA, France) using a curvilinear probe (bandwidth 1–6 MHz). The examinations were performed by two radiologists with 10 and 6 years’ experience in abdominal ultrasound and 5 and 3 years’ experience in liver elastography, respectively. Liver and spleen SWE examinations were performed through intercostal spaces with the patients lying supine with arms behind their heads. Each liver measurement was taken through intercostal spaces while the patients were holding their breath (during suspended breathing). The ROI was located in the right lobe of the liver at least 1.5-cm deep in the liver tissue in the area of most homogeneous elasticity on the colour map in an area without bigger vessels. Each patient had five SWE measurements of the liver and the average was taken as the final result. SWE measurements of the spleen were taken through the intercostal spaces after deep inspiration. There is no established protocol for SWE of the spleen. Some authors prefer suspended breathing; others prefer examining after deep inhalation.6 In our experience, deep inhalation allows better visualization of the spleen and gives fewer artefacts. The operator chose the best static shear wave elastographic display images onto which a rectangular electronic ROI and a circular ROI (placed within the centre of the rectangular ROI) for analysis were positioned within 1–3 and 0.5–2 cm, respectively, from the capsular surface of the liver and spleen (Figures 1 and 2). Once the optimal sizes of the ROIs were chosen, they were fixed for subsequent measurement in each subject. Special attention was paid to avoid any focal lesion, vessels, biliary tracts or artefacts from nearby lung gas or cardiac movement. SWE measurements were taken in the central splenic parenchyma in areas without bigger vessels. The ROI was placed in the area of most

Figure 1. Shear wave elastography of a normal spleen (mean stiffness of 12.5 kPa). A box is placed in the central splenic parenchyma. The region of interest is placed in the area of highest homogeneity.

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Figure 2. Shear wave elastography of an abnormal spleen (mean stiffness of 22.8 kPa).

homogeneous elasticity. Each participant had three SWE measurements and the average value was calculated. The mean standard deviation and minimum and maximum kilopascal values were recorded. The average values from the three readings in the spleen were used for subsequent statistical analysis. Measurements with a large standard deviation were not included in the study. Statistical analysis Normal distribution was verified using the Kolmogorov– Smirnov test. The SWE of the spleen had no normal distribution, and non-parametric tests were used for further analysis. The comparison of the SWE of the spleen between the groups (hepatitis C, hepatitis B and healthy subjects) was calculated using the Mann–Whitney U-test. For further analysis, spleen stiffness in patients with HBV and HCV with a liver SWE below 6.5 kPa (the cut-off value for healthy subjects) was used to repeat the comparison of the spleen SWE between groups using the Mann–Whitney U-test again. To analyze the correlation between the SWE of the liver and spleen in patients with HBV and HCV, Spearman’s rank correlation coefficient was calculated. Statistical analyses were carried out using the Statistica software v. 10 (StatSoft, Tulsa, USA). The criteria for statistical significance were set at p , 0.05. RESULTS 133 patients were examined during routine abdominal ultrasound examination, of whom 39.8% (N 5 53) were healthy controls, 26.3% (N 5 35) were patients with HBV with liver stiffness below 7.1 kPa and 33.8% (N 5 45) were patients with HCV and with liver stiffness below 7.1 kPa. The mean liver value in patients with HBV was 6.0 6 0.75 kPa and it was 5.9 6 0.71 kPa in patients with HCV, whereas in healthy subjects, liver stiffness was 5.5 6 0.46 kPa. In

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patients with HBV and liver stiffness below 6.5 kPa (N 5 23), mean liver stiffness was 5.6 6 0.55 kPa and in patients with HCV and liver stiffness below 6.5 kPa (N 5 34), it was 5.6 6 0.58 kPa. Liver stiffness values for all the groups are documented in Table 1. Spleen stiffness was significantly different between the HBV group and the healthy subjects (p 5 0.0018) as well as between patients with HCV and healthy participants (p 5 0.0000). No significant difference was noted between groups of patients with HBV and HCV (p 5 0.0599). Considering patients with liver stiffness below 6.5 kPa, spleen stiffness differed significantly between the HBV group and the healthy subjects (p 5 0.0041) as well as between the patients with HCV and the healthy participants (p 5 0.0000). A comparison of the groups of patients with HBV and HCV revealed no significant difference (p 5 0.3251) in splenic stiffness (Table 2). No statistical correlation between liver and spleen stiffness in patients with hepatitis B (p 5 0.3216) and hepatitis C (p 5 0.0626) was found. DISCUSSION In patients with hepatitis caused by a viral infection, extrahepatic manifestations are common, especially in cases of HBV and HBC. HCV has been recognized to be both a hepatotropic and lymphotropic virus.7 The spleen is considered as one of the extrahepatic reservoirs of HCV.3,4 It was also found that the longitudinal diameter of the spleen, as measured by ultrasound, was higher in patients with chronic HCV-related hepatitis than in the healthy controls.8 HBV has similar characteristics. HBV DNA was detected in the spleen among other tissues9 and extrahepatic replication of HBV in the spleen was also proved.5 This suggests that splenic changes may occur in patients with chronic hepatitis even during the early stages of the disease, with an absence of fibrotic changes in the liver. Our study confirmed that spleen stiffness was significantly higher in patients with hepatitis but without hepatic fibrosis than in healthy controls.

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Table 1. The clinical characteristics of the study group with liver stiffness values

Value—133 patients Normal volunteers Mean: 5.5 kPa 6 0.46

HBV (SWE ,7.1 kPa) Mean: 6.0 6 0.75 kPa

HCV (SWE ,7.1 kPa) Mean: 5.9 6 0.71 kPa

HBV (SWE ,6.5 kPa) Mean: 5.6 6 0.55 kPa

HCV (SWE ,6.5 kPa) Mean: 5.6 6 0.58 kPa

53 (39.6%)

35 (26.3%)

45 (33.8%)

23

34

Number of males

22

21

16

15

10

Number of females

31

14

29

8

24

40 (21)

35 (10.25)

Parameter

Number of patients

a

Age (years)

36 (28)

38 (23.5)

35 (11)

HBV, hepatitis B virus; HCV, hepatitis C virus; SWE, shear wave elastography. a Median; interquartile range is in brackets.

The condition of the spleen in patients with chronic hepatitis, as assessed by SWE, is rarely reported in the literature. In our study, we examined patients with chronic hepatitis but without liver fibrosis. Our study revealed a significant difference in spleen stiffness between both HCV- and HBV-related hepatitis groups and healthy subjects, but no significant difference was found between patients with HBV and HCV infections. At the same time, in patients with liver stiffness similar to the control group (below 6.5 kPa), a significant difference in spleen stiffness between both the groups of patients with hepatitis and the healthy subjects was found, while no significant difference occurred between patients with HBV and HCV infections. No correlation between SWE values of the liver and spleen was found. Elastography is a relatively new technique and therefore, its use is limited owing to insufficient information about its usefulness and accuracy, as well as norms and ranges. Elastography of the liver is more frequently used than elastography of the spleen.10,11 The procedure for liver examination and clinical recommendations were presented in the European Federation for Ultrasound in Medicine and Biology (EFSUMB) Guidelines.2 The cut-off value for significant liver fibrosis in the SWE technique was set at 7.1 kPa.6,7 Much less is known about spleen elastography, which was not included in the guidelines, and no standard examination procedure exists.6,12 In the present study, spleen stiffness was measured through an intercostal approach after deep inhalation. To avoid ambiguity in interpretation, Table 2. The comparison of shear wave elastography of the spleen between the study groups

Spleen stiffness in all patients

p-value

Between HBV group and healthy group

0.0018a

Between HCV group and healthy group

0.0000a

Between HBV group and HCV group

0.0599

Spleen stiffness in patients with liver stiffness below 6.5 kPa Between HBV group and healthy group

0.0041a

Between HCV group and healthy group

0.0000a

Between HBV group and HCV group

0.3251

HBV, hepatitis B virus; HCV, hepatitis C virus. a Statistically significant.

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the examination was performed by two radiologists with extensive experience in ultrasound and elastography, because a higher reproducibility of SWE measurements was reported for expert operators.11 Some researchers choose transient elastography for the assessment of the spleen13,14 and others SWE.15 To date, no superiority of one method over the other has been proved; however, some studies suggest that SWE may serve as a more precise tool for identifying patients with the early stages of fibrosis (F0–F1).6,16 Patients with chronic viral hepatitis develop liver cirrhosis over time, which may have an effect on the condition of the spleen. An increase in portal pressure due to increased resistance in the hepatic vessels leads to a variety of complications, one of which is the enlargement and increased stiffness of the spleen. A correlation has been proved between liver and spleen stiffness and clinically significant and severe portal hypertension.13–15 Researchers have pointed out the potential usefulness of SWE in the estimation of risk of oesophageal varices in patients with liver cirrhosis or portal hypertension or in assessing liver fibrosis.6,15,17 The value of spleen elastography in these cases is based on direct relation between liver cirrhosis, portal hypertension and spleen enlargement due to congestion.18 Changes in the spleen developing as a consequence of hepatic cirrhosis are obvious and well documented and can serve as a prognostic factor in hepatic hypertension. On the contrary, in patients without fibrosis of the liver, an examination of the spleen does not provide any information about the increased portal pressure. In patients with viral hepatic infections but without any significant fibrosis, signs and symptoms of portal hypertension are absent. Hence, their spleens should have the same elasticity parameters as in healthy subjects and should not be considered as only an indicator of portal hypertension. In the present study, in patients with hepatitis with liver stiffness below 6.5 kPa, which is the level for healthy people, stiffness of the spleen was significantly higher than in healthy controls. Moreover, we found no correlation between liver and spleen stiffness in our study group. Our findings suggest that fibrosis of the liver is not the only factor responsible for the increased stiffness of the spleen. Based on the current literature, the association between liver and spleen stiffness in patients with viral hepatitis but without fibrosis is not clear, a factor which inspired us to perform this study. Leung et al6

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found that SWE of the liver correlated with SWE of the spleen; however, this association was weak during stages F1–F3 of liver involvement. Also, an overlap in SWE of the spleen between F0, F1, F2 and healthy control subjects was observed. Another study which is worth mentioning was performed by Rizzo et al.19 Although they used acoustic radiation force impulse elastography for the assessment of stiffness of the liver and spleen, they found that in healthy subjects, patients with chronic hepatitis C (fibrosis stages F1–F3), patients with cirrhosis without oesophageal varices and for those with varices, splenic stiffness was 2.19, 2.37, 2.7 and 3.37, respectively. The study did not aim to compare healthy controls with patients with HCV-related hepatitis without cirrhosis, but it shows a relatively small difference between those groups.19

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At the moment, it is not possible to predict whether the results of our study and the extrahepatic “existence” of viruses are connected. The main limitation of this study is a lack of information about the level of viraemia. Therefore, it is not possible to distinguish whether the spleen is less elastic strictly owing to the main disease or, for e.g., owing to a non-specific response of the immune system. In our opinion, studies considering viraemia and its changes over time and during treatment should be performed. In conclusion, the results of our study may become a starting point for further investigations into the role of the spleen in HCV and HBV infections and perhaps in introducing spleen elastography into diagnostic and follow-up procedures.

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