Non-invasive Diagnosis of Liver Clinical Condition by Real-time Tissue Elastography and Shear Wave Measurement : Get More Accessible by One Probe

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1 XXXXXXXXXX Non-invsive Dignosis of Liver Clinicl Condition y Rel-time Tissue Elstogrphy nd Sher Wve Mesurement : Get More Accessile y One Proe Norihis Yd Mstoshi Kudo Deprtment of Gstroenterology nd Heptology, Fculty of Medicine, Kinki University Ultrsound Elstogrphy is considered to e useful for non-invsive ssessment of liver firosis, nd cn e clssified into two min groups, sher wve imging nd strin imging, ccording to the excittion method used nd physicl quntity mesured. Hitchi Alok Medicl, Ltd. hs recently developed sher wve elstogrphy technology nd offers the strin imging method using convex proe. Its sher wve elstogrphy, nmed Sher Wve Mesurement (SWM), provides the disply of unique reliility indictor nmed VsN, which enles the opertor to esily judge whether mesured Vs vlue is correct or not. Additionlly, Rel-time Tissue Elstogrphy *1 (RTE) supported y convex proe fcilittes exmintions in oese ptients. Comintionl Elstogrphy, the concept of using oth sher wve elstogrphy nd strin imging to gin etter understnding of the clinicl condition of liver, is now chievle with one proe. It cn e sid tht non-invsive dignosis of the clinicl condition of the liver hs ecome more ccessile. Key Words: Sher Wve Mesurement, Rel-time Tissue Elstogrphy, Convex Proe, Comintionl Elstogrphy 1. Introduction It is very importnt to understnd the stge of liver firosis nd the level of inflmmtion oth in tretment pln setting nd for predicting the prognosis of virl nd other diffuse liver diseses. Liver iopsy is considered s the gold stndrd ut it hs prolems relting to its invsiveness (pin nd leeding) nd the possiility of is due to smpling error. Recently, ultrsound elstogrphy hs een reported s n effective method for evluting the level of heptic firosis noninvsively. The possiility of using elstogrphy for evluting liver cncer risk hs lso een studied. 1) 2) Other pulictions suggest tht liver stiffness significntly vries under the influence of inflmmtion, jundice nd congestion. 3) 6) Mny devices cple of ultrsound elstogrphy re ville, feturing mesurements of different physicl prmeters nd using different excittion methods (genertion of the physicl phenomen for mesurement). The pproprite method should e selected fter crefully studying these different fetures (Tle 1). 2. Sher Wve Imging Sher wves propgte fster in hrder sustnces thn in softer ones. The eqution E = 3ρVs 2 (E: elstic modulus [kp], ρ: density [kg/m 3 ], Vs: sher wve propgtion ve- Tle 1: Clssifiction of Ultrsound Elstogrphy Techniques re clssified y the excittion method nd physicl quntity mesured. RTE: Rel-time Tissue Elstogrphy; VTI: Virtul Touch Imging; VTQ: Virtul Touch Quntifiction; SWE: Sher Wve Elstogrphy. Cited from, with some modifictions, Shiin JSUM Ultrsound Elstogrphy Prctice Guidelines. J Med Ultrsonics 2013 nd Shiin T., Kudo M. et l: WFUMB Prctice Guideline on Ultrsound Elstogrphy. UMB2015. Physicl quntity mesured Excittion method Mnul compression (virtion, hert et) ARFI (Acoustic Rdition Force) Mechnicl impulse Strin imging Strin elstogrphy - RTE: Hitchi Alok Medil - Elstogrphy ARFI imging - VTI Sher wve imging Point sher wve elstogrphy - SWM: Hitchi Alok Medicl - VTQ - ElstPQ Sher wve elstogrphy - SWE Trnsient elstogrphy - FiroScn 1 MEDIX-E008 (VOL63, 13-17, 2015)

2 locity [m/s]) cn e pplied using the ssumption tht ody tissues re uniform. So, tissue stiffness cn e clculted y mesuring the propgtion velocity of sher wves. Some devices generte sher wves in the liver tissue y virtion of the proe itself, other devices do it y genertion of focused ultrsound pulse. Mesurement results re displyed s liver stiffness (elstic modulus), Vs vlues or color mpping. The method tht clcultes liver stiffness y mesuring Vs is termed Sher Wve Imging. Liver stiffness or Vs vlues grdully increse with the progression of liver firosis, nd re regrded s effective for stging liver firosis, heptic cirrhosis in prticulr. It hs een shown in chronic heptitis C nd B tht higher incidence of liver cncer is 1) 2) relted to higher liver stiffness vlues. 3. Sher Wve Mesurement (SWM) Sher Wve Imging is the method currently most studied for liver firosis ssessment. This method is now ville on the HI VISION Ascendus *2 (Hitchi Alok Medicl), performed using convex proe nd clled Sher Wve Mesurement (SWM). Similr to other elstogrphy techniques, the ptient lies on his/her ck nd lifts the right rm. The right loe of liver is imged through right intercostl spce while the ptient holds their reth in nturl respirtion. Sher wves re generted from focused ultrsound pulse once the mesurement utton hs een pressed, nd the Vs vlue is displyed within pproximtely 2 seconds. The 1cm x 1.5cm region of interest (ROI) needs to e positioned crefully elow the liver cpsule nd where there re no lrge vessels included in the ROI. This helps to generte sufficient quntity of sher wves from uniform push pulses. SWM is n elstogrphy technique tht mesures the Vs vlue t point, nd is clssified s point sher wve elstogrphy method. When one mesurement from series is exceptionlly out-of-rnge, the ccurcy of tht vlue could e questioned. However, if no dispersion of the mesurement results is displyed, the result would e regrded s correct, despite the fct tht ll of the mesurements could e inccurte. The gretest feture of SWM is the disply of the reliility of the mesurement results. SWM smples multiple points inside the ROI in one mesurement, nd displys the medin s the result. The distriution of Vs vlues is presented s histogrm, nd the interqurtile rnge (IQR) is lso shown. Thus, the dispersion of mesured vlues cn e checked t glnce. Additionlly, mesurements significntly out-of-rnge nd vlues from distured wveforms re excluded from the clcultion of the medin Vs vlue. The rtio of ccurte smples used in the clcultion is quntified nd displyed s VsN (Figure 1). We mesured Vs on 186 ptients with heptic disese using SWM nd 3 other different Sher Wve Imging devices to compre the mesurement results. The Vs vlues from the 4 devices showed high correltion (Figure 2). When there ws lrge difference of Vs vlues (dispersion) etween the 4 devices, Δ Vs [the difference of inter-equipment Vs vlues] ws compred to the VsN. We found shrp increse in the vlue of Δ Vs ove 0.75m/s when VsN ws less thn 60. Further, when the distnce etween the skin nd liver cpsule exceeded 2cm, the numer of VsN vlues elow 60 incresed (Figures 3 & 4). Therefore, we conclude tht the reliility of the mesurement is high if VsN is 60 or ove. If, conversely, VsN is less thn 60, the mesurement vlues my not represent the true stiffness of the liver. Figure 1: Sher Wve Mesurement Exmples When the mesurement is pproprite, the histogrm shows norml distriution with high pek, nd IQR is low. Most of the mesurement vlues re considered ccurte nd VsN tkes high vlue (). When the mesurement is inpproprite (e.g. lrge vessels re present in the ROI), the histogrm lcks pek, IQR is high nd VsN is low (). 2 MEDIX-E008 (VOL63, 13-17, 2015)

3 Compny A (m/s) Compny B (m/s) Compny C (m/s) Compny B (m/s) Compny B (m/s) Compny C (m/s) c Compny A (m/s) Compny A (m/s) Compny C (m/s) d e f Figure 2: Correltion of Vs vlue Mesured y Different Devices SWM showed good greement with other equipment mesuring sher wve velocity. SWM Compny A (), SWM Compny B (), SWM Compny C (c), Compnies A B (d), Compnies A C (e), Compnies C B (f) Rtio (% ) VsN Figure 3: Reltion etween VsN nd Δ Vs If VsN flls to less thn 60, the difference of Vs mesurement etween devices ( Δ Vs) increses, showing tht correct mesurement is difficult. VsN (%) Distnce to Liver Surfce (mm) Figure 4: Reltion etween Distnce from Skin to Liver Cpsule nd VsN When the distnce etween the ody surfce nd liver cpsule exceeds 2cm, VsN tends to fll to less thn MEDIX-E008 (VOL63, 13-17, 2015)

4 4. Strin Imging RTE is method tht displys the reltive strin of tissues s color mp in rel time, the so-clled Strin Imging technique. When tissue is sujected to n externl force, hrder res of the tissue show reltively less strin thn softer prts. The RTE technique mesures displcements in the ROI nd clcultes strin y sptil differentition. The hrder res re displyed in lue nd the softer res in red, with intermedite res shown in green. The rel-time color mp uses 256 grdtions. When RTE is performed in ptients with diffuse chronic liver disese such s chronic heptitis C, the low strin re (%lue) increses nd ecomes more complex in shpe s heptic firosis dvnces. Such reltive strin chnges in chronic liver disese represent the progression of heptic firosis 7) nd hve een descried using severl independent imge fetures: MEAN (verge vlue of verge strin) grdully decreses s firosis progresses while SD (stndrd devition of verge strin) increses grdully. AREA (re of low strin region in lue) lso grdully increses. A multiple regression eqution for liver firosis index (LFI) for ojective dignosis of the degree of heptic firosis hs een derived sed on these nd other imge feture vlues nd compred to liver iopsy dignosis dt from chronic heptitis C cses (used s trining dt). LFI is utomticlly clculted using the mesurement tool in the ultrsound system. 8) LFI grdully increses with the progression of firosis with significnt differences etween the stges. AUROC for firosis dignosis using LFI of F4, F3 nd F2 tkes high vlue of 0.800, nd 0.846, respectively. 9) 11) Additionlly, RTE imges re considered to fithfully reflect the level of firosis with no significnt influence from inflmmtion, jundice or congestion. RTE ws originlly developed for the exmintion of the thyroid nd mmmry glnds, so liner proe, EUP-L52, whose frequency ndwidth is 3 to 7MHz ws used. But, this proe is not lwys optiml for liver exmintions due to its high frequency. Penetrtion is not dequte especilly for ptients with lrge mounts of sucutneous nd viscerl ft nd ftty liver, with these prts often displyed in lue, mistkenly leding to n overestimtion of firosis. For correct dignosis, n ROI hs to e selected tht contins low sucutneous ft to void insufficient penetrtion, nd multiple reflections nd lood vessels hve to e excluded from the ROI; technique which requires prctice. A convex proe, EUP-C715, whose frequency ndwidth is 1 to 5MHz (140mm or greter depth penetrtion) hs recently ecome ville which improves penetrtion significntly. The dignostic cpility is lso improved ecuse the oservtion re is enlrged in oth the depth nd lterl directions, enling more esy selection of the exmintion re. With the convex proe, exmintion is esier in ptients with thick sucutneous ft, high-level oesity nd ftty liver; ptients which re difficult to exmine with liner proe (Figure 5). LFI dt mesured with liner nd convex proes shows high correltion, indicting tht conventionl mesurement results cn now e more redily otined y ll opertors. (Figure 6). Convex proe Liner proe Figure 6: Comprison of Liver Firosis Indices Mesured with Convex nd Liner Proes Similr LFI vlues were otined with convex nd liner proes. 5. Comined Approch to Elstogrphy Figure 5: Rel-time Tissue Elstogrphy with Liner nd Convex Proes In ptients with thick sucutneous ft, the RTE imge cn e oscured y lue coloring due to insufficient penetrtion with the liner proe, often preventing dequte evlution (). When using convex proe, the wider FOV nd improved penetrtion fcilittes RTE mesurement (). Vs vlues mesured with Sher Wve Imging vry significntly under the influence of not only firosis ut lso inflmmtion, jundice or congestion. On the other hnd, chnges in the reltive strin in chronic liver disese exmined y RTE reflects only the progression of liver firosis nd the mesurement is seldom ffected y these fctors. Therefore, the level of inflmmtion, jundice nd congestion cn e estimted y simultneously performing Sher Wve Imging nd Strin Imging (Comintionl Elstogrphy) nd nlyzing the difference in the dt etween these 2 techniques. This interprettion method is descried using the cse of 27-yer old mle suffering from cute 4 MEDIX-E008 (VOL63, 13-17, 2015)

5 heptitis B. Mild enlrgement of the liver nd smll volume of scites were found in B-mode exmintion, nd the ALT ws incresed to 1290IU. Jundice nd congestion were not found. LFI ws 1.2 efore tretment, equivlent to n estimted firosis stge of F1. In Sher Wve Imging, on the other hnd, liver stiffness y FiroScn *3 ws 8.8kP, which is equivlent to F3. The divergence is most proly due to the influence of inflmmtion ecuse the ptient hd no jundice or congestion. We my consider tht, ssuming F1 is in the pproximte rnge of 3 to 4kP, tht 3 to 4 out of the 8.8kP efore tretment is ccounted for y the influence of firosis nd the remining 4 to 5kP reflects the influence of inflmmtion. Actully, liver stiffness grdully decresed with decresing ALT nd recovered to 3.8kP fter 6 weeks. The divergence etween the sher wve nd strin imging results hd lso disppered (Figure 7). Comintionl Elstogrphy using the Vs mesurement otined y Sher Wve Imging, with evlution using RTE t the sme time is useful for correctly ssessing the clinicl condition of the liver. Development of the SWM technique nd RTE with convex proe hs mde it possile to perform Comintionl Elstogrphy in series following the norml ultrsound exmintion, using the one proe. Non-invsive dignosis of liver disese hs ecome more esily ccessile using ultrsound elstogrphy. 6. Acknowledgment We would like to express our grtitude to those people in Hitchi Alok Medicl with whom technicl mtters relted to evlution of clinicl usefulness of this function hve een discussed repetedly in ll stges from prototyping to vilility on-ord the ultrsound mchines. *1 Rel-time Tissue Elstogrphy nd *2 HI VISION Ascendus nd Ascendus re registered trdemrks of Hitchi Medicl Corportion. *3 FiroScn is the trdemrk of ECHOSENS. References: 1) Msuzki R, et l. : Prospective risk ssessment for heptocellulr crcinom development in ptients with chronic heptitis C y trnsient elstogrphy. Heptology 2009 ; 49 : ) Jung KS, et l. : Risk ssessment of heptitis B virusrelted heptocellulr crcinom development using liver stiffness mesurement (FiroScn). Heptology 2011 ; 53 : ) Aren U, et l. : Acute virl heptitis increses liver stiffness vlues mesured y trnsient elstogrphy. Heptology 2008 ; 47 : ) Sgir A, et l. : Trnsient elstogrphy is unrelile for detection of cirrhosis in ptients with cute liver dmge. Heptology 2008 ; 47 : ) Millonig G, et l. : Extrheptic cholestsis increses liver stiffness (FiroScn) irrespective of firosis. Heptology 2008 ; 48 : ) Colli A, et l. : Decompensted Chronic Hert Filure: Incresed Liver Stiffness Mesured y Mens of Trnsient Elstogrphy. Rdiology 2010 ; 257 : ) Shiin T, et l. : Mechnicl model nlysis for quntittive evlution of liver firosis sed on ultrsound tissue elsticity imging. Jpnese Journl of Applied Physics 2012 ; 51 : 07GF ) Fujimoto K, et l.: Noninvsive Evlution of Liver Firosis Using Rel-time Tissue Elstogrphy Stge Judgment y Liver Firosis Index (lf Index). Knzo[in Jpnese] 2010 ; 51 : ) Yd N, et l. : Assessment of liver firosis with reltime tissue elstogrphy in chronic virl heptitis. Oncology 2013 ; 84 Suppl 1 : ) Yd N, et l. :Noninvsive Dignosis of Liver Firosis: Utility of Dt Mining of Both Ultrsound Elstogrphy nd Serologicl Findings to Construct Decision Tree. Oncology 2014 ; 87 Suppl 1 : ) Fujimoto K, et l. : Novel imge nlysis method using ultrsound elstogrphy for non-invsive evlution of heptic firosis in ptients. Oncology 2013 ; 84 Suppl 1 : Figure 7: Tretment Course nd Interprettion in n Exmple Cse ALT improved quickly s result of tretment. Likewise, liver stiffness lso improved. T-Bil nd LFI remined t the sme level throughout tretment (). Blue-shded re is considered to reflect firosis nd the red-shded re inflmmtion (). 5 MEDIX-E008 (VOL63, 13-17, 2015)