Evangelos Chartampilas Bioclinic Hospital Thessaloniki, Greece

Hepatospecificcontrast agents Gadobenate dimeglumine (Multihance) Gadoxeticacid (Primovist) 3-5% liver uptake 50% liver uptake Hepatobiliary phase: 2h Transported via MOAT Hepatobiliary phase: 20min Transported via OATP(B1,B3) Relaxivityr1 : 6,3 [l mmol -1 s] Relaxivityr1: 6,9 [l mmol -1 s] Dosage: 0.1 mmol/kg (0.2 ml/kg) Dosage:0.025 mmol/kg (0.1 ml/kg) MOAT: multispecific organic anion transporter OATP: organic anion transporting polypeptides

Transport mechanism for Gd-EOB-DTPA ChoiY, BJR 2015

Uses of hepatospecificcontrast agents As they are taken up by functioning hepatocytes(and then excreted in the bile), they can be used to: 1. Evaluate liver function In cirrhosis, fibrosis and reduced number of functioning hepatocytes decrease contrast uptake 2. Identify early hepatocellular carcinoma (HCC) During hepatocarcinogenesis, the ability to take up the contrast is gradually lost 3. To differentiate FNH from adenoma 4. To depict the biliary tree (eg possible leaks) 5. To detect metastases

Evaluation of liver function Reduced liver enhancement in cirrhosis may be caused by Decrease in the number of functioning hepatocytes Impairment of transport mechanism Slight decrease in OATP1 activity in cirrhotic rats and Significant up-regulation of MRP2 activity, leading to elimination of the drug Tsuda N, Radiology 2010

Ways to evaluate liver function I 1. Direct measurement of liver signal intensity Liver to spleen ratio Liver to muscle ratio Relative enhancement (SI post SI pre )/SI pre Liver to spleen ratio and liver volume ( ) Correlation with indocyaningreen clearance, hepatic function parameters, Child-Pugh score and MELD score was found Motosugi U, JMRI 2009 Yamada A, Radiology 2011 Verloh N, Eur Radiol 2014 Lee S, JMRI 2016 ( ) Non absolute, non comparable measurements

Direct measurement of liver signal intensity Normal liver Ishak 6 (cirrhosis) Lee S, JMRI 2016 Verloh N, SciRep 2015

Ways to evaluate liver function II 2. MR perfusion (DCE-MRI) labor intensive 3. MR relaxometry Measurement of T1 relaxation time (ms) T1 values significantly longer in cirrhosis on gadoxetate enhanced MRI ( )Absolute values, independent of technical factors ( ) Technically demanding method

Evaluate cirrhotic nodule-early HCC Arterial Portal Typical pattern of arterial enhancement and portal washout is absent in 20-50% in HCC<3cm Arterial enhancement absent in 15-25% Portal washout absent in 40-60% The smaller the lesion, the higher the probability for atypical vascular kinetics Diagnosis of early HCC is associated with longer time to recurrence and a higher 5-year survival rate

Early HCC -definition Clinically: <2cm (very early) or <3cm and <3 in number (early)[barcelona stage 0 & A] Both hypervascularin arterial phase (classic HCC) Pathologically: < 2cm, in an early stage of carcinogenesis Vascular invasion or intrahepatic metastasis extremely rare Well differentiated HCC is not necessarily early HCC!

Early HCC pathological Small HCC <2cm Grows by replacing and not expansively Fatty change is common No fibrous capsule Well differentiated Unpaired arteries poorly developed Not easily seen in arterial phase May retain some portal venous supply Not easily seen in portal phase Vaguely nodular (early) Distinctly nodular (not early) HytiroglouP, Gastroent. Clin. N. Am 2007

Vascular kinetics and hepatospecific contrast uptake Early HCC Kitao et al, EurRadiol 2011

Role of Gd-EOB-DTPA in diagnosis I Loss of metabolic function might precede development of neoangiogenesis Bartolozzi, Abdom Imaging 2013 More than 90% of early HCCs showed no or decreased expression of OATP1B3 transporters Hypointensity on hepatobiliary phase Ichikawa T, Liver Cancer 2014 With the use of Gd-EOB-DTPA, diagnostic accuracy of HCC is 95% Sano K, Radiology 2011 KitaoA, EurRadiol2011

Role of Gd-EOB-DTPA in diagnosis II Borderline HCC (Kudo Μ, Dig Dis2011)

Role of Gd-EOB-DTPA in diagnosis III Comparison to other techniques Ichikawa T, Liver Cancer 2014

60-year-old man with cirrhosis SPIR T1 pre-gd DWI Arterial HB

Hypointensenodules I Not all hypointensenodules are early HCC; some represent dysplastic nodules However even if early HCC is ruled out on biopsy, there is high probability this nodule will transform to hypervascular, typical HCC, especially when large (>10mm) Other risk factors: presence of fat, restricted diffusion, T2 hyperintensity Incidence rates are approximately 18%, 25% and 30% at 1, 2 and 3 years respectively Suh CH, AJR 2017 JoishiD,Magn Reson Med Sci. 2013 Kim, Radiology 2012

Hypointensenodules II Whether HCC or HGDN, the hypovascular, hypointense lesion is suspicious (especially if large, T2, DWI or has intralesional fat) but not urgent Management Follow up? Biopsy? CEUS? Benefit from intervention in early HCC? RFA: despite lower local progression, similar OS and PFS with hypervascular(overt)hcc [Lee DH, Radiology 2017] Surgery: marginal survival benefit [Midorikawa Y, J Hepatol 2013]

HypovascularhypointenseHCC Τ2 DWI Art HB

HyperintenseHCC A significant percentage (9-20%) of typical hypervascular HCC show paradoxical gadoxetate uptake (iso/hyperintense in hepatobiliary phase) Overexpression of OATP1B3 transporters Less aggressive biological behaviour Less frequent portal vein invasion Lower recurrence rate compared to hypointense Greater lipiodol uptake post TACE Choi JW, Radiology 2013 Kim JW, EurJ Radiol2017

Hyperintense HCC & histology Are hyperintense HCCs better differentiated? Although controversial, most evidence suggests that there is an association between degree of enhancement on HB phase and degree of differentiation Jin YJ, Medicine 2017; Tong H, Clin Imaging 2017 Grade IV Grade I Well differentiated HCC Art T2 SPIR T1 HB

HyperintenseHCC & differential DDx: Dysplastic nodules Regenerative nodules FNH like nodules Focal defect in uptake, hypointense rim, nodule-innodule appearance, portal washout HCC SuhJY, AJR 2011 HCC DN

50-year-old man with cirrhosis DWI T1 FS ART HB 1,5 years later DWI T1 FS ART HB Typical HCC characteristics but the lesion unchanged in size!

Additional features with Gd-EOB-DTPA Detection of microscopic vascular invasion Seen as a hypointensehalo in HB phase (Nishie A, J Gastroenterol Hepatol 2014)

Pitfalls with Gd-EOB-DTPA imaging Genetic polymorphisms in the expression of OATP transporters may lead to reduced hepatic enhancement Cirrhosis is associated with reduced liver enhancement Bilirubin, PT activity, MELD score, indocyaninegreen clearance correlate with degree of HB enhancement Patients with compromised liver function may not benefit from hepatospecific agent use Acute transient dyspnea(14% with Gd-EOB-DTPA vs 5% with Gd-BOPTA) Davenport MS, Radiology 2013

Overall performance of Gd-EOB-DTPA When the nodule is enhancing in the arterial phase and is hypointense in the HB 100% specificity Wang YC, PLOS ONE 2017; Golfieri, JMRI 2012 Excellent sensitivity (79 95%) and specificity (89 92%) for lesions 2cm Suboptimal performance for lesions 1cm Arterial hyperenhancementand HB hypointensitymost common pattern Apply ancillary imaging features

38-year-old man with HBV cirrhosis US Art HB CT post TACE

Same patient, 4 years later US T2 DWI T1 pre Art Portal 30 Images courtesy of Dr Michailidis N

Conclusions Hepatospecificcontrast agents are useful for the assessment of liver fibrosis They have achieved a major breakthrough for diagnosis of early HCC Closely follow-up hypovascular, HB hypointense nodules Diagnosis of HCC is based on all sequences (T1, T2, DWI) HCC may appear hyperintense in HB phase; associated with better prognosis

Thank you! Zongolopoulos Umbrellas,Thessaloniki