1. SMALL FOR SIZE IN LIVER SURGERY Ghent, 11 th March 2005 THE HEMIPORTOCAVAL SHUNT R. Troisi, MD PhD Hepatobiliary and Liver Transplantation Service Ghent University Hospital Medical School GHENT - BELGIUM

2. Living Donor Liver Transplantation The Evolution  3 D Reconstructive imaging for graft selection - precise 3D map of vascular and biliary anatomy and calculation of remnant at risk  Strategies for small for size grafts - intragraft responses to shear stress - inflow modulation techniques  Operational Tolerance - induction with policlonal AB’s - combined stem cells / living donor Tx

3. ELTR 06/2003 Evolution of the Number of Living Related Liver Transplantations in Europe (n = 1286)

4. ELTR 06/2003 Right liver (5, 6, 7, 8): 540 (93%) Left liver (seg. 2,3,4) : 25 (4%) Left lobe (S 2, 3) : 16 (3%) Type of Graft used for Adult LRLT 25 18 12 231 377 540

5. ELTR 06/2003 Graft Survival according to the Type of Living Related Graft in LRLT- Adults 61 73 57 65 33 41 0 20 40 60 80 100 012345 Right liver : 537 Left lobe : 15 Left liver : 29 (%) Yrs Total Log rank test p< 0.001

6. Living Donor Liver Transplantation Causes of Graft Loss / Mortality in Adults Sepsis53% Hemorrhage14% Vascular14% Recurrent Disease 2-3% Other16% (Broelsch, LT 2003) Graft dysfunction (?) SFSS (?) Outflow insufficiency (?)

7. Living Donor Liver Transplantation Relationships between Techniques and Complications Small for Size Syndrome Vascular thrombosis Bleeding Biliary complications leaks stenosis Venous outflow insufficiency New surgical techniques

8. Small-For-Size Syndrome FUNCTIONAL GRAFT MASS GV Fatty liver / Age Parenchymal disease GRAFT INJURY WI / CI Rejection Venous Outflow Graft Inflow METABOLIC DEMAND Pre-Tx status Post-Tx complications

9. ENHANCED HEPATOCYTE INJURY DELAYED SYNTHETIC FUNCTION PROLONGED CHOLESTASIS RENAL FAILURE ASCITES FORMATION SEPTIC COMPLICATIONS SEVERE GRAFT DYSFUNCTION REDUCED GRAFT SURVIVAL LESS OUTCOME Manifestations of the SFSS

10. Macroscopic appearance Sinusoidal congestion Biliary thrombi vacuolar degeneration Single apoptotic change in hepatocytes Man K, Ann Surg 2003 Pathology of SFSG: Parenchymal Cells Lines

11. Microscopic features sinusoidal disruption hepatocytes ballooning vacuolar degeneration mitochondrial swelling Pathology of SFSG: Parenchymal Cells Lines Man K, Ann Surg 2003

12. The Intragraft Responses Portal hyperperfusion Small functional mass CONGESTION Intragraft Responses SHEAR STRESS Cytokines Macrophages Adhesion molecules Egr – 1 (a) ET-1 (c) HSPs (a) HO-1 (b,c) a)Ting-Bo Liang, Transplantation 2003 b)Zhen-Fan Yang, AJT 2003 c)Man K, Ann Surg 2003 DOWN UP

13. Variations in Graft Arterial and Portal Flow between the Physiological Setting (Donors) and following Graft Reperfusion (Recipients) (Troisi R, Ann Surg 2003)

14. Effects of Splenic Artery Ligation on Graft Inflow (Troisi R, Ann Surg 2003)

15. Effects of Splenic Artery Ligation on Outcome (Troisi R, Liver Transplantation 2003) (n = 14) (n = 10)

16.  Mean flows  diastolic / systolic  Diastolic filling  patency  Pulsatile index  quality anastomosis  Flow curve  Outflow Spasm Kinking Transit Time Flow Measurement (TTFM)

17. Rationale for HPCS Mean of 90 ml/min/100 g liver = Normal PVF in donors Mean of 270 – 350 ml/min/100 g liver = ± 3 x PVF after reperfusion → SAL Mean PVF of > 360 ml/min/100 g liver =SAL + PVB or HEMI PORTO CAVAL SHUNT

18. HPCS: Standard Technique for SFSG

19. Left Lobe LDLT: Outflow Reconstruction Advantages of a Left Liver No congestion (since including the MHV) Liver function less depressed (bigger remnant) Less overall donor morbidity Disadvantages of a Left Liver Difficult position/risks of HV twist Artery smaller Less liver mass

20. Calibration of HPCS in Left Lobe

21. Hemodynamic Features in Shunted Left Lobe HPCS LPV HPCS LHA

22. Effects of HPCS for Inflow Modulation on the Outcome of SFSG in LDLT Graft hemodynamics in SFSG Features of non-parenchymal cell lines following portal shunt Clinical outcome (Troisi R, Am J Transplantation 2005)

23. ParameterG1 (n = 5)G2 (n = 10)P* Mean age (years  SD)52.6 ± 2.156.6 ± 4.80.09 Median FU (months  SD)5 ± 1317 ± 50.52 UNOS Status 2(n)5/59/10- MELD score (  SD)20 ± 618 ± 40.9 Esoph Varices gr. II/III(n)58- Right Liver (n)45- Left Liver (n)15 0.56** * Mann-Whitney U-test; ** Fisher exact test Patient’s Demographics

24. ParameterG1 (n = 5)G2 (n = 10)P* Mean GW (gr.)662 ± 136 (464 – 890)589 ± 265 (404 – 836)0.39 Mean GRBWR0,73 ± 0,1% (0,58 - 0,80)0,70 ± 0,1% (0,56 - 0,80)0.69 RIHV anastomosed2/5 (40%)4/10 (40%)- S5 – S8 drainage2/5 (40%)4/10 (40%)- OP Time (min)630 ± 104 (420 – 820)621 ± 149 (450 – 811)0.43 Blood Loss (ml)2300 ± 2700 (500 – 4000)2350 ± 2720 (200 – 6000)0.53 CIT (min.)216 ± 78 (170 – 360)193 ± 51 (120– 250)0.83 WIT (min.)53,7 ± 14,3 (35 – 70)64 ± 12,9 (45– 92)0.72 PART (min.)51,2 ± 14,3 (30 – 60)58,4 ± 7,9 (45–65)0.35 *Spearman rank order correlation Donor’s Characteristics

25. ParameterLeft Livers (n = 6)Right Livers (n = 9)P* dPVF 462 ± 75719 ± 2160.04 (ml/min) dPVF/GW 121  40116 ± 130.87 (ml/min/100 g liver) * Wilcoxon matched pairs test. Donor’s Graft Hemodynamics: Left vs Right Livers

26. ParameterG1 (n=5)Parameter G2 (n = 10) P * Cardiac Index a 4.7 ± 1.6Cardiac Index4.6 ± 0.9. 0.8 HPCS/GW b -HPCS/GW 330 ± 230 (60-620) - rPVF1/GW460 ± 30 (140-1080) rPVF2/GW 190 ± 70 (15-260) 0.002 rPVF1/GW/CI c 80 ± 20 (50-100)rPVF2/GW/CI 50 ± 160 (3-71) 0.018 rHAF1/GW9 ± 8 (2-20)rHAF2/GW 32 ± 20 (10-63) 0.030 rHAF1/GW/CI 2 ± 1 (0.6-1)rHAF2/GW/CI 7 ± 3 (2-16) 0.030 * Mann-Whitney U-test; a L/min/m2; b Graft Weight (ml/min/100 g liver); c Cardiac index HPCS: portal flow shunted away; rPVF 1: total portal vein flow to the graft; rPVF 2: portal flow to the graft after opening of the HPCS; rHAF 1: hepatic artery flow to the graft; rHAF 2: hepatic artery flow to the graft after opening of the HPCS. Inflow Modulation by HPCS

27. Portal vein flow (cm/sec.)G1 (no shunt)G2 (shunt)P* POD 173.4 ± 18.132.4 ± 17.60.006 POD 770.8 ± 9.531 ± 12.5 0.004 > 1 month65 ± 737.8 ± 9 0.095 Hepatic artery flow POD 132.6 ± 7.562 ± 25.1 0.065 POD 731 ± 3.458.7 ± 20.20.004 > 1 month30 ±14.161.8 ± 12.50.095 * Mann-Whitney U-test;POD: postoperative day US-Doppler in Non-Shunted vs Shunted Grafts

28. Graph.1: Evolution of total bilirubin * p = 0.005 ** p = 0.008 *** p = 0.001 * * ** *** G1 G2 *, **, *** Mann-Whitney U-test

29. Graph.2: Evolution of prothrombin time G1 G2 * p = 0.272 ** p = 0.012 *** p = 0.008 * ** *** * ** *** *, **, *** Mann-Whitney U-test

30. Graph.3: Evolution of ascites leak G1 G2 * p = 0.067 ** p = 0.372 *** p = 0.018 * * ** *** *, **, *** Mann-Whitney U-test

31. Graph.4: Serum creatinine at POD 21 * p = 0.005 * * * Mann-Whitney U-test

32. Fig. 1: Serial relative changes in liver volume. Relative changes in liver volume (%) *p = ns * *

33. ComplicationsG 1G 2P* Enkephalopathy1/5 (20%)0/100.3 Massive ascites leak4/5 (80%)1/10 (10%)0.01 SFSS3/5 (60%)0/100.02 Retransplantation3/5 (60%)1/10 (10%)0.06 Sepsis/MOF3/5 (60%)1/10 (10%)0.06 Acute Rejection2/5 (40%)3/10 (30%)1.0 Thrombosis HPCS-0/10- * Fisher’s exact test Overall Results

34. No HPCS (n = 5) 80% HPCS (n = 10) OVERALL GRAFT SURVIVAL Log Rank P = 0.0289 20%

35. Enhanced portal graft hyperperfusion in SFSG is significantly correlated to postoperative graft dysfunction and SFSS The RE system is irreversibly damaged in these grafts whereas HPCS do preserve lobular architecture Hemi-Porto-Caval shunt permits an extensive reduction of the graft inflow improving hepatic artery flow HPCS do not worsens postoperative graft function, graft regeneration. General outcome is generally improved Careful perioperative management is however recommended (i.e. risks of sepsis) Conclusions (1)

36. Basing on the Asian data on reduced donor morbidity with the use of the left livers, upon this experience could we implement the use of left liver grafts for adult recipients? Conclusions (2)