Simplifying living donor liver transplantation

See Ching Chan, Chung Mau Lo and Sheung Tat Fan

Hong Kong, China

Review Article

Simplifying living donor liver transplantation

See Ching Chan, Chung Mau Lo and Sheung Tat Fan

Hong Kong, China

BACKGROUND:Living donor liver transplantation is a complex surgical operation. Treatment policies and operative techniques evolved in the last two decades.

DATA SOURCES:Our center's experience in living donor liver transplantation was reviewed in conjunction with relevant publications in the literature.

RESULTS:The surgical techniques and perioperative surgical therapeutics could be modified towards simplicity. Examples include regular inclusion of the middle hepatic vein without compromising the venous outflow of the donor's remnant left liver. This provides excellent venous outflow, which is crucial for a small-for-size graft. Immunosuppression and hepatitis B suppression are steroid free and hepatitis B immunoglobulin free respectively.

CONCLUSION:The most practical way to achieve high graft and recipient survival rates with an acceptably low donor risk is through design of a protocol that simplifies the surgery and postoperative management.

(Hepatobiliary Pancreat Dis Int 2010; 9: 9-14)

simplifying;right liver; living donor; liver transplantation

Introduction

Soon after Starzl demonstrated the technical feasibility[1]and long-term survival of recipients of deceased donor liver transplantation (DDLT),[2]Smith[3]envisaged and proposed living donor liver transplantation (LDLT). The original intention was to obtain a liver graft of reliable quality from a living donor in days when donation was made after cardiac death. Today, LDLT is the only life-saving treatment alternative to DDLT in the face of a global shortage of deceased donor liver grafts. However, donor risks are inevitable and undeniable. The liver graft is often small-for-size as when the recipient has a large body size or when the left liver is used as a graft. There has been no shortage of cautionary notes in the practice of LDLT.[4-6]

In the development of LDLT from birth to early adulthood,[7]some operative techniques and surgical measures came about from intuition instead of the bench-to-bedside sequence. Retrospective validation of concepts practiced clinically from the bedside to the bench inevitably has a lag phase. This is further handicapped by the caveats of experiments that are often performed on laboratory animals without portal hypertension. LDLT is always a compromised situation and the surgeon as the moderator in securing dual success in saving the life of the recipient under very safe circumstances of the donor. Over a decade of time, through accumulation of experience, we have simplified LDLT, which remains a procedure of high complexity. Here, we give a synopsis of our learning process in this endeavor.

Operative techniques

Small-for-size graft

The partial graft of LDLT in adult-to-adult transplantation is usually smaller than the recipient's standard liver volume. This becomes clinically significant when the graft size is smaller than half of the standard liver volume of the recipient. Graft survival further worsens incrementally with a decrease in the graft-to-standard liver volume ratio.[8]Such graft size requirement alsobecomes higher in the presence of portal hypertension of the recipient.[9]

The functional liver graft size only includes parenchyma with unimpeded venous drainage.[10]The deleterious effect on liver graft without adequate venous drainage has been well described.[11]The importance of venous outflow capacity in relation to functional graft size was conceptualized.[12]Concerns for donor safety have generated the reluctance of including the middle hepatic vein (MHV) in the right liver graft. Right liver grafts without the MHV nevertheless have the anterior sector drained by reconstruction of segments 5 and 8 by interpositional venous graft.[13]In an experienced center, intraoperative Doppler ultrasonography identification of collaterals draining the right anterior sector by right hepatic vein (RHV) determines if reconstruction is deemed necessary.[14]In order to expedite venous anastomosis, techniques using a venous patch[15,16]or double inferior vena cava (IVC) were described.[16]

Inclusion of the entire MHV with multiple branches draining the right anterior sector while preserving segment 4b hepatic vein of the remnant left liver secures the most reliable and uniform venous drainage of the right liver graft.[17]On the back-table, the MHV and RHV often at a distance of up to 2 cm can be drawn together for fashioning of a single venous cuff.[18]Exploiting the stretchability of the hepatic veins and resilience of the liver parenchyma in between, the single-cuffed hepatic veins after venoplasty maintain a triangular form ensuring unimpeded venous triphasic inflow and outflow through the IVC.[19]Venous patch[20]is not required in this venoplasty, which allows short warm ischemic time for a simpler anastomosis to the IVC. False perception of an inadequate length of the MHV wall portion of the venoplasty for anastomosis to the IVC is often resulted from misleading planar schematic drawings. At operation, the IVC which is tubular and has a venotomy made over the RHV stump faces the venoplasty of the MHV and RHV of the graft. The portion of the recipient IVC in between the RHV and MHV also makes up for the deficit in length on the MHV not included in the graft in order to preserve the segment 4b hepatic vein for venous drainage of the remnant left lobe of the donor. Interpositional venous graft[21]is not required. When the graft is small-for-size substantially, caudal shifting of the venous anastomosis provides advantage and makes duct-to-duct anastomosis easier.[22]

The damage to the small-for-size partial liver graft incriminates portal hyperperfusion[23,24]and portal hypertension.[25]Flow through the graft, a function of portal pressure, increases with graft outflow capacity. The alleviation of the portal pressure is also dependent on the graft outflow capacity. Taken these altogether, hyperperfusion is a phenomenon resulted from recipient portal hypertension and good graft outflow capacity. While persistent portal hypertension reflects the inadequacy of graft size compound by poor outflow capacity, portal hyperperfusion has to be interpreted in the context of portal hypertension even after graft implantation. In the absence of portal hypertension, "portal hyperperfusion" is merely an observation compatible with normal graft functioning. The damage to the graft from portal hypertension needs histological verification of the changes of the sinusoidal structure.[25]

Efforts to alleviate portal pressure and portal hyperperfusion have been made by principles of portal inflow shunting and modulation. The former includes mesocaval shunting and ligation of the superior mesenteric vein down stream to the shunt[26]and hemiporto-caval shunt.[27]Modulation by splenic artery ligation is also described.[28]These are, however, not in the setting of a graft with reliable and excellent outflow capacity by including the MHV in total with venoplasty guaranteeing anastomotic patency.

Graft handling

The clinical application of University of Wisconsin (UW) solution has greatly extended the graft preservation time and improved DDLT outcomes.[29]Designed as an intracellular preservation agent with high potassium content, the UW solution requires flushing out of the potassium before reperfusion of the graft. In LDLT, every millimeter of the portal vein is not wasted. The use of UW requires cannulation of the graft portal vein for flushing with either plasma or lactate solution. The portion of the portal vein ligated has to be excised so that portal vein anastomosis could be performed on healthy portal vein tissue. This introduces difficulties when the length is already limited, not to mention the situation of a portal vein trifurcation in the donor. Histidine-tryptophan-ketoglutarate (HTK) solution with a near physiological and low potassium content allows restoration of graft circulation without prior flushing.[30]By applying a vascular clamp onto the graft portal vein, circulation through the IVC could be restored before portal vein anastomosis.[31]Sooner restoration of inferior vena caval circulation has the advantage of hemodynamic stability even without venovenous bypass. The duration of IVC cross-clamping was 41 minutes (19 to 78) and portal vein anastomosis 16 minutes (12 to 20) (n=148). Our early practice of veno-venous bypass has been shown to be associated with worse outcomes that were related to hypothermiaand bleeding diathesis.[32]There is clinical[33]and laboratory[34]evidence of a lower biliary complication rate by using HTK solution, which is of lower viscosity. The lower cost of HKT solution confers further advantage of its use.[35]The longer preservation time allowed by UW solution is irrelevant in LDLT.[36-38]

Abdominal drains

The deployment of abdominal drain is customary in hepatobiliary surgery and liver transplantation. We have shown in our series that abdominal drain is associated with a higher wound infection rate in liver resection of cirrhotic livers.[39]Abdominal drains are also not required in donor right hepatectomy, which is on normal livers.[40]Abdominal drains placed in the proximity of liver transection surface serve to detect and contain bile leakage. By meticulous liver transection using the Cavitron Ultrasonic Surgical Aspirator (CUSA, Valleylab, CO, USA) and ligation and clipping of the vasculo-biliary channels, bile leakage and bleeding could be avoided. The drain as a foreign body transgresses the body barrier but invites infection. Therefore, drains should be avoided whenever possible. The no drain policy has been extended to DDLT.[41]A partial liver graft with good venous outflow capacity could be treated the same way.

Coupled with this policy is the reliable biliary anastomosis preferentially duct-to-duct[42]and as appropriate, hepaticojejunostomy. Absence of common bile duct stone of the recipient is confirmed by choledochoscopy. Biliary anastomosis splintage tubes are not deployed as they could not be removed until 3 months after operation. There is no evidence of whether stent will increase or decrease biliary complication rates.[43]

Surgical therapeutics

Donor workup

A stepwise workup for potential donors also in the high urgency situation allows an up to 32.1% of potential donors to undergo surgery.[44]Liver transplant surgeons as donor advocates provide the most updated information of the recipient for potential living donors to consider donation. This includes hospital mortality for acute liver failure patients and long-term tumor-free survival for recipients with hepatocellular carcinoma. Currently, donor mortality rates of up to 0.5% (right liver) and 0.1% (left liver)[45]are needed to achieve a 5-year recipient survival of 80%. While there is no compromise on any increased risk of the donor, recipient survival does vary on an individual basis. This takes into account of increased hospital mortality for potential recipients with comorbidities like renal impairment and sepsis, etc. While most centers employ the Milan criteria[46]for listing potential recipients for DDLT, a modest extension of such criteria is adopted by centers. The worsened long-term survival from tumor recurrence ought to be knowledgeable to potential recipients and donors in the contemplation of LDLT.

Preoperative assessment of donor liver is made by computed tomography. Three-dimensional hepatic artery images are reconstructed from contrast scan, and maximal image projections of portal and hepatic veins are also generated for easier appraisal of vascular anatomy.[44]Preoperative demonstration of biliary anatomy could be made by endoscopic retrograde cholangiogram or magnetic resonance imaging. It is a matter of donor selection policy whether biliary anatomy which is not so straight forward should override the enthusiasm of the donor. There are, nevertheless, rare occasions when complicated biliary anatomy becomes prohibitive.[47]As the ductal cells follow the development of the connective tissues of the portal vein branches, the venous drainage of the ductal branches is via the portal vein branches.[48]Understanding this embryological anatomical relationship, detection of abnormal portal vein anatomy from imaging prompts the performance of a magnetic resonant image of the bile ducts in the donor assessment.

Hepatitis B

Before the advent of hepatitis B immunoglobulin (HBIg) and neucleoside analogue, namely lamivudine, liver transplantation for hepatitis B recipients was met with poor results due to hepatitis B reactivation. There came a policy of adequate recipient protection only through exogenous HBIg.[49]A combination of HBIg and lamivudine produced the lowest hepatitis B recurrence rate versus HBIg or lamivudine alone.[50]Nevertheless, our experience has shown that lamivudine monoagent prophylaxis against hepatitis B was adequate.[51]In a consecutive series of 173 recipients with a median follow-up of 40.7 months, only 19 (10.35%) of the recipients developed lamivudine resistant strains. Amongst them, 138 (80%) were hepatitis B surface antigen negative. A high proportion of these recipients (93/173, 53.8%) had production of hepatitis B surface antibody. Adoptive immunity, which may have conferred upon them, provided protection against hepatitis B reinfection.[52]This immunity adopted may mimic the role of HBIg, which is withdrawn from the liver transplant recipients.[53]

Recipients with lamivudine resistant strain hepatitis B virus before or after liver transplantation havealso been successfully managed by add-on adefovir and without HBIg.[54]Though there are no post-liver transplant data, the clinical application of the more potent Entecavir[55]will gain wider acceptance of nucleoside analogue monoprophylaxis and without HBIg. Hepatitis B core antibody positive donors with normal liver function test are not contraindicated for liver donation.[56]Should the recipient be hepatitis B naive, prophylaxis with lamivudine is effective.

Immunosuppression

Introduction of calcineurin inhibitors, cyclosporine A[57]and then tacrolimus,[58]has much improved the graft survival of solid organ transplantation. There is also a trend of multi-drug regimen often including steroid for prevention of acute cellular rejection. Steroid may induce post-transplant diabetes while calcineurin inhibitor predisposes to the development of renal impairment, hypertension and diabetes. Interleukin-2 receptor antagonist that specifically inhibits T-lymphocytes allows sparing of steroid and greatly reduces the chance of development of posttransplant diabetes. This lowers the costs generated from managements of diabetes and shortens hospital stay. The tacrolimus intake and serum trough levels are also lower, so is cytomegalovirus antigenemia.[59]In the absence of over-immunosuppression, there is brighter outlook for development of tolerance[60]or a significant degree of tolerance (called "prope tolerance").[61]This takes place in the presence of microchimerism which perpetuates tolerance by combined mechanisms of clonal exhaustion-deletion and immune ignorance.[62]Tacrolimus at the minimal permissive dose should remain the cornerstone of immunuosuppressant therapy for LDLT and safely be supplemented by other agents. It has also successfully eliminated the routine use of corticosteroids after transplantation.

Conclusion

LDLT is a complex treatment modality that is very expensive not only in monetary terms but also in the risk incurred upon the living donor. Urging on to the safe side could only be the policy of the transplant community. Unnecessary procedures or precautions, however, do not only increase the costs but could also pose a disadvantage to the patient, be it the recipient or the donor. The technical maturation goes hand-inhand with deeper understanding of the underlying mechanism of graft survival or failure and brings to light the most practical way to achieve a high success rate justifying the donor risks. This could only improve the field strength of LDLT, which remains the only legitimate alternative in regions where deceased donor organs fall short of supply for the need.

As Edward de Bono[63]put it "In order to make something simple you have to know your subject very well indeed," simplicity as a measure of maturity of technique could well be the best policy to avoid technical misadventures. Several issues should be borne in mind when interpreting this synopsis. It is from a center with a decade of experience in right liver living donor liver transplantation operated by a constant team of experienced surgeons. The results may not be reproducible by centers that are still in a steep learning curve. This exercise nevertheless endeavors to facilitate other centers to reach technical maturity more expeditiously. The right liver graft that includes the entire MHV provides the best venous outflow and thus the highest proportion of functional liver parenchyma for the graft. A graft without the MHV may not have an excellent outflow capacity and compromised surgical outcomes.

Funding:None.

Ethical approval:Not needed.

Contributors:CSC wrote the main body of the article. LCM and FST developed the various techniques described in the article and revised the manuscript. FST is the guarantor.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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October 7, 2009

Accepted after revision December 24, 2009

Author Affiliations: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China (Chan SC, Lo CM and Fan ST)

Sheung Tat Fan, Professor, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China (Tel: 852-2855 4703; Fax: 852-2986 5262; Email: stfan@ hku.hk)

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