Transplant Course: The Art of Liver Transplantation

Date:

25 March 2010 (Thursday)

Time:

08:30–17:30

Venue:

Auditorium, China National Convention Center

Course Directors:

Sheung-Tat Fan, Hong Kong

 

John J. Fung, Cleveland

Welcome Remarks

Sheung-Tat Fan, Hong Kong

08:30–10:00

Session 1: Patient Selection

Moderator

Zhong-Yang Shen, Tianjin

 

Didier Samuel, Villejuif

08:30–08:50

TC-01 Indications for Liver Transplantation

 

Seng-Gee Lim, Singapore

08:50–09:10

TC-02 Overview of MELD/PELD

 

Chung-Mau Lo, Hong Kong

09:10–09:30

TC-03 Milan Criteria and Beyond

 

Kyung-Suk Suh, Seoul

09:30–09:50

TC-04 Cadaveric Donors: Assessment, Management and the Use of Expanded Criteria Donor Livers

 

John J. Fung, Cleveland

09:50–10:00

Discussion

10:00–10:15

Coffee Break

10:15–12:30

Session 2: Liver Transplant Centers—Experience and Challenges

Moderator

Shu-Sen Zheng, Hangzhou

 

Sandy Feng, San Francisco

 

Established Centers

10:15–10:25

TC-05 The Seoul Experience

 

Deok-Bog Moon, Seoul

10:25–10:35

TC-06 The Tokyo Experience

 

Yasuhiko Sugawara, Tokyo

10:35–10:45

TC-07 The Hong Kong Experience

 

See-Ching Chan, Hong Kong

10:45–10:55

TC-08 The Sydney Experience

 

Geoffrey W. McCaughan, Sydney

10:55–11:05

TC-09 The New Delhi Experience

 

Arvinder S. Soin, New Delhi

11:05–11:35

Discussion

 

Small Centers

11:35–11:45

TC-10 The Riyadh Experience

 

Mohammed Al-Sebayel, Riyadh

11:45–11:55

TC-11 The Ho Chi Minh City Experience

 

Dong A. Tran, Ho Chi Ming City

11:55–12:05

TC-12 The Quezon City Experience

 

Benito V.C. Purugganan,Quezon City

12:05–12:30

Discussion

12:30–14:00

Lunch

14:00–15:30

Session 3: Management of Liver Transplantation Patients

Moderator

Xue-Hao Wang, Nanjing

 

Koichi Tanaka, Kobe

14:00–14:20

TC-13 Pediatric Issues in Liver Transplantation

 

Chao-Long Chen, Kaohsiung

14:20–14:40

TC-14 Liver Support System for the Management of Liver Failure

 

Robert G. Gish, San Francisco

14:40–15:00

TC-15 Liver Transplantation for Hepatocellular Carcinoma

 

Shu-Sen Zheng, Hangzhou

15:00–15:20

TC-16 Prevention and Management of Recurrence of HBV and HCV Infection following Liver Transplantation

 

Ed Gane, Auckland

15:20–15:30

Discussion

15:30–16:00

Coffee Break

16:00–17:30

Session 4: Current Status and Future Prospect

Moderator

Lv-Nan Yan, Chengdu

 

Yasutsugu Takada, Ehime

16:00–16:20

TC-17 The China Liver Transplant Registry

 

Hai-Bo Wang, Hong Kong

16:20–16:40

TC-18 Korea Liver Transplant Registry

 

Shin Hwang, Seoul

16:40–17:00

TC-19 Australian–New Zealand Liver Transplant Registry

 

Ed Gane, Auckland

17:00–17:20

TC-20 Critical Issues in Liver Transplantation Community

 

Sandy Feng, San Francisco

17:20–17:30

Discussion

LT-01 Indications for Liver Transplantation

Seng Gee Lim

Chief, Department of Gastroenterology and Hepatology, National University Health System, Singapore

Liver transplantation is now standard of care therapy for patients with acute or chronic liver disease where long term or short term patient survival is compromised. Uncommonly, liver transplantation is undertaken for symptomatic systemic or liver disease, or as a form of surgical gene therapy. Unfortunately, the number of people who need liver transplantation are increasing much faster than the donor organs available. Over the years, the indications for liver transplantation have become generally accepted, however there are still particular areas of contention, particularly in areas of alcoholic liver disease and HIV disease. In addition, the criteria for liver transplantation for hepatocellular carcinoma continues to be re-evaluated. What is also not as clear is the setting where patients are too unwell to benefit from liver transplantation, particularly where end stage liver disease or acute liver failure has resulted in multiorgan failure or severe systemic disease. Cadavaric transplantation has provided clear criteria for liver transplanation as donor livers are a public resource, and prioritization must be based on objective criteria which is related to transplant free survival such as the MELD score. However, in some situations the MELD score does not really apply, particular for symptomatic liver disease and for surgical gene therapy. We must put indications for liver transplant in context. Having an indication for transplant is the starting point, as the patient needs to be evaluated for contraindications, medical and psychological fitness for transplant. The patient will need to have a battery of tests and evaluations performed after which the transplant team will meet to decide on listing of the patient. After this process, patient selection is based on prioritisation, most centres currently use MELD score for organ allocation, but this may not apply in cases where there is symptomatic systemic or liver disease or in cases of surgical gene therapy. While the process of patient selection has been refined based on cadaveric organ donation, in cases of living donor organ transplant, the resource is no longer public but considered a dedicated gift which comes with considerable risk. There is still debate about the best timing and indication for transplantation.

LT-03 Milan Criteria and Beyond

Kyung-Suk Suh

Seoul National University Hospital, Seoul, Korea

In the setting of living donor liver transplantation (LDLT), specific living donor-related factors should be taken into account. A living donor is uniquely matched to a certain recipient in most LDLT situations, and this special relationship between a donor and recipient can provide a patient with the opportunity to undergo liver transplantation even in sub-optimal patients with advanced hepatocellular carcinoma (HCC). However, a high probability of tumor recurrence should evoke ethical issues concerning risk to the living donor. There are no accepted criteria for patients with tumors that lie outside the conventional criteria (e.g. Milan criteria).

To expand the Milan criteria, prognostic factors other than size and number of tumor may be necessary. Between November 1997 and December 2005, 104 cases of liver transplantation for patients with HCC were performed at our center. Twenty-four patients did not meet the Milan criteria preoperatively. Among these 24 patients, 19 had no major vascular invasion at the time of surgery. We analyzed the survival and prognostic factors of these 19 patients. The mean follow-up period was 33 months (range 6–89). Three-year survival rate in 19 patients was 67.4%. Three-year survival rates were significantly higher when preoperative alpha-fetoprotein was less than 400 ng/ml (86.2 vs. 0%, p < 0.001) when Edmonson–Steiner’s histological grade 1 or 2 (100 vs. 40%, p = 0.036) and when microvascular invasion was absent (78.6 vs. 30%, p = 0.039).

Positron emission tomography using F-18 fluoro-2-deoxy-d-glucose (¹⁸F-FDG-PET) imaging is now well established as a non-invasive diagnostic tool for the detection of a variety of malignant tumors. However, in the case of HCC, several investigators have reported controversial conclusions and an inadequate sensitivity for PET (50–55%). Nevertheless, a high positive rate of FDG accumulation has been reported in patients with high-grade HCC and in those with markedly elevated alpha fetoprotein (AFP) levels. When we analyzed the association between tumor factors and PET (+) (greater PET lesion uptake) in liver, preoperative AFP level and vascular invasion were found to be significantly associated with PET (+) (p = 0.003 and p < 0.001, respectively). The 2 year recurrence-free survival rate (2 year RFSR) of PET (−) patients was significantly higher than that of PET (+) patients (85.1% vs. 46.1%) (p = 0.0005). PET imaging may be a useful preoperative tool for estimating the post-LT risk of tumor recurrence, because histological grade and vascular invasion cannot be determined preoperatively.

Conclusion If pre-operative alpha-fetoprotein is less than 400 ng/ml, and PET scan is negative in the tumor, a good prognosis is expected after liver transplantation for HCC even in patients who do not meet the Milan criteria.

LT-04 Cadaveric Donors: Assessment, Management and the Use of Expanded Criteria Donor Livers

John J. Fung

Cleveland Clinic, United States

Since the first successful solid organ transplant in 1954, significant improvement in survival of patients and grafts has occurred, in part due to improved immunosuppression, diagnostic skills, technical improvements and improved donor management. The increasing disparity between the number of candidates awaiting transplantation and the number of available donors, highlight the need for optimal identification and utilization of donors, including those who would not have been considered as cadaver donors in the past. In particular, donation after cardiac death (DCD, previously known as non-heart beating donors) and older donors, represent an underutilized organ donor pool.

The major advance in donor management came with the acceptance of the concept of “brain death”, which equate complete cessation of cortical and brain stem function with the ultimate demise of organ function. Stringent clinical and diagnostic examinations assure potential donor safety and advocacy. Following declaration of death and consent for donation, careful management of donor physiologic parameters optimizes allograft function and thus recipient outcomes following transplantation. The goal is to achieve maintain adequate circulatory, oxygenation, and metabolism prior to organ procurement. This can be difficult in the face of cardiac instability, neurogenic shock, unstable intravascular fluid status, loss of the normal hormonal milieu, and depletion of high energy stores for organ function.

As the waiting list for liver transplant continues to increase, the need to increase the number of donor liver will become more apparent. For example, older donors have historically constituted only a small percentage of cadaver donors, although the trend of increased utilization for older donors has increased over the past 10 years. While cadaver donors have increased only 20% in the past 5 years, donors >65 years of age have increased over 500%. In addition, prior to the acceptance of brain death, donors were required to have cessation of heart function, in order to procure organs for transplantation. In some countries, were brain death legislation has not been passed, DCD represent a significant source of organs for transplantation. A growing international experience using these donors has shown that the outcome of DCD livers has been poorer that for heart beating donors, but still acceptable––the primary risks are higher risk of hepatic artery thrombosis, primary non-function and ischemic biliary strictures. Current attempts to quantify the risk of using such livers has focused on formulas based on known pre-procurement risk factors, including donor age, cause of death, serum sodium, technical variants, and donor size. This donor risk index or DRI, can then be used to assess the risk to any given recipient, in order to better utilize these livers.

As more experience in the utilization of “expanded donors” is gathered, one should be careful not to use this information merely as a means to cull “blue ribbon donors”, but serve as an impetus to further expand our knowledge of biologic or physiologic alterations in these donors, which can be minimized by newer technology. In this manner, “expanded donors” can be viewed as a means to help alleviate the organ shortage.

LT-05 The Seoul Experience

Deok-Bog Moon, Sung-Gyu Lee, Shin Hwang, Ki-Hun Kim, Chul-Soo Ahn, Tae-Yong Ha, Gi-Won Song, Dong-Hwan Jung

Hepato-Biliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Ulsan, Korea

The technical success of cadaveric whole-size liver transplantation and better immunosuppressive drugs have extended the application of this life-saving procedure to irreversible acute and chronic liver diseases. However, because of the scarcity of cadaveric liver grafts, living donor liver transplantation (LDLT) has emerged as an alternative to cadaveric donor liver transplantation (CDLT), especially in Asia. In Korea, 8% of the population are hepatitis B virus (HBV) carriers, and the resultant HBV cirrhosis, with or without hepatocellular carcinoma, is common in those between 40 and 60 years old. Hence, many patients require orthotopic liver transplantation. In 1992, we started performing CDLT at the Asan Medical Center. In 1994, the first successful pediatric LDLT was performed in Korea on a 9-month-old infant with biliary atresia. In 1997, the first successful adult LDLT was performed in our department, using a left lobe, on a 37-year-old patient with HBV cirrhosis associated with hepatocellular carcinoma. Even after the first successful right-lobe LDLT, we faced the obstacle of anterior segment congestion of the right-lobe graft, and initiated reconstruction of the middle hepatic venous tributaries of the right-lobe graft in 1998. In 1999, we performed more than 100 orthotopic liver transplants a year. Insufficient graft size has hindered the expansion of adult LDLT, when the remaining left-lobe of potential donors is too small to assure donor safety. Dual two-left-lobe graft LDLT (transplanting from two donors into one recipient) was developed in 2,000 to solve graft size insufficiency and minimize donor risk. Each year, more than 200 liver transplants have been performed since 2004, while broadening the indications for adult LDLT to near complete obstruction of the portal vein, with the application of intraoperative portography and portal vein stenting, and Budd–Chiari syndrome, with interposition graft between the atrium and supra-renal inferior vena cava. As a novel approach to overcome ABO-incompatible LDLT, we started donor exchange LDLT in September 2003, and 16 recipients have undergone LDLT to date. However, we recently have performed ten cases of ABO-incompatible LDLT because the donor exchange program has a limitation to expand the donor pool. In 2008, 326 liver transplants were performed, including 261 LDLT (253 adult and 12 pediatric LDLTs) and 61 CDLTs. A total of 1878 LDLTs and 297 CDLTs had been performed until December 2008. There has been no donor mortality in LDLT. With technical refinement and advanced perioperative care, the in-hospital mortality of recipients has dropped to 4%, which is attributed to the dedication of our liver transplantation team members.

LT-06 The Tokyo Experience

Yasuhiko Sugawara, Norihiro Kokudo

Artificial Organ and Transplantation Division, Department of Surgery, University of Tokyo, Japan

Living donor liver transplantation (LDLT) is now widely performed for adult patients to resolve the critical shortage of cadaveric organs. Between 1996 and November 2009, 443 LDLT were performed at the University of Tokyo. The recipients were comprised of 72 children and 341 adults. Viral related liver cirrhosis with or without hepatocellular carcinoma was the most common indication (35%), followed by cholestatic liver disease (including primary biliary cirrhosis, primary sclerosing cholangitis, 22%), biliary atreasia (20%) and fulminant hepatic failure (9%). The patients with hepatocellular carcinoma were carefully selected by the tumor status (the number ≤ 5 and maximum size ≤ 5 cm). Graft types were decided according to the Tokyo algorithm for graft selection (minimum estimated graft volume should be more than 35–40% of the recipient’s standard liver volume). Donors with volunteer wills were selected from the relatives within the third degree consanguinity in principle. The right liver graft without the middle hepatic vein trunk was most commonly used for the adults, followed by the left liver graft with caudate lobe, right liver graft with the middle hepatic vein trunk, and right lateral sector. Graft volume corresponded to 31–147% of the recipient’s standard liver volume. The 1, 3, and 5 year cumulative patient and graft survival rates were 91, 87, and 84%, respectively. Long-term liver function remains excellent. All the donors have returned to normal daily lives with an uneventful course. LDLT is an efficacious procedure that provides excellent short-term and long-term survival. Cautious expansion of this procedure may be justified under the situation of serious shortage of cadaveric donors.

LT-07 The Hong Kong Experience

See Ching Chan

Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China

The first adult right liver living donor liver transplantation (LDLT) was performed in Hong Kong on 9 May 1996 on a patient who had developed acute liver failure from Wilson’s disease. A priori, the middle hepatic vein was included in the right liver graft in order to recruit all venous drainage of the right anterior section. As a new procedure, adult right liver LDLT was initially performed only on patients with acute liver failure in a high-urgency situation. These patients were to die without liver transplantation while waiting for a deceased donor liver graft, which was seldom available. The modest success achieved in the development period propelled the extension of LDLT to the semi-urgent and then elective situations. The latter includes patients with small unresectable hepatocellular carcinoma.

Maturation of our center was demonstrated by a remarkable reduction of recipient in-hospital mortality from 16 to 2.2% after the first 50 cases of adult right liver LDLT. The 5 year survival of recipients without hepatocellular carcinoma is 93%, whereas that of recipients with hepatocellular carcinoma and within the Milan criteria is 72%. A predictably high recipient success rate in LDLT is to be expected given the estimated donor mortality of up to 0.5% and morbidity of 20%. Through accumulation of experience, refinement, and modification of techniques and meticulous perioperative care, a partial graft, often small-for-size, has become less important as a factor conducive to recipient hospital mortality.

Inclusion of the middle hepatic vein in the right liver graft facilitates relief of recipient portal hypertension with an often corresponding high portal flow. Technical advancement toward simplicity is exemplified by the avoidance of veno-venous bypass in the recipient operation. Abdominal drains are no longer used in the living donor, and seldom in the recipient. The hepatic vein to inferior vena cava anastomosis is now direct and without interposition venous grafts, facilitated by fashioning a single venous cuff in the middle to right hepatic venoplasty in the graft.

The experience from LDLT can be applied to deceased donor liver transplantation, in particular, that with split grafts, and to major hepatectomy. Though deceased donor liver transplantation represents one-third of the transplant volume, the 1 and 5 year recipient survivals are 93 and 88%, respectively. LDLT training best equips the next generation of liver surgeons with the abilities to perform complex hepatobiliary pancreatic surgery safely. Extensive experience gained from complex liver resections in return renders donor hepatectomy safe and uneventful. In the end, improvement of donor safety and recipient survival increase the benefit–cost ratio of LDLT.

LT-09 The New Delhi Experience

Arvinder S. Soin

Liver Transplantation, Sir Ganga Ram Hospital, New Delhi 110060, India

Background

In the last 15 years, living donor liver transplantation (LDLT) has evolved into an established alternative to deceased donor liver transplantation (DDLT) with excellent recipient and graft survival.

Our initial focus was on DDLT. However, after 3 years of failure to develop it, we changed our strategy to LDLT by modeling our facility on AMC, Seoul and QMH, Hong Kong. In the beginning we did only ten transplants in 3 years up to 2004. Gradually, the number and the success rates picked up. We currently perform around 150 transplants a year with a 1 year actuarial survival of 97%.

We have reviewed our experience of 465 consecutive LDLTs, most of which (435) were done in a relatively short period of the last 4 years. Thirty-one of these were for acute liver failure. The results are analyzed in successive cohorts of the first 65 and then 4 blocks of 100 transplants each in the context of evolving policies on contentious issues, surgical technique and post-transplant care.

Selection and indications: All donors were first or second degree relatives. Approximately, a third of the donors fell in the category of extended criteria living donors (ECLD) on the basis of low graft to recipient weight ratio (GRWR), steatosis, abnormal liver function tests or anatomy, or, if they participated in a weight modification program, swap, domino or dual lobe transplant. The minimal acceptable remnant was 30%, and GRWR 0.7. Macrovescicular steatosis of up to 20% was accepted for right and 30% for left lobe grafts. Vascular and biliary anatomical anomalies rarely contraindicated donation. All patients with hepatoma without extrahepatic spread or tumoral involvement of the major hepatic vessels were accepted for transplant. Eight patients with liver and kidney failure or primary hyperoxaluria underwent combined liver and kidney live donor transplants.

Technique

The anterior sector in right lobe grafts was always drained (except in the first six), mostly by including the middle hepatic vein. Graft hepatic ducts were harvested with the hilar plate and Glissonian sheath envelope and biliary reconstruction in the recipient was performed with interrupted PDS sutures without ductoplasty.

Results

One year actuarial recipient survival improved from 77% for the first 65–97% for the last 100 LDLTs due to a progressive decline in sepsis related mortality. The overall hepatic vein, portal vein, and hepatic artery complication rates were 0.2, 2, and 1.2%, respectively, and did not differ between the successive cohorts of LDLTs. The biliary complication rate progressively dropped from 14% in the first 65–2% in the last 100 transplants. There was no difference in 1 year survival between recipients of ECLD and non-ECLD grafts. The overall and disease-free actuarial survival of 94 LDLT recipients with HCC (43 within and rest outside Milan criteria) was 91 and 85% at 3 years. One donor (1/465, 0.2% mortality) became brain dead from hypoxic damage due to status epilepticus soon after reversal from an uneventful hepatectomy with 37% remnant. He had no evidence of intracranial vascular accident, sepsis, hepatic or renal dysfunction until circulatory arrest on day 11.

Conclusion

We and others have found that viable liver transplant programs in the East require LDLT with or without DDLT. With experience and technical refinements, mortality after LDLT has fallen to under 5% and biliary complications are no longer the Achilles heel. LDLT is possible for all types of recipients and indications. ECLD criteria enable safe utilization of 35% extra donors. Donor safety remains the primary concern with LDLT.

LT-10 The Riyadh Experience

Al Sebayel M, Al Sofayan M, Khalaf H, Al Saghier M, Abdo A, Al Homodi W, Al Masri N, Abalkhail F, Al Dakheil W, Al Jedai A, Sabbagh R, Al Anazi A, Saleh M,Balkheir A and Shaheen F.

Department of Liver Transplantation and HBP Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Introduction

Organ shortage remains the major challenge facing liver transplant programs. Various strategies to alleviate this shortage are partially successful but still inadequate. The experience of the liver transplant program at KFSH&RC in facing such adversity is reported which included two main approaches: introduction of living donor liver transplant and promotion of cadaveric donation.

Method

From 2001 to 2009, a total of 241 transplants were performed with the highest number in 2009 (46 transplants). Living donors were used in 78 (32%) cases. Mortality and morbidity were compared between living donor (LDLT) and cadaveric transplants (DDLT). The mortality on the waiting list continued to be more than 25%.

Between 2006 and 2009 an aggressive approach to cadaveric organ donation resulted in more than threefold increase in organ donation in Riyadh region. This was done through the creation of a Mobile Donor Action Team (MDAT), a joint effort between the liver transplant program at KFSH&RC and the Saudi center for organ transplantation (SCOT which is the national donor organization in Saudi Arabia). This team works directly with ICU personnel to address logistical issues related to the donation process.

Result

The overall patient survival was 87.4 and 80% at 1 and 5 years, respectively. There was no difference in the overall survival of LDLT versus DDLT. Early graft survival were better in the DDLT group which then became statistically non significant at 2 years. Biliary morbidity, however, was higher in LDLT group (32 vs. 3.4%). There was no statistical significance difference in other type of morbidities in particular technical complications. After the introduction of MDAT, the rate of cadaveric donation in Riyadh rose from an average of 4 donors per million populations (pmp) before 2006 to 13 donor pmp after 2006.

Discussion and conclusion

In Saudi Arabia, despite the successful introduction of LDLT, the problem of organ shortage remains. Death on the waiting list continues to be high. Aggressive approach towards cadaveric donation in Riyadh, however, led to significant increase in the number of donors and therefore a decrease in wait list mortality. It is our opinion that LDLT should never undercut efforts to increase cadaveric donation whenever that is feasible. Transplant programs should work closely with other parties to this effect within the accepted ethical framework.

LT-12 The Quezon City Experience

Benito V. Purugganan

Department of Organ Transplantation and Vascular Surgery, National Kidney and Transplant Institute, Quezon City, Philippines

The first Liver Transplantation (LT) in the Philippines was performed at the state-owned National Kidney and Transplant Institute (NKTI) in August 1990. After two decades, the number of LT cases has not significantly increased with only 21 LT cases done. Of this total, two patients underwent combined liver-kidney transplant while one patient was a split liver transplant whose organ came from a living donor.

The first three indications of LT are hepatocellular carcinoma, cirrhosis secondary to hepatitis B and alcoholism. To date, only three are still alive and the rest lived only between 5 and 9 months (>1 year) after transplantation. This translates to a low success rate of 14.3%.

A host of factors that are economic, socio-cultural, legal and logistical in nature are the constraints and obstacles to the (rapid) improvement in organ transplant and LT per se in our country. Cost is a decision factor whether an LT candidate should or should not undergo LT. Admittedly, LT comes out very expensive with or without government subsidy given the low economic status of majority of LT candidates, and a government that operates on a limited and deficit driven budget with too many competing needs and priorities. Consequently, an insufficient number of liver allografts is the net effect of all these factors. With the enactment of Republic Act 9208 by the Congress and its Implementing Rules and Regulations (IRR) last year (2009), that govern organ transplant and organ donation in the country, this is seen as a signed that will lead to a faster growth and development of organ transplantation (i.e. LT) in the Philippines.

LT-13 Issues in Pediatric Liver Transplantation

Chao-Long Chen

Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan

Pediatric living donor liver transplantation (LDLT) is more challenging than adult LDLT due to the small size of structures to be identified, isolated, preserved, and then reconstructed in the recipient. This is complicated even more by low recipient weight. The use of microsurgical techniques in LDLT later improved the outcome of transplantation.

In Asia, the first LDLT was performed in a child with biliary atresia in 1989. Experience led to a wider application in biliary atresia (BA), neonatal hepatitis (NH), in fulminant liver failure, and other metabolic diseases of the liver treatable by transplantation. The development of LDLT was driven by the perennial lack of deceased donor organ donation and a response to the growing demand for liver replacement. Keys to the success of LDLT relied heavily on technical innovations as commonly accepted techniques used in deceased donor liver transplantation may not be suitable for the live liver donor and recipient.

At the Chang Gung Memorial Hospital-Kaohsiung Medical Center, we have performed more than 170 BA, 26 metabolic liver diseases (14 glycogen storage disease (GSD), 9 Wilson’s disease, 3 others), and 10 NH patients. From our experience with the first 100 cases of BA who underwent LDLT, the mean follow-up period was 85.5 months. The mean age was 2.4 years. The mean preoperative weight, height, and computed GFR were 12.2 kg, 82.5 cm, and 116.4 ml/min/1.73 m², respectively. 27 patients were below 1 year of age, and 49 patients were below 10 kg at time of transplantation. There were one in-hospital mortality and one re-transplantation. The rejection rate was 20%. The 6 month, 1 year, and 5 year actual recipient survival rates were 99, 98, and 98%, respectively. In our update review of 120 LDLT for BA patients, the 6 month and 1 year actual, non-estimated recipient survival rates were both 97%; and the 5 year actuarial survival rate was 95%.

All patients afflicted with GSD were not responsive to medical treatment. Ten patients had GSD type I and four had GSD type III. The metabolic abnormalities were corrected and renal function remained normal. In patients with growth retardation, catch-up in growth was achieved post-transplant. Three of the four GSD type III patients had hepatic adenoma at the time of transplantation. There was a single mortality at 2 months post-transplantation due to acute pancreatitis and sepsis. LDLT restores normal metabolic balance in patients with GSD and long-term follow-up after transplantation shows excellent graft and patient survivals.

Ten (7.2%) children were diagnosed with end-stage liver disease secondary to NH. The mean follow-up was 60.2 months (SD ± 22.3 months). The mean Child-Turcotte-Pugh score was 9 (SD ± 1.9) and the mean Pediatric End-stage Liver Disease score was 15.6 (S.D.±7.6). The 6-month, 1- and 5-year recipient survival rates were 90, 80 and 80%, respectively.

LT-14 The Current Status of Artificial Liver Support (ALS)

Robert G. Gish¹ and Norman Sussman²

¹ Medical Director Liver Transplant Program, Chief: Division Complex GI, California Pacific Medical, Center, 2340 Clay St. #233, San Francisco, CA 94115, United States ² Professor of Medicine, Director of Hepatology, University of Utah, 30 North 1900 East, 4R118 School of Medicine, Salt Lake City, Utah 84132, United States

Fulminant hepatic failure (FHF) is a disease state that affects approximately 2,000 patients nationwide each year in the US and an unknown number world-wide. It is a condition that is associated with a high mortality, and for which there is currently no accepted treatment short of intensive supportive care and liver transplantation. Acute liver failure (ALF) is a more expansive disease state that encompasses both FHF and AoC (acute on chronic) liver failure. Additional needs for ALS include the support of patient with AoC liver disease as well as decompensated liver disease with chronic medical issues such as encephalopathy.

AoC and decompensated chronic liver disease with progressive liver failure is much more common than ALF, and has become the fifth most common cause of death in the United States. In fact, the death rate from chronic liver disease continues to increase, largely related to the “maturation” of the hepatitis C virus epidemic that occurred in the late 1960s and early 1970s and has only now gone onto produce end-stage liver disease and liver cancer.

There has been a long-standing interest in the research setting, clinical development and corporate biotechnology to bring an ALS device to clinical use. The belief is that these would function much like hemodialysis for patients with end-stage renal disease. One major difference is that liver support would be, by design, for patients with acute liver failure, only a temporary measure, leading to one of two positive outcomes, adequate liver regeneration or successful liver transplantation. Techniques that have been tried in the past include, use of whole animal organs such as porcine or simian sources, cross perfusion between the affected patient and another healthy person, and various techniques of toxin absorption, such as resins, charcoal hemoperfusion or other specially designed filters. To date, none of the BAL devices has proven effective in large randomized trials with the probable exception of the recent Vital Therapies ELAD device. In one trial with the Circe device, there was a clinical benefit using subset analyses excluding patients with primary graft nonfunction. Other BAL devices are under development including the HEPAHOPE porcine liver slice product as well as the Minnesota BAL device and HepaLife. In addition, there are a number of on-going attempts to develop filtrations devices in the US and globally such as the MARS device, ARBIOS and possibly Hemolife.

While chronic disease is much more common that FHF, much of the research on artificial liver support systems has focused on managing the syndrome of FHF since it has a more narrow definition, making trial design potentially simpler. The reason for this focus is the belief that if patients can be maintained for a long enough period of time on the BAL or filtration device, their livers can regenerate, sparing the need for liver transplantation, leading ultimately to normal liver function and no long-term sequelae. Clearly, a key question is how long these patients need to be supported for this to occur.

A second important question is what aspect of liver function must be replaced for patients with FHF to be adequately supported. The liver performs a number of functions including synthesis of various proteins, detoxifying natural toxins, e.g. ammonia, as well as certain xenobiotics, and excretion. Which of these is most important for survival is not at all clear. The two most common causes of death in patients with FHF are intracranial hypertension caused by cerebral edema, and multi-system organ failure. The difficulty is that the pathophysiology of each entity is not well understood and thus, we do not have a specific assay to determine whether we are providing an adequate amount of liver support to prevent either complication.

The ultimate goal of liver support should be to allow the patient with FHF time for his or her own liver to regenerate. The goals of AoC require further definition. We would like to shorten hospital stays, improve quality of life, and get more patients safely to liver transplantation. Utility and cost effectiveness will be more difficult to prove, but a safe, effective device could help many more patients.

LT-15 Liver Transplantation for Hepatocellular Carcinoma

Shusen Zheng

Division of Hepatobiliary-Pancreatic Surgery and Liver Transplantation, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 QingChun Road, Hangzhou, 310003, P.R.China.

In the era of liver transplantation (LT), the curing of hepatocellular carcinoma (HCC) seems more realstic than ever. However, the population with HCC that benefit from LT remains the minority. The shortage of donor organ and advanced tumor stage constitute the main shackle of the further achievements of LT for HCC. Due to the heterogeneity, HCC with distinct characteristics, in different stages take different response to therapeutic methods and result in different outcomes. Advanced tumor stage at transplantation of HCC exposes the patient in the high risk of tumor recurrence. Better selection of candidate for LT may be a reasonable solution. Up to now, there are several selection criteria available for HCC patients, whereas which one is best remains controversial. As a classic criteria proposed in 1996, Milan criteria is a landmark in the history of LT for HCC. In 2001, UCSF criteria was put forward as the first successful attempt to expand the Milan criteria. There are also some newly arisen criteria, such as Tokyo and Asan criteria. However, these criteria emphasized the value of tumor size and tumor number but ignored the biological characteristics with prognostic value,such as the degree of tumor grading and serum biomarkers, thereby, might underestimate its predictive value of prognosis to a certain degree. Based on our own experience over 10 years, we proposed Hangzhou criteria. HCC patients meeting Hangzhou criteria must fulfill one of the two following items: (a) Total tumor diameter ≤8 cm; (b) total tumor diameter >8 cm, with histopathologic grade I or II and preoperative AFP level ≤ 400 ng/mL, simultaneously. In our center, we have finished more than 300 cases of LT for HCC and those fulfilling Hangzhou criteria had a post-transplant 1, 3, and 5 year overall survival rate of 93.0, 78.5, and 74.1%, respectively. The difference between survival curves of patients fulfilling Milan criteria and patients fulfilling Hangzhou criteria did not achieve statistical significance. The most important advantage of Hangzhou criteria superior to other criteria, which rely solely on size and number of tumor nodules, is that it allows more patients to benefit from liver transplant. Hangzhou criteria identified the part of patients with good prognosis who exceed Milan criteria in a different way, thus 37.5% additional patients exceeding Milan criteria in our study benefit from liver transplantation. According to reference, the candidates expansion of Hangzhou criteria is more than that achieved by the University of California, San Francisco criteria (16%), Tokyo criteria (6%), and Kyoto criteria (11.4%). In our series, the patients receiving living donor liver transplantation also had similar prognosis to those after cadaveric donor liver transplantation. As an important part of comprehensive therapy strategy, the pre- and post-transplant use of sorafenib is now one of the focuses and may be a valuable direction. Further research may also take into account the findings of genomics and proteomics, in addition to the clinical characteristics and biological behaviors.

LT-16 Prevention and Management of Recurrence of HBV and HCV Infection Following Liver Transplantation

Edward J. Gane

New Zealand Liver Transplant Unit, Auckland City Hospital

1. Liver transplantation for Hepatitis B

Chronic hepatitis B is the leading cause of liver-related mortality in Asia–Pacific, accounting for over 1 million deaths per annum. Liver transplantation has become a cost-effective treatment of liver failure and HCC with excellent 5 year survival. Improving economies and live-related liver donation have allowed a rapid expansion of liver transplantation within the Asia–Pacific region where hepatitis B is the most common indication for both acute and chronic liver failure. Currently, more than 4,000 adult liver transplants are performed annually in Asia–Pacific, of which more than 75% are for chronic hepatitis B. Most transplants for chronic hepatitis B are now performed for hepatocellular carcinoma rather than chronic liver failure, which can usually be rescued with potent antiviral agents.

Without prophylaxis, HBV recurs in more than 80% of cases and in all cases which are HBV DNA positive prior to transplant, resulting in accelerated liver disease and reduced graft and patient survival.

Although passive immunoprophylaxis with high-dose intravenous hepatitis B immunoglobulin may prevent overall recurrence rate by 60%, this strategy is prohibitively expensive (USD$20,000 per annum, life-long) and is less effective in HBV DNA positive transplant candidates. Lamivudine monotherapy is associated with a high-rate of late recurrence because of the emergence of lamivudine resistance. This appears to be less common in Asian centers, a phenomenon attributed to the high rate of adoptive immune transfer from HBV immune, related live donors, resulting in protective de novo anti-HBs production in recipients. Adding lamivudine to hepatitis B immunoglobulin (HBIG) reduces recurrence rates to less than 5% and improves long-term survival. The substitution of high-dose intravenous HBIG dose by low-dose intramuscular HBIG appears to be safe and effective. In this multicentre study, the actuarial risk of HBV recurrence was only 4% after 5 years and at a cost of approximately 10% of the cost for high-dose intravenous HBIG. Five year survival approached 90%. Suppression of pre-transplant viral replication will reduce the risk of post-transplant recurrence and may rescue some patients with decompensated cirrhosis.

Late (at least 12 months post-transplant) HBIG substitution by adefovir will prevent late HBV recurrence and reduce long-term costs.

Combination HBIG plus lamivudine prophylaxis can be replaced by lamivudine monotherapy 12 months post-transplant in certain “low-risk” patient groups, including patients who were HBV DNA negative pre-transplant, and those with sustained protective levels of anti-HBs production following post-transplant vaccination.

In a recent prospective open-labelled study, the combination of ADV plus lamivudine from the time of listing for liver transplantation prevented the development of LAM-resistance before and after transplant, irrespective of baseline HBV DNA status. This regimen was well tolerated and removed the need for post-transplant HBIG including in the immediate perioperative phase, further reducing the cost of prophylaxis to <5% that of the current combination regimen.

In patients with lamivudine resistance pre-liver transplantation, the combination of lamivudine and adefovir dipivoxil (ADV) is effective for preventing re-infection of the graft, with or without concomitant HBIG. A study in patients without HBV recurrence at least 12 months post-liver transplantation showed that combination ADV plus lamivudine provided equivalent protection against recurrent HBV infection, but with better tolerability and less cost compared with combination HBIG plus lamivudine prophylaxis. Future prophylactic strategies are likely to include entecavir and tenofovir, with the latter also effective in patients with established lamivudine resistance prior to transplant.

Almost 75% of all donors in the Asia–Pacific region have acquired HBV immunity (anti-HBcore positive). A liver from such a donor may result in de novo HBV infection in 40–80% of HBV-naïve recipients. This risk becomes negligible if the recipient receives long-term prophylaxis with either lamivudine or HBIG or if the recipient is seronegative for HBsAg but positive for anti-HBs.

1. Liver transplantation for chronic hepatitis C

Almost 200 million people are currently infected with chronic hepatitis C virus, with highest rates reported in the Middle East, Eastern Europe and South-East Asia. Although the incidence of HCV infections has fallen following the reduction in the incidence of transfusion-acquired and intravenous drug use (IDU)-associated HCV, this is an aging cohort and the proportion with cirrhosis will double over the next decade. The demand for liver transplantation for HCV-related hepatocellular carcinoma and liver failure is projected to treble by 2030.

Recurrent hepatitis C infection is universal and occurs at the time of reperfusion. Unfortunately, the trials to-date of passive immunoprophylaxis with either polyclonal or monoclonal high-dose intravenous hepatitis C immunoglobulin have not demonstrated any benefit in terms of incidence of re-infection, time of onset and rate of progression of recurrent hepatitis C.

The natural history of recurrent hepatitis C is accelerated, with 20–40% progressing to cirrhosis within 5 years. Recurrent hepatitis C is associated with reduced graft and patient survival is compared to HCV-negative recipients.

The best predictor of rapid fibrosis progression is the grade of necroinflammation at one year post-transplant. In addition, multiple host, donor and viral pre-transplant predictors have been identified, including pre-transplant viral load, donor age and high-dose steroid therapy for acute rejection.

The lack of improvement in long-term outcomes following transplantation for hepatitis C during the last 20 years is attributed to the direct effects of increasing donor age and changes in immunosuppression regimens on the natural history of recurrent hepatitis C. Maintaining patients on low-dose prednisone long-term or the addition of azathioprine may actually protect against rapid progression of recurrent hepatitis C.

Early reports of reduced outcome in liver transplant recipients of live donors compared to recipients of deceased donor have been dismissed by large prospective studies which have incorporated protocol allograft biopsies.

Successful antiviral therapy is the only factor associated with improved graft and patient survival following transplantation for hepatitis C. However, current standard-of-care (SOC), pegylated interferon plus ribavirin, has poor efficacy and tolerability in transplant recipients. More than 80% of patients must dose reduce and almost 30% must cease therapy because of adverse effects. The biggest problem is severe haemolysis because of reduced renal clearance of ribavirin. Overall SVR rates with SOC are 20–30%, significantly lower than in nontransplant hepatitis C. Favourable baseline predictors for response include low pretreatment viral load, non-1 genotype, fibrosis stage and reduced interval between transplant and commencing SOC. Early on-treatment responses are also useful––RVR has excellent positive predictive value, whilst EVR has excellent negative predictive value and should be adopted as an early stopping rule.

The impact of recurrent hepatitis C on graft and patient survival and the poor efficacy and tolerability of SOC in this population has created an urgent need to develop more effective and better tolerated antiviral regimens for this area of unmet need. The introduction of direct acting antivirals (polymerase and protease inhibitors) may provide new opportunities in the treatment of established recurrence. Combinations of multiple direct acting antivirals with different mechanisms of action and without cross-resistance could eventually be able to rescue patients with advanced liver disease from the waiting list, whilst perioperative administration may achieve the ultimate aim of universal prophylaxis against recurrent infection of the allograft.

LT-17 The China Liver Transplant Registry

Haibo Wang, Sheung Tat Fan

Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

The China liver transplant registry (CLTR) is the official national scientific registry for liver transplantation in China. The University of Hong Kong was authorized by 21 liver transplant centers in China in 2005 and subsequently by the Ministry of Health, China in 2008 to conduct the registry. All liver transplant centers in China are obligated to report data to the CLTR. Prospective collection of data is performed through a computer network. Cutting-edge technologies are implemented to ensure data quality. The data are further verified by on-site auditing of hospital records by the personnel of The University of Hong Kong.

From 1993 to 2008, 11,888 adult (≥18 years old) liver transplant operations performed at 61 hospitals were recorded in the registry. The majority of the transplants were performed in the last 6 years. The organs were derived from non-heart-beating donors (n = 11,030), brain dead donors (n = 85) and living donors (n = 773). Male recipients predominated (85.1%). Malignant tumors were documented in 49.5% of the explants. The in-hospital mortality rate was 8.8%. The median follow-up period was 9.4 months (range 0–118.3 months). The 1, 3 and 5 year patient survival rates were 73.7, 60.1, and 55.6%, respectively. There was an improvement of overall survival rates over the years (p < 0.001). Compared with the patients with benign disease, patients with malignant disease had less favorable survival (5 year survival rate of 41.7% vs. 67.8%, p < 0.001). For patients with tumor status within the Milan criteria (n = 1,905, 46.4%), the estimated 5 year survival rate was 60.4% and was higher than that of those with tumor status beyond the Milan criteria (n = 2,200, 53.6%, 5 year survival rate of 32.3%). Living donor liver transplantation emerged as a major treatment method in the last 2 years after the Ministry of Health, China implemented stringent organ donation policies. The 1 year survival rate of patients receiving living donor liver transplantation was 83.9%, which was higher than that of those receiving deceased donor liver transplantation during the same period (n = 11,029).

The CLTR is now the third largest database for liver transplantation in the world. The Registry has documented a change in the practice of liver transplantation in China. Living donor and brain-stem death organ donations are emerging. The practice of liver transplantation is expected to conform to that of the rest of world in the coming future.

LT-20 Critical Issues for the Liver Transplantation Community

Sandy Feng

University of California San Francisco, 505 Parnassus Avenue, Box 0780, San Francisco, CA 94143-0780, United States of America

As the last talk of the APASL 2010 Liver Transplant Course, I am called to assess the challenges that thwart the full realization of success for liver transplant candidates and recipients. I will touch on three primary concerns.

Insufficient access to transplantation

The shortage of organs is a major limitation to the applicability of liver transplantation. While the dire need for organs has engendered some remarkable innovations such as split and living donor transplantation, the primary solution has been to utilize organs that were previously declined for transplantation. This “solution” has, however, come at the high cost of worsening transplant outcomes as exemplified by the emergence of terminology like the “marginal” or “expanded criteria” donor. Therefore, resources should be directed to promote innovation in donor management and organ preservation to improve the function of sub-optimal organs. Moreover, these advances can expand donor horizons and augment organ supply while maintaining or even improving the survival benefit of transplantation.

Recurrent disease

The primary threat to graft survival today is recurrent hepatitis C. This frequently translates into recipient mortality since re-transplantation for hepatitis C is rarely undertaken. Substantial effort and resources are being devoted to the development and testing of novel anti-viral medications, albeit in the pre-transplant setting. Without a doubt, the most promising approaches will cautiously percolate into the post-transplant realm as the increased complexity of transplant recipients along with the many potential pharmacologic interactions deserve careful attention. Ultimately, epidemiologic data indicating dramatically decreased rates of new infection ensures that hepatitis C will soon be a decreasing indication for transplantation.

As hepatitis C wanes, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) will, without a doubt, mount an impressive surge. Currently, the burden of recurrent and even de novo disease remains poorly defined.

Toxicities of our current immunosuppression regimens

It is very clear that today’s immunosuppression drugs have successfully mitigated the incidence and impact of immunologic damage to the liver allograft. Tacrolimus-based regimens with or without mycophenolate and corticosteroids dominate. There is a modest incidence of acute rejection; chronic rejection is thankfully rare. These advances have, however, incurred an extensive array of medical conditions that, singly or in combination, impose substantial morbidity and/or mortality on liver recipients. Although the direct impact of calcineurin inhibitors on the development of chronic kidney disease is well-recognized, the contribution of various immunosuppression agents on the incidence, prevalence, severity, and consequence of hypertension, diabetes, dyslipidemia, and obesity remain poorly defined. Without a doubt, this burden will only increase over time because candidates accepted for transplantation are older with more medical problems. Clearly, new paradigms of immunosuppression of comparable efficacy but lower toxicity are desperately needed.

Tolerance, defined as the maintenance of normal allograft function without histologic evidence of acute or chronic rejection in the absence of immunosuppression, has been called the holy grail of transplantation. Successful induction of tolerance, typically through a carefully designed regimen delivered around the time of transplantation such that the patient is minimally exposed to immunosuppression would be ideal. As this is indeed a tall order, we may be able to learn from liver transplant recipients with spontaneous or operational tolerance uncovered through successful cessation of immunosuppression. Recently, a microarray profile dominated by NK cell gene expression has been proposed by the Barcelona group as predictive of operational tolerance. Prospective validation of this signature is currently underway, along with cross-sectional characterization of liver transplant cohorts. If validated, this sentinel discovery will likely alter patient management dramatically and lead to future advances that may revolutionize liver transplantation.