When to consider liver transplantation Nam-Joon Yi, MD Division of HBP Surgery, Department of Surgery, Seoul National University College of Medicine Liver transportation has been the treatment of choice for a end stage liver disease and the early stage of hepatocellular carcinoma. Recently, there has been a gradual expansion of indications for liver transplantation due to the excellent survival rate after liver transportation. However, due to the organ shortage in Asia, including Korea, compared to the Western countries, there has been no guideline about how to preparation and when to consideration for liver transplantation for individual patients with terminal liver diseases. Herein, this article reviews the present status of liver transplantation and how to preparation of liver transplantation in Korea. Keywords: Liver transportation; Hepatocellular carcinoma; Survival rate; indications Introduction The first human liver trial was attempted on March 1, 1963 in an unconscious and ventilator-bound child with biliary atresia by Dr. Starzle. In 1988, the first deceased donor liver transplantation (DDLT) in Korea was successful in a 14-year-old girl suffering from acute Wilson s syndrome. 1 Although liver transplantation is still complex procedures, its outcome had been highly improved even in very sick patients and it had become the accepted of last appeal for essentially all non-neoplastic end-stage liver disease and for selected patients with otherwise unresectable hepatocellular carcinoma (HCC) by the early 1990s. 2 However, major hamper to liver transplantation is organ shortage. The mean waiting time for DDLT in Korea is recently 1,054 days in potential candidates of liver transplantation (LT). 3 The patients on the waiting list can be lost without LT due to just long waiting time in Korea unless timed registration is made. Herein, taking all into consideration, when to consider LT and what to consider for registration of LT in Korea will be discussed in this article. When to refer the patients with cirrhosis Patients should be considered for LT only if they are thought to be capable of surviving the perioperative period and complying with the intense chronic medical regimen and follow-up required of transplant recipients. The list of indications for LT is as wide s the spectrum of liver disease itself. Generally, any form of end-stage liver disease that is irreversible and curable with LT is an indication for LT. Based on the panel s review of published date, they recommended that a Child-Pugh score of 7 -S264-
Nam-Joon Yi/When to consider liver transplantation Table 1. The mean waiting time of liver transplantation of the 2009 annual report of KONOS A. The mean waiting time of recipients for a deceased donor liver transplantation according to the blood type Year Blood type Mean (day) A B O AB 2007 285 215 340 399 239 2007 223 190 276 269 108 2009 225 253 251 108 244 B. The mean waiting time of recipients for a a living donor liver transplantation according to the relationship Year Blood type Mean (day) Related Unrelated 2007 73 67 112 2007 95 91 177 2009 78 71 199 C. The mean waiting time of potential recipients for a deceased donor liver transplantation according to the organ Mean (day) Kidney Liver Pancreas Heart Lung Islet cell Small intestine Bone marrow Cornea 1,161 1,299 1,054 1,206 915 963 779 481 550 1,522 or higher be correlated with a survival rate of 90% or less at 1 year as a result of the morbidity associated with decompensation. 2 Therefore, the patients with Child-Pugh score of 7 or higher (or MELD score > 15) and any kinds of complications (bleeding, ascites, hepatic encephalopathy, or jaundice), although they are under control, must be referred to a transplantation center once for assessment according to a guideline (Table 1). 2,4-6 This is the way of saving the patients with cirrhosis on the waiting list, as well as a successful liver transplantation. Although the protocol of evaluation varies from center to center, most programs require a basic battery of lab tests to examine the patient s general chemistry and hematological counts, elements of liver disease, a search for occult infection and malignancy, and imaging of the abdomen and hepatic parenchyma and vasculature. In addition, because the patient s psychosocial status and social support may have an impact on compliance related with post-transplant mortality and morbidity, a thorough evaluation of the patient s psychiatric and socioeconomic challenges is important. SYMPOSIUM 6 Contraindications of LT When dealing with a scarce resource, the team should perform LT only on candidates in whom a reasonable chance of graft and patient survival is predicted. However, some contraindications are relative; if ameliorated before LT, the transplant operation can proceed. Most contraindication to LT relate to co-morbid conditions; alcohol or drug abuse within 6 months, extrahepatic malignancy (not including nonmelanoma skin cancer or those who meet the oncological definition of cure), and systemic sepsis. It is important to note that relative contraindications, particularly for living donor liver transplantation (LDLT), vary from center to center. 2 -S265-
SYMPOSIUM 6. End-Stage Liver Disease Table 2. The KONOS registration form for liver transplantation STATUS 1 관리일자 : 년월일 - 18세이상의전격성간부전증 (Fulminant liver failure) 환자가 7일이내에간이식을받지않으면생명연장의희망이없는상태로다음중한가지이상에해당하는경우를말한다. 만성간질환없이간질환의증상이나타난후 8주이내에급성전격성간부전증이발생하고뚜렷한간성혼수가동반된경우 flapping tremor hyperbilirubinemia prothrombin time > 20초 or INR> 2.5 또는 hypoglycemia ( 간성혼수에관한세부규정 ) 전격성간부전증은 Grade III/IV 의뇌질환 (encephalopathy) 을동반하여야하며, 이에관련된다음의의무기록이있어야한다. 의식상태평가 - 시간및장소 Orientation - Pain response - Verbal response - Hepatc Encephalopathy Grade(Ⅰ/Ⅱ/Ⅲ/Ⅳ) HEP Grade : Discription of mental status Grade Ⅰ : Lethergy Grade Ⅱ : Drowsy Grade Ⅲ : Deep drowsy / Stuporous Grade Ⅳ : Semi-coma/Coma B 형간염및 C 형간염바이러스보균자및기타만성간질환자는 ( 알코올성간경화포함 ) Status 1 으로등록하지못한다. 간이식후 7 일이내에이식된간이기능을하지못하는경우 간이식후 7 일이내에간동맥성혈전증 (hepatic artery thrombosis) 이있는경우 윌슨병 (Wilson's disease) 환자에게급성간기능부전이동반된경우 STATUS 2A - 만성간부전증 (Chronic liver failure) 환자가집중치료실에입원해야만하는상태로 7 일이내에간이식을받지않으면생명연장의희망이없는경우 - CTP 가 10 점이상이면서다음중한가지이상에해당해야한다. CTP 점 (CTP 세부규정 ) CTP 점수는등록시점의 24 시간이내의결과에의거하여측정하며, 이에관련된의무기록이있어야한다. 치료에반응하지않는활동성정맥류출혈 (active variceal hemorrhage) 로판명된경우내시경으로확인된식도또는위정맥류로내시경을통한내과적인지혈치료에도불구하고하루 4unit 이상의수혈이필요한상태로 TIPS 또는수술적인치료가불가능하거나실패한경우 간신증후군 (Hepatorenal syndrome) 쇼크나진행되는세균성감염, 신독성물질, 체액소실에의한것이아니어야하며, 적극적인대증치료에도불구하고 2 일동안하루소변량이 500 cc이하이면서혈청크레아티닌 2.0 mg/dl 인경우, 다만혈액투석을시행했을경우혈액투석시행전 2 일간을기준으로한다. ( 간신증후군세부규정 ) 등록일기준으로 2 일간의빈뇨 ( 하루소변량 500cc 이하 ) 에대한섭취 / 배설량측정기록이있어야한다. 단, 혈액투석을시행했을경우혈액투석시행전 2 일간의소변량을기준으로한다. 등록일기준으로 2 일간혈중크레아티닌농도가 20.mg/dL 보다높아야한다. 단, 혈액투석을시행했을경우혈액투석시행전 2 일간의혈청크레아티닌수치를기준으로한다. 난치성복수 / 간 - 흉수증 (ascites/hepato-hydrothorax) 복수를조절하기위해시행한 TIPS 치료방법에반응하지않거나적응증이되지않는환자로이뇨제나소금의절제와같은내과적치료방법이실패하여등록일기준으로 1 주일에 1 회이상 4 L 이상의복수또는흉수천자가필요한 -S266-
Nam-Joon Yi/When to consider liver transplantation 환자 ( 난치성복수 / 간흉수증세부규정 ) 등록일기준으로 7 일이내의섭취 / 배설량측정기록혹은진료기록에복수또는흉수천자기록이있어야한다. 복수에대한영상의학과적인판독이있어야한다. 내과적치료에반응하지않는 stage Ⅲ 나 Ⅳ 인뇌질환 (encephalopathy) ( 간성혼수에관한세부규정 ): 상동 Status 1 과 2A 에등록하려면응급도서식을등록후 24 시간내에 KONOS 로보내야하고, 연장은 1 회에한하여가능하며, 7 일이내재등록하지않으면자동적으로 STATUS 2B 로변경됨. 연장을원할시에는마감일 24 시간이전에 KONOS 에서류를보내야함. STATUS 2B - CTP 점수가 10점이상이거나 7점이상이면서다음하나이상해당해야한다. CTP 점 치료에반응하지않는활동성정맥류출혈 (active variceal hemorrhage) 로판명된경우내시경으로확인된식도또는위정맥류로내시경을통한내과적인지혈치료에도불구하고하루 4unit이상의수혈이필요한상태로 TIPS 또는수술적인치료가불가능하거나실패한경우 특발성세균성복막염 (Spontaneous bacterial peritonitis) 특별한복막염의원인이없는상황에서복수에서검출된다중구의수가 250/mL 이상인경우 난치성복수 / 간-흉수증 (Refractory Ascites/Hepato-hydrothorax) 복수를조절하기위해시행한 TIPS 치료방법에반응하지않거나적응증이되지않는환자로이뇨제나소금의절제와같은내과적치료방법이실패하여 1주일에 1회이상 4L 이상의복수천자가필요하거나심한호흡곤란이발생하는환자 간세포암 (Hepatocellular Ca) 의경우 Stage Ⅰ이나 Ⅱ로판명된환자 STATUS 3 지속적인치료를요하고 CTP 점수가 7점이상이나 2B에해당하지않는경우 CTP 점 간세포암 (Hepatocellular Ca) 이면서 stage Ⅲ이상인환자 STATUS 7 - 일시적인비활동성상태의질환을가진이식대기자 - 대기시간이최고 30 일까지누적 Status 2B 로등록하려면응급도서식을등록후 24 시간내에 KONOS 로보내야하고, 6 개월이내재등록되지않으면자동적으로 status 3 로변경됨. 연장을원할시에는마감일 24 시간이전에 KONOS 에서류를보내야함. SYMPOSIUM 6 HCC The early results of liver transplantation (LT) in patients with advanced HCC were poor because of frequent tumor recurrence. Since the introduction of the Milan criteria by Mazzaferro and colleagues 7 in 1996, the survival outcome has improved. Now, LT is regarded as the best treatment modality for patients with early HCC. Current standard selection criteria of LT for HCC are Milant criteria (single nodule 5 cm, or 3 nodules and each 3 cm, without major vessel invasion and metasatsis). 7,8 Four-year survival rate in patients within Milan criteria was 75% after LT, which was comparable with that of patients trnasplanted for benign disease. However, some HCC patients beyond Milan criteria who could benefit from LT are unfairly excluded because of the restrictive nature of LT selection criteria. Expanding selection critiera beyond Milan criteria suggested by some pioneers results in more patients with HCC being cured by LT at the expense of a higher rate of recurrence of HCC; some of these patients achieved long-term disease-free survival and were probably cured, but the others experienced early tumore recurrence. In contrast, about 10-20% of patients still experience recurrence, even though they meet the Milan -S267-
SYMPOSIUM 6. End-Stage Liver Disease Table 3. The mean waiting time of liver transplantation of the 2009 annual report of KONOS A. The mean waiting time of recipients for a deceased donor liver transplantation according to the blood type 구분 평균 A B O AB 2007 285 215 340 399 239 2008 223 190 276 269 108 2009 225 253 251 108 244 B. The mean waiting time of recipients for a a living donor liver transplantation according to the relationship 구분 평균 혈연 비혈연 2007 73 67 112 2008 95 91 177 2009 78 71 199 C. The mean waiting time of potential recipients for a deceased donor liver transplantation according to the organ 평균 신장 간장 췌장 심장 폐 췌도 소장 골수 각막 1,161 1,299 1,054 1,206 915 963 779 481 5,550 1,522 A B Figure 1. Patient survival outcome of liver transplantation in the 2009 annual report of KONOS. (A) Patient survival outcome according to the transplanted organ from the deceased donor. (B) Patient survival outcome according to the transplanted organ from the live donor criteria. Therefore, adequate staging is essential to identify suitable cadiadates to get the best results, and additional prognostic factors associated with each the tumor biology must be valuable through the application of moleculre biological technique or emerging technique. 5,6 The KONOS criteria for registration of the patient On being accepted onto an transplant center s waiting list, the patient is registered with the KONOS organ center. KONOS runs a centralized computer network that includes all transplant hospitals waiting lists and links all hospital based organ procurement organizations (HOPOs). To optimize the allocation and distribution of organs, a organ allocation system was built -S268-
Nam-Joon Yi/When to consider liver transplantation on the Child-Pugh score, complications of decompensation reflecting medical urgency, and a waiting-time based (Table 2). 3 Based on the KONOS criteria, the potential recipients compatible with status 1 or 2A can be prioritized on the waiting list at list for 2 weeks. Current status of liver transplantation in Korea In many Asian countries including Korea, a LDLT has been replaced a DDLT because of scarce of deceased donors. According to the 2009 KONOS annual report, the number of waiting list for LT was 3,142 cases now. However, a total number of LTs performed was only 1,020 in 2009 consisting 237 cases (23%) of DDLTs and 783 cases of LDLTs. The mean waiting time for LT in Korea is as long as 225 days for a DDLT and 78 days for a LDLT in the recipients, but much longer (1,054 days) in the potential patients on the waiting list as noted (Table 3). Major indication of LT is hepatitis B (Hep B) related liver disease and more than one thirds of the patients with Hep B had HCC. 1,8,9 The patient survival outcome of LT has been improved due to the improvement of perioperative care, surgical technique and selection criteria of the recipients. Between 2000 and 2009 in Korea, the patient survival rate was 81.3%, 77.6%, 72.7%, and 70.4% at 3 months, 1 year, 3 year, and 5 year after DDLT, and 91.6%, 86.4%, 80.2%, and 78.0% at 3 months, 1 year, 3 year, and 5 year after LDLT (Fig.1). 3 Summary Timing of LT involves determining the period when the patient will derive the maximum benefit from receiving a new liver. Because the goal is to avoid futile transplantation, it is a subject of active investigation with considerable attention from the transplant and hepatology community. If the transplant is performed too early, the risk of transplantation in terms of morbidity and mortality will outweigh the benefit. In contrast, if the doctor waits toll long to list a patient for transplantation, the risks of the procedure can overshadow its benefits. Better definition of prognostic factors and more prudential selection of the patients may be result in significant improvement. Therefore, further investigation for these is required not only by transplant surgeons but also by hepatologists. SYMPOSIUM 6 References 1. Lee SG. Introduction and Presence of liver transplantation. In: Park YH, Lee KU, Kim SW, Suh KS, ed., Hepato-biliary-Pancreatic Surgery 2nd ed. Seoul: Medrang, 2006: 553-562. 2. Transplantation of the liver, Busuttil & klintmalm. 2nd ed. Elsevier Saunders, 2005. 3. www.konos.go.kr KONOS 2009 Annual report. 4. Donor action and organ procurement: the role of coordinators, KODA. Ha J, edt. 1st ed. Seoul: Gabonwor, 2009. 5. Yang SH, Suh KS, Lee HW, et al. The role of (18)F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Liver Transpl 2006;12:1655-1660. 6. Yang SH, Suh KS, Lee HW, et al. A revised scoring system utilizing serum alphafetoprotein levels to expand candidates for living donor transplantation in hepatocellular carcinoma. Surgery 2007;141:598-609. 7. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. -S269-
SYMPOSIUM 6. End-Stage Liver Disease 8. Hwang S, Lee SH, Joh JW, Suh KS, Kim DG. Hepatocellular carcinoma in Korea: Comparison between cadaveric donor and living donor liver transplantations. Liver Transpl 2005;11:1265-1272. 9. Yi NJ, Suh KS, Cho JY, et al. Recurrence of hepatitis B is associated with cumulative corticosteroid dose and chemotherapy against hepatocellular carcinoma recurrence after liver transplantation. Liver Transpl 2007;13:451-458. -S270-