Introduction
The history of surgery begins with traditional medicine in India (Ayurveda since 2000 BCE) and China (Yin-Yang since 3000 BCE). Surgery began with the first attempt to control bleeding from a vessel. A compelling body of evidence indicates that Sushruta (600 BCE), a surgeon in ancient India, first performed ligation of blood vessels. Sushruta was the first surgeon of antiquity, and his monumental treatise was the first surgical textbook. Although the original manuscript has been lost, several translations from Sanskrit have survived until the present time.
The Chinese surgeon Hua Tuo (145–220 CE) first performed surgery under general anesthesia using a formula made from herbal extracts. In the modern era, as the first reliable documentation of an operation performed under general anesthesia using the same herbal formula as Hua Tuo, Hanaoka Seishu (1760–1835), a Japanese surgeon, performed the first mastectomy for breast cancer in 1804. The technology of general anesthesia and surgery spread in Asian countries through the Second World War. Regarding the Asian history of liver transplantation (LT), deceased donor LT (DDLT) was first performed by Nakayama in 1964 for a 5-month-old patient with biliary atresia. However, the first successful DDLT operation was performed by CL Chen in Taiwan in 1984.
According to the United Nations, there are 48 countries in Asia today. The population of Asia is 4.5 billion, which constitutes approximately 60% of the world’s population. Although Asia is the fastest-growing economic region in the world, there are huge economic and religious disparities ( Fig. 41.1 ).
Major religions have their origins in Asia. The majority of Asian people hold onto the strong cultural belief that the body should go to the grave without any part missing and are therefore reluctant to donate their organs. The religions of Asia include Buddhism, Taoism, Confucianism, Shintoism, Islam, and Hinduism; traditionally, most of these religious groups do not encourage deceased donor organ donation; however, as awareness of donation has increased, modern religious views have changed to encourage donation in the context of a “selfless act” or “an act of righteousness” ( Table 41.1 ).
| Religion | Tenets | Views on Transplantation |
|---|---|---|
| Buddhism | “Spiritual consciousness” remains in the body for days after the last breath; its departure is the actual moment of death; during this time, the body must not be disturbed because it might adversely affect the person’s next rebirth; selfless giving | Opposes deceased organ donation; individual’s decision |
| Confucianism | One is born with complete body and should end the same way Modern Confucians: Jen and righteousness are valued more than preserving the integrity of the dead body | Unfilial and disrespectful; approves deceased organ donation |
| Shintoism | The body after death is impure, dangerous, and powerful; interfering with a corpse brings bad luck and might injure the relationship between dead and bereft | Opposes deceased organ donation; individual’s decision |
| Taoism | Naturalness, vitality, peace, and nonaction (to flow of nature) Modern Taoist: body is only shelter to more important parts of life | Seen as attempt to change natural process; opposes deceased organ donation Approves deceased organ donation |
| Islam | Violating human body (living or dead) is forbidden; customary to bury dead within 24 h. Necessity overrides prohibition | Opposes deceased organ donation Uncertainties: seek advice of local imam |
| Hinduism | Selfless giving, physical integrity of body is not crucial for reincarnation | Approves deceased organ donation |
| Sikhism | Physical body is not crucial for cycle of rebirth | Approves deceased organ donation |
| Christianity | Act of selflessness | Approves deceased organ donation |
Conversely, this strong creed might also be the reason for the success of living donor LT (LDLT) in Asia. The first successful pediatric LDLT operation was performed in 1989 by Russel Y Strong and colleagues in Australia and brought new light to the field of LT, particularly in Asia. This technical innovation was soon implemented for the treatment of pediatric patients with end-stage liver disease in Japan (1989), Hong Kong (1993), Taiwan (1994), South Korea (1994), and mainland China (1995) because of the lack of DDLT. Asian pediatric liver transplant (PLT) physicians have made great innovations—from the initial adult-pediatric LDLT to young adult LDLT, and from using a left lateral segment graft to left/right lobe and a monosegment graft for small babies. Furthermore, donation by hepatitis B core antibody-positive and ABO-incompatible donors can be safely performed with perioperative anti-hepatitis B virus treatment and desensitization of antibodies.
Liver Transplantation in Japan
Organ Allocation System in Japan
When a patient is registered in the Japan Organ Transplant Network (JOT), the patient’s clinical and laboratory data, including the Child-Pugh score, model for end-stage liver disease (MELD) score, and pediatric end-stage liver disease (PELD) score or disease-oriented prognostic score (such as primary sclerosing cholangitis, Wilson disease, and acute liver failure), are revised. Each candidate is allocated a clinical priority score by the National Assessment Committee of Indication for Liver Transplantation according to the MELD/PELD system.
Split LT has been considered by transplant centers for donors under 50 years of age without significant steatosis of the graft liver. In addition, each transplant center in the municipality may decide to perform a split LT according to the recipient’s medical condition, the characteristics of the deceased donor, the estimated ischemic time, and other factors.
The pediatric DDLT waiting list mortality in Japan is almost 3.0% with the backup of LDLT, which is significantly low in comparison with Western countries. LDLT has been implemented as a lifesaving procedure for end-stage liver disease patients, although various ethical considerations and potential constraints remain because of the short duration available for the psychological evaluation and the emotional stress of the potential donor candidate and family.
Pediatric Liver Transplantation in Japan
The first LT operation in Japan was conducted in 1964 from a non-heart-beating donor. Subsequently, LT from a non-heart-beating donor was only performed in one case until 1989 when adult-to-child LDLT was first performed.
In 1997, the Organ Transplantation Law was established in Japan. At that time, DDLT became legally available. However, the demand of patients waiting for organ transplantation has not been sufficiently satisfied. Given this lack of significant progression in DDLT, LT in Japan has largely been centered on LDLT using partial liver grafts from healthy relative donors.
The first LDLT operation in Japan was performed for a pediatric patient with biliary atresia in 1989. In the 28-year period from November 1989 to December 2017, LT has been performed in 8347 cases ( Fig. 41.2 ). Currently, 350–400 LDLTs and 50–60 DDLTs are performed each year in 15 major centers. Overall, 3173 LDLTs were performed in children of under 18 years of age over the same period, which accounts for 36.8% of all living donor transplant procedures. In the United States, PLT cases accounted for 7.3% of the total LT volume. Of note, the proactive performance of pediatric LDLT in Japan has led to such enormous differences in comparison to most Western countries, including the United States and Europe. One reason for this might be the somewhat limited access of adults, who may benefit from LT, throughout Japan.
In Japan, the annual number of LDLT cases has decreased since 2005. Donor deaths caused by adult-to-adult LDLT with an extended right lobe graft were, for example, reported in May 2003. This was paralleled by an overall 50% increase in deceased liver donation since the revision of the organ transplant law in 2010. Maximal efforts have been made to reduce living donor morbidity/mortality and to increase the number of deceased donors in Japan. Indeed, during the same period, DDLT was indicated in 447 cases, 63 (14.1%) of which were pediatric cases.
Regarding the indication of PLT in Japan, cholestatic liver diseases—represented by biliary atresia—account for 64.0% of cases, followed by metabolic liver disease in 9.0% (urea cycle disorders, 50%; organic acidemia, 19%; Wilson disease, 10%; glycogen storage disease, 9%; etc.) and acute liver failure in 9.0% ( Fig. 41.3 ).
PLT in Japan can be considered a successful procedure with an excellent 1-year patient survival rate of 89.9%, a 5-year survival rate of 87.2%, a 10-year survival rate of 84.8%, and a 20-year survival rate of 81.0% ( Fig. 41.4 ). PLT can therefore be considered an established medical treatment in Japan.
Pediatric Liver Transplantation in Other Asian Countries
Taiwan
The first successful DDLT operation in Asia was done in Taiwan in 1984 by Chao Long Chen from Chang Gung Memorial Hospital, Kaohsiung City. The promulgation of the first “brain dead law” in Asia was also made in Taiwan in 1987 and spread to other Asian countries (Singapore in 1987, India in 1994, Thailand in 1994, the Philippines in 1994, Japan in 1997, and Hong Kong in 1998). As for the significant effort to the standardize pediatric LDLT procedure with excellent patient and graft survival, Taiwan has played an important role in the outreach LDLT program throughout the world. Currently, transplant centers in Taiwan are helping in the diffusion of knowledge by providing training opportunities for doctors from various continents and are actively helping in the establishment of many transplant centers overseas.
There were 24 centers approved by the Ministry of Health and Welfare, which performed 3017 LTs in Taiwan until 2012, with an overall 3-year survival rate of 82%. The main indication for PLT in Taiwan is biliary atresia. Biliary atresia occurred in 1:5600 live births in Taiwan, which was 2–3 times as high as the incidence in Western countries. Taiwan is the first country to implement universal stool color card screening for the early diagnosis of biliary atresia; the practice was introduced in 2004.
South Korea
In South Korea, the first pediatric DDLT operation was performed in 1988, and the first LDLT operation was performed in 1994. Since 2000, approximately 60 PLT operations have been performed annually. Four hospitals perform PLT (Asan Medical Center, Seoul National University, Samsung Medical Center, and Yonsei University). The indications for LT were biliary atresia (57.7%), fulminant hepatic failure (10.3%), Wilson disease (5.1%), congenital hepatic fibrosis (3.9%), Alagille syndrome (2.8%), hepatic malignancy (2.8%), neonatal hepatitis (2.2%), glycogen storage disease (1.9%), and other diseases (13.4%). The median age of the patients was 20 months. The mean Child-Pugh score was 8.5 ± 2.2, whereas the mean PELD score was 18.2 ± 10.4. Although there is a significant difference in the center experience, the 1-, 3-, 5-, and 10-year patient survival rates were 87.8%, 84.5%, 82.2%, and 78.1%, respectively.
The most impressive achievement by the Korean Society of Organ Transplantation was the significant increase of the deceased donation rate based on social education activities. A mandatory split LT policy was initiated in 2013. LDLT accounts for the major proportion of LT conducted in South Korea, and in 2015, the living donation rate was 18.73 per million population (pmp). The numbers of LDLTs have remained static over the past few years, whereas the proportion of DDLTs has increased steadily. In 2015, DDLT accounted for 32.6% of LT cases (deceased donation rate: South Korea, 9.07 pmp; Spain, 47.45 pmp; United States, 31.7 pmp). The percentage of pediatric LDLT operations has decreased in recent years.
Mainland China
In mainland China, the first clinical trials of DDLT and LDLT were in 1977 and 1995, respectively. In 2007, China’s first Human Organ Transplantation Regulations were officially implemented, and the Ministry of Health issued relevant supporting regulations, marking a crucial step in the legalization and standardization of China’s organ transplantation practices.
Currently, China leads the world in the number of PLT operations, with 1054 PLT operations performed in the year 2018. The percentage of pediatric DDLT operations dramatically increased from 0% in 2009 to 30% in 2018. Biliary atresia is the major indication for PLT, accounting for 78% of all PLT operations. The pediatric transplant center is centralized. There are three high-volume centers in mainland China, with each center performing 200–600 PLT operations per year (Shanghai Renji Hospital, 600 cases/year; Tianjin First Center Hospital, 300 cases/year; Beijing Friendship Hospital, 200 cases/year).
The lack of age- and size-matched organs results in higher waiting list mortality in pediatric recipients. Organs from deceased newborns and infants are a valuable source to increase the donor pool in PLT; however, the prognosis of recipients is dismal because of surgical complications. It has been reported that the utility of neonatal donors < 3 months old in PLT has been well established, with patient survival rates of more than 90% in mainland China.
Hong Kong
The first PLT operation in Hong Kong was performed in 1993. A single institution (Queen Mary Hospital) is approved by the Ministry of Health and Welfare to perform LT in Hong Kong. The annual number of PLT operations is 10 to 20, with 70% of the recipients receiving LT for biliary atresia. DDLT is performed in 30% of cases. The overall 1-year graft survival rate is reported to be 84.2%.
India
Over the last decade, India has seen tremendous growth in the field of LT. Although PLT accounts for less than 10% of all transplant activity, extrapolating the data from the United States, India requires approximately 3000 PLTs/year. However, less than 150 PLTs are currently performed in India each year. It has been reported that the reasons for this wide gap include delayed diagnosis and referral, concerns regarding the long-term success, and the financial burden on the family. There has been a steady increase in the number of centers offering adult LT; however, PLT remains a niche area with only around 5 centers performing more than 20 procedures each year (Rela Institute, Medanta Hospital, Max Hospital, Global Hospital, and Aster Hospital). Financial constraints seem to remain the most important factor that determines a child’s access to this lifesaving treatment in India. A way of improving access is by provision of means-tested financial support for families from local authorities, charity organizations, and even crowdfunding, and several private transplantation centers are currently being initiated.
Pakistan
Pakistan’s first LT was performed in 2003. LT activities were on hiatus until 2011, when a team of local doctors performed a DDLT operation in Lahore. From 2012 onward, a number of centers across the country undertook the challenges of developing LDLT programs. The Punjab and Sind provinces have been at the forefront of LT activity in Pakistan. Insurance coverage is not widespread in Pakistan because of various sociopolitical and financial reasons. Information asymmetry and moral hazards have been matters of concern regarding the sustainability of insurance programs in developing countries. In recent years, however, there has been increased support from the government and philanthropic organizations. Financial restrictions continue to be the biggest hurdle in making LT accessible to patients in need.
Iran
There has been a debate among scholars on the allowance of transplantation from deceased donors, based on the constitution of the Islamic Republic of Iran. The start of the LT program in Iran was based on a historical fatwa (religious approval) issued by Ayatollah Khomeini in 1989, which confirmed the validity of brain death from a religious standpoint, the first such fatwa in the Shia sect. The law passed on brain death by the Iranian parliament, which was based on these fatwas, was the first among Islamic countries. There are no laws on this in many Islamic countries; thus, the Iranian and Shiite jurisprudence is pioneering in its provision of the opportunity for the expansion of DDLT among Islamic countries. Most of these Islamic countries other than Iran still rely heavily on living donation. Iran had the highest deceased organ donor rate in Asia and Islamic countries. The first successful LT procedure in Iran was performed in 1992 at Shiraz University. There are two high-volume LT centers in Iran (Shiraz and Teheran), and 150 PLT operations were performed in 2018. The major indication for pediatric transplantation is Wilson disease, which accounts for 22% of all indications. Further study is necessary to identify specific mutations in the adenosine triphosphate hinge region in exon 18 because Iran has turned out to be a hotspot for such mutations. The LT program has been fully supported by government subsidies since 2005, which has resulted in decreased disparity in the use of this treatment.
Indonesia
Indonesia is the world’s largest island country, with more than 17,000 islands, and is the world’s fourth most populous country as well as the most populous Muslim-majority country. The first pediatric LDLT operation was performed in 2010 at Cipto Mangunkusumo Hospital, Jakarta. Although the initial pediatric LDLT series showed excellent results, the number of pediatric LDLT operations is limited because of the accessibility of specialized hospitals and the associated financial burden. From 2015, government support and public education have increased the number of pediatric LDLT cases (30 cases/year). The major indication for pediatric LDLT is biliary atresia; Kasai portoenterostomy is performed for 50% of biliary atresia cases. The implementation of the DDLT program is under discussion among societies of religious, political, and medical professionals.
Kazakhstan
Kazakhstan is the world’s largest landlocked country and the ninth largest country in the world. The LT program in Kazakhstan started in December 2011. There are two LT centers in Kazakhstan (Almaty and Astana). Because of the historical background between Kazakhstan and Korea, which dates back to the 19th century, there are 100,000 ethnic Koreans living in Kazakhstan (known as Koryo-saram). Kazakhstan and Japan have a had strong relationship for 70 years based on their opposition of nuclear weapons; Kazakhstan was the site of the first atomic bomb test in the Soviet era, with more than 450 nuclear devices tested in Semey during that period, and two atomic bombs were detonated over Hiroshima and Nagasaki in Japan during the Second World War. In this background, LT in Kazakhstan has developed with the cooperation of South Korea and Japan. Nowadays, 10 PLT operations are performed per year utilizing living donors. The main problem for the wide implementation of LT is poor development of a regular deceased donor organ donation system because of the imperfect legislation system.
Other Asian Countries
Self-sufficiency in liver transplant infrastructure will reduce the reliance on international collaboration while providing sustainable care for pediatric patients with liver disease. In Japan, South Korea, and Taiwan, national health insurance covers all costs associated with PLT. Financial constraints will play a major role in expanding PLT numbers and the sustainability of PLT programs in Asian countries. Pediatric LDLT has flourished after its establishment in a number of Asian countries (mainland China [1100 cases/year], India [150 cases/year], Singapore [10 cases/year], Iran [150 cases/year], Japan [100 cases/year], South Korea [60 cases/year], Taiwan [40 cases/year], Thailand [40 cases/year], Indonesia [30 cases/year], Malaysia [20 cases/year], the Philippines [10 cases/year], Kazakhstan [5 cases/year], Vietnam [5 cases/year], and Myanmar [5 cases/year]). Some of these countries have performed PLT with support from experienced Asian countries such as Taiwan, mainland China, South Korea, India, and Japan ( Fig. 41.5 ). In countries where the LDLT program is sporadic and socioeconomic issues exist, PLT is carried out overseas. Every Asian country is making efforts to establish a sustainable PLT program so that PLT can be performed there in the future.
