Though biliary atresia remains the leading indication for liver transplant in children [8], improving outcomes have encouraged expanding indications to include liver-based metabolic defects [9]. Where these defects cause liver damage, liver transplant is curative by replacing the diseased organ as in other disorders of liver architecture leading to synthetic dysfunction and decompensation. The other group includes disorders whereby a genetically inherited enzymatic defect, wholly or partially liver based with a structurally normal liver, causes neurological/multiorgan involvement that may be prevented by replacing the liver. Liver transplant should be performed early before irreversible damage occurs in target organs. These include Criggler Najjar syndrome, urea cycle defects and organic acidemias to achieve intact neuro-logical status, familial hypercholesterolemia to prevent cardiac disease and/or sudden death, and primary hyperoxaluria where an early liver transplant prevents renal failure or else a combined/sequential liver kidney transplant would be required to prevent systemic oxalate overload and its multiorgan consequences. With the availability of next generation sequencing (NGS) based tests, precise and timely genetic diagnosis can now be made and timely therapy instituted.

Livers from patients with Maple syrup urine disease (MSUD) and familial hypercholesterolemia may be donated to cirrhotic patients as they are structurally and functionally normal apart from an enzyme deficiency, which may be compensated by other body tissues to sustain function. Such transplants, known as domino transplants, have been successfully reported from India [10]. As our programs are primarily living-related, the majority of the donors are parents who are carriers of the recipients’ metabolic or genetic disorders with autosomal recessive inheritance. Use of such heterozygous donors has been debated. Data from the Japanese multicenter registry [11] has reported that outcome after employing heterozygous donors was excellent with better long-term survival rate. Portal vein thrombosis (PVT), a known sequelae of cirrhosis, especially more frequently seen in infants with biliary atresia due to portal vein hypoplasia, is no longer a contraindication to liver transplant despite the technical difficulty and higher risks of post-transplant vascular thrombosis endangering the graft [12].

Pediatric liver transplant has now progressed beyond the ABO blood group barrier. ABO incompatible (ABOi) transplants are being increasingly performed when blood group compatible donor from the family is not available. Despite concerns about liver graft regeneration, antibody mediated rejection (AMR), higher incidence of biliary strictures and sepsis, both pediatric and adult ABOi liver transplant survival has improved markedly and has become comparable to ABO-compatible liver transplant with the introduction of rituximab prophylaxis before transplant [13]. Rituximab and/or other B cell desensiti-zation strategies including plasmapheresis and IVIg are used to bring down isoagglutinin titers to less than 1/8 pre liver transplant. Children younger than 2 years of age may not require these desensitization therapies as blood group isoagglutinins titers are low and complement system activation is not robust, thus minimizing the risks of AMR [14]. ABOi liver transplant grafts in acute liver failure in infants have thus been used more often as lack of time window for desensitization strategies may limit use of this modality in older children and adults with acute liver failure [15]. Most busy centers in India have successfully performed ABOi transplants since the initial reports of success in 2014 [16].

Studies on long term morbidities, effects of immuno-suppression and quality of life post liver transplant are lacking from our country. LT requires lower immuno-suppression compared to other organs. Indian patients have been shown to do well on lower immunosuppression as infections are more common in our scenario [4,5]. Regimens vary across different programs but cortico-steroids remain the induction agents of choice with dual agent regimens including calcineurin inhibitors and renal sparing mycophenolate for the first year, with the aim to come down to a single agent by the second year. The desired ideal outcome is attainment of prope tolerance, i.e., almost immune tolerant state where the recipient is alive with first allograft with no ongoing rejection episode on tacrolimus therapy with trough levels less than 3 ng/mL, three years post LT. Studies indicate that almost 20% pediatric patients may attain such immune tolerance with maximal chances for those transplanted in infancy [18]. However, the SPLIT database analysis has revealed that the ideal triad of normal growth, stable allograft function on single-agent immunosuppression, and an absence of immunosuppression-related complications is achieved in only about a third of recipients 10 years after LT [1]. Steroid free protocols using antibody induction (ATG/basiliximab) along with tacrolimus are not yet in vogue but steroid-free tacrolimus-based immuno-suppression may result in an enhancement of graft acceptance in the long term as well as in a higher proportion of children becoming prope tolerant [19,20].

Lack of a database greatly inhibits accurate analysis of trends, outcomes and long term results. Non-availability of long term followup from many recipients from overseas is another disadvantage. With the formation of the Liver Transplant Society of India, efforts are on for a national registry, hopefully more data should be available in the coming years. Low numbers for DDLT, especially in Northern India, is amongst the foremost immediate concern that requires intense campaigning and education to change the social mindset. Encouraging organ donation is the need of the hour.

Perhaps, the most crucial limiting factor in our country has been the cost of liver transplant. The programs are largely driven through the private sector, and health care insurance is still not widely prevalent in our country. Moreover, most insurance companies do not provide cover for diseases of perinatal onset or genetic etiology. The advent of crowd funding platforms where strangers come together on the internet to fund a medical catastrophe for an unknown person is heart-warming and provides an insight into the social responsibility the community is prompt to take up when transparency is assured. These campaigns run on social media with tight timelines ranging from a week to a month, and at times funds have been raised in a day or two for emergency transplants. Crowd funding with the support of few philantrophic organizations and individuals dedicated to funding liver transplants has thus made transplantation attainable for those with limited resources. Crowd funding works best for children awaiting trans-plants, perhaps due to the emotive pull of images and videos of innocent children struggling to wade off certain death that a transplant could prevent. The predicament of the parents, one of whom is the organ donor most of the time, also touches a cord. With this active support of the community in facilitating transplants for children, liver transplant seems to have finally come of age in our country.

High-resolution sequence mapping of DNA variation is now feasible and liver tissue transcriptional signatures are being studied to identify candidates likely to achieve tolerance and withdrawal of immune suppression. Genome wide association studies or NGS for cytokine genotyping to detect single nucleotide polymorphisms in cytokine gene promotor regions may help identify recipients at low risk for rejection.

Meanwhile, expansion of this facility in the public sector is needed as liver transplant is still not available routinely to those with limited resources. We wait to realize the dream of DDLT becoming the primary modality, as it is in the Western countries, by concerted efforts to promote organ donation.

1. Ng VL, Alonso EM, Bucuvalas JC, et al., for Studies of Pediatric Liver Transplantation (SPLIT) Research Group. Health status of children alive 10 years after pediatric liver transplantation performed in the US and Canada: Report of the studies of pediatric liver transplantation experience. J Pediatr. 2012;160:820-26.

2. Poonacha P, Sibal A, Soin AS, Rajashekar MR, Raja-kumari DV. India’s first successful pediatric liver trans-plant. Indian Pediatr. 2001;38:287-91.

3. Sibal A, Bhatia V, Gupta S. Fifteen years of liver transplan-tation in India. Indian Pediatr. 2013;50:999-1000.

4. Mohan N,　Karkra S,　Rastogi A,　 et al. Outcome of 200 pediatric living donor　liver　transplantation in　India. Indian Pediatr.　2017;54:913-19.

5. Sibal A,　Malhotra S,　Guru FR,　et al. Experience of 100 solid organ transplants over a five year period from the first successful pediatric multi organ transplant program in India.　Pediatr Transplant.　2014;18:740-5.

6. Kakodkar R, Soin A, Nundy S. Liver transplantation in India: its evolution, problems and the way forward. Natl Med J India. 2007;20:53-56.

7. Narasimhan G, Kota V, Rela M. Liver transplantation in India. Liver Transpl. 2016;22:1019-24

8. Malhotra S, Sibal A, Bhatia V, et al. Living related liver transplantation for biliary atresia in the last 5 years: Experience from the first liver transplant program in India. Indian J Pediatr. 2015:82:884-9.

9. Mazariegos G, Shneider B, Burton B, et al. Liver trans-plantation for pediatric metabolic disease. Mol Genet Metab. 2014;111:418-27.

10. Mohan N, Karkra S, Rastogi A, Vohra VK, Soin AS. Living donor liver transplantation in maple syrup urine disease. Case series and world’s youngest domino liver donor and recipient. Pediatric Transplant. 2016;20: 395-400.

11. Kasahara M, Sakamoto S, Horikawa R, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transpl. 2014;18:6-15.

12. Conzen KD, Pomfret EA. Liver transplant in patients with portal vein thrombosis: medical and surgical requirements. Liver Transpl. 2017;23:S59-S63.

13. Yamamoto H, Uchida K, Kawabata S, et al. Feasibility of monotherapy by rituximab without additional desensiti-zation in ABO-incompatible living-donor liver trans-plantation. Transplantation. 2018;102:97-104.

14. Honda M, Sugawara Y, Kadohisa M, et al. Long-term outcomes of ABO-incompatible pediatric living donor liver transplantation.　Transplantation. 2018;102:1702 09.

15. Yamamoto H, Khorsandi SE,　　Cortes Cerisuelo M,　et al. Outcomes of liver transplantation in small infants. Liver Transpl. 2019;25:1561-70.

16. Soin AS, Raut V, Mohanka R, et al.　Use of ABO-incom-patible grafts in living donor liver transplantation – First report from India. Indian J Gastroenterol. 2014;33:72-6.

17. Lan X, Zhang H, Li HY, et al. Feasibility of using marginal liver grafts in living donor liver transplantation.　World J Gastroenterol.　2018;24:2441-56.

18. Mazariegos GV, Sindhi R, Thomson AW, Marcos A. Clinical tolerance following liver transplantation: Long term results and future prospects. Transpl Immunol. 2007; 17: 114-19.

19. Gras JM,　Gerkens S,　Beguin C,　 et al. Steroid-free, tacro-limus-basiliximab immunosuppression in pediatric liver transplantation: Clinical and pharmacoeconomic study in 50 children Liver Transpl.　2008;14:469-77.