Pediatric Liver Transplantation




© Springer International Publishing Switzerland 2016
Stefano Guandalini, Anil Dhawan and David Branski (eds.)Textbook of Pediatric Gastroenterology, Hepatology and Nutrition10.1007/978-3-319-17169-2_73


73. Pediatric Liver Transplantation



Nigel Heaton 


(1)
King’s Health Partners, Institute of Liver Studies, Kings College Hospital FT NHS Trust, SE5 9RS Denmark Hill, London, UK

 



 

Nigel Heaton



Keywords
Pediatric liver\transplantationSplit liverLiving donor liver transplantationLiver disease



Introduction


Liver transplantation (LT) continues to be the only effective treatment for children with end-stage liver disease. Thomas Starzl performed the first liver transplant in a child in March 1963 [1]; however, it was not until 1967 that he reported the first recipient with significant survival. Following his early series of seven children aged between 13 months and 16 years [2], more than 15,000 pediatric liver transplants have been carried out in the USA and 10,000 in Europe, with 3- and 5-year survival of 80 and 75 %, respectively. There have been continued improvements in all aspects of care of the child with liver disease coming to LT including surgical, anesthetic, intensive care, and postoperative management. The large numbers of recipients currently surviving beyond 15 years are informing clinical practice and providing more information for families currently facing transplantation. As the majority of children are transplanted at a young age and have little memory of the events surrounding their transplant continuing patient and family education are increasingly recognized as important. There has been a change of emphasis in care from a focus on survival to long-term outcomes centered on well-being, psychosocial and physical development, and educational attainment. It is clear that adolescence and transition to adulthood and follow-up within an adult environment pose further significant challenges, and late death due to non-adherence to medication and follow-up are significant problems. The emergence of models of care to manage these challenges will hopefully help lead to further improvement in long-term outcomes. In addition, the timing of transplant and its influence on subsequent development and outcome is coming under increasing scrutiny.


Pre-transplant


Historically, children have been listed for LT based on criteria adopted from adult experience. However, children present with a different spectrum of diseases, with two thirds of children coming to LT in the first 5 years of life, and consideration has to be given to emotional, social, intellectual, and physical development. The timing of LT has to be considered with the long-term development of the child in mind, and there remains a lack of data regarding this topic .


Indications for LT


LT should be considered for any child with end-stage liver disease with a predicted prognosis of less than 18 months . Indications for LT are in general derived from adult liver transplant experience, but are modified for children and include :



  • Liver decompensation (prolonged international normalized ratio (INR), low serum albumin, ascites)


  • Disordered metabolism (jaundice, loss of muscle mass, osteoporosis)


  • Portal hypertension (variceal bleeding, intractable ascites)


  • Encephalopathy


  • Spontaneous bacterial peritonitis


  • Hepatopulmonary syndrome


  • Pulmonary hypertension


  • Recurrent cholangitis and intractable pruritus


  • Quality of life (failure to growth, poor concentration, lethargy)


  • Tumors

Extrahepatic biliary atresia (BA) is the most common indication for LT and accounts for 40–50 % of cases listed worldwide. Other common causes include metabolic disorders, tumors, and acute liver failure (ALF). The majority of pediatric recipients under 2 years old have cholestatic diseases, particularly BA, which accounts for 74 % of cases in this age group. Metabolic disorders and ALF are less common indications and account for 9 % each of the overall number [3] .


Chronic Liver Diseases



Biliary Atresia

Extrahepatic BA is a destructive inflammatory obliterative cholangiopathy that affects the intrahepatic and extrahepatic bile tree. Type 3 BA is the most frequent form of the disease accounting for 90 % of cases and is the most severe form with a solid porta hepatis, microscopic ductules, and a solid gallbladder or mucocele [4]. The majority of children coming to transplant have undergone Kasai portoenterostomy (KP) within the first 3 months of life. Early portoenterostomy and expertise of the multidisciplinary team have a significant impact on outcome and the need for LT in early life [5, 6]. The results of concentrating expertise in a small number of centers each performing more than five cases per year have led to a 4-year survival with the native liver intact of 41–51 % and an overall survival of 87–89 %. More recently, survival of 96 % at 10 years has been reported for the UK with an integrated program of KP and LT [4]. Mortality is distributed equally between deaths on waiting list for liver transplant and in the post-transplant period. By the age of 18 years, approximately 80 % of children with BA will have been treated by LT. Outcomes have been reported for 5- and 10-year actuarial graft and patient survival of 76.2 and 72.7 % and 87.2 and 85.5 % for cadaveric [7] and 84.9 and 76.6 and 86.7 and 80.8 % for living donor LT (LDLT) [8], respectively .

The majority of young children (under 5 years of age) with BA will come to transplant with jaundice and synthetic failure. In a small number of children (6 % of cases), acute decompensation secondary to ischemic hepatitis may occur following a viral illness or infection. Children at risk of ischemic hepatitis and liver decompensation are those with a hepatic artery resistance index of greater than one on Doppler ultrasound who are dependent on arterial inflow [9]. Children older than 5 years of age may present with failure to grow and a falling serum albumin (synthetic failure), but without jaundice. Adolescents coming to transplantation will invariably have portal hypertension as a dominating feature, which in association with adhesions from previous surgery can make for a difficult surgical challenge.

Congenital anomalies associated with “syndromic” BA (15 % of all cases) include polysplenia/asplenia, absent inferior vena cava (IVC), portal hypoplasia, preduodenal portal vein (PV), malrotation, and situs inversus and may complicate surgery and influence graft choice.


Cholestatic and Metabolic Disorders

Cholestatic liver diseases excluding BA account for 10 % of liver transplants in children. These include Alagille syndrome , progressive familial intrahepatic cholestasis (PFIC), and sclerosing cholangitis. LT is often used to treat symptoms, such as severe pruritus. Children with Alagille syndrome are at risk of growth failure and morbidity from pruritus, xanthomas, and complications of vitamin deficiency. PFIC defines a group of disorders characterized by chronic, unremitting cholestasis and autosomal recessive inheritance with a shared pattern of biochemical, clinical, and histological features. LT is reserved for those with severe symptoms including pruritus or progressive liver disease. Earlier transplant may lessen future growth and developmental impairment in some, but not all of these conditions [10]. In Alagille syndrome , the biliary hypoplasia is associated with other congenital malformations, the most important of which is pulmonary artery stenosis. This needs to be assessed preoperatively due to the risk of mortality post reperfusion if cardiac output is limited by the pulmonary stenosis. Dobutamine stress testing has been used to identify at-risk children who are unable to increase their cardiac index by 50 %.

Inborn errors of metabolism, collectively as a group, form a relatively common indication for LT accounting for 9 and 26 % of children under and over 2 years of age at the time of transplant, respectively. Metabolic diseases resulting in cirrhosis include alpha-1-antitrypsin deficiency, tyrosinemia, Wilson’s disease, neonatal hemochromatosis , respiratory chain disorders, fatty acid oxidation defect, glycogen storage disease type IV, among many others. Metabolic diseases without structural liver disease include Crigler–Najjar syndrome type 1, glycogen storage disease type 1, propionic acidemia, primary hyperoxaluria type 1, hereditary tyrosinemia, factor VII deficiency, ornithine transcarbamylase deficiency, familial hypercholesterolemia, and protein C deficiency. Two series from the USA from the Scientific Registry of Transplant Recipients (SRTR) of 551 transplants [11] and Europe from King’s College Hospital of 112 transplants reported excellent outcomes for this group [10]. Although the presence of cirrhosis did not appear to be a risk factor for worse outcomes, recipient black race, simultaneous organ transplantation, ALF, hospitalization before transplant, and age less than or equal to 1 year were predictors. The study from Sze et al. reported 11 auxiliary liver transplants (ALTs) with similar outcomes to whole liver replacement for noncirrhotic liver disease with an absent enzyme/gene product such as Crigler–Najjar type 1 [10].


Tumors

LT for liver tumors in children accounts for 2–6 % of all cases in European and American series. The most common indication is unresectable hepatoblastoma (following appropriate chemotherapy). Other tumors treated by LT include hepatocellular carcinoma (HCC), hemangioma , infantile hemangioendothelioma, and epithelioid hemangioendothelioma. Angiosarcomas should not be transplanted as they invariably recur early. However, differentiation from more benign vascular tumors can be difficult. Clinical features such as pain, rapid deterioration, or disease progression indicate sarcoma. The outcome of LT for unresectable hepatoblastoma is excellent with long-term patient and graft survival rates for cadaveric transplantation of 91, 77.6, and 77.6 % at 1, 5, and 10 years, respectively [12]. Patient and graft survival for children undergoing LDLT is 100, 83.3, and 83.3 % at 1, 5, and 10 years, respectively. Two North American series of 25 (HCC, 10 cases; hepatoblastoma, 15 cases) and 12 patients (HCC, 6 cases; hepatoblastoma, 6 cases) reported similar medium- and long-term survival rates for both tumors [13, 14]. Salvage transplantation for recurrent hepatoblastoma after conventional liver resection is less satisfactory with 5-year survival of 40 % with a high rate of further recurrence. An analysis of the United Network for Organ Sharing (UNOS) data of 336 patients with liver tumors which included 237 hepatoblastomas, 58 HCC, and 35 hemangioendotheliomas noted that patient survival for the latter was inferior to that of hepatoblastoma (5-year survival of 72 %) and rare liver tumors (5-year survival of 78.9 %), but better than HCC (5-year survival of 53.5 %) [15]. Tumor recurrence was the major cause of death in hepatoblastoma and HCC, but not in hemangioendothelioma.

The development of HCC has been reported in BA, Alagille syndrome , and progressive intrahepatic cholestasis. Children with tyrosinemia have a high risk of HCC before 2 years of age which appears to be markedly reduced by the use of 2-(2-nitro-4-3 trifluoromethylbenzoyl)-1,3-cyclohexanedione (NBTC) therapy [16]. For HCC, there are no criteria for selection comparable to the Milan criteria in adult patients. Macrovascular invasion continues to be a contraindication.


Acute Liver Failure


ALF is defined by the onset of severe impairment of liver function in the absence of previous liver disease. Coagulopathy is always present, but in young children hepatic encephalopathy may be absent and is a late feature associated with a poor outcome. ALF is an indication for LT in 9 % of under and 16 % of over 2 years old in Europe and 15 % of children in the USA. The cause of ALF cannot be determined in the majority of children (49 % of all children and 54 % of those aged 1 year) [17]. Other causes include metabolic, paracetamol intoxication, autoimmune hepatitis (AIH) , viral hepatitis, drugs, Wilson’s disease, and vascular and Amanita phalloides poisoning. The risk of death or LT is highest in children under 3 years of age. Logistic regression analysis has identified total serum bilirubin > 5 mg/dL, INR > 2.55, and hepatic encephalopathy as risk factors for death or LT. Of note, grade IV hepatic encephalopathy on admission was associated with higher rate of spontaneous recovery than those children who progressed to grade IV during the course of admission (50 vs. 20 %). Indications for LT are different from adults and an INR > 4 (in the absence of disseminated intravascular coagulopathy) identifies the at-risk population.

Two recent series reported 5-year patient survival of 70 % in children with ALF [18, 19]. Farmer et al. identified four factors which predicted graft or patient survival in 122 children with ALF which included creatinine clearance (cCrCl) < 60 mL/min/1.73 m (graft and patient), pediatric end-stage liver disease (PELD) > 25 (graft), recipient age < 24 months (graft), and time from the onset of jaundice to encephalopathy < 7 days (patient) [18]. The presence of two or more of these factors was associated with a significant reduction in graft and patient survival to about 25–40 %. Other series have also noted lower graft survival in children aged less than 2 years with ALF possibly reflecting technical challenges in small babies [20]. This population is the most challenging group, and further improvements in perioperative surgical and intensive care are needed to make progress.

ALF in neonates is a rare but often fatal event characterized by a failure of synthetic function with coagulopathy. Hepatic encephalopathy is a late event and difficult to diagnose in infants [21]. Causes of ALF in neonates include metabolic, infectious and hematological disorders, congenital vascular/heart abnormalities, and drugs. Congenital hemochromatosis is the commonest indication and the challenge is to provide a graft in time. Neonates and young children with ALF should only be treated in specialized pediatric hepatology centers with facilities for LT which continues to be the only therapeutic option with a long-term survival of over 60 %.


Timing of Transplantation


The timing of LT in children has been based on criteria established in adults and thus is focused on graft and patient survival . Optimal timing was viewed as listing for LT when expected survival was less than 2 years. Children with liver disease may not develop physically, intellectually, and socially at a time of deteriorating liver function, and the timing of transplant needs to take this into account. There is general agreement that KP should be performed for BA and that LT is reserved for those who develop progressive liver disease (apart from rare cases of late presentation > 4 months).

The model for end-stage liver disease (MELD) was introduced in 2002 as a response to increasing waiting list mortality. It provides a means of allocating livers based on likelihood of dying while on the waiting list. PELD was a similar mathematical tool based on data derived from the Studies of Pediatric Liver Transplantation (SPLIT) research group using bilirubin, INR, serum albumin, age > 1 year, and growth [22]. The introduction of MELD (and subsequently PELD) significantly decreased death or removal from the waiting list for being too sick within 2 years for both adults and children [23]. Cowles et al. [24]in reviewing a cohort of 71 children transplanted for BA (61, KP before LT; 10, primary LT) considered that PELD monitoring identified those in need of transplantation. Children with a PELD greater than 12 ( n = 47) had a higher rate of post-LT mortality and retransplantation than those with a PELD of 10 or less. The authors suggested that a PELD score approaching 10 should trigger discussion of LT. PELD is the only scoring system currently used in children and although helpful in advanced liver dysfunction; it is of limited value in the very young (under 1 year of age) and in older recipients, particularly with complications such as recurrent cholangitis, severe portal hypertension, pulmonary hypertension, and hepatopulmonary syndrome [2529]. Because of these limitations, PELD use has been largely restricted to North America. More research is needed to define optimal timing of transplantation in children to gain most benefit in terms of survival, growth, and intellectual and social development .


Intraoperative



Whole LT


Whole liver replacement is relatively uncommon in children under 5 years of age at the present time . Above the age of 5 years, it is more common. The transplant involves excision of the diseased liver, by division of the common bile duct (or Roux loop if there has been previous biliary surgery), hepatic artery, PV, and IVC above and below the liver. Orthotopic liver replacement is accomplished by anastomosis of the corresponding structures with the donor liver and achieving hemostasis; the alternative is the use of the piggyback technique. Management of intraoperative coagulopathy is an essential component of the operation. The technique is very similar to adult LT, but the smaller size of the vascular structures demands a more refined surgical technique, especially for arterial reconstruction. The use of cell salvage has led to bloodless surgery becoming a practical proposition. Closure of the abdomen should only be performed if there is no risk of graft compression .


Partial Liver Grafts


The use of partial grafts was the solution to both organ shortage and size restriction in children. In Europe, more than 10,000 LT have been performed in recipients under 16 years old. Of these, approximately 38 % have been performed with whole organs. Partial grafts account for 80 and 52 % of all LT performed among patients aged 0–2 and 2–15 years old, respectively. Early experience was with reduced-size grafts, either left lobe or left-lateral segment (LLS) which then led onto to split and LDLT with both techniques being incorporated into routine clinical practice from 1991 onwards. Roberts et al. analyzed the data of 6467 LTs performed in patients under 30 years old from the SRTR–Organ Procurement and Transplantation Network (OPTN) database [30]. It was noted that patient and graft survival during the first year after transplant for each donor graft type varied according to the recipient age group. For children of 2 years and under, living donor (LD) grafts had a 51 and 30 % lower relative risk (RR) of graft failure than deceased donor split (DD-S) and deceased donor full (DD-F), respectively. A similar difference in mortality risk in the same group of age favored recipients of LD grafts over DD-S (RR = 0.71, p = 0.08). Recipients in the 0–2-year age group had higher risk of mortality and graft failure with DD-S livers than DD-F livers (RR = 1.31, p = 0.04 for mortality; RR = 1.42, p < 0.001 for graft failure). For patients aged 2–10 years, the RRs of mortality and graft loss were higher after LD than after DD-F (RR = 1.78, p = 0.02 for mortality; RR = 1.53, p = 0.02 for graft loss) but not after DD-S. In the 11–16-year age group, a significantly higher RR of graft failure was observed after LD than after DD-F transplant (RR = 3.63, p = 0.0001) or DD-S transplant (RR = 2.87, p = 0.02), although mortality risks were similar for all three donor graft types. Subsequent publications have confirmed the excellent outcomes with LDLT in young children, but published experience with children over 12 years of age remains limited outside of India and the Far East.

Publications of outcomes of LLS reduced-size LT tend to be from the early 1990s, and there are few direct comparisons with those observed after split LT (SLT). SLT has become an established technique which has successfully addressed organ shortage in children while preserving the pool of liver grafts for adults. A recent study of 251 LTs, which included 138 reduced and 30 split, reported 1-year patient and graft survivals that were comparable at 73 and 67 %, respectively [31]. In addition, no differences in vascular complications were observed. Of note, biliary complications were significantly more common after split when compared with reduced-size grafts (21 vs. 4 %, p < 0.0001). The most common biliary complication after SLT was late stricture, in contrast to reduced-size LT (RLT), which was a cut-surface bile leak. Patients undergoing SLT had a 6.7-fold increased risk of biliary complications compared to those receiving an RLT; however, these complications did not appear to impact on graft or patient survival. A further series from the University of California Los Angeles (UCLA) has compared the outcome of whole and partial grafts in both adult and pediatric recipients [31]. Of 442 LTs, 284 were whole, 109 were split-LLS (SL-LLS), and 49 were LD-LLS. The 10-year patient survival for children was similar for all graft types. Multivariate analysis confirmed that history of previous LT and SL-LLS was independent predictors of reduced survival. Chronic rejection and hepatic artery thrombosis were the most common reasons for graft loss. The largest study from Hong et al. of outcomes after partial liver grafting in children analyzed data from the SPLIT registry and compared the outcome of each variants with that of whole organ transplantation (1183 whole, 261 split, 388 reduced, and 360 live donor (LDLT)) [32]. There was a clear difference in outcomes at 1 year (W, 93 %; R, 82 %; S, 87 %; L, 89 %) and 4 years (whole liver transplantation (WLT), 89 %; RLT, 79 %; SLT, 85 %; LDLT, 85 %) after transplant. However, the groups were not strictly comparable in terms of era of transplant, recipient selection, and center. Children receiving a technical variant waited on average 2.3 months less than those receiving a whole liver and tended to be younger. Complications were significantly higher after partial grafts: At 24 months, the incidence of biliary complications was WLT, 17.3 %; SLT, 28.5 %; RLT, 25.3 %; LDLT, 40.1 % and vascular complications were WLT, 16.5 %; SLT, 23.8 %; RLT, 23.5 %; LDLT, 24.4 % [33].

Trying to understand and balance the increased opportunity of being transplanted against the higher incidence of complications and potential graft loss associated with SLT is difficult. Merion et al. tried to address this issue by comparing the predicted lifetimes for SLT for an adult and a child recipient with WLT for an adult to determine the best use of this limited supply of organs [34]. They analyzed mortality risk for 48,888 patients on the waiting list: 907 SLT and 21,913 WLT recipients (between 1995 and 2002). Of 23,996 donor livers used for transplantation, 533 were split. Donors aged 10–39 years comprised 81.6 % of split livers and 48.5 % of livers used for WLT. Only 11.8 % of livers that were split were from donors older than 40 years. They analyzed years gained per SLT performed against the waiting list death ratio and concluded that “the potential annual net gain in life years could be as high as 169 patient-years in the first 2 post-transplant years, if all livers meeting accepted criteria were used for splitting.” For every 100 donor livers, an extra 11 years of life were predicted over the first 2 years of follow-up if organs were split rather than transplanted whole. In addition, they identified a significant survival benefit for pediatric recipients of SLT compared with children continuing on the waiting list and concluded that it could provide enough organs to satisfy the entire current demand for pediatric donor livers.


Living Donor Liver Transplantation


LDLT has become an important source of grafts for children worldwide. Following on from the first description by Raia et al. in 1988 [35], the first long-term survivor from Strong et al. in 1989 [36], and the early series published by Broelsch et al. [37], the technique has become established with excellent short- and long-term survival. The LLS is the most commonly used graft [38]. Full left or right lobe grafts are used less commonly and tend to be in young adults. Donation is most commonly from parents, although other family members and altruistic donation have been well reported. The ethics and understanding of the desire to donate are easily understood, and the risks appear to be low, but not negligible. Donor mortality for LSS grafts is of the order of 1:1500. The incidence of other significant donor complications which include bile leak (1–2 %), bleeding and the need for transfusion (1–2 %), deep vein thrombosis and pulmonary embolus, and incisional hernia (5 %) are considered acceptable. Risks of donor mortality are similar for left liver and rise to 0.5 % for right lobe donation. The risks of bile leak are also higher for the donor, particularly with the right lobe grafts where the incidence may be as high as 5 %. Donor age above 55 years has become generally accepted as a contraindication (especially for the right lobe) due to the slower regeneration and the increased risk in this population .

The LLS segment graft accounts for approximately 20–25 % of the adult liver, but provides a full-sized “liver” for the child. Assessment of the donor is designed to ensure that the liver segment is anatomically and functionally suitable for transplantation and to identify additional risk factors such as procoagulant abnormalities, smoking, and steatosis within the liver. Many centers continue to follow the two-stage assessment and consent model reported by Brolesch et al. which includes psychiatric/psychological assessment of the donor and family [37]. Depending on the availability of cadaveric transplantation, suitability for living donation will vary from 50 to 90 % when assessing families. The techniques of surgery have been standardized and outcomes are excellent for all liver diseases. The advantages of living related LT (LRLT) include the ability to perform surgery electively with an excellent quality graft, dry cut surface (minimal blood loss), and excellent outcome. The incidence of early rejection is similar to that of cadaveric transplantation, but long term it is considered, although the supporting evidence is limited, that these recipients may be tolerant of their grafts and that immunosuppression (IS) withdrawal may be more likely .

Morioka et al. reported the long-term outcome of LRLT in 46 children who underwent LDLT for metabolic disorders [39]. Mean age at diagnosis and LDLT was 48.6 (0–196) and 86.5 (1.4–199) months, respectively with survival rates of 86.9 and 81.2 % at 1 year and 5 and 10 years post-transplant. Patient survival was significantly better in children with liver-centered disease which included Wilson disease, ornithine transcarbamylase deficiency, tyrosinemia type 1, Crigler–Najjar syndrome type 1, and bile acid synthetic defect than in those with non-liver centered disease (glycogen storage disease, propionic acidemia, methylmalonic acidemia, and erythropoietic protoporphyria; p = 0.003). Statistical analysis showed that cumulative survival of patients with normal or slightly delayed physical growth at the time of LDLT was significantly better than for those with delayed physical growth ( p = 0.012).

LDLT is an excellent option in the management of ALF in children. The workup can be performed rapidly if the unit is regularly performing elective LDLT. Ethical concern has been expressed regarding the ability of the donor to appreciate the risk in these circumstances [40]. The lower risk of LLS donation has led to the use of LDLT as an accepted therapy. Greater debate surrounds the use of right lobe living donation for ALF particularly in countries with effective cadaveric organ donation .


Recent Developments in Transplant Surgery


Over the past 30 years, surgical techniques have become standardized worldwide. LLS and left and right liver LT are used to overcome size discrepancy and to engraft the majority of children. Split and LRLT have been key to sustaining the reduction in deaths on the waiting list. Auxiliary LT offers scope for native liver regeneration in children presenting with ALF and is able to withdraw from IS in the majority. Hepatocyte transplants remain experimental and have been used to bridge young children with metabolic liver disease through the liver replacement. The current challenge is to minimize technical complications that impact on graft survival, such as hepatic artery thrombosis and biliary strictures, and continue to improve outcomes. New technologies are emerging that are currently under evaluation and will impact on practice, and normothermic organ perfusion is perhaps the most prominent.


Auxiliary LT


ALT was first described in a dog by Welch in 1955 [41] . The auxiliary liver was placed in a heterotopic position in the right paravertebral gutter, with portal venous inflow from the iliac vein. The idea of heterotopic ALT was attractive as it avoided the need for native hepatectomy with the idea that it would improve hemodynamic stability during surgery. The first experience of ALT in a human was reported in 1964, using a heterotopic graft, with the aim of avoiding obstacles presented by whole liver replacement. Chenard-Neu et al. reported long-term survival of 2 out of 47 patients who underwent heterotopic ALT between 1964 and 1980 [42]. From 1986 onwards, outcomes of ALT began to improve, although only small numbers were performed [43]. The technique of ALT proved to be more difficult than that of LT with a higher rate of technical complications and inferior graft function and outcome. The development of HCC in the cirrhotic liver remnant of one long-term survivor led to the abandonment of ALT as a treatment for chronic liver disease .

The technique has become an established indication, however, for ALF especially in children. ALT has also been used to treat noncirrhotic inborn errors of metabolism based in the liver [44]. For ALF, the aim is to treat children satisfying established criteria for transplantation, with survival equivalent to that obtained with whole liver replacement with subsequent native liver regeneration and IS withdrawal. Children have the most to gain from avoiding the complications of lifelong IS. An early multicenter European experience identified that recipients under 40 years of age and particularly children were most likely to survive, have successful liver regeneration and withdraw from IS [43]. In addition, patients with hyperacute liver failure were more likely to regenerate than those with subacute liver failure and that orthotopic rather than heterotopic ALT had a better outcome. IS withdrawal has been possible in more than 70 % of survivors [4547] .

ALT has included the use of whole liver, right lobe, left lobe, or LLS grafts. A proportion of the native liver is resected to make room for the graft. The graft is piggy-backed onto the cava, portal inflow is established by end-to-side anastomosis, and arterial inflow is established using either a donor iliac conduit or a branch of the native hepatic artery. Biliary drainage is achieved with either a short Roux-en-Y hepatico-jejunostomy or by anastomosis to the native bile duct. In children, the majority of ALTs are performed using LLS grafts to overcome donor–recipient size discrepancy. Selection of the recipient includes satisfying existing criteria for LT for ALF, no neurological or cardiovascular contraindication and a suitable graft. The donor liver should be of excellent quality to ensure that good early function is achieved. Marginal livers are difficult to use as partial grafts and provide inferior function and should be avoided .

Postoperatively, patients are managed with conventional IS. Early graft dysfunction is due to technical complications, particularly inadequate venous inflow or outflow, and poor quality or small for size grafts. The serum aspartate aminotransferase (AST) and INR may be slower to settle than with conventional transplantation. Persistent elevation of the serum bilirubin indicates complications with the graft. Postoperative bleeding with the need for relaparotomy is more common due to the presence of two cut surfaces .

Patients are followed with CT or MR imaging with guided biopsies of both graft and native livers in the early postoperative period and at 6-month intervals to assess liver recovery. Hepatobiliary dimethyl iminodiacetic acid (HIDA) scintigraphy is also of value in assessing the differential function of the two livers and documenting native liver recovery. The decision to begin IS withdrawal is usually made at 6 months or when signs of regeneration are observed on biopsy. Gradual weaning is necessary to avoid severe graft rejection and infarction. The graft will usually atrophy and disappear completely. IS withdrawal may need to be started to stimulate native liver regrowth. Even after massive hepatic necrosis the liver regenerates fully . However, the larger the graft transplanted the slower the regeneration of the native liver is without reduction in IS. In the subacute group, regeneration is less rapid, as observed by sequential imaging. Successful IS has been reported up to 4 years after auxiliary partial orthotopic LT (APOLT). Histopathological assessment of the native liver at the time of ALT has identified patterns of hepatocyte cell loss which insight into the likelihood of regeneration. A diffuse pattern with uniform cell loss throughout was associated with hyperacute liver failure and with excellent regeneration with restoration of normal histology in over 70 % of patients [48] . A map-like pattern was associated with seronegative hepatitis and adults had a mixed outcome; however, in children the results were excellent. In a small number of cases, no viable hepatocytes could be identified and this group did not regenerate effectively. Of five cases in our series of over 60 adults and children with this pattern, three died and two were retransplanted. ALT has become the gold standard for the treatment of children with ALF requiring transplantation .


Donation After Circulatory Death Donation


The use of donation after circulatory death (DCD) liver grafts has become common in Western countries over the past 10 years. The majority have been from controlled donation (within the hospital intensive care environment) and usually have unrecoverable brain injury. Withdrawal of support occurs, and death is pronounced clinically and with ECG. There follows a 5-min standoff before surgical retrieval is initiated. Warm ischemia is calculated from the onset of systolic blood pressure (BP) < 50 mmHg or PaO2 < 70 % to cold perfusion of the liver. The organs have been used successfully in children, either as whole or reduced-size grafts with excellent outcomes. Selection criteria for liver reduction include donor age < 40 years, warm ischemic time of < 30 min, good liver function, and no steatosis with the cold ischemic time being kept under 8 h. Several centers including our own have reported significant numbers of RLT with excellent early and late graft and patient survival and no biliary complications such as cholangiopathy [49].


Post-transplant



Postoperative IS


Over the 30 years, pediatric LT has seen serial improvements in morbidity and mortality. These improvements are related to IS, donor selection and maintenance, surgical technique, and complex team working. The focus of IS has been on the prevention of acute rejection and graft loss; however, in children, morbidity and mortality rates from infections exceed those from rejection and can also impair growth and renal function and increase the risk of some cancers. Getting the balance of IS right in the short and long term is key to a successful LT program. Evidence is also accumulating that children may be more likely to develop graft tolerance and to wean from IS in the long term [50].

Early post-transplant IS has been associated with increasing use of induction therapy (26 %), particularly with interleukin (IL)-2 receptor antibodies either to supplement IS or as a renal sparing regimen. For maintenance IS, calcineurin inhibitors (CNI) remain the cornerstone; but cyclosporin has been largely replaced by tacrolimus. Children often receive an anti-proliferative agent such as azathioprine or mycophenolate mofetil to supplement IS or for CNI/renal sparing. Tacrolimus trough levels of 8–10 ng/l in the first 3 months and 5–8 ng/l thereafter are usually sufficient. Longer-term tacrolimus levels can be further weaned to low levels, if graft function is normal with no rejection episodes. Moderate-to-severe acute rejection is treated with steroid boluses and if unresponsive antithymocyte globulin can be given.

Over-IS is associated with long-term side effects including renal impairment, hypertension, lymphoproliferative disease, and cancer and may hinder the process of immune engagement and the development of immune tolerance. There has been a move toward progressive minimization of IS, including steroid withdrawal which is associated with a growth advantage without any significant rejection-related complications [51, 52]. Many units discontinue steroids during the first or second post-transplant year and more than 50 % of children are on monotherapy tacrolimus by 18 months post LT [53]. It has been suggested that early steroid withdrawal may be associated with a higher risk of acute and chronic rejection and the development of de novo AIH [54]. The pathogenic mechanisms behind de novo AIH remain unclear, but it appears to be related to under IS and affects 2–5 % of pediatric LT recipients [55, 56] .

CNI share a number of side effects in common including nephrotoxicity, neurotoxicity, and hyperlipidemia [57]. There are, however, some differences between tacrolimus and cyclosporin. Cyclosporin is associated with hirsutism and gum hyperplasia while tacrolimus is associated with diabetes and hair loss. For teenagers, especially in females, tacrolimus is often the CNI of choice because of the lower incidence of gum hyperplasia and hirsutism. Tacrolimus has greater water solubility and less dependence on bile salt absorption, thus resulting in improved bioavailability over cyclosporin. However, it has larger interindividual variations. The introduction of once-daily preparations of CNI may help reduce variations in drug levels and improve adherence to medication [58]. Tacrolimus may be superior to cationic steroid antibiotic (CsA) with regard to steroid withdrawal and the incidence of acute and chronic graft rejection. CNI sparing or substitution with mammalian target of rapamycin (mTOR) inhibitors such as sirolimus or everolimus is used for patients with nephrotoxicity, but their efficacy requires validation in long-term studies in large cohorts.
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Jul 12, 2016 | Posted by in HEPATOPANCREATOBILIARY | Comments Off on Pediatric Liver Transplantation

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