Historical Overview

Thomas Starzl attempted the first human liver transplantation in 1963 in a 3-year-old child with biliary atresia. Unfortunately, the child died in the operating room from uncontrollable hemorrhage (Starzl, 1992), but subsequently, in 1967, Starzl successfully performed liver transplantation in eight children. All survived the operation, and half survived more than 1 year (Starzl et al, 1968).

Since those heroic beginnings 4 decades ago, advances in immunosuppression, surgical technique, and critical care have made liver transplantation a reliable, lifesaving procedure performed every day at liver transplant centers throughout the world. In children with end-stage liver disease (ESLD), liver transplantation has become the accepted therapy, and its use is limited only by the availability of suitable grafts.

In 2007, there were 5887 adult liver transplantations and 602 pediatric transplantations (Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients [OPTN/SRTR], 2008). Currently, approximately 15,500 adults and 540 children are awaiting liver transplantation (United Network for Organ Sharing [UNOS], 2009). Potential recipients who are infants, toddlers, or young children have narrow constraints with regard to graft size. Historically, the lack of size-matched organ availability, coupled with the disproportionate number of adults on the waiting list, has significantly disadvantaged children awaiting transplantation. Compared with adults who have liver disease, children have much less time to await transplantation; an infant with decompensated liver disease from cirrhosis typically cannot survive on a waiting list for several years (McDiarmid, 2002). Furthermore, waiting-list mortality for children younger than 1 year continues to far exceed that of other children and adults (OPTN/SRTR, 2008), in part because of the lack of size-matched organs.

The shortage of donor organs has motivated surgeons to develop innovative techniques to increase the number of potentially usable organs for pediatric transplantation. Initially, adult cadaveric livers were made smaller by removing the right lobe and medial section of the left lobe to enable grafting of the left lateral section into small recipients. In this way, the size restrictions imposed on any particular donor-recipient combination could be overcome. The application of reduced-size grafts led to a shift of cadaveric livers to children and small adults, but it did not increase the total graft pool.

Progressive improvements in surgical technique have evolved such that now the left lateral section and the right trisegment graft each can be used, meaning that a single liver potentially can be divided and transplanted into two recipients. With this innovative technique, the split-liver procedure, important progress in the effort to expand donors available to children has been accomplished without disadvantaging adult recipients. Except in unusual circumstances, the use of a reduced-size liver allograft in which the remnant is discarded is theoretically rarely justified. In 2007, partial or split-liver transplantations accounted for approximately 4% of all deceased-donor liver transplantations (OPTN/SRTR, 2008). The use of reduced-size liver grafts declined from 23% to 16% of pediatric liver transplantations over the last decade, but during this same time, split-liver allografts increased from 9% to 16% (Anderson et al, 2008).

Favorable outcomes transplanting reduced-size and split livers led to the development of techniques for using liver segments from living donors for pediatric grafts. With increasing experience, donations from living donor livers are no longer confined to left lateral sections or left hepatic lobes but have expanded to include full right hepatic lobe grafts, which contributes to the adult organ pool as well (Hong et al, 2008). Today, living-related and unrelated living-donor liver transplantation (LDLT) accounts for approximately 10% of all pediatric liver transplantations and 4% of adult liver transplants (OPTN/SRTR, 2008), and it has been one of the most exciting and challenging advances in liver transplantation.

Indications

Box 98C.1 lists common indications for pediatric liver transplantation. Biliary atresia is a progressive, inflammatory, fibrosing cholangiopathy of unclear pathogenesis (see Chapter 40). It occurs in only 1 in 8000 to 18,000 live births; and although it is rare, it remains the most common cause of infant death owing to hepatic disease and accounts for approximately 50% of all pediatric liver transplantations (Bassett & Murray, 2008; Bezerra, 2005; Perlmutter & Shepherd, 2002). Most children with this disease lack an extrahepatic biliary tree, resulting in impaired bile flow, conjugated hyperbilirubinemia, acholic stools, and hepatomegaly. The hepatic parenchyma becomes congested, and progressive damage leads to secondary biliary cirrhosis. Although portoenterostomy, also known as the Kasai procedure (Kasai & Suzuki, 1959), may yield some clinical improvement and is the first-line treatment (Ohi, 2000; Ryckman et al, 1998), approximately 70% to 80% of children with biliary atresia eventually require liver transplantation (Karrer et al, 1996; Lowell et al, 1996).

Other causes of cholestasis in children include idiopathic neonatal hepatitis; infection by both viral and bacterial pathogens, including toxoplasmosis and syphilis; progressive familial intrahepatic cholestasis (Byler disease); metabolic and genetic diseases; familial arteriohepatic dysplasia (Alagille syndrome); choledochal cyst; and ischemia-reperfusion injury. Cholestasis may progress to cirrhosis and has also been associated with parenteral nutrition in children with short bowel syndrome (Baker et al, 1998).

Pediatric liver transplantation is also indicated in cases of noncholestatic liver failure secondary to infectious, metabolic, genetic, and neoplastic etiologies. Although less frequent in children than in adults, postnecrotic liver cirrhosis is the indication for transplantation in approximately 10% of pediatric patients and is most commonly the result of viral hepatitis or idiopathic cryptogenic cirrhosis (Malatack et al, 1983).

Metabolic liver diseases are genetic disorders that lead to the production of aberrant transport proteins or enzymes and altered metabolic pathways. These inborn errors of metabolism, such as α₁-antitrypsin (AAT) deficiency or Wilson disease, may cause direct injury to the liver and result in liver failure, with or without injury to other organs; it may also lead to abnormal liver metabolism, including urea cycle disorders or oxalosis, that can lead to injury of other organs. Altogether, such diseases account for approximately 10% of all pediatric liver transplantations (Hansen & Horslen, 2008).

AAT deficiency is a genetic disorder that leads to defective production of the serine protease α₁-antitrypsin (see Chapter 70A), an enzyme produced in the liver to protect the lungs from neutrophil elastase. The abnormal protein accumulates in the liver, apparently causing liver damage, although the mechanism of injury remains unclear. Synthetic AAT has some utility in the treatment of AAT deficiency–related lung disease, but it has no role in the treatment of the associated liver disease (Köhnlein & Welte, 2008; Silverman & Sandhaus, 2009).

Wilson disease is an inborn error of metabolism characterized by defective copper excretion and the accumulation of toxic amounts of copper in the liver, basal ganglia, kidney, and cornea, which may lead to the characteristic Kayser-Fleischer rings (see Chapter 70A). The defect is located on chromosome 13, is inherited in an autosomal recessive fashion, and affects 1 in 50,000 births. Initial symptoms are nonspecific and include lethargy, anorexia, vague abdominal pain, and weight loss. Some patients present with asymptomatic hepatomegaly, and others present with fulminant hepatic failure (FHF) (Riordan & Williams, 2001).

Other metabolic liver diseases—such as urea cycle disorders, Crigler-Najjar (CN) syndrome, or familial hypercholesterolemia—do not result in primary hepatic disease but cause extrahepatic disease as a result of dysfunctional hepatic gene products or metabolites that affect extrahepatic tissue. Urea cycle defects result in the accumulation of nitrogenous waste and severe, potentially lethal hyperammonemia. Two diseases within this group of disorders are described by their respective enzyme deficiencies: carbamyl phosphate synthetase (CPS) deficiency and ornithine transcarbamylase (OTC) deficiency. Three others are described by the primary metabolite that accumulates in affected individuals: citrullinemia, argininosuccinic aciduria (AS), and argininemia (AL).

CN syndrome is caused by mutations of the gene that codes uridine diphosphate glucuronosyltransferase-1, resulting in unconjugated hyperbilirubinemia. Untreated neonates develop a condition of severe neuronal damage called kernicterus. Homozygous familial hypercholesterolemia (HFH) is a rare disease caused by mutations in the gene that codes the low-density lipoprotein (LDL) receptor. The receptor may be defective or completely absent, and affected individuals have dramatically elevated plasma cholesterol levels, leading to accelerated atherosclerosis, childhood coronary artery disease, and premature death from myocardial infarction (Hansen & Horslen, 2008). Liver transplantation corrects these conditions by providing the required cellular machinery to synthesize the correct gene product or metabolite (Florman & Shneider, 2001; Meyburg & Hoffmann, 2005). Occasionally, auxiliary hepatic transplantation has been performed in these circumstances (Bismuth et al, 1996; Sze et al, 2009; Van Hoek et al, 1999). In AAT deficiency, the potential for development of hepatocellular carcinoma (HCC) precludes auxiliary liver transplantation and mandates total hepatectomy.

Cystic fibrosis (CF) is an autosomal recessive multiorgan disorder that is the most common lethal inherited disease affecting the white population. As management of these patients continues to improve, CF liver disease (CFLD) is increasingly recognized as a significant cause of morbidity and mortality. Approximately 5% to 10% of CF patients will progress to cirrhosis, with the most frequently recognized complications attributable to portal hypertension with an associated nutritional and pulmonary decline. A significant number of patients with CFLD may be helped with an isolated liver transplantation or a concomitant liver and lung transplantation; however, the debate is ongoing in the literature regarding the timing of liver transplantation in these patients (Colombo et al, 2006; Fridell et al, 2003; Nash et al, 2008).

Although more common in adult patients, chronic Budd-Chiari syndrome with severe hepatic congestion and focal areas of liver fibrosis or cirrhosis may be an indication for liver transplantation in older children (see Chapter 77). Pretransplantation evaluation should be performed to recognize predisposing factors or underlying diseases such as myeloproliferative disorders, primary hepatic protein deficiencies—of proteins C and S, antithrombin III, and activated protein C resistance—or secondary protein deficiencies, such as increased intestinal protein loss in inflammatory bowel disease (Slakey et al, 2001).

FHF (see Chapters 73 and 97C) is associated with a mortality rate greater than 70%. It is essential to transfer children with FHF to a transplant center immediately for management and urgent evaluation and listing for liver transplantation. Because cerebral edema develops rapidly, careful monitoring and intensive supportive care are required. Mild elevation of intracranial pressure (ICP) may be managed acutely by hyperventilation and elevation of the patient’s head, although maintenance likely requires strict sodium and osmolar and intravascular volume control. Placement of an ICP monitor should be considered, but regardless, attention to maintenance of cerebral perfusion pressure (CPP) is paramount. Transplantation in patients with signs of cerebral edema is urgent, as edema may lead to irreversible brain damage or death (Tanaka et al, 1994). Poor prognostic factors for liver transplantation in children with FHF include age younger than 10 years, liver disease other than viral hepatitis, grade 2 or 3 hepatic encephalopathy, coagulopathy (prothrombin time >30 seconds), and increasing jaundice (bilirubin >9 mg/dL) (Uemoto et al, 2000).

Liver tumors account for less than 3% of all indications for pediatric liver transplantation (Austin et al, 2006). Hepatoblastoma, HCC, and fibrolamellar HCC represent the most frequent tumors (see Chapter 82). In contrast to adults, the predisposing factors for malignant liver tumors in children are not viral hepatitis or alcoholism but are more often metabolic disorders, such as AAT deficiency, tyrosinemia, or glycogen storage disease. In patients without cirrhosis, hepatic resection is the treatment of choice. Liver transplantation should be considered in the case of unresectable tumors confined to the liver (Chen et al, 2006; Otte et al, 2004). In patients with advanced cirrhosis and HCC meeting Milan criteria, transplantation is indicated (Austin et al, 2006; Beaunoyer et al, 2007; Perilongo et al, 2004). Rarely, giant arteriovenous malformations and benign liver tumors—when they replace the whole liver, or when they have the potential for malignancy (e.g., hepatic adenomatosis or multiple adenomas in glycogen storage disease [Fig. 98C.1])—may be indications for total hepatectomy and liver transplant (Malatack et al, 1987; Wellen et al, 2009; see Chapter 79A).

FIGURE 98C.1 Multiple giant adenomas in an explanted liver.

Evaluation of the Potential Recipient

A multidisciplinary evaluation of a child with decompensated liver disease should be completed with the involvement of surgeons, hepatologists, nurses, anesthesiologists, psychologists, and social workers. Early referral to a transplant center allows maximum time to develop a management strategy and to optimize pretransplantation clinical status. The timing of liver transplantation is crucial, because late referral of patients with significant hepatic complications and malnutrition results in a poorer outcome. The expected waiting time on the transplant list may vary based on the geographic region, and this should be taken into account. In infants younger than 2 years who weigh less than 10 kg, it is often difficult to maintain metabolic and nutritional support. Ideally, children should be considered for liver transplantation before the complications of malnutrition, such as weight loss and growth failure, occur (Kimura et al, 2004; McDiarmid et al, 2004). With chronic liver disease, prolonged clotting times, intractable ascites, recurrent variceal bleeding secondary to portal hypertension, and recurrent cholangitis with severe cholestasis are indications for liver transplantation (Hendrickson et al, 2004).

The prognosis after liver transplantation for chronic liver disease is influenced by preoperative comorbidities. The advent of the Pediatric End-Stage Liver Disease (PELD) and Model for End-Stage Liver Disease (MELD) scores (Malinchoc et al, 2000; Wiesner et al, 2001) has made it possible to better predict mortality and progression of liver disease while awaiting transplantation (Desai et al, 2004; Barshes, et al, 2006). The pertinent factors in the PELD score are the international normalized ratio (INR), total bilirubin, serum albumin, age younger than 1 year, and weight or length less than 2 standard deviations (SDs) from the mean for age and gender. The PELD score is used for patients younger than 12 years, and the scores range from a negative value (−10) to 50. Adolescents aged 13 to 18 years are allocated organs based on the MELD score, similar to adults. Box 98C.2 presents the formulas for calculating the MELD and PELD scores.

Comparing the periods before and after the introduction of the MELD and PELD scores, a similar percentage of children are being transplanted, but mortality rates have decreased (Freeman et al, 2004; Yao et al, 2004). Small size and young age are no longer contraindications, and many transplantations for biliary atresia are now done in infants who weigh less than 10 kg (Colombani et al, 1996; Sokal et al, 1990). Whereas posttransplantation mortality has improved, waiting-list mortality for infants younger than 1 year remains high, unfortunately (OPTN/SRTR, 2008). Consideration should be given to referring these young and small infants to pediatric specialty centers that have expertise with these challenging cases. Contraindications to pediatric hepatic transplantation are listed in Box 98C.3.

Recipient Hepatectomy

The recipient hepatectomy is typically difficult, because more than half of the pediatric patients have had a prior laparotomy. Severe portal hypertension with abdominal wall and perihepatic venous collaterals is common, and these technical challenges may be exacerbated by severe coagulopathy and thrombocytopenia. Thrombosis of the portal vein can be an additional complicating factor, and preservation of the retrohepatic inferior vena cava contributes to hemodynamic stability during the hepatectomy.

Before beginning the transplantation, a Broviac central venous catheter is placed for intraoperative and postoperative fluid resuscitation, monitoring, and postoperative laboratory draws, the same as an arterial catheter. Pressure points are well padded, and convective heating blankets are used. The abdomen is entered through a curved transverse subcostal incision. Meticulous hemostasis must be maintained throughout the procedure, because ongoing bleeding may lead to dilutional coagulopathy and fibrinolysis. Abdominal wall venous collaterals must be carefully controlled as they are encountered, and adhesions to the liver are carefully dissected to allow access to the portal region (Fig. 98C.2).

FIGURE 98C.2 Recipient hepatectomy. The hilum is examined carefully, and a previous portoenterostomy (PE) is taken down. The portal vein (PV) and hepatic artery (HA) are divided high in the porta hepatis.

If the child has had a previous Kasai procedure, the jejunal loop is taken down, the enterostomy is closed, and the Roux-en-Y loop is preserved for later biliary drainage of the graft, if it is of suitable quality. The porta hepatis is dissected carefully with isolation of the hepatic artery and portal vein. Although transection of the hepatic artery is performed early in hepatectomy, the portal vein is divided after total mobilization of the liver, just before removal of the native liver, to avoid unnecessary congestion in the mesentericoportal system. Alternatively, a temporary portocaval anastomosis may be performed by ligating and dividing the portal vein at the level of the bifurcation and creating an end-to-side anatomosis to the infrahepatic vena cava. This avoids mesenteric venous congestion and also helps maintain venous return and hemodynamic stability.

The hepatic artery and portal vein are dissected high in the hilum to preserve adequate length for later anastomosis with the graft. The portal vein may be quite small; in this setting, dissection to the level of the confluence of superior mesenteric vein and splenic vein posterior to the pancreas may allow for anastomosis to a larger inflow vessel. The liver is mobilized further by dividing the ligamentous attachments and the short hepatic veins that drain the right liver and caudate directly into the vena cava.

For orthotopic whole-liver transplantation, the small retrohepatic caval segment can be removed with the native liver, or the vena cava can be preserved and the donor liver anastomosed in a piggyback fashion to the confluence of the recipient’s right, middle, and left hepatic veins. With a segmental graft, the recipient inferior vena cava must be preserved. A vascular clamp is placed across the hepatic veins so that they can be joined to form a common opening to sew to the donor suprahepatic cava or, in case of segmental grafts, the left hepatic vein (Fig. 98C.3). Complete hemostasis of the retroperitoneum should be accomplished before removing the donor liver from cold storage.

FIGURE 98C.3 Recipient hepatectomy. A, The liver has been removed, and the inferior vena cava (IVC) is preserved in preparation to receive a segmental graft. B, Note the portocaval shunt (arrow) and vascular clamp occluding only the hepatic veins (arrowhead), allowing venous return from both the systemic and mesentericoportal systems. Sutures mark the ligated hepatic artery and bile duct. HV, hepatic vein.

Graft Procurement and Engraftment

The techniques used for recovering whole, deceased-donor livers for transplantation from children are similar to the techniques used in adult-adult transplantation. Special attention should be paid to donor serum sodium levels and to dynamic liver function tests. High sodium levels (>170 mmol/L) may be associated with severe reperfusion injury and poor graft function (Totsuka et al, 1999).

The donor liver is anastomosed using the full vena cava—or the left hepatic vein, with or without the middle hepatic vein, in the case of a reduced-size left graft—to the confluence of the recipient hepatic veins. Before securing the final caval sutures, the donor liver is flushed through the donor portal vein with cold Ringer’s lactate to flush out the preservation solution, usually Viaspan (University of Wisconsin solution) or Custodiol (histidine-tryptophan-ketoglutarate [HTK]), which may be high in potassium. The portacaval shunt is taken down and oversewn, and the portal venous anastomosis is completed, leaving a large growth factor in the continuous suture to prevent a waist, or narrowing of the anastomosis, when the vessels are refilled with portal blood.

The arterial anastomosis is performed with sutures of fine (7-0 or 8-0) monofilament material using microsurgical loupes. A microscope may be useful in anastomosing arteries with a diameter smaller than 1 to 2 mm. The anastomosis is performed most commonly in an end-to-end fashion directly to the native hepatic artery. If the native artery is not of adequate size, or if there is an intimal dissection, an extension allograft using saphenous vein or donor iliac artery from the infrarenal or supraceliac aorta may be used (Yamaoka, 1996).

The bile duct anastomosis is the final step in the procedure. If present, the donor gallbladder is removed. If the recipient has an intact bile duct that is of suitable size, an end-to-end choledochocholedochostomy can be performed with or without placement of a T-tube or an internal stent; however, most children who undergo transplantation have either biliary atresia or common bile ducts that are very small or sclerotic, so a choledochojejunostomy is necessary. Use of a segmental allograft requires hepaticojejunostomy, if the common bile duct has been resected. In case of a previous Kasai procedure, the jejunal loop of the portoenterostomy can be used again, although it must be shortened, and a fresh segment must be anastomosed.

Reduced-Size Segmental Liver Transplantation and Split-Liver Transplantation

Reduced-Size Segmental Liver Transplantation

The use of reduced-size grafts for pediatric recipients is one of the most important advances in liver transplantation. The disproportionate shortage of grafts for very young children, compared with older children, motivated surgeons to develop innovative operative techniques to overcome the restrictions imposed by donor and recipient size mismatch. With these techniques, livers can be reduced to a functional unit of appropriate size for the recipient. The optimal ratio between the required volume of liver and the actual “tailored” hepatic mass is between 1 : 1 and 1 : 2. In this way, livers from donors 10 or 20 times the size of the recipient can be used (Broelsch et al, 1988).

The liver comprises eight anatomically defined segments, each with its own arterial and portal blood inflow and separate biliary drainage (Strasberg, 1997; see Chapter 1B). Similarly, segmental hepatic venous outflow is independent, but major liver veins run along sectional borderlines, receiving blood from several adjacent segments (Couinaud, 1954). For purposes of transplantation, the liver can be divided into several functional grafts. The most commonly used reduced-size graft is the left lateral section graft, composed of segments II and III (Fig. 98C.4; Botero & Strasberg, 1998). To preserve a single donor portal vein, the liver is transected just to the right of the falciform ligament, and branches of the ascending (umbilical) portion of the left portal vein to segment IV are carefully suture ligated. The left hepatic vein is used for hepatic venous drainage. It is anastomosed directly to the recipient’s vena cava, which must be preserved during hepatectomy. The full left graft (segments I, II, III, and IV or segments II, III, and IV) is used in small adults or older children who require a graft slightly larger than the left lateral section.

FIGURE 98C.4 The most commonly used segmental graft uses segments II and III of the left liver. The recipient’s inferior vena cava (IVC) is preserved, and the left hepatic vein (LHV) is sutured to a large triangular venotomy cut on the anterior aspect of the IVC. The portal vein (PV), hepatic artery (HA), and bile ducts (BD) are depicted before anastomosis.

Bismuth and Houssin (1984) first reported success with transplantation of a left hepatic allograft; in the same year, Broelsch and colleagues (1984) reported the successful grafting of the left lateral section. Since then, most pediatric transplant centers have adopted segmental transplant techniques using reduced-size livers. The results after these segmental grafts are comparable to the results achieved with whole-organ orthotopic liver transplants (Hong et al, 2008

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