Optimal preparation for pediatric liver transplantation (PLT) is accepted to be one of the cornerstones of favorable outcomes. Preparation depends on many factors spanning timely referral to emergent management at the time of an organ offer. Most of these factors will be covered in this chapter and are summarized in Fig. 6.1 .
Timely referral depends on the diagnosis, with earlier referral generally preferred by most transplant centers, affording the transplant center the opportunity to manage the patient optimally to ensure satisfactory outcomes in their hands. Generally, patients with biliary atresia and chronic liver disease (CLD) including cystic fibrosis are referred early in the course of the disease, as referring physicians anticipate the need for transplant in the face of persistent cholestasis, progressive portal hypertension, nutritional impairment, or recurrent cholangitis. Emergent referral is the norm for acute liver failure (ALF). In a case of hepatoblastoma or hepatocellular carcinoma (HCC) with or without inborn errors of metabolism (IEMs), the child generally is referred promptly to the transplant center for two reasons: first, to assess if the tumor is resectable by expert liver surgeons; and second, to have transplant as a backup if necessary.
A qualified multidisciplinary team is essential for a successful program. It is recommended that it be composed of hepatologists, surgeons, radiologists, pathologists, and subspecialty pediatrician consultants. Other essential caregivers include transplant coordinators, specialized nurses, psychologists, dietitians, and social workers. Transplant coordinators are central to coordinating patient transfer and emergent care on the day of transplant. This includes oversight of specific patient needs, including dietary requirements of patients with IEMs and obtaining samples for studies.
A pre-transplant evaluation is usually performed when the transplant center deems it is necessary or when a referring medical team requests an evaluation. The pre-transplant evaluation may be organized as a short inpatient stay or as a series of outpatient visits during which patients undergo a standardized head-to-toe, multidisciplinary evaluation. Table 6.1 summarizes the workup of a patient for liver transplant, including laboratory tests and specialist consults. The recommended follow-up by system while on the list will be discussed later in this chapter. The goals of the medical pretransplant assessment are threefold: first, to evaluate the indication for transplant; second, to anticipate and mitigate recipient risk to ensure optimal outcomes; and third, to tailor care to the needs of each patient before liver transplantation (LT). Indeed, patient condition at listing varies according to diagnosis, age, and time of referral. Novel frailty tools may be of use to evaluate the general condition of the child and therefore anticipate management. The pre-transplant evaluation is the time to elaborate a standardized and personalized road map for the day of transplantation and ensuing weeks. An example is presented in Fig. 6.2 .
The evaluation is usually complete upon review by the institutional multidisciplinary review board, which confirms the indication and feasibility and places the patient on the waiting list.
The importance of a close and meticulous follow-up before transplant cannot be overemphasized. Fig. 6.3 summarizes the major risks while on the transplant list. Teamwork with the family is essential, and they should be counseled with tips and tricks for the time on the waiting list ( Fig. 6.4 ).
Anesthesiology management, surgical strategy, and imaging will be essential for optimal preparation of LT. These topics are covered elsewhere in this book.
The first step in any liver evaluation is to confirm the initial diagnosis, the rationale being twofold: there are rare liver diseases that may benefit from other treatment modalities, thereby repealing the need for transplant; and (2) multisystem disease may not be resolved with transplantation or may require special management following LT. Therefore it is imperative to ask referring teams for any relevant information, especially biopsy specimens and, increasingly, genetic results. When in doubt, the transplant center may repeat liver biopsy, genetics, and metabolic workup if relevant.
From a hepatology standpoint, the next step in a transplant evaluation is to estimate the severity of liver involvement. This is typically achieved using biology, ultrasonography, and, increasingly, noninvasive methods of quantifying liver fibrosis. The severity of liver disease is assessed by the presence and number of liver-related complications at the time of listing and throughout the time on the waiting list. Rarely, some centers use indocyanine green to assess liver function, but its clinical utility is a matter of debate.
Typically, the complications of portal hypertension are those warranting the most medical attention. Ascites is due to abnormal sodium and water retention and is treated by spironolactone, low-sodium diet, fluid restriction, intravenous (IV) albumin and furosemide, and, exceptionally, by paracentesis in case of respiratory compromise. Sodium management warrants a special mention here. Avoiding sodium supplementation is advisable, as low plasma sodium is usually due to water dilution combined with total body sodium overload. Nonetheless, plasma sodium < 130mmol/l should be avoided, as hyponatremia is associated with increased mortality before transplantation. Monitoring of urinary sodium is useful to confirm natriuresis; in severe sodium depletion, urinary Na+ can drop even in patients on diuretics.
The management of varices is debated in children. Variceal ligation is clearly indicated in the case of bleeding. Primary prophylaxis is practiced in some centers. Variability in practice and approach depends on physician know-how and on access to care for patients living in remote areas. Another factor that might weigh in on the decision to perform variceal band ligation is the expected wait time on the list. In addition, systematic screening is generally not recommended by an expert panel, and there is no consensus for the use of nonselective beta-blockers as prevention of variceal bleeding in children. Some centers may choose to perform surgical portocaval shunts to palliate portal hypertension either as an alternative or as a bridge to transplant.
Three indications warrant special attention at the time of evaluation, during follow-up, and at the time of transplant: liver malignancies, liver-based IEMs, and ALF. In the case of unresectable liver cancer warranting LT, the patient has generally been extensively worked up per SIOPEL (Société Internationale d’Oncologie Pédiatrique – Epithelial Liver Tumor Study Group) protocol before LT. The transplant center then just completes the workup they require.
For liver-based IEMs, the indication to perform pre-transplant evaluation is failure of conventional therapy or onset of extrahepatic complications that can be corrected or stabilized even partially by LT. One of the most important aims of the pre-transplant evaluation is to prepare the protocol for the day of transplant when the patient is made nothing by mouth. This is usually a joint effort with the metabolic team. This is also the time to discuss if any samples should be collected during transplant (blood, urine, liver) and to check for ethical authorization should this be indicated.
In the case of ALF, pre-transplant assessment may be limited, mostly owing to time constraints. Suggestions for a modified pre-transplant evaluation in the case of ALF are outlined in Table 6.1 . This is relevant for pre-transplant assessment because the administration of blood products may skew laboratory interpretation. It is good practice to try to perform as much of the workup before initiating any therapy involving blood products. This is particularly relevant in the case of neonatal ALF where double-exchange transfusion is often first-line therapy. Management of ALF is presented elsewhere.
Nutritional management is critical and challenging during the pre-transplant period in patients with CLD and, of course, in those with IEMs. In Fig. 6.5 , we present the different aspects of nutritional management according to age for a child with CLD on the waiting list. Specific needs are summarized in Table 6.2 . Weight alone is insufficient for evaluation of nutritional status owing to visceromegaly, ascites, and sarcopenia. Nutritional support should be implemented quickly, even if there are no signs of malnutrition, because cholestasis and progressive liver disease almost invariably are associated with malnutrition and the side effects thereof (sarcopenia, osteopenia). Volume restriction is often necessary for the management of ascites. To this end, the caloric density of formula may need to be enriched to a maximum of 1.1kcal/mL, beyond which infants may develop osmotic diarrhea. What more, small infants with cholestasis often require nutritional support via a nasogastric tube. Bolus feeding or continuous feeds are a matter of patient tolerance, parent preference, and center experience. Gastrostomy placement is usually not indicated, owing to portal hypertension and the prospect of improvement of per oral feeding after LT. Special formulas for cholestatic liver disease are available, although cost and regional availability may limit their use. Dieticians are essential to inform families on the use of nutritional supplements and to recommend ways of optimizing caloric intake.
|Sodium||Maximum 3–4 mmol/kg/day without portal hypertension/ascites |
Maximum 1–2 mmol/kg/day if ascites/portal hypertension
|Monitoring via urine and plasma sodium|
|Protein||3–4 g/kg/d |
10% branched amino acid (BAA); more if sign of liver failure
|Protein restriction not advised even in case of hyperammonemia |
BAA: improve nutritional status and body composition
|Carbohydrates||24–28 g/kg/d |
20%–60% energy intake
Continuous nutrition or frequent smaller portions
|Risk of hypoglycemia because of impaired gluconeogenesis and glycogen storage|
|Lipid / FAT||6–7 g/kg/d |
30%–70% energy intake
Minimum 50% medium-chain triglyceride (MCT) (should not exceed 80%)
10% polyunsaturated fatty acid (PUFA)
|Malabsorption of long-chain triglycerides because of intraluminal bile salt depletion |
Preferred fat supplementation because of bile salt independent absorption
Avoid essential fatty acid deficit crucial for neurodevelopment
|Mineral||Calcium: 25–100 mg/kg/d |
Selenium: 1–2 ug/kg/d
Zinc: 1 mg/kg/d
Phosphate: 25–50 mg/kg/d
|Deficits related to malabsorption and vitamin D deficiency |
Deficit: From gastrointestinal occult blood loss, malabsorption, or secondary to multiple blood draws. Consider IV supplementation if enteral not tolerated
Deficit: From gastrointestinal bicarbonate loss, supplementation to prevent growth failure.
|VitaminsFat-soluble vitamins |
Cholecalciferol: 800–4000 U daily (oral)
Cholecalciferol: 30,000 IU 1–3 monthly (intramuscular)
Calcitriol: 2–5 ug/kg/d (oral)
< 10 kg 5000 IU or > 10 kg 10,000 IU daily oral (water-miscible preparation)
50 000 IU single dose 1–2 monthly (intramuscular)
2 mg/kg (max 10 mg) daily, twice weekly or weekly (oral)
2 mg/kg (max 10mg) every week or twice a week (intramuscular, intravenous)
25 U/kg/day oral (water soluble)
10 mg/kg (max, 200 mg) every other week (intramuscular)
100% of recommended daily intake
|Oral supplementation even without symptoms |
Parenteral (IM or IV) if conjugated bilirubin levels > 60 mM/l
Deficit: hepatic osteodystrophy
Deficit: decreased nocturnal visual acuity
Deficit: decreased vitamin K-dependent coagulation factors
Deficit: peripheral neuropathy
The prevalence of obesity may be as high as 18.5% in the pediatric population and may rise to 15% to 21% among LT candidates, 20% of whom may display some features of metabolic syndrome. Although transplantation for end-stage nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in the pediatric age group is extremely rare, weight stabilization is recommended before LT. Evidence regarding efficacy to prevent post-LT complications is still lacking.
The aim of the pre-transplant evaluation is twofold: prevention and anticipation of infectious complications before and after LT with viral, bacterial, or fungal pathogens.
Routine viral studies help inform post-transplant management decisions such as the use of post-transplant prophylaxis, something in practice in many centers. Many centers check viral serology/polymerase chain reaction (PCR) both at the time of evaluation and at transplant (see Table 6.1 ). For example, cytomegalovirus (CMV)-negative and Epstein-Barr virus (EBV)-negative recipients are at risk of primary infection if the donor is positive. The reason these viruses need close monitoring is because they come with their own set of risks: CMV can lead to CMV disease or trigger rejection, and EBV is problematic because de novo post-transplant infection may progress to post-transplant lymphoproliferative disorder or to rejection secondary to lower immunosuppression required to mitigate viral replication.
Hepatitis B and hepatitis C carrier states or infection before LT are rare in children. Therefore treatment before or after LT is anecdotal and inspired by adult experience. Although hepatitis E virus infection can remain silent, in the immunocompetent host with CLD it may also lead to ALF, something noteworthy if the child presents with an acute-on-chronic picture. Chronic HEV infection after LT can lead to extrahepatic complications including neurological dysfunction, further validating the importance of HEV monitoring pre-LT.
Given that patients with CLD are at increased risk for severe bacterial infections, many have received antibiotics repetitively prior to transplant. They may harbor resistant strains of bacteria. Therefore a careful infectious history is important for all patients, especially if it is not well-known to the transplant center. Colonization with resistant strains should be sought in all patients. In cystic fibrosis patients, the risk of resistant organisms is all the more likely and will inform post-transplant management. Antibiotic prophylaxis during the immediate post-transplant period is routine but not standardized. Typically, it is adapted to the patient’s infetious disease history and microbiology. Typically, broad spectrum coverage is the preferred approach, considering both Gram negative organissm and enterocci. A stepwise approach is outlined in Figure 6.2 .
Susceptibility to infections before LT is increased for several reasons: (1) less opsonization capacity by the liver, (2) impaired reticuloendothelial system function owing to abnormal liver architecture, and (3) possible immunoglobulin loss in ascites or through portal hypertensive enteropathy. Any acute infection in a patient on the waiting list should be treated aggressively and temporary inactivation on the list considered depending on acuity.
Patients with biliary atresia and a Roux-en-Y loop incur a risk of cholangitis. Prompt treatment with broad-spectrum antibiotics is indicated in the face of rising aminotransferases or markers of cholestasis significantly elevated above baseline, especially if fever is present. The use of prophylactic antibiotics is still a matter of debate. In practice, and although evidence is lacking, patients with infected bile lakes may benefit from long term per oral antibiotics to avoid acute decompensation while on the list.
There are several strategies for optimizing protection against vaccine-preventable diseases (VPDs) during the pre-transplant period. Table 6.3 outlines immunization recommendations in the pre-transplant patient.
|HAV a||R||> 2 m||0, 1||2–3||X||2 doses > 24 m |
3 doses < 24 m
|HBV a||R||> 2 m||0, 1, 2||3||X|
|Pneumococcus P13 conjugated||R||> 2 m||0, 1, 2||3||X|
|Pneumococcus P23 polysaccharidic||R||> 24 m||0||1||X||Booster/5 y|
|Polio, tetanus, diphtheria, pertussis, HiB||R||> 2 m||0, 1, 2||3||X||Avoid use of life polio (oral) |
Pertussis-tetanus booster/10 y
|b Measles, mumps, rubella||L||> 6 m||0, 1||2||X||Give 2 doses at least 1 month apart before LT |
4 weeks on hold prior to LT
|b Varicella||L||> 6 m||0, 1||2||X||4 weeks on hold prior to LT|
|HPV||R||9–26 y||0, 6, 12||2–3||2 doses < 15 y |
3 doses > 15y
|b Rotavirus||R, oral||> 2 m||0, 1, 2||2–3||Schedule according to manufacturer|
|b Quadrivalent meningococcus A, C, W, Y||R||> 2 m||0||1||Planning travel to endemic area|
|b Meningococcus B||R||> 2 m||0, 1, 2, 12||2–4||Schedule variable according to age|
|b Yellow fever vaccine||L||> 6 m||Planning travel to endemic area|
|Influenza||R||> 6 m||Annual||< 1 y: 2 half doses 1 m apart|