Indications and Contraindications for Pediatric Liver Transplant

Introduction

Liver transplantation has become the standard of care for children with an array of disease processes. Collectively, progressive hepatic disease with complications of end-stage liver disease (ESLD), metabolic disease with and without hepatic structural involvement, pediatric acute liver failure (PALF), and unresectable hepatic malignancies constitute the majority of current indications for liver transplant in children. Improvement in both patient and graft survival, in addition to advancements in operative techniques aimed at extending the donor pool, has enabled an expansion in disease etiologies and patient populations for which liver transplant can act as a lifesaving intervention and/or provide a more optimal treatment strategy. The aim of this chapter is to review the evolution of liver transplantation and current relative contraindications and focus on novel and controversial indications. Although not an exhaustive list, highlighted later are several of the current etiopathologies pushing the boundaries of liver transplant and continuing the evolutionary process.

Evolution

Liver transplantation has historically been pioneered in the pediatric setting. The first liver transplant was performed by Thomas Starzl on a child with biliary atresia in 1963. Although this initial experience resulted in the patient’s death intraoperatively, advancements that were made over the ensuing years enabled Dr. Starzl to perform the first successful liver transplant in 1967 on a 19-month-old infant with hepatocellular carcinoma (HCC). Since this initial experience, liver transplant has evolved dramatically from a mostly futile endeavor with dismal outcomes into a lifesaving treatment with excellent and improving patient and graft survival ( Fig. 5.1 ).

The indications for pediatric liver transplant have been refined regarding disease type and timing. Our center’s experience ( Fig. 5.2 ), like others, including the US Organ Procurement and Transplantation Network, reveals that cholestatic diseases (biliary atresia, Alagille syndrome [AGS], etc.) and those resultant from dysfunction in metabolic processes constitute about two-thirds of all liver transplants performed in children. Areas of recent expansion, where the value and curative capacity was once less well established, include children with fulminant liver failure and those with hepatic malignancies ( Fig. 5.2 ).

A further example that underscores the evolving role of liver transplant can be seen in patients with cystic fibrosis–associated liver disease (CFLD). The historically poor prognosis for patients with cystic fibrosis often meant that nonrespiratory morbidities, such as CFLD, were rarely encountered and, even in their presence, were often found only in older patients with a substantial cardiorespiratory disease burden such that they were considered poor candidates for liver transplant. Over the last two decades, in parallel with the significant expansion of therapies for CF patients and increased life expectancy, CFLD has emerged as a leading cause of morbidity and mortality in this population. Consequently, there has been an expansion of the role of liver transplant with definitive demonstration of the benefit that liver transplant can provide to CF patients. Although the timing of liver transplant in CFLD may be variable, driven by the degree of hepatic synthetic dysfunction and severity of complications from portal hypertension, there remains little controversy regarding the role of liver transplant in the management of CFLD.

Controversial Indications

The distinct diseases, clinical susceptibilities, physiological responses, and neurodevelopmental aspects of liver transplant in the pediatric population have resulted in published guidelines regarding the evaluation of children for liver transplantation. And yet, the decision to list a patient for liver transplantation ultimately resides with individual transplant centers. Thus there remain instances where the clarity around the decision process may be less, and the choice to proceed with liver transplant may be controversial.

Pruritus: Pruritus is a disabling, possibly devastating and destructive manifestation of chronic cholestasis. In several diseases such as AGS and progressive familial intrahepatic cholestasis, it may be the dominant feature driving morbidity. The pathogenesis is poorly understood, and the response to therapies is often heterogeneous ( Table 5.1 ).

Table 5.1

Medical management of pruritus in children

Medicine	Dose	Mechanism of action
Ursodeoxycholic acid (UDCA)	600 mg/m ²/d	• Tertiary BA • Increases bile secretion • Reduces ileal absorption of hydrophilic BAs
Rifampicin	Initial dose: 5 mg/kg (max dose: 20 mg/kg/d)	• PXR agonist • Induces CYP3A4 • Increases metabolism and renal excretion of pruritogenic substances • Antibacterial effect may modify intestinal metabolism of pruritogenic substances
Cholestyramine	Initial dose: 2 g BID (max dose: 24 g/d)	• Ion exchange resin that acts as BA binder in the intestine • ↓ ileal BA absorption, ↑ BA excretion (in feces)
Naltrexone	Initial dose: 0.25–5mg/kg/d (max dose: 50 mg/d)	• Opioid antagonist • Block the permissive activity on pruritus neuronal signaling
Sertraline	Initial dose: 1 mg/kg/d (max dose: 4 mg/kg/d)	• Serotonin reuptake inhibitor • Proposed mechanism includes increase in central serotonergic tone, which regulates pruritus

BA, Bile acid; PXR, pregnane X receptor.

Albumin-based extracorporeal dialysis and plasmapheresis are alternative invasive measures that have reported benefit in adults; however, their efficacy in children remains unclear. Surgical interruption of the enterohepatic circulation (i.e., biliary diversion) as a more permanent antipruritic measure has shown inconsistent benefit, with variability in the clinical course noted in progressive cholestatic diseases following diversion. The decision to proceed with liver transplant for children with refractory pruritus can be complicated by relatively preserved synthetic function and little evidence of complications of ESLD.

Hemophagocytic lymphohistiocytosis: Hemophagocytic lymphohistiocytosis (HLH) is a multisystemic clinicopathologic syndrome characterized by ongoing abnormal and overwhelming stimulation of the immune system. Primary or “familial” HLH is associated with known underlying genetic defects, whereas secondary or “acquired” HLH results from an abnormal immune response to triggers such as a viral infection, malignancy, and/or disease process. Although uncommon, PALF can be the initial presentation of HLH or can complicate the clinical course. Historically, HLH was considered a contraindication to liver transplant given its relapse risk, poor outcomes, and potential for alternative treatment options with chemotherapy and bone marrow transplant (BMT). The clinical experience of liver transplant as a treatment for PALF associated with HLH is presented ( Table 5.2 ). In the single-case reports, cumulative 6-month survival rates were poor, at approximately 33%. However, in the largest series by Amir et al., a 67% patient survival was reported. The authors suggest that liver transplant, combined with HLH-directed therapy (chemotherapy and/or BMT), may have a role in the therapeutic approach to children with HLH and a clinical phenotype dominated by PALF.

Table 5.2

Liver transplantation and hemophagocytic lymphohistiocytosis

Author	No. of patients	HLH type	Clinical course and outcome
DiPaola et al	1	Secondary	• Met HLH criteria before transplant, genetics negative • Treated for HLH (dexamethasone and etoposide) post-transplant • Underwent allogenic SCT because of disease progression • Died 80 days post-SCT from disseminated adenovirus infection
Kaperlari et al	1	Primary	• Presented with PALF; received LLS liver transplant from mother • HLH diagnosis made after liver transplant • Treated for HLH (dexamethasone and etoposide) post-transplant • Haploidentical SCT (mother donor) performed 74 days post–liver transplant • Patient alive at 5 years post-transplant (8/2004)
Parizhskaya et al	1	Not reported	• Presented with PALF • Died 44 days post–liver transplant from progressive HLH
Senger et al	1	Not reported	• Neonatal ALF • Liver transplant DOL 43 • Died POD 14 from Candida infection, HLH progression, and MOSF
Nakazawa et al	1	Secondary	• Presented with PALF • Liver transplant 33 days after initial presentation • Died from allograft failure resulting from veno-occlusive disease 93 days post–liver transplant
Amir et al	9	Secondary ( n = 9)	• All presented with PALF • 7/9 had HLH diagnosis established only after liver transplant • All received HLH-directed therapy in addition to liver transplant • 1/9 required BMT • 5/9 developed disease recurrence • 1/9 required repeat liver transplant • 3/9 died • Overall graft and patient survival: 60% and 67% (median follow-up, 24 months)

ALF, Acute liver failure; BMT, bone marrow transplant; DOL, day of life; HLH, hemophagocytic lymphohistiocytosis; LLS, left lateral segment; MOSF, multiorgan system failure; PALF, pediatric acute liver failure; POD, post-operative day; SCT, stem cell transplant.

Cognitively Impaired Patients: Hyperammonemia resulting in irreversible neurological impairment is a dreaded complication of many disease processes affecting children and results either from a reduction in hepatocyte function (i.e., PALF, ESLD) or, more commonly, from a primary defect of enzymes in inborn errors of metabolism (i.e., urea cycle disorders, organic acidurias) ( Table 5.3 ).

Table 5.3

Etiology of hyperammonemia

Increased ammonia production	Decreased ammonia elimination
• Infection • Urease-producing bacteria ( Proteus , Klebsiella ) • Herpes infection • Increased protein load/catabolism • Seizures • Trauma/burns • Steroids • Chemotherapy • Starvation • Gastric bypass • Gastrointestinal hemorrhage • TPN • Other • Malignancy	• Liver failure • Acute liver failure • End-stage liver disease • Portosystemic shunt • TIPPS • Congenital (Abernethy sy) • Secondary to portal hypertension • Medications • Glycine • Valproate • Others • Urea cycle disorders • CPSI deficiency • OTC deficiency • Citrullinemia • Arginino-succinic aciduria • Argininemia • NAGS deficiency • Organic acidurias • PA • MMA • Fatty acid oxidation defects • Mitochondrial disorders • Other

Increased ammonia production

Decreased ammonia elimination

•

Infection
- •
  
  Urease-producing bacteria ( Proteus , Klebsiella )
- •
  
  Herpes infection
•

Increased protein load/catabolism
- •
  
  Seizures
- •
  
  Trauma/burns
- •
  
  Steroids
- •
  
  Chemotherapy
- •
  
  Starvation
- •
  
  Gastric bypass
- •
  
  Gastrointestinal hemorrhage
- •
  
  TPN
•

Other
- •
  
  Malignancy

•

Liver failure
- •
  
  Acute liver failure
- •
  
  End-stage liver disease
•

Portosystemic shunt
- •
  
  TIPPS
- •
  
  Congenital (Abernethy sy)
- •
  
  Secondary to portal hypertension
•

Medications
- •
  
  Glycine
- •
  
  Valproate
- •
  
  Others
•

Urea cycle disorders
- •
  
  CPSI deficiency
- •
  
  OTC deficiency
- •
  
  Citrullinemia
- •
  
  Arginino-succinic aciduria
- •
  
  Argininemia
- •
  
  NAGS deficiency
•

Organic acidurias
- •
  
  PA
- •
  
  MMA
•

Fatty acid oxidation defects
•

Mitochondrial disorders
•

Other

CPSI, Carbamoylphosphate synthetase I; MMA, methylmalonic acidemia; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase; PA, propionic aciduria; TIPPS, transjugular intrahepatic portosystemic shunt.

The clinical manifestations of the resultant hepatic encephalopathy include reduced neural metabolic function and acute cerebral edema. A critical threshold of 200 umol/L has been identified, above which mortality is greatly increased in children. In many instances, liver transplantation can enable near complete correction of underlying defect, and earlier intervention, particularly in the metabolic population, can translate into improved neurodevelopmental prognosis. However, forecasting the neurological outcomes for these children can be difficult, as multiple factors, including frequency and duration of hyperammonemic events, peak levels of ammonia, and age at transplantation, are all known to correlate with outcomes. Ultimately, the degree of cognitive impairment (CI) continues to be an important factor in the difficult decisions both for the family and healthcare providers in assessing the child’s transplant candidacy.

Importantly, CI may result from any number of insults in patients who may require a liver transplant, and questions surrounding the allocation of scarce organs to individuals with significant CI are not unique to the liver transplant population. Additionally, the degree of CI is important because there is a spectrum ranging from mild forms to severe vegetative states. Proponents of transplantation for patients with CI argue that cognitive function should not be a basis for allocating organs because it enables healthcare providers to determine that some lives are more valuable than others. Opponents believe that CI is one of several legitimate criteria on which allocation decisions may be based. The reality of organ scarcity means a decision to transplant a patient with CI will often mean that another patient with no (or milder) impairment may die for lack of a transplant. Furthermore, difficulties in following post-operative recovery programs and adhering to immunosuppressive regimens could limit the benefits of transplantation for CI patients. However, in a large study of 254 children with definite or probable intellectual disabilities, both short-term graft and patient survival were comparable with children without intellectual disabilities. Although CI is unlikely to be the sole reason to deny a child access to liver transplantation (with the possible exception of patients with the most severe impairment), children with diseases that expose them to the development of CI likely receive inconsistent care across transplant centers.

Mitochondrial Disease: Mitochondrial diseases affecting the liver, also called mitochondrial hepatopathies (MH), are a group of rare multisystem disorders involving dysfunction of the respiratory chain and other mitochondrial pathways, often caused by mutations of nuclear genes coding for mitochondrial DNA (mtDNA) replication, translation, and repair. Both acute and chronic phenotypes can occur ( Table 5.4 ).

Table 5.4

Mitochondrial diseases with liver involvement

Electron transport (Respiratory Chain) defects	Fatty acid oxidation defects
• Neonatal liver failure • Complex I deficiency • Complex IV deficiency ( SCO1 ) • Complex III deficiency ( BCS1 ) • Multiple Complex Deficiencies • Mitochondrial DNC depletion syndromes • DGUOK mutations • MPV17 mutations • POLG mutations • Alpers-Huttenlocher syndrome • POLG mutations • Pearson’s marrow-pancreas syndrome • mtDNA depletion • Mitochondrial neuro-gastrointestinal Encephalomyopathy • TP mutations • Navajo neurohepatopathy • MPV17 mutations • mtDNA depletion	• Long-chain hydroxyacyl CoA dehydrogenase deficiency • Acute fatty liver of pregnancy • LCHAD enzyme mutations • S/MCHAD • CPT I/II deficiency • Carnitine-acylcarnitine translocase deficiency • Fatty acid transport defect • ETF and ETF-dehydrogenase deficiencies

Electron transport (Respiratory Chain) defects

Fatty acid oxidation defects

•

Neonatal liver failure
- •
  
  Complex I deficiency
- •
  
  Complex IV deficiency ( SCO1 )
- •
  
  Complex III deficiency ( BCS1 )
- •
  
  Multiple Complex Deficiencies
•

Mitochondrial DNC depletion syndromes
- •
  
  DGUOK mutations
- •
  
  MPV17 mutations
- •
  
  POLG mutations
•

Alpers-Huttenlocher syndrome
- •
  
  POLG mutations
•

Pearson’s marrow-pancreas syndrome
- •
  
  mtDNA depletion
•

Mitochondrial neuro-gastrointestinal Encephalomyopathy
- •
  
  TP mutations
•

Navajo neurohepatopathy
- •
  
  MPV17 mutations
- •
  
  mtDNA depletion