Liver Transplant - Peds

8/12/2019 Liver Transplant - Peds

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donors, or from split-liver transplantation , where twografts are created from a single donor organ for tworecipients, usually an adult and an infant. 1

MELD and PELDThe United Network for Organ Sharing in the UnitedStates has devised the Model for End-stage Liver Disease(MELD ) and Pediatric End-stage Liver Disease ( PELD ),which are numerical scales that are currently used forliver allocation. 2 Similar systems exist in other coun-tries. These scores are based on a patients risk of dyingwhile waiting for a liver transplant, derived from objec-tive and veriable medical outcomes data. The MELD

DEFINITIONS AND EPIDEMIOLOGY

Types of Liver TransplantsLiver transplantation refers to the surgical replacementof a diseased liver with a donor-grafted organ. This ismost commonly orthotopic (complete removal andreplacement), but occasionally heterotopic , where thenative organ is left in situ. The transplant may be wholeliver, a reduced-size liver, or a liver segment, the latter asmeans of overcoming donor organ scarcity, particularlyfor pediatric recipients (Figure 291). Reduced-size livergrafts , such as a left-lateral segment or hemireductiongraft, can be derived from either cadaver or living

Liver TransplantationYumirle Turmelle andRoss W. Shepherd

CHAPTER29

Orthotopic liver transplantation Reduced-size liver transplantation

Brisbane technique

PV

IVIVII+III

II+III

II+III

II+III

PV

CA

CA

CBD

CBD

LHV

Standard hemi reduction technique

Recipient : Donorsize ratiousually 4:1

Recipient : Donorsize ratioup to 13:1

DonorIVC

RecipientIVC

Donorsaphenofemoral

junction Rec. PV

Aortoceliacanastomosis

Whole liver withhepatic andportal veins,hepatic arteryand bile duct tobe attached torecipient structures

FIGURE 291 Surgical techniques for liver transplantation in children. Orthotopic whole-organ replacement, and reduced-size techniques.Donors are matched for size and blood type.

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404 Section 4: Disorders of the Liver

score, used for patients aged 12 years and older, is basedon bilirubin, international normalized ratio (INR), andcreatinine. The PELD score is based on bilirubin, INR,albumin, growth failure, and age, factors which betterpredict mortality in children. These scores do not alonedetermine the likelihood of getting a transplant. Otherfactors include matched (blood group and size) organavailability, the occurrence of higher priority exceptions(e.g., those with fulminant hepatic failure), and the dis-tribution of MELD/PELD scores for other patients in alocal area or region, and consideration for living dona-tion. The PELD/MELD system also has designatedexception scores assigned to specic liver conditionsthat have preserved liver synthetic function and thuscorresponding low allocation scores, such as those chil-dren with metabolic liver diseases (e.g., urea cycle disor-ders) and hepatoblastoma. In addition, a program canrequest a higher exception score if the calculated scoredoes not truly represent the patients condition. This is

done by submitting an exception score request to theirUNOS regional review board for consideration.

EpidemiologyThe annualized incidence of liver transplantation in theUnited States is 1012 per million total population, thatis, 5060 cases per million children/year (1/16,000 chil-dren), or about 600 children, one-third of these beinginfants. Approximately 55% of these transplants are forend-stage chronic liver disease, the majority of thesedue to biliary atresia (BA); about 25% are for metabolicliver diseases, 10% for acute liver failure, and 5% forliver tumors (Figure 292). 3,4 BA (Chapter 23) occurs in

about 1/14,000 live births in the United States, but notall cases of BA require transplant (see below). Pediatricacute liver failure (PALF) has estimated annualized inci-dence of about 2 per million, and about 50% recover

without transplant. 5 It is notable that the number oflong-term survivors of liver transplantation is currentlyabout 10 times these annualized gures. Thus, childrenwho require liver transplantation or are being followedafter liver transplantation are likely to be encounteredwith some frequency in pediatric practice, and the num-ber of these children is expanding.

CLINICAL PRESENTATION ANDREASONS FOR REFERRALA wide range of chronic liver diseases in children, anumber of liver-specic metabolic diseases, some raretumors of the liver, and presentations of acute liver fail-ure are potentially cured by liver transplantation. Theseconditions, although individually rare, are collectivelynot uncommon, and are accompanied by medical andsocial demands of lifelong aftercare.

IndicationsEnd-stage chronic liver diseases , such as BA, form the com-monest indication, accounting for more than half of allpediatric liver transplant recipients, and the majority ofinfant recipients (Table 291). BA has an incidence of57/100,000 live births in the United States and Europe,and 1015/100,000 in Asia, and in about two-third of cases,the initial attempt at a bile drainage procedure (hepatopor-toenterostomy) fails, and the infant/child develops chronicliver failure.6 Considered together, liver-specific metabolicdiseases represent approximately 25% of pediatric livertransplants and are the second most common indications

for liver transplant after BA. These can be divided into:(1) those that lead to liver injury, with or without otherorgan involvement, such as alpha-1-antitrypsin deciency,Wilsons disease, tyrosinemia, familial cholestasis, and cys-tic brosis (CF); and (2) diseases due to a metabolic defectexpressed solely or predominantly in the liver but leadingto injury to other organ systems, such as the urea cycledisorders, CriglerNajjar syndrome, and hyperoxaluria.Acute liver failure accounts for about 10% of cases. Mostcases are of indeterminate cause, followed by acetamino-phen toxicity, other drug toxicities, Wilsons disease, auto-immune hepatitis, and perinatal hemochromatosis. Finally,unresectable liver tumors such as hepatoblastoma, embryo-nal sarcomas, and hemangioendotheliomas are rare butimportant indications for timely liver transplantation.

ContraindicationsSome conditions associated with serious liver involve-ment are not curable by liver transplantation, namelythose with life-threatening extrahepatic disease areabsolute contraindications to liver transplantation

Chronic endstage liver diseasesMetabolic liver diseases

Liver tumorsAcute liver failure

FIGURE 292 Relative frequency of types of liver disease forwhich liver transplantation is indicated in children. Of all pediatricliver diseases, biliary atresia is the most common indication (50%).



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CHAPTER 29 Liver Transplantation 405

(Table 292). Although in the past there have been sometechnical and management restrictions with regard toage, size, and the occurrence of hepatopulmonary syn-drome and portal vein thrombosis, successful livertransplantation is now possible even in the neonatalperiod, and the various technical issues have been over-come, and these are considered only relative contraindi-cations. There are some conditions in which thetransplant should be temporarily deferred, such as acuteactive infections and recent live virus immunizations.

Reasons for ReferralThose who might benet from liver transplantationpresent with a range of clinical problems, some not

necessarily with initial obvious links to the liver(Table 293). Early referral for evaluation is emphasizedin all cases in which transplantation is even remotely anoption to allow for timely assessment, full and frankdiscussion of options, psychological preparation, appro-priate pre-transplant aggressive management, and eval-uation of donor options.

PresentationBA is a special case, in which a failed Kasai procedurein infancy, manifesting as a failure to clear jaundicewithin 36 weeks, virtually always portends complica-tions of cirrhosis within weeks to a few months. Thus,as soon as a failed Kasai is realized, referral for transplant

Indications for Liver Transplantation in Children

Frequency (% of Transplants)

Chronic end-stage liver diseases (60%) Biliary atresia 55 Chronic active hepatitis 4 Primary sclerosing cholangitis 1

Liver-specic genetic/metabolic diseases (25%) Causing chronic liver injury other organ involvement

alpha-1-antitrypsin deciency10

Familial cholestasis 5 Cystic brosis 2 Tyrosinemia 1 Glycogen storage diseases 1 Alagille syndrome 5 Metabolic defect expressed solely or predominantly in the liver

but leading to other organ injury/morbidity

Urea cycle disorders 2 Hyperoxaluria 1 CriglerNajjar syndrome 1 Maple syrup urine disease 1 Ornithine transcarbamylase deciency 1

Acute liver failure (10%) Indeterminate cause 5 Acetomenophin toxicity 2 Other drug toxicities 1 Wilsons disease 1 Perinatal hemochromatosis 1 Some fatty acid oxidation defects 1 Vira l hepatitis (hepati tis A, B, C, EBV, adeno, CMV,

echo, herpes, parvo) 1

Autoimmune hepatitis

Primary unresectable liver tumors (5%) Hepatoblastoma 2 Embryonal sarcoma 1 Hemangioendothelioma 1

Table 291.



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evaluation should be made. Similarly, recurrent cholan-gitis, which can be life-threatening and can result indevelopment of acute or chronic synthetic failure,should be a consideration for transplantation. Beyond

that, any presentation with features of end-stage liverdisease, such as ascites, portal hypertension, and nutri-tional growth failure, is a clear indication for referral.

Causes and complications of chronic

end-stage liver diseaseAny child with chronic liver disease and/or cirrhosisrequires regular follow-up, evaluating for signs of end-stage disease, as listed in Table 293, the occurrence ofwhich should provoke referral. The complications ofchronic liver disease and cirrhosis (listed in Table 293)are due to impaired hepatic function and cholestasis ,which cause nutritional disturbances, jaundice, pruri-tus, and coagulopathy, and portal hypertension , whichcauses varices, hypersplenism, and hepatorenal orhepatopulmonary syndrome. Encephalopathy andascites occur as a result of both of these major pathophys-iologic events. In addition, impaired immunity withresulting bacterial infection may complicate cirrhosis.Hepatocellular carcinoma can complicate cirrhosis inchildhood, particularly in chronic hepatitis B andtyrosinemia type I.

The presentation of some complications can besubtle, such as nutritional growth failure. In some

Contraindications to Liver Transplantation in Children

Absolute Curative alternative therapy available Uncontrolled systemic sepsis Irreversible neurological injury Extrahepatic malignancy Progressive terminal non-hepatic disease Mitochondrial disorders with progressive neurological

involvement

Relative Severe hepatopulmonary syndromeactionable management Portal vein thrombosisvein graft availability Active primary peritonitistemporary deferment Active viral infectiontemporary deferment Recent liver virus immunizationstemporary deferment

Table 292.

Reasons for Referral for Liver Transplant Evaluation

Chronic end-stage liver diseases

Specific to biliary atresia Failed hepatoporoenterostomy (persisting jaundice) Recurrent ascending cholangitis Any cirrhosis complications listed below

Complications of end-stage liver disease and cirrhosis of any cause Nutritional disturbances, growth failure, malabsorption Portal hypertension and variceal hemorrhage Hypersplenism Ascites Liver synthetic dysfunction (coagulopathy, hypoalbuminemia) Hepatorenal and hepatopulmonary syndromes Encephalopathy Bacterial infections, spontaneous bacterial peritonitis Hepatocellular carcinoma

Liver-specic genetic/metabolic diseases Those causing complications of end-stage liver disease listed above related morbidities, such as alpha-1-antitrypsin

deciency, familial cholestasis, cystic brosis, tyrosinemia, glycogen storage diseases, Alagille syndrome Metabolic defects expressed in the liver but leading to other organ injury and/or serious morbidity, and compromised quality of

life, such as urea cycle disorders (life-threatening recurrent hyperammonemia and hyperoxaluria (renal failure)), CriglerNajjarsyndrome (brain injury), maple syrup urine disease (brain), ornithine transcarbamylase deciency

Acute liver failure , presenting as any combination of sudden onset of jaundice, encephalopathy coagulopathy, hypoglycemia,markedly elevated liver transaminases

Primary liver tumors where there is any doubt as to resectability, prior to chemotherapy

Table 293.



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patients, portal hypertension can progress slowly, mani-festing only as splenomegaly and hypersplenism(bruising tendency, recurrent epistaxis, and thrombocy-topenia). Encephalopathy in children can be very subtlein chronic disease, presenting only as deterioration ofschool performance, sleep inversion, or intermittent

somnolence. In other cases, complications can be dra-matic, such as massive ascites and GI bleeding fromesophageal varices, and can be the initial presentation ofthe underlying chronic liver disease.

Metabolic liver diseases causing liver injury arediagnosed following an initial, usually neonatal pre-sentation with cholestasis. Typical of these are alpha-1-antitrypsin deciency, familial cholestasis, Alagillesyndrome, and CF. Metabolic liver diseases in whichthe defect is expressed in the liver, leading to signi-cant injury of other organs, should also be consideredfor liver transplantation, as the disease is cured by liverreplacement. Each case has to be considered on itsmerits, in relation to mortality risk, such as in orni-thine transcarbamylase deciency and some urea cycledisorders, risk to the end-organ, such as the brain (inthe case of hyperammonemic syndromes and CriglerNajjar syndrome) and the kidney (as in hyperoxalu-ria), and the poor quality of life associated with thesedisorders.

PALF presents most commonly with new-onset jaundice, variable encephalopathy, a coagulopathy,

hypoglycemia, and markedly elevated transaminases. Bydenition, there is no known chronic liver disease, acoagulopathy uncorrected by vitamin K, where the pro-thrombin time (PT) 15 seconds, and the INR 1.5,and if no encephalopathy, a PT 20 seconds, and INR

2.0 (Figure 292).The peak age of onset is in infancy

(25% of cases), where jaundice is late feature, earlyhypoglycemia is common, and most cases are of inde-terminate cause. 5 There is another peak of incidence inadolescents, where the etiology is more likely drug tox-icity or viral. A good clinical history concerning onset,history of exposures to drugs, viruses, toxins, extrahe-patic symptoms, rate of progress of symptoms andsigns, and family history may point to an etiology, but atleast 50% of cases are idiopathic. Signs of acute hepaticencephalopathy can be staged for monitoring and prog-nostic purposes, and vary according to age, as listed inTable 294. Some metabolic diseases causing ALF canhave apparent encephalopathy due to non-hepaticcauses, such as hypoglycemia and lactic acidosis. Earlyreferral of suspected cases of PALF to a transplant pro-gram is vital, where intensive aggressive supportivetherapy can be instituted, urgent attempts at determin-ing the etiology can be instituted, and patients can belisted for a donor search if transplantation is consideredan option (Figure 293).

Primary liver tumors in children present most com-monly as an incidental nding of a painless enlarging

Stages of Hepatic Encephalopathy in Children

Stage Clinical Reexes Neurological EEG

Infant

Early (I and I I) Inconsolable crying, sl eepreversal

Unreliable normal orhyperreexia

Untestable

Mid (III) Somnolence, stupor,combativeness

Unreliable, may behyperreexia

Most likely untestable

Late (IV ) Comatose, arouses with painfulstimuli (IVa) or no response(IVb)

Absent Decerebrate ordecorticate

Older child

0 Normal Normal Psychtesting only Normal1 Confused, poor sleep habits,

forgetfulNormal Tremor, apraxia,

impairedhandwriting

Normal or diffuseslowing

2 Drowsy, decreased inhibitions Hyperreexia Dysarthria, ataxia Generalized slowing3 Stuporous, obeys simple

commandsHyperreexia, up-going

toes ( Babinski)Rigidity Generalized slowing

4 Comatose, arouses with painfulstimuli (IVa) or no response(IVb)

Absent Decerebrate ordecorticate

Abnormal, very slowdelta activity

Table 294.



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abdominal mass, or sometimes found on abdominalexam after presentation with abdominal discomfort, pal-lor, or weight loss, confirmed on imaging studies(Figure 294). Total surgical excision and adjunctive che-motherapy are cornerstones of treatment of primaryhepatic malignancies in children, and the only option fortotal surgical excision for unresectable tumors is livertransplantation, which has good long-term outcomes. It

is generally recognized that survival after rescue trans-plantation after incomplete resection is poor, and thus

timely assessment for transplantation in the setting ofquestionably resectable tumors is indicated. 7 Consultationwith a transplantation program at the time of diagnosisand assessment before any chemotherapy should avoidinappropriate attempts at resection and allow appro priateplanning of transplantation in relation to chemotherapy.

TREATMENT Liver Transplantation Evaluationand PreparationThe primary goals of the evaluation process (Table 295)are to (1) identify the risks versus benets of transplan-tation; (2) identify the need for and timing oftransplantation; (3) identify technical feasibility andappropriate donor options; (4) establish a pre- transplantmanagement plan; (5) have fully informative, frank dis-cussion of the above with the parents, and patient if pos-sible, to help prepare them to accept and deal with all theissues and possible outcomes of the procedure. The stepstaken in this evaluation are detailed in Table 295.

Pre-transplant ManagementThe primary goal of pre-transplant treatment is to keepthe patient as well as possible for as long as possible, bya combination of proactive monitoring, active aggressivetreatment of complications of liver disease, and multi-

FIGURE 293 Management algorithm of suspected pediatric acute liver failure (PALF).

Diagnosis and treatment of Treatable causes (Tables 29-6 and 7)

Early referralIntensive supportive care

Evaluation of progress and donor options

Suspect PALFA liver related illness-elevated transaminases +/ jaundiceNo known chronic liver diseaseCoagulopathy, uncorrected by vitamin K,PT > 15s, INR > 1.5 +/ encephalopathy

Donor available Progression of liver failure Risk factors No contraindication

Transplant if Do not transplant if Objective improvement Contraindicated

Futile

Contraindications S pecialty tests Genetic causes

Otherinvestigations:

FIGURE 294 Computerized tomography of the liver from a childpresenting with vague abdominal pains, and a palpable mass onabdominal examination. A central, bilobar tumor without a plane ofresection where liver transplant is the only method for completeresection.



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disciplinary psychosocial support. Good communica-tion systems should be in place between primaryphysicians and transplant centers to facilitate involve-ment, set expectations, manage medical and non- medicalissues, and provide guidance for both families and allhealth care professionals toward the common goal ofachieving a good outcome for the patient. Because oftheir long-term relationship with patients and families,primary care physicians/pediatricians are in an advanta-geous position to detect the early signs of complications,and help families cope with this stressful time.

End-stage chronic liver diseasesThe pre-transplant management plan while on the wait-ing list is developed by the transplant team, in conjunc-tion with the primary care physician, and the family(Table 295, item 8). Key features include immuniza-tion update, nutritional support, regular monitoring ofprogress, including active management/notication ofintercurrent illness, psychosocial support, and activetreatment of complications of liver disease.

Immunization update It is important to ensure thatroutine immunizations are up to date, and that protec-tion for pneumococcus, Haemophilus , and hepatitis Aand B be prescribed if possible, and any vaccinationrequiring live vaccines is administered prior to trans-plantation.

Nutritional support The liver has a central role inregulating fuel and metabolism, nutrient homeostasis,and absorption of a number of nutrients (Table 296).

These factors result in a catabolic state, particularly dur-ing fasting, a deciency of proteins and calories, which,when combined with anorexia and a poor intake, make

Pre-transplant Evaluation

1. Establish the need for and urgency for transplantation 2. Assess technical feasiblity. Abdominal ultrasound with Doppler,

size of portal vein on US, vascular studies if necessary 3. Consider severity of liver disease (PELD score or exception),

based on liver synthetic function, other risk factors, risks, andpossible contraindications

4. Assessment of donor optionsblood group, size,suitability for reduced-size or split-liver donation

5. Identication of complications of liver disease andextrahepatic conditions

Nutritional statusglobal (weight, height, fat folds,mid-am muscle), vitamin, protein, and mineral levels

Portal hypertensionascites, varices on endoscopy,hypersplenism

Cardiac assessment, including echocardiogram Repiratory assessment: If cyanosed, perform O 2 saturation,

bubble test, ventilation/perfusion, and pulmonary functiontesting

Renal function tests Neurodevelopmental assessment Dental assessment Immunization status, and serology for CMV, EBV,

varicella, measles, hepatitis A, B, and C serology 6. Evaluate social systems, issues, and logistic issues 7. Prepare the patient and parents by full, frank discussion 8. Develop a pre-transplant active management plan

including Immunization update Nutritional support Ongoing monitoring Psychosocial support Aggressive management of other complications of

liver diseaseasci tes, coagulopathy, variceal bleeding,encephalopathy, and infections

Table 295.

Nutritional Support for End-stage Liver Disease

Vitamin Received Dose Preparation

A 525,000 IU/day Water soluble *ADEKs

Aquasol IV

D 6002000 IU ADEKs0.02 g/kg Drisdol

1250 HD IV**

E 50100 IU Tocopherol polyethyleneglycol succinate

1525 IU/kg Liqui E

Aqua E

ADEKsK 2.510 mg 2 /week Mephyton

Aqua Mephyton injection

Provide adequate absorbed calorieshigh-energy, semi-elementalsupplements, for example, Pregestimil for infants a nd Peptamen Junior forchildren. Supplement protein with branched chain amino acids, for example,Tarvil 5 g/20 mL. Avoid fasting and provide calories by nocturnal N/G or G-tubefeeding if necessary. Additional fat-soluble vitamins A, D, E, and K.* Also provide minerals: calcium, zinc ,and phosphate. Axcam.

Mayne.Sano Winthrop.** Abbott.Twinlab.Yasoo.Merck.

Table 296.



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malnutrition common in chronic liver disease, particu-larly if the onset is in infants (Figure 295). Malnutritionitself may induce further derangements of liver functionbecause the liver requires energy for a number of syn-thetic, storage, and detoxication functions. Thus, poornutritional status is a signicant but potentially modi-able risk factor adversely affecting outcome both beforeand after transplantation, making nutritional support amajor focus of pre-transplant management. Efforts tooptimize nutritional support by providing adequate pro-tein energy, avoiding fasting, and using specialized aminoacid and vitamin formulations including enteral nutri-tional supplementation can improve nutritional status.

Regular monitoring While on the waiting list, regularmedical monitoring is essential. The progression of theliver disease is evaluated by recalculation of the PELDscore at intervals, and assessment for development ofcomplications of liver disease, which should be aggres-sively treated (see below). Any change in mortality riskshould prompt re-evaluation of donor options, particu-larly if cadaver donors via the organ sharing system arelikely limited because of size or blood group constraints.

Similarly, any intercurrent illness needs aggressive man-agement, and notication to the transplant center.

Psychosocial support Families and patients nd thewaiting time very stressful. Mortality on the waiting list,although improved as a result of earlier referral andaccess to more donor options, is still a possibility. Ongo-ing counseling and preparation of a fully informed childand family through a multidisciplinary approach,including primary care physicians and family membersas part of the team, is essential. The pre-transplant andpost-transplant morbidity and mortality and the needfor long-term immunosuppression require full, frankdiscussion, and acceptance of these risks as well as thepotential benets is arguably the most important part ofthe preparation of a family for liver transplantation.

Treatment of complications of chronic liver dis-ease Ascites is a common complication of cirrhosis,

and it is a sign of advanced liver disease (Table 297).Extravascular uid accumulation in chronic liver diseaserepresents a breakdown of intravascular volume homeo-stasis, which is controlled by capillary hydrostatic pres-sure and plasma colloid osmotic pressure. This processmay develop insidiously or be precipitated by eventssuch as gastrointestinal bleeding, infection, or the devel-opment of hepatoma. It is manifested by abdominal dis-tension, pitting edema, sometimes pleural effusion, and/or the development of hernias. Treatment includes nutri-tional support, the judicious use of aldosterone antago-nist and thiazide diuretics, and maintenance of plasmaoncotic pressure by albumin infusion, but in some casesthis becomes refractory. Tense ascites may require large-

volume paracentesis and albumin infusion.Coagulopathy in chronic liver disease is due to a

combination of vitamin K malabsorption and deciency,reduced synthesis of coagulation factors, and thrombocy-topenia secondary to hypersplenism. These disturbancesare particularly important in prognostic assessment, andin the genesis and management of gastrointestinal bleed-ing, and may lead to serious complications such as intrac-erebral bleeding and intravascular consumption coagul-opathy. Management is directed at prevention/correctionof vitamin K deciency with oral or parenteral vitamin Ksupplements. If refractory, or there is active bleeding, orhigh risk of bleeding or for procedures, fresh frozenplasma infusions, platelet infusions, or the use of desmo-pressin may achieve temporary hemostasis.

Variceal bleeding , one of the major causes of mor-bidity and mortality, is a manifestation of portalhypertension, caused by a combination of increased por-tal blood ow and increased portal resistance. Signs andsymptoms of portal hypertension are primarily the resultof decompression of this elevated portal blood pressurethrough portosystemic collaterals, manifest as splenom-

FIGURE 295 Malnutrition is a signicant potentially modiablerisk factor adversely affecting outcome in children with chronic liverdisease, both before and after transplantation, making nutritionalsupport a major focus of pre-transplant management.



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egaly and hypersplenism, the development of ascites,and the occurrence of esophageal, gastric, and rectalvarices. Splenomegaly and hypersplenism rarely requirespecic intervention, and ascites is considered above.Bleeding from esophageal varices may be life-threatening

and may precipitate liver failure, and requires promptdiagnosis and treatment (Figure 296). Salient pointsinclude: a secure intravenous infusion line; urgent bloodtransfusion; achieving hemostasis via parenteral vitaminK and plasma infusion; consideration for octreotide

Treatment of Complications of Chronic End-stage Liver Diseases

AscitesNutritional supportAvoid sodium intakes 2 mmol/kgSpironolactone chlorothiazide, for example, Aldactazide: 3 years 12.5 mg qid, 3 years, up to 50 mg qidAlbumin infusions (if serum albumin 25 g/L) in a dose of 2 g/kg + frusemide 2 mg/kgIf refractory and symptomaticparacentesis albumin infusion

CoagulopathyVitamin K supplements (see Table 295)Fresh frozen plasma 10 mL/kgactive bleeding, invasive procedures, PT 40 seconds, unresponsive to vitamin K Platelet infusionfor active bleeding and count 20,000Desmopressinfor active bleeding with global coagulation protein deciencies (ii, vii, ix, x)

Variceal bleedingSecure IV access, and hemostasis with vitamin K and fresh frozen plasma Treat hypovolemia with blood transfusion and stabilize patientAdminister short-acting splanchnic vasoactive agent, for example, octreotide 25 mg/hour IVRefer to center experienced in pediatric endoscopy, transcutaneous shunts, and liver transplantationPrevent recurrence with endoscopic ablation, beta-blockersLiver transplantation

EncephalopathyAvoid precipitating factorsAvoid prolonged fasting, ensure nutritional supportLactulose 0.4 mL/kg/day and PO vancomycin divided into three doses

Bacterial infectionsHigh index of suspicion in biliary atresia (cholangitis) or ascites (primary peritonitis)Minimize risk by nutritional support, active Rx of ascites, immunization for pneumococcus, hemophilusProphylactic antibiotics for invasive procedures, prevention of recurrenceBacteriological studies and early institution of an extended-spectrum beta-lactam antibiotic

Table 297.

Supportive treatmentendoscopy

Transfer to center with pediatric endoscopy,TIPPS, and transplant capability

Secure IV access Hemostasis (Vit K and/or plasma) Blood transfusion IV octreotide

Bleeding varices

Elective sclerotherapy or banding Beta blockers Consider TIPPS as bridge

Bleeding stops

Emergency sclerotherapy or banding If portal vein patent, consider TIPPS Emergency surgery

Bleeding continuesIV octreotide

FIGURE 296 Management algorithm for upper gastrointestinal bleeding in children with chronic liver disease.



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infusion; and referral (when stable) to a tertiary centerwith experience in endoscopic sclerotherapy or banding,transcutaneous intrahepatic portosystemic shunts(TIPSS), and liver transplantation. Prevention of recur-rence with vasoactive pharmacotherapy (e.g., beta-blockers), endoscopic ablation, or TIPSS may be indicatedas a bridge to transplantation, but surgical shunts arebest avoided in prospective transplant patients.

Encephalopathy in children with chronic liver dis-ease is difcult to recognize, particularly in infants.Pathogenesis is related to four major processes: porto-systemic shunting, hepatocellular dysfunction, interac-tion of nitrogen metabolites from the intestine with thecentral nervous system, and altered neurotransmitterfunction. Early symptoms are subtle and include neu-rodevelopmental delay, school problems, lethargy, orsleep reversal (somnolent by day and insomnia bynight). Intellectual impairment and personality changemay occur in older children, while clouding of con-

sciousness, asterixis, ataxia, stupor, and coma are latesigns, these tending to develop in conjunction with pre-cipitating events, such as gastrointestinal bleeding orthe use of sedatives. It is also common following shuntsfor portal hypertension. Treatment is directed at remov-ing precipitating factors, avoidance of fasting, andreducing intestinal protein load with lactulose, andbroad-spectrum antibiotics (Table 297). Proteinrestriction is not usually necessary, and not recom-mended in children due to the risk of further nutri-tional compromise.

Bacterial infections may precipitate other compli-cations, such as encephalopathy, ascites, and hepatorenalsyndrome, and are predisposed to liver disease by

immune dysfunction, neutropenia, and alterations inmucosal barriers. Portal hypertension makes patientssusceptible to bacteremia, perhaps by inducing bacterialtranslocation of the gut. Spontaneous bacterial peritoni-tis is a serious complication of ascites and should be con-sidered in all children with ascites who show signs ofsepsis. In BA, recurrent cholangitis is a risk factor fordeath on the waiting list. Urinary and respiratory tractinfections are also frequent, and bacteremia commonlyresults from invasive investigations. Other risk factorsfor infection are low serum albumin, gastrointestinalbleeding, ascites, intensive care unit admission for anyreason, and endoscopy. Certain agents are more virulentand more common in patients with liver disease, includ-ing Klebsiella ,E. coli ,Campylobacter ,Yersinia ,Plesiomonas ,Enterococcus ,Aeromonas , and Listeria species. Preventativemeasures such as pneumococcal and Haemophilus vac-cination, prophylactic antibiotics for invasive procedures,nutritional support, and management of ascites mayreduce risk. When infection is suspected, immediatebacteriological studies and early institution of antimi-crobial therapy with a broad-spectrum antibiotic (e.g.,

an extended-spectrum beta-lactam antibiotic such astazobactam piperacillin (Zosyn)) are recommended,while awaiting culture and sensitivities.

Pediatric acute liver failureWhenever PALF is suspected, as indicated above and inFigure 293, early referral to a transplant center is advis-able. Key features of management involve simultane-ously supporting the patient, evaluating the cause, par-ticularly medically treatable causes (Table 298),monitoring the progress of the liver failure, and assess-ing possible donor options in case liver transplant isavailable.5 However, 50% of cases recover without trans-plantation, that is, 50% will die without transplantation,there are some contraindications, and some situationswhere a transplant becomes futile.

Supportive measures Most cases require intensivecare, with aggressive management of coagulopathy andencephalopathy, often requiring ventilatory and hemo-dynamic support. Hepatorenal syndrome and infectionare not uncommon complications that require furtheraggressive management. Medical treatment for treat-able causes should be instituted without delay (Table298). Investigations are listed in Table 299, and aredivided into those required for monitoring and sup-portive treatment, those required to rule out medicallytreatable causes, and those to evaluate other known

Medically Treatable Causes of PALF

Drugs and toxins Acetominophen N -acetyl cysteine (NAC) by continuous

infusion Amanita phalloides steroids, silibinin, penicillin Otherscease/avoid the drug

Immune diseases Autoimmune hepatitissteroids/azathiaprine Hemophagocytic (macrophage activation) syndrome

high-dose of steroids, etopaside, cydosporin

Metabolic liver diseases Tyrosinemia Initisinone (NTBC) Wilsons diseasechelation with penicillamine, zinc Galactosemialactose-free diet Neonatal hemochromatosisantioxidant cocktail

-IV NAC, selenium 3 mcg/kg/day Tocopherol PEG succinate 25 IU/kg/day, vitamin

C 25 mg/kg/day

Viral infections Herpes virusesacyclovir Enterovirusespleconaril Other virusesconsider IVIG

Table 298.



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causes, including those where transplant might be con-traindicated.

Indications for transplantation Unless there is acontraindication to transplant, most patients are listedfor a donor search, and the decision as to whether toproceed is made when a donor becomes available. Thedecision to go ahead with a transplant at that time is

based on rate of progression of liver failure or lack ofsigns of improvement, and the presence of dened poorprognostic indicators, including age 1 year, progres-sive encephalopathy, vitamin K-unresponsive PT 40seconds and INR 4, hypoglycemia with ongoing highdextrose requirement, serum bilirubin 300 mol/L(17.5 mg/dL), a rapid reduction in liver size clinically(plus precipitous fall in AST), and/or no regenerativefeatures and extensive hepatic necrosis ( 20% viablehepatocytes/HPF) on liver biopsy. For acetaminophenliver injury, where specic treatment with N -acetylcysteine should be instituted, consider transplant if pH

7.3, creatinine 0.3 mmol/L, and/or INR 6.5 withno improvement on treatment. While waiting for adonor organ, if there are signs of stabilization or evidenceof recovering function (improved coagulation parame-ters and encephalopathy), transplantation may bedeferred. Similarly, if circumstances arise in which atransplant becomes futile, then transplantation is not

indicated. Examples include uncontrolled systemic sep-sis, irreversible neurological injury, or a diagnosis ofunderlying non-hepatic disease, such as malignancy ora mitochondrial disorder.

Post-transplant ManagementThe goals of post-transplant management are to man-age and treat postoperative complications, and developa balanced long-term immunotherapy regimen thatminimizes infection and side effects but controls rejec-tion (Figure 297). There must be provision for long-term follow-up, with proactive treatment of commonproblems. As with pre-transplant management, good

communication systems should be in place betweenprimary physicians and transplant centers. Because oftheir accessibility and long-term relationship withpatients, primary care physicians are in the best position

Investigating Pediatric Acute Liver Failure

Routine patient monitoring HematologyFBC, ESR, reticulocyte count CoagulationPR/INR, APTT, brinogen, factor V Glucose homeostasis Blood gases Blood/urine cultures Liver bilirubin tests direc t/indirect, ALP, GGT, AST,

ALT, total protein, albumin, globulins Biochemistrysodium, potassium, BUN, creatinine,

calcium, phosphate, magnesium, chloride, amylase, uricacid, ammonia

ECG, echocardiogram Imaging CXR, abdominal ultrasound and Doppler,

head CT if cornatose

Treatable causes of PALF Infantneonatal iron storage, tyrosinemia, fructosemia,

galactosemia Specic investigationsferritin Urine-reducing substances and galactose-1-phosphate

uridyltransferase plasma and urine organic acids,amino acids, urine succinylacetone

Child/adolescentacetaminophen toxicity, autoimmunehepatitis, Wilsons disease

Specic investigationsacetaminophen level IgG, protein electrophoresis, 24-hour urine copper, split

lamp eye exam, liver biopsy

Other diagnostic tests Virology HBV, CMV, EBV, HAV, HCV, HSV, HIV, varicella ,

measles, parvovirus, HHV-6 PCR Serology toxoplasmosis, leptospirosis Special tests Fasting pyruvate/lactate Acylcarnitine prole Alpha-fetoprotein Very-long-chain fatty acids Plasma and urine organic acids, amino acids Plasma and urine toxicology screen Bone marrow Skin biopsy WBC enzymes Muscle biopsy Abdominal ultrasound and Doppler Liver biopsy

Table 299.

Graft dysfunctionRejectionVascular complicationsBiliary complications

ImmunosuppressionInfectionSide effectsMetabolic effects

FIGURE 297 Post-transplant management. The ideal balance inimmunotherapy, graft function, and patient well-being.



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to detect the early signs of complications, recognize orsuspect poor compliance with immunosuppressivetherapy, manage common problems, and provide ongo-ing support to families.

Although most children who have had liver trans-plants can expect cure of their liver disease andimproved quality of life (see the section Outcomes),they require indenite follow-up and often requiremedical attention for complications or co-morbid con-ditions related to their immunosuppressive drug ther-apy. While modern immunosuppressant regimes havereduced rates of graft loss due to rejection, they impartmajor risks for infection, growth failure, metaboliccomplications, and malignancy. 4,8,9 Indeed, there is sig-nicantly more post-transplant morbidity and mortal-ity from infection than from rejection, particularly ininfants. This has led to a trend toward minimization ofimmunosuppression, which is supported by evidencethat some rejection facilitates graft tolerance and thus

is not necessarily always harmful in liver transplanta-tion (as distinct from other solid organ transplants).

Complications after liver transplantationSerious post-transplant complications are dividedinto those that occur in the rst 312 months (early),and these are relatively common, and those occurringafter 12 months (late), which are generally uncom-mon (Table 2910). In addition, there are many com-mon medical issues, and some specic long-termissues that require medical attention in relation to thelong-term use of immunosuppressive medications(Table 2911). Most early complications relate tosurgical issues, and/or immunosuppression, most

notably infection, vascular complications of the graft,and biliary leaks. Infection (detailed below) is themost common cause of post-transplant mortality. 9 Rejection (see below) does occur but usually respondsto treatment with steroid pulse dosing, and appearsnot to contribute to either graft or patient mortality.Late complications include biliary strictures, whichare uncommon and generally respond to percutane-ous biliary dilatation and stent procedures. Most latecomplications are primarily related to the effects oflong-term immunosuppression, notably infectionssuch as EpsteinBarr virus and associated post-trans-plant lymphoproliferative disease (PTLD), warts, skincancers, and side effects of immunosuppression suchas renal dysfunction, hypertension, and immune dys-regulation. Late or chronic rejection is most often amanifestation of compliance, and late graft losses aremost commonly related to this.

Outline of immunosuppression regimensThere is some variability among transplant centers inthe details of immunosuppressive therapy. The goals areto avoid rejection and graft injury, to encourage some

Post-transplant Complications

Early: rst 12 months First month Primary graft non-function Vascular complication Infections/bacterial sepsis Wound and drain issues Biliary leaks Intra-abdominal uid collections Rejection 13 months Infections (CMV, EBV) Biliary strictures Hepatic vein stenosis Rejection 312 months PTLD

CMV infections Biliary strictures Rejection Hypertension Poor growth

Late 12 months PTLD Unusual infections Renal dysfunction Hypertension Non-compliance with medications Growth failure Late biliary strictures

Table 2910.

Post-transplant Immunization Schedule for LiverTransplant Recipients

Starting 6 months post-transplantHepati tis B 6, 8, 10 months i f not previously givenDTP Resume standard scheduleH. influenzae type b Resume standard schedulePolio Resume standard schedule; patient and

siblings must receive inactivated poliovaccine *

Measles, mumps,rubella

At 6 months if not previously given,conrmed by vaccine response withtiters

Varicella At 7 months if not previously given,conrmed by vaccine response withtiters

Pneumavax Required for patients with splenectomyor asplenia

Hepatitis A At 12 monthsInuenza Yearly

* NA live viruses.Patients may experience low-grade fever and vesicles at injection site.Penicillin prophylaxis is also recommended for these patients.

Table 2911.



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early allorecognition (not necessarily to eliminate rejec-tion altogether), and to minimize immunosuppressiveside effects.4,8,9 Most commonly, the immunotherapyplan is based on initial high-dose steroids, progressionto oral steroids, introduction of an oral calcineurininhibitor (CNI), usually tacrolimus (TAC), and oralmycophenylate mofetil (MMF), with individualizedprogressive tapering and cessation of steroids over 312months, followed by cessation of MMF. Some centersinclude induction therapy with monoclonal antibodiesto reduce the need for steroids. Most patients achievelow-level TAC monotherapy by 1224 months post-transplant. The use of cyclosporine, an earlier CNI, isdeclining because of a higher side-effect prole. TAC,0.150.3 mg/kg/day, is administered orally, with titra-tion of TAC dose to achieve trough levels between 8 and10 ng/mL on routine monitoring over the rst 12 months,beyond which levels of around 5 ng/mL are consideredacceptable. If used, MMF is given orally at 150600 mg/

m2

/dose and is discontinued after a rejection-free inter-val of 36 months post-transplant. Patients aged 12 years, patients with primary liver tumors, or patientswho are leukopenic, with white blood count 3000, arenot given MMF. Monitoring of kidney function isimportant in patients on CNIs, assessed by occurrenceof systemic hypertension, and serial measurement ofserum creatinine. In addition, creatinine clearance stud-ies are done after 1 and 3 years.

Infection prophylaxis and surveillanceProphylactic antibiotics are given intravenously for48 hours post-transplant, and then usually discontin-

ued. Any invasive procedure thereafter is usually man-aged with antibiotic cover, including dental procedures.A prophylactic antifungal agent (such as uconazole) isadministered orally for 23 months. Prophylactic anti-viral medications are used in all patients. Acyclovir isprescribed for 3 months if both donor and recipientwere CMV and EBV negative, and ganciclovir for6 months if either donor or recipient was positive foreither CMV or EBV. CMV and EBV naive patients havesurveillance serum CMV and EBV viral load by poly-merase chain reaction (PCR), usually on a monthlybasis while heavily immunosuppressed, or as indicatedif there is presentation with an illness. A post- transplantimmunization schedule is summarized in Table 2911.Despite these precautions, serious bacterial infectionsoccur in about one-third of patients, mostly in the rst3 months post-transplantation, and serious viral infec-tions caused by CMV or EBV occur in about 10% ofpatients. 8,9 Risks for bacterial/fungal infections included young recipient age, Hispanic race, use of donor organvariants, higher bilirubin, prolonged anhepatic time,and use of cyclosporine instead of TAC. 9 Serious viralinfection risks include young age (PTLD is 10-fold

higher in infants), donor organ variants, and experienc-ing rejection episodes causing immunosuppression tobe increased. Any illness characterized by fever, respira-tory, abdominal, urinary, or gastrointestinal symptomsrequires careful evaluation, and, in selected cases, viral,bacterial, and other diagnostic workup. Empiric pre-emptive therapy should be used as indicated.

The cornerstone of treatment for serious infec-tions is the temporary reduction or cessation of immu-nosuppression, along with appropriate antiviral orantimicrobial drug therapy. PTLD caused by EpsteinBarr virus is a potentially life-threatening consequenceof CNI therapy, resulting in inability of the immunesystem to control the proliferation of EBV-infected Bcells. Presenting features are variable, and includemononucleosis-like symptoms (fatigue, fevers, andlymphadenopathy), or localized or disseminated lym-phoproliferation with tumors involving the lymphnodes, liver, lung, kidney, bone marrow, central nervous

system, or small intestine. Because increases in EBVviral load in peripheral blood typically precede thedevelopment of PTLD, measurement of viral load byquantitative PCR is useful in monitoring. Tissue biopsyof associated tumors shows plasma cell hyperplasia,B-cell hyperplasia, B-cell lymphoma, or immunoblasticlymphoma. Immunostaining can be used to reveal theclonality of the proliferating B cells in these tumors orin circulating leukemic cells. These may be monoclonal,oligoclonal, or polyclonal; patients with polyclonallesions have the best prognosis. The diagnosis is con-rmed by demonstrating EBV proteins in biopsy tissue.Treatment involves cessation or reduction of immuno-suppression, surgical removal of local lymphoprolifera-

tive lesions, especially in the gastrointestinal tract,ganciclovir, monoclonal-antibody therapy with ritux-imab, a monoclonal antibody directed against the CD20B-cell antigen, and in some cases cytotoxic chemother-apy. The latter has been effective for patients with lym-phoma or who have had no response to a reduction inthe dose of immunosuppressive drugs or to other thera-pies. Complete cessation of CNIs is used in high-riskpatients with low rejection risk (young age and use ofcyclosporine or antilymphocyte products).

Monitoring, diagnosis,and treatment of rejectionRoutine monitoring of liver biochemistry and CNItrough levels is undertaken frequently during the earlypost-transplant period, reducing to monthly, unlessotherwise indicated. Rises in transaminases without anyevidence for biliary or vascular etiology or intercurrentillness are presumptive for acute cellular rejection (ACR)without biopsy. Doubtful cases require diagnostic liverbiopsy. Rejection episodes are treated with a 3-day pulseof prednisone (25 mg/kg/day) and an increase in TACto temporarily achieve trough levels of 1012 ng/mL. If



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patients do not respond to a 3-day steroid pulse, thenother options include higher dose intravenous steroidpulses, and/or addition of other immunosuppressivedrugs. As noted above, rejection rarely is a factor inpatients of graft losses. 4,8,9 Risks are lowest in infants,higher in adolescents, and highest in those of any agereceiving blood type-mismatched organs. 9 Biopsy-proven chronic rejection is uncommon, and is treatedwith continuation of TAC to achieve levels of 1012 ng/mL, and the addition of azothioprine at 2 mg/kg/day. Inadolescents, this chronic rejection is most commonlyrelated to poor compliance.

Common problemsPatients on long-term immunosuppression are boundto encounter issues related to common illnesses such asvomiting, diarrhea, and fevers (Table 2912). These ill-nesses should be treated on their merits, but generallyalways require medical consultation, in case of serious

or progressive illness. Missed immunosuppressant med-ications should not be double dosed, but simply resumedat normal doses as soon as possible. Gastroenteritis ill-nesses often spuriously result in elevated TAC levels andmild elevations of liver transaminases. Infection contacts ,particularly with serious viral infections such as vari-cella , require consideration of prophylactic therapy.Regular dental care is mandatory, due to the frequencyof pre-existing poor dentine, high caries rate and delayedtooth development in patients with liver diseases, andthe need for ongoing dental hygiene in immunosup-pressed patients. Major dental work requires prophy-laxis with antibiotics because of high occurrence of bac-teremia during these procedures. 10 Compliance with

medications is a common issue in adolescents particu-larly, and poor compliance can have serious conse-quences. This is suspected when monthly surveillanceTAC levels show a large variability, and/or there areunexplained increases in liver transaminases. Systemssuch as mobile phone reminder, text messages, daily

diaries, and closer monitoring have been shown toimprove compliance. 11 Unexplained elevations oftransaminases should be evaluated. Although most aretemporary due to intercurrent illness or lapses in com-pliance, persistent changes could indicate late graft dys-function and require investigation with imaging and/orliver biopsy. Follow-up of growth and development with yearly monitoring is the norm for all pediatric trans-plant recipients. Deviations require more detailed eval-uation and treatment. Skin conditions such as eczemaand warts are more common in immunosuppressedpatients. These often require specialist referral and man-agement. Skin cancers should be minimized with activelifelong solar prophylaxis. Finally, issues of fertility and pregnancy are increasingly being raised in long-termsurvivors of pediatric liver transplantation. Many suc-cessful pregnancies have been recorded, and the currentevidence suggests that pregnancy is safe after trans-plant. 12,13 Pregnancy does require close management by

a team of experienced physicians. Signicant experiencehas indicated that the use of CNIs, azathioprine, andprednisolone is safe during pregnancy, but few data areavailable for newer immunosuppressants such as MMF,and thus these agents are not recommended. 13,14

OUTCOMES

Patient and Graft OutcomesCurrent 1-year patient and graft survival rates acrosspediatric centers of expertise are 9095% and 8085%,respectively, and at 3 years approximately 85% and 80%,

with only minimal decline after that.4,8

These overallgood outcomes have been achieved by early referralwith excellent pre-transplant care (particularly ofhepatic complications and nutritional support), theimproved donor options mentioned above, and advancesin post-transplant management, particularly more tar-geted and age-specic immunosuppression. Unfortu-nately, there is still a small but signicant risk of dyingwhile on the waiting list. Waiting list mortality risk fac-tors include the infant age group, a high PELD score of

20, poor nutrition, and acute liver failure. 4 Early post-transplantation mortality risk factors include infantrecipients, poor nutritional status, need for re-transplantation, usually secondary to surgical complica-tions, and acute liver failure. 4 Overall, infection is thesingle most important cause of death, contributed to byimmunosuppression and surgical complications. 9 Earlyepisodes of rejection ( 6 months after transplantation)do not contribute to mortality or graft failure. Graftfailure risks include poor nutrition, the use of cadavericreduced-size donor segments, the use of cyclosporineversus TAC, and recurrent/chronic rejection. 4,9

Common Issues in Post-transplant Follow-up

Managing CommonProblems

Managing SpecicProblems

Vomiting ComplianceDiarrhea Liver dysfunctionFever GrowthMissed medications DevelopmentInfection contact Skin problemswarts,

eczema, solar cancersDental care Pregnancy and fertility

Table 2912.



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Functional and Long-term OutcomesWith careful follow-up management and close attentionto detail, most pediatric liver transplant recipients canexpect an excellent long-term outcome. There is remark-able recovery from the effects of their liver or metabolic

disease, an expectation of long-term survival with goodgraft function, catch-up growth (albeit sometimesincomplete), and a good quality of life. 8,15 In general, inthe rst 5 years post-transplant, parents report higheremotional stress and disruption of family activitiescompared to a normal population, although the level offamily function appears normal. At 10 years post-trans-plant, 95% of survivors have normal graft function,and self-report good to excellent quality of life and nor-mal school achievements. 16,17 Non-adherence to themedical regimen is perhaps the most important predic-tor of late graft dysfunction, and health-related qualityof life may independently correlate with non-adherence.As improvements are being realized in long-term immu-nosuppression regimens, notably minimizing immuno-suppression, a diminishing number of patients sufferlong-term complications of immunosuppression. Theseinclude altered diabetes, decreased renal function,hypertension, cancer, and osteopenia.

Information on OutcomesIn the United States, all transplants and transplant out-comes are monitored by the Organ Procurement andTransplant Network (OPTN), whose primary purposesare to operate and monitor equitable allocation of organsdonated for transplantation, maintain a waiting list of

potential recipients, match recipients with donor organsaccording to established criteria, and facilitate the ef-cient, effective placement of organs for transplantation.Outcome data are available in the public domain, andpractitioners and families can view national, regional,and individual center risk-adjusted waiting times, andoutcomes by accessing the OPTN website.

REFERENCES 1. Yersiz H, Cameron AM, Carmody I, et al. Split liver trans-

plantation. Transplant Proc . 2006;38(2):602603. 2. Freeman RB Jr, Wiesner RH, Roberts JP, McDiarmid S,

Dykstra DM, Merion RM. Improving liver allocation:MELD and PELD. Am J Transplant . 2004;4(suppl 9):114131 [review].

3. Magee JC, Krishnan SM, Beneld MR, Hsu DT, ShneiderBL. Pediatric transplantation in the United States, 19972006. Am J Transplant . 2008;8(4 Pt 2):935945.

4. Martin SR, Atkison P, Anand R, Lindblad AS, SPLITResearch Group. Studies of Pediatric Liver Transplanta-tion 2002: patient and graft surv ival and rejection in pedi-atric recipients of a rst liver transplant in the UnitedStates and Canada. Pediatr Transplant . 2004;8(3):273283.

5. Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liverfailure in children: the rst 348 patients in the pediatricacute liver failure study group. J Pediatr . 2006;148(5):652658.

6. Bassett MD, Murray KF. Biliary atresia: recent progress. JClin Gastroenterol . 2008;42(6):720729 [review].

7. Chen LE, Shepherd RW, Nadler ML, Chapman WC, KotruA, Lowell JA. Liver transplantation and chemotherapy inchildren with unresectable primary hepatic malignancies:development of a management algorithm. J PediatrGastroenterol Nutr . 2006;43(4):487493.

8. Turmelle YP, Nadler ML, Anderson CD, Doyle MB, LowellJA, Shepherd RW. Towards minimizing immunosuppres-sion in pediatric liver transplant recipients. PediatrTransplant. 2009 Aug;13(5):553559.

9. Shepherd RW, Turmelle Y, Nadler M, et al., SPLIT ResearchGroup. Risk factors for rejection and infection in pediatricliver transplantation. Am J Transplant . 2008;8(2):396403.

10. Glassman P, Wong C, Gish R. A review of liver transplan-tation for the dentist and guidelines for dental manage-ment. Spec Care Dent . 1993;13(2):7480.

11. De Bleser L, Matteson M, Dobbels F, Russell C, De GeestS. Interventions to improve medication-adherence aftertransplantation: a systematic review. Transpl Int .2009;22(8):780797.

12. Surti B, Tan J, Saab S. Pregnancy and liver transplantation.Liver Int . 2008;28(9):12001206.

13. Coscia LA, Constantinescu S, Moritz MJ, RadomskiJS, Gaughan WJ, McGrory CH, Armenti VT; NationalTransplantation Pregnancy Registry. Report fromthe National Transplantation Pregnancy Registry(NTPR): outcomes of pregnancy after transplanta-tion. Clin Transpl. 2007:2942.

14. Anderka MT, Lin AE, Abuelo DN, Mitchell AA, Rasmus-sen SA. Reviewing the ev idence for mycophenolate mofetilas a new teratogen: case report and review of the litera-ture. Am J Med Genet A . 2009;149A(6):12411248.

15. Bucuvalas JC, Campbell KM, Cole CR, Guthery SL. Out-comes after liver transplantation: keep the end in mind. JPediatr Gastroenterol Nutr . 2006;43(suppl 1):S41S48.

16. Bucuvalas JC, Alonso E, Magee JC, Talwalkar J, Hanto D,Doo E. Improving long-term outcomes after liver transplan-tation in children. Am J Transplant . 2008;8(12):25062513.

17. Alonso EM, Neighbors K, Barton FB, et al., Studies ofPediatric Liver Transplant Research Group. Health-relatedquality of life and family function following pediatr ic livertransplantation. Liver Transpl . 2008;14(4):460468.

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