Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects




Abstract




Liver transplantation is the standard of care for end-stage liver disease in children and the vast majority of transplant recipients experience successful outcomes. Better preoperative care, enhanced surgical techniques, and improved immunosuppression strategies have led to the appropriate expectation of good short- and long-term outcomes. Increased indications for liver transplant have led to an ever-increasing number of liver transplant candidates and evaluation of past policies and practices has necessitated changes in allocation policy. Collaboration has also led to better outcomes. Fortunately, continued efforts to expand the use of the donor pool through varied surgical techniques and advanced technology allows more children to benefit from this life-saving and enhancing procedure.





Chapter 43 Liver Transplantation in Children: Indications and Surgical Aspects


M. Kyle Jensen , Marianne A. Kavan , and Manuel Rodriguez-Davalos



Introduction


Liver transplantation is the standard of care for end-stage liver disease in children and the vast majority of transplant recipients experience successful outcomes. Better preoperative care, enhanced surgical techniques, and improved immunosuppression strategies have led to the appropriate expectation of good short- and long-term outcomes. Increased indications for liver transplant have led to an ever-increasing number of liver transplant candidates and evaluation of past policies and practices has necessitated changes in allocation policy. Collaboration has also led to better outcomes. Fortunately, continued efforts to expand the use of the donor pool through varied surgical techniques and advanced technology allows more children to benefit from this life-saving and enhancing procedure.



Transplant Evaluation


The primary aim of a transplant evaluation is to identify candidates for whom liver transplantation (LTx) is the optimal treatment[1]. Multidisciplinary evaluation by transplant surgeons, hepatologists, transplant coordinators, social workers, nutritionists, pharmacists and other specialties such as cardiology, anesthesiology, dentistry and psychiatry, when indicated, prepare the patient and family for transplant.


Patients should be considered for transplant evaluation once they are diagnosed with any disease known to progress to liver failure. This includes infants with biliary atresia (BA) who remain jaundiced after hepatoportoenterostomy and individuals with metabolic conditions that cannot be controlled by diet or medications. The progression of liver disease is often exponential, suggesting that early warning signs of hepatic compromise, such as deteriorating synthetic function or refractory nutritional failure should lead to prompt evaluation and referral to transplant centers. Patients with acute hepatitis with mild coagulopathy should be considered for early transfer if necessary, to allow transplant evaluation. In children with acute liver failure (ALF) or rapidly progressive decompensation of chronic disease, aggressive critical care intervention is essential to maintain all other physiologic systems until a suitable donor organ becomes available.


It is generally better to contact the transplant center early and often regarding the patient status to facilitate transfer before the patient’s condition deteriorates. Timely referral for transplantation must occur before the expected progressive deterioration associated with liver disease, and before life-threatening complications, or contraindications to transplantation occur.


Table 43.1 summarizes key questions to answer with each transplant evaluation.




Table 43.1 Key Questions when Performing a Transplant Evaluation










  1. 1. Will liver transplantation improve both short-term and long-term survival compared to no transplantation?



  2. 2. Will transplantation improve quality of life?



  3. 3. Is there irreversible and progressive non-hepatic disease that will negate the effects of liver transplantation on outcome?



  4. 4. Is liver transplantation futile?



  5. 5. Is there psychosocial support sufficient to optimize outcome?


The transplant evaluation also ensures that medical and surgical management is optimized and that an effective pretransplant care plan is developed. This includes identifying non-hepatic complications of liver disease that might adversely affect the operative and postoperative outcome. A full cardiopulmonary and renal assessment is vital in these individuals. Nutritional assessment ideally includes mid-arm circumference or triceps skin fold thickness in addition to standard anthropometric measurements. Malnourished patients should have their nutritional intake optimized using nasoenteric feeding tubes with high calorie formulas, fat-soluble vitamin supplementation, or potentially using parenteral nutrition as required. Medications to treat encephalopathy, ascites, or complications of liver disease such as pruritus may be optimized. Patients should receive prophylaxis for bacterial peritonitis or recurrent cholangitis when indicated.


As nearly half of pediatric liver transplant patients are under six years old, with approximately 10% under one year, many have not been fully immunized. Immune status related to prior viral exposures and routine childhood immunizations should be assessed. Immunizations, particularly attenuated live viruses, and preventive dental care should be administered if time permits (usually four weeks). Current guidelines recommend no administration of live vaccines in an immunosuppressed transplant recipient. As these guidelines change periodically, review of published recommendations by the American Society of Transplantation is prudent.


Imaging studies help define vascular anatomy and allow screening for potential hepatic malignancies that affect listing status. Use of magnetic resonance imaging (MRI) and Doppler ultrasound should be given to limit excessive radiation exposure from serial computed tomography (CT) scans.


The patient and family should be educated regarding the expectations once placed on the waiting list. The evaluation should inform the family regarding the expected course before and after transplantation, and possible complications that may result. In autoimmune hepatitis (AIH), progressive familial intrahepatic cholestasis (PFIC) type 2 (BSEP deficiency) and primary sclerosing cholangitis (PSC), for example, the disease may recur. It is beneficial to discuss the indications for living related liver transplantation, such as the survival benefit in younger patients, and the risk to the donors who are often the parents.


Further evaluation from a psychosocial standpoint is critical. An appropriate support system (i.e., two caregivers) is needed. Other challenges such as financial stressors, barriers to learning, or unrealistic expectations by parents or patient may impact the child’s care and outcome and should be identified. Older patients should be encouraged to ask questions and if possible should provide assent to the operation. It is prudent to begin educating adolescent or pre-teen patients regarding medication adherence, alcohol or other substance avoidance.



Indications and Contraindications


The most common clinical presentations prompting transplant evaluation in children can be classified as follows: (1) cholestatic liver disease; (2) chronic liver disease with extra-hepatic complications; (3) metabolic disease correctable with liver replacement; (4) acute liver failure; and (5) unresectable liver tumors including vascular malformations which may lead to progressive heart failure. Table 43.2 reviews characteristics of children who received liver transplantation over time.




Table 43.2 USA Pediatric Transplant Recipient Characteristics Over Time


























































2006 (number) Percentage (%) 2016 (number) Percentage (%)
Age


  • <1 year



  • 1–5 years



  • 6–10 years



  • 11–17 years





  • 65



  • 250



  • 174



  • 234






  • 9



  • 35



  • 24



  • 32






  • 53



  • 191



  • 96



  • 145






  • 11



  • 39



  • 20



  • 30


Indication


  • Cholestatic-BA



  • Cholestatic-other



  • Metabolic



  • ALF



  • Hepatoblastoma



  • Retransplant





  • 256



  • 96



  • 59



  • 44



  • 8



  • 189






  • 35



  • 13



  • 8



  • 6



  • 1



  • 11






  • 151



  • 58



  • 71



  • 20



  • 12



  • 145






  • 31



  • 12



  • 15



  • 4



  • 3



  • 9


Medical Urgency


  • Status 1A/1B



  • 35+



  • 30–34



  • 15–29



  • <15



  • Inactive





  • 6



  • 23



  • 47



  • 100



  • 183



  • 364






  • 1



  • 3



  • 7



  • 14



  • 25



  • 50






  • 31



  • 66



  • 55



  • 89



  • 115



  • 129






  • 6



  • 14



  • 11



  • 18



  • 24



  • 27


Exceptions granted 69 10 149 31
Wait time


  • <31 days



  • 31–90 days



  • 3-<6months



  • 6–12 months



  • 1–2 years



  • >2 years





  • 688



  • 408



  • 290



  • 187



  • 85



  • 62






  • 40



  • 23



  • 17



  • 11



  • 5



  • 3






  • 538



  • 447



  • 303



  • 206



  • 127



  • 62






  • 32



  • 27



  • 18



  • 12



  • 7.5



  • 4


ABO


  • Compatible



  • Incompatible





  • 1688



  • 38






  • 98



  • 2






  • 1602



  • 81






  • 95



  • 5


Donor type


  • Deceased



  • DCD



  • Living





  • 1552



  • 14



  • 174






  • 90



  • 0.8



  • 10






  • 1490



  • 6



  • 193






  • 89



  • 0.4



  • 11



Absolute contraindications to transplantation include: (1) primary extra-hepatic unresectable malignancy; (2) progressive terminal non-hepatic disease; (3) uncontrolled systemic sepsis; and (4) irreversible, severe neurologic injury. Relative contraindications to transplantation which must be individually evaluated and addressed include: (1) AIDS; many centers also consider HIV positive serology a contraindication; (2) advanced or partially treated systemic infection; (3) advanced hepatic encephalopathy-grade IV; (4) severe psychosocial abnormalities, including substance abuse; (5) malignancy metastatic to the liver; and (6) metastatic liver tumors unresponsive to chemotherapy.



Primary Liver Diseases Leading to Liver Transplantation



Cholestatic Syndromes


Children with BA constitute approximately 50% of the pediatric liver transplant population. Hepatoportoenterostomy (the Kasai procedure) should be the primary surgical intervention for all infants with BA unless the initial presentation is late in infancy (>120 days of age), the liver biopsy shows advanced cirrhosis, or the clinical course is unfavorable. In these rare patients, primary LTx is indicated [3]. Approximately 20% of patients with BA who undergo the Kasai procedure may not require LTx during childhood [4]. The sequential use of the Kasai procedure and LTx optimizes overall survival and organ utilization [5].


Clinical failure of the Kasai procedure can manifest as persistent bilirubin >2 mg/dL three months post-Kasai or various complications such as portal hypertension with refractory ascites or variceal bleeding even in patients with successful biliary drainage. Malnutrition, and/or progressive hepatic synthetic failure, or recurrent bacterial cholangitis are also indications to consider transplantation. Approximately 50% of all infants with BA will have one or more of these complications and will require LTx within the first two years of life. Later complications such as hypersplenism with variceal hemorrhage or complications of portal hypertension such as hepatopulmonary syndrome typically lead to LTx after the child is over two years of age.


Other cholestatic conditions, such as PFIC or Alagille syndrome may also cause cirrhosis with synthetic liver dysfunction and/or portal hypertension causing variceal bleeding. In children afflicted with these conditions, indications for transplant also include intractable pruritus, marked osteodystrophy with recurrent fractures recalcitrant to medical therapy or rarely hepatocellular carcinoma [6].



Hepatic-Based Metabolic Disease


A leading indication for liver transplantation in children is hepatic-based metabolic disease of which alpha-1 antitrypsin deficiency is most common. Please refer to relevant chapters for additional information on each topic. The frequency of LTx for urea cycle defects (UCD) and organic acidemias has also increased substantially over the past decade [7]. In metabolic patients, LTx can be lifesaving when end-stage liver disease results, but can also accomplishes phenotypic and functional cure of the disease. Liver replacement corrects the metabolic defect and should be considered before other organ systems are significantly or irreversibly affected, or irreversible quality-of-life compromises or complications develop that would preclude transplantation. Patients with UCD, for example, who have repetitive hyperammonemic crises, sustain significant neurologic injury with resulting developmental disability. Early transplantation allows the potential for neurologic protection and recovery with preservation of neurologic function and quality of life. The use of living donors who are heterozygous carriers of UCD has also been successful and allows planned early transplantation [8].


Patients with tyrosinemia historically had a high risk of developing liver failure or hepatocellular carcinoma (HCC), requiring LTx before extrahepatic spread of the tumor occurred. Currently, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) or nitisinone is considered to be first-line therapy for tyrosinemia. Nitisinone, through inhibition of 4-hydroxyphenylpyruvate oxidase, prevents dysplasia and HCC, thus obviating the need for LTx.


Gestational alloimmune liver disease (GALD), also known as congenital alloimmune hepatitis and formerly known as neonatal iron storage disease [9], presents a challenge in diagnosis and management. Most patients present at birth or within weeks with acute liver failure with hypoglycemia, marked coagulopathy, but minimal elevation of liver enzymes [10]. Diagnosis is made by MRI demonstration of extrahepatic iron deposition or by buccal biopsy demonstrating hemosiderin deposition within the salivary glands. The use of exchange transfusion and IVIG therapy has shown promise by increasing survival and reducing the need for LTx [11]. Of the patients who do respond to medical therapies, hypoglycemia often improves within 24 hours of starting treatment, although coagulopathy does not normalize for several weeks. Nevertheless, survival is poor among live-born infants with liver failure, both among those medically treated as well as infants who have undergone liver transplantation.



Acute Liver Failure


Patients with acute liver failure (ALF) pose diagnostic and prognostic difficulties [12]. Rapid clinical deterioration frequently makes establishment of a primary diagnosis impossible before the need for urgent transplantation. The most common cause of ALF in children is a presumed, yet unidentified, viral illness; this is followed in relative incidence by drug toxicity, toxin exposure, and previously unrecognized metabolic disease. In infants, causes of ALF such as GALD or mitochondrial diseases must be considered.


Mitochondrial respiratory chain abnormalities, representing disorders in the electron transport proteins, present as ALF or as progressive liver disease with sudden decompensation [13]. Mitochondrial diseases are especially important to recognize during the evaluation process, if possible, as they represent multi-organ progressive diseases, which may not become evident until after LTx. Special attention should be given to patients with deoxyguanosine kinase (DGUOK) mutations, the most common type of mitochondrial DNA depletion associated with a hepatocerebral phenotype. Current literature would suggest that these individuals may be considered for transplantation if they do not manifest any neurologic abnormalities, however if abnormalities such as developmental delay or nystagmus exist, LTx is not appropriate since LTx does not improve survival for these patients [14]. A thorough evaluation of commonly affected, high energy utilizing organs (central nervous system, cardiac or skeletal muscle, etc.) must be carried out. In patients with multisystem involvement, albeit mild, transplantation is not curative, nor indicated. Additionally, patients with valproic acid-induced ALF are not transplant candidates, as one-year survival is significantly lower in this cohort of patients, even without a clear diagnosis of mitochondrial disease [15].


Patients may also present with primary or secondary hemophagocytic lymphohistiocytosis (HLH)-induced ALF. In children with HLH, inappropriate macrophage and natural killer cell activation causes severe hepatocyte injury. Epstein–Barr or other viruses may trigger the acquired form in an immunocompromised host. The primary treatment is hematologic, rather than organ replacement, as recurrence in the allograft frequently occurs, is suboptimal and data limited to small case reports [16].


Selection of ALF candidates for transplantation is difficult, as the natural history of each specific etiology is not clearly established. The King’s College Institute of Liver Studies has developed a scoring system for children with ALF, stratifying their risk [17]. Factors predictive of poor outcome included INR>4, serum bilirubin > 235 µmoles/L (13.8 mg/dL), age < 2 years, and WBC > 9,000/mm3. Sensitivity and predictive ability increase when multiple factors are present. Similarly, poor prognostic factors in other independent studies include the time to onset of encephalopathy >7 days, prothrombin time >55 sec, ALT < 2,384 IU/L on admission, grade 4 encephalopathy, infants <1 year, or the need for dialysis [18, 19]. Although these criteria are helpful, careful observation for progression and clinical change including worsening encephalopathy remains most valuable.


The role of liver biopsy is limited in ALF as these patients have marked coagulopathy necessitating a transjugular or open approach. Sampling error may also limit the accuracy of diagnosis or prognosis. When autoimmune hepatitis is considered, however, biopsy may be helpful as individual patients may respond to immunosuppression.


Patients who present with grade III–IV encephalopathy or those with progression to severe encephalopathy have worse outcomes [20]. When candidates undergo transplantation before developing irreversible neurologic abnormalities, survival improves greatly [20]. Patients who undergo LTx or recover spontaneously from ALF, however, may have suboptimal neurologic outcomes. Failure to maintain adequate cerebral perfusion pressure (mean arterial blood pressure (MAP) minus intracranial pressure [ICP]) of >50 mm Hg and an ICP <20 mm Hg) has been associated with very poor neurologic recovery post-transplantation [21].


For short-term stabilization, repetitive courses of plasmapheresis may be performed to ameliorate the clinical manifestations of ALF. Daily exchanges of volume equal to the extracellular volume (20% of body weight) are undertaken. Replacement fluids include fresh frozen plasma, platelets, and cryoprecipitate as needed. This will lead to temporary correction of coagulopathy and biochemical improvement. Plasmapheresis is also beneficial in preventing fluid overload that can result from factor replacement alone. Neurologic improvement is common but not sustained. There is no evidence that plasmapheresis enhances native liver recovery. Ultimately, LTx is the only effective treatment modality.



Liver Tumors


Liver tumors represent up to 10% of LTx cases. Liver malignancy can be primary, metastatic, or result from an underlying liver condition such as hepatocellular carcinoma in tyrosinemia or cholangiocarcinoma in sclerosing cholangitis. Children have undergone transplant for (1) hepatoblastoma; (2) hepatocellular carcinoma (HCC); (3) infantile hepatic hemangioma (IHH) with associated heart failure or Kasabach–Merritt syndrome; (4) metastatic neuroendocrine tumor (NET); (5) cholangiocarcinoma; or (6) sarcomas (biliary and vascular origin).


Hepatoblastoma (HBL) is the most common liver tumor requiring LTx. Children with biopsy-proven hepatoblastoma PRETEXT III or IV (SIOPEL classification) in which tumor size or central location prevents complete resection, or who have metastatic disease, should be referred to a transplant center for evaluation and multidisciplinary care. In the USA, these children, who have no lung metastases (before or after chemotherapy) qualify for additional priority (status 1B) on the waiting list. Children with metastatic pulmonary lesions may be considered for transplantation without 1B priority if pulmonary metastases remain after chemotherapy, although surgical resection of the metastases pre-LTx may be required.


Complete tumor resection remains the most crucial intervention to achieve long-term survival. According to the current Children’s Oncology Group algorithm, any tumor that remains unresectable after several rounds of chemotherapy requires complete hepatectomy with transplantation. Attempts at partial liver resection are ill-advised as survival rates after “rescue transplant” are far inferior. [22] For unresectable lesions, transplantation occurs ideally before completing chemotherapy, to allow an additional one to two cycles of chemotherapy post-LTx.


Hepatocellular carcinoma is the second most common hepatic malignancy in the pediatric population, primarily affecting children ten years or older who do not have metabolic liver disease [23]. Given the low incidence of HCC in children, experience with LTx for HCC was limited, but is rapidly increasing. HCC can present in patients with known liver disease and cirrhosis, but 20–60% of pediatric HCC occurs in non-cirrhotic livers. Important predisposing factors include prenatally acquired HBV and metabolic liver diseases such as tyrosinemia and PFIC II and IV. Glycogen storage disease (type 1), and portosystemic vascular (Abernethy) malformations each lead to adenomatous changes with infrequent transformation to HCC. Recent data showed HCC in Abernethy malformations typically develops later in life [24]. Screening for HCC is indicated in these conditions [24, 25]. Rare reports of HCC in patients with BA and Alagille also exist.


In children with HCC confined to the liver and associated metabolic disease, LTx is indicated with 1B prioritization. Although adults must fit within the Milan or UCSF criteria, cumulative data from the Pediatric Liver Unresectable Tumor Observatory registry suggests these criteria do not apply to pediatric HCC that is not associated with metabolic disease. Extrahepatic metastases remain an absolute contraindication to transplant. Chemotherapy alone does not appear to offer a survival advantage, unless complete tumor resection is also offered.


Additional liver tumors that may lead to LTx consideration include biopsy-proven embryonal sarcoma that has not metastasized or vascular malformations with Kasabach–Merritt syndrome or high-output cardiac failure requiring pressor or ventilatory support. Current policy suggests these children may receive 1B priority, but inadequate evidence exists currently to support additional priority for rhabdoid tumors or angiosarcoma.


Candidates with metastatic neuroendocrine tumor NET also benefit from LTx in select circumstances [26]. The primary malignancy must result from gastro-entero-pancreatic origin with portal system drainage and this and any extra-hepatic disease must be resected without recurrence for six months. Primary NET from other areas do not receive the same priority. Extra-hepatic solid organ metastases (i.e., bones, lungs) are permanent exclusion criteria [27].


Candidates with cholangiocarcinoma (CCA) must meet strict criteria as outlined in the OPTN policies [28]. This includes having an unresectable lesion after receiving chemotherapy followed by operative staging that excludes regional, intra- or extrahepatic metastases. Diagnosis of CCA requires a malignant appearing stricture on cholangiography and at least one of the following: biopsy or cytology with malignancy, CA-19–9 >100 U/mL in absence of cholangitis, or aneuploidy. Endoscopic ultrasound aspiration of regional hepatic lymph nodes may identify patients with obvious metastases, but percutaneous/transperitoneal biopsies of the primary tumor should be avoided due to seeding risk.



Cystic Fibrosis


Prolonged survival of patients with cystic fibrosis (CF) has increased consideration of selected individuals for liver transplantation. Liver disease occurs in up to one-third of children with CF depending on definition used. Significant portal hypertension develops in approximately 10% [29]. Direct management of portal hypertensive variceal bleeding by variceal banding and portosystemic shunting allows prolonged survival, but in the uncommon patient with hepatic synthetic decompensation, LTx should be considered. Signs of advanced portal hypertension, including hepatic encephalopathy (HE), diuretic refractory ascites, and recurrent variceal bleeding, are late complications that warrant referral for LTx evaluation. Traditionally, malnutrition and poor growth were treated as an indication for LTx. Data, however, does not show uniform improvements in this scenario, however, for which we recommend advanced portal hypertension as the primary LTx indication [30]. Combined liver-lung transplantation has been performed for patients with pulmonary compromise (FEV1 <50%) and because of the increased mortality rate without transplantation, exception points are available for patients with FEV1 <40% according to UNOS policy on liver allocation in patients with cystic fibrosis [31].


Special considerations include the impact of cystic fibrosis-related diabetes and infectious considerations which may require modifications of standard antimicrobial prophylaxis. A recent review also advocated for immediate treatment of chronic sinusitis, nasal polyps, or bronchoscopy in the setting of >6 months wait time or changes in pulmonary status to evaluate the respiratory flora [29]. Optimizing pulmonary status before and preparing for needed respiratory therapies after are vital. Postoperative long-term survival is compromised primarily by cardio-pulmonary events, but the increased risk of polymicrobial or fungal sepsis and potential malnutrition also influences survival.



Retransplantation


In children, vascular complications most commonly cause early retransplantation with chronic rejection being the leading cause of late retransplantation. The overall incidence of retransplantation ranges from 3–20%. Although the technical complexity of LTx in children increases with surgically reduced allografts, the incidence of retransplantation is similar between primary whole organ and reduced-size allografts. Special attention should be paid to the renal function in these patients as well as their increased risk of bleeding and bowel injury during the hepatectomy phase of retransplantation. Although limited data exists, experience suggests good outcomes are achievable with appropriate preparation [32].



Prioritization and Allocation


In 1984, the US government established the Organ Procurement and Transplantation Network (OPTN) to develop a system to distribute organs equitably. The amount of time accrued on the pre-transplant waiting list and severity of illness, as expressed by patient location (home, hospital, intensive care unit), were the primary factors used to stratify patients. In 1996, the Child-Turcotte-Pugh (CTP) scoring system was adopted to stratify patients based on disease severity. This system utilized total bilirubin, albumin, INR, presence and severity of ascites and hepatic encephalopathy to classify patients into three categories based on survival rates. With only three categories, however, waiting time again became a dominant factor in organ allocation. Later studies demonstrated that in this system, waiting time had no relationship to risk of death, except for urgent status 1 patients, leading to dissatisfaction with the existing system [33].


A re-evaluation of this system by the Health Resources and Services Administration in 1998 established the “Final Rule,” requiring allocation policies to be based on sound medical judgment using defined criteria in order to achieve the optimal use of donated organs [34]. Using knowledge gained from the Mayo End-Stage Liver Disease model, the Model for End-Stage Liver Disease (MELD) was established using three biochemical values: serum creatinine, serum bilirubin, and INR. The resulting score prioritizes adolescents aged 12–17 years and adults.


Using information derived from the Studies of Pediatric Liver Transplantation (SPLIT), the Pediatric End-Stage Liver Disease (PELD) scoring system which utilizes total bilirubin, INR, serum albumin, age less than one year, and growth failure (either height or weight two standard deviations below normal), was adopted in 2002 for children less than 12 years of age. The details of these scoring algorithms are shown in Figure 43.1. As the biochemical values or patient condition changes, so does individual MELD/PELD score. At a minimum, labs should be repeated, and the patient’s score recalculated, every seven days for status 1 A or 1B, every 14 days for MELD/PELD ≥25, 30 days if 19–24, every 90 days for scores 11–18 and 365 days if <10. Table 43.4 reviews criteria to list a patient status 1 A or status 1B.


Liver candidates less than 18 years old can be listed:




  • Status 1A



  • Status 1B



  • Calculated MELD/PELD score



  • Exception MELD/PELD score



  • Inactive status


Criteria to list a patient status 1 A or 1B are listed in Table 43.3.












  • MELD Formula (12–18+ years of age)



  • MELD Score = 0.957 x Loge(creatinine mg/dL)



  • + 0.378 x Loge(bilirubin mg/dL)



  • + 1.120 x Loge(INR)



  • + 0.643



  • MELD-Na = MELD Score – Na – 0.025 x MELD x (140-Na) + 1401



  • PELD Formula (<12 years old)



  • PELD Score = 0.480 x Loge (bilirubin mg/dL)



  • + 1.857 x Loge (INR)



  • – 0.687 x Loge (albumin g/dL)



  • + 0.436 if the patient is less than 1 year old



  • + 0.667 if the patient has growth failure (<-2 Standard deviation)



  • (Scores for patients listed for liver transplantation before the patient’s first birthday continue to include the value assigned for age (< 1 Year) until the patient reaches the age of 24 months)



  • For both formulae multiply the score by 10 and round to the nearest whole number. Laboratory values less than 1.0 are set to 1.0 for the purposes of the MELD/PELD score calculations.




Figure 43.1 Details related to MELD/PELD calculation




Table 43.3 Criteria to List Pediatric Patients Status 1













Status 1A



  1. 1. Acute liver failure with encephalopathy and one of the following:




    1. a. Ventilator dependence



    2. b. Dialysis or continuous veno-venous hemofiltration (CVVH) or CVVD



    3. c. INR >2.0




  2. 2. Primary non-function of a transplanted liver within 7 days of implantation



  3. 3. Hepatic artery thrombosis within 14 days of transplantation



  4. 4. Acute decompensated Wilson Disease

Status 1B



  1. 1. Biopsy-proven hepatoblastoma without evidence of metastatic disease



  2. 2. Organic acidemia or urea cycle defect and an approved MELD or PELD exception meeting standard criteria for metabolic disease for at least 30 days



  3. 3. Chronic liver disease with a calculated MELD or PELD greater than 25, and has at least one of the following criteria:




    1. a. Is on a mechanical ventilator



    2. b. Has gastrointestinal bleeding requiring at least 30 mL/kg of red blood cell replacement within the previous 24 hours



    3. c. Has renal failure or renal insufficiency requiring dialysis, continuous veno-venous hemofiltration (CVVH), or continuous veno-venous hemodialysis (CVVHD)



    4. d. Has a Glasgow coma score (GCS) less than 10 within 48 hours before the status 1B assignment or extension




  4. 4. Chronic liver disease and is a combined liver-intestine candidate with an adjusted MELD or PELD score greater than 25 and has at least one of the following criteria:




    1. a. Is on a mechanical ventilator



    2. b. Has gastrointestinal bleeding requiring at least 10 mL/kg of red blood cell replacement within the previous 24 hours



    3. c. Has renal failure or renal insufficiency requiring dialysis, continuous veno-venous hemofiltration (CVVH), or continuous veno-venous hemodialysis (CVVHD)



    4. d. Has a Glasgow coma score (GCS) less than 10 within 48 hours before the status 1B assignment or extension



Initial concerns that identification and transplantation of “sicker patients first” would lead to decreased survival did not prove correct. In the first year of PELD, allograft and patient survival remained unchanged from the prior allocation system [35]. Of greater concern was the perceived failure of the PELD system to quantify candidate risk appropriately as the majority of infants and children allocated organs have achieved a PELD score sufficient for transplantation through special exception points, or status 1 (emergency transplantation).


Initial evaluation of this scoring system demonstrated ability to predict three-month mortality while on the waiting list [35]. Since the inception of PELD, great debate has occurred that PELD underestimates the risk of death, especially in infants. Later studies demonstrated that MELD/PELD scores can be improved upon if hyponatremia is considered in the scoring calculation [36, 37]. This allowed MELD-Na to became standard in 2016 when standard MELD score is >11 [38]. More recent data suggests PELD may not allow timely allocation of livers to children leading to ~10% risk of death on the pediatric liver waitlist [39]. Recent SRTR data demonstrated that children under one year of age have a higher rate of mortality (19 deaths per 100 waitlist years) [2]. Furthermore, under prior UNOS policy, adults listed locally and regionally on the waitlist were prioritized above children listed nationally for the same organ [39].


When a PELD/MELD score does not adequately reflect the patient’s need for transplant, the provider can request additional points termed “exceptions.” Recent data demonstrates dramatic increases in the use of exceptions over the past ten years [2]. Under OPTN policy, standardization of specific MELD/PELD exception scores are awarded for certain risk factors not represented by the MELD/PELD equations including: hepatopulmonary or portopulmonary syndrome, urea cycle defects, hepatic neoplasms, CF with respiratory compromise, primary hyperoxaluria or amyloidosis. These automatic exceptions do not require evaluation of the NLRB as long as criteria are met.


Transplant programs may also request individual exception scores for candidates by the procedure set forth in OPTN Policy 9.4 (MELD or PELD score exceptions). With proposed changes the median PELD at transplant (MPaT) would be employed to assist in the standardization of exception points. MPaT is calculated by using the median of the PELD scores at the time of transplant of all recipients less than 12 years of age in the nation and median MELD at transplant will be based on MELD in a particular donor service area (DSA). The MPaT is the same for all transplant programs in the nation with PELD exception candidates. This value will be recalculated every 180 days using the previous 365-day cohort. The MPaT calculations exclude recipients with a status 1 A or 1B at the time of transplant and those who received livers from living or DCD donors.


At the time of writing, UNOS proposed changes aimed to improve equity in allocation policy. Specific changes include replacement of the regional review system with a National Liver Review Board. The new liver distribution system aims to prioritize livers from deceased donors younger than 18 years to any candidates younger than age 18 listed at any transplant hospital within 500 nautical mile radius of the donor hospital, ahead of adult candidates of the same medical urgency.

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Feb 26, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects
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