For end-stage liver disease, liver failure, and inherited metabolic liver disease in children (less than 16 years of age) with various causes, surgical implantation of a complete or partial allogeneic liver into the child to restore normal liver function or inherited metabolic disorders is called pediatric liver transplantation.
Introduction to pediatric liver transplantation
Liver transplantation in children was born alongside clinical liver transplantation in humans, and in 1963, Thomas Starzl performed the world’s first attempt at liver transplantation in a 3-year-old child with biliary atresia, Bennie Solis, which failed but undoubtedly ushered in a new era of transplantation surgery. After nearly half a century of development since then, liver transplantation in children has continued to improve in terms of surgical technique, anesthesia management, donor liver acquisition and preservation, immunosuppression, and management of postoperative complications, and has become the best treatment for end-stage liver disease, liver failure, inherited metabolic liver disease, and liver malignancies in children for which conventional treatments are ineffective.
Liver transplantation in children is divided into cadaveric liver transplantation and living liver transplantation depending on the source of the donor. The donor for cadaveric liver transplantation is mainly from organ donation after brain death or cardiac death after brain death. The method of surgically obtaining the whole liver or part of the liver of the organ donor to replace the whole or part of the diseased liver of the child is called cadaveric liver transplantation in children. The surgical removal of a portion of the liver of a healthy child’s immediate family member within three generations for implantation into the child to replace part or the entire diseased liver is called pediatric living liver transplantation. The development of cadaveric liver transplantation in children has been limited by the late start of organ donation in China, the low percentage of organ donation, the limited number of cadaveric donor livers from organ donation sources, and the mismatch between cadaveric donor livers and donor-recipient sizes in pediatric liver transplantation. Living liver transplantation is a mature technique with clear therapeutic results, alleviating the problem of organ shortage, and is the most commonly used pediatric liver transplantation procedure in China, Japan, Korea, Singapore and other Asian regions.
Indications for pediatric liver transplantation
Liver transplantation is the best treatment for children with end-stage liver disease, liver failure, hereditary metabolic liver disease and liver malignancies for which conventional treatment is ineffective (see table below) due to various causes. Biliary atresia is the most common disease in pediatric liver transplantation. In countries and regions with early development of pediatric liver transplantation, such as Europe, America, Japan, Korea and Taiwan, biliary atresia disease accounts for more than 50% of pediatric liver transplantation, and in mainland China, biliary atresia disease accounts for more than 80% of all pediatric liver transplantation procedures performed. For children with biliary atresia who have undergone kasai surgery successfully, if the post-kasai regression is not satisfactory (total bilirubin over 100umol/L at 3 postoperative hours), liver transplantation should be considered as soon as possible, and for children with biliary atresia who have clear post-kasai regression, if they have refractory cholangitis, growth retardation, upper gastrointestinal tract hemorrhage due to cirrhotic portal hypertension, hypoproteinemia, hypoglycemia, and atresia, they should be considered for liver transplantation. If a child with biliary atresia has refractory cholangitis, growth retardation, upper gastrointestinal bleeding due to portal hypertension, hypoproteinemia, ascites, prolonged coagulation time and other clinical manifestations of cirrhosis, liver transplantation should be considered.
Indications for liver transplantation in children
Cholestatic diseases.
Biliary atresia.
Byler’s disease – progressive familial abnormalities of intrahepatic bile duct development.
intrahepatic bile duct dysplasia.
Syndromic type (Alagille syndrome) – familial abnormal development of the hepatic arteries.
Non-syndromic type.
Sclerosing cholangitis.
Familial cholestasis.
Fulminant hepatic failure.
Viral (hepatitis A, hepatitis B).
Toxic (pharmacologic, fungal plants).
Metabolic.
Pharmacologic (acetaminophen, isoniazid).
Metabolic.
Alpha1-antitrypsin deficiency disease.
Wilson’s disease – abnormal copper metabolism.
Crigler-Najjar syndrome-glucuronosyltransferase deficiency.
Hypertyrosinemia.
Urea cycle disorders-hyperammonemia.
Familial hypercholesterolemia.
Selective lipid deposition disorders.
Glycogen accumulation disorders.
Neonatal iron deposition disease.
Hyperoxaluria.
Niemannpick disease.
Selective organic acidemia-propionic acidemia, etc.
Chronic active hepatitis, liver cirrhosis.
Autoimmune disorders.
Idiopathic neonatal hepatitis.
Chronic hepatitis B or C.
Cryptogenic cirrhosis.
Neoplasms.
Hepatoblastoma.
Hepatic hemangioendothelioma.
Hepatic sarcoma.
Hepatocellular carcinoma.
Langerhans histiocytic proliferative syndrome.
Others.
Budd-Chiari syndrome.
Trauma to the liver.
Congenital portacaval shunt.
Congenital hepatic fibrosis.
Cystic fibrosis.
Total parenteral nutrition secondary to cirrhosis.
Contraindications to liver transplantation in children.
Absolute contraindications.
Extrahepatic metastases and rapidly progressive hepatocellular liver cancer.
Broad extrahepatic malignancies (except hepatoblastoma with intrapulmonary solitary metastatic lesions).
Uncontrollable systemic infections.
Severe multisystemic mitochondrial disease.
Hepatic failure due to sodium 2-propylvalerate.
Niemannpick’s disease type C.
Severe pulmonary hypertension that is refractory to drug therapy.
Relative contraindications.
Hepatocellular hepatocellular carcinoma with vascular invasion.
Rapid tumor progression despite chemotherapy.
Non-adherence that remains highly established after multidisciplinary intervention and support.
Phagocytic lymphohistiocytic hyperplasia.
Difficult status that remains unchanged despite psychosocial interventions.
Preoperative examination and evaluation for liver transplantation in children.
Prior to pediatric liver transplantation, the child requires a systematic preoperative examination and evaluation within his or her chosen liver transplantation medical facility.
Components of the preoperative examination and evaluation of the recipient (biliary atresia as an example).
Laboratory examination component: liver and kidney function, blood lipids, blood glucose, routine blood tests, coagulation series, arterial blood gases, blood electrolytes + calcium, phosphorus, magnesium, blood group, antibodies to hepatitis B two-to-one, hepatitis C, HIV, syphilis, methemoglobin, blood ammonia, EBV, CMV-DNA, EBV, CMV- IgG IgM)
Imaging evaluation of the liver and its blood vessels.
1, complete set of liver vascular ultrasound (to assess the size and morphological echogenic changes in the liver, as well as the size of the morphological structures of the hepatic artery, hepatic vein and portal vein, the presence of thrombus and the blood flow, with particular attention to the direction of portal blood flow).
2. CTA of the upper abdomen: assessment of the morphology and structure of the liver and adjacent organs, morphology and structure of the hepatic artery, portal vein, inferior vena cava, presence of thrombus, varices, etc.).
3.Evaluation of important organ functions
(1) Cardiac ultrasound: mainly used to exclude congenital heart disease and pulmonary hypertension, if abnormalities occur, further evaluation by pediatric cardiology is needed
(2) Electrocardiogram: mainly used to assess the presence of pathological arrhythmias
(3) Pulmonary CT scan and airway reconstruction: to assess the presence of pulmonary infections and abnormalities of the thorax and airway development Arterial blood gas analysis to assess pulmonary oxygenation
The main purpose of the recipient examination and evaluation is to clarify the indications for liver transplantation and to exclude contraindications to liver transplantation. Liver transplantation is the most common form of liver transplantation in children.
Preoperative Examination and Evaluation of the Donor
General medical history: Age must be older than 18, younger than 60, height, weight, BMI less than 28, diabetes mellitus, hypertension, dyslipidemia, smoking.
Hypertension, dyslipidemia Smoking, alcohol abuse History of abdominal surgery
2. Laboratory examination part: liver and kidney function, blood lipids, blood glucose, blood routine, coagulation series, arterial blood gas, blood electrolytes + calcium, phosphorus, magnesium, blood type, hepatitis B two-to-one, hepatitis C, AIDS, syphilis antibodies, methemoglobin, blood ammonia, EBV, CMV-DNA, EBV, CMV-IgG IgM, tumor markers AFP, CEA, CA199, CA125, women need to HCG check.
Imaging evaluation of the liver and its vasculature.
(1) Complete set of hepatic vascular ultrasound (to assess the size and morphological echogenic changes of the liver, as well as the morphological and structural canal size of the hepatic artery, hepatic vein and portal vein).
(2) CTA of the upper abdomen: the ratio of liver to spleen CT values is used to determine the presence of fatty liver, for liver/spleen CT values less than 0.75, the need to correct fatty liver through dietary control, exercise, assessment of the morphology and structure of the liver and adjacent organs of the liver, hepatic artery, portal vein, hepatic vein, morphology and structure, the presence of vascular variants that are not suitable for graft acquisition.
(3) MRCP: It is used to assess the morphology and structure of the biliary tract. For infant living liver transplantation, the left lateral lobe of the donor’s liver is usually removed as a graft, and intraoperative cholangiography is generally not used to dissect the bile ducts, but it is still needed for cases where the direction of the biliary tract cannot be accurately determined.
3.Evaluation of important organ functions
(1) Cardiac ultrasound: mainly used to exclude potential heart disease, if there is an abnormality, further evaluation by the cardiology department is required.
(2) Electrocardiogram: mainly used to assess the presence of pathological arrhythmias.
(3) Pulmonary CT: to assess the presence of lung infections, tumors and abnormalities of the thoracic structure Arterial blood gas analysis to assess the oxygenation function of the lungs.
After completion of the donor matching test, a systematic evaluation is performed, and if the donor requirements for living liver transplantation are met, the appropriate time is chosen for living liver transplantation. It is important to emphasize that if the donor is preoperatively positive for hepatitis B core antibodies, the recipient is at significantly higher risk of postoperative hepatitis B infection, and the incidence of hepatitis B infection in this group of children is significantly reduced with prophylactic use of nucleoside analogues.
Vaccination planning for children undergoing liver transplantation
Some children requiring liver transplantation lack systematic vaccination before surgery, and some live attenuated vaccines cannot be administered after liver transplantation due to the use of immunosuppressive drugs. Therefore, it is necessary to improve vaccination planning according to the specific conditions of preoperative vaccination of the children. The vaccines that children need to be routinely vaccinated before liver transplantation include: varicella, measles, pneumococcal, hepatitis A and hepatitis B.
Name of vaccine.
Inactivated/attenuated
Recommended prior to transplantation.
Recommended post-transplant.
Diphtheria.
Inactivated.
Recommended.
Recommended.
Whooping cough.
Inactivation.
Recommended.
Recommended.
Tetanus.
Inactivation.
Recommended.
Recommended.
Inactivated poliomyelitis.
Inactivation.
Recommended.
Recommended.
Haemophilus influenzae B.
Inactivation.
Recommended.
Recommended.
Pneumococcus.
Inactivation.
Recommended.
Recommended.
Diplococcus meningitidis.
Inactivation.
Recommended.
Recommended.
Influenza virus.
Inactivation.
Inactivation.
Recommended.
Not recommended.
Recommended.
Not recommended.
Hepatitis A.
Inactivation.
Recommended.
Recommended.
Hepatitis B.
Inactivation.
Recommended.
Recommended.
Measles.
Decrease in activity.
Recommended.
Not recommended.
Mumps :
Less active.
Recommended.
Not recommended.
Rubella.
Decrease in activity.
Recommended.
Not recommended.
Chickenpox.
Less active.
Recommended.
Not recommended.
Rotavirus.
Inactivated.
Recommended.
Not recommended.
Human papillomavirus.
Inactivation.
Recommended.
Recommended.
BCG vaccine.
Decrease in activity.
Recommended.
Not recommended.
Rabies vaccine.
Inactivated.
Recommended.
Recommended.
Smallpox.
Attenuated.
Not recommended.
Not recommended.
Anthrax.
Inactivation.
Not recommended.
Not recommended.
Remarks: Vaccinations required routinely before liver transplantation in children: varicella measles pneumococcal hepatitis A hepatitis B
live attenuated vaccines are usually contraindicated after liver transplantation.
varicella vaccine is not recommended in children on long-term immunosuppressive therapy
some biosynthetic vaccines are safe for children with liver transplants vaccination also produces a good immune response in low immunosuppressed states
annual influenza vaccination is required for the child and the parents caring for the child
Preoperative immunization of one kind should be completed two weeks before surgery.
Use of immunosuppression after liver transplantation in children
Effective immunosuppression should be routinely used after surgery for both pediatric cadaveric and live liver transplantation. The use of immunosuppression is a key factor in preventing acute and chronic rejection and ensuring the long-term survival of the graft. Cyclosporine A and Tacrolimus are both calcium phosphatase inhibitors (CNI) and have been widely used in pediatric liver transplantation since their introduction. Both have similar mechanisms of action, inhibiting the activation of T lymphocytes by suppressing the production and expression of related multicytokines, significantly reducing the incidence of acute and chronic rejection reactions. This significantly reduces the incidence of acute and chronic rejection, thereby significantly improving the long-term survival of the graft and the child. Tacrolimus and cyclosporine A are the first-line immunosuppressive drugs in children after liver transplantation, and the blood levels of immunosuppressive drugs need to be monitored regularly after surgery, and the dose of immunosuppressive drugs should be adjusted according to the level of blood levels and the liver function status and systemic condition of the children. Most pediatric liver transplantation centers use tacrolimus as the base drug in the post-transplantation immunosuppression regimen, and its immunosuppressive efficacy is closely related to its blood levels. The genotype of CYP3A5 enzyme system is closely related to the metabolism of tacrolimus, and the genotype combination of CYP3A5 enzyme system is divided into two types: fast metabolism and slow metabolism.
In children with tacrolimus or cyclosporine A-based immunosuppressive regimens after liver transplantation, a combination of glucocorticoids, primaquine (morte-macrolimus capsules) and sirolimus is often required in the early postoperative period to prevent the development of acute rejection. children can maintain normal graft function with tacrolimus (blood levels <6ng/ml) or cyclosporine (blood levels <100ng/ml) alone (as determined by blood collection for liver function). In some pediatric liver transplant patients with renal impairment and underlying renal disease, due to the nephrotoxicity of CNI drugs, a gradual reduction in the dose of CNI drugs is required after liver transplantation to prevent further impairment and deterioration of renal function and to achieve minimal use of CNI drugs. Minimization of immunosuppressive drugs (defined as once-daily dosing of CNI analogs) needs to be considered in children more than 5 years after liver transplantation if there is no history of chronic rejection, normal liver function tests, and liver biopsy tissues suggesting minimal or no manifestation of inflammatory reaction and less than grade III fibrosis in the hilar region. Some transplantation centers in Japan, Korea, and Europe and the United States have also reported a small percentage of children who have achieved a state of functional immune tolerance with complete withdrawal of immunosuppression after liver transplantation.
Postoperative complications after liver transplantation in children
Complications after liver transplantation in children include primary liver non-function, hepatic artery thrombosis or portal vein thrombosis, sepsis and multi-organ failure (<10%<) are the main causes of graft loss at 1 week after liver transplantation in children, and some other complications include acute kidney injury, acute rejection, chronic rejection, biliary fistula or biliary stricture, infections (especially cytomegalic and EB virus infection), post-transplantation lymphocytic disorder (PTLD), hypertension, diabetes, hyperlipidemia, chronic renal impairment, malignancy, etc. The timely detection and diagnosis of complications and effective intervention and treatment can improve the prognosis of children. The use of color Doppler ultrasound to assess hepatic artery hemodynamics during pediatric living liver transplantation and early post-transplantation in infants and children (<3 years old) is important in predicting early complications of hepatic artery thrombosis. In infants and children with liver transplantation, because the recipient is often EBV serologically negative prior to transplantation and the donor is often EBV serologically positive, EBV infection often occurs after liver transplantation with the use of immunosuppressive drugs, and long-term chronic EBV infection can lead to post-transplantation lymphocytic proliferation disorder (PTLD), in which children develop unexplained fever, anemia, abdominal pain, superficial Symptoms such as unexplained fever, anemia, abdominal pain, superficial lymph node enlargement, and enlarged lymph nodes seen on abdominal ultrasound or enhanced CT or foci with abnormal metabolic activity seen on PET-CT are of great value for the diagnosis of PTLD. If the lesion remains uncontrolled or continues to progress after these treatments, treatment with melphalan and, if necessary, surgical resection may be considered.
Long-term prognosis after liver transplantation in children
Liver transplantation in children has accompanied the history of human liver transplantation, from 1963 when Thomas Starzl performed the world’s first liver transplantation attempt on Bennie Solis, a 3-year-old child with biliary atresia, to 1988 when Dr. Raia reported the living liver transplantation in children. With the continuous improvement of perioperative management and the establishment of effective long-term postoperative follow-up mechanism, most post-transplant children have achieved long-term survival.
Pediatric liver transplantation has significantly altered the prognosis of children with end-stage liver disease, liver failure, and metabolic disease. Studies have shown that the main factors affecting survival after pediatric liver transplantation are the recipient’s primary disease, the recipient’s preoperative weight and nutritional status, the pediatric end-stage liver disease (PELD) score, the recipient’s preoperative ICU monitoring and need for mechanical ventilation, and the donor-recipient ABO blood type match. Some advanced pediatric liver transplantation centers in China and abroad have survival rates of more than 90% at one year after liver transplantation and 75% at 15 to 20 years, and these long-term surviving pediatric post-liver transplant patients have a good quality of life.