Pediatric Liver Transplantation as Enzyme Replacement Therapy for Rare Metabolic Diseases with No Structural Liver Damage

Objective: Very rare monogenic metabolic diseases without structural liver damage can be cured by liver transplantation. This process is a surgical enzyme replacement therapy, and defective enzymes may or may not be confined to the liver. The aims of this single center study of children with metabolic diseases showing structurally normal liver parenchyma were to analyze the indications and post-operative outcomes of liver transplantation, identification of developmental and metabolic benefits of the procedure with recognition of peri-operative difficulties to improve the success rate. Materials and Methods: Patients under the age of 19-year-old who underwent liver transplantation for metabolic disorders with no structural liver injury between January 2015 and June 2021 analyzed retrospectively. Patient and graft survivals, indications for transplantation, presence of extra-hepatic enzyme deficiency causing other organ damage, inclusion of simultaneous or sequential kidney transplantation, immunosuppressive protocols, post-transplant complications, and metabolic outcomes were identified. Results: Eight children with primary hyperoxaluria type 1 (n = 4), Maple syrup urine disease (n = 1), Crigler-Najjar syndrome type 1 (n=1), familial hypercholesterolemia (n=1) and propionic acidemia (n = 1) received left lobe (n=6) and left lateral segment (2) allografts from living donors. The median age of 4 girls and 4 boys at time of transplantation was 6.8 years (range 2.2-12.7 years). The median follow-up time was 3.3 years (range 1.5-5.7 years). The most common post-transplant complications were biliary system complications and infections and, two patients died because of sepsis. Six patients are alive with normal functioning allografts and metabolically stable on unrestricted diet. Conclusion: Liver transplantation is a lifesaving treatment and improves patient’s and parent’s life quality for metabolic disorders with no parenchymal injury despite strict dietary restrictions and medical therapies. Especially, living donor liver transplantation is very important for populations with very low organ donation rates.


INTRODUCTION
Very rare monogenic metabolic diseases without structural liver damage can be cured by liver transplantation (LT). This process is a surgical enzyme replacement therapy, and the defective enzymes may or may not be confined to the liver (Table-1). Transplantation decision is simple for metabolic disorders with liver injury leading liver failure, but systemic consequences of deficient enzymes are the main reasons for LT when there is no liver distortion in histological evaluation. Transplantation might be a lifesaving or an organ saving procedure and/or an option for better quality of life due to severe systemic manifestations in this particular group of patients [1][2][3][4][5][6][7][8][9].
The aims of this single center study of children with metabolic diseases presenting structurally normal liver parenchyma were to analyze the indications, appropriate timing and post-operative outcomes of liver transplantation, identification of developmental and metabolic benefits of the procedure along with recognition of peri-operative difficulties to improve the success rate.

MATERIALS and METHODS
Between January 2015 and June 2021, patients under the age of 19-year-old who underwent liver transplantation at Acibadem University Hospital with diagnosis of metabolic disorders without structural liver damage were analyzed retrospectively. Operative techniques, patient and graft survivals, post-transplant surgical and medical complications, immunosuppressive protocols, and metabolic status of patients were identified. Donor and recipient characteristics were documented at time of transplantation and descriptive statistics were defined as median with minimum and maximum values. Patient and graft survivals were given according to primary diagnoses of the patients.
This study was approved by institutional review board with 2021/11-21 protocol number.

RESULTS
Between January 2015 and June 2021, eight children with five different hereditary metabolic disorders with no liver injury received liver allografts via living donor liver transplantation (LDLT). These included primary hyperoxaluria type 1 (PHO1, n = 4), Maple syrup urine disease (MSUD, n = 1), Crigler-Najjar syndrome type 1 (CN1, n=1), familial hypercholesterolemia (FHC, n=1) and propionic acidemia (PA, n = 1). Six patients received left lobes (LL) and 2 were transplanted with left lateral segments (LLS) from living related donors. The median age of 4 boys and 4 girls at time of transplantation was 6.8 years (range 2.2-12.7 years). The body weight distribution of the patients was 18.7 kg median weight with range of 9.4-36 kg. The median follow-up time was 3.3 years (range 1.5-5.7 years) after LDLT. Two patients with PHO1 died because of pneumonia related sepsis and urinary sepsis at 0.15 and 3.9 years respectively after their transplantations. Other 6 patients are alive with normal liver function on mono or dual immunosuppressive therapies. All patients are metabolically stable on unrestricted diet. There Propionic academia is an autosomal recessive inherited metabolic disease with defective propionyl-CoA carboxylase enzyme. Although there is partial correction of metabolic defect, liver transplantation is indicated in case of frequent metabolic crises despite optimum medical therapy to improve the quality of life and limit the neurocognitive impairment and/or cardiomyopathy. Barshes et al reported 72% patient survival in their review after LT on unrestricted diet. Generally, organic acidemia patients are allowed to have approximately 0.8 grams protein/kg body weight protein-limited diet or specially designed enteral formulas [1,[24][25][26]. We transplanted one patient with PA who had very early diagnosis and started strict diet with medical therapy. Unfortunately, patient experienced multiple hyperammonemia episodes and hospitalizations at times of simple infections and injuries. Patient received LDLT at age of 2.2 and had no metabolic crises since then on unrestricted diet.
Crigler-Najjar syndrome type 1 is a rare autosomal recessive inherited metabolic disorder with severe indirect hyperbilirubinemia. Total deficiency of uridyl-diphosphate glucuronosyl transferase enzyme (UGT1A1) activity causes accumulation of unconjugated bilirubin leading severe encephalopathy. Patients require phototherapy to decrease bilirubin levels and prevent irreversible kernicterus. Despite prolonged phototherapy (12 to 20 hours/day), the children remain jaundiced, and neurologic damage may occur at any time and more than 20% of young adults develop permanent neurological lesions under extensive phototherapy. Thirty percent hepatic UGT1A1 activity is required to preserve normal bilirubin homeostasis in total body and LT is recommended as a cure within the first year of life before the onset of neurological sequela besides improving patients' and families' quality of life. Strauss et al reported 100% patient and graft survival in their 16 CN1 patient series with normal bilirubin levels [1,27]. We performed LDLT for one CN1 patient who was diagnosed very late and neurologically affected with poor school performance. Patient was treated as Gilbert syndrome until 8 years old and after that she was on no therapy. Her indirect bilirubin levels were around 17-18 mg/dL at time of transplantation and normalized in 12 days at post-operative follow up. Her school success has been improved drastically since LT with normal bilirubin levels.
Familial hypercholesterolemia is an autosomal dominant inherited disorder characterized by isolated elevation of plasma low-density lipoprotein (LDL) cholesterol. LDL receptor defects or anomalies of Apolipoprotein B cause high plasma LDL cholesterol levels and it is associated with high risk of very early cardiovascular problems. LT is indicated before advanced cardiovascular disease to minimize the operative risks and to avoid combined heart and liver transplantation. Near normal levels of LDL receptors and cholesterol can be achieved since normal liver contains 50-75% of LDL receptors but statin use might be required after the transplantation to maintain completely normal blood cholesterol levels. LDLT is a good option in regions with limited deceased donation but it might be hard to find a normolipidemic living related donor and parents are deemed as unsuitable candidates since they might be undiagnosed FHC heterozygotes in homozygous FHC cases. There are controversial statements in the literature but many successful LTs with normolipidemic heterozygote parental donors were reported with or without need of statin use in their post-transplantation follow up. Unfortunately, side effects of immunosuppressant therapies can also give rise to renal damage, heart failure, and bone marrow suppression and especially cyclosporine may cause hyperlipidemia but according to literature 10-year survival rate exceeds 70% [1,[28][29][30][31][32][33]. We performed LDLT for one homozygous FHC patient from her cousin. Patient's parents were heterozygotes for LDLR gene mutation with slightly high cholesterol levels. Patient was diagnosed at age of 4 years and was already affected with very high LDL cholesterol levels. Her cardiac work up showed aortic calcification and mild aortic insufficiency with intimal thickening in bilateral common carotid arteries. Patient's lipid profile was normalized and stayed normal with no statin use after LT.
As a conclusion, liver transplantation is a lifesaving treatment and improves patients' and parents' quality of life for children with metabolic disorders with no parenchymal injury despite dietary restrictions and several medical treatment modalities. Timing of the liver transplantation is crucial not to allow for neurocognitive and other organ impairment. Especially, LDLT is a good option for populations with very low organ donation rates enabling appropriate timing of the operation with extra immunological benefits.