Perioperative management of pediatric patients with inborn errors of metabolism during liver transplantation

Table 1 Classification of metabolic disorders from a perspective of liver transplantation

Category	Description	Examples
A	Disorders with enzyme defect only in the liver and LT is done predominantly for ESLD and its related complications	Tyrosinemia (HT-1); A1AT deficiency; galactosemia (type 1); WD; hereditary fructosemia; GSD 3 and 4; CDG
B	Disorders with enzyme defects limited to the liver. These patients rarely have ESLD; LT is performed for extrahepatic organ involvement	UCD; porphyrias; GSD type 1 PH, FH; Crigler-Najjar syndrome
C	Disorders having enzyme defect in the liver and extrahepatic tissue and LT only partially corrects underlying metabolic disease and alleviates symptoms of extrahepatic organ involvement	MMA; PA; MSUD; MH

ESLD: End-stage liver disease; HT-1: Hereditary tyrosinemia type 1; A1AT: Alpha-1 antitrypsin; WD: Wilson disease; GSD: Glycogen storage disorder; CDG: Congenital disorder of glycosylation; LSD: Lysosomal storage disorders; UCD: Urea cycle disorders; PH: Primary hyperoxaluria; FH: Familial hypercholesterolemia; LT: Liver transplantation; MMA: Methyl malonic acidemia; PA: Propionic acidemia; MSUD: Maple syrup urine Disease; MH: Mitochondrial hepatopathies.

Table 2 Summary of various metabolic disorders and their common clinical features

Metabolic defect involving	Disorders	Extrahepatic organs involved	Major clinical features
Carbohydrate	Glycogen storage disease Ia	Kidneys, pancreas	Hypoglycemia, lactic acidosis, HCC and adenoma
	Glycogen storage disease Ib	WBC, colon, small bowel	Features of type 1a along with recurrent infections and inflammatory bowel disease, liver cancers and adenoma
	Glycogen storage disease III and IV	Skeletal muscle	Chronic liver disease (IV > III), hypoglycemia (rare), myopathy (proximal)
	Transaldolase deficiency	Hematological, cardiac, renal	Cirrhosis, cardiac malformations, seizures, renal tubular acidosis
	Fructosemia	Renal	Cirrhosis, HCC, sweet aversion, poor growth, renal tubular defects,
	Galactosemia	Brain, Eyes, Renal	Cirrhosis, neonatal liver failure, hypoglycemia, oil drop cataract, autism
Amino acids	Tyrosinemia type I	Renal, peripheral nerves, pancreas	Neonatal liver failure, cirrhosis, HCC, adenomas in liver, neurological crises, RTA, islet cell hyperplasia, cabbage odor in urine
	Maple syrup urine disease	Brain	Recurrent seizures, cycling movements in infancy, ataxia, dystonia, maple syrup odor in body secretions
	Urea cycle disorders	Brain	Hyperammonemia coma, developmental delay, seizures, liver dysfunction (rare) (Reye syndrome)
	Methyl malonic Acidemia	Brain, renal, hematological cardiac and skeletal muscle	Developmental delay, metabolic crises and strokes, chronic renal failure (mainly after 2nd decade), bone marrow suppression, cardiomyopathy
	Propionic acid acidemia	Brain, skeletal muscle, hematological cardiac	Metabolic crises, bone marrow suppression, cardiomyopathy, muscle weakness, strokes (rare)
Fatty acids	Fatty acid oxidation defects	Muscle, cardiac	Acute liver failure and Reye like illness, muscle weakness, cardiomyopathy and conduction defects (sudden deaths)
Peroxisomal	Primary hyperoxalosis type 1	Kidneys, musculo-osseous, eyes, cardiac	Chronic kidney failure, hyperostosis and fractures, myopathy, cardiac infiltration with oxalate and dysfunction, oxalate retinopathy
	Zellweger syndrome	Brain, cardiac, kidneys, musculoskeletal	Developmental delay, hypotonia, seizures in infantile variant, liver cirrhosis and HCC in late variant, chondrodysplasia punctata, renal cysts
Bile transporter defects	PFIC-1, VI	Intestines, pancreas, sensory hearing	Cholestasis, liver cirrhosis, protein loosing enteropathy, pancreatic insufficiency, hearing loss, sweat chloride elevation: Type 1 tufting enteropathy: Type VI
	Non 1 PFIC	Nil	Cholestasis, liver cirrhosis, HCC, gall stones (Type III), acute liver failure like presentation (Type V)
Mitochondrial disorders and energy cycle defects	DNA depletion defect	Kidneys, intestines, brain, muscle	Liver: ALF and Reye syndrome (common drug triggered), Cirrhosis (rare), cholestasis. Brain: Recurrent seizures, developmental delay, extra pyramidal issues. Muscles: Skeletal and cardiac myopathy; Small bowel: Enteropathy, pseudo-obstruction. Pancreas: Insufficiency. Eye: Retinitis pigmentosa. Ear: Sensory hearing loss
Bilirubin Conjugation	Crigler Najjar syndrome	Brain	Acute bilirubin encephalopathy, Kern icterus causing developmental delay, extra pyramidal movements
Heme metabolism	Porphyrias	Liver, skin, dental, peripheral nerves	Recurrent pain abdomen; porphyric crises (can cause respiratory failure), seizures, peripheral neuropathy, chronic liver disease (rare), photosensitivity, erythrodontia (73)
Cholesterol excretion	Familial hypercholesterolemia	Skin, joints, cardiovascular	Generalised atherosclerosis, disfiguring skin and tendon xanthomas, aortic root dilatation

RTA: Renal tubular acidosis; HCC: Hepatocellular carcinoma; WBC: White blood cell count; ALF: Acute liver failure; PFIC: Progressive familial intrahepatic cholestasis.

Table 3 Anesthetic implications in inherited metabolic disorders during liver transplantation

Metabolic defect involving	Disorders	Specific anesthetic considerations
Carbohydrate	Glycogen storage disease I	Dextrose infusion. In case of hyperglycemia-insulin to be started along with dextrose infusion. Avoid Ringer’s Lactate. Difficult IV access and airway
	Glycogen storage disease III and IV	Dextrose infusion. In case of hyperglycemia - insulin to be started along with dextrose infusion. Avoid Succinylcholine. Difficult IV access and airway
Amino acids	Tyrosinemia type I	Dextrose infusion. Fracture prone hence caution while positioning
	Maple syrup urine disease	Ensure BCAA free supplements, isoleucine and valine supplements are give preoperatively. Dextrose infusion. Avoid Ringer’s lactate and resuscitation with Albumin. Hemodialysis standby
	Urea cycle disorders	Intraoperatively use Ammonia scavenging agents such as sodium benzoate and/or phenylbutarate and arginine infusion along with serial ammonia monitoring. Dextrose infusion along with intralipid infusion and low protein parenteral nutrition. Avoid Ringer’s lactate and resuscitation with Albumin. Hemodialysis standby
	Methyl malonic Acidemia	Avoid propofol, atracurium, cisatrcurium, Nitrous oxide, Naproxen, Ketoprofen. Intraoperatively use ammonia scavenging agents such as sodium benzoate and Carnitine along with serial ammonia monitoring. Dextrose infusion. Avoid Ringer’s lactate and resuscitation with Albumin. Metronidazole prophylaxis. Hemodialysis standby. Continue carnitine postoperatively. Renal sparing immunosuppression
	Propionic acid acidemia
Fatty acids	Fatty acid oxidation defects	Dextrose infusion. Perioperative seizure prophylaxis. Avoid Ringer’s lactate and resuscitation with Albumin. Hemodialysis standby
Peroxisomal	Primary hyperoxalosis type 1	Perioperative CRRT. Platelet dysfunction. Hypertensive crises. Renal sparing Immunosuppression. Fracture prone hence caution while positioning
Bile transporter defects	PFIC-1, VI	Malnutrition/growth retardation. Fracture prone hence caution while positioning
Mitochondrial disorders and energy cycle defects	DNA depletion defect	Perioperative seizure prophylaxis. Avoid succinylcholine, isoflurane and propofol
Bilirubin conjugation	Crigler Najjar syndrome	Malnourished/growth retardation. Fracture prone hence caution while positioning
Cholesterol excretion	Familial hypercholesterolemia	May need planning for lipid apheresis 2-4 weeks prior to surgery. If on Preoperative blood thinners, appropriate bridging and safe discontinuation to be planned. Anticipate Difficult airway due to facial asymmetry and xanthomas. Anticipate difficult vascular access Perioperative thromboembolic events

Table 4 Standard Glucose infusion rates as per age cut offs in the pre transplant period

Age	Glucose infusion rates	10% glucose infusion rate
< 2 years	10 mg/kg/minute	150 mL/kg/day
2-6 years	8 mg/kg/minute	120 mL/kg/day
> 6 years weight < 30	6 mg/kg/minute	90 mL/kg/day
> 6 years weight 30-50	4.5 mg/kg/minute	67 mL/kg/day