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Mitochondrial respiratory chain defect: a new etiology for neonatal cholestasis and early liver insufficiency
I Goncalves1, D Hermans, D Chretien
1Service de Pédiatrie, Cliniques St Luc-Université Catholique de Louvain, Bruxelles, Belgium.
Insights
Neonatal liver disease caused by mitochondrial respiratory chain enzyme defects leads to hypoglycemia and hyperlactacidemia. Liver transplantation offers a cure for this severe condition.
Area of Science:
- Biochemistry
- Genetics
- Pediatric Hepatology
Background:
- Neonatal cholestasis and liver insufficiency are critical conditions requiring prompt diagnosis.
- Mitochondrial respiratory chain (MRC) disorders can present with diverse clinical manifestations, including liver dysfunction.
Observation:
- Two siblings presented with neonatal cholestasis, hypoglycemia, hyperlactacidemia, and progressive liver insufficiency.
- Standard work-up excluded known causes of neonatal cholestasis, and gluconeogenesis was normal.
- Persistent hypoglycemia and post-prandial hyperlactacidemia prompted investigation into mitochondrial function.
Findings:
- Selective defects in mitochondrial respiratory chain complexes I, III, and IV, encoded by mitochondrial DNA, were identified in liver tissue.
- These defects were confirmed in both siblings.
- Control liver tissues from patients with end-stage liver disease showed normal enzyme activities.
Implications:
- Mitochondrial respiratory chain enzyme deficiency in the liver is a potential cause of severe neonatal liver disease.
- This condition is characterized by hypoglycemia and post-prandial hyperlactacidemia.
- Liver transplantation is a curative treatment for this specific type of neonatal liver failure.
Abstract:
Two siblings presented with neonatal cholestasis and early liver insufficiency. The older was admitted for end-stage cirrhosis with severe hypoglycemia and had long-term successful liver transplant at the age of 15 months. The second child presented a similar neonatal history of cholestasis, hypoglycemia, hyperlactacidemia, liver insufficiency and progressive cirrhosis. Extensive work-up excluded all known causes of neonatal cholestasis. Gluconeogenesis was found normal following alanine and fructose infusion. Repeated hypoglycemia with early post-prandial hyperlactacidemia led us to investigate the mitochondrial respiratory chain enzyme activities. Selective defects of complexes I, III and IV, coded by mitochondrial DNA, were detected in liver tissue of this patient and on preserved frozen tissue from his sibling, whilst normal activities were found in liver tissue samples from control patients with end-stage liver diseases. No extrahepatic manifestations were found. We conclude that liver deficiency of mitochondrial respiratory chain enzymes may cause liver disease in neonates, associated with hypoglycemia and post-prandial hyperlactacidemia. The disease is cured by liver transplantation.