Role of Aluminum as a Toxic Element in Causing Parenteral Nutrition Associated Cholestasis
Parenteral nutrition (PN) is an essential life sustaining therapy for premature and critically ill infants. However, prolonged PN therapy can lead to life-threatening liver damage, and cause parenteral nutrition associated cholestasis (PNAC). There has been some recent evidence that aluminum accumulation in the livers of PN-fed subjects may lead to hepatic damage leading to liver injury. This dissertation aimed to investigate the role of aluminum as a toxic component of parenteral nutrition and as a risk factor in developing PNAC. The project composed of two main studies. The objectives of the first study were: 1) Evaluate the early morphological changes in piglet liver after intravenous administration of aluminum chloride hexahydrate at a dose of 1500 µg/kg/d.; 2) Determine whether the morphological changes deteriorate further with increasing duration of exposure and whether these changes correlate with changes in biochemical markers of cholestasis; 3) Identify the appropriate imaging technique for studying the ultrastructural changes in the liver; 4) Determine if intravenous injection of high dose aluminum into neonatal piglets disrupts iron homeostasis in the liver. The results showed that intravenous infusion of aluminum in neonatal piglets led to marked elevation in serum total bile acids, and transmission electron microscopy-energy dispersive microanalysis (TEM-EDX) was suitable in detecting the site of Al deposition in the liver and in demonstrating histopathological changes associated with Al infusion. The objectives of the second part were to: 1) Investigate the role of aluminum as a toxic component of parenteral nutrition and as a risk factor in causing liver injury; 2) Evaluate the effect of reducing aluminum content of parenteral nutrition on liver iron homeostasis; 3) Investigate the effect of low aluminum PN and high aluminum PN (regular PN) on the mRNA expression of Bsep and Mrp2. The results showed that administration of PN solution with lower Al content led to reduced levels of serum and hepatic Al in low Al PN group compared to regular PN group. This reduction was associated with less histopathological changes in the liver. On the other hand, administration of regular PN in piglets led to decreased expression of transporter Mrp2. This work suggests that reducing Al content in PN may reduce the development and severity of liver injury in the piglets.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorMiller, Grant; Zello, Gordon
CommitteeArnold, Chris; Alcorn, Jane; Bandy, Brian; Moser, Mike
Copyright DateFebruary 2014