Metabolic Control Patterns in Acute Phase and Regenerating Human Liver Determined In Vivo by 31-Phosphorus Magnetic Resonance Spectroscopy

Abstract

ObjectiveTo elucidate the metabolic changes occurring within hepatocytes during acute phase reaction and liver regeneration. Summary Background DataThe metabolic events occurring within the liver during the hepatic stress response are poorly understood. The authors used in vivo 31-phosphorus magnetic resonance spectroscopy to study hepatic metabolism after surgical trauma with and without loss of liver cell mass. MethodsThree groups were studied: five patients undergoing partial hepatectomy; five patients in whom laparotomy and colonic resection was performed; and five patients treated by thyroidectomy. Hepatic metabolism was evaluated by 31-phosphorus magnetic resonance spectroscopy before surgery and serially thereafter on postoperative days 2, 4, 6, 14, and 28. Estimation of liver volume by magnetic resonance imaging and blood sampling for biochemistry were performed at the same time points. ResultsThe authors found that alterations in hepatocyte phospholipid metabolism occurred after surgery that were correlated with changes in circulating acute phase proteins. Liver regeneration after hepatectomy was also associated with a derangement in energy metabolism, measured by a decrease in the ratio of ATP to its hydrolysis product inorganic phosphate. The depleted energy status was mirrored in biochemical indices of liver function, and restitution paralleled the course of restoration of hepatic cell mass. ConclusionsThese findings indicate that changes in liver metabolism after surgery reflect the magnitude of tissue injury and the quantity of functioning liver cells. Acute phase responses dominate the initial recovery period at the expense of less important endergonic functions. When liver parenchyma is lost, the acute phase reaction is maintained and further supported by a rapid replenishment of hepatocytes, which can even be considered a continuation of acute phase physiology. Modulation of liver function within the framework of overall hepatic energy economy is one mechanism for matching energy supply with increased demands during these processes.The liver plays a central role in the coordinated metabolic response to injury. Somatic tissue damage is associated with an acute phase reaction at the hepatocyte level characterized by a major redirection of protein synthesis, designed to restore bodily homeostasis.1 This response is maintained even after a sudden reduction in the number of hepatocytes induced by injury or surgery, when it is supplanted by a rapid compensatory replenishment of lost liver cells.2 The mechanisms of metabolic control and maintenance of liver function during these dynamic events are incompletely understood. Traditionally, the assessment of liver function has relied on indirect measurement based on circulating blood proteins and biochemical indices. We have applied the technology of image-guided in vivo 31-phosphorus mag-

Impact of Perioperative Phosphorus and Glucose Levels on Liver Regeneration and Long-term Outcomes after Major Liver Resection

“…24 To an extent, these tasks are competing, as cells that undergo mitosis do not contribute towards detoxification while functioning cells cannot enter the mitotic phase to aid in liver regeneration. 7,25 Both tasks, however, increase the metabolic requirements and necessitate adequate energy production; as the capacity to produce energy increases, liver function recovers. 7 Phosphorus is central to biologic energy transformation and a major ingredient of ATP which, in turn, induces the expression of genes that activate the hepatocyte cell cycle and therefore liver regeneration.…”

“…7,25 Both tasks, however, increase the metabolic requirements and necessitate adequate energy production; as the capacity to produce energy increases, liver function recovers. 7 Phosphorus is central to biologic energy transformation and a major ingredient of ATP which, in turn, induces the expression of genes that activate the hepatocyte cell cycle and therefore liver regeneration. To date, nearly all previous studies have only indirectly assessed the role of phosphorus by using clinical surrogates of liver regeneration such as postoperative liver failure and delayed recovery of liver function.…”

“…7 More recently, several studies have explored the potential role of perioperative biochemical metabolites in postoperative liver insufficiency that, in turn, may act as surrogate markers of impaired liver regeneration. [8][9][10] For example, given that energy for hepatic metabolism is primarily obtained from ATP breakdown, a derangement in perioperative hepatic phosphorus content has been correlated with hepatic regeneration.…”

“…[8][9][10] For example, given that energy for hepatic metabolism is primarily obtained from ATP breakdown, a derangement in perioperative hepatic phosphorus content has been correlated with hepatic regeneration. 7 To this end, George et al demonstrated that high serum phosphorus levels in the perioperative period indicated a decreased influx of phosphate into the liver which in turn decreased the ATP synthesis necessary for the regenerating liver. 9 Conversely, other studies have questioned an association between hyperphosphatemia and decreased liver regeneration ascribing these perioperative changes to kidney-related mechanisms.…”

Research update for articles published in EJCI in 2016

“…48,49 Our group has previously demonstrated that in humans, intraoperative deterioration in mitochondrial oxidative phosphorylation can be caused by prolonged hepatic pedicle clamping and is associated with an increased risk of complications and worse posthepatectomy liver function. 47 More recently, we have explored mitochondrial function and biogenesis in twostage hepatectomies with portal vein ligation and confirmed these findings.…”