Evaluation of Ketogenesis in Seriously Reduced Hepatic Mitochondrial Redox State an Analysis of Survivors and Non-Survivors in Critically Ill Hepatectomized Patients

Abstract

Ketogenesis was evaluated in 33 critically ill hepatectomized patients in relation to the arterial ketone body ratio (acetoacetate to 3-hydroxybutyrate), which reflects hepatic mitochondrial redox state. In 15 patients whose arterial ketone body ratio decreased to below 0.4, blood ketone body levels were significantly increased concomitant with marked increase of blood lactate and plasma alanine levels. In the 6 survivors of these 15 patients, the arterial ketone body ratio was restored within the next 2 days, and blood ketone body levels were decreased. By contrast, in the nine non-survivors, the arterial ketone body ratio remained below 0.4, and blood ketone body levels were decreased, accompanied by significant increases in blood lactate and plasma alanine levels in the terminal stages. These results suggest that ketogenesis acts as an alternative process for ATP synthesis in the liver in critically ill patients. Death occurs when the liver falls into an energy crisis concomitant with the cessation of ketogenesis.

Mitochondrial bioenergetics and posthepatectomy liver dysfunction

“…The importance of our findings is twofold. First, markers of mitochondrial dysfunction can be used for earlier diagnosis of PHLF . Currently, diagnosis of PHLF is only possible on or beyond the fifth postoperative day, and predicting liver dysfunction earlier would be attractive .…”

A Look into Liver Mitochondrial Dysfunction as a Hallmark in Progression of Brain Energy Crisis and Development of Neurologic Symptoms in Hepatic Encephalopathy

“…In fact, the liver performs a myriad of functions, and in addition to filtering toxins, plays a unique role in the regulation of blood glucose homeostasis, crucial for normal cerebral function, since the brain neither synthesizes nor stores the required amount of glucose [ 59 ]. As a result, unstable blood glucose and oxygen delivery to the brain, for even a short period, causes brain damage, while chronic deficiency in these substrates leads to irreversible brain injury, thereby triggering cognitive impairment, coma development, and death [ 20 ]. Additionally, when glucose is not readily available, the liver can produce ketone bodies, which are used by the brain as an alternative energy source.…”

“…We previously showed that acute hyperammonemia leads to rapid and significant decrease in both acetoacetate and β-hydroxybutyrate levels in the liver and blood of non-starved rats. This suggests that hepatic ketogenesis can be inhibited immediately after increasing ammonia levels in the liver [ 60 ], highlighting the role of deterioration of homeostatic liver functions in the occurrence of a brain energy crisis [ 20 ].…”

“…This process maintains adequate amounts of glucose for the brain and reflects its obligate dependence on the liver, indicating that under physiological conditions, the liver elaborates vital metabolites that assure normal cerebral function [ 19 ]. As a result, unsteady blood glucose and oxygen delivery to the brain for even a short period causes brain damage, while chronic deficiency in these substrates leads to irreversible brain injury, thereby provoking coma development and death [ 20 ].…”

“…Nevertheless, both liver ketogenesis and gluconeogenesis are understudied areas (with the exception of a few studies) in terms of their impact on the adequate supply of the brain with energy substrates and clinical manifestations of HE [ 20 ]. Moreover, based on scattered and conflicting data from patients with fulminant liver failure or chronic liver diseases [ 22 , 23 , 24 ], it is impossible to assess how the reduction in ketone body and glucose output in the liver may be related to brain pathology.…”