Mechanisms of hepatocellular dysfunction during multiple systems organ failure

Despite extensive investigation the causes of this hepatic dysfunction remain controversial. The two main hypotheses put forward, which are not mutually exclusive, are changes due to a reduction or heterogeneity of nutrient hepatic blood flow, and the metabolic consequences of the release of inflammatory mediators that are involved in the systemic response generating multiple systems organ failure. In experimental models using cecal ligation and puncture, an early reduction in nutrient blood flow was observed with a reduction in bioenergy status and oxygen consumption. These changes occur early and before other metabolic alterations. The liver may be particularly sensitive to this form of hypoxia as metabolic autoregulation of flow does not occur. Unfortunately, not all the evidence points to impaired hepatic perfusion, as both animal and human studies have found that there is an increased hepatic blood flow and oxygen consumption during the early hyperdynamic stages of sepsis. Furthermore, isolated hepatic mitochondria from endotoxic rats demonstrated depressed function even when placed in aerobic conditions. Nevertheless, it is still possible that any increase in global oxygen consumption may not be adequate to supply all metabolic demands during stressed states.

Even in the absence of global changes in hepatic blood flow, heterogeneity of sinusoidal perfusion may be an important mechanism resulting in marked reduction in nutrient delivery to some areas of the liver parenchyma. Such heterogeneity has been demonstrated in normal humans, and the fat-storing Ito cells within normal sinusoids have been shown to contract actively to a range of vasoactive mediators including endothelin-1. During stressed states, interruption to sinusoidal flow is exaggerated when Ito cells become activated and are transformed to myofibroblasts which exhibit increased responses to exogenous activators, or when sinusoids are blocked by activated neutrophils and platelets.

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