Chapter 14Integrative Hepatic Response to Hemorrhage

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The hepatic response to hemorrhage is an elegant example of interactive homeostatic mechanisms functioning to compensate for a severe homeostatic disturbance. In this chapter I will briefly review the hepatic vascular responses that have been discussed in several chapters in this monograph. In addition, I will incorporate the metabolic responses that regulate glucose metabolism and are intimately connected with both vascular and metabolic emergency responses.

A rapid hemorrhage leads to an immediate decrease in hepatic blood volume. The liver compensates for approximately 20% of either an increase or a decrease in circulating blood volume. Hepatic blood volume is able to be actively decreased (unstressed volume) by high levels of vasopressin or angiotensin (small effects) or by blood-borne catecholamines (small effect) or by activation of hepatic sympathetic nerves. Hepatic sympathetic nerve stimulation represents the most powerful regulator of hepatic blood volume. However, if all of these active regulators are eliminated by removing the pituitary and adrenal glands and kidneys and by hepatic denervation, the ability of the liver to respond to hemorrhage is impaired only slightly, as the passive effect of decreased portal flow and blood pressure result in a reduction in stressed blood volume [204]. Hemorrhage can result in expulsion of up to 50% of the entire blood content of the liver, which is equivalent to a 6–7% infusion of total blood volume. Hemorrhage appears to result in hepatic blood volume changes primarily through changes in stressed volume, as reducing portal inflow to the same extent as is produced during hemorrhage results in a similar level of capacitance response. Furthermore, the change in unstressed volume caused by nerve stimulation is unaltered if stressed volume is already reduced by hemorrhage. Thus, the effects of changes in stressed and unstressed volume can be additive (Figure 14.1).

FIGURE 14.1. Effects of hepatic nerve stimulation in one cat before and after hemorrhage.


Effects of hepatic nerve stimulation in one cat before and after hemorrhage. After the reduction in stressed volume after hemorrhage, change in unstressed volume produced by nerve stimulation is almost unchanged. Effects of passive and active mobilization (more...)

The major decrease in hepatic blood flow that occurs in response to hemorrhage is a result of arterial vasoconstriction of the splanchnic organs feeding the portal venous flow. This dramatic reduction in portal flow activates the hepatic arterial buffer response, which leads to dilation of the hepatic artery and thereby protects the oxygen supply of the liver [227].

The glycogenolytic response of the liver is also a major component of the homeostatic compensatory responses. Blood loss results in a rapid activation of glycogen breakdown in the liver leading to blood glucose increasing from a normal range of 100 mg% to as high as 800 mg%. This response is mediated by a redundant control system [210]. The system is redundant in that the hepatic glycogenolysis can be equally activated by the hepatic sympathetic nerves or the adrenal secretions of catecholamines. Elimination of either regulator produces minor impairment of the glycogenolytic response, whereas elimination of both regulators essentially eliminates the hyperglycemic response to hemorrhage. This demonstration is extremely important in that it is an example for the need for caution in interpretation of ablation studies. Lack of impact of elimination of one putative regulator does not allow the conclusion to be made that the regulator is not a significant factor. As long as either the hepatic nerves or the adrenal glands are intact, the response is maintained.

In addition to this neural homeostatic role, the hepatic nerves decrease peripheral insulin sensitivity, thereby preserving the elevated glucose levels as a fuel to be transported to the brain and eyes in high concentration in spite of the reduced blood supply. This mechanism appears to be mediated by hepatic nerves that release somatostatin within the liver and cause blockade of insulin-induced release of a hepatic insulin-sensitizing substance (HISS). Insulin secretion is also blocked, also apparently by somatostatin. The discussion of the HISS hypothesis and the hepatic metabolic regulation of peripheral insulin resistance is beyond the purview of this monograph but has been recently reviewed [202].

The increase in hepatic glucose concentration contributes to increased extracellular osmotic fluid pressure, thereby drawing fluid from the large intracellular fluid compartment. Intracellular water accounts for approximately two thirds of total body water and as much as 1 liter has been estimated to be reabsorbed into the plasma compartment over a 1- to 2-h period in humans [154].

Activation of the hepatic sympathetic nerves therefore results in both a dramatic vascular response and metabolic response. If the vasoconstriction at the arterial or portal venous resistance sites increases regional shear stress, nitric oxide is released from the endothelial cells and results in inhibition of the vasoconstriction but potentiation of the hyperglycemic response to catecholamines (see Chapters 5, 9, and 11).

The sympathetic nerves cause vasoconstriction in the hepatic artery and portal vein. If portal blood flow has decreased in response to the hemorrhage, vasoconstriction at the portal site may produce little or no change in portal pressure as the increase in resistance compensates for the decrease in flow. Vasoconstriction in the hepatic artery occurs rapidly and dramatically in response to either norepinephrine or electrical nerve stimulation. The vasoconstriction reaches a peak within 2 min and then may undergo vascular escape so that blood flow returns toward control levels. This vascular escape from neurogenic vasoconstriction is a result of shear stress-induced release of nitric oxide (Chapter 11). If blood pressure is reduced in response to hemorrhage, the shear stress-induced inhibition of vasoconstriction will not occur. However, the second major intrinsic vascular regulator, adenosine, in situations of reduced total hepatic blood flow, can result in suppression of the vasoconstriction in the hepatic artery with little or no inhibitory effect on sympathetic nerve-induced constriction of the portal vein or capacitance vessels (Chapter 10).

Thus, the hepatic autonomic nerves play a major role in the integrated hepatic response to hemorrhage. The sympathetic nerves constrict the hepatic artery, portal vein, and hepatic capacitance vessels, and trigger glycogenolysis. Flow escape in the artery can occur as a result of either shear stress-induced nitric oxide action (less likely because arterial pressure is reduced) or activation of the hepatic arterial buffer response, secondary to reduced portal flow. The hepatic parasympathetic control of skeletal muscle insulin sensitivity is blocked by intrahepatic somatostatin release, thereby contributing to hemorrhage-induced hyperglycemia.