Studies on the Role of the Sympathetic Nervous System in Cirrhosis of the Liver

MacGilchrist, Alastair John (1988) Studies on the Role of the Sympathetic Nervous System in Cirrhosis of the Liver. MD thesis, University of Glasgow.

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This thesis is a result of the observation that plasma noradrenaline is increased in cirrhosis with ascites. Three specific questions were addressed: is this increase the result of increased spillover of noradrenaline into plasma (and thus increased activity of the sympathetic nervous system) or of reduced clearance from plasma? What are the implications of sympathetic activation for the various theories of ascites formation? Why does sympathetic overactivity fail to correct the reduced peripheral vascular resistance characteristic of cirrhosis? The kinetics of exogenous tritiated noradrenaline were measured, using an HPLC separation of the radiolabelled noradrenaline in plasma, in 14 cirrhotics with ascites and 13 controls. The cirrhotics had a marked increase in noradrenaline spillover with plasma clearance also slightly increased. Therefore the increased plasma noradrenaline in cirrhosis is due to increased sympathetic activity. Noradrenaline, dihydroxyphenylglycol (DHPG), renin and atrial natriuretic peptide (ANP) were then measured in peripheral venous blood in 41 cirrhotic patients and 34 control patients. Noradrenaline was increased in cirrhotics both with and without ascites, in contrast to renin which was only increased in those cirrhotics with ascites. Therefore sympathetic overactivity in cirrhosis appears to precede the development of ascites. This supports the "underfilling" theory of ascites, which suggests that the effective central intravascular volume is reduced in cirrhosis. The degree of sympathetic activity was shown to parallel the degree of hepatic impairment, and plasma noradrenaline was a useful prognostic indicator in cirrhosis. This may prove of clinical value in assessing the timing of hepatic transplantation. It has been speculated that a deficiency of ANP may contribute to the sodium retention of ascites. In fact plasma ANP was not reduced, but was marginally increased in the presence of ascites. This suggests that ANP is responding appropriately to sodium overload occurring for other reasons. Despite this sympathetic overactivity, patients with cirrhosis demonstrate reduced peripheral vascular resistance and cutaneous vasodilatation. A series of experiments was performed to try to identify the site of this "block" to normal sympathetic vasoconstriction. One theoretical possibility would be an autonomic neuropathy, particularly in alcoholic liver disease. Autonomic function was assessed by a standard battery of parasympathetic and sympathetic tests in 20 cirrhotics and 20 controls. The parasympathetically-mediated heart rate responses to deep breathing, to facial immersion in water and to the Valsalva manoeuvre were all reduced in cirrhotics with severe hepatic impairment. The sympathetically-mediated blood pressure response to isometric exercise was also reduced. However, the absence of clinical evidence of neuropathy in these patients suggested that the changes demonstrated might be a result of impaired vascular responsiveness rather than neuropathic damage. To consider this question, the blood pressure responses to steady state intravenous infusions of noradrenaline and angiotensin II were measured in 20 cirrhotics and 20 controls. Dose response curves were constructed from a minimum of 4 doses using a quadratic fit, allowing calculation of individual PD2O, dose of agent required to raise blood pressure by 20 mmHg. The rise in blood pressure was attenuated to both noradrenaline and angiotensin II in the cirrhotics with severe disease. Therefore the site of the ''block" is distal to the sympathetic nerves. The attenuated response to both sympathetic and non-sympathetic vasoconstrictors could indicate a direct vascular abnormality. Alternatively, there could be parallel desensitisation to the effects of noradrenaline and angiotensin II, both of which are frequently raised in cirrhosis. The question of sympathetic desensitisation was therefore considered in more detail by examining the cardiovascular responses to selective sympathetic agonists in 10 cirrhotics with severe disease and 10 controls, using similar methods to the previous experiment. The blood pressure responses to phenylephrine (an alpha1 agonist) and alphamethylnoradrenaline (an alpha2 agonist) were both impaired in the cirrhotic group, in contrast to the heart rate response to isoprenaline (a beta agonist) which was normal. There is thus no generalised sympathetic desensitisation, but all responses mediated by the peripheral vasculature are impaired, pointing to a defect at this site. Such a defect could involve the adrenergic receptors, by prior occupancy of the receptor site either by the increased circulating noradrenaline or by some catecholamine-like substance (c.f. the "false neurotransmitter" theory) or by "down-regulation" of the receptor number in response to sustained sympathetic overactivity. The alpha1 adrenoceptor on peripheral vessels is inaccessible to study in man, and therefore as a compromise the alpha2 receptors on platelets were studied in 10 cirrhotics and 10 controls. The method involved incubation of the isolated platelets with tritiated yohimbine, measurement of free and bound radioactivity, and calculation of receptor affinity and number by Scatchard analysis. In fact both the number and affinity of the platelet alpha2 receptors were normal, i.e. there was no down-regulation nor receptor site interference. If this reflects the alpha1 adrenoceptor on peripheral vessels, it would suggest a "post-receptor" defect within the vascular smooth muscle cell itself. This probable localisation should assist in the on-going search for the vasodilator(s) responsible for the reduced vascular resistance. Beta adrenoceptors were also assessed, using the beta2 receptor on circulating lymphocytes. The radioligand employed was [131I] iodocyanopindolol. Again, normal receptor number and affinity were demonstrated, which is in keeping with the normal heart rate response to the beta agonist isoprenaline. This study therefore does not support the hypothesis that down-regulation of beta receptors contributes to reduced efficacy of the beta adrenergic antagonist propranolol in variceal haemorrhage in ''decompensated" cirrhosis. The studies described above are in keeping with, but do not provide proof of, the following hypothesis: that in cirrhosis one or more vasodilatory substances accumulate, perhaps due to failure of hepatic inactivation, which act at an intracellular level on the peripheral vasculature. The resulting vasodilatation causes peripheral blood pooling with relative underfilling of the central vascular space. A baroreceptor-mediated increase in sympathetic activity, and possibly other neurohumoral mechanisms, ensues. This sympathetic activation could be one of the factors which cause sodium retention leading to ascites, and ultimately renal vasoconstriction leading to functional renal failure. It appears that the sympathetic nervous system does play a significant role in the complications of cirrhosis of the liver.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine, Neurosciences
Date of Award: 1988
Depositing User: Enlighten Team
Unique ID: glathesis:1988-77775
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53

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