F. J. Dudley

Increased Sympathetic Nervous Activity and the Effects of Its Inhibition with Clonidine in Alcoholic Cirrhosis

OBJECTIVE To study disturbances in sympathetic nervous system function in patients with alcoholic cirrhosis and the effect of clonidine on such disturbances. DESIGN Cross-sectional physiologic and neurochemical evaluation of patients with cirrhosis and of healthy controls; an uncontrolled trial of intravenous clonidine in the cirrhotic patients. PATIENTS Forty-four hospitalized patients with biopsy-proven alcoholic cirrhosis and 31 healthy controls. INTERVENTIONS Intravenous clonidine. MAIN OUTCOME MEASURES Radiotracer-derived measures of norepinephrine release to plasma, central hemodynamics, wedge hepatic vein pressure, and measures of renal function. MAIN RESULTS In patients with cirrhosis, clonidine reduced previously elevated norepinephrine overflow rates for the whole body, kidneys, and hepatomesenteric circulation. This sympathetic inhibition was accompanied by the following potentially clinically beneficial effects: the lowering of renal vascular resistance (median reduction, 24%; 95% CI, 14% to 31%), the elevation of glomerular filtration rate (median increase, 27%; CI, 14% to 39%), and the reduction of portal venous pressure (median reduction, 25%; CI, 18% to 32%). The norepinephrine and hemodynamic responses to graded clonidine dosing (1, 2, and 3 micrograms/kg body weight intravenously) indicated that the sympathetic outflow to the hepatomesenteric circulation was more sensitive to pharmacologic suppression with clonidine than was the sympathetic outflow to the systemic circulation. CONCLUSIONS The sympathetic nerves to the kidneys, heart, and hepatomesenteric circulation are stimulated in patients with cirrhosis. Clonidine inhibits these activated sympathetic outflows differentially, which could possibly provide a basis for the selective pharmacologic treatment of portal hypertension in patients with cirrhosis.

SYMPATHETIC TONE MODULATES PORTAL VENOUS PRESSURE IN ALCOHOLIC CIRRHOSIS

Sixteen alcoholic cirrhotic patients with portal hypertension were studied before and after 2.5 micrograms/kg intravenous clonidine. In six patients portal venous pressure was assessed simultaneously by wedged hepatic vein and transhepatic portal vein cannulation. Wedged hepatic vein pressure accurately reflected portal venous pressure both before and after clonidine (r = 0.912 and 0.940; p less than 0.01). In all the other ten patients, sympathetic tone, measured by total plasma noradrenaline spillover, was high (755 +/- 123 ng/min; normal 296 +/- 29 ng/min). It fell significantly after clonidine (378 +/- 95 ng/min; p less than 0.01). This fall was associated with a decrease in corrected wedged hepatic vein pressure (18.6 +/- 1.1 to 13.4 +/- 0.5 mm Hg; p less than 0.01) but no change in estimated hepatic blood flow (934 +/- 94 to 976 +/- 102 ml/min), indicating a fall in postsinusoidal hepatic vascular outflow resistance. Clonidine-induced changes in mean arterial pressure and cardiac output were independent of the change in portal venous pressure. The results suggest that in alcoholic cirrhosis there is a labile component of hepatic vascular resistance which is partly under sympathetic nervous control and is thus potentially sensitive to pharmacological control.

Total and renal sympathetic nervous system activity in alcoholic cirrhosis

Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.

Primary hepatic lymphoma in a patient with chronic hepatitis C

The case is presented of a woman with chronic active hepatitis C who developed primary hepatic lymphoma. The possible roles of viral hepatitis and therapeutic interferon in the pathogenesis and progression of this unusual maligancy are discussed. In addition, the importance of accurate tissue diagnosis to identify potentially treatable hepatic tumours is emphasized.

Suppressive effect of alcoholic liver disease sera on lymphocyte transformation

The effect of alcoholic patient sera on in vitro lymphocyte transformation was studied using mitogen-induced uptake of 3H-thymidine to measure blastogenesis. With pokeweed mitogen as the stimulus, transformation of normal lymphocytes in sera of alcoholics with either normal or fatty livers was not significantly different from that obtained in pooled human serum (PHS). However, in sera of patients with either alcoholic hepatitis or inactive cirrhosis mean transformation was significantly reduced (P <0·001, <0·02 respectively). With phytohaemagglutinin-P or concanavalin A as mitogens, suppression of transformation was not as marked but followed the same pattern. A significant negative correlation was observed between the magnitude of transformation and serum bilirubin and aspartate aminotransferase levels. An intra-patient comparison of the effects on transformation of normal lymphocytes by simultaneously collected peripheral and portal venous sera, and of peripheral sera obtained before and after portasystemic shunt surgery, indicated that the factor(s) responsible did not originate in the splanchnic circulation nor did it accumulate in the serum because of failed hepatic clearance. By performing transformation experiments in the presence of inhibitory patient sera diluted with PHS it was possible to show that these sera caused true inhibition of transformation rather than suppression due to failure to sustain cell culture because of nutritional deficiencies. Inhibitory sera did not contain high levels of the enzyme thymidine phosphorylase and did not significantly inhibit binding of 125I-labelled mitogens to the lymphocyte surface. These findings indicate that the inhibitory effect of sera from alcoholics is of potential in vivo importance, that the effect increases with the degree of heptocyte damage, and that it is unrelated to the nonhepatic metabolic affects of chronic alcoholism.

The hypotensive effect of oral nitroglycerin on portal venous pressure in patients with cirrhotic portal hypertension

Abstract Nitroglycerin was administered orally to seven patients with cirrhosis and portal hypertension, to determine whether portal venous pressure (PVP) may be lowered without the systemic effects associated with its intravenous or sublingual use. PVP was measured via direct cannulation of the portal vein transhepatically using a Chiba needle. PVP decreased from 29 (s.d. = 4) to 22.7 (s.d. = 3.7) mmHg (22% mean fall) following 1.2 mg nitroglycerin with onset 7–15 min following ingestion, and the response persisted for up to 150 min. This was not associated with headache in any patient. Although a decrease in blood pressure was seen in most patients, this temporally followed the fall in PVP suggesting that it was a secondary response. Sublingual nitroglycerin was given to two patients without change in PVP yet both experienced severe headache. These findings support the hypothesis that oral nitroglycerin is delivered differentially to the portal venous bed with differential effects on PVP. Further studies are needed to evaluate this agent and this strategy for their potential role in long‐term control of portal pressure.

Coagulopathy of peritoneovenous shunts: studies on the pathogenic role of ascitic fluid collagen and value of antiplatelet therapy.

The role of ascitic fluid collagen in the pathogenesis of the coagulopathy that follows peritoneovenous shunting was examined. Collagen was partially purified from ascitic fluid and infused into rabbits. All animals developed changes in their haemostatic profile consistent with intravascular coagulation. Aspirin therapy, for five days before the collagen infusion, prevented these changes. Seven patients undergoing a total of eight peritoneovenous shunts for intractable ascites received antiplatelet therapy (aspirin and dipyridamole) in the immediate pre- and postoperative period. After six shunts no thrombocytopenia or prolongation of clotting times developed to suggest decompensated consumptive coagulopathy. Complicating factors may have contributed to the deterioration in haemostasis in the other two patients. There was no early shunt occlusion. The results support the hypothesis that ascitic fluid collagen is important in the pathogenesis of intravascular coagulation postascitic fluid infusion and indicate that antiplatelet drugs may be of value in preventing this complication.

The relationship between portal pressure and plasma albumin in the development of cirrhotic ascites

Ascites develops as a result of avid renal sodium retention together with an imbalance of Starlings equilibrium at the level of the hepatic sinusoid and mesenteric capillary. This study aimed to examine the effect of the imbalance between portal pressure, measured as corrected wedged hepatic vein pressure (cWHVP) and plasma oncotic pressure, measured as plasma albumin on the development of cirrhotic ascites. Fifty‐two patients with biopsy‐proven alcoholic cirrhosis were studied on 72 separate occasions. The absence of ascites was determined by the combination of lack of signs of free intraperitoneal fluid and normal prothrombin time in patients not receiving diuretics. If signs of free intraperitoneal fluid were found, the presence of ascites was confirmed by ultrasonography or diagnostic paracentesis and graded clinically as mild, moderate or severe.

Serum enzyme pattern in acute liver disease: Relation to type of cell death

To examine the hypothesis that different histological forms of liver cell death result in a characteristic serum enzyme pattern, the serum concentration of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase (LD) enzymes were measured in three aetiologically distinct groups of patients with acute hepatocellular injury. Thirty patients had serologically confirmed acute viral hepatitis B, twenty had histologically proven ischaemic hepatitis and five had paracetamol hepatotoxicity. Serum AST and ALT levels were similar in the patients with viral and ischaemic hepatitis, but the serum LD was significantly higher (P < 0.001) in the ischaemic hepatitis group. The pattern of enzyme elevation in the patients with paracetamol hepatotoxicity was similar to that found in ischaemic hepatitis. AST/LD and ALT/LD ratios, which were greater than 2 and 3 respectively, usually distinguished the patients with viral hepatitis from those with ischaemic hepatitis or paracetamol hepatotoxicity. Because of differences in the clearance of these enzymes from the serum it is likely that the AST/LD ratio will prove of greater discriminatory value and that this will be most evident early in the patients clinical course and become progressively less with time.