Sodium retention is triggered in rats with experimental liver injury at a critical threshold of liver function. We compared liver function and sodium retention in serially studied patients with alcoholic cirrhosis to determine whether a similar threshold exists in human beings. Antipyrine, caffeine, and cholic acid clearance were measured in 35 men with alcoholic liver disease. Nineteen patients were evaluated on two or more occasions; between studies, 28 remained in sodium balance (group NN), six spontaneously developed sodium retention and ascites formation (group NY), and seven spontaneously lost ascites (group YN). A threshold between patients with and without sodium retention did not exist for any of the clearance measurements. Indeed, values overlapped widely between the two groups. Antipyrine and cholate clearance were significantly reduced in patients with sodium retention, but caffeine clearance was similar in the two groups. Antipyrine and caffeine clearance declined significantly between the first and second study in group NY; cholate clearance did not change. No significant differences were observed between studies in group YN. In several patients of this group, liver function worsened as ascites spontaneously resolved. Impaired liver function commonly but not invariably accompanies sodium retention in patients with cirrhosis. A threshold at which sodium retention occurs or resolves does not exist.

Objectives: Elevation of plasma norepinephrine concentration in patients with cirrhosis and ascites is attributed to sympathetic activation due to arterial underfilling. Plasma norepinephrine should thus be normal in patients, without sodium retention. We examined the prevalence and determinants of elevated plasma norepinephrine concentration in compensated cirrhosis. Methods: Forty-six studies were performed on 37 patients; nine were studied twice. Between studies, elevated plasma norepinephrine concentration fell to normal in eight patients. Standard clinical and laboratory methods were used for all measurements. Results: Plasma norepinephrine was elevated (>1.89 nmol/L) in 31 studies. Patients with normal and elevated values were similar with respect to arterial pressure, cardiac output, systemic resistance, heart rate, plasma renin activity, and plasma atrial natriuretic factor concentration. Liver function, as indicated by plasma clearance of cholic acid, antipyrine, and caffeine, was similar in the two groups, but patients with elevated norepinephrine concentration had significantly increased plasma caffeine concentrations. Plasma norepinephrine concentration significantly correlated with plasma caffeine concentration but not with any hemodynamic or neurohormonal variables. Arterial pressure fell in repeatedly studied patients in whom plasma norepinephrine concentration declined. Moreover, the changes in arterial pressure and plasma norepinephrine concentration were significantly, directly correlated. Conclusions: Sympathetic activation is common in ''compensated'' cirrhosis. This is not because of arterial underfilling. Indeed, blood pressure and norepinephrine concentration maintained a normal physiological relationship in repeatedly studied patients. Elevated plasma caffeine concentration as a consequence of impaired hepatic metabolic function may contribute to sympathetic activation in some patients.

PURPOSE:To test the peripheral arterial vasodilation hypothesis of sodium retention in cirrhosis. This states that sodium retention is triggered by arterial underfilling and predicts that development of sodium retention will be associated with significant and related declines in indices of arterial filling that reverse when sodium retention resolves.DESIGN:Longitudinal evaluation of a cohort of patients with alcoholic liver disease.PATIENTS AND METHODS:Eighteen men, 8 of whom were studied twice, 3 three times, 2 four times, and 5 five times (40 between-study comparisons). Between 23 studies, the patients were ascites-free (Group NN). Ascites spontaneously disappeared between seven studies (Group YN), appeared between six studies (Group NY), and remained present between four studies (Group YY). Between-study changes in blood volume, arterial blood pressure, cardiac output, systemic vascular resistance, left atrial volume, left ventricular diastolic diameter, aortic root diameter, aortic blood velocity, plasma norepinephrine and atrial natriuretic factor concentrations, plasma renin activity, and urinary sodium excretion were evaluated by paired t-tests. These changes were also compared among groups by analysis of variance. In addition, correlations among the changes were sought.RESULTS:Systolic, diastolic, and mean arterial pressures, left ventricular diastolic diameter, aortic root diameter, stroke volume, cardiac output, plasma norepinephrine concentration, and systemic vascular resistance were unchanged between studies. Left atrial volume increased between studies in Group NY. Pulse pressure fell more in Group NY than in Groups NN and YN, principally as a result of a decline in systolic blood pressure. Plasma norepinephrine concentration, plasma renin activity, and blood volume rose more in Group NY than in Groups NN, YN, and YY. Changes in both systolic and pulse pressures were directly correlated with the change in sodium excretion but unrelated to the change in plasma norepinephrine concentration. Changes in plasma norepinephrine concentration and plasma renin activity were unrelated to changes in blood pressure, systemic vascular resistance, and urinary sodium excretion.CONCLUSIONS:None of the indices of arterial filling tested except pulse pressure were related to sodium retention. Reduced pulse pressure is inconsistent with arterial underfilling, as peripheral vasodilation instead increases pulse pressure by increasing diastolic run-off. These data do not support the hypothesis that arterial underfilling is the stimulus for sodium retention in alcoholic cirrhosis.

HepatologyVolume 16, Issue 6 p. 1505-1505 Book ReviewFree Access Diseases of the liver and biliary tract. Edited by G. Gitnick, D.R. LaBreque and F.G. Moody, 692 pp. St. Louis: Mosby—Year Book, 1992. $89 William G. Rector Jr. M.D., William G. Rector Jr. M.D. University of Colorado Health Sciences Center Denver, Colorado 80205Search for more papers by this author William G. Rector Jr. M.D., William G. Rector Jr. M.D. University of Colorado Health Sciences Center Denver, Colorado 80205Search for more papers by this author First published: December 1992 https://doi.org/10.1002/hep.1840160633AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume16, Issue6December 1992Pages 1505-1505 RelatedInformation

As part of a study of community-acquired non-A, non-B hepatitis, liver biopsy specimens of 29 anti-HCV positive and four anti-HCV negative patients were evaluated in order to characterize the histopathologic changes of chronic hepatitis C. Liver biopsies were performed 6 to 46 mo after onset of the disease and repeat biopsies were obtained in 10 anti-HCV positive patients. The histologic diagnoses were chronic persistent hepatitis (45%), chronic active hepatitis (35%), and chronic lobular hepatitis (21%). Irrespective of the tissue diagnosis, the majority of the patients showed characteristic histologic abnormalities in the liver, particularly damage of the small and medium-sized bile ducts (76%), lymphoid aggregates in portal tracts (45%), enlarged macrophages (48%), and steatosis (31%). In 59% of the patients, two or more of these histologic abnormalities were combined. Similar histologic changes have previously been observed in non-A, non-B hepatitis, but only uncommonly in hepatitis A or hepatitis B. We conclude that the histopathologic findings in chronic hepatitis C are highly characteristic, although not pathognomonic. The liver biopsy findings of bile duct abnormalities and lymphoid aggregates in portal tracts, particularly in combination, strongly suggest the diagnosis of chronic hepatitis C.

Organized around specific clinical problems, this book contains a current review of the treatment of complications of cirrhosis. It also features chapters on gastro-intestinal complications of cirrhosis, and methods of evaluation of the severity and prognosis of chronic liver disease. The book is aimed at gastroenterologists, hepatologists, primary care physicians and general surgeons.

Less complex methods of measuring hepatic metabolic capacity are needed. A simplified caffeine clearance test was evaluated in 23 patients with stable alcoholic liver disease. First, saliva caffeine concentrations were measured over a 24-h caffeine-free interval. Clearance was calculated from the rate of elimination of caffeine and an assumed volume of distribution and compared with the results of a formal clearance test using sequential plasma and saliva samples following a 300 mg oral dose. The simplified method was then assessed in 11 hospitalized patients with cirrhosis. Saliva caffeine concentrations remained measurable over the interval of study in 82% of patients. Caffeine clearance as determined by the simplified method did not differ from plasma caffeine clearance after an oral dose. Application of this method was achieved in 11 of 12 patients hospitalized for complications of severe liver disease, and revealed markedly diminished clearance. Thus, caffeine clearance can be accurately estimated in patients with severe liver disease using two or more samples of either saliva or plasma. This simplified determination of caffeine elimination rate provides a more practical assessment of hepatic metabolic capacity than a formal clearance test.

A pathological state of arterial vasodilation has been postulated to cause the increased cardiac output commonly observed in cirrhosis. Further, subsequent arterial underfilling has been proposed as the stimulus to sodium retention and ascites formation. Left ventricular size during the cycle of a cardiac contraction is predictably altered by a decrease in afterload. Specifically, increased systolic emptying should be observed. The relationship of left ventricular size during the cardiac cycle to systemic hemodynamic indices and urinary sodium retention was investigated in patients with alcoholic cirrhosis to test these hypotheses. Echocardiographic studies were performed on 24 male patients with alcoholic cirrhosis and compared with the results obtained in 10 age-matched male controls. Patients with cirrhosis had increased cardiac output and heart rate and decreased arterial pressure compared with normal subjects, confirming the presence of a hyperdynamic circulation. Patients with cirrhosis had enlarged left ventricular diameter at both end diastole (0.08 +/- 0.01 vs. 0.07 +/- 0.007 cm/kg dry body wt; P less than 0.001) and end systole (0.06 +/- 0.01 vs. 0.05 +/- 0.005 cm/kg; P less than 0.05). Left ventricular end-diastolic diameter was directly related to blood volume (r = 0.56, P less than 0.005). No significant differences in cardiac output, arterial pressure, or systemic resistance were found between patients with and patients without ascites. Increased cardiac output in cirrhosis occurs in conjunction with an enlarged ventricle throughout the cardiac cycle. The increase in left ventricular end-systolic diameter indicates that diminished afterload is not responsible for the increase in cardiac output. As the diameter of the ventricle during diastolic filling correlates with vascular volume, cardiac output in cirrhosis may be primarily determined by an increase in vascular volume.

PURPOSE AND PATIENTS AND METHODS: The relationship of plasma renin activity (PRA) to indices of circulatory filling and other possible determinants of renin secretion was studied in 31 men with alcoholic liver disease. Characteristics of patients with normal and increased PRA values were examined. Significant differences guided ed subsequent simple and multiple regression analysis.RESULTS: Supine PRA was increased (greater than 2.4 ng/mL/h on a 200 mEq/d intake of sodium, ranging as high as 33 ng/mL/h) in 14 of 57 studies. Nonascitic patients with elevated PRA values were significantly younger than those with normal PRA values. Among patients without ascites, the plasma atrial natriuretic factor concentration correlated inversely with PRA. Ascitic patients with elevated PRA values had a significantly reduced serum sodium concentration, urinary sodium excretion, creatinine clearance, and arterial pressure. Systemic vascular resistance, plasma norepinephrine and caffeine concentrations, and left atrial volume were similar in patients with and without increased PRA values. Univariate followed by multiple regression analysis identified age and plasma atrial natriuretic factor concentration as significant independent correlates of PRA in patients without ascites (R2 = 0.54). Serum sodium concentration and urinary sodium excretion were significant correlates of PRA in patients with ascites (R2 = 0.80).CONCLUSION: The associations of PRA in alcoholic liver disease are diverse and potentially complex. Age and plasma atrial natriuretic factor concentration are important in patients without ascites. In patients with ascites, tubular delivery of sodium to the macula densa, as modified by the filtered load and proximal reabsorption, appeared to be a principal association of PRA. Indices of circulatory filling did not emerge as clearly independent associations of PRA. Increased PRA values in patients with ascites may be an effect of sodium retention rather than part of its cause.

Portal pressure was monitored by means of an indwelling hepatic vein balloon catheter in patients with alcoholic cirrhosis and bleeding varices to determine the safety and feasibility of the technique and its value in predicting recurrence of bleeding. Forty patients were enrolled. Central venous access could not be achieved in 4 patients (10%). Hepatic vein catheterization was accomplished in the remaining 36 patients. Fourteen patients were either later found to have nonalcoholic liver disease or had already received treatment that excluded them from the protocol. The remaining 22 patients, who were treated with blood and fluid replacement, were monitored for up to 72 hours. Portal pressure was greater than 11 mm Hg in all patients (normal, less than 5 mm Hg) and did not change significantly over the 3 days of study. Portal pressure was significantly higher in the 9 patients who continued to bleed or rebled compared with the 13 patients who remained stable. The lowest pressure associated with continued bleeding or rebleeding was 16 mm Hg. Continuous monitoring of portal pressure in patients with bleeding esophageal varices due to alcoholic cirrhosis is safe and feasible and permits rapid stratification of the risk of continued bleeding or early rebleeding.

Vasopressin is often used to treat variceal hemorrhage. However, its efficacy is uncertain, and its portal hemodynamic effects in this setting are unknown. Eleven patients with alcoholic liver disease and bleeding varices were given vasopressin (0.2 U/min for the first hour, then 0.4 U/min for 24 hours). Portal pressure was monitored using an indwelling hepatic vein balloon catheter. Seventeen patients with variceal bleeding who remained stable over 26 hours of initial treatment with crystalloid and blood products served as a comparison group. Vasopressin infusion (0.2 U/min) produced a significant decrease in wedged hepatic venous pressure, hepatic venous pressure gradient (wedged minus free hepatic venous pressure), and heart rate. Increases in the rate of infusion did not produce further decreases in the parameters measured, but the changes were sustained over the course of the infusion. Hemodynamics remained stable in the control group. Portal pressure did not increase when vasopressin was abruptly discontinued in the 3 patients in whom postinfusion measurements were made. Vasopressin retains its portal hypotensive effects in the setting of variceal hemorrhage. Tachyphylaxis does not develop over 26 hours, and a "rebound" increase in portal pressure probably does not occur when the infusion is discontinued.

We investigated the occurrence of alcoholic autonomic dysfunction in patients with alcoholic cirrhosis in order to define its prevalence and relationship to renal sodium retention. Forty-seven alcoholics and 16 age-matched normal subjects were evaluated. Thirty-seven patients had liver disease (13 with and 24 without ascites), and 10 patients had normal hepatic function. Autonomic nervous system function was ascertained by skin sudomotor responses and the response of blood pressure and plasma norepinephrine concentration to upright tilt (sympathetic nervous system function), and by heart rate responses to deep breathing, Valsalva maneuver, and upright tilt (parasympathetic and sympathetic nervous system function). Heart rate responses to deep breathing and Valsalva maneuver were diminished, and skin sudomotor responses were significantly worse, in alcoholics than in control subjects. Alcoholic patients also had significantly lower supine mean arterial pressure (93 +/- 10 vs. 116 +/- 8 mm Hg, p less than or equal to 0.0001), and significantly greater increases in arterial pressure during passive upright tilt, than control subjects (mean increase 6.5 +/- 6.6 vs. 0.1 +/- 1.6 mm Hg, p = 0.0003). All of these findings were present to similar degrees in patients with and without liver disease and in cirrhotic patients with and without ascites. Supine heart rates, however, differed among the groups evaluated. Heart rate was significantly greater in patients with cirrhosis than in alcoholic patients without liver disease (83 +/- 11 vs. 71 +/- 13 bpm, p = 0.006), and in patients with ascites than in patients without ascites (88 +/- 12 vs. 80 +/- 10 bpm, p = 0.04). Plasma norepinephrine concentration was elevated in most patients with cirrhosis and was significantly higher in patients with ascites than in patients without ascites (789 +/- 238 vs. 388 +/- 185 pg/ml, p less than 0.0001; nl range: 65-320 pg/ml). Autonomic nervous system function is similarly impaired in alcoholics with and without liver disease. Patients with cirrhosis also have increased heart rate and elevated plasma norepinephrine concentration, abnormalities that are most pronounced in patients with sodium retention. Their is uncertainty as to the stimulus for norepinephrine release, and its source, in these patients. However, the similarity of supine blood pressure in patients with and without ascites and the occurrence of orthostatic hypertension rather than orthostatic hypotension following upright tilt suggest that arterial underfilling is not responsible.

Nitroglycerin is reportedly an effective treatment for portal hypertension. However, the effects of graded doses have not been examined. We administered nitroglycerin intravenously to 10 patients with alcoholic cirrhosis, beginning at 10 μg/min and doubling the dose every 10 min thereafter until mean arterial pressure fell 10–15 mmHg. We compared the response to that of 10 patients receiving a control infusion. The median infusion rate of nitroglycerin was 40 μg/min (range 10–160μg/min). Nitroglycerin significantly reduced cardiac output as well as pulmonary artery, pulmonary capillary and mean arterial pressure. The overall effects of nitroglycerin on the hepatic venous pressure gradient and azygous (gastroesophageal collateral) blood flow were heterogeneous. However, the hepatic venous pressure gradient significantly increased in nitroglycerin-treated patients with high pulmonary capillary pressures (≥ 12 mmHg) compared to control patients with similar cardiac filling pressures at both median and maximum rates of infusion. Nitroglycerin is therefore not a uniformly effective treatment for portal hypertension. Cardiac filling pressure may be a determinant of the splanchnic hemodynamic response to nitroglycerin.

The aim of this study was to determine whether liver function and portosystemic shunting are related to renal sodium retention in alcoholic liver disease. Twenty-three studies were performed; 10 patients had ascites. Liver function was assessed from the plasma elimination rates of antipyrine, caffeine and stable isotopes of cholic acid, the latter administered both orally [2,2,4,4-2H] and intravenously [24-13C]. Portosystemic shunt fraction was calculated as the ratio of the intravenous and oral clearances of the isotopes of cholic acid. Portosystemic shunt fraction was similar in patients with and without ascites (61% +/- 16% vs. 64% +/- 11%) and unrelated to urinary sodium excretion in patients with ascites (r = -0.145). Patients with ascites had significantly lower elimination rates of all administered compounds as compared with patients without ascites (antipyrine = 0.012 +/- 0.007 vs. 0.031 +/- 0.016/hr, p less than 0.001; caffeine = 0.014 +/- 0.013 vs. 0.061 +/- 0.041/hr, p less than 0.002; intravenous cholic acid = 1.355 +/- 0.442 vs. 2.284 +/- 0.885/hr, p = 0.005; orally administered cholic acid = 2.178 +/- 0.841 vs. 4.056 +/- 1.837/hr, p = 0.007). However, urinary sodium excretion in patients with ascites was not related to the elimination constants of these compounds (r = 0.360, 0.319, 0.067, -0.073, respectively). Ascites complicating alcoholic liver disease is associated with impaired liver function but not the extent of portosystemic shunting.

A rapid and sensitive method of quantitation of caffeine and antipyrine in plasma and saliva is described. Caffeine, antipyrine and phenacetin, the internal standard, are readily extracted from alkalinized plasma and saliva into dichloromethane. After evaporation of the organic solvent, the residue is analyzed by HPLC using a mobile phase of 25% acetonitrile in 0.02 M phosphate buffer at a flow rate of 1.5 ml/min. and a C18 reverse phase column. Baseline separation of all peaks is achieved with retention times for all compounds of less than 10 minutes. There is no interference from endogenous compounds or metabolites of caffeine or antipyrine.

We tested the hypothesis that increased plasma glucagon concentration resulting from portal-systemic shunting or liver dysfunction causes arterial vasodilation and thereby stimulates sodium retention in cirrhosis. Twenty-seven studies were performed in patients with alcoholic liver disease, 11 of whom had ascites. Liver function was quantitated as the elimination rate of antipyrine, caffeine, and stable isotopes of cholic acid administered both orally (2,2,4,4-2H) and intravenously (24-13C). Portal-systemic shunt fraction was calculated as the ratio of the intravenous and oral clearances of the isotopes of cholic acid. Cardiac output was measured by using Doppler echocardiography. Plasma glucagon concentration was increased in patients with ascites when compared with that in patients without ascites (474 +/- 180 pg/ml vs 245 +/- 120 pg/ml, p = 0.0007) but was unrelated to urinary sodium excretion, heart rate, mean arterial pressure, cardiac output, and systemic vascular resistance (r = -0.48, 0.35, -0.13, 0.18, and 0.22, respectively). Plasma glucagon concentration correlated with the half-lives of all model compounds (r = 0.58, p = 0.002; r = 0.62, p = 0.0008; r = 0.62, p = 0.001; and r = 0.64, p = 0.0005; for caffeine, antipyrine, oral and intravenous cholic acid, respectively) but not with shunt fraction (r = 0.14). Increased plasma glucagon concentration in cirrhosis is probably a result of diminished hepatic clearance. However, increased plasma concentration of glucagon does not appear to cause a hyperdynamic circulatory state or sodium retention.