Role of Vasopressin in Abnormal Water Excretion in Cirrhotic Patients

Title:	Role of Vasopressin in Abnormal Water Excretion in Cirrhotic Patients
Authors:	Bichet, Daniel G.; Schrier, Robert W.; Szatalowicz, M.D., Victoria; Chaimovitz, M.D., Cidio
Publisher:	Annals of Internal Medicine
Date Published:	April 01, 1982
Reference Number:	241

Abstract • Article

Twelve stable cirrhotic patients with ascites received a 20 mL/kg water load. Seven patients had abnormal water excretion (27.3% +/- 5.4% of the water load in 5 hours) and a minimal urine osmolality of 262 mosmol/kg water. Five patients excreted 82.6% in 5 hours and had a minimal urine osmolality of 65 mosmol/kg water. Mean plasma arginine vasopressin values after water load were significantly higher in Group 1 (1.34 +/- 0.36 pg/mL) than in Group 2 (undetectable). An effective blood volume lower in Group 1 than Group 2 patients was suggested by a lower plasma albumin (2.5 versus 3.3 g/dL, p less than 0.02), a higher pulse rate (96 versus 72, p less than 0.001), a higher plasma renin activity (7.8 versus 1.5 ng/mL . h, p less than 0.005), a higher plasma aldosterone (66 versus 21 ng/dL, p less than 0.05), and a lower urinary sodium excretion (2.7 versus 14.2 meq Na/5 h, p less than 0.005). The results suggest that nonosmotic stimulation of vasopressin secondary to a decrease in effective blood volume is an important factor in the abnormal water excretion of cirrhosis.

Reprinted from Annals of Internal Medicine, 1982, Vol 96(4):413-7 with permission from the American College of Physicians for educational use within the NDI community. No part of this article may be reproduced in any way without permission in writing from the publisher.

Hyponatremia with impaired ability to excrete a water load occurs in a substantial number of patients with cirrhosis of the liver (1-4). The incidence of impaired renal water excretion in cirrhosis is difficult to assess because the level of hyponatremia depends on the patient's water intake. Previous studies have shown that decompensated patients (cirrhotic patients with ascites, edema, or both) have an abnormal response to water administration and cirrhotic patients without ascites or edema excrete water normally (3, 4). The mechanisms responsible for this defect in water excretion have been debated for many years. Intrarenal factors such as diminished delivery of fluid to the distal nephron or an extrarenal mechanism involving vasopressin release have been suggested. Studies in experimental models with altered liver function (5-7) have shown a decrease in distal fluid delivery; a predominant role for vasopressin release, however, was shown.

In our study, a sensitive radioimmunoassay technique was used to measure plasma arginine vasopressin (8, 9), the mammalian antidiuretic hormone, in 12 patients with variable degrees of decompensated liver disease. Our results show the importance of nonosmotic stimulation of vasopressin in impaired water excretion. This nonosmotic vasopressin stimulation appears to be mediated by a decrease in effective blood volume, an effect that may also alter intrarenal factors affecting water excretion.

Methods

Thirteen studies were done in 12 patients with alcoholic liver disease, as shown by history and physical examination in all cases and by pathologic findings in liver in five cases. The patients were stable for at least 2 weeks before the study and had various amounts of ascites (minimal to tense ascites) or peripheral edema. No patients had clinical evidence of alcoholic hepatitis including absence of fever and leukocytosis at the time of the study. Tense ascites was designated 3+, obvious ascites 2+, ascites disclosed by percussion only 1+. Peripheral edema was designated 2+ when it extended to the midthigh or back, and 1+ when it was found only by manual pressure on legs. Studies were done at the Clinical Research Center of the University of Colorado School of Medicine. This study was approved by the Human Research Committee of the University Hospital and all patients gave informed consent.

All patients except Patients 8, 9, and 10 had a 2 g sodium diet for 1 week before the study. Patients 8, 9 and 10 had a normal sodium diet. Water intake was unrestricted in all patients. Diuretics were discontinued at least 5 days before the experiment. Eleven patients were men. The mean age was 48 years (range, 36 to 62 years). A water load test was done on each patient. After an overnight fast, patients were awakened at 0700 h and weighed. A short plastic catheter was introduced percutaneously for blood collection in one arm and a similar catheter to give intravenous fluid or solution in the other arm. An inulin and para-aminohippurate infusion was started at a constant rate (1 mL/min) and continued during the study. At 0800 h a 20 mL/kg of body weight water load of 5% glucose in water was given intravenously over 20 to 30 minutes. Hourly blood and urine samples (from spontaneous voiding) were taken from 0800 h until 1300 h. Blood was analyzed for sodium, potassium, chloride and bicarbonate concentrations, osmolality, creatinine, inulin, para-aminohippurate, urea nitrogen, total protein, albumin, hematocrit, liver function tests, plasma renin activity, aldosterone, and vasopressin levels. Urine was analyzed for sodium, potassium, chloride, urea nitrogen, creatinine, inulin, para-aminohippurate concentrations, and osmolality. Blood taken to measure aldosterone and vasopressin levels was collected in chilled heparinized tubes placed immediately on ice, centrifuged at 0°C at 3000 rpm for 20 min and frozen in plastic tubes at 0°C for later analysis. Blood taken to measure plasma renin activity was collected similarly on edetate disodium.

Sodium and potassium concentrations were analyzed by flame photometry. Chloride, bicarbonate, glucose, urea nitrogen, creatinine, inulin and para-aminohippurate concentrations, bilirubin, alkaline phosphatase, aspartate aminotransferase (AsAT), and lactic dehydrogenase were analyzed by autoanalyzer (Technicon, Tarrytown, New York) procedures. Plasma aldosterone, plasma renin activity, and vasopressin levels were measured by radioimmunoassay (8-11). Osmolality was measured using an Advanced Osmometer (Advanced Instruments, Inc., Needham Heights, Massachusetts).

Statistical analysis was done using a two-tailed unpaired t test and least-square regression analysis. Results are given as mean ± SE. Clinical characteristics and detectable versus undetectable vasopressin values were compared using nonparametric statistical analysis.

Results

Thirteen water-load tests were done in 12 patients (Patient 4 was studied twice) with alcoholic liver disease and variable amounts of ascites, edema, or both (Table 1). Patients were divided into two groups according to their response to the water load. Patients excreting less than 80% of the water load over the next 5 hours were labeled nonexcretors and patients excreting 80% or more of the water load over the next 5 hours were labeled excretors. Seven patients were nonexcretors (eight studies, Patients 1-7, Group 1); they excreted 27.2% ± 5.4% of the water load in 5 hours and had a minimum urine osmolality of 262 ± 57 mosmol/kg water. Five excretors (Patients 8-12, Group 2) had normal water excretion, 82.6% ± 1.0% of the water load in 5 hours, and had a minimum urine osmolality of 65.6 ± 6.0 mosmol/kg water (Table 1). The serum sodium concentration before the water load was lower in Group 1 (134.8 ± 1.5 meq/L) than in Group 2 (139.6 ± 0.74 meq/L), p < 0.02. Non-excretors could not always be identified by the presence of hyponatremia; Patients 3, 4, and 5 were not hyponatremic at the time of the water load. Patient 4 received a second water load and was hyponatremic (plasma sodium, 130 meq/L) at that time (Table 1).

Table 1. Water Excretion in Excretor and Nonexcretor Cirrhotic Patients


	Patient	Age	Ascites*	Peripheral Edema*	Water Load Excreted	Serum Sodium Basal	Minimum Urine Osmolality

		yrs			%	meq/L
Group 1 nonexcretors	1	54	3+	2+	14	133	213
	2	45	2+	0	30	135	108
	3	58	2+	2+	46	142	188
	4	41	3+	2+	14.4	140	318
	4	41	3+	2+	13.5	130	488
	5	62	3+	2+	13	137	510
	6	58	3+	2+	47	130	182
	7	36	3+	0	40	132	93
Mean ± SE		50.5 ± 3.7			27.3 ± 5.4	134.8 ± 1.58	262 ± 57
Group 2 excretors	8	38	+	+	81	139	76
	9	40	0	+	82	141	77
	10	55	0	+	86	141	54
	11	53	0	+	84	140	48
	12	41	2+	0	80	137	73
Mean ± SE p Value (Group 1 versus Group 2)		45.4 ± 3.5			82.6 ± 1.0 < 0.001	139.6 ± 0.74 < 0.02	65.6 ± 6 < 0.01

* See Methods for definitions.

There were some clinical differences between these two groups of patients. All non-excretor patients had moderate to tense ascites with various degrees of peripheral edema. By contrast, Patients 8 through 11 (excretors) had minimal or no ascites and Patient 12 had a stable, moderate degree of ascites (Table 1). Patients 8 and 9, although not decompensated at the time of the study, had a long history of alcohol intake, signs of liver disease, and had been treated for ascites before the study. Patients 10 and 11 also had a long history of alcohol intake, signs of liver disease, and both had a liver biopsy showing micronodular cirrhosis.

Results of arginine vasopressin measurements using a sensitive radioimmunoassay are shown in Table 2. Measurements were made before and at regular intervals after the water load. Although baseline arginine vasopressin values in Group 1 were higher than the baseline values in Group 2 (2.49 ± 0.54 versus 0.98 ± 0.50 pg/mL), these values were not significantly different. Mean arginine vasopressin values after water load were significantly higher in the nonexcretor group (Group 1), 1.34 ± 0.36 versus 0.26 ± 0.18 pg/mL (undetectable). Plasma vasopressin values measured at 2, 3, and 5 h after water load were significantly higher in the non-excretor, as compared to the excretor group (2 hours, 0.64 ± 0.18 versus undetectable; 3 hours, 1.43 ± 0.48 versus undetectable; 5 hours, 1.07 ± 0.35 versus undetectable, all p < 0.05) (Table 2). When the values after water load in the non-excretor and excretor groups were compared by chi-squared analysis, a significant difference was found at p <0.005 level.

*Table 2. Plasma Arginine Vasopressin Levels in Excretor and Nonexcretor Cirrhotic Patients During Water Load**

	Basal Level	Minutes After Water Load					Mean Arginine Vasopressin
		+60	+120	+180	+240	+300

	<----------------------------------------------------------------pg/mL--------------------------------------------------------------->
Group 1 nonexcretors, n Mean ± SE Group 2 excretors, n Mean ± SE p Value	8 2.49 ± 0.54 5 0.98 ± 0.5 . . .	6 1.9 ± 0.95 5 0.34 ± 0.34 . . .	7 0.64 ± 0.18 5 Undetectable <0.05	8 1.43 ± 0.48 4 Undetectable <0.05	7 1.44 ± 0.54 5 0.55 ± 0.25 . . .	7 1.07 ± 0.35 4 Undetectable <0.05	8 1.34 ± 0.36 5 0.26 ± 0.40 <0.025

*Lower limit of sensitivity in the measurement of arginine vasopressin is 0.5 pg/mL.

A significant correlation was found between the mean plasma arginine vasopressin level after water load and the percentage of the water load excreted (r = 0.71, p < 0.01). The patients with the poorest water excretion (Patients 1, 4, and 5) had the highest mean plasma arginine vasopressin after the water load (2.2 pg/mL, 1.92 pg/mL, and 3.25 pg/mL, respectively). The significant positive correlation found between urine osmolality and plasma arginine vasopressin (r = 0.64, p < 0.001, n = 53) after the water load showed a relation between high plasma levels of arginine vasopressin and the inability to excrete a water load in cirrhotic patients. This finding indicated that high levels of vasopressin were associated with marked hydroosmotic effects on the collecting duct as shown by urine osmolality.

An analysis was done to detect any differences between the excretor and nonexcretor patients (Table 3). Mean arterial blood pressure was similar between the two groups (86.5 ± 2.7 mm Hg in Group 1 versus 82.0 ± 2.07 mm Hg in Group 2) as well as hematocrit (37.4% versus 39.4%). The nonexcretor group had a higher serum bilirubin than the excretor group (4.8 ± 1.0 versus 2.1 ± 0.7 mg/dL, p < 0.05). Serum alkaline phosphatase, AsAT, and serum lactic dehydrogenase were also similar. Prothrombin and plasma thromboplastin times were similar for both groups (15.2 ± 1.1 and 37.0 ± 1.5 for nonexcretors; 12.9 ± 0.94 and 37.0 ± 2.8 for excretors). There were other differences between the two groups. Group 1 (nonexcretors) had lower plasma albumin (2.5 ± 0.14 versus 3.4 ± 0.3 g/dL, p < 0.05), higher pulse rate (96 versus 72, p < 0.005), higher plasma renin activity (7.8 ± 1.55 versus 1.4 ± 0.3 ng/mL ± h, p < 0.005), higher plasma aldosterone (66.2 ± 17.7 versus 21.3 ± 2.09 ng/dL, p < 0.05), lower creatinine clearance (77 ± 7 versus 116 ± 14 mL/min, p < 0.05), and excreted less sodium in the 5 hours after water load (2.8 ± 1.08 versus 14.2 ± 2.4 meq Na/5 h, p < 0.005) than Group 2 (excretors).

Table 3. Summary of Clinical and Biochemical Characteristics in Cirrhotic Patients

	MAP*	Pulse	C_Cr†	C_in‡	C_PAH§	Plasma Albumin	Plasma Aldosterone	Plasma Renin Activity	Urinary Sodium Excretion

	mm Hg	beats/min	<—————— mL/min · 1.73 m² ——————>			g/dL	mg/dL	ng/mL · h	meq
Group 1 nonexcretors (n = 8)	86.5 ± 2.7	96.2 ± 2.7	77.9 ± 7.4	78.9 ± 10.7	371.2 ± 47.6	2.5 ± 0.14	66.2 ± 17.7	7.8 ± 1.5	2.8 ± 1.0
Group 2 excretors (n = 5)	82.0 ± 2.0	72.8 ± 2.6	116.2 ± 14.6	97.9 ± 23.9	421.4 ± 103.1	3.36 ± 0.23	21.3 ± 2.0	1.48 ± 0.3	14.2 ± 0.3
p Value	. . .	< 0.001	< 0.05	. . .	. . .	< 0.02	< 0.05	< 0.005	< 0.005

*MAP = means arterial pressure. †C_Cr = creatinine clearance. ‡C_in - inulin clearance. §C_PAH = para-aminohippurate clearance.

Discussion

There has been a controversy over the role of antidiuretic hormone in mediating the abnormal water excretion of cirrhosis. In some decompensated cirrhotic patients (12) the use of alcohol, an inhibitor of the antidiuretic hormone release, caused an increase in urine flow and a decrease in urine osmolality. Other indirect evidence implicating antidiuretic hormone has been provided by de Troyer and associates (13) who reported increased urine flow and decreased urine osmolality in cirrhotic patients receiving demeclocycline. Some of these patients, as well as our own (14), had increased urine sodium excretion after demeclocycline; therefore, the exact mechanism of increased urine flow was not clear. When measured by bioassay, antidiuretic hormone levels in the blood and urine of patients with cirrhosis have yielded conflicting results (1, 15, 16).

Previous studies have examined the mechanism of impaired water excretion in experimental models with liver dysfunction, including acute portal vein constriction in the dog as a model of portal hypertension (5), chronic bile duct ligation in the rat as a model of obstructive jaundice (6), and carbon tetrachloride-induced liver disease in the rat as a model of chronic cirrhosis (7). Removal of the endogenous source of vasopressin by acute hypophysectomy increased renal water excretion in the dog with acute portal vein constriction. A residual defect in water excretion persisted, however, implicating intrarenal factors. Vasopressin release was the sole factor in abnormal water excretion associated with chronic bile-duct-ligated rats, because rats with hypothalamic diabetes insipidus (homozygous Brattleboro rats) had normal water excretion (6). Linas and associates (7) recently showed an inability of rats with carbon tetrachloride-induced cirrhosis to excrete a water load. In these animals plasma arginine vasopressin concentrations measured by radioimmunoassay were increased after a water load. The defect in water excretion was not present in vasopressin-free Brattleboro rats with carbon tetrachloride-induced cirrhosis, comparable liver dysfunction, and histologic evidence of liver disease. Taken together, these studies show a predominant role for vasopressin in experimental models of liver dysfunction. There is also evidence that diminished distal nephron fluid delivery contributes to the abnormal water excretion associated with experimental liver disease.

In the present study only five of 12 patients had suppressed plasma arginine vasopressin at undetectable levels and normal acute water load excretion. The seven cirrhotic patients with abnormal water excretion did not have suppressed plasma arginine vasopressin concentrations despite a mean plasma sodium concentration lower than that of the five patients with normal water excretion. These seven patients had various degrees of impaired water excretion, from 13% to 46% excretion of the acute water load. This impaired water excretion related to the inability to suppress plasma vasopressin. Also of note was the finding that the three patients with the greatest impairment in water excretion (Patients 1, 4, and 5) had the highest mean plasma arginine vasopressin concentrations after the water load (2.2 pg/mL, 1.92 pg/mL, and 3.25 pg/mL, respectively). Because the level of plasma hypoosmolality was lower in the nonexcretor group, arginine vasopressin release must have been stimulated by nonosmolar pathways (5). The seven nonexcretor patients had significantly lower plasma albumin concentrations, higher pulse rates, and higher plasma renin activities and plasma aldosterone concentrations. These findings are compatible with a decrease in effective arterial blood volume in decompensated cirrhotic patients, thus providing a nonosmotic (baroreceptor) stimulation of arginine vasopressin release. A lower effective blood volume in the nonexcretor group was also shown by a lower urinary excretion of sodium over the 5 hours of the water load. Although our results support the established view of a decrease in effective blood volume in patients with decompensated cirrhosis and ascites, the overflow theory (17, 18) may also contribute. If, however, the effective circulation was overexpanded due to a primary renal defect causing sodium and water retention, nonosmotic suppression of plasma arginine vasopressin, renin, and aldosterone should have occurred. On the other hand, if diminished plasma oncotic pressure, splanchnic venous pooling, and peripheral vasodilatation lower effective arterial blood volume in cirrhosis, the result would be baroreceptor-mediated nonosmotic stimulation of arginine vasopressin. Our patients with impaired water excretion not only had higher plasma arginine vasopressin concentrations but also more ascites, lower plasma albumin concentrations and higher plasma renin activities and aldosterone concentrations.

Although we did not measure metabolic clearance rates of arginine vasopressin, different rates of vasopressin degradation do not explain our results. Vasopressin is metabolized in a roughly equal proportion by the liver and the kidney (19, 20) and renal clearance appears to be independent of glomerular filtration rate (20). The slight difference in glomerular filtration rate between the two groups should not influence plasma arginine vasopressin levels. Although preliminary results suggest that liver disease may prolong plasma arginine vasopressin half-life (21), the resultant water retention and hypoosmolality would suppress arginine vasopressin release if only osmotic pathways were activated. In cirrhotic patients, although impaired arginine vasopressin metabolism may contribute to elevated plasma levels, nonosmotic release of arginine vasopressin must be primarily responsible for their continuation.

The present study shows the effects of high concentrations of plasma arginine vasopressin in patients with decompensated cirrhosis, hyponatremia, and impaired water excretion. The lower creatinine clearances and urinary sodium retention in the nonexcretor cirrhotic patients is compatible with a contributing role of intrarenal factors. As with experimental models of liver disease, nonosmotic release of arginine vasopressin and intrarenal factors both contribute to the impaired water excretion in decompensated, hyponatremic, cirrhotic patients. The availability of structural antagonists of the hydroosmotic effect of arginine vasopressin (22, 23) will aid the study of the relative importance of increased plasma levels of the antidiuretic hormone versus intrarenal factors with impaired water excretion in cirrhotic patients.

ACKNOWLEDGMENTS: The authors thank Dr. Gary L. Robertson, University of Chicago, Pritzker School of Medicine, for some of the radioimmunoassay measurements of arginine vasopressin, and Ms. Linda M. Benson for secretarial assistance.

Grant support: Grant RR-00051 from the General Clinical Research Center Program of the Division of Research Resource, National Institutes of Health. Dr. Bichet is a recipient of a grant from Le Conseil de la Recherche en Sante du Quebec.

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From the Department of Medicine, University of Colorado Health Sciences Center; Denver, Colorado.

1982

Address correspondence and reprint requests to American College of Physicians.

Role of Vasopressin in Abnormal Water Excretion in Cirrhotic Patients

cirrhotic

DEFINITION:

ascites

DEFINITION:

water load

DEFINITION:

water load

DEFINITION:

urine osmolality

DEFINITION:

urine osmolality

DEFINITION:

water load

DEFINITION:

pulse rate

DEFINITION:

vasopressin

DEFINITION:

factor

DEFINITION:

cirrhosis

DEFINITION:

permission

DEFINITION:

NDI

DEFINITION:

permission

DEFINITION:

hyponatremia

DEFINITION:

water load

DEFINITION:

cirrhosis of the liver

DEFINITION:

renal

DEFINITION:

cirrhosis

DEFINITION:

hyponatremia

DEFINITION:

decompensated

DEFINITION:

cirrhotic

DEFINITION:

ascites

DEFINITION:

edema

DEFINITION:

administration

DEFINITION:

cirrhotic

DEFINITION:

ascites

DEFINITION:

edema

DEFINITION:

intrarenal

DEFINITION:

distal nephron

DEFINITION:

extrarenal

DEFINITION:

vasopressin

DEFINITION:

altered

DEFINITION:

liver

DEFINITION:

distal

DEFINITION:

vasopressin

DEFINITION:

radioimmunoassay

DEFINITION:

antidiuretic hormone

DEFINITION:

decompensated

DEFINITION:

liver disease