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HEPATOLOGY
Copyright C by the American Association for the Study of Liver Diseases

Vol. 8, No. 5, pp. 1151-1157,1988

Printed in U.S.A.

SDecial Article
Peripheral Arterial Vasodilation Hypothesis: A Proposal for
the Initiation of Renal Sodium and Water Retention in
Cirrhosis
ROBERTW. SCHRIER,VICENTEARROYO,MAUROBERNARDI,MURRAY
EPSTEIN,JENSH. HENRIKSEN
AND
JOAN
RODES
University of Colorado School of Medicine, Denver, Colorado 80262; Liver Unit, Hospital Clinic i Provincial, University of
Barcelona, Barcelona, Spain; Istituto di Patologia Speciale Medica e Metodologia Clinica, University of Bologna, Bologna, Italy;
Nephrology Section, Veterans Administration Medical Center and Division of Nephrology, University of Miami School of
Medicine, Miami, Florida 33125; Departments of Clinical Physiology and Hepatology, Hvidovre Hospital, and Department of
Internal Medicine and Endocrinology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

Renal sodium and water retention and plasma volume

expansion have been shown to precede ascites formation
in experimental cirrhosis. The classical underfilling
theory, in which ascites formation causes hypovolemia
and initiates secondary renal sodium and water retention, thus seems unlikely. While the occurrence of primary renal sodium and water retention and plasma volume expansion prior to ascites formation favors the
overflow hypothesis, the stimulation of the renin-angiotensin-aldosterone system, vasopressin release and
sympathetic nervous system associated with cirrhosis is
not consonant with primary volume expansion.
In this present article, the Peripheral Arterial Vasodilation Hypothesis is proposed as the initiator of sodium and water retention in cirrhosis. Peripheral arterial vasodilation is one of the earliest observations in
the cirrhotic patient and experimental animals with cirrhosis. Arterial vasodilators and arteriovenous fistula
are other examples in which renal sodium and water
retention occur secondary to a decreased filling of the
arterial vascular tree. An increase in cardiac output and
hormonal stimulation are common features of cirrhosis,
arteriovenous fistula and drug-induced peripheral arterial vasodilation. However, a predilection for the retained sodium and water to transudate into the abdominal cavity occurs with cirrhosis because of the presence
of portal hypertension. The Peripheral Arterial Vasodilation Hypothesis also explains the continuum from
compensated to decompensated cirrhosis to the hepatorenal syndrome.

The pathogenesis of sodium and water retention in

cirrhosis has been a topic of extreme interest for many
years. Two theories (Figure 1) have emerged to explain
this phenomenon of enhanced renal sodium and water
avidity in patients with cirrhosis. First, the classical
underfilling theory proposed that the hepatic venous
block and portal hypertension in cirrhosis initially cause

Address reprint requests to: Robert W. Schrier, M.D., University of

Colorado School of Medicine, 4200 East 9th Ave., Box C281, Denver,
Colorado 80262.

ascites formation (1,2). This sodium and water transudation into the abdominal cavity then decreases
intravascular volume and secondarily results in the wellestablished hypovolemia-induced increase in renal sodium and water retention (3, 4). This classical underfilling theory was first challenged by Lieberman et al. (5)
when they found increased, not decreased, total blood
volumes in cirrhotic patients with ascites and these total
blood volumes were not higher when some of the cirrhotic
patients underwent a spontaneous diuresis. These authors, therefore, proposed the overflow hypothesis of
sodium and water retention and ascites formation in
cirrhosis (6). They proposed that ascites formation was
a secondary phenomenon which resulted from primary
renal sodium and water retention, primary in the sense
that the renal response was not produced by a decrease
in intravascular volume. The cause of the primary sodium retention was not delineated but presumably was
due to some hepatorenal reflex which predominated over
the normal volume regulatory mechanism (7). The sodium and water retention then leads to overflow ascites
formation secondary to the hypervolemia and the increased pressure in the portal system. Support of this
overflow hypothesis has emerged from careful studies of
experimental models of cirrhosis in the rat and dog in
which blood volume expansion and renal sodium and
water retention were clearly demonstrated to precede
ascites formation (8-12).
In this article we propose yet a third hypothesis to
account for renal sodium and water retention and ascites
formation in cirrhosis. This hypothesis has characteristics of both the classical underfilling and overflow hypotheses, but neither ascites formation and hypovolemiainduced renal sodium and water retention nor primary
renal sodium and water retention, blood volume expansion and overflow ascites are considered to be the initiation or primary mechanism of the renal sodium and
water retention in cirrhosis. We would like to term our
hypothesis the Peripheral Arterial Vasodilation Theory of renal sodium and water retention in cirrhosis.
This hypothesis (Figure 2) proposes that peripheral ar-

1151

1152

SCHRIER ET AL.
CLASSICAL UNDERFILLING

VERSUS
OVERFLOW HYPOTHESES

Undertilhg*
Hypothesis

Ovanow
Hypothesis

Portal Hypertension
I

Primary R e d Sodium
md water Retention+

Ascites Formation

IntnvAulu
Hypervolemu

lntravasculu
Hypovolemia

P0rt.I
Bypertdon

\ /
Asfites Formation

Secondary R e n d Sodium
and Water Retention
F I G . 1. (*)Since renal sodium retention has been shown to occur
prior to ascites formation in experimental cirrhosis in both the rat and
dog and plasma volume has been shown to be increased, not decreased,
in patients with cirrhosis, the classical underfilling hypothesis does not
seem to explain adequately the renal sodium retention of cirrhosis.
(+)Primaryrefers to renal sodium and water retention which occurs
in the absence of intravascular hypovolemia. While the observation
that renal sodium retention and plasma volume expansion precede
ascites formation in cirrhosis supports the classical overflow hypothesis, the stimulation of plasma hormones which normally accompany
intravascular hypovolemia including plasma renin, norepinephrine,
aldosterone and vasopressin is not adequately explained by the overtlow
hypothesis.

terial vasodilation is the initiating event of sodium and

water retention in cirrhosis.
COMPENSATED CIRRHOSIS
Systemic hemodynamic changes characterized by primary peripheral arterial vasodilation and a secondary
increase in cardiac output occur prior to ascites formation in experimental cirrhosis and compensated cirrhosis
in man (13-17). We propose this peripheral arterial
vasodilation to be the initial event in intravascular underfilling, not because the intravascular blood volume is
decreased, but rather because the intravascular compartment is enlarged. This theory is compatible with the
definition of effective arterial blood volume (EABV),
in which the relationship between cardiac output and
peripheral vascular resistance dictates the fullness of the
arterial vascular circulation and, thus, the regulation of
renal sodium excretion in edematous disorders (18, 19).
For example, while a fall in cardiac output decreases
EABV in cardiac failure, peripheral arterial vasodilation
decreases EABV in cirrhosis (18, 19).
The initial peripheral arterial vasodilation and, thus,
the underfilling of the arterial circulation in cirrhosis
is associated with several compensatory events which
characterize early cirrhosis. As already cited, the systemic response to peripheral vasodilation, and thus car-

HEPATOLOGY

diac after-load reduction, is a rise in cardiac output (13,

14). In addition, transient renal sodium and water retention occurs to refill the intravascular compartment. At
this stage of cirrhosis, total blood volume is expanded,
cardiac output is increased and peripheral arterial vasodilation is present (13, 14, 20). These cirrhotic patients
do not have ascites on a normal sodium diet and without
diuretics; they have been termed compensated. By use
of lZ5I-labeledalbumin circulatory transit times, compensated cirrhotic patients recently have been found to have
decreases in central blood volume as defined by the
volume of blood in the heart, pulmonary circulation and
aorta (21). This finding is compatible with an increased
cardiac output and vascular run-off secondary to peripheral arterial vasodilation and the resultant diminished cardiac after-load. While several other sites may
be involved in the arteriolar vasodilation which accompanies cirrhosis (e.g. skin, muscle and lung), the major
documented site of the peripheral arteriolar vasodilation
is the splanchnic circulation (15, 22). The hepatic blood
flow, however, may be normal or reduced in these patients, since as much as 80% of the blood from the
splanchnic bed may flow through collaterals, thereby
bypassing the hepatic circulation (23, 24). The cause of
the arteriolar vasodilation of the splanchnic circulation,
which seems to be related to the increase in portal
pressure (25, 26), is unknown. Various bioactive substances have been suggested to contribute to or totally
account for the peripheral arterial vasodilation in cirrhosis (27-30), but none have been implicated definitively.
The use of specific antagonists to these potential vasodilating hormones in cirrhosis will be necessary to examine the various possibilities.
In this early compensated state of cirrhosis without
ascites, persistent elevation of plasma renin, aldosterone,
vasopressin and norepinephrine is not demonstrable (13,
31-34). However, in the context of the overflow hypothesis the increase in total plasma volume in compensated
cirrhotic patients should be associated with suppression
of these plasma hormone concentrations. Moreover,
transient elevation of these hormones during compensatory renal sodium and water retention with subsequent
volume expansion and return of these hormones to normal is proposed to occur in context of the Peripheral
Arterial Vasodilation Hypothesis (Figure 2). Urinary
prostaglandins are also not increased in compensated
cirrhosis (35). Several subtle abnormalities compatible
with the Peripheral Arterial Vasodilation Hypothesis
are, however, present in compensated cirrhotic patients.
In contrast to normal subjects, some compensated cirrhotic patients do not escape from exogenously administered mineralocorticoid hormone and indeed develop
peripheral edema and ascites (36). The mechanism for
mineralocorticoid escape in normal subjects involves
blood volume expansion which then increases distal sodium and water delivery by enhancing the filtered load
and/or decreasing proximal reabsorption of sodium and
water. This increased tubular flow and sodium delivery
to the distal nephron then override the sodium-retaining
effect of aldosterone in the collecting duct, thus causing
mineralocorticoid escape (37). We propose that in compensated cirrhosis the peripheral vasodilation-induced

1153

PERIPHERAL ARTERIAL VASODILATION HYPOTHESIS

Vol. 8, No. 5, 1988

PERIPHERAL VASODlLATION B Y P O T H E d
Cotuperrrated Cirrhosis+

Moderate Peripheral
Vasodilation (e.g. Splanchnie)

Moderate Deerease Effective

M e r i a l Blood Volume (EABV)

Moderate Increase Plasma

Renin. Aldosterone.
Norepinephrine and
Vasopressin Concentrations

Moderate Renal Vasorolritriction

with Renal sodium
and Water Retention

Plasma Volume Expansion

Return of Plasma Renin

udaterme. Norepinephrine
and Vasopressin Concentration
t o Normal Values

Hepatorerul s y n b e +

l)eCommted Cirrhais+*

Severe Renal Vasoconstriction

with Renal Sodium
and Water Retention

P b m a Volume Expansion
may be modified by
hyponlbuminenia

Inadequate td N o r m d m
Renal Hemodymoies.
Plasma Renin. Aldataone,
Norepinephrine and
V u o p r a i n Coneantration

ASeitar Formation

Extreme Peripheral
Vasodilation

Severe Decrease
EABV

Severe Rise'in Plasma

Renin. AIQsterone.
Norepinephrine and
Vasapressin Concentrations

Severe Peripheral
Vasodilation

Extreme &crease
in EABV with Bypotension

Extreme Elevation of Plasma

Renin. AlQsterone.
Norepinephrine and
Vasapressin Concentrations

Extreme Renal Vasoconstriction -Renal

with Renal Sodium
Failure
M d Water Retention

Plasma Volume Expansion

may be modified by

hypollbuninemia

Pmma Renin.' MQsterone

Norepinephrine and
Vuopraain Concentrations
remain at high levels

Further Aacits Formation

FIG.2. (#)The Peripheral Arterial Vasodilation Hypothesis can explain virtually all of the manifestations of the spectrum of systemic and
renal hemodynamics, plasma hormones and effects on sodium and water excretion observed in the cirrhotic patient. (+)In many cirrhotic patients
the peripheral vasodilation decreases cardiac pre-load and is associated with an increase in cardiac output. (*)Somepatients (approximately onethird) with decompensated cirrhosis, as defined by the presence of ascites, may have normal renal hemodynamics because of increasing synthesis
of renal vasodilatory prostaglandins. These patients demonstrate a severe diminution in renal function with administration of nonsteroidal
antiinflammatory drugs in contrast to no effect observed in the compensated (i.e. no ascites) cirrhotic patient.

underfilling of the arterial circulation may prevent increased distal delivery and thus mineralocorticoid escape
in some patients with compensated cirrhosis. An impaired response to an acute salt load has also been
demonstrated in compensated cirrhotic patients (38). In
general, compensated cirrhotic patients excrete an acute
water load normally (39, 40). Other subtle abnormalities
may, however, be present in compensated cirrhosis which
provide further evidence of vasodilation-induced underfilling and enhanced sodium and water retention prior to
ascites formation. Abnormal diurnal variations of plasma
renin, urinary catecholamines and perhaps plasma aldosterone have been shown to occur in compensated
cirrhotics (41). On the other hand, as compared to normal
subjects on the same sodium intake, on assuming and
maintaining the supine position these patients may exhibit a greater negative sodium balance, suggesting a
greater increment in EABV in compensated cirrhotics
than normal subjects when changing from the upright to
supine position (42). This may be because of peripheral
vasodilation and distal pooling of fluid in the upright
position; this fluid is then translocated to the central
blood volume on assuming the supine position. This
translocation of fluid may also explain the low supine
plasma renin activity in some patients with compensated
or decompensated cirrhosis (31, 43). Thus, cirrhotic patients should probably always be studied in the upright
and supine positions (44,45).

DECOMPENSATED CIRRHOSIS

The decompensated cirrhotic patient, as defined by

ascites accumulation, represents a more advanced stage
on the continuum in the process of vasodilation-mediated
vascular underfilling. At this stage of cirrhosis, the increase in blood volume secondary to the transient sodium
and water retention is no longer sufficient to maintain
circulatory homeostasis. Moreover, a diminution in
plasma colloid oncotic pressure may be a factor in addition to the peripheral arteriolar vasodilation in decreasing EABV. Therefore, as arteriolar baroreceptors sense
a decrease in filling of the arterial vascular tree, three
vasoconstrictor systems are activated, namely the nonosmotic release of vasopressin, renin-angiotensin-aldosterone system and sympathetic nervous system (33, 4650). Approximately 25% of decompensated cirrhotic patients with ascites do not, however, exhibit persistent
elevations in plasma vasopressin (50, 51), renin (31, 43)
and norepinephrine (32,47, 51, 52), presumably because
of less severe peripheral vasodilation. Renal function in
these patients, as assessed by inulin and para-aminohippurate clearances, are also normal. Renal hemodynamics
are, however, usually diminished in most decompensated
cirrhotic patients (approximately 75%), and, in general,
there is a correlation between the degree of rise in the
plasma concentration of the renal vasoconstrictor hormones, including angiatensin, norepinephrine and vaso-

1154

SCHRIER ET AL.

pressin, and the degree of fall in renal blood flow and

glomerular filtration rate in decompensated cirrhotic
patients (50,531. The reversal of the renal abnormalities
in decompensated cirrhotic patients by the intrarenal
administration of vascular antagonists of these vasoconstrictors, alone and in combination, will be necessary to
quantitate the relative role of these vasoconstrictors. It
is also clear that the half-life of any such antagonists
should be quite short so as not to affect the systemic
circulation and thus obscure the intrarenal effects. Moreover, while together these three potent vasoconstrictors
seem adequate to account for renal vasoconstriction in
decompensated cirrhotics, an increase in other renal
vasoconstrictors (e.g. leukotrienes) (54) or a decrease in
renal vasodilators (e.g. prostaglandins PGEB and PGI2)
(35,55,56) may be involved in the renal vasoconstriction
of decompensated cirrhosis. The role of angiotensin and
the sympathetic nervous system in counteracting the
peripheral vasodilation of cirrhosis is quite clear since
saralasin, an angiotensin antagonist, converting enzyme
inhibitors or a-adrenergic blockers profoundly lower
blood pressure in decompensated cirrhotic patients
(57-60).
It should be mentioned that the approximately 25% of
decompensated ascitic cirrhotic patients who do not exhibit either an elevation in plasma renin, aldosterone
and norepinephrine or diminished renal perfusion may
respond to aldosterone antagonists (61, 62). Spironolactone inhibition of the action of aldosterone in these
patients causes a natriuresis, an observation not found
in normal subjects (63). This finding suggests that an
increased tubular sensitivity to aldosterone in the decompensated cirrhotic patient may occur. This possibility of
tubular hypersensitivity to aldosterone, as well as the
mechanism, deserves further study in cirrhosis. It should
also be examined whether an increased vascular sensitivity to angiotensin and norepinephrine may occur in the
decompensated cirrhotic patients who have normal
plasma renin and norepinephrine values. This possibility
is not unlikely since an increase in total body sodium is
known to enhance the vascular sensitivity to angiotensin
and norepinephrine (64, 65). In this regard, the effect of
angiotensin and/or a-adrenergic blockers on blood pressure in the 25% of decompensated cirrhotic patients with
normal plasma renin and norepinephrine concentrations
should provide important information.
The counteracting role of the renal vasodilator prostaglandins, namely PGEB and PGI2, in decompensated
ascitic patients with cirrhosis seems rather clear. Specifically, inhibitors of prostaglandin synthetase cause a
dramatic fall in renal blood flow and glomerular filtration
rate in the majority of decompensated cirrhotic patients,
which is most pronounced in the approximately 75% of
decompensated cirrhotic patients who have elevated
plasma vasoconstrictor concentrations. For this reason,
prostaglandin synthetase inhibitors are contraindicated
in this setting (66-68). The urinary excretions of the
vasodilating prostaglandins are increased in decompensated cirrhotic patients who respond to nonsteroidal
antiinflammatory drugs (i.e. prostaglandin synthetase
inhibitors) with a diminution of renal perfusion (53,55).
It should be pointed out, however, that urinary prosta-

HEPATOLOGY

glandin excretion may actually decrease to subnormal

levels as these patients glomerular filtration rates decline and they approach the hepatorenal syndrome (35,
53, 56). It is important to emphasize, however, that in
this setting of diminished renal function urinary prostaglandins may not be an adequate index of renal vascular prostaglandin synthesis, since inhibitors of prostaglandin synthetase may have dramatically different
effects on renal perfusion in patients who have comparable urinary excretion rates of prostaglandins (50).
Of the 75% of decompensated cirrhotic patients who
have elevated plasma concentration of vasoconstrictors,
approximately 25% have normal renal perfusion (13, 43,
53). These normal renal hemodynamics seem likely to be
attributable to a compensatory stimulation in renal vasodilator systems, particularly the prostaglandin (67, 68)
and the kallikrein-kinin system (69). Specifically,
changes in renal hemodynamics do not occur in response
to administering inhibitors of prostaglandin synthesis to
compensated patients with normal renal hemodynamics
and normal plasma vasoconstrictors concentration. In
contrast, however, decompensated cirrhotic patients with
normal renal hemodynamics but elevated plasma vasoconstrictors concentration exhibit a dramatic fall in renal
blood flow and glomerular filtration rate with administration of nonsteroidal antiinflammatory drugs (66-68).
ATRIAL NATRIURETIC HORMONE

A word about plasma atrial natriuretic factor (ANF)

in cirrhosis seems appropriate since low (70), normal (21,
71,72) and even high (73-76) values have been reported.
If the decrease in effective blood volume in cirrhosis were
primarily sensed a t a low pressure site in the heart, such
as the right and/or left atria, a decrease in plasma ANF
might be expected in cirrhosis (77). The absence of
consistent diminution in plasma ANF in either compensated or noncompensated cirrhotic patients therefore is
compatible with the major site of peripheral vasodilation
and vascular underfilling to be present in the arterial
circulation. Thus, with arterial vasodilation, arterial baroreceptors would be expected to sense a decrease in
EABV and increase in the plasma concentration of vasopressin, angiotensin and norepinephrine but not ANF
reIease. The three arterial vasoconstrictor hormones are
also powerful venoconstrictors (78, 79); thus, a rise in
their plasma concentration would be expected to diminish splanchnic capacitance and, thus, maintain cardiac
pre-load and normal plasma ANF values. It should also
be pointed out that increased release of ANF into the
coronary sinus has been described in cirrhosis (76), and
this may contribute to elevated plasma ANF concentrations.
FURTHER EVIDENCE FOR PERIPHERAL
ARTERIAL DILATION THEORY

Evidence for the Peripheral Arterial Vasodilation Theory is also derived from studies in hyponatremic ascitic
patients with cirrhosis. Normalization of sodium and
water excretion in these patients required not only central blood volume expansion with head-out water immersion (HWI) but also increasing peripheral vascular re-

Vol. 8, No. 5, 1988

PERIPHERAL ARTERIAL VASODILATION HYPOTHESIS

sistance with an exogenous norepinephrine infusion (80,

81). Mean renal perfusion pressure increased significantly from 83 mmHg with HWI to 98 mmHg with HWI
and norepinephrine. This increased renal perfusion pressure enhanced sodium and water delivery to the site of
action in the distal nephron of vasopressin, ANF and
aldosterone, thus accounting, at least in part, for the
normalization of the sodium and water excretion in these
cirrhotic patients with ascites.
HEPATORENAL SYNDROME

1155

tors in addition to portal hypertension must contribute

to the peripheral arterial vasodilation of cirrhosis.
CONCLUSION

In conclusion, we propose the Peripheral Arterial Vasodilation Theory rather than either ascites formation
(classical underfilling hypothesis) or primary renal sodium retention (overflow hypothesis) as the initiating
event of renal sodium and water retention in cirrhosis.
This hypothesis is compatible with the renal sodium and
water retention and plasma hormone elevations found in
association with arteriovenous fistulae and high output
cardiac failure (86). Levy and Allotey (11) have attempted to examine the time course in which sodium and
water retention and peripheral vasodilation occur in
early cirrhosis. In their studies of nitrosamine-induced
cirrhosis in the dog, a small positive sodium balance (20
mEq per day) occurred prior to the early detection of
peripheral vasodilation. A fall in blood pressure was,
however, present at the time of the earliest detection of
sodium retention, thus suggesting that the method for
measuring cardiac output and thus calculating peripheral
vascular resistance may not have been sensitive enough
to detect the earliest occurrence of peripheral arterial
vasodilation in this experimental model of cirrhosis. A
recent study in rats with carbon tetrachloride-induced
cirrhosis, showing that stimulation of the renin-angiotensin system occurs in close chronological relationship
with the onset of renal sodium retention and before
ascites formation (87), is compatible with the Peripheral
Arterial Vasodilation Hypothesis. Additional studies
will, however, be necessary to assess the temporal relation between the occurrence of the decrease in peripheral
vascular resistance and renal sodium retention in cirrhosis to test further the Peripheral Arterial Vasodilation
Hypothesis.
Lastly, it is worth emphasizing that several indicators
of poor prognosis in cirrhosis are those which may occur
in association with extreme peripheral arterial vasodilation, namely, a low mean arterial pressure which correlates with the degree of peripheral vasodilation (88, 89),
portal hypertension (90) which may be the trigger of the
splanchnic arteriolar vasodilation and elevations of
plasma concentrations of renin, norepinephrine and vasopressin which accompany peripheral vasodilation (8892). Considered in this light, we propose that a substantial number of cirrhotic patients may not die primarily
because of their hepatic dysfunction but rather because
of the consequences of the circulatory and humoral abnormalities which accompany and are secondary to the
liver disease. Thus, further study of these circulatory and
humoral abnormalities may lead to approaches which
could decrease morbidity and prolong the life of the
cirrhotic patient.

With the Peripheral Arterial Vasodilation Hypothesis

of the pathogenesis of the circulatory, hormonal and
sodium and water abnormalities in cirrhosis, the hepatorenal syndrome can be proposed as the extreme extension of underfilling of the arterial circulation (Figure 2).
The diminution in the urinary excretion of vasodilating
prostaglandins in the hepatorenal syndrome (35, 53, 56)
may be a result of the decline in renal function or,
alternatively, may be a primary factor in the extreme
renal vasoconstriction which characterizes the hepatorenal syndrome, presuming that a parallel fall in synthesis of vascular prostaglandins also occurs. The initial
proposal for a role of increased thromboxanes in the
renal vasoconstriction of the hepatorenal syndrome (82)
has not been confirmed in subsequent studies (32, 56)
and the syndrome has also not been reversed by thromboxane antagonists (83). On the other hand, the plasma
concentrations of the three major vasoconstrictors in
patients with the hepatorenal syndrome are among the
highest observed in patients with liver disease (50, 53).
This finding is, therefore, compatible with the hepatorenal syndrome as the most extreme manifestation of
the Peripheral Arterial Vasodilation Theory in cirrhosis.
It should be mentioned, however, that the worsening
of renal function and sodium and water retention in
cirrhosis not only correlates with the elevation in plasma
vasopressin, renin, aldosterone and norepinephrine, but
also with the degree of portal hypertension (13,32). This
correlation with portal hypertension could be interpreted
to mean that ascites formation is a contributory factor
along with the peripheral vasodilation in perpetuating
the vascular underfilling and thus the renal sodium and
water retention in cirrhosis. On the other hand, partial
constriction of the portal vein in the experimental setting
without liver disease has been shown to cause a rapid
increase in splanchnic blood flow secondary to a marked
splanchnic arteriolar vasodilation (25). Thus, whether
worsening of the portal hypertension in cirrhosis contributes to progression of the circulatory, hormonal and
renal excretory abnormalities primarily by increasing
peripheral vasodilation, or by increasing ascites formation, or a combination thereof, is at present an unanswered question. It is of note, however, that a rapid large
volume abdominal paracentesis without colloid replaceAcknowledgment: We would like to thank Jennifer
ment is usually followed by worsening of vascular underfilling in cirrhosis as assessed by a rapid rise in plasma Graves for her excellent secretarial support.
vasoconstrictor hormones (84,85).On the other hand, it
REFERENCES
is important to point out that renal sodium and water 1. Atkinson M, Losowsky MS. The mechanism of ascites formation
retention has been shown to occur in experimental cirin chronic liver disease. Q J Med 1961; 30153-166.
rhosis in the dog when portal hypertension has been 2. Sherlock S, Shaldon S. The aetiology and management of ascites
in patients with hepatic cirrhosis: a review. Gut 1963; 495-105.
prevented by prior portacaval shunting (10). Thus, fac-

1156

SCHRIER E T AL.

3. Eisenmenger WJ. Role of sodium in the formation and control of

ascites in patients with cirrhosis. Ann Intern Med 1952; 37:261272.
4. Papper S. The role of the kidney in Laennecs cirrhosis of the liver.
Medicine 1958; 37:299-316.
5. Lieberman FL, Ito S, Reynolds TB. Effective plasma volume in
cirrhosis with ascites: evidence that a decreased volume does not
account for renal sodium retention, a spontaneous reduction in
glomemlar filtration rate (GFR), and a fall in GFR during druginduced diuresis. J Clin Invest 1969; 48975-981.
6. Lieberman FL, Denison EK, Reynolds TB. The relationship of
plasma volume portal hypertension, ascites, and renal sodium and
retention in cirrhosis: the overflow theory of ascites formation.
Ann NY Acad Sci 1970; 170:202-206.
7. Kostreva DR, Castaner A, Kampine JP. Reflex effects of hepatic
baroreceptors on renal and cardiac sympathetic nerve activity. Am
J Physiol1980; 238R390-R394.
8. Levy M. Sodium retention and ascites formation in dogs with
experimental portal cirrhosis. Am J Physiol1977; 233:F572-F585.
9. Levy M. Sodium retention in dogs with cirrhosis and ascites:
efferent mechanisms. Am J Physioll977; 233:F586-F592.
10. Levy M, Wexler MJ. Renal sodium retention and ascites formation
in dogs with experimental cirrhosis but without portal hypertension
or increased splanchnic vascular capacity. J Lab Clin Med 1978;
91520-536.
11. Levy M, Allotey JBK. Temporal relationship between urinary salt
retention and altered systemic hemodynamics in dogs with experimental cirrhosis. J Lab Clin Med 1978; 92560-569.
12. Lopez-Novoa JM, Rengel MA, Hernando L. Dynamics of ascites
formation in rats with experimental cirrhosis. Am J Physiol 1980;
238F353-F357.
13. Bosch J , Arroyo V, Betriu A, et al. Hepatic hemodynamics and the
renin-angiotensin-aldosteronesystem in cirrhosis. Gastroenterology 1980; 7892-99.
14. Bredfeldt JE, Groszmann RJ. Hemodynamic aspects of portal
hypertension. In: Epstein M, ed. The kidney in liver disease, Ed.
2. New York Elsevier Biomedical, 1978 281-292.
15. Vorobioff J, Bredfeldt JE, Groszmann RJ. Increased blood flow
through the portal system in cirrhotic rats. Gastroenterology 1984;
87:1120-1126.
16. Fernandez-Munoz D, Caramel0 C, Santos JC, et al. Systemic and
splanchnic hemodynamic disturbances in conscious rats with experimental liver cirrhosis without ascites. Am J Physiol 1985;
249:G316-G320.
17. Linas SL, Anderson RJ,Guggenheim SJ, et al. Role of vasopressin
in impaired water excretion in conscious rats with experimental
cirrhosis. Kidney Int 1981; 20173-180.
18. Schrier RW. Pathogenesis of sodium and water retention in high
and low output cardiac failure, cirrhosis, nephrotic syndrome, and
pregnancy. N Engl J Med 1988 (in press).
19. Bichet D, Schrier RW. Cardiac failure, liver disease and nephrotic
syndrome. In: Schrier RW, Gottschalk CW, eds. Diseases of the
kidney, Vol. 90, Ed. 4. Boston: Little, Brown and Co., 1987: 27032742.
20. Lieberman FL, Reynolds TB. Plasma volume in cirrhosis of the
liver: its relation to portal hypertension, ascites and renal failure.
J Clin Invest 1967; 461297-1308.
21. Henriksen JH, Schutten HJ, Bendtsen F, et al. Circulating atrial
natriuretic peptide (ANP) and central blood volume (CBV) in
cirrhosis. Liver 1986; 6361-368.
22. Kotelanski B, Groszmann RJ, Cohn JN. Circulation times in the
splanchnic and hepatic beds in alcoholic liver disease. Gastroenterology 1972; 63:102-111.
23. Cohn JN, Khatri JM, Groszmann RJ, et al. Hepatic blood flow in
alcoholic liver disease measured by an indicator dilution technique.
Am J Med 1972; 53:704-714.
24. Groszmann RJ, Kotelanski B, Cohn JN, et al. Quantitation of
portasystemic shunting from the splenic and mesenteric beds in
alcoholic liver disease. Am J Med 1972; 53:715-722.
25. Vorovioff J , Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol 1983;
244G52-G57.
26. Blanchet L, Lebrec D. Changes in splanchnic blood flow in portal
hypertensive rats. Eur J Clin Invest 1982; 12:327-330.
27. Benoit JN, Barrowman JA, Harper SL, et al. Role of humoral

HEPATOLOGY

factors in the intestinal hyperemia associated with chronic portal

hypertension. Am J Physioll984; 247:G486-G493.
28. Kravetz D, Arderiu M, Bosch J, et al. Hyperglucagonemia and
hyperkinetic circulation after portocaval shunt in the rat. Am J
Physiol1987; 252G257-G261.
29. Hortnagl H, Singer EA, Lenz K, et al. Substance P is markedly
increased in plasma of patients with hepatic coma. Lancet 1984;
1:480-483.
30. Benoit JN, Granger DN. Splanchnic hemodynamics in chronic
portal hypertension. Semin Liver Dis 1986; 6287-298.
31. Bernardi M, Trevisani F, Santini C, et al. Aldosterone related
blood volume expansions in cirrhosis before and during the early
phase of ascites formation. Gut 1983; 24761-766.
32. Henriksen JH, Ring-Larsen H, Kanstrup IL, et al. Splanchnic and
renal elimination and release of catecholamines in cirrhosis. Evidence of enhanced sympathetic nervous activity in patients with
decompensated cirrhosis. Gut 1984; 25:1034-1043.
33. Bichet D, Szatalowicz V, Chaimovitz C, et al. Role of vasopressin
in abnormal water excretion in cirrhotic patients. Ann Intern Med
1982; 96413-417.
34. Campus J, Sola J , Arroyo V, et al. Temporal relationship between
the impairment of free water excretion and antidiuretic hormone
hypersecretion in rats with experimental cirrhosis. Gastroenterology 1987; 93:498-505.
35. Laffi G, La Villa G, Pinzani M, et al. Altered renal and platelet
arachidonic acid metabolism in cirrhosis. Gastroenterology 1986;
90274-282.
36. Denison EK, Lieberman FL, Reynolds TB. 9-a-fluorohydrocortisone induced ascites in alcoholic liver disease. Gastroenterology
1971; 61~497-503.
37. Alexander EA, Doner DN, Auld RB, et al. Tubular reabsorption of
sodium during acute and chronic volume expansion in man. J Clin
Invest 1972; 51:2370-2379.
38. Naccarato R, Messa P, DAngelo A, et al. Renal handling of sodium
and water in early chronic liver disease. Evidence for a reduced
natriuretic activity of the cirrhotic urinary extracts in rats. Gastroenterology 1981; 81:205-210.
39. Epstein M. Derangement of renal water handling in liver disease.
Gastroenterology 1985; 891415-1425.
40. Vaamonde CA. Renal water handling in liver disease. In: Esptein
M, ed. The kidney in liver disease, Ed. 2. New York Elsevier
Biomedical, 1983: 55-86.
41. Bernardi M, De Palma R, Trevisani F, et al. Chronobiological
study of factors affecting plasma aldosterone concentration in
cirrhosis. Gastroenterology 1986; 91:683-691.
42. Bernardi M, Trevisani F, De Palma R, et al. Chronobiological
evaluation of sympathoadrenergic function in cirrhosis. Relationship with arterial pressure and heart rate. Gastroenterology 1987;
93:1178-1186.
43. Arroyo V, Bosch J, Mauri M, et al. Renin, aldosterone and renal
hemodynamics in cirrhosis with ascites. Eur J Clin Invest 1979;
969-73.
44. Bernardi M, Trevisani F, Santini C, et al. Plasma norepinephrine,
weak neurotransmitters with renin activity during active tilting in
liver cirrhosis: relationship with cardiovascular homeostasis and
renal function. Hepatology 1983; 354-64.
45. Bernardi M, Santini C, Trevisani F, et al. Renal function impairment induced by change in posture in patients with cirrhosis and
ascites. Gut 1985; 26629-635.
46. Epstein M, Levinson R, Sancho J , et al. Characterization of reninaldosterone system in decompensated cirrhosis. Circ Res 1977;
41:818-829.
47. Ring-Larsen H, Hesse B, Henriksen JH, et al. Sympathetic nervous
activity and renal and systemic hemodynamics in cirrhosis: plasma
norepinephrine concentration, hepatic extraction and renal release.
Hepatology 1982; 2304-310.
48. Bichet DG, Van Putten VJ, Schrier RW. Potential role of increased
sympathetic activity in impaired sodium and water excretion in
cirrhosis. N Engl J Med 1982; 307:1552-1557.
49. Nicholls KM, Shapiro MD, Van Putten VJ, et al. Elevated plasma
norepinephrine concentrations in decompensated cirrhosis: association with increased secretion rate, normal clearance rate and
suppressibility by central blood volume expansion. Circ Res 1985;
56457-561.
50. Perez-Ayuso RM, Arroyo V, Camps J, et al. Evidence that renal
prostaglandins are involved in renal water metabolism in cirrhosis.

Vol. 8, No. 5, 1988

PERIPHERAL ARTERIAL VASODILATION HYPOTHESIS

Kidney Int 1984; 2672-80.

51. Epstein M, Weitzman RE, Preston S, et al. Relationship between
plasma arginine-vasopressin and renal water handling in decompensated cirrhosis. Mineral Electrolyte Metab 1984; 10155-165.
52. Henriksen JH, Ring-Larsen H, Christensen NJ. Circulating noradrenaline and central hemodynamics in patients with cirrhosis.
Scand J Gastroenteroll985; 20:1185-1190.
53. Arroyo V, Planas R, Gaya J, et al. Sympathetic nervous activity,
renin-angiotensin system and renal excretion of prostaglandin E2
in cirrhosis. Relationship to functional renal failure and sodium
and water excretion. Eur J Clin Invest 1983; 13:271-278.
54. Huber M, Kastner S, Scholmerich J, et al. Enhanced urinary
excretion of cysteinil leukotrienes in patients with hepatorenal
syndrome (Abstract). J Hepatol 1987; 5(Suppl. 1):S34.
55. Zipser RD, Hoefs JC, Speckart PS, et al. Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab 1979; 48985-900.
56. Rimola A, Gines P, Arroyo V, et al. Urinary excretion of 6-ketoprostaglandin F1, thromboxane B2 and prostaglandin E2 in cirrhosis with ascites. Relationship to functional renal failure (hepatorenal syndrome). J Hepatol 1986; 3:111-117.
57. Schroeder ET, Anderson GH, Goldman SH, et al. Effect of blockade of angiotensin I1 on blood pressure, renin and aldosterone in
cirrhosis. Kidney Int 1976; 9511-519.
58. Arroyo V, Bosch J , Mauri M, et al. Effect of angiotensin I1 blockade
on systemic and hepatic hemodynamics and on the renin-angiotensin-aldosterone system in cirrhosis with ascites. Eur J Clin Invest
1981; 11~221-229.
59. Willett JR, Jennings G, Esler M, et al. Sympathetic tone modulates
portal venous pressure in alcoholic cirrhosis. Lancet 1986; 2:939943.
60. Pariente EA, Bataille C, Beroff E, et al. Acute effects of captopril
on systemic and renal hemodynamics and on renal function in
cirrhotic patients with ascites. Gastroenterology 1985; 88:12551259.
61. Perez-Ayuso RM, Arroyo V, Planas R, et al. Randomized comparative study on efficacy of furosemide versus spironolactone in
nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the renin-aldosterone system.
Gastroenterology 1983; 84961-968.
62. Bernardi M, Servadei U, Trevisani F. Importance of plasma aldosterone on natriuretic effect of spironolactone in patients with liver
cirrhosis and ascites. Digestion 1985; 31:189-193.
63. Liddle GW. Specific and non-specific inhibition of mineralcorticoid
activity. Metabolism 1961; 101021-1030.
64. Dawson-Hughes BF, Moore TJ, Dluhy RG, et al. Plasma angiotensin I1 concentration regulates vascular but not adrenal responsiveness to restriction of sodium intake in normal man. Clin Sci 1981;
61527-534.
65. Rankin LI, Luft FC, Henry DP, et al. Sodium intake alters the
effects of norepinephrine on blood pressure. Hypertension 1981;
3~650-656.
66. Boyer TD, Zia PK, Reynolds TB. Effect of indomethacin and
prostaglandin A on renal function and plasma renin activity in
alcoholic liver disease. Gastroenterology 1979; 77:215-222.
67. Epstein M. Renal prostaglandins and the control of renal function
in liver disease. Am J Med 1986; 8O(Suppl. lA):46-55.
68. Arroyo V, Gines P, Rimola A, et al. Renal function abnormalities,
prostaglandins, and effects of nonsteroidal anti-inflammatory
drugs in cirrhosis with ascites. Am J Med 1986; 81(Suppl.2B):104122.
69. Perez-Ayuso RM, Arroyo V, Camps J , et al. Renal kallikrein
excretion in cirrhotics with ascites: relationship to renal hemodynamics. Hepatology 1984; 4:247-252.
70. Bonkovsky H, Hartle D, Simon D, et al. Decreased plasma arterial
natriuretic peptides in cirrhotic ascitic patients (Abstract). Hepatology 1986; 6:1213.
71. Burghardt W, Wernze H, Diehl KL. Atrial natriuretic peptide in
hepatic cirrhosis: relation to stage of disease, sympathoadrenal
system and renin-aldosterone axis. Klin Wochenschr 1986;

1157

64(Suppl. VI):103-107.
72. Shenker Y, Sider RS, Ostafin EA, et al. Plasma levels of immunoreactive atrial natriuretic factor in healthy subjects and in patients with edema. J Clin Invest 1985; 76:1684-1687.
73. Gerbes Al, Arendot RM, Ritter D, et al. Plasma atrial natriuretic
factor in patients with cirrhosis. N Engl J Med 1985; 313:16091610.
74. Fernandez-Cruz A, Marco J , Caudrado LM, et al. Plasma levels of
atrial natriuretic peptide in cirrhotic patients. Lancet 1985;2:14391440.
75. Morgan T, Imada T, Inagami T. Atrial natriuretic protein (ANP)
in the hepatorenal syndrome (HRS) (Abstract). Hepatology 1986;
6:1215.
76. Gines P, Jimenez W, Arroyo V, et al. Atrial natriuretic factor in
cirrhosis with ascites: plasma levels, cardiac release and splanchnic
extraction. Hepatology 1988, 8636-642.
77. Epstein M, Loutzenhiser R, Friedland E, et al. Relationship of
increased plasma atrial natriuretic factor and renal sodium and
handling during immersion-induced central hypervolemia in normal humans. J Clin Invest 1987; 79738-745.
78. Eckstein JW, Hamilton WK. The pressure-volume responses of
human forearm veins during epinephrine and norepinephrine infusions. J Clin Invest 1957; 36:1663-1671.
79. Wood JE. Peripheral venous and arteriolar responses to infusions
of angiotensin in normal and hypertensive subjects. Circ Res 1961;
9~768-774.
80. Shapiro MD, Nichols KM, Groves BM, et al. Interrelationship
between cardiac output and vascular resistance as determinants of
effective arterial blood volume in cirrhotic patients. Kidney Int
1985; 28206-211.
81. Nicholls KM, Shapiro MD, Kluge R, et al. Sodium excretion in
advanced cirrhosis: effects of expansion of central blood volume
and suppression of plasma aldosterone. Hepatology 1986; 6235238.
82. Zipser RD, Radvan G, Kronborg J, et al. Urinary thromboxane B2
and prostaglandin E2 in the hepatorenal syndrome: evidence for
increased vasoconstrictor and decreased vasodilator factors. Gastroenterology 1982; 84:697-703.
83. Zipser RD, Kronborg J , Rector W, et al. Therapeutic trial on
thromboxane synthesis inhibition in the hepatorenal syndrome.
Gastroenterology 1984; 87:1228-1232.
84. Gines P, Tito L1, Panes J , et al. Paracentesis vs paracentesis plus
iv albumin in the treatment of ascites. Preliminary results of a
comparative study (Abstract). J Hepatol 1986; 3S23.
85. Simon DM, McCain JR, Bonkovsky HL, et al. Effects of therapeutic paracentesis on systemic and hepatic hemodynamics and on
renal and hormonal function. Hepatology 1987; 7:423-429.
86. Epstein FH, Post RS, McDowell M. Effects of arteriovenous fluids
on renal hemodynamics and electrolyte excretion. J Clin Invest
1953; 32~233-240.
87. Jimenez W, Martinez-Pardo A, Arroyo V, et al. Temporal relationship between hyperaldosteronism, sodium retention and ascites
formation in rats with experimental cirrhosis. Effect of spironolactone. Hepatology 1985; 5245-250.
38. Llach J , Gines P, Arroyo V, et al. Prognostic value of arterial
pressure, endogenous vasoactive systems, and renal function in
cirrhosis with ascites. Gastroenterology 1988; 94482-487.
89. Tristani FE, Cohn JN. Systemic and renal hemodynamics in oliguric hepatic failure: effect of volume expansion. J Clin Invest
1967; 461894-1906.
90. Tage-Jensen U, Henriksen JH, Christensen E, et al. Plasma catecholamine level and portal venous pressures as guides to prognosis
in patients with cirrhosis. J Hepatol 1988; 6350-358.
91. Arroyo V, Bosch J, Gaya-Bertran J, et al. Plasma renin activity
and urinary sodium excretion as prognostic indicators in nonazotemic cirrhosis with ascites. Ann Intern Med 1981; 94198-210.
92. Genoud E, Gonvers J J , Schaller MD, et al. Valeur prognostique du
syst6me reneine-angiotensine dans la r6ponse a la restriction sodie
et le pronostic de lascite cirrhotique dorigine alcoolique. Schweiz
Med Wschr 1986; 116:463-469.