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Copyright by the American Association for the Study of Liver Diseases

HEPATOLOGY

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, ICENTEARROYO,MAU RO ERNARD I, URRAY PSTEIN,JENS . HENRIKSENN D

JOAN

ODES

University

o

Colorado School o Med icine Denv er Colorado 80262; Liver U nit Hospital Clinic i Provincial Univ ersity o

Barcelona Barcelona Spain ; Istitu to di Patologia Speciale Medica e Metodologia Clinica Univ ersity

o

Bologna Bologna Italy;

Nephrology Section Veteran s Admin istration Medical C enter and Division o Nephrology University o Miam i School of

Medicine Miam i Florida 33125; Depa rtments o Clinical Physiology and Hepatology Hvid ovre Hospital and Dep artme nt o

Interna l Med icine and Endocrinology Herlev Hospital Un iver sity o Copenhagen Copenhagen Denmark

Renal sodium and wate r retention an d plasma volume

expansion have been shown t o precede ascites formation

in experimental cirrhosis. The classical “underfilling”

theory, i n which ascites formation causes hypovolemia

and initiates secondary renal sodium and w ater reten-

tion, thus seems unlikely. While the occurrence of

pri-

mary r enal sodium and wa ter retention a nd plasma vol-

ume expansion prior to ascites formation favors the

“overflow” hypothesis, th e stimulation of the renin-an-

giotensin-aldosterone system, vasopressin release and

sympathetic nervous system associated with cirrhosis is

not consonant w ith pr ima ry volume expansion.

In this present article, the “P eripheral Arterial Vas-

odilation Hypothesis”

is

proposed

as

the initiator

of

so-

dium and water retention in cirrhosis. Periph eral

arte-

rial

vasodilation

is

one of the earliest observations in

the cirrhotic patient and experimental animals with cir-

rhosis. Art eria l vasodilators a nd arteriovenous fistula

are

other examples in which renal sodium and water

retention occur secondary to a decreased filling of the

arte rial vascular

tree.

An increase in cardiac output and

hormonal stimulation

are

common feature s of cirrhosis,

arteriovenous fistula and drug-induced peripheral ar-

terial vasodilation. However,

a

predilection for the

re-

tained sodium and water to tran suda te into the abdom-

inal cavity occurs with cir rhosis because of th e presence

of portal hypertension. The Peripheral Arterial Vaso-

dilation Hypothesis also explains the continuum from

compensated to decompensated cirrhosi s to the hepato-

rena l 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 transu-

dation into the abdominal cavity then decreases

intravascular volume and secondarily results in the well-

established hypovolemia-induced increase in renal so-

dium and water retention (3,

4 .

This classical underfill-

ing 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 au-

thors, 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

so-

dium retention was not delineated but presumably was

due to some hepatorenal reflex which predominated over

the normal volume regulatory mechanism

7).

The so-

dium and water retention then leads to “overflow” ascites

formation secondary to the hypervolemia and the in-

creased 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 characteris-

tics of both the classical underfilling and overflow hy-

potheses, but neither ascites formation and hypovolemia-

induced renal sodium and water retention nor primary

renal sodium and water retention, blood volume expan-

sion and overflow ascites are considered to be the initi-

ation or primary mechanism of the renal sodium and

water retention in cirrhosis. We would like to term our

hypothesis the “Peripheral Arterial Vasodilation The-

ory’’ of renal sodium and water retention in cirrhosis.

Thi s hypothesis (Figure

2)

proposes that peripheral ar-

1151



1152

SCHRIER ET AL.

HEPATOLOGY

Undertilhg*

Hypothesis

Portal Hypertension

CLASSICAL UNDERFILLING

VERSUS

OVERFLOW HYPOTHESES

Ovanow

Hypothesis

Primary R e d Sodium

md

water Retention+

Ascites Formation

I

I n t n v A u l u +

P0rt.I

Hypervolemu B y p e r t d o n

lntravasculu

Hypovolemia

\

Asfites Formation

Secondary R e n d Sodium

and Water Retention

FIG. 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.

(+)“Primary” efers 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 th e classical overflow hypothe-

sis, 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 pri-

mary peripheral arterial vasodilation and a secondary

increase in cardiac output occur prior to ascites forma-

tion in experimental cirrhosis and compensated cirrhosis

in man (13-17). We propose this peripheral arterial

vasodilation to be the initial event in intravascular un-

derfilling, not because the intravascular blood volume is

decreased, but rather because the intravascular compart-

ment 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. A s already cited, the sys-

temic response to peripheral vasodilation, and thus car-

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

(13,

14). In addition, transient renal sodium and water reten-

tion occurs to “refill” the intravascular compartment. A t

this stage of cirrhosis, total blood volume is expanded,

cardiac output is increased and peripheral arterial vaso-

dilation

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-labeled lbumin circulatory transit times, compen-

sated 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 pe-

ripheral arterial vasodilation and the resultant dimin-

ished cardiac after-load. While several other sites may

be involved in the arteriolar vasodilation which accom-

panies 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 pa-

tients, 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 sub-

stances have been suggested to contribute to or totally

account for the peripheral arterial vasodilation in cirrho-

sis (27-30), but none have been implicated definitively.

The use of specific antagonists to these potential vaso-

dilating hormones in cirrhosis will be necessary to ex-

amine 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 hypoth-

esis 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 compen-

satory renal sodium and water retention with subsequent

volume expansion and return of these hormones to nor-

mal 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 cir-

rhotic patients do not “escape” from exogenously admin-

istered 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 so-

dium 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 com-

pensated cirrhosis the peripheral vasodilation-induced



Vol.

8, No. 5, 1988

PERIPHERAL ARTERIAL VASODILATION HYPOTHESIS

1153

PERIPHERAL VASODlLATION

B Y P O T H E d

H epa torerul s y n b e +

Cotuperrrated Cirrhosis+ l )eCommted Cirrhais+*

Moderate Peripheral Sev ere Peripheral

w

Extreme Peripheral

Vasodilation (e.g. Splanc hnie) Vasodilation Vasodilation

Moderate Deerease Effective t Severe

Decrease

Extreme

crease

M e r i a l

Blood

Volume (EABV ) EABV

in EABV with Bypotension

Moderate Increase Plasma

evere Rise'in Plasma

xtreme Elevation

of

Plasma

Renin. Aldosterone.

Renin. AIQsterone.

Renin. AlQsterone.

Norepinephrine and

Norepinephrine and

Norepinephrine and

Vasopressin Concentrations

Vasapressin Concentrations Vasapressin Concentrations

Failure

with Renal Sodiumwith Renal Sodium

and

Water Retention and Water Retentio n M d Water Retentio n

Moderate Renal Vasorolritriction evere Renal Vasoconstriction xtreme Renal Vasoconstriction -Renal

with Renal sodium

Plasma Volume Expansion t

P b m a

Volume Expansion t lasma Volume Expansion

may

be

modified by

may be modified

by

hyponlbuminenia hypollbuninemia

Return of Plasma Renin

Inadequate td

N o r m d m

t

m ma Renin.' MQsterone

and Vasopressin Concentration

lasma

Renin. Al da ta on e, Vuo pra ain Concentrations

udaterme. Norepinephrine Renal Hemo dymo ies. Norepinephrine and

to Normal Values Norepinephrine and remain at high levels

u o p r a i n C o n ea n tr a ti o n

t urther Aacits Formation

Seitar 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 cirrhot ic patients

the peripheral vasodilation decreases cardiac pre-load and is associated with an increase

in

cardiac output. (*)Somepatients (approximately one-

third) 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 in-

creased distal delivery and thus mineralocorticoid escape

in some patients with compensated cirrhosis. An im-

paired 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 under-

filling and enhanced sodium and water retention prior to

ascites formation. Abnormal diurnal variations

of

plasma

renin, urinary catecholamines and perhaps plasma al-

dosterone 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 ex-

hibit 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 pa-

tients should probably always be studied in the upright

and supine positions

44,45).

D E C O M P E N S A T E D C I RR H O S IS

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 th is stage of cirrhosis, the in-

crease 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 addi-

tion to the peripheral arteriolar vasodilation in decreas-

ing EABV. Therefore, as arteriolar baroreceptors sense

a decrease in filling of the arterial vascular tree, three

vasoconstrictor systems are activated, namely the non-

osmotic release

of

vasopressin,

renin-angiotensin-aldos-

terone system and sympathetic nervous system (33, 46-

50). Approximately 25%of decompensated cirrhotic pa-

tients 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-aminohip-

purate 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 hor-

mones, including angiatensin, norepinephrine and vaso-



1154

SCHRIER ET AL. HEPATOLOGY

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

glomerular filtration rate in decompensated cirrhotic

patients (50,531. The reversal of th e renal abnormalities

in decompensated cirrhotic patients by the intrarenal

administration of vascular antagonists of these vasocon-

strictors, 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. More-

over, 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

It should be mentioned that the approximately

25

of

decompensated ascitic cirrhotic patients who do not ex-

hibit either an elevation in plasma renin, aldosterone

and norepinephrine or diminished renal perfusion may

respond to aldosterone antagonists (61, 62). Spironolac-

tone 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 decom-

pensated cirrhotic pati ent 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 sensitiv-

ity 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 t his regard, the effect of

angiotensin and/or a-adrenergic blockers on blood pres-

sure 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 pros-

taglandins, namely PGEB and PGI2, in decompensated

ascitic patients with cirrhosis seems rather clear. Specif-

ically, 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 decompen-

sated 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-

(57-60).

glandin excretion may actually decrease to subnormal

levels as these patients’ glomerular filtration rates de-

cline and they approach the hepatorenal syndrome (35,

53, 56). It is important to emphasize, however, that in

this setting of diminished renal function urinary pros-

taglandins may not be an adequate index of renal vas-

cular prostaglandin synthesis, since inhibitors of pros-

taglandin synthetase may have dramatically different

effects on renal perfusion in patients who have com-

parable 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 vaso-

dilator 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 vaso-

constrictors concentration exhibit a dramatic fall in renal

blood flow and glomerular filtration rate with adminis-

tration 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 compen-

sated 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 bar-

oreceptors would be expected to sense a decrease in

EABV

and increase in the plasma concentration of va-

sopressin, 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 dimin-

ish 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 concentra-

tions.

FURTHER EVIDENCE FOR PERIPHERAL

ARTERIAL DILATION THEORY

Evidence for the Peripheral Arterial Vasodilation The-

ory

is

also derived from studies in hyponatremic ascitic

patients with cirrhosis. Normalization of sodium and

water excretion in these patients required not only cen-

tral blood volume expansion with head-out water immer-

sion (HWI) but also increasing peripheral vascular re-



Vol.

8,

No. 5, 1988 PERIPHERAL ARTERIAL VASODILATION HYPOTHESIS 1155

sistance with an exogenous norepinephrine infusion (80,

81). Mean renal perfusion pressure increased signifi-

cantly from 83 mmHg with HWI to 98 mmHg with HWI

and norepinephrine. This increased renal perfusion pres-

sure 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

With the Peripheral Arterial Vasodilation Hypothesis

of the pathogenesis of the circulatory, hormonal and

sodium and water abnormalities in cirrhosis, the hepa-

torenal syndrome can be proposed as the extreme exten-

sion 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 hepato-

renal syndrome, presuming that a parallel fall in synthe-

sis 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 throm-

boxane 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 hepato-

renal 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 con-

tributes to progression of the circulatory, hormonal and

renal excretory abnormalities primarily by increasing

peripheral vasodilation, or by increasing ascites forma-

tion, or a combination thereof, is at present an unan-

swered question. It is of note, however, that a rapid large

volume abdominal paracentesis without colloid replace-

ment is usually followed by worsening of vascular under-

filling in cirrhosis as assessed by a rapid rise in plasma

vasoconstrictor hormones 84,85). n the other hand, it

is important to point out that renal sodium and water

retention has been shown to occur in experimental cir-

rhosis in the dog when portal hypertension has been

prevented by prior portacaval shunting

(10).

Thus , fac-

tors in addition to portal hypertension must contribute

to the peripheral arterial vasodilation of cirrhosis.

CONCLUSION

In conclusion, we propose the Peripheral Arterial Vas-

odilation Theory rather than either ascites formation

(classical underfilling hypothesis) or primary renal

so-

dium 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 at-

tempted 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 a t 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-angio-

tensin 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 rela-

tion between the occurrence of the decrease in peripheral

vascular resistance and renal sodium retention in cirrho-

sis 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 vasodila-

tion, namely, a low mean arterial pressure which corre-

lates 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 va-

sopressin which accompany peripheral vasodilation

88-

92). Considered in this light, we propose that a substan-

tial number of cirrhotic patients may not die primarily

because of their hepatic dysfunction but rather because

of the consequences of the circulatory and humoral ab-

normalities 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.

Acknowledgment:

We would like to thank Jennifer

Graves for her excellent secretarial support.

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MS.

The mechanism

of

ascites formation

in chronic liver disease. Q

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Med 1961; 30153-166.

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1156

SCHRIER ET AL. HEPATOLOGY

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

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272.

4. Papper S.The role of the kidney in Laennec’s cirrhosis of the liver.

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