REVIEW

Sympathetic nervous regulation in patients with cirrhosis:

Pathogenesis of fluid retention and formation of ascites

JENS H 1-ll:NRIKSEN, MD, H ELMER RING-L ARSEN, MD, NIEL:. JUEL Cl IRISTENSEN, MD

JH HENRIKSEN, H RING-LARSEN, NJ CHRISTENSEN. Sympathetic nervous regulation in patients with cirrhosis: Pathogenesis of fluid retention and formation of ascites. Can J Gastroentcrol 1991 ;5(3 ): 103- 111. Increased cir­culati l'~ noraJrenaline in pat ients with cirrhosis is Jue to enhanced sympathetic nervous activity and is not merely the result of decreased clearance of cate­cholamines. There is a direct relation between the level of arteria l nornJrenaline and severity of c irrhosis, increased portal pressure and !luid accumulation; patients with the hepatorenal syndrome exhibit the highest values of plasma noradrenaline. In patients with cirrhosis, the kidneys have been idcnt ificJ as an unportant source of noradrenaline 'spillover' into plasma, which indicates en­hanced sympathetic nervous activity in these orgam. Moreover, the level of plasma noradrenaline is inversely related to renal bloodflow and urinary excre­tion of sodium, and directly related to plasma renin, vasopressin and aldosterone. An increased spi llover of noradrenaline has recently been demonstrateJ in the splanchnic system and superior portosystemic colla tera ls. ReduceJ centra l and arterial blood volume and low arterial blood pressure seconda,y to peripheral vasodilation are probably important afferent stimuli for enhanced sympathetic nervous activity, a lthough a nonvolume-dependent hepatic baroreceptor may also be present. The authors conclude that the sympathetic nervous system, in concert with other regulatory systems, plays an important ro le in sodium-water homeostasis and fluid retention, as well as in the systemic and hepatosplanchnic circulatory derangement seen in patients with c irrhosis. (Pour resume, voir page 104)

Key Words: Adrenaline, Ascites, Cirrhosis , Noradrenaline, Sympathetic over­activity, Underfilling, V asodilation

DeparrrnenL, of Clinical rliysiology and Hc/1acology, f ll•idovre Hospira/ . and Dc/>arcmenc of lniemal Medicine ,md Endocrinology. Herlet• I los/>iral. Urnt•ersiry of Copenhagen , Copenhagen, Denmark

Correspondence and re/>rint1: Dr Jens H Hemiklen , Assoczaw Professor of Cl mica/ Physiology, Department ofClirncal rhysrology n9, H111dovre Urnvernr"I I losf>iwl , DK-2650 Hl'l(lovre, Denmark

Received for />ublicauon January I I , 199 / . Acce/>ted May 3, I 99 J

CAN J GASTROENTcROL VOL 5 No 3 MAY/JUNE 1991

A IWANCED LIVER DISEASE (,IVES

rise to serious ahnormalities in fluid dynamics anJ neurohumora l rcgulat ion (1 ). The renin-angiotcnsin­aldosteronc system, neurohypophyseal release of vasoprcssin anJ the sym­pathetic nervous system exhibit major changes in patients with c irrhosis. Recent reviews in these areas have dealt with renin, angiotensin, aldo­stcmnc and vasopressin (2-4 ). The past decade has seen a major advance in knowledge of the physiology anJ pathophysiology of the sympathetic nervous system. The sympathet ic nerv­ous system and c irculating catechola­mines arc considered in th is review.

Shaldon and co-workers (5) , report­ed in 1961 that there were high levels nf noradrenaline and aJrenaline in the ponal venous plasma of patients with c irrhnsis, and suggested that cat echnl ­amines play a role in ponal wnous hy­pertension. However, subsequent studies with fluorometric assays were unable to confirm their h1oassay find­ing (6-9). Fluoromecric methods have now been replaced hy a spt.'Cific isotope­derivative technique (1 0, l I) and high performance liquid chromatography ( l 2). In a 1981 study wh ich employed an 1socopc-derivacive technique, the

103

HENRIKSEN et a/

Regulation du systeme nerveux sympathiquc chez les cirrhotiques: Pathogenese de la retention hydrique et formation d'ascite

RESUME: L'augmentation de la noradrenaline circulante chez les cirrhociques est due i'l !'intensification de l'activitc nervcusc sympathiquc et ne rcsu lte pas sculement d'une dim1m1t1on de la clairance des catecholamines. II existc un lien direct entre les taux arteriels Jc noradrenaline et la gravitc de la cirrhosc, l'clevation de la pression porrnle et l'accumulation li4u1dicnne; les patients atteims J'un syndrome heparo-rcnal presencent les valcurs lcs plus clcvecs de noradrenaline plasmatique. Chez les patients ponems Jc cirrhnsc, on a Jctcrm inc que lcs reins sont une source importance de devcrsemcnt de noradrenaline dans le plasma, ce qui mdique unc majorar1on de l'acnv1te nerveuse sympathique au niveau <le cet organc. De plus, lcs tnux plasmatiqucs de noradrenaline som inversement relies au debit sanguin renal et a l'excrcoon de sodium Jans les urines, et directemem relies a la renine, a la vasoprcssme ct a l'aldosrerone plasmatiques. Une augmentation du devcrsemenr de noradrenaline a rcccmment ere demontree au niveau du sysccme splanchnique et Jes branches cnllaterales porto-sysrem1ques superieures. Une reduction Ju volume sanguin aneriel ct central, ct unc baisse Jc la pression artcrielle consecutive a unc vasodilatatton penphenque constituent probablemenc des srunuli afferents importants, qui intens1fient l'activite ncrveuse sympathique bicn que !'action J'un barorcccptcur hepatiquc ne rcpondant pas au volume puisse aussi etrc incriminee. Les auteurs concluent quc, chez les patients souffrant de cirrhosc, le systemc ncrveux ~ym­pathiquc, agissant de concert avec d'autres mecanismes de regulatton, iouc un role important dans l'homeostase sodium-eau ct la retention hydrique, ains1 quc les perturbations de la circulation sysremique ct hepato-splanchniquc.

present authors found increased levels of circulating noradrenal inc and adre n­aline in patients with cirrhosis and por­tal hypertension, which suggested that sympatheu c nervous activity was e n­hanced in these patients ( 13 ).

The present review deals with the role of the sympathetic n ervous system in homeostatic derangement, fluid re­tention and hemodynamic changes in the splanchnic, renal and systemic c ir­culations m patients with c irrhosis.

PLASMA NORADRENALINE AND ADRENALINE

Sympathetic activity may be as­sessed by measuring noradrenaline in plasma or by recording impulses m sym­pathetic nerves by microneurography. Noradrenaline is the ma in neurotrans­mitter of the sympathe tic nervo us sys­tem. It leaks from the synaptic cleft mto plasma, where its concentration re­flects its neurotransmitter function (l 1, 14-16). T ungsren microelectrodes can be used to record sympathetic ac­tion potentials in human peripheral nerves at rest and during various

maneuvres. A c lose correlation has been observed between plasma nor­adrenaline in forearm venous blood and sympathetic nerve acttvity m muscles not on ly at rest but also durmg dynamic exercise, mental stress and hypoglycemta. Both plasma noradren­aline and sympathetic nervous activity increase with age (16, I 7).

The arterial plasma concentratio ns of noradre na line and adrenaline are determined from the dynamic equili­brium between overall neuronal and adrenal 'spillover', respectively, as well as from removal of the catecholamines from organs and tissues (18-21). The metabo lic clearance rate can be deter­mined using intravenous infusion of tritium-labelled noradrena line and adrenaline and measuring the steady­stare concentration of the tracer in arterial blood. However, the clearance values thus obtained reflect the clearance of catecholamines from all tissues and organs into the systemic c ir­culat ion. The clearance concept pro­posed by Esle r et a l ( 19) i:; not valid for n euronally released noradrenaline

(22). C learance of adren a line can l,e interpreted with confiJencc, ~mce it can be pred icted that Lhc specific ac, Livity of adrenaline in plasma ts the same as that at hreakJnwn sites, a pre requisi te for va lid clcarnnce measure, men ts.

Sympathe tic nervous activity min­te rnal organs may be stuJicd by measur­mg the release of noradrenaline from these organs. The difference between arterial and venous noradrcnalmc 1, corrected for cxrrac.uon of noradren­aline across the organ mcasureJ using intravenous infusion of tritium-labelled noradrenaline mulcipl icd by hloodflow to the organ ( 16,20). S tudies m animal1 have mdicaceJ that overspill 1~ corre, lated to impube activity in sympa1het1c nerves. Presynapnc receptors anJ lex 11

factors, such as bloodflow and capillary permeability, may influence noradren­aline release and overflow (16,20). The effect of activation of the sympatho­aJrenal system is dependent not only on impulse activity in nerves or amounts of noradrenaline and adren­al me relea ed, but also on the respon­sivenci>S of tissue to ca techolamines. This may be altered during vanou, physiological and pathophys1olog1cal states by changes in the number anJ affinity of receptors, as well as by fll.N synaptic mechanisms. Sympathetic nervous system acttvity is highly d1f. fcrenrimed; sympathoadrenal activ1r,, sens1 t1v1ty to catecholamines anJ respom1veness should therefore h.: measured in specific organs or tissues.

The circulating level of nora<lren aline is normal or a lmost normal in cirrhotic patients without flu id reten­tion, whereas patients with asrne, generally have highly elevated value (13,23-28). The increased circulating noradrenaline seen m c irrhosis 1, caused by inc reased release of nor­adrenaline from po t gang lionic ym­pathetic nerve fibres because of enhanced sympathetic ne rvous activ1, ty, and is not merely the result of decreased clearance of catecholamines in liver and other tissue (23,29-31). Floras and co-workers (3 2) receml1· found a close relationship between burst frequency in sympathetic nerve fibres to skeleta l muscles and circulat·

104 CAN J GASTROENTEROL VOL 5 No 3 MAY/JUNE 1991

Noradrenaline and ascites formation

PRC • mlU /1 ,.-... 60 0)

2000 I E

• E 50 1000 ...._, Q)

• .... ~

40 • 50 0 U) -U)

• Q) .... Q. • • C 30- • 200 • ·m ••• > • •

100 •• 0 20 -+= •

0 .. r= 0.86 • Q. • 50 Q) • P<0.001 • .c. 10 -• r = 081 D

• P<OOOI Q)

20- • 0) 0 • D I I I

•• • Plasma NA Q) 1.50 10 • • I I I s 0.0 0.50 1.00

0 00 050 100 150ng/ml Plasma NA ng/ml

Figure 1) Relatmn between plasmll renrn concenrrntwn ( PRC) and I plasma noradrenalin<! (NA) in />arienrs wir/1 m,·lwsis. ( ReJm1duced from

reference 34)

Figure 2) Relacion ht!tween />cmal />ressure ( assessed as 1uedged he/)CHic 1•em />ressurc) and ancnal plasma noradrenaline (NA) rn J)atiencs with cirrhmi5. ( Rcprnclucecl from reference 13)

ing n0raJ rcnaline in patients with cir­rhosis, thus confirming the u5efulne5s o( plasma noradrenaline as an index of sympathetic nervous activity in these patients. Diurnal variat ion in plasma noradrena line anJ urinary excretion of noradrenaline and catecholamine me­tabolites ind icate that even in the com­pensated state some pmien ts have a moderate increase in sympatheuc nerv­ous activity (33).

In patients with c irrhosis, c irculat ­ing norad renaline is d irectly corrclateJ wi th plasma renin activity anJ plasma concentrations of a lJostcrone and vasopressin (24,27,34 ), ind icating that the sympathetic nervous system acts in concert with o the r important regula­tory systems (Figure I ).

HEPATOSPLANCHNIC HEMODYNAMICS

Using tritium-labelled noradren­aline, significant proJuction and spill­overof noradrenaline has recen tly been demonstrated in the heparosplanchnic system of patients with c irrhosis, but not in normal subjects (35 ). Cathe ter­ization of the azygos vein substantiated

noradrenaline spillover in the prehc­patic splanch nic area :md superior portosystemic collaterals, including esophageal var ices (36). These resu lts indicate that sympathetic nervous ac­tivity is enhanced in different parts of the hepatosplanchnic system, inc luJ­ing porrosystemic collatera ls in patients with ci rrhosis. Moreover, the arteria l level of noradrena line is d irectly relat­ed tu portal venous pressure and azygos bloodnow (Figure 2) (13.23.37).

T he exact role of the sympathetic nervous system in the progression of porta l hypertension and increased splanch nic bloodflow is not known; however, Mena et a l (38) reported chat rhentolamine, an alpha-adrcnergic antagonist , lowered hepatic venous wedge pressure. C lo nidine, a cen trally acting a lpha-a<lrcnergic blocker, de­c reases both circu lating noraJ renaline and porta l pressure (37 ), and propran ­o lol, a nonselect ive beca-adrenc rgic blocke r, decreases porta l p ressu re in some patients (39-43). These find ings suggest that the sympathetic nervous system docs play a role in portal hyper­tension . O n the o ther hand, a sym-

CAN J GASTROENTEROL VOL 5 NO 3 MAY/JUNE 1991

pathetic hepatic baroreccptor has been described m animal experiments, in which a primary inc rease in porral anJ sinusoidal pressure enhances sympathe­tic nervous activity in heart and kidney ( 44 ). Dogs with experimenta l cirrhosis, but without sinusoiJal hype rtension , do not retain soJ ium and water (45). That such a nonvolume-depcn<lcnt hepauc baroreceptor r lays a role in the increased renal sympathetic tone seen in cirrhotic patients has a lso been sug­gcstctl ( 46). Thus, the sympathetic nervous system may have imporrnn t af­ferent as well as effe rent functions in the pathophysio logy of hepacosplanch­nic vascular derangement in ci rrhosis.

SODIUM-WATER HOMEOSTASIS

Stimulation of renal sympathetic nerve fibres brings abou t a decrease in rena l bloodflow and glo merular filtra­tion anJ an increase in sodium resorp­tion in the proximal t ubules, the latter occurs because of a combination of decreased bloodflow a.nJ glomerular filtration and a direct effect on alpha­adrcnoccptors in the proximal tubules;

105

HENRIKSEN et al

Renal Blood Flow Renal Blood Flow ml/g -min ml/g ·min

5.0 00 r:-0.71 5.0 0 r= - 0.69 4.0

0 0 P<0.001 4.0 0 P<OOOl

3.0 • q,o 3.0 • Bo 0 • 0 • . ~. • • •

2.0 • 2.0 ~ • •

I • J' • •• •• ..- .. • • ,.,. ..

• ,/A • • • • • • •

1.0 • • • 1.0 I • • •

05 0.5

0.3 0 .6 1.2 1.8 3.0 6.0 12 nmol/1

0.3 0.6 1.2 1.8 3.0 6.0 12 nmol/l

Arterial Plasma NA Renal Venous Plasma NA

Figure 3) Relarion between renal bloodflow and arterial and renal venous noradrenaline (NA) . • Cirrhosis wicliow rucire.1; 0 Comrols; • Pau~m with ascites. (Retmxlucedfrom reference 84)

(46-50). In addition , the sympathetic nervous system activates the renin­angiotensin-aldosterone system secm, ­c.lary to a ltered autoregulation, decreased d 1ivery of so<l ium to the dis­tal tubules and a direct effect on the macula densa suhsequent to heta-a<lreno­cepcor stimulation (46-48,5 1,52).

Experiments in dogs have shown that gra<led stimulation of the renal nerves, increasing renal sympathetic nervous activity, causes a graded in­crease of noradrenaline spillover into the renal veins (53). In patients with cirrhosis, the kidneys have been iden­tified as a major source of increased circulating noradrena line ( 13,23.25).

Renal bloodflow is inversely corre­lated with the plasma concentration of noradrenaline in the renal artery as well as the renal vein (54), which indi­cates that enhance<l renal sympathetic nervous activity is important for renal vasoconstriction (Figure 3). It is still unclear at which point in the natural history of ascites the sympathetic nerv­ous system begins to play a role. Thus, in the early stages of asc ires some patients may have elevated nor­adrenaline, but normal renal bloodflow and glomerular filtration rate (31). Using kinetic techniques, considerable spillover of noradrenaline into renal

106

veins has been demonstrated in most patients with fluid retention (23,30, 31 ), as well as a significantly negative corre lat ion between the plasma con­centration of noradrenaline and the urinary excretion of sodium (24 ). Moreover, there is an inverse relation­ship between plasma noradrenaline and the tubular rejection fraction of sodium, and it has been proposed that the sympathetic nervous tone seen in proximal tuhular sodium reabsorption, independent of flow and glomerular filtration, plays a role in patients with ci rrhosis (55). These results suggest that enhanced sympathetic nervous ac­tivity plays an important role in the reduced rena l bloodflow and the avid sodium-water retention seen in decom­pensated cirrhosis and functional renal failure - the hepatorenal syndrome (56).

T he hemodynamic changes point cowards renal hypoperfusion being, at least initially, a normal response to changes in the systemic or splanchnic circulation , leading to decreased uri­nary excretion of sodium and water ( 46,56). It seems like ly that enhanced sympathoadrenal activity is a primary pathogenic factor, but several connect­ed systems regulating hemodynamics and sodium water homeostasis are secondarily activated (2-4). Nearly a ll

studies of these syMems in chronic liwr disease in<licate that they counteract <lecreascd systemic vascular resistance. In addition, increased urinary excre· tion of proscaglandin Ez has been o~­served in patients with decompensateJ cirrhosis; there is decreased excretion in patients with the hepatorenal syn­drome. A deficit of local vasodilato~ such as prostaglan<lim has therefore been suggeste<l as a concurrent cause of renal failure in patients with hepato· renal syndrome (27).

Stimulation of renal sympathetic nerves or infusion of noradrenaline into the renal artery in dog~ has revealed that the autoregulation curve may be shifted to the right, so that renal blood flow is diminished at a higher per­fusion pressure than normal (52,57). Since the renal perfuskm pressure (te, arterial mean rressure minus renal venous pressure) in advanced cirrhosis is often reduced to a c rit ical level (about 70 mmHg), such a mechanism may play a role in the renal hypoper· fusion seen in patients with decornpen­sated c irrhosis. The importance of low renal sympathetic tone and a sufficient­ly high renal perfusion pressure for filtration and sodium-water excretion has been demonstrated by Lenz and CO·

workers (58). In patients with decom-

CAN J GA!:>'TROENTEROL VOL 5 No 3 MAY/JUNE 1991

Arterial Plasma Noradrenaline Concentrat ion ng I ml

- p < 0.01 - •

1.0 - • • -

- • •

• • I 0.5 - • -a-

- 1- • • •

I •

0.0 I I T

CHILD A CHILD B CHILD C

Figure 4) Circulating l>la.sma noradrenaline and severity of cirrhosis as assessed by different C/1i/d classes (A, Band C). Normal range of arterial />lasma noradrenaline: 0.0R to 0.35 ng/mL. (Reproduced from reference 43)

pensate<l c irrhosis they demonstrated that an increase in a rte rial blood pres­sure maintained by o rnithine-vasopres­sin infusion, increased the glomerular fil tration rate from 26 to 43 ml/min an<l decreased plasma noradrenaline from 1.74 to 0.87 ng/mL (indicat ing a fall in sympathetic nervous activity). This presumahly was the result nf stimulus to rhe arterial baroreceptors.

There is a better diu retic respome in supine patients than in upright and am­bulant ones; th is is probably due to a decrease in enhanced sympathetic nervous activity in the supine position (59), but in the study of Ring-Larsen ct al (59) it was probably due to stimula­uon of receptors in the venous pan of the circulation. Recent animal experi­ments have shown that symp:nhetic renal denervation normalizes sodium and water excretion in experimental cirrhosb (60), and that lumbar sympa­thetic block improves renal function in cirrhotic patients with severely im­paired renal function (61 ), confirming the central role of the sympathetic

nervous system in the pathogenesis of ascites. Moreover, enhanced renal sym­pathetic nervous activity seems to play a role in the decreased responsiveness to atrial natriuretic factor observed in decompcnsated c irrhosis (62). This is consistent with the concept of an im­portant sympathetic neuronal contri­hution to the development of refractory ascites.

Fina lly, increased renal sodium and water excretion follows normalization of c irculating noradrenaline after im­plantation of a peritoneal-venous shunt (63). T hese resu lts stress the virnl role played by the sympathetic nervous sys­tem in lluiJ homeostasb in patients with c irrhosis.

SYSTEMIC HEMODYNAMICS The leve l of plasma noradrenaline is

directly related to the severi ty of cir­rhosis determined by C hild-Turcotte classes (41) (Figure 4), and changes in the systemic circulation are related co deranged splanchnic hemodynamics and portal hypertension (27,56,64.65).

CAN J GA~TROENTEROl VOL 5 No 3 MAY/JUNE 1991

Noradrenaline and ascites formation

The etiology of the hyperkinet ic cir­cu lat ion seen in cirrhosis is unknown. The find ing of increased lol:11 p lasma volume in human and experimental c irrhosis suggests overfill ing of the cir­culation (66,67). On the other hand, the effect of head-tiut water immersion or implantation of a peritoneal-venous shun t hringing ahout natriuresis in some patients suggests central under­filling (63,68). Thu~. the me of t he 'effective blood volume' in cirrhosis i~ not settled (69). However, using car­diac output and mean circulatory tran­sit time, centra l anc.l arter ial blood volume has recently been shown to he reduced in patients with c irrhosis ( 70) and inversely related to the level of arteria l noradrenaline, as well as to renal venous noradrenaline (unpub­lished data). This finding indicates that 'unloaded' volume-receptors and ham­receptors may serve as a stimulus for the increased sympathetic nervous activity seen in patients with cirrhosis. In line with this theory, it has been hypo­thesized that peripheral arteriola r vaso­dilation is an initiator of enhanced sympathetic nervous acuvrty and sodium-water reten tion in the presence of c irrho~is (65).

Enhanced sympathet ic nervous ac­tivity is important in maintaining the level of arterial blood pressure in cir­rhosis. Thus, administration of alpha­adrenergic blocking agents such as phentolam ine results in a decrease in the arterial blood pressure of dccom­pensated p,itients, a result which un­derl ines the importance of the sympa­thetic nervous system in counteracting the effect of peripheral vasodilation in c irrhosis (3, 7 I). Beta-adrenergic hlock~ ers, such as propranolol, increase cir­culating noradrenaline (43), possib ly due to the comhined effect of a decrease in the whole-body clearance of ca techolamines and a further increase 111 sympathet ic nervous tone (36). Fur­ther enhancement of sympathetic nervous activity after beta-adrenergic blockade may be caused by: unopposed alpha-adrenergic receptors; induction tif hernodynamic changes with reduced arteria l hlood pressure and cardiac and splanchnic flow rates; and metabol ic <.: hanges (42). A relationship between

107

H ENRIKSEN et al

CUMULATIVE SURVIVAL PROBABILITY IN 81 PATIENTS WITH CIRRHOSIS

I. 0

0 .8

!L------, f," : 11 ... ,

11 ... , ... ... , ...... I

f1, a NA ~1.5 nmol/1 -1~ -· - ·-1 - · - · ·:... _; .............. ( ........ ..... . ,

0. 6

1 ·-·- · - · - · , , .... . .. ... . ... b l.5<NA~25nmol/l -: ·- ·- · - · - · - · - · c 2.5<NA=i;;5.0nmol/l

0 4

-------, 0 . 2 1 --- ---- -d 5.0nmol/l<NA

0.0-!.--~-~-- ~-~~-~-~--,---, 0 2 3 4 5 6 7 8

Observation period (years )

Figure 5) Cumulative survival probability in 8 / Cirrhotic />auenr.s with different leveL~ of circulating noradrenaline (NA). ( Heproduced from reference 88)

sympathetic ne rvous ac tivity anJ vasn­dilaror systems (cg, glucagon, prosrn­glandins, substance P, cnkephalin , cal­c ironin gcn e- rclateJ peptide, amt endothclia l-J erived relaxing facrnr) has been described (27 ,71 -7 5) , but the role of sympa thetic ne rvous activity in hemodyna mic adjustment anJ parho­physio logy of the ci rculato ry derange­ment seen in c irrhosis is stilt unclear.

VASCULAR REACTIVITY AND SYMPATHETIC NEUROPATHY

Head-up til t increases sympathetic nervous acn vity anJ c irc ulating no r­adrena line in patients wirh c irrhosis (25 ) as well as in norma l subjects. Ho w­ever, autonomic J ysfunct i\ln in ci r­rhosis, owing to fab e o r we,1k neurotransmiucrs, has been implied. Bernardi ct a l (28 ) repo rted that oc­topamme a nd bcta-phe nylechano l­a mine inc reased in pa rallel with noradrena line in patients with cirrhosis during head-up tilt. The patients did no t achieve an adequate rn rdiovascul,1r response, and the <1uthors concluded that hyperproduct iun of weak neuro­transmitters was, at least in pa rt, responsible for the attenuatio n. How­ever, post synaptic alpha-adrenoccp­tors might already be occupied by endogenous catecho lamines Jue to en­hanceJ sympathetic nervou~ rest ing tone, consistent with the blunted prcs­sor response co exogeno us no radrena­line in the pre ence of cirrhosis (76). Reduced vascular reactivity to angio­tensin II and noradrena line has been

described in experimental ponal hyper­tension an<l c irrhosis (77,78), but the results produced by exogenous vaso­conscric tivc agents on vascular reac­t iv ity in humans are conflicting. In patients with advanced liver <liscase, Lenz ct a l (79) recorded a normal in­c rease in systolic blood pressure in respo nse to infusion of vasoconscrictive agem s, noradrenaline and angiorcnsin II. In fact. t he response was greate r than m a group of young healthy controls.

By tilting cirrho tic patients to a 60° head-up position , Ring-La rsen e t a l (25 ) observed a no nnal noradrenaline response, ic, rapi<lly increasing con­centrations of noradrenaline in .-1rterial plasma. The a bsolute level of arterial noradrenaline was well above no rmal in t hcse patients, but the incre ment was normal, which indicates cha t their volume and ba rorecep tor-mediated responses were intact.

A lte red hcta-adrcnc rgic respo nsive­ness may a lso play a role in sqme of the hemodyn amic disturbances in liver dis­ease. Gerhes ct a l (80) found evidence of decreased betaadrcnocepwrs in leukocytes, and Ramond e t al (81) found a decreased sensitivity to iso­prc na line in patients with c irrhosis. Lee ct al (82) recently fo un<l evidence for a selective down-regula tion of bc ta- 1-adrenergic receptors in experimenta l ci rrhosis whc ih may be responsible for the ohscrveJ myocardia l hyporcspon­sivcncss ro catecho lamines.

An alcoho lic sympathetic neuro­pathy has been suggcsteJ and accor<l-

ingly there arc indications that sym­pathet ic fi bres may he damage<l in al­coho lics ( 83 ,84). Most paticncs with ad vanced alcoho lic liver disease have raised levels of c irculating noradren· a line indicating a high degree of sym· pa the tic react iv it y, al t hough the maxi­mal sympathetic response may be somewhat blunted. T hus, alcoholic sympathe tic ncurop,llhy remains to he proven (85 ).

CONCLUSIONS Most of the current knowledge of

the sympathetic ne rvous ~ystcrn has been gaincJ from stud ies of groups of patients wi th c irrhosis of varying seve rity. Longitudinal srud ies of the s ingle pa t ient from the we ll compen. sate stage to inc ipie nt fl uid retention to tense asc ites, and full -blown hepato· renal syndrome may reveal unknown facets of the sympathet ic nervous sys­tem and other regulatory systems in cir­rhosis. T his ho lds especia lly tnic forche time course of activat ion of the sym· pathetic nervous system, the renin-an­gio tcnsin-aldostcronc sysrem, anJ vasoprcssin release. The re lat ivc con­tribu tions of these sys tems to main­tenance o f a rteria l hlood pressure is not suffic ientl y elucidated. Peripheral bloodflow (shunt flow and capillary bloodflow in ske letal muscles, suh­cutancous tissue, fau y tissue and skin) and the coronary circula tion are poorly investigated in re la tion to sympathetic nervous activity.

C ha nges in body position, phy,ical exerc ise and food intake arc m hcr is­sues which involve rhe sympathcuc nervous system, hue knowledge ts limi ted in patients with c irrhosis. The role of a numbe r of o ther important regulatory systems, incluJing atrial natriuretic fac to r, po tent vasoJ ilator systems and important humoral meta­bo lic mediators such ,ls insu lin anJ g

0

lucagon , a rc also top ics for future re· search . A ltered renal au toreguh1tion, fa lse neurotransmitters, c hangcJ af­finity of a lpha- and bern-adrenocept<m, and auto nomic neuropathy a lso Jc. mand furt her research ( 86,87), as docs rena l sympa thetic de nervation , either surgical o r pharmacological.

A lthough major prob lems arc un·

108 CAN J ClASTROE:.NTl:ROL VOi 5 No> M A Y/jUNF 1991

solved, it is the authors' v iew that the sympathetic nervous system plays a vital role in the pathophysiology of the circulato ry and homeostatic derange­ment seen in c irrhosis (88). This view 1s partly borne out by thc- fact that the

ACKNOWLEDGEMENTS: The author, txpress their gratitude to Ms Bente Henrik­sen and MsGri th lngemann for their skillfu l secretarial help.

REFERENCES l. Sknreck, KL. Brenner BM. BoJ y nuiJ

homc,i,tasis in patients w1rh cirrh,1s1, of the liver. Am J MeJ 1982;72:323-38.

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