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vasodilatation and increased cardiac output [14,6,7]. Therefore, nearly all patients with decompensated cirrhosis

essentially show an obvious hyperdynamic circulatory state. However, the presence of portal hypertension,

rather than liver failure , is a sine qua non for the development of hyperdynamic circulation. Patients with prehe-

patic portal hypertension secondary to portal vein obstruction, hepatic schistosomiasis, and noncirrhotic portal

fibrosis have a normal or near-normal hepatocellular function and hyperdynamic circulation

[14]. Animal mod-

els of portal vein stenosis or ligation, with prehepatic portal hypertension but no parenchymal liver disease, have

confirmed this finding

[8,9].

Hyperdynamic splanchnic circulation is associated with several complications. The gut and the liver receive

approximately 33% of the cardiac output; therefore, abnormalities in this vascular bed directly or indirectly con-

tribute to ascites and variceal bleeding, which represent the most distressing and challenging complications of

cirrhosis

[10]. An increase in the total cardiac output results in increased mesenteric blood flow [8,9]. Moreover,

studies in both humans and animal models of cirrhosis or portal hypertension have confirmed that mesenteric

hyperemia is attributable to mesenteric vasodilatation (an increase in the percentage of the overall cardiac output

that perfuses mesenteric organs) in addition to a passive increase in blood flow as a part of the increased cardiac

output

[2,4,8,9]. Portal venous pressure is measured as resistance 3 flow; therefore, mesenteric hyperemia contri-

butes to portal hypertension (the “forward flow” mechanism). Furthermore, portal hypertension promotes the

development of portosystemic collaterals (gastroesophageal varices), which affect the local and systemic circula-

tion in addition to causing serious adverse events secondary to variceal bleeding. Doppler ultrasonography

allows us to examine haemodynamics of abdominal vessels, including the hepatic and portal system. For exam-

ple, the doppler hepatic waveform in the healthy subjects is triphasic, and this pattern is the conse quence of var-

iations in the central venous pressure because of the cardiac cycle. In portal hypertension, the presence of

abnormal biphasic or monophasic hepatic vein waveforms has been incontrovertibly demonstrated by several

studies. The exact cause of these changes remains unclear. However, it is hypothesized that hepatic venous com-

pliance can be easily reduced by parenchymal fibrosis and fatty infiltration because the hepatic vein wall is thin

and surrounded by the hepatic parenchyma (

Fig. 14.1) [11].

Portal hypertension causes activation of the sympathetic nervous system. The higher heart rate and cardiac

output usually observed in patients with portal hypertension are attributable to an increased sympathetic firing

rate. Subsequent biochemical investigations in these patients show a high rate of norepinephrine outflow

throughout the body, as well as in the individual organs and vascular territories

[12]. Studies have reported

direct measurement of the sympathetic nerve fraction using microneurographic electrophysiological techniques

to co nfirm the increased sympathetic nerve firing rates observed in portal hypertension

[13]. The clinical conse-

quences of sympathetic system activation are uncertain. With regard to the sympathetic nervous system, it is

commonly recognized that the homeostatic sympathetic response can be maladapti ve in some disease states

[14].

Increased sympathetic activity in patients with cirrhosis may possibly cause adverse effects. Specifically, the sym-

pathetic mechanisms associated with the hepatic mesenteric circulation can contribute to portal venous hyperten-

sion and sodium retention in the kidneys.

Lately, bacterial translocation has been implicated in bacterial expression of pathogen-associated molecular

patterns (PAMPs). Bacterial infection is recognized as a risk factor for variceal bleeding

[15], although the mecha-

nism underlying this phenomenon remains unknown. However, the leading theory is that humoral agents,

FIGURE 14.1 Classification of Doppler hepatic vein waveform with schematic drawing.

204 14. Peripheral vasculature in portal hypertension

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including endotoxins and cytokines such as tumor necrosis factor-α (TNF-α) released in patients with sepsis,

exacerbate the hyperdynamic circulatory state and increase variceal blood flow.

According to the “primary peripheral vasodilatation” hypothesis, peripheral vasodilatation is considered the

main pathogenetic determinant that results in renal sodium and water retention

[16] (see Chapter 18). The

peripheral vasodilatation hypothesis accounts for some of the mechanisms underlying progressive decompensa-

tion in cirrhosis, although other factors such as cardiac dysfunction are known to contribute to reduction of effec-

tive hypovolemia in advanced stages when the heart fails to compensate for the pronounced vasodilatation.

Knowledge of cardiac dysfunction in patients with cirrhosis has established the concept of cirrhotic cardiomyopa-

thy as a clinical entity, and vasodilatation of the pulmonary vasculature is known to cause hepatopulmonary

syndrome.

Pathogenesis of hyperdynamic circulation

The exact pathogenetic mechanisms associated with hyperdynamic circulation remain unclear; humoral

agents, bile acids, central neural activation, inflammation, tissue hypoxia, and hypervolemia are among the sev-

eral factors implicated in this regard.

Fig. 14.2 shows the proposed schema.

Portal venous hypertension is a prerequisite for the development of hyperdynamic circulation; therefore, an

investigation into the pathophysiology of this condition is important to better understand the altered hemody-

namics in these patients. Portal hypertension by itself or associated effects such as mesenteric congestion or por-

tosystemic collateralization initiate a sequence of events that eventually lead to hyperdynamic circulation

[17].

Gastrointestinal congestion favors translocation of bacteria or endotoxins into the portal circulation and subse-

quently into the systemic circulation via intrahepatic or extrahepatic portosystemic collateral shunts. Moreover,

these factors stimulate other vasoactive substances, such as cytokines, nitric oxide (NO), carbon monoxide (CO),

and endocannabinoids

[18]. Portal or mesenteric venous hypertension also triggers neuronal activation of subcor-

tical structures, including the brainstem and hypothalamic central cardiovascular-regulatory areas, such as the

ventrolateral medulla and the nucleus of the solitary tract (NTS) with a consequent complex interplay of factors

FIGURE 14.2 The pathogenetic mechanisms associated with hyperdynamic circulation.

205Hyperdynamic circulation

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that results in an exaggerated cardiovascular response via neurohormonal mechanisms, such as the sympathetic

nervous system and arginine vasopressin secretion.

Intrahepatic or portal hypertension also leads to an expansion of the total blood and plasma volumes via a

direct signal from the liver/gut to the kidney, or via signals to the vasculature to promote peripheral vasodilata-

tion. Vasodilatation decreases the effective circulating volume and increases renal sodium and water retention,

which expands the extracellular fluid volume

[5]. The expanded fluid volume remains ineffective owing to pool-

ing in the mesenteric venous reservoir. The decreased effective circulatory volume together with the action of

humoral agents, such as NO and cytokines, induces tissue hypoxia, which in conjunction with other humoral

agents triggers an oxidative stress response leading to production of reactive O

and nitroxy intermediates.

Moreover, central neural centers that are sensitive to tissue hypoxia and reduced effective circulatory volume

transmit signals to stimulate the heart and vasculature

[19].

Based on this schema, hyperdynamic circulation is understood as a reactive compensatory attempt by the cen-

tral nervous system (CNS) to relieve mesenteric congestion and/or tissue hypoxia. Progressive liver failure

results in pronounced hemodynamic alterations associated with hyporesponsiveness to vasoconstrictors,

increased shunt formation, and autonomic neuropathy. This highlights the role of several positive-feedback

loops, involving humoral and neurohormonal agents that are instrumental in aggravating cardiovascular changes

in such cases.

Nitric oxide

NO, a powerful endogenous vasodilator released from many different sources, including vascular endothelial

cells, is synthesized from

L-arginine by three distinct isoforms of NO synthase (NOS), neuronal or brain NOS

(nNOS, bNOS, NOS1), inducible NOS (iNOS, NOS2), and endothelial NOS (eNOS, NOS3). In 1991, Vallance and

Moncada proposed that gut-derived endotoxemia upregulates iNOS in cirrhosis, and the overproduction of NO

triggers a hyperdynamic circulatory state

[20]. This hypothesis was subsequently tested by numerou s studies

[21]. Currently, there is abundant evidence that NO contributes to the development or maintenance of hyperdy-

namic circulation;

[2225] several studies in humans and in animal models of cirrhosis have proved that a hyper-

dynamic circulatory state is associated with increased NO synthesis and that NOS inhibition suppresses

hyperdynamic circulation

[2628]. Increased NO levels diminish endothelin- and vasopressin-induced vasocon-

striction in cirrhosis. Studies have shown that NO activity varies across different vascular beds in patients with

cirrhosis; however, the exact origin of elevated NO levels remains unknown.

It is conclusively established that increased NOS activity plays an important role in the hyperdynamic circula-

tory state observed in cirrhosis; however, the NOS isotype involved in this process remains unclear. A recent

study that used aminoguanidine (a preferential iNOS inhibitor) showed that the hyperdynamic circulation in a

mouse model of portal hypertension was reversed in vivo

[29]. However, another study that used aminoguani-

dine did not report an in vitro effect of this agent on the hyporeactivity of aortic rings in cirrhotic rats

[30]. Liu

et al. investigated the activity of the L-arginine-NO pathway at different levels

[31]. Although iNOS mRNA

expression was detected in the aorta in a setting of cirrhosis, the authors did not identify the iNOS protein.

However, a sustained increase in eNOS mRNA expression and protein levels was observed in cirrhotic rats.

Evidence-based research has shown increased shear stress in vascular endothelial cells to be a major mechanism

involved with eNOS upregulation. However, this alternative hypothesis of eNOS upregulation constitutes “the

chicken or egg paradox” owing to the fact that shear stress is attributable to peripheral vasodilatation and

increased blood flow. Proponents of the eNOS hypothesis suggest the role of other upregulatory mechanisms,

including heat-shock protein-90, endocannabinoids, and bacterial translocation with subsequently increased

TNF-α production and elevated tetrahydrobiopterin levels

[3234]. The increased eNOS production could be

attributed to the action of other factors such as estrogen, which is known to upregulate eNOS activity, and estro-

gen levels are typically high in patients with cirrhosis

[35,36].

Studies in gene-knockout mice that lack the eNOS gene have shown conflicting results. Theodorakis et al.

reported that portal vein stenosis does not induce most features of hyperdynamic circulation in such mice

[37].

However, a study performed by Iwakiri et al. in a portal stenosis knockout mouse model lacking eNOS, as well

as in other mouse models lacking both iNOS and eNOS

[38] observed a persistent hyperdynamic circulatory state

in both models. It is possible that nNOS compensates for eNOS following inhibition or downregulation of eNOS.

It is observed that increased nNOS partially compensates for the absence of eNOS in the aortae of eNOS-

knockout mice

[39]. The contribution of nNOS upregulation in the pathogenesis of cirrhosis is also supported by

other studies. Xu et al. treated rats with carbon tetrachloride-induced cirrhosis with 7-nitroindazole (a selective

nNOS inhibitor) for 1 week

[40] and observed that this treatment reversed the hyperdynamic circulation in these

206 14. Peripheral vasculature in portal hypertension

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rats, without affecting renal function. The results of these studies indicate that eNOS is the likely source of

the increased NO levels in portal hypertension and cirrhosis; however, nNOS may also contribute, particularly in

situations where eNOS is inhibited.

Endocannabinoids

The psychotropic properties of exogenous cannabinoids derived from the plant Cannabis sativa were discov-

ered centuries ago; however, endogenous cannabinoids or endocannabinoids have been detected in mammals,

including humans, only in recent times

[41]. Endocannabinoids produce vasodilatation via a ligand-specific

G-protein coupled receptor, the cannabinoid receptor type 1 (CB1) receptor

[42]. Cirrhosis is associated with

increased blood levels of endocannabinoids and activation of vascular CB1 receptors

[4345]. SR141716A, a CB1

receptor antagonist was shown to increase arterial pressure and reduce the increased mesenteric blood flow and

portal pressure in a cirrhotic rat model. Studies in humans and experimental rat models have shown that the

monocyte-derived endocannabinoid levels were higher in humans and cirrhotic rats than in controls

[44,45].

Therefore, it can be inferred that increased endogenous cannabinoid levels and activation of vascular CB1 recep-

tors in the mesenteric vasculature may contribute to splanchnic vasodilatation and portal hypertension. In addi-

tion to vasodilatation, anandamide (at 25 μmol/L) induces rapid apoptosis in a dose-dependent manner in

primary culture-activated and activated hepatic stellate cells in vivo, with . 70% cell death observed after 4 hours

[46]. This effect could alter the hepatic sinusoidal microcirculation and promote portal hypertension that leads to

hyperdynamic circulation. Varga et al. observed that bacterial endotoxins stimulate endocannabinoid production

in cirrhosis

[47]. The endocannabinoid system is upregulated in human and experimental rat models of cirrhosis,

which can be concluded from the higher plasma anandamide levels observed in patients

[48] and experimental

rat models of cirrhosis

[49,50]. A study has shown that compared with controls, anandamide produced stronger

CB1 and transient receptor potential vanilloid 1 receptor-dependent vasodilatation of mesenteric arteries but not

the femoral arteries isolated from cirrhotic rats

[51]. In contrast, anandamide caused vasoconstriction in the iso-

lated perfused liver, which was more pronounced in rats in whom cirrhosis was induced by bile duct ligation.

CB1 receptor blockade induced by acute or chronic rimonabant administration and/or CB1 receptor deficiency

increased the splanchnic vascular resistance in cirrhotic animals, leading to a concomitant decrease in the mesen-

teric arterial blood flow, reduced liver fibrosis, and decreased portal hypertension. The opposite effects were

observed in an experimental cirrhotic mouse model with CB2 receptor-deficient mice or in patients with the

Q63R variant of the CB2 receptor that impairs its immunomodulatory function

[49]. Studies show conflicting

results; a recent study reported elevated endocannabinoid levels in patients with cirrhosis without an association

between these levels and any hemodynamic parameter

[45]. However, another recent study reported improve-

ment in hepatic endothelial dysfunction associated with lower expression of hepatic CB1 and a higher expression

of hepatic CB2 in experimental cirrhotic rats treated with ciprofloxacin

[52]). Therefore, it can be tentatively con-

cluded that modulation of hepatic microcirculation might occur through inhibition of hepatic endocannabinoid

levels.

Heme oxygenase and carbon monoxide

Heme oxygenase (HO), an enzyme that catalyzes the oxidation of heme to iron, biliverdin, and CO, exists in

the indu cible (HO-1) and constitutive (HO-2) isoforms. Similar to NO, CO is a short-lived gas that causes

vasorelaxation by stimulating guanylate cyclase to generate cyclic guanosine-3

-monophosphate.

Circumstantial evidence implicates the HOCO pathway in the modulation of vascular tone in portal hyper-

tension. HO-1 upregulation is observed in cirrhosis accompanied by portal hypertension

[5355].Aratmodel

of portal hypertension has shown that NOS inhibition does not completely sup press relaxation of isolated arte-

rial smooth muscle cells and h yporeactivity to vasoconstricto rs, which suggests the role of a NO-independent

local mechanism in this condition. HO inhibition was shown to partially restore the depressed reactivity to

potassium chloride-induced vasoconstriction of isolated perfused mesentery in a rat model of portal hyperten-

sion

[53]. However, the mechanism(s) of HO-1 induction and the physiological role of the induced hepatic

HO-1 in portal hypertension remain unclear. A recentstudycomparedtheexpressionofmRNAthatencodes

HO-1 in the liver of patients with and without portal hypertension and reported that HO-1 mRNA levels were

significantly higher in the portal hypertension group. In contrast, the gene expression of nonspecific

d-aminolevulinate synthase (which is downregulated by heme in the liver), was the same in both groups.

These results suggest that HO-1 may play an important role in the pathophysiology of portal hypertension

heme-independent stimuli

[56].

207Hyperdynamic circulation

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Role of other humoral agents

Studies have reported a possible role of several vasoactive humoral agents, including adrenomedullin, gluca-

gon, adenosine, prostaglandins, substance P, and calcitonin gene-related peptide in the pathogenesis of portal

hypertension and hyperdynamic circulation

[34,5760].

Bile acids

It is speculated that elevated serum bile acids are associated with cirrhotic cardiomyopathy (see Chapters 15 and 16).

The deleterious effects of bile on cardiac function were first described in the 19th century. Intravenous injection of bile

acids in animals induced profound bradycardia and even cardiac arrest (at high doses) despite heart denervation.

Interestingly, hyperdynamic circulationobservedinportalhypertensionisshown to be affected or regulated by bile

acids. In vitro and in vivo studies suggest that bile acids could be involved in splanchnic hyperemia and circulatory

dysfunction leading to a hyperdynamic circulatory state

[59]. Recently, Desai et al. observed that high-serum bile acid

levels were associated with an increased ejectionfractionandshorteningfraction of the left ventricle but a lower heart

rate

[61]. These authors proposed the term “cholecardia” (see Chapter 16) to describe the cardiodepressant effects of

bile acids and used a double knockout model (Fxr 2/2 ;Shp2/2 ) to establish similarities between experimental models

of severe bile acid overload and human cases of cirrhotic cardiomyopathy

[62]. These results further confirm the direct

and reversible effect of bile acids on cardiomyocytes. It is reasonable to presume that bile acids in cholemia exert similar

effects on myocytes in vascular smooth muscle.

Central neural mechanisms

Usually, the cardiovascular system is regulated by specific nuclei in the brainstem and hypothalamus,

including the NTS, the ventro lateral medulla, as w ell as the supraoptic and paraventricular nuclei. These areas

serve as processing and integration centers for the afferent and efferent nerve traffic that directly controls the

cardiac and peripheral vascular tone. Notably, c-fos is an i mmediate-early gene, which plays an important role

in cellular signal transduction and transcriptional regulation as a result of membrane depolarization and

voltage-gated calcium influx

[63]. Fos, the nuclear phosphoprotein encoded by the c-fos gene is a well-

established marker of neurons and neuronal pathways that have been activated by physiological and

pathophysiological stimuli

[63]. Breitman et al. first documented the role of Fos expression-induced central

neuronal activation in the medullary cardiovascular control centers

[64]. Subsequent research has shown t hat

central neuronal activation through a c-fos-mediated pa thway is a crucial initiating factor in the pathogenesis

of hyperdynami c circulation observed in animal models of cirrhosis and portal hypertension

[6467].Fos-

immunoreactivity in several central nuclei preceded the development of hyperdynamic circulation in a rat

model of portal hypertension

[65]. It is noteworthy that inhibition of Fos-mediated neuronal activation in the

NTS following local microinjections of c-fos antisense oligonucleotides completely eliminated the hyperdy-

namic circulatory state in a rat model of portal hypertension

[65]. Therefore, it is reasonable to conclude that

the activation of c entral cardiovascular regulatory nuclei through a c-fos-dependent pathway is a prerequisite

for the devel opment of hyperdynamic circulation in a rat model of portal hypertension.

Several questions remain unanswered; the exact central neurons that are activated remain unknown. Studies

have shown that the sympathetic catecholaminergic neurons are only modestly activated

[66,68]. More impor-

tantly, the cause of this central neural activation remains unclear. Administration of capsaicin, which denervates

sensory afferent nerves, significantly reduces baseline central Fos expression in a rat model of portal hyperten-

sion and cirrhosis

[67], and also prevents the development of both ascites and hyperdynamic circulation [69].

This indicates that interruption of peripher al-to-central afferent signaling, presumably from the gut/liver to the

cardiovascular regulatory nuclei, blocks central neuronal activation and stabilizes the altered hemodynamic state.

The exact origin of the peripheral signal remains unknown; however, a recent study has reported the role of an

afferent pathway from the gut to the central cardiovascular regulatory nuclei in a vagal capsaicin-treated rat

model of portal hypertension

[70]. Perivagal capsaicin treatment is shown to have blocked Fos expression in car-

diovascular regulatory subnuclei; moreover, this blockade prevented hyperdynamic circulation in a rat model of

portal hypertension. These authors speculated that the CNS responds to a portal hypertension-induced gut signal

(perhaps mesenteric congestion or ischemia), and this signal from the gut is transmitted to the CNS via the vagus

nerve. Therefore, central cardiovascular dysregulation plays a significant role in the pathogenesis of hyperdy-

namic circulation in portal hypertension and cirrhosis.

208 14. Peripheral vasculature in portal hypertension

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Increased blood and plasma volume/decreased effective circulating volume

Cirrhosis is characterized by an expansion of the total blood and plasma volumes secondary to renal sodium

and water retention. Other factors associated with hypervolemia, particularly the mechanisms underlying renal

dysfunction remain highly controversial. The debate regarding the “overload” theory versus the “underfill” or

“peripheral vasodilatation” theory remains unresolved over more than three decades. Based on these theories,

the central blood volume, defined as the volume of blood in the heart, aorta, and lungs, is either expanded or

reduced. Studies have reported both high and low central volumes, and this point remains debatable

[71].

Studies have documented volume-dependent effects on systemic and splanchnic circulation in patients with

cirrhosis

[72]. It is observed that compared with controls, hypervolemia and consequent natriuresis are more pro-

nounced in well-compensated cirrhosis during acute volume expansion by head-out water immersion [73].In

contrast, depletion of circulating volume after furosemide administration reduces portal pressure and hyperdy-

namic circulation

[74]. These observations indicate that significant volume expansion or depletion may regulate

hyperdynamic circulation in well-compensated cirrhosis. Stated differently, it can be deduced that hypervolemia

might be involved in the development of hyperdynamic circulation in early cirrhosis. The following two-phase

pathogenetic model of hyperdynamic circulation has been proposed:

[1] (a) The first phase in early pre-ascitic cir-

rhosis may include extracellular volume expansion secondary to subclinical sodium retention and subsequent

passive relaxation of the vasculature to accommodate the increased volume. Sodium retention could occur sec-

ondary to either a direct hepatorenal interaction through sinusoidal portal hypertension and/or hepatic dysfu nc-

tion (overload theory), or secondary to peripheral vaso dilatation and a subsequent decrease in the effective

volume (peripheral vasodilatation theory) and (b) The second phase comprises worsening vasodilatation second-

ary to hyporesponsiveness to vasoconstrictors, activation of neurohormonal systems, such as the renin-

angiotensin-aldosterone, sympathetic, and endothelin systems, and increased portosystemic shunting, which may

account for the greater degree of hyperdynamic circulation observed in advanced stages of cirrhosis

[1].

Peripheral venous “sump” effect due to venous pooling

Cirrhosis is characterized by circulatory impairment and deranged volume homeostasis leading to a signifi-

cantly increased blood volume; it is important to understand the mechanisms that regulate this volume to restore

homeostasis. Veins are referred to as capacitance vessels of the ci rculation, and gut veins constitute the main res-

ervoir. A Danish study that performed whole-body scintigraphy using indicator dilution methods confirmed

sequestration of the expanded blood volume in the mesenteric veins

[71,75]. Owing to considerable mesenteric

vasodilatation in cirrhosis, these patients show significant pooling of blood in the gut veins along with significant

dilatation of the vasculature to accommodate a possible further volume expansion or other dilatory stimuli. A

question that is asked in this regard is why do they not mobilize the increased blood volume effectively to defend

the circulation? Bile duct ligation performed in a rat model of cirrhotic hepatic vasculature showed an enhanced

dilatory response to sodium nitroprusside (a NO donor) and volume expansion. In contrast, the constrictive

responses to norepinephrine and hemorrhage were diminished in this aforementioned rat model compared with

controls

[72]. This finding is attributed to the “sump” effect, which refers to distention of vessels that are unable

to constrict to expel the extra blood volume into the arterial circulation, thus allowing the excess blood volume to

pool in the gut veins. However, administration of N-nitro-

L-arginine methyl ester (a nonspecific NOS inhibitor)

or selective neuronal NOS inhibitors corrected this diminished homeostatic response, which indicates that nNOS-

derived NO is instrumental in the development of this defect. These data strongly support the dominant role of

nNOS-derived NO in the pathogenesis of the sump effect

[21].

Abnormalities of arterial vascular tone

Vasoactive molecules

The hypothesis is well established that arterial splanchnic vasodilation is an important physiological basis for

the development of portal hypertension and hyperdynamic circulatory changes

[76]. As mentioned above, the

peripheral arterial vasodilatation hypothesis combines arterial underfilling with a forward increase in hepatos-

planchnic capillary pressure and filtration with increased lymphogenesis

[77]. The combination of liver failure

209Abnormalities of arterial vascular tone

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and portosystemic shunts bypassing the blood in the liver increases circulatory vasodilators such as NO, arachi-

donic acid metabolites, and calcitonin gene-related peptides (CGRP) (

Table 14.1) [78,79]. These vasodilators

increase plasma- and blood volumes and cardiac output and lead to a hyperdynamic circulatory state.

Furthermore, this stimulates the overproduction and release of vasodilators in the spleen circulation, preferen-

tially by shear stress

[80]. The splanchnic vasodilatation also leads to a decrease in arterial blood pressure with a

decrease in SVR, a decrease in the effective blood volume, and activation of a powerful vasoconstrictor system

such as the renin-angiotensin-aldosterone system, sympathetic nervous system (SNS), and vasopressin

[81,82].As

a result, there is experimental and clinical evidence that it precedes opposing regulatory neurohumoral activa-

tion, renal sodium, and fluid retention.

Inflammation

Patients with cirrhosis are highly susceptible to bacterial infections, including spontaneous bacterial peritonitis,

urinary tract, and pulmonary infections, which is attributable to the following factors: impaired cellular immune

TABLE 14.1 Vasodilators and vasoconstrictors involved in portal hypertension.

Production, occurrence

Vasodilators

Adrenomedullin

• Production by endothelial and vascular smooth muscle cells, upon cytokine stimulation

• Production in the atrium of the heart

Atrial natriuretic protein

• Cardiac production in response to ventricular overload

Calcitonin gene-related

peptide, CGRP

• Released by neurons

• Released by vanilloid receptor stimulation, (e.g., after CB1 receptor)

Carbon monoxide (CO)

• Production in the vessel wall by heme oxygenase-1 (HO-1)

• Paracrine/autocrine factor

Endocannabinoids

(anandamide, 2-AG)

• Increased production by monocytes

• Circulating hormones

Glucagon • Production in pancreas

• Circulating hormone

Prostacyclin

• Production by COXs

• Released from endothelial cells

Adenosine

• Released by nitric oxide (NO) dependent adenosine A1 receptor stimulation

Bradykinin

• Endothelium-dependent vasodilator and inflammatory mediator

Brain natriuretic peptide

• Expressed in myocytes of failing left ventricles

Endothelin-3

• Released by activation of ET-B receptors, which is mediated by enhanced NO and prostacyclin production

by the endothelial cell.

Endotoxins

• Induce the synthesis of NO

Nitric oxide

• A potential vasodilator, produced by NO synthase (NOS)

Substance P

• Production by the enteric nervous system and partly cleared by the liver

Vasoconstrictor

Angiotensin II

• Released by activation of the renin-angiotensin system

Endothelin-1 (ET-1)

• A potent vasoconstrictor from porcine endothelial cells

Neuropeptide Y

• A sympathetic neurotransmitter facilitating adrenergic vasoconstriction on the vascular smooth muscle

Renin-angiotensin-aldosterone

system

• Enzyme cascade starting with the degradation of angiotensinogen by circulating renin to form angiotensin I

• Binding of Angiotensin II to the AT1 receptor mediates vasoconstriction and sodium hemostasis

Vasopressin (Copeptin)

• Production in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure,

and reductions in cardiac volume

210 14. Peripheral vasculature in portal hypertension

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function of macrophages and monocytes, inhibition of neutrophil-mediated phagocytosis and intracellular death,

as well as lack of complement systems, all of which prevent effective elimination of bacteria from the body

[8385]. In addition to an immunocompromised state, cirrhosis is associated with increased intestinal permeabil-

ity, which promotes bacterial overgrowth and consequent transition of bacteria from the gastrointestinal tract to

the mesenteric lymph nodes. Bacteria or their products in the splanchnic lymph nodes, ascitic fluid, or in the gen-

eral circulation disturb the hemodynamic balance and precipitate a hyperdynamic circulatory state

[86].

Bacterial translocation activates monocytes and lymphocytes and increases levels of circulating pro-

inflammatory cytokines such as TNF-α and interleukin-6, resulting in a sequence of events referred to as a “cyto-

kine storm” with subsequent NO activation

[87]. PAMPs are recognized by pattern recognition receptors

expressed in immune cells and the epithelium, and this inflammatory response worsens vasodilatation and the

hyperdynamic circulatory state

[88]. Several clinical studies have convincingly proved bacterial infection-induced

kidney, heart, brain, and lung dysfunction, particularly in a setting of severe inflammatory reaction syndrome.

With regard to the pathogenesis of organ failure, inflammation can lead to more complex pathophysiological

pathways than hypothesized by the peripheral arterial vasodilatation hypothesis. Recent studies have proposed a

modified version of the arterial vasodilatation hypo thesis, referred to as an uncompensated “systemic inflamma-

tion hypothesis” of cirrhosis

[82].

Nervous system and peripheral vascular changes

Autonomic dysfunction

The autonomic nervous system plays a key role in modulation of cardiac performance and vasomotor activity.

Patients with cirrhosis show impaired autonomic cardiovascular reflexes

[8991], and the prevalence and sever-

ity of autonomic dysfunction increase wi th progressive hepatic dysfunction in patients with cirrhosis

[92].

Approximately 80% of patients with advanced cirrhosis show evidence of autonomic dysfunction

[93,94].

Reportedly, vagal neuropathy predicts reduced survival in patients with compensated cirrhosis

[9092]. The

prevalence of autonomic neuropathy was similar in patients with alcoholic and nonalcoholic cirrhosis, which has

important implications with regard to pathogenesis

[93]. The parasympathetic system appears to be more com-

monly affected in all types of cirrhosis. Vagal dysfunction is reported in 30%60% of patients, whereas only

10%20% of patients show sympathetic dysfunction

[9092].

Autonomic reflex function evaluation is performed using standardized cardiovascular tests that quantify

changes observed in the heart rate and blood pressure during a Valsalva maneuver, deep breathing, posture

changes, sustained handgrip, and pharmacological stimulation

[8994]. Baroreceptor function can also be

quantified using intravenous phenylephrine administration to achieve a rapid increase in blood pressure.

Sudden onset of hypertension stimulates baroreceptors to transmit afferent signals to the brainstem cardiovas-

cular centers, which subsequently increase parasympathetic traffic via the vagal efferent to reduce heart rate

and contractility. This baroreflex function is known to be depressed in patients with cirrhosis awaiting liver

transplantation

[90,91].

Reportedly, autonomic dysfunction is associated with hyperdynamic circulation

[92,94]. Notably, some

patients without evidence of autonomic dysfunction show hyperdynamic circulation; therefore, it is reasonable to

conclude that autonomic dysfu nction is not a prerequisite for the development of circulatory a bnormalities.

However, autonomic dysfunction may amplify the hyperdynamic circulatory state

[94]. Furthermore, the severity

of hyperdynamic circulation is shown to be associated with the degree of autonomic dysfunction

[94].

Autonomic dysfunction can contribute to circulatory abnormalities via several mechanisms. Parasympathetic dys-

function reduces the inhibitory vagal tone, resulting in unregulated cardioacceleration. Moreover, sympathetic

dysfunction may contribute to the diminished cardiovascular response to vasoconstrictors

[14]. The clinical con-

sequences of baroreflex dysfunction include postural hypotension and a reduced ability to maintain circulatory

homeostasis after cardiovascular insult. These effects may partially explain the high susceptibility of patients

with advanced cirrhosis to infection, hemorrhage, and volume depletion.

Cerebral circulation

Cerebral blood flow (which can be measured by various methods) appears to be decreased in patients with

cirrhosis

[2,9597]. Virtually all studies that have investigated this subject have documented regional redistribution

211Nervous system and peripheral vascular changes

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of blood flow, usually from the cortical to subcortical regions. Although the exact subcortical regions to which

blood flow is directed and redistributed remain unclear, most studies have observed that the volume of blood flow

is greater in the basal ganglia, thalamus, and the cerebellum than in cortical areas such as the frontal and temporal

lobes

[9597]. Disparities in the findings across studies reported in the literature may reflect heterogeneity in

patient populations. Alcohol is a well-known neurotoxin, and frontal cortical atrophy and reduced blood flow to

the region are more pronounced in patients with alcoholic cirrhosis than in those with nonalcoholic cirrhosis.

Cerebral circulation is usually protected against changes in systemic hemodynamics owing to a homeostatic

vascular autoregulatory mechanism. For example, cerebral perfusion is unaffected by arterial hypertension or

hypotension across a broad range of arterial blood pressures. Usually, this autoregulatory mechanism appears to

be intact in patients with cirrhosis; however, some studies have reported defective autoregulation in patients

with severe liver failure or hepatic encephalopathy

[96,97]. Additionally, whether disturbances in cerebral blood

flow are associated with functional neurological disorders, such as encephalopathy, abnormalities in cerebral

ammonia metabolism, or altered permeability of the bloodbrain barrier remains controversial. Research has

shown evidence for and against these notions; therefore, a clear consensus is currently unavailable

[2,97].

Management of hyperdynamic circulation

Several studies have reported strategies to reverse the hyperdynamic circulation in patients with cirrhosis and

portal hypertension; however, most studies have investigated the pathogenesis and not the approach to optimal

treatment in these cases. Currently, pharmacotherapy for a hyperdynamic circulatory state focuses on drugs such

as vasopressin, terlipressin, somatostatin, octreotide, and β-blockers, including propranolol and nadolol, all of

which affect systemic and splanchnic hemodynamics

[98,99]. These drugs are ad ministered for their specific

effects on the splanchnic circulation, such as control of variceal bleeding or treatment of hepatorenal syndrome.

For decades, to treat acute variceal bleeding, pharmacologic treatment has been used in together with endoscopic

therapy

[100,101]. Early administration of terlipressin, somatostatin, and octreotide helps for easier handling of

endoscopy. As endoscopic treatments, banding ligati on is preferable for the bleeding from esophageal varices.

We restrict our discussion to other treatment methods relevant to hyperdynamic circulation.

NO is a key mediator of circulatory dysfunction; therefore, its role has been investigated in greater detail. A

study has reported that acute administration of N(G)-monomethyl-

L-arginine (L-NMMA, a nonspecific NOS

inhibitor) corrected the altered systemic hemodynamics and improved renal function in these patients

[28],

whereas another study showed that this agent led to elevated arter ial pressure without any change in renal func-

tion

[102]. All studies that have reported the use of NOS inhibitors have described acute administration of this

agent; therefore, the effects of chronic treatment remain unknow n. A theoretical concern associated with the

chronic use of NOS inhibitors is their role in worsening portal hypertension via aggravation of NO deficiency in

the hepatic microcirculation. However, a study performed by the Edinburgh group showed no effect of an acute

dose of

L-NMMA on portal pressure in patients with cirrhosis [103]. The optimal therapeutic strategy involves

selective NOS blockade of a specific vascular bed or selective delivery of NO to the hepatic microcirculation. NO-

selective delivery by NOS gene transfer to the liver has shown promising results in animal models of cirrhosis

[104]. The other major concern is the widespread physiological roles of NO; thus chronic blockade of these func-

tions may lead to numerous potentially deleteri ous consequences. For example, NO is a major regulator of penile

vessels that produce erections (need ref here), so many people may object to the predictable side effect of erectile

dysfunction that will accompany chronic NO blockade.

Two recent studies have reported the oral administration of the antibiotic norfloxacin to reduce bacterial endo-

toxin levels in patients with cirrhosis. A Spanish study observed

[105] that 42% of 71 patients showed high levels

of the lipopolysaccharide-binding protein (LBP), a presumed marker of endotoxin activation (although 60% of

patients with high-LBP levels had normal endotoxin levels). A 4-week course of norfloxacin improved SVR and

cardiac output only in the high-LBP subgroup. An Australian study in which 14 patients with alcoholic cirrhosis

received norfloxacin for 4 weeks

[106] reported reduced forearm blood flow and increased SVR and arterial pres-

sure associated with significantly decreased endotoxin levels. Notably, renal function remained unchanged in

both aforementioned studies. These studies highlight the important role of gut bacteria in the pathogenesis of

hyperdynamic circulation; however, large-sized randomized studies are warranted to confirm these results.

Studies that report the administration of ursodeoxycholate (UDCA) in humans and in experimental animal

models emphasize the role of bile acids in hyperdynamic circulation. UDCA is a highly hydrophilic bile acid that

improves biochemical parameters and was, until recently, the only approved therapy for primary biliary

212 14. Peripheral vasculature in portal hypertension

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cholangitis (PBC). Bomzon et al. administered therapeutic doses of UDCA for 1 month to patients with PBC and

postnecrotic cirrhosis, based on a presumed cardiohemodynamic effect of UDCA. The authors reported a reduc-

tion in the diastolic volume in patients with PBC and a slightly lower cardiac output in patients with postnecrotic

cirrhosis; however, the heart rate or blood pressure remained unchanged

[107]. The effects of UDCA were

assessed in patients with refractory ascites, and no change was observed in these systemic hemodynamic para-

meters during or after treatment completion, although the authors observed reduced-sodium clearance and

weight gain in all patients, which led to the conclusion that UDCA causes sodium retention

[108]. More recent

studies have yielded similar results.

Obeticholic acid is synthesized from chenodeoxycholic acid as a selective potent farnesoid X receptor agonist

with anticholestatic properties. Recent reports have described the effects of obeticholic acid on portal circulation.

Verbeke et al. showed that the mean portal pressure was 15%21% lower in cirrhotic rats who received obeti-

cholic acid than in controls, without a decrease in mean arterial pressure, which suggests a liver-specific effect of

obeticholic acid, most likely secondary to increased intrahepatic eNOS activity

[109]. However, whether obeti-

cholic acid could minimize the deleterious effects of hyperdynamic circulatory syndrome or even cirrhotic cardio-

myopathy is debatable.

Conclusions

We reviewed various aspects of abnormal peripheral vasculature in portal hypertension, focusing mainly on

the hyperdynamic circulation, but also including the concept of decreased effective circulating volume, the

peripheral venous ‘sump’ effect or venous blood pooling in cirrhosis, and other topics involving the peripheral

arterial and venous circulations in portal hypertension. Portal hypertension leads to splanchnic and peripheral

arterial vasodilatation with the onset of a hyperdynamic circulatory state, which is characterized by increased

cardiac output and decreased peripheral vascular resistance with low arterial pressure. The arterial vasodilation

is determined by increased levels of circulating vasodilators secondary to portosystemic shunting, as well as a

decreased vascular responsiveness to endogenous vasoconstrictors and bacterial translocation. A complex inter-

play between multifactorial pathogenetic mechanisms underlies this abnormal peripheral vasculature; notably,

NO, endocannabinoids, bile acids, and neurohumoral activation are among the factors that contribute to the path-

ogenesis of both hyperdynamic circulation. Extensive research has improved our understanding of the patho-

physiology of abnormal peripheral vasculature in portal hypertension to enable the development of novel

treatment modalities in this patient population.

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