Review ArticleClinical implications of the hyperdynamic syndrome in cirrhosis
Introduction
Patients with advanced chronic liver disease show varying degrees of portal hypertension (PH) and splanchnic vasodilatation, which are often associated with a hyperdynamic circulatory state. The hyperdynamic syndrome (HS) is a consequence of cirrhosis of varying etiologies [1], [2]. This syndrome has been defined by high cardiac output, increased heart rate and total blood volume, reduced total systemic vascular resistance, and low, normal or decreased arterial pressure [1], [2], [3]. In this review, we will attempt to describe and explain the pathophysiological and clinical manifestations related to HS.
Among all hemodymanic alterations typical of advanced phases of cirrhosis, vasodilatation is the first of vascular changes that finally lead to multi-organ involvement. However, the mechanisms of vasodilation are still not entirely understood [2].
Development of PH due to architectural changes typical of cirrhosis plays a fundamental role in the genesis of HS. In fact, PH consists of an increase in portal pressure gradient (HVPG), defined by the difference between the portal vein and the inferior vena cava pressures [4]. It is caused by an increased resistance to portal outflow and inflow, with an abnormal distribution of the blood volume, which increases mostly in the splanchnic district. This alteration of blood volume distribution with underfilling of arterial circulation triggers baroreceptor activation to release vasoconstrictor factors to restore integrity of the circulation [5]. Usually, the HVPG ranges from 1 to 5 mmHg, becoming clinically significant when it reaches 10 mmHg [6]. In clinical practice, an increase in HPVG values of at least 12 mmHg is usually associated with the presence of esophageal varices [2], [6]. Progressing through the stages of cirrhosis, there is a wide development of a network of collateral vessels, which bypassing the liver, creates communication between the portal vein and the systemic circulation. The main collateral network is the gastro-epiploic system, responsible for the formation of gastro-esophageal varices, which together with the reduction in circulating platelets and hypersplenism are the clinical hallmark of PH [5], [6], [7].
Splanchnic circulation is responsible for the reduction of vascular resistance in the portal hypertensive state. The increase in splanchnic blood flow is related to: 1.) an increase in vasodilatator factors (nitric oxide (NO), prostacyclines, carbon monoxide (CO), endo-cannabinoides); 2.) reduced response to vasoconstrictor factors; and 3.) mesenteric neoangiogenesis [8], [9], [10], [11]. The increase in NO, maintained in pre-sinusoidal areas, is due to endothelial nitric oxide synthase activation by pro-inflammatory cytokines released by bacterial translocation and shear stress. Moreover, the splanchnic vasodilatation is caused by reduced response to vasoconstrictor factors, which, instead, are increased in other organs, such as the kidney and brain. The reduced response to local vasoconstrictors is likely related to increased levels of vasodilatator factors (NO, CO), and functional alterations of smooth muscular and endothelial cells.
At early compensated stages of cirrhosis, hyperdynamic circulation is not clinically manifest, but becomes more evident during the evolution of the disease. Any modification in peripheral resistance is rapidly compensated by variations in cardiac output. Though the reduction in peripheral resistance is slow, compensatory mechanisms play a pivotal role in maintaining and further worsening the hyperdynamic circulation (Fig. 1) [12], [13], [14], [15], [16]. Plasma volume expansion is relevant in these cirrhotic patients, even if distribution between the central and peripheral vascular areas is often not balanced [6], [17]. The splanchnic vasodilation in cirrhosis precedes the increase in cardiac output and heart rate [18]. However, when the splanchnic vasodilatation becomes more pronounced, the hyperdynamic circulation may no longer be sufficient for correcting hypovolemia [12], [17] (Fig. 2). Central arterial blood volume (heart, lungs, and central arterial tree blood volume) is more often decreased, while the non-central blood volume (splanchnic) is usually increased in cirrhotics.
Section snippets
Clinical manifestations
The first described clinical signs of the HS were arterial hypotension, wide pulse pressure, tachycardia, warm extremities and palmar erythema. Splanchnic vasodilatation is the first pathophysiological stage of clinical complications of cirrhosis, while PH and its sequelae are a cause of admission to the hospital, worsening of clinical conditions, and death. In fact, esophageal or gastric variceal bleeding, ascites with consequent spontaneous bacterial peritonitis (SBP), hepatic encephalopathy
Conclusions
The HS is a complex of hemodynamic alterations involving patients with cirrhosis and PH. The pathophysiological mechanisms that characterize the HS are complex and only partially known.
Multi-organ involvement is crucial, and is characterized by a set of more or less explored complications of cirrhosis. Clinical manifestations of PH such as ascites, esophageal varices, and HRS have been described in numerous studies, while the HPS and CC remain among the least explored and understood
Learning points
- •
In clinical practice, portal hypertension has been defined as an increase in the hepatic venous pressure gradient (HPVG), and PPG values of at least 12 mmHg are usually associated with the presence of esophageal varices.
- •
Arteriolar vasodilatation, low systemic vascular resistance, expanded blood volume, and raised sympathetic nervous activity contribute to increased cardiac output, and to configuring the hemodynamic changes typical of hyperdynamic circulation.
- •
Esophageal varices are present in
Conflict of interest
None.
References (86)
- et al.
Pathophysiology, complications, and treatment of ascites
Clin Liver Dis
(1997) - et al.
Functional aspects on the pathophysiology of portal hypertension in cirrhosis
J Hepatol
(2012) - et al.
Angiogenesis in liver disease
J Hepatol
(2009) - et al.
Effects of prostaglandin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver
Gastroenterology
(1985) - et al.
Effect of volume expansion on systemic hemodynamics and central and arterial blood volume in cirrhosis
Gastroenterology
(1995) - et al.
Role of NPY for vasoregulation in the splanchnic circulation during portal hypertension
Peptides
(2007) - et al.
Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression
Hepatology
(2002) - et al.
Down-regulation of genes related to the adrenergic system may contribute to splanchnic vasodilation in rat portal hypertension
J Hepatol
(2008) - et al.
Plasma volume expansion by albumin in cirrhosis. Relation to blood volume distribution, arterial compliance and severity of disease
J Hepatol
(2003) Water and sodium retention in edematous disorders: role of vasopressin and aldosterone
Am J Med
(2006)