Hepatorenal syndrome—Is it central hypovolemia, a cardiac disease, or part of gradually developing multiorgan dysfunction?

Authors


  • See Article on Page 439

  • Conflict of interest: Nothing to report.

Hepatorenal syndrome (HRS) is one of the most serious complications of cirrhosis and is usually observed at the late stage of the disease. A distinction is made between type I HRS and type II HRS according to the progression of the disease. Type I HRS is associated with rapidly progressing renal failure, defined as a two-fold increase in serum creatinine and achievement of a serum level >2.5 mg/dL within 2 weeks, while type II HRS is associated with gradual deterioration of renal function.1 Although the impairment of renal function is, in principle, a reversible phenomenon, the prognosis of the disease after the appearance of HRS is generally poor. Recent pathophysiological findings have led to more effective treatments. However, several pathogenic aspects of HRS are still unclear.

Abbreviations

HRS, hepatorenal syndrome; RAAS, renin-angiotensin-aldosterone system; HVPG, hepatic venous pressure gradient; NE, noradrenaline concentrations; CO, cardiac output; SV, stroke volume; LVSW, left-ventricular stroke work; MAP, mean arterial pressure; PCWP, left ventricular filling pressure.

The primary mechanism responsible for deterioration of renal function is renal hypoperfusion.2 Several explanations have been proposed. A hepatorenal reflex that is activated by an increase in hepatic sinusoidal pressure or a reduction in sinusoidal blood flow is a putative event leading to a decrease in renal blood flow.3, 4 Hypoperfusion is also attributed to enhancement of sympathetic activity and activation of the renin-angiotensin-aldosterone system (RAAS) secondary to activation of baroreceptors, triggered by a reduction in effective blood volume.5 The latter phenomenon occurs despite an increase in the total blood volume and is due to increasing vasodilatation in the splanchnic region, followed by re-distribution of the volume of blood in this region. In HRS urinary excretion of prostaglandins is decreased compared with patients with ascites, which may result from a decreased renal production of PGE2 and 6 oxo PGF.6 However, all these mechanisms are present even at a stage of moderately restricted renal function and are associated with marked renal water and sodium re-absorption, yet with only mild restriction of the glomerular filtration rate.

The nature of subsequent systemic hemodynamic changes associated with impaired renal blood flow and the development of the hepatorenal syndrome are poorly understood. In the current issue of HEPATOLOGY, Ruiz-del-Arbol et al.7 examine the systemic and hepatic circulation and the activity of various endogenous vasoactive systems in a group of 65 patients with cirrhosis and ascites. Twenty-seven of the patients developed HRS (12 patients had type I HRS and 15 patients had type II HRS). After the development of hepatorenal syndrome, the patients underwent repeated hemodynamic and hormonal examinations. Those who developed HRS had a significantly higher hepatic venous pressure gradient (HVPG) and greater activity of RAAS, as well as noradrenaline concentrations (NE) compared with those who did not develop HRS in the follow-up period. In HRS patients these changes were associated with significantly reduced sodium excretion and elevated serum creatinine levels. These findings are indicative of an advanced stage of hepatic decompensation in these subjects. In addition, patients who subsequently developed HRS had, at their first measurement, significantly lower cardiac output (CO), stroke volume (SV), left-ventricular stroke work (LVSW), and mean arterial pressure (MAP), while their left ventricular filling pressure (PCWP) was generally in the lower normal range. After developing HRS the patients experienced a further increase in the activity of vasoconstrictor hormones, HVPG, and a further deterioration of their hemodynamics with a fall in CO, MAP, SV, and LVSW while their heart rate and PCWP remained unchanged. There was no noticeable further decrease in systemic vascular resistance in patients developing HRS.

Was HRS caused by cardiac failure? Impaired cardiac function has long been known to exist in the presence of cirrhosis. In patients with cirrhosis, diastolic dysfunction and thickening of the wall of the left ventricle were observed in several investigations; these changes were reversed after transplantation. Diastolic dysfunction was more pronounced in the presence of ascites and worsened under strain. Abnormal systolic reaction of the left ventricle was also observed under strain. It is speculated that this occurs because neurohumoral hyperactivity leads to growth of the myocardium, resulting in fibrosis and disturbed relaxation.8, 9 Potential functional disorders of the right ventricle have not been investigated thus far. Central hypovolemia, among several phenomena, plays an important role particularly in patients with HRS. Hence, changes in right-ventricular function could be of importance.

Ruiz-del-Arbol et al. observed noteworthy differences between patients who developed type I HRS and those who developed type II HRS. While those with type I HRS experienced a significant fall in MAP, PCWP, CO, and LVSW; a significant increase in vasoconstrictor hormones; and a decreased hepatic blow flow, those with type II HRS exhibited a significant reduction in MAP as a hemodynamic feature. Vasoconstrictor hormones were also significantly increased, while a significant drop in hepatic perfusion was noted. The fact that heart rate did not react to the drop in MAP is worthy of mention.

These results corroborate the findings of earlier investigations of progressive vasodilatation that leads to a compensatory increase in vasoconstrictor hormones.2 Initially this causes blood pressure to remain in the normal range. However, as the disease progresses these compensatory mechanisms lead to prominent vasoconstriction, reducing renal blood flow. Additionally, myocardial function is impaired. Potential causes of this dysfunction include diminished myocardial β-adrenergic receptor signal transduction function as well as the hyperdynamic circulatory state.10 Heart failure appears to be of secondary importance for slow progression of the disease and the development of type II HRS. However, for acute events, the presence of effective compensatory mechanisms is of crucial importance in all patients, particularly in those with cirrhosis. Compensatory mechanisms, such as activation of vasoconstrictor hormones, can be enhanced only to a limited extent. In the presence of restricted function, the ejection performance of the heart also cannot be adequately enhanced. Such impairment of ejection performance is also recognized in other diseases associated with hyperdynamic circulation. For instance, mortality was significantly increased in patients with sepsis and an inadequate increase in CO.11 However, this may as well result from accentuation of arterial hypovolemia. The drop in CO registered by Ruiz-del-Arbol et al. in patients who developed HRS indicates that hypovolemia was an important reason for the fall in CO. Hypovolemia in this setting may be caused by infection,12 hemorrhage, or even by medication such as diuretics.13 Additionally, infection worsens the systolic function of the heart.14

Ruiz-del-Arbol's hemodynamic investigations add a further element to the HRS puzzle.

  • Type II HRS is a renal dysfunction that arises from the deterioration of several organ systems and is primarily caused by liver failure and portal hypertension. It is part of a gradually developing multiorgan dysfunction, with each organ failure affecting the function of others, although central hypovolemia and cardiac dysfunction are the main pathogenic triggers. In principle, this phenomenon can be reversed only if the causal factor is controlled. Currently, the only therapeutic approach is to control portal vein pressure or vasodilatation in the splanchnic region through vasopressor substances or portosystemic shunts.15 Liver assist devices might exert an effect by improving hepatic function.16

  • Type I HRS is triggered by an acute event in a patient whose circulation is able to ensure adequate blood supply to the organs only through activation of compensatory mechanisms. An imbalance between the severity of the causal factor and the effectiveness of compensatory mechanisms (hormonal, cardiocirculatory) leads to renal failure. Early application of adequate therapeutic measures may be able to balance this deficit in the body's compensatory mechanisms. For instance, in patients with spontaneous bacterial peritonitis the administration of albumin balanced hypovolemia and improved the prognosis of the disease.17 However, as Ruiz-del-Arbol et al.'s study shows, hypovolemia is possibly a very important hemodynamic change. Yet it is not the only one. Therapeutic measures for early prevention of HRS should consist of a combination of volume therapy, vasopressor measures, and, perhaps, positive inotropic measures, as is commonly applied in the early phase of patients with severe sepsis and septic shock.18 Further studies are needed to define specific therapeutic goals that will assist in targeted application of the different therapies.

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