Progress in treatment of massive ascites and hepatorenal syndrome

Abstract

Massive ascites and hepatorenal syndrome (HRS) are frequent complications of liver cirrhosis. Thus, effective therapy is of great clinical importance. This concise review provides an update of recent advances and new developments. Therapeutic paracentesis can be safely performed even in patients with severe coagulopathy. Selected patients with a refractory or recurrent ascites are good candidates for non-surgical portosystemic shunts (TIPS) and may have a survival benefit and improvement of quality of life. Novel pharmaceutical agents mobilizing free water (aquaretics) are currently under test for the therapeutic potential in patients with ascites.

Prophylaxis of hepatorenal syndrome in patients with spontaneous bacterial peritonitis is recommended and should be considered in patients with alcoholic hepatitis. Liver transplantation is the best therapeutic option with long-term survival benefit for patients with HRS. To bridge the time until transplantation, TIPS or Terlipressin and albumin are good options. Albumin dialysis can not be recommended outside prospective trials.

Key Words: Albumin dialysis, Aquaretics, Free water clearance, Liver cirrhosis, Liver transplantation, Paracentesis, Pathophysiology, Portosystemic shunt, Spontaneous bacterial peritonitis, Terlipressin

INTRODUCTION

Haemodynamic alterations and activation of neurohumoral systems are essential in the pathophysiology of ascites formation[1,2]. The most common circulatory alterations in patients with cirrhosis of the liver are portal hypertension and peripheral arterial vasodilatation which results in a decrease of centrally effective blood volume. As a consequence, neurohumoral systems are activated in an attempt to maintain intravascular volume (Figure 1). Among those, activation of the renin-angiotensin-aldosterone system, the sympathetic nervous system and the non-osmotic release of arginin-vasopressin play the major role. These neurohumoral systems induce renal sodium and water retention leading to the formation of ascites. The most severe form with renal vasoconstriction and a decrease of renal blood flow leads to hepatorenal syndrome. Recently, it has been suggested that a decrease in cardiac output may contribute to HRS[3].

Figure 1 Pathogenesis of ascites formation and hepatorenal syndrome in patients with cirrhosis.

Novel therapeutic strategies for ascites and hepatorenal syndrome thus focus to counteract the initial changes of this pathophysiological cascade: controlled reduction of portal hypertension and/or peripheral vasoconstriction combined with plasma expanders.

TREATMENT OF MASSIVE ASCITES

In order to achieve fast relief, patients with massive ascites undergo therapeutic paracentesis[4]. Apart from the risk of infection which can easily be prevented, major concerns have been raised regarding the risk of bleeding and haemodynamic instability. It has been shown that large volume paracentesis can be safely performed even in patients with severely impaired coagulation parameters[5,6]. In a study investigating more than 500 patients with cirrhosis of the liver， an average paracentesis of 9 g/L was performed[5]. Although the majority of patients exhibited less than 50 × 10⁹/L platelets and more than a quarter had severely prolonged prothrombin time, no case had severe complication or bleeding.

Following large volume paracentesis rapid re-formation of ascites may effectively reduce central blood volume and compromise systemic haemodynamic and renal function. To prevent intravenous administration of plasma expanders, a paracentesis has been established[2,7]. For large volume paracentesis (more than 6 L) 20% human albumin in a concentration of at least 6 g per liter ascites seems to be the safest strategy. Recent work demonstrated that the incidence of paracentesis-induced circulatory disfunction following paracentesis of less than 6 L is only 7% with albumin or saline as plasma expanders with almost no clinical complications[8]. Thus, it may be safe and cost-effective to perform paracentesis of up to 6 L without albumin.

REFRACTORY AND RECURRENT ASCITES

Refractory and recurrent ascites have been defined according to a consensus conference of the International Ascites Club[9] (Table 1). Repeated large volume paracentesis in addition to diuretic treatment is the standard treatment for these patients. Reduction of portal hypertension with non-surgical shunts (transjugular intrahepatic portosystemic shunt = TIPS) has the potential to markedly increase renal sodium excretion[10]. This has prompted several prospective randomized controlled trials comparing repeated paracentesis with insertion of a TIPS (Table 2). The unequivocal result of all four trials[11-14] has a highly significant advantage in the control of ascites by TIPS. Regarding survival, two trials have shown a significant advantage. Possibly, inclusion of patients with more severely impaired liver function and a bilirubin above 5mg/100mL at inclusion may be responsible for the lack of survival benefit following TIPS[15] (Table 3). Encephalopathy following TIPS should be avoided as the major obstacle for improvement of quality of life as compared to paracentesis patients[13]. Thus, careful selection of patients and management in experienced centers are the prerequisite for a TIPS benefit. Patients with ascites resolution following TIPS insertion enjoy a markedly improved quality of life[16].

Table 1 Definition of refractory and recurrent ascites according to the consensus of the International Ascites Club[9].

Refractory ascites	cannot be mobilized by diuretics because of a lack of response (mean weight loss less than 200g/d during the last 4 d) or the development of diuretic-induced complications such as hyponatremia, hypokalemia, renal impairment, hepatic encephalopathy, precluding an effective diuretic dosage
Recidivant ascites	recurs at least on 3 occasions within 1 year despite prescription of dietary sodium restriction and adequate diuretic dosage

Table 2 Important features of large prospective trials[11-14] comparing TIPS with paracentesis for massive ascites.

	Rossle[11]	Gines[12]	Sanyal[13]	Salerno[14]
Patients/selected from pts.	60/155	70/119	109/525	66/137
Complete response (%)	79 vs 24	51 vs 17	58 vs 16	61 vs 3
Survival benefit of TIPS	yes	no	trend	yes
Number of centers	2	≥5	6	3
Child-Pugh C (%)	38	37	?	76
Athyltox. Zirrhose (%)	79	51	62	42
Severe encephalop. (%)	23 vs 13	60 vs 34	29 vs 18	61 vs 39
Mean TIPS Ø (mm)	9	8→10	10	?

Table 3 Serum bilirubin concentration at study inclusion and during follow-up (μmol/L, mean±SD).

	Rossle[11]	Gines [12]	Sanyal [13]	Salerno [14]
Cut-off for study inclusion	5	10	5	6
Baseline	1.7 ± 0.2	2.0 ± 0.2	1.9 ± 0.2	1.6 ± 0.1
Follow-up(mo)	2.9 ± 0.9	4.6 ± 2.0	2.2 ± 2.1	2.1 ± 0.2

AQUARETICS

Vasopressin-V2-receptor antagonists mobilize free water and thus might be an excellent alternative or adjunct to diuretic treatment. The efficacy and safety of these new compounds in patients with cirrhosis have recently been demonstrated[17,18]. In these patients, urine volume increased and urine osmolarity dose-dependently decreased, thus demonstrating an increase of free water clearance. Moreover, while patients in the placebo group gained weight, body weight was stable with a lower dose and clearly decreased with a higher dose of the V2-receptor antagonist. This promising new pharmaceutical concept is currently under investigation in international phase II/III trials.

HEPATORENAL SYNDROME

According to established criteria, hepatorenal syndrome can be classified into type 1 and type 2[9] (Table 4). Rapid progressive type 1 exhibits a very poor prognosis with a 3-month mortality rate of above 90%[19]. Thus, prophylaxis of HRS is an important task and effective treatment is a highly desirable goal.

Table 4 Definition of hepatorenal syndrome according to the consensus of the International Ascites Club[9].

HRS Type 1: Rapidly progressing renal failure (< 2 wk) ≥ 2-fold increase of serum creatinine to > 221μmol/L or 50% decrease of creatinine clearance to < 20mL/min

HRS Type 2: Not rapidly progressing renal failure

Serum creatinine > 132.6 μmol/L or

Creatinine clearance < 40mL/min

Absence of shock, ongoing bacterial infection, current or recent treatment with nephrotoxic drugs, gastrointestinal or renal fluid loss

No sustained improvement upon withdrawal of diuretics and plasma volume expansion

Proteinuria < 0.5g/d, no abnormalities of renal ultrasound

PROPHYLAXIS OF HRS

In patients with severe alcoholic hepatitis, the TNF-α inhibitor pentoxyfillin significantly reduces the incidence of HRS, HRS-related and over-all mortality[20]. Spontaneous bacterial peritonitis is often followed by deterioration of renal function and even hepatorenal syndrome. Interestingly, a randomized prospective trial[21] showed that intravenous albumin administration (1.5g/kg per day on day one and 1g/kg per day on day three) together with antibiotic treatment with cefotaxim is clearly superior to antibiotic treatment alone because renal failure and moreover mortality were significantly reduced in hospital and during a 3-month follow-up period.

TREATMENT OF HEPATORENAL SYNDROME TYPE 1

Following liver transplantation, patients with HRS may reach 5-year survival probability of 60%[22]. While this is a tremendous improvement compared to the spontaneous prognosis, survival rates are significantly lower than those in patients undergoing liver transplantation with normal renal function. Moreover, in many Western countries, waiting lists for liver transplantation are steadily growing, thus increasing the need to bridge severely sick patients to transplantation. Therapeutic concepts are needed to normalize renal function in patients with hepatorenal syndrome type 1. As stated in the introduction, very early interventions in the pathomechanistic cascade would seem more promising.

Indeed, controlled reduction of portal hypertension with TIPS seems to be rather effective. In an uncontrolled trial, the average mean survival time was around 4 mo in 14 out of 23 patients with HRS type 1 who received TIPS[23]. Nine of the 23 patients, however, were at high risk for liver failure and therefore did not receive TIPS. For these severely ill patients, strategies should be used to counteract peripheral vasodilatation combined with volume expansion.

Several studies suggest that vasopressin analogues combined with albumin may be suitable to reverse hepatorenal syndrome[24-26]. Terlipressin (average daily dose of 3 mg) could be a valuable option for patients with HRS type 1 and very poor liver function to bridge the time to transplantation if combined with plasma expanders[27]. In this retrospective analysis best results with terlipressin were seen in patients with Child-Pugh score below 12 points, receiving at least 3 mg per day. However, only one randomized controlled trial on terlipressin has shown improvement of renal function in patients with HRS type 1 compared to no response in the placebo group[28]. No survival data are provided.

In numerous uncontrolled observations extracorporeal albumin dialysis (MARS) has been suggested as a beneficial therapy for patients with acute-on-chronic liver failure. There are only two randomized trials investigating the effects of MARS, comprising a total of 23 patients with hepatorenal syndrome[29,30]. No 30-d survival benefit has been demonstrated, disqualifying this procedure for the use outside of controlled trials[30].

ACKNOWLEDGEMENTS

The assistance of Anne Esmark in preparing and editing the manuscript is greatly appreciated.