Current management of refractory ascites in patients with cirrhosis

Introduction

Ascites is one of the most common complications of cirrhosis, along with hepatic encephalopathy (HE), hepatorenal syndrome, and upper gastrointestinal bleeding. Development of ascites is associated with an impaired health-related quality of life and poor prognosis. ¹ Approximately 60% of patients with cirrhosis will develop ascites within 10 years after diagnosis of this disease. ² Refractory ascites, which develops in 5%–10% of all patients with cirrhotic ascites, has a high mortality rate. ³ The mean 1-year survival rate of refractory ascites is approximately 50%.^2,4 Ascites can be treated by large-volume paracentesis (LVP), transjugular intrahepatic portosystemic shunt (TIPS), vasoconstrictive drugs, and an automated low-flow ascites pump (ALFApump; Sequana Medical AG, Zurich, Switzerland) system, but liver transplantation is the most effective treatment modality. However, liver transplantation is costly and the number of donors is limited. Moreover, some patients with refractory ascites have contraindications to liver transplantation. This article focusses on current non-transplant treatments for refractory ascites.

Diagnosis and definition

Approximately 75% of ascites cases are due to liver cirrhosis, and other causes include malignancy, cardiac failure, tuberculosis, and pancreatitis. ⁵ Ascitic fluid is tested to determine the cause of ascites. Ascites is divided into exudates and transudates to facilitate determination of the cause. The serum–ascites albumin gradient (concentration of serum albumin minus that of ascites albumin) is a precise means of detecting ascites. Portal hypertension is associated with a serum–ascites albumin gradient ≥11 g/L and inflammation with a gradient of ≤11 g/L. ⁶

In 1996, the International Ascites Club divided patients with refractory ascites into two subgroups: patients who did not respond to maximum doses of diuretics (diuretic-resistant ascites) and those who developed complications related to diuretic therapy that preclude using an effective dose of diuretic (diuretic-intractable ascites).^7,8 The following criteria for diagnosing refractory ascites were proposed in 2003 ⁹ : 1) treatment duration, intensive diuretic therapy (spironolactone [400 mg/day] and furosemide [160 mg/day]) for at least 1 week with a salt-restricted diet (<5.2 g of salt/day); 2) lack of response, mean weight loss of <0.8 kg over 4 days and a urinary sodium output less than the sodium intake; 3) early recurrence of ascites, reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization; and 4) diuretic-induced complications, diuretic-induced hepatic encephalopathy (defined as development of encephalopathy without any other precipitating factor). Diuretic-induced renal impairment is defined as an increase in the serum creatinine level of >100% to a value > 2 mg/dL in patients with treatment-responsive ascites. Diuretic-induced hyponatremia is defined as a decrease in the serum sodium level of >10 mmol/L or a serum sodium level of <125 mmol/L. Diuretic-induced hypokalaemia or hyperkalaemia is defined as a change in serum potassium to <3 mmol/L or >6 mmol/L, despite appropriate measures. ⁹

Pathophysiology

Portal flow in refractory ascites is constricted because of the presence of cirrhosis and portal hypertension subsequently develops. The widely accepted hypothesis for refractory ascites is that the initial step that leads to ascites is portal hypertension following liver cirrhosis. This leads to an increased release of local vasodilators, such as nitric oxide, leading to vasodilation of splanchnic vessels. ¹⁰ In patients with advanced cirrhosis, splanchnic arterial vasodilation decreases the volume of arterial blood volume and makes maintaining blood pressure difficult. Circulatory dysfunction and neurohumoral activation are remarkable in these patients. ¹¹ For compensation of this situation, vasoconstrictors and antinatriuretic factors are activated (e.g., the renin–angiotensin–aldosterone system and sympathetic nervous system), resulting in sodium and water retention. ¹¹ Intestinal capillary pressure and permeability are affected by vessel vasodilation and portal hypertension, resulting in retained fluid in the abdominal cavity. Marked impairment in renal excretion of free water, renal vasoconstriction, and sodium reabsorption are factors that contribute to developing refractory ascites ¹²

Therapies

Vasoconstrictive drugs

Several oral drugs are available for treating refractory ascites. These drugs increase the systemic atrial volume by inducing vasoconstriction. Midodrine is an α1-adrenergic agonist that is used in cirrhotic patients with ascites. Midodrine increases the effective arterial blood volume by causing splanchnic vasoconstriction, and it improves renal perfusion and glomerular filtration. ³⁹ The American Association for the Study of Liver Diseases guidelines recommend midodrine for refractory ascites. ⁴⁰ Clonidine is an α2-adrenergic agonist with effects that are similar to those of midodrine, which theoretically reduces central sympathetic outflow and release of norepinephrine. Clonidine combined with standard medical treatment is effective for controlling ascites.^41,42 Large-scale clinical trials comparing the efficacy of midodrine and clonidine for controlling refractory ascites are required.

Vasopressin V2 receptor antagonists, also known as vaptans, competitively bind and block arginine vasopressin V2 receptors in renal collecting ducts. A meta-analysis showed that vasopressin V2 receptor antagonists were effective for patients with ascites, especially refractory ascites, and functioned by elevating serum sodium concentrations. ⁴³ The US Food and Drug Administration issued a warning for tolvaptan. This was issued because a potential risk of liver injury was identified during a clinical trial of tolvaptan to treat autosomal dominant polycystic kidney disease. ⁴⁴ Patients in this previous study who were treated with 120 mg/day of tolvaptan for 3 years showed significantly higher serum bilirubin and alanine aminotransferase levels. However, 120 mg/day of tolvaptan is considerably higher than the tolvaptan dose used to treat patients with cirrhosis. The typical treatment-emergent adverse event caused by vaptans is excessive correction of serum sodium concentrations (>145 mmol/L), which can lead to osmotic demyelination and myelinolysis. ⁴⁵ Therefore, serum sodium levels should be monitored in patients with ascites who are treated with vaptans.

Summary

Ascites can be treated using various modalities, the most effective of which is liver transplantation. Non-transplant modalities are frequently used for this condition because of the small number of donor livers available and the cost of transplantation. Moreover, a means of reducing the incidence of side effects of conventional treatments, including LVP and TIPS, should be investigated. ALFApumps show promise, but they must be evaluated in large-scale, randomized, controlled, multicentre studies.