Ascites is the accumulation of fluid in the abdominal cavity beyond the normal physiological range (200 ml) and is one of the most common complications of cirrhosis. The appearance of ascites signals the entry of cirrhosis into the decompensated phase, suggesting a poor prognosis and affecting the patient’s quality of life. About 50% of patients with compensated cirrhosis will develop ascites within 10 years, and about 44% of patients with ascites will die within 5 years. Timely and standardized treatment can effectively improve the survival rate of patients. In recent years, there have been many new experiences in the control and treatment of ascites at home and abroad that have been proven effective.
1.Treatment classification
The 2012 American Association for the Study of Liver Diseases (AASLD) guidelines for ascites in cirrhosis recommend classifying ascites treatment into three lines of treatment, emphasizing etiologic treatment and control of lifestyle, while recommending caution in the use of NSAIDs, drugs acting on the renin-angiotensin-aldosterone system (RAAS) and semi-blockers in patients with ascites.
2.First-line treatment
Etiological treatment
For patients with cirrhotic ascites, it is important to treat and control the primary disease. Effective antiviral therapy for decompensated hepatitis B cirrhosis can still restore liver function and improve survival to some extent. Abstinence from alcohol is key to help control liver damage in patients with alcoholic cirrhosis, and early abstinence from alcohol can reverse portal hypertension and sodium retention. Baclofen can be effective in helping patients with alcoholic cirrhosis prolong their abstinence from alcohol.
The sodium restriction debate
Patients with cirrhotic ascites have varying degrees of water and sodium metabolism disorders, and an increase in sodium can lead to water retention, which can worsen ascites. A sodium-restricted diet can accelerate the regression of ascites and is therefore one of the routine therapeutic measures for patients with ascites. The latest guidelines and consensus also agree that sodium intake should be restricted (80-120 mmol/d).
However, excessive sodium restriction is detrimental to the nutritional status, and patients with combined hyponatremia have reduced sensitivity to diuretics and are at risk for hepatic encephalopathy. It has been suggested that the use of diuretics without sodium restriction will improve renal perfusion and improve hyponatremia, which is beneficial for diuresis and ascites reduction. Similar conclusions have been made in national studies, but high-quality evidence is still lacking to clarify the relationship between whether or not sodium restriction is associated with a survival benefit for patients.
Nutritional support
Patients with end-stage liver disease are often in poor nutritional status, and sodium restriction may affect the intake of energy-supplying substances and lead to anabolic deficiencies, and nutritional status is considered an important factor in the prognosis of patients with end-stage liver disease, making additional nutritional supplementation necessary for patients with ascites. A meta-analysis that included 37 trials showed that oral supplementation with nutrients reduced the incidence of ascites in patients with cirrhosis. In patients after massive laparotomy fluid release (LVP), parenteral nutrition is more effective than oral nutrition in reducing morbidity and mortality.
Diuretic measures
Sodium retention in patients with cirrhotic ascites is mainly due to increased proximal and distal renal tubular sodium reabsorption rather than decreased sodium filtration, making aldosterone antagonists more effective than tab diuretics in the treatment of ascites. The International Club of Ascites guidelines recommend spironolactone as the first choice, with furosemide and others as adjunctive therapy. It has been suggested that spironolactone alone is safe and convenient in the treatment of outpatients with moderate amounts of ascites.
The AASLD guidelines for ascites recommend spironolactone in combination with furosemide, whereas the European Association of Liver Diseases (EASL) guidelines recommend the combination of these two drugs only for refractory ascites.
Even with sodium restriction and the above diuretics, diuretic resistance still occurs in 20-30% of patients, and there is a risk of side effects such as renal insufficiency with the application of both diuretics. Furosemide may lead to hypokalemia, hypochloremic alkalosis and hyponatremia as well as a potential risk of hypovolemia; there is a side effect of gynecomastia with long-term use of spironolactone.
In some patients with diuretic-resistant ascites, intravenous mannitol has been reported to initially mobilize ascites, but the long-term benefit is unknown. abecasis R et al confirmed the effectiveness of torasemide in the treatment of ascites. It has been found that better outcomes are obtained after replacing tachyphylaxis with torasemide. Amiloride and bumetanide are also used in the treatment of ascites, but they are expensive and can be applied as an alternative treatment option if necessary.
3. Management of massive ascites
laparotomy fluid release
Laparotomy with massive release of fluid for the treatment of tension ascites has been widely accepted because the treatment is safe and effective, has a low complication rate, and can effectively reduce the morbidity and mortality rate of patients hospitalized with ascites. However, massive release of ascites can cause a series of serious complications such as acute and severe blood volume drop, hepatic encephalopathy, renal failure and electrolyte disorders, and ascites can quickly reaccumulate after surgery. Therefore, it is necessary to perform colloid expansion after fluid release surgery. Massive release of ascites combined with intravenous infusion of albumin is a rapid, safe and effective method for the treatment of tension ascites in cirrhosis.
Colloid replacement
The efficacy of albumin in expanding blood volume and restoring plasma colloid osmotic pressure has been well established and may prevent the development of renal failure and circulatory dysfunction after LVP. the EASL guidelines affirm the use of albumin in the treatment and prevention of complications, but because of its expensive price, the AASLD considers that its use in primary ascites requires further analysis.
Human recombinant albumin is functionally and structurally similar to human albumin and has received attention due to its higher purity and safety. The possible efficacy of human recombinant albumin in cirrhotic ascites was identified in animal studies as early as 1998 by Satoshi H et al. In a prospective analysis, Nakamura T et al found a significant reduction in serum renin mass concentrations in patients following the use of human recombinant albumin.
In Kasahara A’s trial, human showed good tolerance to recombinant albumin, and patients had a significant increase in plasma albumin mass concentration and decrease in body mass after treatment. Therefore, human recombinant albumin is expected to replace human blood albumin in the treatment of patients with cirrhotic ascites.
For other bulking agents such as dextran, there is no evidence yet that their bulking effect is superior to that of albumin, especially for patients with massive ascites.
4. Intractable ascites
The definition of intractable ascites has been largely agreed upon: i.e., 1, insensitivity to dietary sodium restriction and high-dose (spironolactone 400 mg/d and furosemide 160 mg/d) diuretic therapy; 2, rapid recurrence of ascites after therapeutic laparotomy and occurrence of significant diuretic-related side effects. Persistent ascites may require the addition of the following measures to first-line therapy.
Protans Vaptans
Vaptans are non-peptide vasopressin receptor antagonists, classified as non-selective antagonists, VI receptor antagonists and V2 receptor antagonists, which promote water excretion but do not affect electrolyte excretion for the treatment of hyponatremia and promote the regression of ascites. A meta-analysis of 12 trials with 2266 patients showed that proguanil (including tolvaptan, satavaptan, and lixivaptan) elevated serum sodium levels, reduced body mass, and decreased the frequency of puncture fluid release, but did not differ significantly from controls in terms of morbidity and mortality, incidence of hepatic encephalopathy, incidence of SBP, and increased adverse effects and therefore does not support routine use in patients with cirrhosis.
Tolvaptan
Okita K et al found that tolvaptan dose-dependently reduced body mass and abdominal girth, improved ascites and edema, and showed a strong pro-drainage effect. 7.5 mg/d is a safe and tolerable dose with good efficacy. In a multicenter randomized controlled double-blind trial, Sakaida I concluded that in the treatment of hepatic edema and ascites, the addition of tolvaptan to diuretics was effective, and therefore this may be a new option for the treatment of patients with ascites with hyponatremia.
Satavaptan
After short-term treatment with satavaptan, patients with ascites have a significant reduction in body mass and relapse can be reduced with small doses, but there are adverse effects such as elevated blood creatinine. Hyponatremia is associated with a risk of hepatic encephalopathy, but a randomized, double-blind trial by Watson H that included 1200 patients found that satavaptan did not reduce the incidence of hepatic encephalopathy. He also found that in a trial with LVP as an endpoint, the rate of death was higher in patients using sartaputan. Therefore, sartaputan may not be beneficial for the long-term management of cirrhosis. In addition, due to the high morbidity and mortality rate that can be caused by sartaputan, it was requested to terminate the study early and was not approved by FDA.
5. Other measures
Transjugular intrahepatic portosystemic stent shunt (TIPS)
TIPS reduces portal vein pressure and has been shown to be effective in controlling ascites recurrence. In the short term TIPS can increase cardiac output, right atrial pressure and pulmonary artery pressure, causing a decrease in systemic vascular resistance and effective arterial blood volume.
Several meta-analyses have evaluated the efficacy of TIPS versus LVP and found that it effectively controlled ascites, delayed the time to ascites recurrence, and improved the quality of patient survival, but did not contribute to the improvement in morbidity and mortality, and, moreover, it can cause hepatic encephalopathy which needs to be given adequate attention.
Peritoneal shunt and reflux
For patients with refractory ascites who are not responding to usual treatment and who relapse soon after LVP, abdominal venous shunts offer an option. In addition to the direct return of ascites, ultrafiltration of concentrated return reduces the incidence of associated complications. Compared with concentrated return of ascites to the vein, return of abdominal can remove large amounts of ascites in a short period of time without changing blood pressure or central venous pressure, and it reduces hepatic venous wedge pressure in patients with cirrhosis, avoiding possible upper gastrointestinal bleeding and pulmonary edema. However, all of the above methods have their own drawbacks, the device needs further improvement, and there is a lack of evidence for clinical extension of use.
Liver transplantation
In March 2014 the AASLD and the American Society for Transplantation Research (ATS) jointly published the Guidelines for the Evaluation of Adult Liver Transplantation, stating that liver transplantation evaluation should be considered in patients with cirrhosis once complications such as ascites have developed. For patients who fail conventional drug therapy, 21% will die within 6 months. Since most chronic liver diseases are rarely reversible, at the time of ascites, patients are best referred for liver transplant evaluation rather than prolonged pharmacological treatment. However, long waits and high costs in the list have kept many ascites patients from liver transplantation.
In conclusion, standardized treatment can bring improvement in the quality of survival of patients with cirrhotic ascites. For different patients with cirrhotic ascites, in addition to conventional treatment, personalized treatment strategies should be developed, which can reduce patient suffering, prolong survival time and reduce other complications to some extent.