Chinese guidelines on the management of ascites in cirrhosis

Editor's note：In 2023, the Chinese Society of Hepatology of the Chinese Medical Association updated the 2017 guidelines on managing ascites and associated complications in cirrhosis. These revised guidelines, now termed "Guidelines on the Management of Ascites in Cirrhosis," provide comprehensive recommendations for the diagnosis and treatment of cirrhotic ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS). This article summarizes these guidelines, emphasizing the importance of evidence-based practices and individualized patient care.

Overview

Ascites, the pathological accumulation of fluid in the peritoneal cavity, is a common and serious complication of decompensated cirrhosis. The presence of ascites marks a critical point in the progression of liver disease, with a 1-year mortality rate of approximately 20% and a 5-year mortality rate of about 44%. Managing ascites effectively is crucial in improving patient outcomes and quality of life.

Pathogenesis

The development of ascites in cirrhosis is multifactorial. Portal hypertension is the primary cause, leading to increased pressure in the portal vein and subsequent fluid leakage into the peritoneal cavity. Hypoproteinemia, imbalances in the renin-angiotensin-aldosterone system (RAAS), lymphatic obstruction, and bacterial translocation further contribute to ascites formation. Understanding these mechanisms is essential for effective diagnosis and treatment.

Diagnosis

Diagnosis of ascites involves a combination of clinical assessment and imaging studies. Patients may present with symptoms such as abdominal distension, oliguria, and lower limb edema. Physical examination often reveals abdominal distension and shifting dullness. Abdominal ultrasonography is the preferred imaging modality to confirm the presence of ascites, estimate fluid volume, and guide paracentesis. Additional imaging, such as CT or MRI, may be necessary in complex cases.

The Serum-Ascites Albumin Gradient (SAAG) is a critical diagnostic tool that differentiates ascites due to portal hypertension (SAAG ≥ 11 g/L) from other causes, such as malignancy or tuberculosis (SAAG < 11 g/L). This distinction guides the management approach.

Grading and Classification

Ascites is graded based on severity:

• Grade 1 (Mild): Detectable only by ultrasound, with no significant symptoms.
• Grade 2 (Moderate): Evident abdominal distension, often with discomfort.
• Grade 3 (Large): Marked abdominal distension, sometimes leading to respiratory distress or umbilical hernia.

Cirrhotic ascites is further categorized into uncomplicated, refractory, and recurrent ascites. Refractory ascites does not respond to sodium restriction and diuretics or recurs quickly after paracentesis. Recurrent ascites returns at least three times within a year despite optimal management.

Treatment

The management of ascites in cirrhosis involves a stepwise approach, prioritizing patient safety and efficacy.

First-line Treatment

1. Etiological Treatment: Addressing the underlying cause of cirrhosis is fundamental. This includes antiviral therapy for hepatitis B and C, cessation of alcohol consumption, and addressing metabolic or autoimmune liver diseases. Effective etiological treatment can slow the progression of cirrhosis and reduce the incidence of ascites.
2. Sodium Restriction: Limiting sodium intake to 4-6 g/day to reduce fluid retention.
3. Diuretics: Spironolactone (initially 40-80 mg/day, up to 400 mg/day) and furosemide (initially 20-40 mg/day, up to 160 mg/day) are commonly used. Spironolactone, an aldosterone antagonist, helps counteract the effects of RAAS activation, which is common in cirrhotic patients. Furosemide, a loop diuretic, increases sodium and water excretion. The combination of these two diuretics is often required to achieve optimal fluid balance. Monitoring for side effects such as hyperkalemia (with spironolactone) and hypokalemia (with furosemide) is essential.

Second-line Treatment

1. Vasoconstrictors: Terlipressin and midodrine help manage refractory ascites by reducing splanchnic vasodilation. Terlipressin, a vasopressin analog, reduces splanchnic vasodilation and improves renal perfusion. Midodrine, an alpha-agonist, increases vascular tone and blood pressure, aiding in the reduction of ascites.
2. Tolvaptan: Effective for patients with refractory or recurrent ascites, especially those with hyponatremia. Tolvaptan is a selective vasopressin V2 receptor antagonist that promotes free water excretion without significant sodium loss. Initial doses range from 7.5-15 mg/day, up to 60 mg/day. Tolvaptan can be used in combination with conventional diuretics to improve ascites control while minimizing the risk of worsening renal function.
3. Large-Volume Paracentesis: This procedure involves the removal of large volumes of ascitic fluid, which can provide rapid symptom relief. To prevent paracentesis-induced circulatory dysfunction (PICD), it is recommended to infuse human serum albumin during the procedure. Albumin helps maintain intravascular volume and reduces the risk of renal impairment. The guidelines suggest administering 6-8 grams of albumin per liter of ascites removed.

Third-line Treatment

1. Transjugular Intrahepatic Portosystemic Shunt (TIPS): TIPS is a procedure that creates a pathway between the portal and systemic circulation, reducing portal hypertension and thereby decreasing ascites production. It is particularly beneficial for patients with refractory or recurrent ascites who do not respond to medical therapy. TIPS can improve quality of life and reduce the need for repeated paracentesis.
2. Liver Transplantation: For patients with decompensated cirrhosis and refractory ascites, liver transplantation offers the best chance for long-term survival. Transplantation can completely resolve ascites and other complications of cirrhosis. Patients should be evaluated for transplantation early to ensure timely intervention.

Special Types of Ascites

• Chylous Ascites: This type of ascites is characterized by a milky appearance due to high triglyceride content. It often results from lymphatic obstruction or damage. Management includes dietary modifications, such as a low-fat diet with medium-chain triglycerides, and in some cases, TIPS or paracentesis.
• Hemorrhagic Ascites: This form of ascites presents with bloody fluid and is usually due to malignancy, severe infection, or peritoneal variceal bleeding. Diagnosis requires careful evaluation to rule out other causes. Management focuses on treating the underlying condition and stabilizing the patient.
• Hepatic Hydrothorax: Hepatic hydrothorax refers to the accumulation of pleural fluid in patients with cirrhosis. It is often right-sided and can lead to significant respiratory distress. Treatment includes diuretics, thoracentesis, and potentially TIPS.

Spontaneous Bacterial Peritonitis (SBP)

SBP is a common and severe infection in patients with cirrhosis, marked by the presence of bacterial infection in ascitic fluid without an apparent intra-abdominal source. Early diagnosis and treatment are crucial to prevent rapid progression to renal and liver failure.

Diagnosis and Treatment:

• Diagnosis: SBP is diagnosed by the presence of symptoms such as fever, abdominal pain, and elevated ascitic fluid PMN count. An ascitic fluid analysis showing PMN count ≥0.25 x 10⁹/L and positive bacterial cultures confirms the diagnosis. Early treatment with broad-spectrum antibiotics like cefotaxime is crucial. Adding albumin to the treatment regimen has been shown to improve survival by preventing renal failure.
• Empirical Antibiotics: Third-generation cephalosporins (e.g., cefotaxime) are preferred. A single broad-spectrum antibiotic can achieve a negative bacterial ascites culture in 86% of patients. Due to the high mortality rate in cirrhotic patients with SBP, paracentesis for laboratory tests of ascites within 12 hours should be conducted to guide early and rational use of antibiotics, which is significant for lowering the mortality of SBP. Hypoalbuminemia increases the clearance rate of drugs and reduces bound antimicrobial medications, which may lower the concentration of these drugs at the site of infection to below the minimum inhibitory concentration (MIC) and result in a lack of efficacy. To ensure that the concentration of unbound drug remains above the MIC, increasing the serum albumin levels and extending the duration of drug infusion can be considered to effectively improve the 30-day survival of patients with cirrhosis.
• Prevention: Primary prevention of SBP includes antibiotic prophylaxis during episodes of gastrointestinal bleeding. Secondary prevention involves long-term antibiotics for patients with a history of SBP to prevent recurrence. Prophylaxis with rifaximin could be beneficial for patients at high risk of SBP, including those with Child–Pugh Class C cirrhosis, diabetes, or malignancies, or low ascitic protein levels (concentration of total protein in ascites of <1.5 g/L).

Acute Kidney Injury (AKI) and Hepatorenal Syndrome (HRS)

Diagnosis:

• AKI in cirrhotic patients is diagnosed by an increase in serum creatinine (Scr) by ≥0.3 mg/dL within 48 hours or ≥50% from baseline within 7 days.
• HRS, a type of AKI, is characterized by renal failure without significant renal parenchymal damage. The diagnostic criteria include cirrhosis with ascites, no response to diuretics, and exclusion of other causes of renal failure.

Treatment:

• Usual Care: High-calorie diet, monitoring of renal function, and infection control. Fluid balance must be maintained to prevent fluid overload and dilutional hyponatremia. Active infection control is a priority.
• Vasoconstrictors: Terlipressin combined with albumin is the first-line treatment for HRS. Terlipressin acts as a vasoconstrictor and may improve hemodynamics in cirrhosis with ascites. It’s effective for patients with cirrhotic ascites with or without AKI. Norepinephrine and midodrine are alternatives. Midodrine can increase the 24-hour urine volume and sodium excretion in patients with refractory cirrhotic ascites. It is particularly effective in non-azotemic patients with cirrhotic ascites. Somatostatin analogs can also be used in combination as a substitute for terlipressin in patients with HRS-AKI. Norepinephrine administered at a dosage of 0.5–3 mg/h in combination with human serum albumin at 10–20 g/day for 7–14 days demonstrated similar effects as terlipressin for HRS. Tolvaptan selectively binds to non-peptide vasopressin receptors inhibiting the functionality of antidiuretic hormones without activating the sympathetic nervous system or the aldosterone system. This leads to a significant increase in urine volume and improvement of hyponatremia without renal function injury or increased risk of hepatic encephalopathy (HE), esophagogastric variceal bleeding (EVB), and HRS.
• TIPS and Liver Transplantation: TIPS improves the renal function of patients with HRS-AKI and HRS-NAKI. It effectively manages ascites and alleviates portal vein pressure, especially for patients with HRS-NAKI. Patients with cirrhotic ascites who develop HRS-AKI are often of severe conditions that they mostly have contraindications for TIPS. Liver transplantation is the preferred treatment for patients with HRS-AKI and HRS-NAKI.
• Blood Purification Therapy: Blood purification therapy can lead to an improvement in renal function in a subset of patients with HRS-AKI. It is principally used in patients with HRS accompanied by severe hyperkalemia, metabolic acidosis, or volume overload. Approximately 40% of patients undergoing blood purification therapy may experience a significant improvement in renal function.

Prevention

Preventive Strategies: Avoiding nephrotoxic drugs, managing infections promptly, and cautious use of diuretics are key strategies to prevent complications. Regular monitoring and individualized care are essential for long-term management. Second strikes such as bacterial infection, excessive use of diuretics, large-volume paracentesis, upper gastrointestinal bleeding, and cholestatic jaundice may induce HRS.

Key Recommendations:

1. Regular Monitoring: Early detection of complications through regular monitoring of renal function, electrolytes, and liver function tests.
2. Individualized Treatment Plans: Tailoring treatment plans based on patient condition, comorbidities, and response to therapy.
3. Patient Education: Educating patients on dietary restrictions, medication adherence, and recognizing symptoms of complications. Appropriate salt restriction is beneficial for resolving ascites and preventing recurrence. However, long-term sodium restriction can lead to loss of appetite and hyponatremia, ultimately exacerbating malnutrition. Most patients with cirrhotic ascites do not require restriction on water intake unless the serum sodium levels are < 125 mmol/L. In patients with severe hyponatremia (serum sodium levels < 110 mmol/L) or hyponatremic encephalopathy, an emergency intravenous dose of 50–100 mL of 3–5% hypertonic saline solution should be administered for 2–3 days. This treatment should be discontinued within 5 days to avoid exacerbating ascites. Tolvaptan is effective and safe for the treatment of cirrhotic patients with ascites and hyponatremia. During tolvaptan therapy, the 24-hour increase in serum sodium level should be kept below 12 mmol/L to prevent an increase in circulatory load or inflict demyelinating damage to the nervous system.

Conclusion

The updated guidelines provide a comprehensive framework for managing ascites and its complications in cirrhosis. By adhering to these evidence-based recommendations, clinicians can significantly improve patient outcomes and quality of life. Ongoing research and clinical trials will continue to refine these guidelines, ensuring they remain at the forefront of clinical practice.