Management of Liver Cirrhosis and Its Complications

Abstract

Liver cirrhosis is a widespread global health concern with various potential causes, such as chronic viral hepatitis, nonalcoholic fatty liver disease, alcohol consumption, and autoimmune diseases. The development of cirrhosis occurs over an extended period of chronic inflammation, leading to the substitution of healthy liver tissue with fibrotic tissue and regenerative nodules, ultimately leading to the onset of portal hypertension. Decompensated cirrhosis, which arises from a compensated stage, is characterized by the emergence of complications such as ascites, esophageal variceal bleeding, hepatorenal syndrome, hepatic encephalopathy, portal vein thrombosis, and hepatocellular carcinoma, which will result in prolonged hospitalization, impaired quality of life, and poor survival. In recent years, a concept known as “cirrhosis recompensation” has gained prominence in the field of liver cirrhosis. Cirrhosis recompensation, as defined by the Baveno VII consensus criteria, involves three core elements: addressing the underlying etiological factors, achieving remission from complications that are characteristic of the decompensated stage of cirrhosis, and achieving improvements in liver function. Consequently, the management of cirrhosis focuses on the elimination of underlying etiologies, surveillance for hepatocellular carcinoma and esophageal varices, assessment of suitability for liver transplantation, and treatment of complications.

1. Introduction

Liver cirrhosis progresses through two main stages: compensated and decompensated. As cirrhotic patients progress to the decompensated stage, they may suffer from a spectrum of complications including ascites, variceal bleeding, hepatorenal syndrome, hepatic encephalopathy, portal vein thrombosis, and hepatocellular carcinoma. Recently, experts have introduced the concept of recompensation [1, 2], where decompensated cirrhotic patients exhibit the recompensation of ascites (without the use of diuretics), absence of hepatic encephalopathy (without the use of lactulose or rifaximin), no recurrence of esophagogastric variceal bleeding (EGVB) for at least 12 months, and sustained stability of liver function parameters upon the suppression and elimination of underlying etiologies. Therefore, treatment of the underlying etiologies and complications is of paramount importance to improve patients’ prognoses.

The etiologies of cirrhosis encompass viral hepatitis, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), autoimmune liver diseases, drug-induced liver injury, genetic and metabolic disorders, and hepatic vascular diseases [3, 4]. Elimination of the underlying causes is the most crucial therapeutic intervention in the management of cirrhosis. Antiviral therapy can effectively eliminate viral replication, which will delay the progression of cirrhosis and result in recompensation in some cases. Alcohol abstinence is the primary treatment strategy for alcohol-related liver cirrhosis and may lead to a shift from decompensated to compensated stage. Cirrhotic patients are advised to abstain from alcohol and smoking, irrespective of etiologies [5, 6]. With the improvement of lifestyle, nonalcoholic fatty liver disease (NAFLD), also named metabolic dysfunction-associated fatty liver disease (MAFLD), affects approximately 30% of the global population and has become the predominant cause of liver diseases worldwide. Weight loss and lifestyle improvements will decrease the incidence of NAFLD and slow down disease progression. Corticosteroids (prednisone) and immunosuppressants (azathioprine) are used as first-line treatment of autoimmune liver disease. However, incomplete elimination of the etiologies [7, 8], advanced age (> 65 years), persistent inflammatory necrotic activity in the liver pathology, and advanced cirrhosis (Child-Pugh class C, MELD score > 20, serum albumin level < 35 g/L, HVPG >16 mmHg) will contribute to non-reversal of liver fibrosis and cirrhosis even when patients receive etiological treatment.

Liver function preservation and nutritional improvement are pivotal strategies in the management of cirrhosis. Pharmacological agents for liver function preservation include glycyrrhizin preparations, silymarin, and polyenylphosphatidylcholine. Ursodeoxycholic acid and tauroursodeoxycholic acid are effective in improving intrahepatic cholestasis [9, 10, 11]. Research indicates that statin usage can slow disease progression and decrease mortality. Statins are recommended for patients classified as Child-Pugh A and B [12]. However, they are not recommended for patients with Child-Pugh C due to unclear adverse effects including hepatotoxicity and rhabdomyolysis in these cases [13]. Malnutrition is an independent risk factor for mortality in patients with decompensated cirrhosis, significantly attributed to inadequate protein intake [14]. It is currently known that plant-based proteins are superior to animal-based proteins in reducing the incidence of hepatic encephalopathy. Given the inadequate hepatic glycogen reserves, prolonged fasting can stimulate muscle glycogen mobilization and fatty acid oxidation, thereby increasing the risk of sarcopenia. Consequently, patients with cirrhosis are recommended to adopt a strategy of frequent, smaller meals, complemented by vitamins, trace elements (such as zinc), and dietary fiber supplementation. Additionally, aerobic and resistance training are highly recommended.

2. Management of esophagogastric varices

2.1 Surveillance

As liver cirrhosis progresses, influenced by angiogenic factors, numerous neovessels emerge, leading to increased hepatic blood flow. This process also stimulates the proliferation of hepatic venous tributaries [15]. Subsequently, obstruction of the left gastric vein and short gastric veins results in the formation of gastroesophageal varices (GOV). Approximately 50% of cirrhotic patients present with GOV, and the severity of GOV is closely correlated with the severity of cirrhosis. Endoscopy serves as the gold standard for the diagnosis of GOV [16]. The presence and grades of GOV can be determined via endoscopic examination, thus guiding therapeutic intervention in clinical practice. For cirrhotic patients without GOV, a repeat gastroscopic examination every 2–3 years is recommended, whereas for those suffering from GOV, a repeat endoscopic examination every 1–2 years is recommended.

2.2 Primary prophylaxis of esophageal variceal bleeding (EVB)

The objective of primary prophylaxis for EVB is to eliminate the underlying causes, lessen the degree of varices, prevent bleeding, and reduce the occurrence of other complications. Different approaches are adopted based on the severity of esophageal varices. Currently, nonselective beta-blockers (NSBBs) and endoscopic variceal ligation (EVL) are preferred methods for primary prophylaxis of esophageal varices, with carvedilol showing significant efficacy among NSBBs [17]. For cirrhotic patients without esophageal varices or with small varices, NSBBs are not recommended for prevention, except for those at higher bleeding risk from small varices. In patients with moderate to large varices, both NSBBs and endoscopic treatments are recommended. For those who cannot tolerate NSBBs, EVL is the preferred option to prevent the first episode bleeding. A meta-analysis of 19 randomized controlled trials indicated no significant difference between the EVL and NSBB groups in terms of bleeding and mortality [18]. EVL should be performed every 2–4 weeks until varices eradication, with follow-up every 3–6 months within the first year. Research on primary prevention for GOV is limited. Currently, primary prophylaxis for GOV1 is similar to that for esophageal varices (EV), while for GOV2 and isolated gastric varices (IGV) 1, the AASLD and the European Association for the Study of the Liver (EASL) recommend NSBB. Endoscopic variceal obturation (EVO), echoendoscopy-guided coil insertion, and balloon-occluded retrograde transvenous obliteration (BRTO) are feasible options. The combination of EVL and NSBB is not recommended.

2.3 Treatment of acute esophageal variceal bleeding (AEVB)

Acute esophageal variceal bleeding (AEVB) represents a prevalent and life-threatening complication among patients with liver cirrhosis, accounting for approximately one-third of mortality in this population. Consequently, managing AEVB is of critical importance. The main treatments include early management, pharmacotherapy, endoscopy, and rescue therapy. Early management principles primarily involve maintaining airway patency, fluid resuscitation, and controlling infection. There is ongoing debate regarding the necessity of Sengstaken-Blakemore tube prior to endoscopic examination or treatment in patients with AEVB. Pharmacotherapy is the preferred treatment for AEVB. Prompt initiation of treatment aimed at reducing portal venous pressure and controlling infection is crucial. Commonly used medications to decrease portal venous pressure include terlipressin, somatostatin, and octreotide. Studies indicate that 20% of cirrhosis patients with active bleeding will develop bacterial infection within 48 hours, underscoring the critical importance of infection prevention [19]. Current guidelines recommend short-term antibiotic prophylaxis (5–7 days), with intravenous ceftriaxone at a dosage of 1–2 g/day being the preferred agent [15, 17, 20, 21].Gastroscopy is the primary treatment for diagnosing and managing AEVB. According to AASLD and EASL guidelines, patients with AEVB should undergo endoscopic examination within 12 hours, whereas APASL advises the timing of endoscopic examination should be within 6 hours. Endoscopic treatment options include endoscopic variceal ligation (EVL), endoscopic injection sclerotherapy (EIS), and endoscopic injection of tissue adhesives. EVL is recommended as the first-line treatment for patients with EV and type 1 gastroesophageal varices (GOV1). Endoscopic injection of tissue adhesives is primarily utilized for patients with bleeding from IGV and GOV2. Studies have shown that the efficacy of EVL and tissue adhesive injection in treating active bleeding is comparable, but the rebleeding rate in patients treated with tissue adhesive injection is significantly lower than that in patients treated with EVL [19]. Transjugular intrahepatic portosystemic shunt (TIPS) is the preferred treatment for patients who remain bleeding after drug or endoscopic therapy. Balloon-occluded retrograde transvenous obliteration (BRTO), which obstructs abnormal shunts via a balloon catheter, targets GOV2, IGV1, and varices at rare sites and is suitable for patients with or at high risk of hepatic encephalopathy.

2.4 Secondary prevention of EVB

The objective of secondary prevention is to avert the recurrence of bleeding from esophagogastric varices. Typically, secondary prevention measures are initiated for patients with a history of EVB or 5 days after treatment for AEVB. A Hepatic Venous Pressure Gradient (HVPG) >20 mmHg serves as an early predictor of rebleeding.

For patients with EV bleeding, the combination of NSBBs and EVL is recommended for secondary prevention. The dosage for NSBBs remains the same as for primary prevention, while EVL is recommended every 1–4 weeks until varices are obliterated. For GOV1 bleeding, due to limited research, recommendations align with those for EV. The American Association for the Study of Liver Diseases (AASLD) suggests NSBBs and EVL (or Endoscopic Variceal Obliteration, EVO) as secondary preventive measures, while the Korean Association for the Study of the Liver (KASL) advocates repeated use of EVO or EVL. For GOV2 and IGV1 bleeding, the AASLD recommends TIPS or BRTO as secondary prevention, whereas KASL suggests EVO or BRTO. Given the absence of unified protocols, secondary prevention should be personalized based on the patient’s specific circumstances and local healthcare resources.

3. Management of ascites

For cirrhotic patients suffer ascites, abstinence from alcohol and treatment of the underlying cause are strongly recommended. Etiological treatment can alleviate liver fibrosis, reduce portal vein pressure, and reverse the progression of liver fibrosis and cirrhosis. For patients unable to undergo etiological treatment, interventions such as antifibrotic therapy, prevention of intestinal bacterial translocation, protection of endothelial cell function, and correction of coagulation abnormalities can also improve the progression of complications. Cirrhotic patients with ascites should focus on nutritional balance to prevent malnutrition. Early detection, diagnosis, and treatment of nutritional deficiencies are crucial. Guidelines recommend small, frequent meals, bedtime snacks, and supplementation with branched-chain amino acids. Moderate salt restriction is beneficial for the alleviation of ascites. The Asia-Pacific Association and the British Society of Gastroenterology along with the British Association for the Study [22, 23] of the Liver suggest a salt intake of 5–6.5 g/L for patients with ascites, while in China, the recommended intake is 4–6 g/L. However, it is essential to be cautious of the risk of hyponatremia (<110 mmol/L) with restricted salt diets.

Albumin plays a vital physiological role in management of ascites. Guidelines recommend supplementing 6–8 g of albumin per 1000 ml of ascites removed, which could significantly increase patients’ survival rates [24]. Diuretics are classified into aldosterone antagonists (spironolactone), loop diuretics (furosemide), and vasopressin V2 receptor antagonists (tolvaptan) according to different mechanisms. Diuretics and its dosage selection is based on the grades of ascites. For patients with grade 1 ascites, spironolactone may be prescribed alone initially, with the option to increase the dose or combine with furosemide if ineffective. For patients with grade 2–3 ascites, it is advised to administrate with a combination of spironolactone and furosemide, monitoring urine output and ascites volume. Large volume paracentesis (LVP) is an effective treatment strategy for grade 3 ascites, refractory ascites, and recurrent ascites. It is essential to administer albumin to counterbalance fluid removal and maintain colloid osmotic pressure during LVP. Transjugular intrahepatic portosystemic shunt (TIPS) is one of the primary treatment strategies for refractory or recurrent ascites and can also serve as a bridging therapy to liver transplantation or as the preferred treatment for patients who are not suitable for transplantation. For cirrhotic patients who is classified with Child-Pugh C or complicating with liver failure, liver transplantation should be considered as a priority treatment. And efforts should be made to minimize the risk of infections for pretransplantation.

4. Spontaneous bacterial peritonitis (SBP)

SBP is a common complication in patients with end-stage liver cirrhosis. Immediate empirical antibiotic therapy is essential upon SBP suspicion, adjusting based on the results of bacterial culture of ascites. Empirical antibiotic treatment depends on whether SBP is community-acquired or hospital-acquired. For community-acquired SBP, treatment primarily targets Gram-negative bacilli, with third-generation cephalosporins (e.g., cefotaxime) as the first choice. Carbapenems are preferred for broad-spectrum coverage in areas with high antimicrobial resistance rates. Piperacillin/tazobactam is chosen in regions with lower resistance rates, while carbapenems are favored in high-resistance areas. The duration of antibiotic administration should be at least 5–7 days. Consensus suggests administering albumin to patients with SBP can reduce drug clearance, significantly enhance anti-infection effects, and improve patients’ survival. Albumin dosage should be administered of 1.5 g/kg within 6 hours on the first day, followed by 1 g/kg on the third day [25]. For SBP prevention, cirrhotic patients with variceal bleeding should receive prophylactic treatment. Patients with low ascitic fluid protein (<1.5 g/L) are at higher risk for SBP. Those with severe liver disease (Child-Pugh score ≥ 9 with serum bilirubin ≥3 mg/dL) or renal impairment (serum creatinine ≥1.2 mg/dL, blood urea nitrogen ≥25 mg/dL, or serum sodium ≤130 mq/L) should receive antibiotic prophylaxis for primary SBP prevention. Long-term prophylactic treatment with oral norfloxacin, ciprofloxacin, or trimethoprim-sulfamethoxazole after correction of SBP is recommended [26].

5. Hepatic encephalopathy (HE)

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of varying severity, resulting from severe liver dysfunction or various abnormalities in the portal-systemic circulation. It is characterized by metabolic disruptions and neurological and psychiatric abnormalities of differing degrees. HE represents a common complication and cause of mortality in severe liver diseases [27]. The West-Haven classification is the most commonly utilized clinical classification system for HE, categorizing HE into grades 0, 1, 2, 3, and 4. According to the SONIC grading criteria, grades 0 and 1 HE are classified as covert hepatic encephalopathy (CHE), while grades 2, 3, and 4 HE are defined as overt hepatic encephalopathy (OHE). OHE is further subdivided into episodic, recurrent, and persistent based on the course of HE. Recurrent HE refers to episodes occurring within a 6-month interval, whereas persistent HE denotes sustained behavioral alterations with no recovery between two episodes, interspersed with recurrences of overt HE. CHE is considered as a risk factor for OHE; thus, treating CHE is a preventative measure for OHE [28]. Research [29] indicates that 30–45% of patients with cirrhosis experience OHE, with an annual incidence rate of 20%. Following TIPS placement, the occurrence rate can escalate to as high as 50%. Blood ammonia levels could be used for the diagnosis of HE, although levels can be high, low, or even asymptomatic [30]. Structural MRI can also be utilized to differentiate HE from other diseases [31]. Treatment principles include removing precipitating factors, nutritional support therapy, and individualized treatment. Lactulose is considered the first-line therapy for all patients with HE, reducing the incidence of OHE and improving cognitive function. Rifaximin, a poorly absorbed antibiotic, is recommended when lactulose fails to prevent recurrent HE episodes. Rifaximin has been proven to reduce the risk of HE recurrence and rehospitalization and improve quality of life. However, the debate between monotherapy and combination therapy for preventing HE recurrence remains contentious and requires further investigation. The use of proton pump inhibitors (PPIs) should be carefully reassessed in patients with cirrhosis due to their potential to increase the incidence of HE [32].

6. Hepatorenal syndrome (HRS)

HRS is a functional renal failure that occurs in patients with advanced liver disease. It is characterized by renal functional impairment, significant alterations in hemodynamics, and marked abnormalities in endogenous vasoactive substances. The exact mechanism of HRS remains unclear, but it is often attributed to severe liver dysfunction leading to hemodynamic changes, severe renal hypoperfusion, decreased renal blood flow, and subsequent renal functional failure. The treatment of HRS involves general measures, pharmacotherapy, and others. General treatment measures include early administration of a high-calorie easily digestible diet, monitoring of blood pressure, urine output, and liver and kidney function. Maintaining fluid balance to prevent fluid overload and dilutional hyponatremia is crucial. Aggressive infection control is also recommended. Pharmacotherapy includes albumin and vasoconstrictor drugs such as norepinephrine, terlipressin, and midodrine combined with octreotide. Guidelines recommend albumin replacement therapy for hepatorenal syndrome-acute kidney injury (HRS-AKI) patients with serum creatinine levels >1.5 mg/dL (132.6 μmol/L). Vasoconstrictor therapy, particularly terlipressin, is recommended for all HRS-AKI patients in combination with intravenous albumin infusion. Terlipressin is administered initially at 2 mg/d continuous infusion, up to a maximum of 12 mg/d, until AKI reversal. In China, the protocol involves terlipressin (1 mg every 4–6 hours) combined with albumin (20–40 g/d) for 3 days, with adjustments based on serum creatinine levels. If terlipressin is ineffective, somatostatin analogs or norepinephrine combined with albumin can be tried as alternative treatments. Liver transplantation is the preferred treatment for HRS-AKI patients, while there is limited evidence to support the use of TIPS and blood purification therapy for HRS. These treatments may be considered in select cases but are not universally recommended.

In conclusion, the timely identification and treatment of cirrhosis and its complications are paramount. Managing cirrhosis is a multidisciplinary endeavor that necessitates the creation of personalized treatment strategies tailored to each patient’s unique situation. As our understanding of the disease mechanisms deepens and treatment modalities continue to advance, there is optimism for further enhancements in patient outcomes. By implementing comprehensive management approaches and staying abreast of emerging therapeutic innovations, we can strive to optimize the care and prognosis of individuals affected by cirrhosis.