Role of Allopurinol in Prevention of Complications Related to Decompensated Cirrhosis of Liver

Cirrhosis of liver accounts for approximately 1 million deaths per year. In addition to its clinical burden, it causes significant morbidity, impairment of health-related quality of life (HRQL), and economic burden (Younossi et al. 2023).

It is the final pathway for a wide variety of chronic liver diseases, a pathologic entity defined as diffuse hepatic fibrosis with the replacement of the normal liver architecture by nodules (Feldman et al. 2015). It is currently the 9th leading cause of death in South East Asia and Europe; 10th leading cause of death in Africa ; and the 5th leading cause of death in the Eastern Mediterranean (Devarbhavi et al. 2023).

According to World Health Organization, cirrhosis of liver is the 〖10〗^th leading cause of death in Bangladesh for both male and female (World Health Organization , 2021).

Alcohol consumption, chronic hepatitis C infection, and NAFLD are the most common causes of cirrhosis in Western countries, while chronic hepatitis B is the predominant cause in the Asia-Pacific region. Other causes include inherited conditions like hemochromatosis and Wilson's disease, along with primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis. In some cases, the cause of cirrhosis is unknown or cryptogenic (Zhou et al. 2014).

Cirrhosis is classified in two main prognostic stages: compensated and decompensated cirrhosis. Decompensation means cirrhosis with one of the following: ascites, bleeding varices, hepatic encephalopathy or jaundice. Median survival in the compensated stage exceeds 12 years where as it is only 2 years in patients who develop decompensation (D'Amico et al. 2006). Cirrhosis advances from a compensated stage to a decompensated stage at a rate of 5%-7% annually (Kaur et al. 2025).

The gut-liver axis functions as a crucial system that helps protect the body from potentially harmful substances and microorganisms, while also preserving the balance and stability of the immune system (Ponziani et al. 2018). Individuals with cirrhosis experience alterations in their gut microbiota. Factors such as reduced small intestinal motility, impaired bile secretion, and disruptions in the production of immunoglobulin A and antimicrobial molecules all contribute to this alteration (Bhat et al. 2016). Alteration of gut microbiota causes increased absorption of endotoxins. As a consequence, systemic endotoxemia develops (Bauer et al. 2002). The raised level of plasma endotoxin is closely related to the severity of cirrhosis and is an important factor (Lin et al. 1995).

The production of Reactive oxygen species (ROS) in the gut is a necessary defense mechanism against pathogens and aids in mucosal recovery, but when produced in excess, it can undermine the integrity of the mucosal lining and the epithelial barrier (Kunst et al. 2023). ROS also play a crucial role in the process of fibrogenesis. Not only that, the majority of hepatocellular carcinomas develop in cirrhotic livers, where the key mechanism behind their formation is long-term inflammation coupled with intense oxidative stress (Muriel et al. 2009). Multiple studies have demonstrated an increase in xanthine oxidase (XO) activity in patients with different types of liver injury including cirrhosis (Stirpe et al. 2002; Ramboer et al. 1972; Aldaba-Muruato et al. 2012). Studies on experimental cirrhosis have indicated subcellular alterations in the intestinal mucosa, which are linked to increased oxidative stress from the overactivity of xanthine oxidase (Spahr et al. 2007).

Therefore, we can postulate that using an intervention that inhibits XO can result in reduced ROS overproduction, intestinal permeability, bacterial translocation, and endotoxemia and its consequences.

Allopurinol, a competitive inhibitor of the enzyme xanthine oxidase, has been proven to exert antioxidant properties (Pacher et al. 2006).

The management of cirrhosis typically focuses on controlling the underlying disease, managing complications, and improving quality of life. However, specific therapies to prevent the complications of cirrhosis are limited.

Allopurinol, a xanthine oxidase inhibitor, has shown promising antioxidant (Spahr et al. 2007) and anti-inflammatory (Aldaba-Muruato et al. 2012) effects in cirrhotic patients. It has also been proven to reduce complications such as ascites, hepatic encephalopathy, Spontaneous bacterial peritonitis (SBP), and Hepatorenal syndrome -Acute Kidny Injury (HRS-AKI) in cirrhosis (Glal et al. 2023).

Allopurinol has a dose-dependent ability to scavenge free radicals, reducing oxidative stress. In inflammatory states, it reduces the levels of oxidative stress, particularly in blood vessels, and decreases the expression of pro-inflammatory molecules like soluble intercellular adhesion molecule-1 (ICAM-1). By decreasing ROS and NF-κB pathway activation, allopurinol reduces the release of pro-inflammatory cytokines such as TNF-α and IL-1. This helps in controlling inflammation and tissue damage during diseases.

Allopurinol suppresses T cell activation by reducing the production of cytokines, such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2), which are key mediators of immune responses. It also attenuates CD69 upregulation, a marker of T cell activation. ROS trigger the NLRP3 inflammasome, a protein complex involved in inflammation. The inflammasome activates pro-inflammatory responses, including the release of IL-1β, a potent inflammatory cytokine. ROS-induced activation of the inflammasome is linked to oxidative stress. TXNIP (thioredoxin-interacting protein) is a pro-inflammatory protein that connects oxidative stress to inflammasome activation. In response to ROS, TXNIP dissociates from thioredoxin (TRX) and binds to NLRP3, triggering the activation of the inflammasome and the release of IL-1β. Allopurinol blocks the effects of TXNIP, preventing it from activating the NLRP3 inflammasome. By interacting with the redox-active domain of thioredoxin (TRX), allopurinol helps reduce ROS production and, in turn, decreases inflammasome activation and inflammation.

Allopurinol inhibits multinucleated giant cell (MGC) formation in monocytes and reduces ICAM-1 expression, limiting immune cell adhesion. It also protects monocytes from cytolysis and downregulates the P2X7 receptor, suppressing inflammasome activation. This suggests that allopurinol may help protect immune cells from excessive damage during inflammation(Schlesinger & Brunetti, 2020).

Recent studies have indicated a potential association between elevated serum uric acid levels and the progression of liver fibrosis, particularly in MAFLD (Yen et al. 2022).

Glal et al. (2023) conducted a quadruple-blinded, randomized, placebo-controlled trial, where patients with cirrhosis were administered 300 mg of allopurinol daily for a duration of six months as a form of secondary prophylaxis. After 6 months of treatment, the incidence of any first cirrhosis-related complication was significantly lower in the allopurinol group compared to the placebo group-32% versus 72%, respectively. This difference corresponds to a hazard ratio (HR) of 0.44 with a 95% confidence interval (CI) of 0.27-0.62, indicating a 56% relative risk reduction in patients treated with allopurinol over the six-month period (P < 0.001). Additionally, the absolute risk reduction (ARR) was 40%, translating to a number needed to treat (NNT) of 2.5.Moreover, allopurinol demonstrated a substantial reduction of 67% in the relative risk of developing overt ascites (HR 0.33; 95% CI, 0.0098-0.94; P = .039), a notable decrease in relative risk of spontaneous bacterial peritonitis by about 75% (HR 0.25; 95% CI, 0.05-0.76; P = .01), and an 80% reduction in the risk of developing hepatorenal syndrome (HR 0.2; 95% CI, 0.04-0.87; P = .033). The allopurinol group showed a statistically significant reduction in the MELD score after 6 months of treatment as compared with placebo (P < .035).

Muruato et al. (2012) stated that allopurinol protects against experimental liver damage by preventing oxidative stress and by inhibiting the translocation of NF-κB to the nucleus, as well as by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Moreover, this drug presents antifibrotic effects, probably because of its ability to reduce TGF-β expression and to increase the activity of MMP-13, a proteolytic enzyme that has a central role in the modulation of the MMP activation cascade.

Spahr et al. (2007) conducted a study to evaluate the effects of allopurinol on oxidative stress in patients with stable cirrhosis. The study included 19 patients with stable cirrhosis, who were treated with 400 mg of allopurinol per day for 10 days. Various markers were assessed at baseline and after the 10-day course, including oxidative stress (via serum malondialdehyde (MDA) levels), intestinal permeability (measured by the lactulose/mannitol (Lac/Man) ratio), and markers of systemic inflammation such as TNF-soluble receptor-1, interleukin-6 (IL-6), and lipopolysaccharide-binding protein (LBP), which indicates endotoxin exposure.

The findings from the study demonstrated that allopurinol therapy led to a significant reduction in oxidative stress, as evidenced by a 23% decrease in serum malondialdehyde (MDA) levels (P < 0.05). MDA is a byproduct of lipid peroxidation and is commonly used as a marker of oxidative stress. The reduction in MDA levels indicated a decrease in oxidative damage, suggesting that allopurinol may help mitigate oxidative stress in patients with cirrhosis.No significant changes were observed in intestinal permeability (measured by the Lac/Man ratio) or in the markers of endotoxin-associated systemic inflammation (TNF-soluble receptor-1, IL-6, and LBP).

This study aims to investigate whether Allopurinol can reduce the incidence or severity of complications (hepatic encephalopathy, ascites, and variceal bleeding, SBP, HRS-AKI) in patients with cirrhosis. The findings may provide important insights into a potentially low-cost, widely available therapeutic option for cirrhotic patients if proven to be effective .

The general objective of this study is to evaluate the role of allopurinol in preventing complications associated with decompensated cirrhosis. The specific objectives are to compare the time to event and overall complication rates between the allopurinol group and the standard medical therapy group; to evaluate the effect of allopurinol in preventing hepatic encephalopathy in patients with cirrhosis; to assess its role in the regression of ascites; to determine its potential in preventing variceal bleeding among cirrhotic patients; to evaluate its effectiveness in preventing spontaneous bacterial peritonitis (SBP); to assess the role of allopurinol in preventing hepatorenal syndrome-acute kidney injury (HRS-AKI) in cirrhosis; and to evaluate the impact of allopurinol on MELD and Child-Turcotte-Pugh (CTP) scores

This study will be conducted as a randomized controlled trial. The sampling technique will be simple random sampling among patients who fulfill the inclusion and exclusion criteria. The study population will consist of patients with decompensated cirrhosis of the liver classified as Child-Turcotte-Pugh (CTP) class B and C. The study will be carried out in the Department of Hepatology at Bangladesh Medical University. The study period will extend from the date of Institutional Review Board (IRB) clearance until November 2026.

Patients admitted to the inpatient department and those attending the Outpatient Department of Hepatology at Bangladesh Medical University will be initially evaluated for participation in the study. Patients of either sex aged between 18 and 70 years will be considered eligible for screening. A detailed clinical history will be obtained and a thorough physical examination will be performed. Baseline demographic and clinical data including age, sex, stigmata of cirrhosis, and complications of cirrhosis such as ascites, variceal bleeding, hepatorenal syndrome, spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy will be assessed and documented. Baseline investigations will include complete blood count (CBC), liver function tests including serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, serum albumin, and prothrombin time; alpha-fetoprotein (AFP); serum creatinine; serum electrolytes; abdominal ultrasonography; and upper gastrointestinal endoscopy.

Patients diagnosed with Child-Turcotte-Pugh (CTP) class B or C liver cirrhosis who fulfill all inclusion criteria and none of the exclusion criteria will be enrolled in the study. Written informed consent will be obtained from all participants after explaining the purpose of the study, along with the potential benefits and risks of allopurinol therapy. Selected participants will then undergo random allocation into two groups using block randomization. Patients will be randomized in a either an allopurinol treatment group or a standard care group with placebo ; 27 participants in each group by block randomization. one group will receive oral Allopurinol (titrated from 100 mg to 300 mg daily for six months) along with standard medical therapy. Another Group will receive same dose of Placebo along with standard medical therapy . Patients will be followed at 6 month to see the progression of cirrhosis-related complications. Continuous communication will be maintained with all participants, and they will be advised to seek immediate medical attention whenever necessary.

Data will be collected using a preformed data collection sheet containing questionnaires along with demographic, baseline, and clinical information. Relevant clinical features and investigation findings will be documented systematically. Biochemical analyses including serum total bilirubin, ALT, AST, serum creatinine, serum electrolytes, serum albumin, and AFP will be performed in the biochemistry laboratory. CBC, C-reactive protein (CRP), prothrombin time with INR, and ascitic fluid cytology will be performed in the Laboratory Medicine Department. Abdominal ultrasonography will be conducted in the Department of Radiology and Imaging, while upper gastrointestinal endoscopy will be performed in the Department of Hepatology at Bangladesh Medical University.

Statistical analysis will be performed using the Statistical Package for Social Sciences (SPSS) version 29.0 (IBM Corp., Armonk, NY, USA). The study will follow an intention-to-treat analysis approach. Categorical variables will be analyzed using the chi-square test and expressed as frequencies and percentages. Continuous variables with normal distribution will be analyzed using Student's t-test and presented as mean ± standard deviation. Time to the first occurrence of any cirrhosis-related complication will be analyzed using the Cox proportional hazards model with a two-sided significance level of 0.05, assuming proportional hazard assumptions are met. Kaplan-Meier survival analysis will also be employed to estimate the proportion of patients experiencing cirrhosis-related complications during the follow-up period.

Ethical approval for the study will be obtained from the Ethical Review Committee of Bangladesh Medical University prior to commencement of the research. Written informed consent will be obtained from each participant after adequate explanation of the study objectives, procedures, potential benefits, possible side effects of the study drug, and available alternative treatment options. Participation in the study will be entirely voluntary, and participants will retain the right to withdraw from the study at any stage without prejudice to their treatment. Confidentiality of participant information will be strictly maintained by assigning a unique identification number to each participant and storing all research data in a secure location accessible only to research personnel. Hospital records and investigation reports will be reviewed for completion of the data collection sheet, and interviews lasting approximately 20-30 minutes will be conducted with participants. Privacy will be ensured during interviews, physical examinations, and procedures. No financial incentives will be provided to participants, and any complications arising during the study period will be managed promptly and appropriately.

Inclusion criteria

• • Adult patients (age : 18-70 years) diagnosed with Decompensated cirrhosis of liver with any etiology of cirrhosis .

• CTP score B or C .

Exclusion criteria

• • Patients with known hypersensitivity or allergy to allopurinol.

• Patients with active HE or SBP or HRS-AKI or a history of any of these events within the last 4 weeks.
• Patients with advanced renal impairment (e.g., creatinine clearance <30 mL/min).
• Pregnant or breastfeeding women.
• Patients with severe comorbidities (e.g., uncontrolled cardiovascular disease, cancer, or severe infections).
• Patients currently using medications that interact with allopurinol (e.g., azathioprine, mercaptopurine, Cyclophosphamide, Thiazide diuretics ,Warfarin, Theophyllin ).