Allopurinol reduces cirrhosis-related complications

Use of allopurinol 300 mg helps prevent the incidence of overall complications associated with liver cirrhosis, reports a study.

“Therefore, allopurinol may constitute a promising agent for patients with hepatic decompensation,” the investigators said. “These positive outcomes could be a result of its ability to reduce bacterial translocation and inflammation.”

A hundred patients with hepatic decompensation were randomly assigned 1:1 to receive either allopurinol 300 mg or placebo tablets once daily for 6 months. The incidence of cirrhosis-related complications (ie, overt ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, and hepatic encephalopathy) was the primary endpoint.

During 6 months of treatment, the relative risk (RR) of any first complication experienced following enrolment decreased by 56 percent (hazard ratio [HR], 0.44, 95 percent confidence interval [CI], 0.27‒0.62; p<0.001) with allopurinol. [Am J Med 2024;137:55-64]

Additionally, allopurinol reduced the RR of overt ascites by 67 percent (HR, 0.33, 95 percent CI, 0.0098‒0.94; p=0.039) and of spontaneous bacterial peritonitis by 75 percent (HR, 0.25, 95 percent CI, 0.05‒0.76; p=0.01). The treatment also resulted in an 80-percent decrease in the RR of developing hepatorenal syndrome (HR, 0.2, 95 percent CI, 0.04‒0.87; p=0.033).

“Ascites and spontaneous peritonitis are highly associated and are considered the most common complications of liver cirrhosis,” the investigators said. “The primary mechanism in the development of spontaneous bacterial peritonitis is believed to be from bacterial translocation.” [Ghana Med J 2019;53:37-43; Front Cell Infect Microbiol 2022;12999418]

Apart from bacterial translocation, the cirrhosis-related immune dysfunction syndrome (a combination of immune deficiency and exacerbated inflammation) influences the appearance of clinical complications of liver cirrhosis. [World J Hepatol 2015;7:1974-1981]

Allopurinol not only improves endothelial function and lowers oxidative stress in the vasculature, but also interferes with the cirrhosis-related immune dysfunction syndrome by diminishing T-cell activation and cytokine production. [Front Immunol 2012;3:295]

Mechanisms

“Several mechanisms are suggested to confer the anti-inflammatory properties of allopurinol, including accumulation of adenosine,” the investigators said. [Semin Arthritis Rheum 2020;50:444-450]

Allopurinol also delivers inhibitory effects on reactive oxygen species, tumour necrosis factor-α, nuclear factor kappa-light-chain-enhancer of activated B cells, and the neuronal apoptosis inhibitor protein, leucine-rich repeat, and amino-terminal pyrin domain domains-containing protein 3 inflammasome that potentially contributes to the pathogenesis of cirrhosis and its progression. [Biochem Biophys Res Commun 2018;505:40-44; Hepatology 2018;67:736-749; World J Hepatol 2016;8:207-210]

“Moreover, allopurinol is the mainstay of urate-lowering therapy for patients with gout and impaired renal function, and has been independently associated with slowing down the progression of renal disease in patients with chronic kidney disease,” the investigators said. [Clin J Am Soc Nephrol 2010;5:1388-1393]

“These support our results, which indicated the beneficial role of allopurinol in reducing the risk of hepatorenal syndrome in patients with cirrhosis,” they added.