History of depression ups risk of hepatic encephalopathy in cirrhosis patients

Patients with cirrhosis who have a history of depression are at greater risk of developing hepatic encephalopathy, reveals a study.

“[P]re-existing depression may increase the odds of developing hepatic encephalopathy in patients with advanced liver disease, independent of age, sex, and disease aetiology,” the researchers said. “Additional research is needed to identify which patients with depression are at the highest for developing this outcome.”

This retrospective cohort study included 447 patients with cirrhosis referred for liver transplant. Participants were divided into two groups: those with a “history of depression” and those with “no history of depression.”

The research team used multivariable logistic regression to determine whether a history of depression is independently predictive of hepatic encephalopathy.

Of the patients, 158 (35 percent) had a history of depression and 233 (52 percent) developed hepatic encephalopathy. Notably, hepatic encephalopathy occurred more frequently among those with a history of depression (63 percent vs 46 percent; p<0.01). [Am J Med 2024;137:872-879.E2]

Multivariate analyses also revealed the independent association of depression history with hepatic encephalopathy (adjusted odds ratio [aOR], 2.3, 95 percent confidence interval [CI], 1.4‒3.6), as well as with alcohol-related cirrhosis (aOR, 2.0, 95 percent CI, 1.3‒3.2), history of ascites (aOR, 3.5, 95 percent CI, 2.1‒5.9), and presence of a trans-jugular intrahepatic shunt (aOR, 9.2, 95 percent CI, 2.6‒32.6).

The significant association between depression history and hepatic encephalopathy persisted in a subgroup analysis of patients with alcohol-related liver disease (p=0.04).

Among patients with a history of depression, prescription with selective norepinephrine reuptake inhibitor (SNRI) was more common in the hepatic encephalopathy group (14 percent vs 3 percent). Moreover, in the multivariable model, SNRI prescription was independently associated with the development of hepatic encephalopathy (OR, 4.8, 95 percent CI, 1.0‒24.6).

“Patients with cirrhosis who have a history of depression should be closely monitored for the development of hepatic encephalopathy,” the researchers said.

“Additionally, incorporating routine depression and hepatic encephalopathy screening into multidisciplinary care models should be considered, particularly in patients with alcohol-associated liver disease who are at high risk for both conditions,” they added.

Pathologic pathway

Several pathologic pathways could explain the link between depression and hepatic encephalopathy. These include hypoperfusion of specific frontal gyri, microglial activation, and astrocyte dysfunction. [Anal Biochem 2022;636:114437; Exp Ther Med 2017;14:1058-1064]

Moreover, reduced hepatic clearance of ammonia and portosystemic shunting cause hyperammonemia and increased movement of ammonia across the blood brain barrier in patients with advanced liver disease. [Clin Liver Dis 2017;10:29]

“Cerebral astrocytes take up and metabolize ammonia to glutamine which can cause astrocyte swelling and degeneration when in excess,” the researchers said. “The breakdown of cerebral ammonia and resultant glutamate-mediate astrocyte swelling is central to the pathogenesis of hepatic encephalopathy.” [J Hepatol 2000;32:1035-1038]

In addition, preclinical evidence shows that astrocyte dysfunction plays a role in the pathogenesis of depressive disorders. [Glia 2017;65:1227-1250]

“Thus, it is plausible that astrocyte dysfunction in patients with depression predisposes for the development of hepatic encephalopathy, though this theory is beyond the scope of this study,” the researchers said.