Age and Sex in the Development of Hepatic Encephalopathy: Role of Alcohol.

Simple Summary: Hepatic encephalopathy (HE) is a major neurological condition that occurs following acute or chronic liver failure. There are two types of HE: acute (Type A) and chronic (Type C). The acute form leads to rapid coma and death due to increased intracranial pressure, while neurobehavioral abnormalities potentially characterize the chronic form. There is currently no available treatment to regress or cure HE. This may be due to various factors, of which age and sex are the most important to consider when treating patients with HE. Accordingly, we examined whether sex and age play a role in the development of HE. We found that drug-induced (thioacetamide, TAA) brain edema was more severe in aged males than in young males or young/aged female rats. Furthermore, adding alcohol to the young male or young/aged female rats aggravated the brain edema. Regarding the behavioral changes, TAA-induced deficits were less pronounced in young and aged females than in aged males, whereas in the chronic type, young and aged males showed no behavioral changes when alcohol was infused along with TAA despite the severe brain edema and death that occurred. These findings suggest that aged males and young/aged females are more prone to developing brain edema in the presence of one or more liver toxins. Hepatic encephalopathy (HE) is a neurological condition linked to liver failure. Acute HE (Type A) occurs with acute liver failure, while chronic HE (Type C) is tied to cirrhosis and portal hypertension. HE treatments lag due to gaps in understanding its development by gender and age. We studied how sex and age impact HE and its severity with combined liver toxins. Our findings indicate that drug-induced (thioacetamide, TAA) brain edema was more severe in aged males than in young males or young/aged female rats. However, adding alcohol (ethanol, EtOH) worsens TAA's brain edema in both young and aged females, with females experiencing a more severe effect than males. These patterns also apply to Type A HE induced by azoxymethane (AZO) in mice. Similarly, TAA-induced behavioral deficits in Type C HE were milder in young and aged females than in males. Conversely, EtOH and TAA in young/aged males led to severe brain edema and fatality without noticeable behavioral changes. TAA metabolism was slower in aged males than in young or middle-aged rats. When TAA-treated aged male rats received EtOH, there was a slow and sustained plasma level of thioacetamide sulfoxide (TASO). This suggests that with EtOH, TAA-induced HE is more severe in aged males. TAA metabolism was similar in young, middle-aged, and aged female rats. However, with EtOH, young and aged females experience more severe drug-induced HE as compared to middle-aged adult rats. These findings strongly suggest that gender and age play a role in the severity of HE development and that the presence of one or more liver toxins may aggravate the severity of the disease progression. [ABSTRACT FROM AUTHOR]