In hospitalized patients treated for presumed overt hepatic encephalopathy who show no meaningful improvement after 48–72 hours of adequate therapy and precipitant management, what is your highest- yield next diagnostic step and what clinical features drive that prioritization?

At this point in the clinical care pathway, I would repeat an infectious workup (blood, urine, diagnostic paracentesis; occult infections are common in our cirrhotic patients) and perform a high-quality multiphasic cross-sectional imaging test to rule out hepatocellular carcinoma (HCC), portal vein thrombosis (PVT), and portosystemic shunting (PSS) that could cause refractory hepatic encephalopathy (HE). If that workup is negative, broaden the differential and assess for non-HE causes of altered mental status (AMS), such as vitamin deficiencies, other infections (syphilis, cryptococcus), and medication review.