Hepatic Encephalopathy and Albumin Lasting Cognitive Improvement (HEAL-LAST)

Randomized Clinical Trial in Hepatic Encephalopathy to Study Lasting Cognitive Improvement With Intravenous Albumin

Hypothesis: Improvement in cognitive dysfunction with IV albumin in patients with cirrhosis with prior HE and MHE lasts for several weeks after albumin infusion has ended, and is due to persistent improvement in inflammatory markers, endothelial dysfunction, albumin function and gut microbial changes. This will be a single-arm, single-blind sequential trial of IV 25% albumin and IV saline over 8 weeks with biological sampling and cognitive and health related quality of life (HRQOL) testing with each subject acting as their own control

In outpatients with cirrhosis with prior HE who have cognitive impairment despite adequate therapy, we need to determine how long the impact of albumin lasts and through which potential mechanism(s). Our recent HEAL trial showed that patients with prior HE and current minimal hepatic encephalopathy (MHE) randomized to albumin experienced significant improvement in cognitive dysfunction and psychosocial quality of life4. Moreover, these improvements persisted a week after the last albumin infusion, which was not seen in the placebo group. This was accompanied by an improvement in endothelial dysfunction, ischemia-modified albumin levels and inflammatory markers that persisted one week even after albumin discontinuation. The reported half-life of IV albumin is 2 weeks, but the function and the length of time of albumin's action in decompensated cirrhosis is lower, and further details surrounding albumin pharmacokinetics in this population remain unelucidated5. The mechanisms and length of time albumin's potential improvement for patients with MHE after treatment discontinuation also require continued study. Study design: This will be a single-arm, single-blind sequential trial of IV 25% albumin and IV saline over 8 weeks with biological sampling and cognitive and health related quality of life (HRQOL) testing with each subject acting as their own control. We will change the order the albumin and placebo infusion and blind the infusions from the subjects and the assessors of the outcoemes.

Subjects will be blinded to which infusions are albumin versus placebo. All infusion tubing and bag will be covered in foil and the subjects will not be aware of the timing of the saline vs albumin infusion to maintain blinding for the patient.

Health-related quality of life change (SIP total, psychosocial and physical scores where a higher score indicates poor HRQOL willl be evaluated)

Inclusion Criteria: Age >18 years Cirrhosis diagnosed using either (a) liver biopsy, (b) transient wave elastography (>20 KPa) (c) radiological evidence consistent with cirrhosis, (d) in a patient with chronic liver disease endoscopic or radiological evidence of varices (e), in a patient with chronic liver disease, platelet count <150,000/mm3 and AST/ALT ratio >1. Cognitive impairment defined by MHE on psychometric hepatic encephalopathy score (PHES), critical flicker frequency (CFF), or EncephalApp Stroop Prior HE controlled by lactulose or rifaximin for at least one month Serum albumin <4gm/dl Exclusion Criteria: Unclear diagnosis of cirrhosis No prior overt HE No cognitive impairment on the tests noted Requiring regular albumin infusions within 3 months or anticipated during the study visit Infection within a month Allergies to albumin Unlikely to be adherent to the study Unable or unwilling to consent West Haven Criteria>2 Alcohol abuse within 1 month Serum albumin >4gm/dl Congestive heart failure