Serum Thyroxine, Microbial Metabolites Predict Risk for Advanced Hepatic Encephalopathy

Researchers sought to identify metabolic biomarkers that could help predict advanced hepatic encephalopathy upon a patient’s hospital admission.

Upon hospital admission, serum levels of thyroxine and specific metabolites associated with gut microbiota predicted the development of advanced hepatic encephalopathy in patients with cirrhosis, according to study findings published in Clinical Gastroenterology and Hepatology.

Researchers conducted a multicenter, prospective study throughout North America, enrolling 602 patients with confirmed cirrhosis without hepatic encephalopathy upon hospital admission to determine serum biomarkers that predicted hepatic encephalopathy, or brain failure caused by acute-on-chronic liver failure.

Of the 602 patients, 144 (24%) developed hepatic encephalopathy in a median of 3 days after admission. Of these 144 patients, 105 developed hepatic encephalopathy in the absence of other organ failures.

Lower total thyroxine, isoleucine, and lysophospholipid serum concentrations as well as higher microbial metabolites, such as aromatic amino acids and benzoate metabolites, significantly correlated with the development of advanced hepatic encephalopathy.

Four metabolites significantly predicted brain failure — low thyroxine, low maltose, high methyl-4-hydroxybenzoate sulfate, and high 3-4 dihydroxy butyrate — with only low thyroxine increasing the clinical model prediction (area under the curve [AUC], 0.72; 95% CI, 0.63-0.75; P =.05).

To confirm their initial findings, the researchers performed a validation study on 81 patients admitted to Virginia Commonwealth University (VCU) Hospital and the Veterans Affairs Medical Center (VAMC) in Richmond, Virginia. Of these 81 patients, 11 developed hepatic encephalopathy within a median of 5.3 days following admission. Again, researchers found that low thyroxine (odds ratio [OR], 0.67; 95% CI, 0.48-0.89; P =.01) significantly predicted development of advanced hepatic encephalopathy in the validation cohort.

“…[A]dmission serum metabolites associated with gut microbiota and low serum thyroxine predicts the future development of advanced [hepatic encephalopathy] independent of clinical biomarkers,” the study authors wrote. “The pattern of low serum thyroxine in patients who developed advanced [hepatic encephalopathy] was also found in a separate small prospective cohort using a clinical laboratory. Therefore, the use of serum metabolites, especially thyroxine, could provide useful prognostication on admission to the hospital and ensure rapid interventions to prevent the development of advanced hepatic encephalopathy.”

Study limitations included lack of analysis of ammonia or inflammatory markers, lack of ability to assess the influence of port-systemic shunts, sarcopenia, or minimal hepatic encephalopathy that correlate with outpatient development of hepatic encephalopathy, lack of applicability to sites other than tertiary care centers, and small sample size in the validation cohort.


Bajaj JS, Tandon P, O’Leary JG, et al. Admission serum metabolites and thyroxine predict advanced hepatic encephalopathy in a multicenter inpatient cirrhosis cohort. Clin Gastroenterol Hepatol. Published online April 14, 2022. doi:10.1016/j.cgh.2022.03.046