Portosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry.

Elective transjugular intrahepatic portosystemic shunt (TIPS) placement can worsen cognitive dysfunction in hepatic encephalopathy (HE) patients due to toxins, including possible microbial metabolites, entering the systemic circulation. We conducted untargeted metabolomics on a prospective cohort of 22 patients with cirrhosis undergoing elective TIPS placement and followed them up to one year post TIPS for HE development. Here we suggest that pre-existing intrahepatic shunting predicts HE severity post-TIPS. Bile acid levels decrease in the peripheral vein post-TIPS, and the abundances of three specific conjugated di- and tri-hydroxylated bile acids are inversely correlated with HE grade. Bilirubins and glycerophosphocholines undergo chemical modifications pre- to post-TIPS and based on HE grade. Our results suggest that TIPS-induced metabolome changes can impact HE development, and that pre-existing intrahepatic shunting could be used to predict HE severity post-TIPS.

Personalized Tacrolimus Dosing After Liver Transplantation: A Randomized Clinical Trial.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance. Methods: In a single-center, randomized, pragmatic clinical trial ( NCT03527238 ), 62 adults were screened, enrolled, and randomized prior to liver transplantation 1:1 to standard-of-care (SOC) clinician-determined or PPM-guided dosing of tacrolimus. The primary outcome measure was percent days with large (>2 ng/mL) deviation from target range from transplant to discharge. Secondary outcomes included percent days outside-of-target-range and mean area-under-the-curve (AUC) outside-of-target-range per day. Safety measures included rejection, graft failure, death, infection, nephrotoxicity, or neurotoxicity. Results: 56 (29 SOC, 27 PPM) patients completed the study. The primary outcome measure was found to be significantly different between the two groups. Patients in the SOC group had a mean of 38.4% of post-transplant days with large deviations from target range; the PPM group had 24.3% of post-transplant days with large deviations; (difference -14.1%, 95% CI: -26.7 to -1.5 %, P=0.029). No significant differences were found in the secondary outcomes. In post-hoc analysis, the SOC group had a 50% longer median length-of-stay than the PPM group [15 days (Q1-Q3: 11-20) versus 10 days (Q1-Q3: 8.5-12); difference 5 days, 95% CI: 2-8 days, P=0.0026]. Conclusions: PPM guided tacrolimus dosing leads to better drug level maintenance than SOC. The PPM approach leads to actionable dosing recommendations on a day-to-day basis. Lay Summary: In a study on 62 adults who underwent liver transplantation, researchers investigated whether a new dosing method called Phenotypic Personalized Medicine (PPM) would improve daily dosing of the immunosuppression drug tacrolimus. They found that PPM guided tacrolimus dosing leads to better drug level maintenance than the standard-of-care clinician-determined dosing. This means that the PPM approach leads to actionable dosing recommendations on a day-to-day basis and can help improve patient outcomes.

Pre- and Post-Portosystemic Shunt Placement Metabolomics Reveal Molecular Signatures for the Development of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a common complication of advanced liver disease causing brain dysfunction. This is likely due to the accumulation of unfiltered toxins within the bloodstream. A known risk factor for developing or worsening HE is the placement of a transjugular intrahepatic portosystemic shunt (TIPS), which connects the pre-hepatic and post-hepatic circulation allowing some blood to bypass the dysfunctional liver and decreases portal hypertension. To better understand the pathophysiology of post-TIPS HE, we conducted a multi-center prospective cohort study employing metabolomic analyses on hepatic vein and peripheral vein blood samples from participants with cirrhosis undergoing elective TIPS placement, measuring chemical modifications and changes in concentrations of metabolites resulting from TIPS placement. In doing so, we identified numerous alterations in metabolites, including bile acids, glycerophosphocholines, and bilirubins possibly implicated in the development and severity of HE.