Graduation Date

Summer 8-14-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Yazen Alnouti

Abstract

Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. We compared the urinary BA profile between 300 patients with hepatobiliary diseases vs. 103 healthy controls. Also, we investigated the use of the urinary BA profile to develop survival models to predict the prognosis of hepatobiliary diseases. The urinary BA profile, a set of non-BA parameters, and the adverse events of liver transplant and/or death were monitored in patients with cholestatic liver diseases for up to 7 years. The BA profile was characterized by calculating BA indices, which quantify the composition, metabolism, hydrophilicity, and toxicity of the BA profile. Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (DCA and LCA) was markedly lower, while the percentage of primary BA (CDCA, CA, and HCA) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients. The increase in non-12α-OH BA was more profound than 12α-OH BA (CA and DCA) causing a decrease in the 12α-OH/non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease (MELD) score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. In general, BA indices had much lower inter- and intra-individual variability compared to absolute concentrations of the individual and total BA. In addition, BA indices demonstrated high area under the receiver operating characteristic (ROC) curves, and changes of BA indices were associated with the risk of having a liver disease as determined by the logistic regression analysis, which demonstrated their use as diagnostic biomarkers for cholestatic liver diseases.

We have developed and validated the bile-acid score (BAS) model (a survival model based on BA indices) to predict the prognosis of cholestatic liver diseases. The BAS model was more accurate and results in higher true-positive and true-negative prediction of death compared to both non-BAS and MELD models. Both 3- and 5-year survival probabilities markedly decreased as a function of BAS. Moreover, patients with high BAS had a 4-fold higher rate of death and lived for an average of 11 months shorter than subjects with low BAS. The increased risk of death with high vs. low BAS was also 2-4-fold greater and the shortening of lifespan was 6-7-month lower compared to MELD or non-BAS. One application for BAS could be to define the most seriously ill liver patients, who may need earlier intervention such as liver transplantation.

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