Epigenetics is defined as heritable changes in gene expression that are, unlike mutations, not attributable to alterations in the sequence of DNA. The predominant epigenetic mechanisms are DNA methylation, modifications to chromatin, loss of imprinting and non-coding RNA. Epigenetic regulation of gene expression appears to have long-term effects and wide-ranging effects on health. Diet and environmental exposures may potentially alter the level and scope of epigenetic regulation, thus interesting developments in the study of epigenetics might explain correlations that researchers have found between lifestyle and risk of disease. Aberrant epigenetic patterns have been linked to a number of digestive diseases including Barrett’s esophagus, cirrhosis, inflammatory bowel disease, and numerous gastrointestinal malignancies. In fact, many exciting discoveries about epigenetics in general have been made by studying diseases of the gastrointestinal tract and hepatobiliary tree. Epigenetic modifications of DNA in cancer and precancerous lesions offer hope and the promise of novel biomarkers for early cancer detection, prediction, prognosis, and response to treatment. Furthermore, reversal of epigenetic changes represents a potential target of novel therapeutic strategies and medication design. In the future, it is anticipated that innovative diagnostic tests, treatment regimens, and even lifestyle modifications will be based on epigenetic mechanisms and be incorporated into the practice of medicine.

Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1^-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.

Wilson disease (WD) is a hepatoneurological disorder caused by mutations in the copper‐transporter, ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurological symptoms. We demonstrate that in Atp7b−/− mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b−/− mice identified dysregulation of nuclear receptors (NRs), especially the liver X receptor (LXR)/retinoid X receptor heterodimer, as an important event in WD pathogenesis. Treating Atp7b−/− mice with the LXR agonist, T0901317, ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized, and liver function and histology were improved. Conclusions: The results demonstrate the major role of an altered NR function in the pathogenesis of WD and suggest that modulation of NR activity should be explored as a supplementary approach to improving liver function in WD. (Hepatology 2016;63:1828‐1841)

Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration–approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL)‐induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half‐life. To overcome this problem, we previously generated PEGylated TRAIL (TRAIL_PEG) that has a much longer half‐life in rodents than native‐type TRAIL. In this study, we demonstrate that intravenous TRAIL_PEGhas a markedly extended half‐life over native‐type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAIL_PEGdirectly induces apoptosis of aHSCsin vivoand ameliorates carbon tetrachloride‐induced fibrosis/cirrhosis in rats by simultaneously down‐regulating multiple key fibrotic markers that are associated with aHSCs.Conclusion: TRAIL‐based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. (Hepatology2016;64:209–223)

Racial and ethnic disparities persist in access to the liver transplantation (LT) waiting list; however, there is limited knowledge about underlying system‐level factors that may be responsible for these disparities. Given the complex nature of LT candidate evaluation, a human factors and systems engineering approach may provide insights. We recruited participants from the LT teams (coordinators, advanced practice providers, physicians, social workers, dieticians, pharmacists, leadership) at two major LT centers. From December 2020 to July 2021, we performed ethnographic observations (participant–patient appointments, committee meetings) and semistructured interviews (N = 54 interviews, 49 observation hours). Based on findings from this multicenter, multimethod qualitative study combined with the Systems Engineering Initiative for Patient Safety 2.0 (a human factors and systems engineering model for health care), we created a conceptual framework describing how transplant work system characteristics and other external factors may improve equity in the LT evaluation process. Participant perceptions about listing disparities described external factors (e.g., structural racism, ambiguous national guidelines, national quality metrics) that permeate the LT evaluation process. Mechanisms identified included minimal transplant team diversity, implicit bias, and interpersonal racism. A lack of resources was a common theme, such as social workers, transportation assistance, non–English‐language materials, and time (e.g., more time for education for patients with health literacy concerns). Because of the minimal data collection or center feedback about disparities, participants felt uncomfortable with and unadaptable to unwanted outcomes, which perpetuate disparities. We proposed transplant center–level solutions (i.e., including but not limited to training of staff on health equity) to modifiable barriers in the clinical work system that could help patient navigation, reduce disparities, and improve access to care. Our findings call for an urgent need for transplant centers, national societies, and policy makers to focus efforts on improving equity (tailored, patient‐centered resources) using the science of human factors and systems engineering.