Mild Thrombocytopenia, a Predictor of Outcomes After Laparoscopic Cholecystectomy: Assessment of Surgical Risk in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: A common cause of mild thrombocytopenia is chronic liver disease, the most common etiology being metabolic dysfunction-associated steatotic liver disease (MASLD). Mild thrombocytopenia is a well-defined, independent marker of hepatic fibrosis in patients with chronic liver disease. Currently, there is a paucity of information available to characterize perioperative risk in patients with MASLD; therefore, the characterization of perioperative morbidity is paramount. We used a platelet threshold of 150×10 9 as a surrogate for fibrosis in patients undergoing laparoscopic cholecystectomy to study its effect on perioperative complications and mortality. PATIENTS AND METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for laparoscopic cholecystectomies occurring from 2005 through 2018. Demographic differences between patients with and without thrombocytopenia were evaluated using the t test or the χ 2 test, whereas adjusted and unadjusted differences in outcome risk were evaluated using log-binomial regression models. RESULTS: We identified 437,630 laparoscopic cholecystectomies of which 6.9% included patients with thrombocytopenia. Patients with thrombocytopenia were more often males, older, and with chronic disease. Patients with thrombocytopenia and higher Aspartate Aminotransferase to Platelet Ratio Index scores had 30-day mortality rates risk ratio of 5.3 (95% CI: 4.8-5.9), with higher complication rates risk ratio of 2.4 (95% CI: 2.3-2.5). The most frequent complications included the need for transfusion, renal, respiratory, and cardiac. CONCLUSIONS: Perioperatively, patients with mild thrombocytopenia undergoing laparoscopic cholecystectomy had higher mortality rates and complications compared with patients with normal platelet counts. Thrombocytopenia may be a promising, cost-effective tool to identify patients with MASLD and estimate perioperative risk, especially if used in high-risk populations.

ETS Proto-oncogene 1 Transcriptionally Up-regulates the Cholangiocyte Senescence-associated Protein Cyclin-dependent Kinase Inhibitor 2A.

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory cholangiopathy (disease of the bile ducts) of unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and that neuroblastoma RAS viral oncogene homolog (NRAS) is activated in PSC cholangiocytes. Additionally, persistent microbial insult (e.g. LPSs) induces cyclin-dependent kinase inhibitor 2A (CDKN2A/p16INK4a) expression and senescence in cultured cholangiocytes in an NRAS-dependent manner. However, the molecular mechanisms involved in LPS-induced cholangiocyte senescence and NRAS-dependent regulation of CDKN2A remain unclear. Using our in vitro senescence model, we found that LPS-induced CDKN2A expression coincided with a 4.5-fold increase in ETS1 (ETS proto-oncogene 1) mRNA, suggesting that ETS1 is involved in regulating CDKN2A This idea was confirmed by RNAi-mediated suppression or genetic deletion of ETS1, which blocked CDKN2A expression and reduced cholangiocyte senescence. Furthermore, site-directed mutagenesis of a predicted ETS-binding site within the CDKN2A promoter abolished luciferase reporter activity. Pharmacological inhibition of RAS/MAPK reduced ETS1 and CDKN2A protein expression and CDKN2A promoter-driven luciferase activity by ∼50%. In contrast, constitutively active NRAS expression induced ETS1 and CDKN2A protein expression, whereas ETS1 RNAi blocked this increase. Chromatin immunoprecipitation-PCR detected increased ETS1 and histone 3 lysine 4 trimethylation (H3K4Me3) at the CDKN2A promoter following LPS-induced senescence. Additionally, phospho-ETS1 expression was increased in cholangiocytes of human PSC livers and in the Abcb4 (Mdr2)-/- mouse model of PSC. These data pinpoint ETS1 and H3K4Me3 as key transcriptional regulators in NRAS-induced expression of CDKN2A, and this regulatory axis may therefore represent a potential therapeutic target for PSC treatment.