Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute-on-Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid-Dependent Monocyte Activation.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. APPROACHES & RESULTS: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14+ monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14+ cells without increasing phagocytic capacity. CONCLUSIONS: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.

Late recurrence after surgery for cholangiocarcinoma: implications for follow-up?

BACKGROUND: Biliary tract cancer is uncommon, but has a high rate of early recurrence and a poor prognosis. There is only limited information on patients surviving more than 5 years after resection. METHODS: We report a patient who developed recurrence 8 years after resection of cholangiocarcinoma. Descriptions of late recurrence after excision of cholangiocarcinoma are reviewed. RESULTS: Few long-term survivors with biliary tract cancer have been reported. The survivors tend to have well differentiated or papillary tumors. The present case had no recurrence for 8 years despite poor prognostic factors including poor differentiation, invasion through the muscle wall and perineural invasion. It has been suggested that tumor cells left after the first operation grow and present as late recurrence. There is a need to differentiate a new primary and field change from recurrence of the previous tumor. CONCLUSIONS: Long-term follow-up after resection of cholangiocarcinoma is needed because late recurrence after 5 years occurs. The mortality rate between 5 and 10 years after resection of cholangiocarcinoma ranges from 6% to 43% in different series. Early detection of local recurrence may give an opportunity for further surgical resection.