Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability

Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis with a high incidence of death from sepsis. Here, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine(LPC)-autotaxin(ATX)-lysophosphatidylcholinic acid (LPA) pathway. METHODS: 96 ALF patients, 71 healthy controls (HC), 104 patients with cirrhosis and 31 septic patients were recruited. The pathways of interest were identified based on multivariate statistical analysis of proton nuclear magnetic resonance (1HNMR) spectroscopy, untargeted ultraperformance liquid chromatography-mass spectrometry (UPLC-MS)-based lipidomics and validated with a targeted metabolomics panel. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. LPA receptor (LPAR) transcript-level expression of monocytes was investigated and the effect of LPAR antagonism was also examined in vitro. RESULTS: LPC 16:0 was found highly discriminant between ALF and HC. There was an increase in ATX and LPA in ALF compared to HC and sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in ALF patients with poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without effect on T and NK/CD56+T cells immune checkpoints. LPAR1 and 3 antagonism in culture reversed the LPA effect on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPARs genes, were differently expressed and upregulated in monocytes from ALF patients compared to controls. CONCLUSION: Reduced amounts of LPCs are biomarkers of poor prognosis in patients with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors. IMPACT AND IMPLICATIONS: Liver disease is the 5th leading cause of death in the UK and rising in incidence. Acute liver failure occurs on the background of normal liver function and mostly in young adults. Acute admissions to hospital and intensive care units are rising in the UK and worldwide. We identified a metabolic signature of acute liver failure and investigated the immunometabolic role of the Lysophosphatdylcholine(LPC)-Autotaxin (ATX)-Lysophosphatidylcholinic acid (LPA) pathway in order to find a mechanistic explanation for monocyte behaviour and find possible therapeutic target(s) to modulate the systemic immune response in ALF. At present, no selective immune based therapies exist. We were able to modulate monocyte phenotype and function in vitro and aim to extend findings to murine models of ALF before could apply this treatment to patients. Future therapies may be based on the enhancement of resolution through metabolic modulation and therefore the role of specific lipids in this pathway require elucidation and the relative merits of ATX inhibition, LPAR blockade or lipid-based therapies answered. This application aims to make a step change in meeting this knowledge gap and definitively elucidate these immune-metabolic pathways using an experimental medicine approach, thus finding the most effective therapeutic targets

Evolution of laparoscopic left lateral sectionectomy without the Pringle maneuver: through resection of benign and malignant tumors to living liver donation

BACKGROUND: Laparoscopic left lateral sectionectomy (LLS) has gained popularity in its use for benign and malignant tumors. This report describes the evolution of the authors' experience using laparoscopic LLS for different indications including living liver donation. METHODS: Between January 2004 and January 2009, 37 consecutive patients underwent laparoscopic LLS for benign, primary, and metastatic liver diseases, and for one case of living liver donation. Resection of malignant tumors was indicated for 19 (51%) of the 37 patients. RESULTS: All but three patients (deceased due to metastatic cancer disease) are alive and well after a median follow-up period of 20 months (range, 8-46 months). Liver cell adenomas (72%) were the main indication among benign tumors, and colorectal liver metastases (84%) were the first indication of malignancy. One case of live liver donation was performed. Whereas 16 patients (43%) had undergone a previous abdominal surgery, 3 patients (8%) had LLS combined with bowel resection. The median operation time was of 195 min (range, 115-300 min), and the median blood loss was of 50 ml (range, 0-500 ml). Mild to severe steatosis was noted in 7 patients (19%) and aspecific portal inflammation in 11 patients (30%). A median free margin of 5 mm (range, 5-27 mm) was achieved for all cancer patients. The overall recurrence rate for colorectal liver metastases was of 44% (7 patients), but none recurred at the surgical margin. No conversion to laparotomy was recorded, and the overall morbidity rate was 8.1% (1 grade 1 and 2 grade 2 complications). The median hospital stay was 6 days (range, 2-10 days). CONCLUSIONS: Laparoscopic LLS without portal clamping can be performed safely for cases of benign and malignant liver disease with minimal blood loss and overall morbidity, free resection margins, and a favorable outcome. As the ultimate step of the learning curve, laparoscopic LLS could be routinely proposed, potentially increasing the donor pool for living-related liver transplantation

An Investigation into the Poor Survival of an Endangered Coho Salmon Population

To investigate reasons for the decline of an endangered population of coho salmon (O. kisutch), 190 smolts were acoustically tagged during three consecutive years and their movements and survival were estimated using the Pacific Ocean Shelf Tracking project (POST) array. Median travel times of the Thompson River coho salmon smolts to the lower Fraser River sub-array were 16, 12 and 10 days during 2004, 2005 and 2006, respectively. Few smolts were recorded on marine arrays. Freshwater survival rates of the tagged smolts during their downstream migration were 0.0–5.6% (0.0–9.0% s.e.) in 2004, 7.0% (6.2% s.e.) in 2005, and 50.9% (18.6% s.e.) in 2006. Overall smolt-to-adult return rates exhibited a similar pattern, which suggests that low freshwater survival rates of out-migrating smolts may be a primary reason for the poor conservation status of this endangered coho salmon population

Residence, income and cancer hospitalizations in British Columbia during a decade of policy change

BACKGROUND: Through the 1990s, governments across Canada shifted health care funding allocation and organizational foci toward a community-based population health model. Major concerns of reform based on this model include ensuring equitable access to health and health care, and enhancing preventive and community-based resources for care. Reforms may act differentially relative to specific conditions and services, including those geared to chronic versus acute conditions. The present study therefore focuses on health service utilization, specifically cancer hospitalizations, in British Columbia during a decade of health system reform. METHODS: Data were drawn from the British Columbia Linked Health Data resource; income measures were derived from Statistics Canada 1996 Census public use enumeration area income files. Records with a discharge (separation) date between 1 January 1991 and 31 December 1998 were selected. All hospitalizations with ICD-9 codes 140 through 208 (except skin cancer, code 173) as principal diagnosis were included. Specific cancers analyzed include lung; colorectal; female breast; and prostate. Hospitalizations were examined in total (all separations), and as divided into first and all other hospitalizations attributed to any given individual. Annual trends in age-sex adjusted rates were analyzed by joinpoint regression; longitudinal multivariate analyses assessing association of residence and income with hospitalizations utilized generalised estimating equations. Results are evaluated in relation to cancer incidence trends, health policy reform and access to care. RESULTS: Age-sex adjusted hospitalization rates for all separations for all cancers, and lung, breast and prostate cancers, decreased significantly over the study period; colorectal cancer separations did not change significantly. Rates for first and other hospitalizations remained stationary or gradually declined over the study period. Area of residence and income were not significantly associated with first hospitalizations; effects were less consistent for all and other hospitalizations. No interactions were observed for any category of separations. CONCLUSIONS: No discontinuities were observed with respect to total hospitalizations that could be associated temporally with health policy reform; observed changes were primarily gradual. These results do not indicate whether equity was present prior to health care reform. However, findings concur with previous reports indicating no change in access to health care across income or residence consequent on health care reform