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Plasma angiopoietin 2 as a novel prognostic biomarker in alcohol- related cirrhosis and hepatitis

Liver Research 2022年第1期6卷 21-29页

作者： victoria tatiana kronsten Josepmaria Argemi Ada Sera Kurt Godhev Mannakat Vijay Jennifer Marie Ryan Ramon Bataller Debbie Lindsay Shawcross Institute of Liver Studies Department of Inflammation BiologySchool of Immunology and Microbial SciencesFaculty of Life Sciences and MedicineKing's College LondonUK Division of Gastroenterology Hepatology and NutritionPittsburgh Liver Research CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA Liver Unit.University of Navarra Clinic Hepatology Program.Center for Applied Medical Research(CIMA)Navarra Research InstitutePamplonaSpain Department of Hepatology Royal Free HospitalLondonUK

Background and aim:Severe alcoholic hepatitis(SAH),the most florid form of alcohol-related liver dis-ease(ALD),has a mortality rate of 16%at 28 days.The angiopoietin-Tie 2 system regulates angiogenesis and inflammation,both of which are implicated in the pathogenesis of ALD.This study examined plasma and hepatic gene expression of angiopoietin 1(ANG1)and angiopoietin 2(ANG2)in patients with SAH and ALD and investigated their roles as prognostic biomarkers.Methods:A case-control study was performed measuring plasma levels of ANG1 and ANG2 by enzyme-linked immunosorbent assay(ELISA)from 30 patients with SAH(Maddrey's discriminant function32),32 patients with ALD cirrhosis and 15 healthy controls(HC).RNA sequencing for ANG1,ANG2,TIE1(codes for Tie1 receptor)and TEK(codes for Tie2 receptor)gene expression from a separate cohort study of 79 patients was also performed.Results:Plasma levels of ANG1 were lower(P=0.010)and ANG2 were higher(P<0.0001)in patients with ALD/SAH compared to HC.The ANG2:ANG1 ratio was higher in those with ALD/SAH compared to HC(P<0.0001).ANG2 levels were the highest in patients who developed sepsis(P=0.030)and those dying within 90 days(P=0.020).ANG2 levels correlated positively with model for end-stage liver disease(MELD)score(r=0.30,P=0.020),Child-Pugh score(r=0.38,P=0.003),international normalized ratio(r=0.41,P=0.001)and white blood cell count(r=0.28,P=0.040)and inversely correlated with albumin(r=0.26,P=0.040).ANG1 gene expression from liver biopsies was higher in SAH than that in HC(P<0.0001),and greater in severe disease(P<0.0001).ANG2 gene expression trended towards being lower in SAH than that in HC(P=0.070)though was upregulated in severe disease(P=0.0003).Conclusions:Plasma ANG2 is raised in SAH and ALD and could be useful as a prognostic biomarker in this patient population.

关键词： Alcohol-related cirrhosis Alcoholic hepatitis Alcohol-related liver disease(ALD) Angiopoietin 1(ANG1) Angiopoietin 2(ANG2)

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Pathophysiology of cerebral oedema in acute liver failure

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World Journal of Gastroenterology 2013年第48期19卷 9240-9255页

作者： Teresa R Scott victoria T kronsten Robin D Hughes Debbie L Shawcross Institute of Liver Studies King’s College London School of Medicine at King’s College Hospital King’s College Hospital London SE5 9RS United Kingdom

Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased intracranial pressure but progression to lifethreatening intracranial hypertension is less frequent than previously described,complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care.The rapid onset of encephalopathy may be dramatic with the development of asterixis,delirium,seizures and coma.Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism.Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema.The mechanism(s)by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis.Current evidence also supports an alternate‘Trojan horse’hypothesis,with glutamine as a carrier of ammonia into mitochondria,where its accumulation results in oxidative stress,energy failure and ultimately astrocyte swelling.Although a complete breakdown of the blood-brain barrier is not evident in human ALF,increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions.At present,there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.

关键词： Cerebral oedema Acute liver failure Ammonia Hepatic encephalopathy Intracranial pressure Intracranial hypertension Cerebral blood flow

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