Hepatology : official journal of the American Association for the Study of Liver Diseases
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Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4(-/-) and wild-type mice were subjected to two models of chronic liver injury (CCl(4) and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus-induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl(4) and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf-beta [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4(-/-) mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8(+) T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. ⋯ The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies.
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The outcomes of patients with acute liver failure (ALF) vary greatly according to etiology. Emergency adult-to-adult living-donor liver transplantation (adult LDLT) would help address the shortage of available organs for patients with ALF, especially in hepatitis B virus (HBV)-endemic areas. We analyzed a prospective database of 110 consecutive adult patients with ALF. ALF was defined as sudden development of severe coagulopathy and encephalopathy within 26 weeks of onset of symptoms. In about 90% of patients, ALF was caused by etiologies that usually result in poor outcomes, including HBV infection (37%). Three cases (3%) were associated with acetaminophen overdose. Of the 99 patients listed for emergency liver transplantation, four (4%) underwent deceased-donor liver transplantation (DDLT), and 40 (40%) underwent adult LDLT. The 1-year survival rate of adult LDLT patients was 85%. Of the 55 patients listed but not transplanted, 45 (82%) died within a median of 7 days (range, 1-90 days). Multivariate analysis showed that adult LDLT (hazard ratio [HR] 0.10, P < 0.01) and DDLT (HR 0.12, P = 0.04) were associated with decreased mortality, whereas older age (HR 1.03, P = 0.01) and higher Model for End-stage Liver Disease (MELD) (HR 1.03, P = 0.04) was associated with increased mortality of patients. There was no living donor mortality. Eight (17.8%) and three (6.7%) living donors experienced grade 1 and 2 complications, respectively. ⋯ Emergency adult LDLT can be performed expeditiously and safely for patients with ALF, and greatly improves the survival rate. As the window during which transplantation is possible is limited, emergency adult LDLT should be considered one of the first-line treatment options in patients with ALF, especially in regions in which ALFs are caused by etiologies associated with poor outcome and the supply of organs is severely limited.
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Review Meta Analysis
Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.
Vasoconstrictor drugs may improve renal function in hepatorenal syndrome (HRS), but the effect on mortality has not been established. We therefore performed a systematic review of randomized trials on vasoconstrictor drugs for type 1 or type 2 HRS. Mortality was the primary outcome measure. Eligible trials were identified through electronic and manual searches. Intention-to-treat random effects meta-analyses were performed. Ten randomized trials on terlipressin alone or with albumin, octreotide plus albumin, and noradrenalin plus albumin were included. The total number of patients was 376. Overall, vasoconstrictor drugs used alone or with albumin reduced mortality compared with no intervention or albumin (relative risk [RR], 0.82; 95% confidence interval [CI], 0.70-0.96). In subgroup analyses, the effect on mortality was seen at 15 days (RR, 0.60; 95% CI, 0.37-0.97) but not at 30 days (RR, 0.74; 95% CI, 0.40-1.39), 90 days (RR, 0.89; 95% CI, 0.66-1.22), or 180 days (RR, 0.83; 95% CI, 0.65-1.05). Subgroup analyses stratified by the treatments assessed showed that terlipressin plus albumin reduced mortality compared with albumin (RR, 0.81; 95% CI, 0.68-0.97). The effect was seen in subgroup analyses of type 1 but not type 2 HRS. The remaining trials were small and found no beneficial or harmful effects of the treatments assessed. ⋯ Terlipressin plus albumin may prolong short-term survival in type 1 HRS. The duration of the response should be considered when making treatment decisions and in the timing of potential liver transplantations. Considering the small number of patients included, the evidence does not allow for treatment recommendations regarding type 2 HRS or any of the remaining treatment comparisons assessed.
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Sepsis is physiologically viewed as a proinflammatory and procoagulant response to invading pathogens. There are three recognized stages in the inflammatory response with progressively increased risk of end-organ failure and death: sepsis, severe sepsis, and septic shock. Patients with cirrhosis are prone to develop sepsis, sepsis-induced organ failure, and death. ⋯ There are no randomized studies that have been specifically performed in patients with cirrhosis and severe sepsis to evaluate treatments that have been shown to improve outcome in patients without cirrhosis who have severe sepsis or septic shock. These treatments include recombinant human activated C protein and protective-ventilation strategy for respiratory failure. Other treatments should be evaluated in the cirrhotic population with severe sepsis including the early use of antibiotics in "non-SBP" infections, vasopressor therapy, hydrocortisone, renal-replacement therapy and liver support systems, and selective decontamination of the digestive tract or oropharynx.