ABSTRACT
INTRODUCTION: Protein C (PrC), a physiological anticoagulant, regulates inflammation and cell death and has known predictive/therapeutic roles in sepsis. Accumulating evidences suggest plasma hypercoagulability results in progression of fibrosis and formation of microclots causing end-organ dysfunction. We investigated a possible association between natural anticoagulants-PrC, protein S (PrS) and antithrombin III (AT)-and clinical outcomes in cirrhotics. METHODS: Functional PrC, PrS and AT were analysed in 515 cirrhotic patients and compared with 229 noncirrhotics. Among those with cirrhosis, we conducted multivariable predictive model on 3-month survival to assess the prognostic ability of anticoagulants. RESULTS: Protein C (P < .001), PrS (P < .001) and AT (P < .001) levels were lower in cirrhotics compared with noncirrhotics. In addition, patients with Child-Pugh (CP)-C had significantly lower (P < .05) functional PrC, PrS and AT levels than CP-B, CP-A and noncirrhotic patients. Low PrC function correlated with markers of liver dysfunction and inflammation: INR(r = -.72, P < .001), bilirubin (r = -.620, P < .001), albumin (r = .539, P < .001), creatinine (r = -.417, P < .001), ferritin (r = -.68, P = .035), procalcitonin (r = -.79, P = .01), raised ESR (r = .56, P < .001) and liver fibrosis (r = -.840, P < .001). Patients who died (n = 160) had significantly lower median PrC function (23.8%, 16.3-33.0]) compared with those who remained alive (74.9%, [59.7-92.5]); P < .001. In a multivariable predictive model using PrC, and MELD score, we found a significant impact of low PrC levels on survival (P < .001, IRR = 0.97, 95% CI = 0.96-0.98). Receiver operating characteristic (ROC) curve analysis revealed that functional PrC levels <52% were associated with increased mortality (P < .001). CONCLUSION: Low functional protein C level correlated with markers of liver dysfunction, inflammation and sepsis and independently predicted mortality at 3 months in cirrhotics, especially if functional levels were <52%.
Subject(s)
Liver Cirrhosis/diagnosis , Protein C/analysis , Adult , Aged , Antithrombin III/analysis , Biomarkers/blood , Case-Control Studies , Female , Humans , Liver Cirrhosis/blood , Male , Middle Aged , Predictive Value of Tests , Prognosis , Protein S/analysis , ROC CurveABSTRACT
BACKGROUND: Severe alcoholic hepatitis patients have high mortality and limited response to corticosteroids. Microvesicles reflect cellular stress and disease conditions. AIMS: To investigate whether microvesicles are associated with severity, response to steroid therapy and inflammation in severe alcoholic hepatitis. METHODS: Microvesicles originating from different cells were studied pre-therapy in 101 patients; (71 responder to corticosteroid therapy and 30 nonresponders) and 20 healthy controls. Microvesicles and cells were determined in peripheral and hepatic vein samples using flow cytometry and correlated with outcomes. Inflammatory signalling pathways and functional alterations of immune cells after stimulation with microvesicles were also investigated. RESULTS: Microvesicles mean levels were higher in nonresponders for T cells (CD3+ CD4+ ; 10.1 MV/µL vs 5.4; P = 0.06), macrophages (CD68+ CD11b+ ; 136.5 vs 121.9 MV/µL; P = 0.01), haematopoietic stem-cells (CD45+ CD34+ ; 116.8 vs 13.4 MV/µL; P = 0.0001) and hepatocytes (ASGPR+ ; 470 vs 361 MV/µL; P = 0.01); the latter two predicting steroid nonresponse in 94% patients at baseline in peripheral plasma. Microvesicle levels correlated with histological and liver disease severity indices. Whereas, in non-responders hepatic vein CD34+ cells were lower (P = 0.02), the CD34+ microvesicles there from were higher (P = 0.04), thus suggesting impaired regeneration. Also, microvesicles of 0.2-0.4 µm size were higher in nonresponders (P < 0.03) at baseline. Microvesicles from patients trigger more (P = 0.04) ROS generation, TNF-α production (P = 0.04) and up-regulate pro-inflammatory cytokine related genes in neutrophils in vitro. CONCLUSIONS: Pre-therapy peripheral plasma levels of CD34+ and ASGPR+ microvesicles are reliable non-invasive markers of steroid nonresponse and mortality in patients with severe alcoholic hepatitis.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Cell-Derived Microparticles , Hepatic Veins/pathology , Hepatitis, Alcoholic/drug therapy , Hepatitis, Alcoholic/pathology , Liver/pathology , Adult , Antigens, CD34/blood , Asialoglycoprotein Receptor/blood , Biomarkers/blood , Drug Resistance , Humans , Liver/blood supply , Middle AgedABSTRACT
AIM: The aim of this study was to investigate the clinical and pathological features of hepatic sarcoidosis in symptomatic cases. METHODS: Twenty-two symptomatic hepatic sarcoidosis cases were included in the study. Hepatic sarcoidosis was determined by typical imaging, histopathology, and high angiotensin-converting enzyme levels. Demographic data, laboratory data, imaging findings, liver biopsies, and clinical findings were analyzed. Portal hypertension (PH) was defined by the presence of ascites and/or varices; imaging findings suggestive of PH-splenomegaly (> 12 cm on longest axis); portal vein dilation (> 13 mm); collateral vessel formation; and hepatic venous pressure gradient ≥ 6 mmHg. RESULTS: Mean age was 49.63 ± 10.7 years. Liver tests showed elevated serum alkaline phosphatase and gamma-glutamyl transpeptidase levels (95%). Serum albumin levels were low (< 3 g/dl) in 32% of the patients. Histologically, hepatic granulomas were located in the portal/periportal areas, with or without parenchymal involvement (77%). Duct damage (27%), absent portal veins (32%), and hepatomegaly (41%) were also observed. Clinically, chronic cholestatic symptoms and PH features were observed in 41% and 50% of the patients, respectively. Three-quarters of patients with PH features were non-cirrhotic. Cirrhosis and bleeding varices were observed in 14%. Hepatic sarcoidosis overlaps with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) was observed in two cases. CONCLUSIONS: Sarcoidosis causes significant hepatic disease. PH and jaundice are main clinical presentations in liver sarcoidosis patients. Imaging findings of PH should be carefully reviewed, as it can occur even before the establishment of cirrhosis. Hepatic sarcoidosis mimics and overlaps with PBC and PSC.
Subject(s)
Bone Marrow/pathology , Bone Marrow/virology , Cytomegalovirus Infections/diagnosis , Granuloma/diagnosis , Adult , Antiviral Agents/therapeutic use , Bone Marrow/drug effects , Bone Marrow/immunology , Cytomegalovirus/drug effects , Cytomegalovirus/immunology , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/pathology , Fibrin/metabolism , Glomerulonephritis/immunology , Glomerulonephritis/pathology , Glomerulonephritis/surgery , Granuloma/drug therapy , Granuloma/immunology , Granuloma/pathology , Humans , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Male , Viral Load/drug effectsABSTRACT
BACKGROUND & AIMS: Serum ferritin is a known marker of hepatic necro-inflammation and has been studied to predict 1 year mortality and post-transplant survival in decompensated cirrhotics. However, there are no studies evaluating ferritin as a predictor of early mortality. We investigated whether serum ferritin levels could predict 15 day and 30 day mortality in patients with decompensated cirrhosis. METHODS: 318 patients with decompensated cirrhosis were included. RESULTS: Patients of decompensated cirrhosis [257 males, mean age of 51 [±13]years, were followed for a median of 31 days. Serum ferritin levels were significantly different between survivors and non-survivors [p<0.001] and showed significant correlation with MELD score [p<0.001], CTP score [p<0.001], leucocyte counts [TLC] [p<0.001], serum sodium [p<0.001], ACLF grades [p=0.005], spontaneous bacterial peritonitis [SBP] [p=0.02], hepatic encephalopathy [HE] [p<0.001] and hepatorenal syndrome [HRS] [p=0.012]. Serum ferritin, etiology, MELD, HE, CTP score, sodium, TLC, and ACLF grades were significant predictors of mortality on univariate analysis. Ferritin [p=0.04, HR 1.66 95% CI (1.02-2.73)] was a significant predictor of early mortality on multivariate analysis along with HE [p=0.006, HR 3.47 95% CI (2.13-8.41)] (Model 1), TLC [p=0.02, HR 1.81 95% CI (1.06-3.07)] (Model 2), ACLF grades [p=0.018, HR 2.013,95% CI (1.126-3.60)], and CTP score [p<0.0001, HR 1.36 95% CI (1.17-1.59)] (Model 3). CONCLUSION: Serum ferritin levels correlate with severity of hepatic decompensation and are associated with early liver related death independent of the MELD score in hospitalized patients with decompensated cirrhosis. This could also have a potential therapeutic implication.