Golgi protein-73:A biomarker for assessing cirrhosis and prognosis of liver disease patients

BACKGROUND Reliable biomarkers of cirrhosis,hepatocellular carcinoma(HCC),or progression of chronic liver diseases are missing.In this context,Golgi protein-73(GP73)also called Golgi phosphoprotein-2,was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells.As a result,GP73 expression was found primarily in biliary epithelial cells,with only slight detection in hepatocytes.However,in patients with acute or chronic liver diseases and especially in HCC,the expression of GP73 is significantly up-regulated in hepatocytes.So far,few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression.AIM To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression.METHODS GP73 serum levels were retrospectively determined by a novel GP73 ELISA(QUANTA Lite®GP73,Inova Diagnostics,Inc.,Research Use Only)in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa,Greece(n=366)and Debrecen,Hungary(n=266).Aspartate aminotransferase(AST)/Platelets(PLT)ratio index(APRI)was also calculated at the relevant time points in all patients.Two hundred and three patients had chronic hepatitis B,183 chronic hepatitis C,198 alcoholic liver disease,28 autoimmune cholestatic liver diseases,15 autoimmune hepatitis,and 5 with other liver-related disorders.The duration of follow-up was 50(57)mo[median(interquartile range)].The development of cirrhosis,liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines.In particular,the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein(AFP)determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients.RESULTS Increased serum levels of GP73(>20 units)were detected at initial evaluation in 277 out of 632 patients(43.8%).GP73-seropositivity correlated at baseline with the presence of cirrhosis(96.4%vs 51.5%,P<0.001),decompensation of cirrhosis(60.3%vs 35.5%,P<0.001),presence of HCC(18.4%vs 7.9%,P<0.001)and advanced HCC stage(52.9%vs 14.8%,P=0.002).GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score[Area under the curve(AUC)(95%CI):0.909(0.885-0.934)vs 0.849(0.813-0.886),P=0.003].Combination of GP73 with APRI improved further the accuracy(AUC:0.925)compared to GP73(AUC:0.909,P=0.005)or APRI alone(AUC:0.849,P<0.001).GP73 levels were significantly higher in HCC patients compared to non-HCC[22.5(29.2)vs 16(20.3)units,P<0.001)and positively associated with BCLC stage[stage 0:13.9(10.8);stage A:17.1(16.8);stage B:19.6(22.3);stage C:32.2(30.8);stage D:45.3(86.6)units,P<0.001]and tumor dimensions[very early:13.9(10.8);intermediate:19.6(18.4);advanced:29.1(33.6)units,P=0.004].However,the discriminative ability for HCC diagnosis was relatively low[AUC(95%CI):0.623(0.570-0.675)].Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline,was prognostic of higher rates of decompensation(P=0.036),HCC development(P=0.08),and liver-related deaths(P<0.001)during follow-up.CONCLUSION GP73 alone appears efficient for detecting cirrhosis and superior to APRI determination.In combination with APRI,its diagnostic performance can be further improved.Most importantly,the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and nonviral chronic liver diseases.

Efficient management of secondary haemophagocytic lymphohistiocytosis with intravenous steroids and γ-immunoglobulin infusions

BACKGROUND Secondary haemophagocytic lymphohistiocytosis(sHLH)is a rare lifethreatening condition mainly associated with underlying infections,malignancies,and autoimmune or immune-mediated diseases.AIM To analyse all sHLH cases that were diagnosed and managed under real-world circumstances in our department focusing on the treatment schedule and the outcome.METHODS Prospectively collected data from all adult patients fulfilling the criteria of sHLH who diagnosed and managed from January 1,2010 to June 1,2018,in our department of the tertiary care university hospital of Larissa,Greece,were analysed retrospectively(n=80;52%male;median age:55 years).The electronic records and/or written charts of the patients were reviewed for the demographic characteristics,clinical manifestations,underlying causes of sHLH,laboratory parameters,treatment schedule and 30-d-mortality rate.Most of patients had received after consent intravenousγ-immunoglobulin(IVIG)for 5 d(total dose 2 g/kg)in combination with intravenous steroid pulses followed by gradual tapering of prednisolone.RESULTS Seventy-five patients(94%)reported fever>38.5°C,47(59%)had liver or spleen enlargement and 76(95%)had ferritin>500 ng/mL including 20(25%)having considerably high levels(>10000 ng/mL).Anaemia and thrombocytopenia occurred in 72%and leucopoenia in 47%of them.Underlying infections were diagnosed in 59 patients(74%)as follows:leishmaniasis alone in 15/80(18.9%),leishmaniasis concurrently with Coxiella Burnetti or non-Hodgkin lymphoma in 2/80(2.5%),bacterial infections in 14/80(17.5%)including one case with concurrent non-Hodgkin lymphoma,viral infections in 13/80(16.3%),fungal infections in 2/80(2.5%),infections by mycobacteria in 1/80(1.3%)and unidentified pathogens in 12/80(15%).Seventy-two patients(90%)had received combination treatment with IVIG and intravenous steroids.Overall,sHLH resolved in 76%of patients,15%died within the first month but 82.5%of patients were still alive 6 mo after diagnosis.Univariate analysis showed older age,anaemia,thrombocytopenia,low fibrinogen,disseminated intravascular coagulation(DIC),and delay of diagnosis as factors that negatively affected remission.However,multivariate analysis showed low platelets and DIC as the only independent predictors of adverse outcome.CONCLUSION sHLH still carries a remarkable morbidity and mortality.Underlying infections were the major cause and therefore,they should be thoroughly investigated in patients with sHLH.Early recognition and combination treatment with IVIG and corticosteroids seem an efficient treatment option with successful outcome in this life-threatening condition.