Bilirubin Molecular Species Play an Important Role in the Pathophysiology of Acute-on-Chronic Liver Failure.

Bilirubin plays a key role in early diagnosis, prognosis, and prevention of liver diseases. Unconjugated bilirubin (UCB) requires conversion to a water-soluble form through liver glucuronidation, producing monoglucuronide (BMG) or diglucuronide bilirubin (BDG) for bile excretion. This study aimed to assess the roles of bilirubin's molecular species-UCB, BMG, and BDG-in diagnosing and understanding the pathogenesis of liver cirrhosis in patients with acute-on-chronic liver failure (ACLF), compensated liver cirrhosis (LC) patients, and healthy individuals. The study included patients with ACLF and compensated LC of diverse etiologies, along with healthy controls. We collected laboratory and clinical data to determine the severity and assess mortality. We extracted bilirubin from serum samples to measure UCB, BMG, and BDG using liquid chromatography-mass spectrometry (LC-MS). The quantification of bilirubin was performed by monitoring the mass charge (m/z) ratio. Of the 74 patients assessed, 45 had ACLF, 11 had LC, and 18 were healthy individuals. Among ACLF patients, the levels of molecular species of bilirubin were UCB 19.69 µmol/L, BMG 47.71 µmol/L, and BDG 2.120 µmol/L. For compensated cirrhosis patients, the levels were UCB 11.29 µmol/L, BMG 1.49 µmol/L, and BDG 0.055 µmol/L, and in healthy individuals, the levels were UCB 6.42 µmol/L, BMG 0.52 µmol/L, and BDG 0.028 µmol/L. The study revealed marked elevations in the bilirubin species in individuals with ACLF compared to those with compensated cirrhosis and healthy controls, underscoring the progression of liver dysfunction. The correlation of BMG and BDG levels with commonly used inflammatory markers suggests a relationship between bilirubin metabolism and systemic inflammation in ACLF.

Association between nonalcoholic steatohepatitis and high serum ferritin levels in type 2 diabetes mellitus.

OBJECTIVE: The aim of this study was to assess the role of elevated serum ferritin levels in the onset, pathological progression and prognosis of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease has been rapidly increasing worldwide. Despite extensive research on the pathogenesis of nonalcoholic fatty liver disease, a lack of sufficient clinical research on the relationship between nonalcoholic fatty liver disease and serum ferritin levels remains. METHODS: We analysed 968 patients with type 2 diabetes mellitus who underwent liver ultrasound examination and had their serum ferritin levels measured. The presence of nonalcoholic fatty liver disease and advanced liver fibrosis was determined through abdominal ultrasound examination and the nonalcoholic fatty liver disease fibrosis score. RESULTS: Compared to that in the non-nonalcoholic fatty liver disease group, the presence of hyperferritinemia was significantly more common in the nonalcoholic fatty liver disease group (83.3 vs. 56.3%, p=0.005). When patients with nonalcoholic fatty liver disease were stratified by the nonalcoholic fatty liver disease fibrosis score, those with advanced liver fibrosis exhibited a higher prevalence of hyperferritinemia (56.3, 78.9, and 88.9% for none, simple steatosis, and advanced fibrosis, respectively; p for trend=0.002). In multivariate logistic regression, liver fibrosis was independently associated with hyperferritinemia (odds ratio [OR] 1.45; 95% confidence interval [CI] 1.18-2.02; p=0.014), and this association remained significant in male patients after adjusting for other risk factors (OR 2.66; 95% CI 1.43-5.48; p=0.026). CONCLUSION: Identifying nonalcoholic fatty liver disease patients at a risk of developing nonalcoholic steatohepatitis and advanced fibrosis is crucial for implementing timely interventions and improving patient outcomes. This study highlights the potential utility of serum ferritin levels as a serum biomarker for identifying nonalcoholic steatohepatitis patients and those at a risk of late-stage fibrosis, particularly in male patients with nonalcoholic fatty liver disease.

Discovery of candidate biomarkers from plasma-derived extracellular vesicles of patients with cirrhosis and hepatocellular carcinoma: an exploratory proteomic study.

Extracellular vesicles (EVs) represent an attractive source of biomarkers due to their biomolecular cargo. The aim of this study was to identify candidate protein biomarkers from plasma-derived EVs of patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Plasma-derived EVs from healthy participants (HP), LC, and HCC patients (eight samples each) were subjected to label-free quantitative proteomic analysis using LC-MS/MS. A total of 248 proteins were identified, and differentially expressed proteins (DEPs) were obtained after pairwise comparison. We found that DEPs mainly involve complement cascade activation, coagulation pathways, cholesterol metabolism, and extracellular matrix components. By choosing a panel of up- and down-regulated proteins involved in cirrhotic and carcinogenesis processes, TGFBI, LGALS3BP, C7, SERPIND1, and APOC3 were found to be relevant for LC patients, while LRG1, TUBA1C, TUBB2B, ACTG1, C9, HP, FGA, FGG, FN1, PLG, APOB and ITIH2 were associated with HCC patients, which could discriminate both diseases. In addition, we identified the top shared proteins in both diseases, which included LCAT, SERPINF2, A2M, CRP, and VWF. Thus, our exploratory proteomic study revealed that these proteins might play an important role in the disease progression and represent a panel of candidate biomarkers for the prognosis and diagnosis of LC and HCC.

Efficacy of blood plasma spectroscopy for early liver cancer diagnostics in obese patients.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide. A considerable proportion of HCC is caused by cirrhosis related to metabolic dysfunction-associated steatohepatitis (MASH). Due to the increasing prevalence of metabolic syndrome, it is estimated that MASH-related HCC will become the most prevalent etiology of HCC. Currently, HCC screening is based on liver ultrasonography; however, the sensitivity of ultrasonography for early HCC stages in obese patients only reaches 23 %. To date, no studied biomarker shows sufficient efficacy for screening purposes. Nevertheless, the usage of spectroscopic methods offers a new perspective, as its potential use would provide cheap, fast analysis of samples such as blood plasma. MATERIAL AND METHODS: We employed a combination of conventional and chiroptical spectroscopic methods to study differences between the blood plasma of obese cirrhotic patients with and without HCC. We included 20 subjects with HCC and 17 without evidence of liver cancer, all of them with body mass index ≥ 30. RESULTS: Sensitivities and specificities reached values as follows: 0.780 and 0.905 for infrared spectroscopy, 0.700 and 0.767 for Raman spectroscopy, 0.840 and 0.743 for electronic circular dichroism, and 0.805 and 0.923 for Raman optical activity. The final combined classification model based on all spectroscopic methods reached a sensitivity of 0.810 and a specificity of 0.857, with the highest area under the receiver operating characteristic curve among all models (0.961). CONCLUSIONS: We suggest that this approach can be used effectively as a diagnostic tool in patients who are not examinable by liver ultrasonography. CLINICAL TRIAL REGISTRATION: NCT04221347.

Omics-based biomarkers as useful tools in metabolic dysfunction-associated steatotic liver disease clinical practice: How far are we?

Unmet needs exist in metabolic dysfunction-associated steatotic liver disease (MASLD) risk stratification. Our ability to identify patients with MASLD with advanced fibrosis and at higher risk for adverse outcomes is still limited. Incorporating novel biomarkers could represent a meaningful improvement to current risk predictors. With this aim, omics technologies have revolutionized the process of MASLD biomarker discovery over the past decades. While the research in this field is thriving, much of the publication has been haphazard, often using single-omics data and specimen sets of convenience, with many identified candidate biomarkers but lacking clinical validation and utility. If we incorporate these biomarkers to direct patients' management, it should be considered that the roadmap for translating a newly discovered omics-based signature to an actual, analytically valid test useful in MASLD clinical practice is rigorous and, therefore, not easily accomplished. This article presents an overview of this area's current state, the conceivable opportunities and challenges of omics-based laboratory diagnostics, and a roadmap for improving MASLD biomarker research.

Neurofilament light chain but not glial fibrillary acidic protein is a potential biomarker of overt hepatic encephalopathy in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis and may cause cerebral damage. Neurodegenerative diseases can induce the release of neuroproteins like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in body fluids, including blood plasma. We investigated whether NfL and GFAP could serve as potential diagnostic plasma biomarkers for overt HE (oHE). MATERIALS AND METHODS: We included 85 patients from three prospective cohorts with different stages of liver disease and HE severity. The following patients were included: 1) 34 patients with primary sclerosing cholangitis (PSC) with compensated disease; 2) 17 patients with advanced liver disease without oHE before elective transjugular intrahepatic portosystemic shunt (TIPS) placement; 3) 17 intensive care unit (ICU) patients with oHE and 17 ICU patients without cirrhosis or oHE. Plasma NfL and GFAP were measured using single molecule assays. RESULTS: ICU oHE patients had higher NfL concentrations compared to pre-TIPS patients or ICU controls (p < 0.05, each). Median GFAP concentrations were equal in the ICU oHE and pre-TIPS patients or ICU controls. Plasma NfL and GFAP concentrations correlated with Model for End-Stage Liver Disease (MELD) scores (R = 0.58 and R = 0.40, p < 0.001, each). CONCLUSIONS: Plasma NfL deserves further evaluation as potential diagnostic biomarker for oHE and correlates with the MELD score.

Development and validation of a noninvasive prediction model for significant hepatic liver fibrosis in Chinese patients with autoimmune hepatitis.

INTRODUCTION AND OBJECTIVES: Autoimmune hepatitis (AIH) is a prevalent noninfectious liver disease. However, there is currently a lack of noninvasive tests appropriate for evaluating liver fibrosis in AIH patients. The objective of this study was to develop and validate a predictive model for noninvasive assessment of significant liver fibrosis (S ≥ 2) in patients to provide a reliable method for evaluating liver fibrosis in individuals with AIH. MATERIALS AND METHODS: The clinical data of 374 AIH patients were analyzed. A prediction model was established through logistic regression in the training set, and bootstrap method was used to validate the models internally. In addition, the clinical data of 109 AIH patients were collected for external verification of the model.The model was expressed as a nomogram, and area under the curve (AUC) of the receiver operating characteristic (ROC), calibration curve, and decision curve analysis were used to evaluate the accuracy of the prediction model. RESULTS: Logistic regression analysis revealed that age, platelet count (PLT), and the A/G ratio were identified as independent risk factors for liver fibrosis in AIH patients (P < 0.05). The diagnostic model that was composed of age, PLT and A/G was superior to APRI and FIB-4 in both the internal validation (0.872, 95%CI: 0.819-0.924) and external validation (0.829, 95%CI: 0.753-0.904). CONCLUSIONS: Our predictive model can predict significant liver fibrosis in AIH patients more accurately, simply, and noninvasively.

A novel non-invasive score for the prediction of advanced fibrosis in patients with chronic hepatitis B.

INTRODUCTION AND OBJECTIVES: Evaluation of liver fibrosis is important for treatment decisions, complications and to predict prognosis in patients with chronic hepatitis B (CHB). Our aim was to develop a new non-invasive fibrosis scoring method and prove its accuracy in the differentiation of no/low grade and advanced fibrosis in patients with CHB. PATIENTS AND METHODS: Our study included 273 chronic hepatitis B patients who underwent liver biopsy from February, 2007 to February, 2019 with medical records retrospectively reviewed. Preparations of these patients were divided into two groups as ≤ 3 no-low grade fibrosis (n=236) and ≥ 4 advanced fibrosis (n=37) according to histological ISHAK fibrosis scoring system. RESULTS: The newly developed AGAP score and other non-invasive fibrosis scores; Fibrosis-4 index, Aspartate aminotransferase to platelets ratio, Gamma glutamyl transpeptidase to platelet ratio, Goteborg University Cirrhosis Index, King's score, Albumin-bilirubin index, Fibrosis cirrhosis index, Fibrosis index, Fibrosis quotient, Lok score and mean and/or median values of Fibroindex were significantly higher in the advanced fibrosis group compared to the no/low grade fibrosis group (p<0.001). However, there was no significant difference in AAR score among the groups (p=0.265). With cut-off value of 4.038, AUROC value of 0.803, sensitivity of 75.7%, specificity of 73.7% and accuracy of 0.740, AGAP score showed the best performance in advanced fibrosis differentiation compared to 12 other non-invasive fibrosis scoring methods. CONCLUSIONS: The newly developed AGAP score showed better performance in patients with CHB compared to 12 other non-invasive fibrosis scores in differentiation of no/low grade fibrosis and advanced fibrosis.

Recovery from Liver Failure and Fibrosis in a Rat Portacaval Anastomosis Model after Neurointermediate Pituitary Lobectomy.

Liver diseases, including cirrhosis, viral hepatitis, and hepatocellular carcinoma, account for approximately two million annual deaths worldwide. They place a huge burden on the global healthcare systems, compelling researchers to find effective treatment for liver fibrosis-cirrhosis. Portacaval anastomosis (PCA) is a model of liver damage and fibrosis. Arginine vasopressin (AVP) has been implicated as a proinflammatory-profibrotic hormone. In rats, neurointermediate pituitary lobectomy (NIL) induces a permanent drop (80%) in AVP serum levels. We hypothesized that AVP deficiency (NIL-induced) may decrease liver damage and fibrosis in a rat PCA model. Male Wistar rats were divided into intact control (IC), NIL, PCA, and PCA+NIL groups. Liver function tests, liver gene relative expressions (IL-1, IL-10, TGF-ß, COLL-I, MMP-9, and MMP-13), and histopathological assessments were performed. In comparison with those in the IC and PCA groups, bilirubin, protein serum, and liver glycogen levels were restored in the PCA+NIL group. NIL in the PCA animals also decreased the gene expression levels of IL-1 and COLL-I, while increasing those of IL-10, TGF-ß, and MMP-13. Histopathology of this group also showed significantly decreased signs of liver damage with lower extent of collagen deposition and fibrosis. Low AVP serum levels were not enough to fully activate the AVP receptors resulting in the decreased activation of cell signaling pathways associated with proinflammatory-profibrotic responses, while activating cell molecular signaling pathways associated with an anti-inflammatory-fibrotic state. Thus, partial reversion of liver damage and fibrosis was observed. The study supports the crucial role of AVP in the inflammatory-fibrotic processes and maintenance of immune competence. The success of the AVP deficiency strategy suggests that blocking AVP receptors may be therapeutically useful to treat inflammatory-fibrotic liver diseases.

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation.

Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1ß were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-ß and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.

Association of IL-9, IL-10, and IL-17 Cytokines With Hepatic Fibrosis in Human Schistosoma mansoni Infection.

This is a case series study to evaluate immunological markers associated with schistosomiasis advanced fibrosis, including 69 patients from an endemic area from the State of Sergipe and from the Hepatology Service of the University Hospital in Sergipe, Brazil. Hepatic fibrosis was classified based on Niamey protocol for ultrasonography (US). Immune response to Schistosoma mansoni antigens was evaluated by stimulating peripheral blood mononuclear cells (PBMCs) from these patients with either adult worm (SWAP-10 µg/ml) or egg (SEA-10 µg/ml) antigens or purified protein derivative of turberculin (PPD-10 µg/ml) or phytohemagglutinin (PHA-1 µg/ml) for 72 h. The levels of IFN-γ, TNF-α, IL-5, IL-10, and IL-17 were measured in these supernatants by ELISA and IL-9 by Luminex. Single nucleotide polymorphisms in IL-17, IL10, and CD209 genes were genotyped using TaqMan probe by qPCR. Higher levels of IL-9, IL-10, and IL-17 were found in PBMC supernatants of patients with advanced hepatic fibrosis. Direct correlations were detected between IL-9 and IL-17 levels with US spleen sizes, portal vein diameters, and periportal thickening. The CD209 rs2287886 AG polymorphism patients produce higher IL-17 levels. Together, these data suggest a role of these cytokines in the immunopathogenesis of advanced fibrosis in human schistosomiasis.

Diagnostic Accuracy of Serum Hyaluronan for Detecting HCV Infection and Liver Fibrosis in Asymptomatic Blood Donors.

Background: The disease caused by hepatitis C virus (HCV) is asymptomatic, silent, and progressive liver disease. In HCV-infected patients the increase in serum HA is associated with the development of hepatic fibrosis and disease progression. Methods: HCV-RNA detection was performed in all serological samples of blood donors that tested positive using HCV Ultra ELISA. Determination of hyaluronan (HA) was performed in positive HCV samples using ELISA-like fluorometric method. The HA content was compared to HCV viral load, genotype of the virus, liver fibrosis as well as ALT and GGT liver biomarkers. Results: Persistently normal ALT (<40 U/L) and GGT (<50 U/L) serum levels were detected in 75% and 69% of the HCV-Infected blood donors, respectively. Based on ROC analysis, the HA value < 34.2 ng/mL is an optimal cut-off point to exclude HCV viremia (specificity = 91%, NPV = 99%). Applying HA value ≥34.2 ng/mL significant liver fibrosis (≥F2) can be estimated in 46% of the HCV-infected blood donors. HA serum level (≥34.2 ng/mL) associated with a high ALT level (>40 U/mL) can correctly identify HCV infection and probable liver fibrosis (sensitivity = 96% and specificity = 90%) in asymptomatic blood donors. Conclusions: A high level of HA (≥34.2 ng/mL) in association with ALT (≥40 U/L) in serum can provide a good clinical opportunity to detect HCV-infected asymptomatic persons that potentially require a liver biopsy confirmation and antiviral treatment to prevent the development of advanced liver fibrosis or cirrhosis.

Concordance between hepatic biopsy and the APRI index (Ast to Platelet Ratio Index) for the diagnosis of cirrhosis in patients with autoimmune liver disease. / Concordancia entre el resultado de la biopsia hepática y el índice APRI (Ast to Platelet Ratio Index) en el diagnóstico de cirrosis en pacientes con enfermedad hepática autoinmune.

INTRODUCTION AND OBJECTIVES: It has been proposed that non-invasive methods may replace liver biopsy for the diagnosis of tissue damage in patients with autoimmune liver disease (ALD). The aim of this study was to determine diagnostic performance and degree of concordance between the APRI index and liver biopsy for diagnosing cirrhosis in these patients. MATERIAL AND METHODS: In a cohort of patients with ALD, the value of the APRI index and liver biopsy results were determined according to the METAVIR score. The AUC and the degree of concordance between an APRI value >2 and a METAVIR score of F4 were evaluated as markers of liver cirrhosis, through a kappa statistic. RESULTS: In total, 70 patients (age 51 ± 13 years) were included. The most common autoimmune liver diseases were primary biliary cirrhosis (PBC) (40%), autoimmune hepatitis (AIH) (24.3%) and AIH-PBC overlap syndrome (32.9%). Cirrhosis was confirmed by biopsy in 16 patients (22.9%). 15 patients (21.4%) had an APRI index >2 (Cirrhosis) and only six met both criteria. The AUC of the APRI was 0.77 (95% CI 0.65-0.88). The degree of concordance between the tests was low for an APRI cut-off point >2 (kappa 0.213; 95% CI 0.094-0.332), as well as for cut-off points >1.5, >1 and >0.5 (kappa 0.213, 0.255, 0.257, respectively) CONCLUSION: Our results suggest that there is little concordance between APRI and liver biopsy for the diagnosis of cirrhosis in patients with ALD. It should therefore not be used as a single diagnostic method to determine cirrhosis.

Hepamet Fibrosis Score in Nonalcoholic Fatty Liver Disease Patients in Mexico: Lower than Expected Positive Predictive Value.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been associated with different negative outcomes in the presence of advanced fibrosis. The Hepamet Fibrosis Score (HFS), a recently described noninvasive score, has shown excellent performance for the detection of advanced fibrosis. The aim of this study was to assess its performance in a Mexican population with NAFLD. METHODS: This was a retrospective cross-sectional study performed in 222 patients with biopsy-proven NAFLD, of whom 33(14%) had advanced fibrosis. We retrieved clinical data from each patient's medical record to compute the HFS, the NAFLD Fibrosis Score (NFS), and the Fibrosis-4 (FIB-4), and assess their performance. RESULTS: When considering the models as continuous variables, the area under the receiving operating characteristics curve of the HFS(0.758) was not different from that of the NFS(0.669, p = 0.09) or FIB-4(0.796, p = 0.1). The HFS had a sensitivity, specificity, positive and negative predictive values of 76.7% (95% CI 57.7-90.1), 90.1% (95% CI 85-93.9), 36.7% (95% CI 19.9-56.1), and 94.3% (95% CI 88.5-97.7), respectively. Indeterminate results (i.e., gray area) were more common with FIB-4 and HFS when compared with NFS [139(63%) and 122(55%) vs 80(36%), p < 0.001]. The variables that were associated with misclassification using the HFS were diabetes [OR 3.40 (95% CI 1.42-8.10), p = 0.006] and age [OR 1.06 (95% CI 1.01-1.11), p = 0.01]. CONCLUSION: The HFS showed sensitivity and specificity similar to that reported in the original publication; however, the positive predictive value was 36.7% at a pretest probability of 14%. The role of the HFS in prospective studies and in combination with other methods should be further explored.

CLIF-C AD Score Predicts Development of Acute Decompensations and Survival in Hospitalized Cirrhotic Patients.

BACKGROUND AND AIMS: Patients with decompensated cirrhosis are at increased risk of mortality, even in absence of ACLF. The CLIF-C AD score (CLIF-C ADs) was proposed as a prognostic score but lacks sufficient validation. Our aim was to describe clinical characteristics and hospital evolution according to score groups and evaluate prognostic capability of CLIF-C ADs alone or in combination with other scores. METHODS: Two hundred and sixty-six patients (55 ± 14 years, ascites in 63%, MELD 14 ± 5) were included, and classified as high, intermediate and low CLIF-C ADs in 13, 60 and 27% of cases. Development of new complications of cirrhosis during hospitalization and survival at 3 months were evaluated. RESULTS: Patients with high CLIF-C ADs had more severe systemic inflammation parameters and higher frequency of organ dysfunction. CLIF-C ADs ≥ 60, when compared to intermediate and low groups, was associated with higher incidence of complications of cirrhosis (90% vs 70% and 49%, p < 0.001) and lower survival (93%, 80% and 50%, p < 0.0001). In multivariate analysis, CLIF-C ADs, ascites and MELD were predictors of survival [(AUROC 0.76 (95% CI 0.69-0.83)]. Absence of ascites or MELD < 14 identified patients with intermediate CLIF-C ADs and good survival (89 and 84%, respectively). CONCLUSION: CLIF-C ADs predicts survival in cirrhotic patients with AD. High CLIF-C ADs is associated with higher frequency of organ dysfunction, increased risk of new complications of cirrhosis and high short-term mortality. On the contrary, individuals with low CLIF-C ADs, as well as those with intermediate score without ascites or with low MELD have excellent prognoses.

Association of liver steatosis and fibrosis with clinical outcomes in patients with SARS-CoV-2 infection (COVID-19).

INTRODUCTION AND OBJECTIVES: Liver function tests (LFT) abnormalities are reported in up to 50% of COVID-19 patients, and metabolic comorbidities are associated with poorer outcomes. The aim of the study was to determine the prevalence of liver steatosis and fibrosis in patients with COVID-19 and their association with clinical outcomes. MATERIAL AND METHODS: Retrospective study in hospitalized COVID-19 patients was conducted. The risk for liver steatosis was estimated by HSI > 36, and risk for advanced liver fibrosis with APRI > 1.0, NAFLD FS > 0.675 and/or FIB-4 > 3.25. Clinical outcomes were admission to Intensive Care Unit (ICU) and mortality. RESULTS: Of 155 patients, 71.6% were male (n = 111), and 28.4% (n = 44) were obese. Abnormal LFT were present in 96.8% (n = 150), prevalence of steatosis was 42.6% (n = 66) and of significative liver fibrosis was 44.5% (n = 69). Liver fibrosis by FIB-4 was associated with risk of ICU admission (OR 1.74 [95%CI 1.74-2.68; p = 0.023]) and mortality (OR 6.45 [95%CI 2.01-20.83, p = 0.002]); no independent associations were found. CONCLUSIONS: The prevalence of steatosis and significant liver fibrosis was high in COVID-19 patients but was not associated with clinical outcomes.

Usefulness of collagen type IV in the detection of significant liver fibrosis in nonalcoholic fatty liver disease.

INTRODUCTION/AIMS: Liver fibrosis assessment is a key issue in the evaluation of nonalcoholic fatty liver disease (NAFLD) patients. In the present study, we aimed to validate a noninvasive marker panel to assess significant and advanced fibrosis in these patients. METHOD: 126 biopsy-proven NAFLD patients were included. NAFLD diagnosis was based on histological criteria. Fibrosis stages were determined according to NASH-Clinical Research Network criteria. Clinical and laboratorial data were collected during the interval of three months before or after liver biopsy. Histological fibrosis stages were classified as significant fibrosis (F2-F4) and advanced fibrosis (F3-F4). Five serum biomarkers [hyaluronic acid (HA), collagen type IV (cIV), procollagen type III (PC III), laminin (LN) and cholylglycine (CG)] were assessed by chemiluminescence immunoassays. RESULTS: Most patients were female (61.61%), mean age: 55.7 ±â€¯9.13 years old and mean BMI was 32.1 ±â€¯5.9 kg/m2. Prevalence of diabetes, dyslipidemia, arterial hypertension, and metabolic syndrome was 68.75%, 82.29%, 63.54% and 81.05%, respectively. Patients with cIV above 30 ng/mL had a 5.57-times (IC: 1.86-16.69) the chance of having significant fibrosis and 7.61-times (IC: 2.27-25.54) the chance of having advanced fibrosis versus patients with values below 30 ng/mL. HA, PC III, LN and CG did not detect the presence of significant and advanced fibrosis. The AUROC of clV for detection of significant (0.718) and advanced fibrosis (0.791) was better than that of other serum biomarkers. CONCLUSION: Type 4 collagen could predict the presence of significant and advanced fibrosis in NAFLD patients and it would be a useful tool in routine clinical practice.

Changes in Liver Stiffness and Noninvasive Fibrosis Scores in Egyptian Adolescents Successfully Treated with Ledipasvir-Sofosbuvir for Chronic Hepatitis C Virus Infection.

OBJECTIVE: To assess changes in noninvasive liver fibrosis measurements after chronic hepatitis C eradication by direct-acting antivirals in Egyptian adolescents. STUDY DESIGN: Liver stiffness measurement (LSM), by vibration-controlled transient elastography and noninvasive fibrosis scores (Firbosis-4, aspartate aminotransferase-platelet ratio index), was obtained before and 12 months after eradication with ledipasvir-sofosbuvir. The primary outcome was a more than 30% decrease in LSM with resulting fibrosis stage regression for initial fibrosis of F2 or higher and nonprogression of F0-F1, using the Ishak score (F0-F6). The secondary outcome was change in noninvasive fibrosis scores after treatment. RESULTS: Analyzing 85 patients, the median baseline LSM was 5.8 (IQR, 4.2-6.5) and at follow-up 5.1 kPa (IQR, 4-6 kPa) (P = .045); 62 (73%) met the primary outcome, 16 patients (19%) experienced regression, and 46 (54%) nonprogression of LSM. Of 18 with initial fibrosis of F2 0r higher, 13 regressed to F0-F1 and 2 from F6 to F5, 1 unchanged at F3, and 1 increased to F3 and 1 to F4. Among 67 patients with a baseline fibrosis of F0-F1, 62 were unchanged and 5 increased-4 to F2 and 1 to F3. Although 23 (27%) had a more than 30% LSM increase, only 7 (8%), with associated comorbidities (4 ß-thalassemia, 3 hepatic steatosis), had increased fibrosis stage. The median baseline FIB-4 and aspartate aminotransferase-platelet ratio index scores were 0.34 (IQR, 0.22-0.47) and 0.35 (0.24-0.57), and at follow-up 0.3 (IQR, 0.22-0.34) and 0.2 (0.18-2.8) (P < .001, <.001), respectively. CONCLUSIONS: Chronic hepatitis C eradication by direct-acting antiviral agents in Egyptian adolescents was associated with nonprogression or regression of liver fibrosis, by noninvasive fibrosis measurements, at 12 months after treatment in the majority of cases.

Brief Report: Accuracy of FIB-4 for Cirrhosis in People Living With HIV and Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) may develop in the absence of cirrhosis in HIV, and determining how often this occurs can provide insights into mechanisms of carcinogenesis. Studies evaluating the prevalence of cirrhosis in the setting of HCC among people living with HIV (PLWH) often rely on noninvasive markers, such as the Fibrosis-4 Index for Hepatic Fibrosis (FIB-4). However, the accuracy of FIB-4 for cirrhosis in the setting of HCC has not been determined among PLWH. METHODS: We conducted a cross-sectional study among PLWH in the Veterans Aging Cohort Study with VA cancer registry-confirmed HCC diagnosed between 1999 and 2015. FIB-4 was calculated using the age, alanine aminotransferase, aspartate aminotransferase, and platelet count obtained closest to, but within 1 year before, HCC diagnosis. Medical records were reviewed within 1 year before HCC diagnosis to determine the cirrhosis status. We evaluated the area under the receiver-operating characteristic curve and performance characteristics of FIB-4 for confirmed cirrhosis. RESULTS: Incident HCC was diagnosed in 302 PLWH. After medical record review, 203 (67.2%, 95% confidence interval: 61.6% to 72.5%) had evidence of cirrhosis. FIB-4 identified patients with cirrhosis with an area under the receiver-operating characteristic curve of 0.67 (95% confidence interval: 0.60 to 0.73). FIB-4 scores >5.0 had a positive predictive value >80% and specificity of >77%, negative predictive value of <41%, and sensitivity of <45%. CONCLUSION: The accuracy of FIB-4 for cirrhosis in the setting of HIV and HCC is modest and may result in misclassification of cirrhosis in this population.

Evaluation of the Biomarkers HMGB1 and IL-6 as Predictors of Mortality in Cirrhotic Patients with Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) affects from 20% to 50% of cirrhotic patients, and the one-month mortality rate is 60%. The main cause of AKI is bacterial infection, which worsens circulatory dysfunction through the release of HMGB1 and IL-6. OBJECTIVES: To evaluate HMGB1 and IL-6 as biomarkers of morbidity/mortality. METHODS: Prospective, observational study of 25 hospitalised cirrhotic patients with AKI. Clinical and laboratory data were collected at the time of diagnosis of AKI, including serum HMGB1 and IL-6. RESULTS: The mean age was 55 years; 70% were male. Infections accounted for 13 cases. The 30-day and three-month mortality rates were 17.4% and 30.4%, respectively. HMGB1 levels were lower in survivors than in nonsurvivors at 30 days (1174.2 pg/mL versus 3338.5 pg/mL, p = 0.035), but not at three months (1540 pg/mL versus 2352 pg/mL, p = 0.243). Serum IL-6 levels were 43.3 pg/mL versus 153.3 pg/mL (p = 0.061) at 30 days and 35.8 pg/mL versus 87.9 pg/mL (p = 0.071) at three months, respectively. The area under the ROC curve for HMGB1 was 0.842 and 0.657, and that for IL-6 was 0.803 and 0.743 for discriminating nonsurvivors at 30 days and three months, respectively. In multivariate analysis, no biomarker was independently associated with mortality. CONCLUSION: HMGB1 levels were associated with decreased survival in cirrhotics. Larger studies are needed to confirm our results.