ALT Ratio Research Articles

Role of Non-Invasive Scoring Systems in Detecting Fibrosis in Chronic Hepatitis B

Objectives: Chronic hepatitis is a clinical and pathological condition defined by etiological, clinical, and pathological aspects, in which inflammation in the liver continues for more than six months. Hepatitis B virus is one of the most important causes of etiology. Although liver biopsy is accepted as the gold standard test, there is a need to search for an alternative method due to the risk of complications, invasiveness, and cost. Our aim in this study was; to evaluate the predictive value of calculating fibrosis four scores (FIB -4), age platelet index (API), AST ALT ratio (AAR), AST platelet ratio index (APRI), Hui score, Goteburg University cirrhosis index (GUCI) indices in relation to liver biopsy in patients with chronic hepatitis B diagnosis who have not received any treatment before. Methods: The study included treatment-naive cases who underwent liver biopsy at Ankara University School of Medicine Hospitals Gastroenterology Clinics between March 2013 and November 2017 and at Ankara City Hospital Gastroenterology Clinic between 2019-2021. Non-invasive scores of the cases were evaluated simultaneously with liver biopsy. Results: A total of 159 patients, 45 (28.3%) female and 114 (71.7%) male, were included in our study. Eight non-invasive fibrosis markers were used, including APRI, FIB-4, AAR, API, CDS, Lok, GUCI, and Hui. GUCI and Hui non-invasive fibrosis markers were numerically superior to all other parameters in differentiating mild hepatitis from severe hepatitis and patients with cirrhosis, without cirrhosis. In the comparison of area under – receiver operating characteristic (AUROC) values ​​using the Hanley-McNeal test to differentiate the cirrhosis patient from the non-cirrhosis patient, statistical superiority was found only against AAR and API (p<0.001, p<0.001). Conclusion: Although many markers were found successful in our study, AUC values ​​were not significantly superior to each other, and we determined that they could not be an alternative to liver biopsy on their own. Keywords: chronic hepatitis B, fibrosis, liver

Abstract 2258: Predictors of hepatocellular carcinoma development in nonalcoholic fatty liver disease

Abstract Background: The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is predicted to increase with increasing worldwide prevalence. We aimed to identify predictors of HCC risk in patients with NAFLD, an unmet clinical need. Methods: We identified all patients diagnosed with NAFLD in the electronic health records (EHR) of a large US-based health system from 2004 to 2018. Information on demographics, body mass index (BMI), smoking status, serum biochemistries, comorbidities, albumin-bilirubin (ALBI) score, AST/√ALT ratio, fibrosis-4 index (FIB-4), and cirrhosis status were extracted from the EHR. Over an average 5.5 year at risk from date of first recorded NAFLD to the last contact with the healthcare system, date of HCC diagnosis or death, whichever occurred first, we identified 371 patients diagnosed with HCC. Cox proportional regression method with a stepwise approach was employed to identify independent predictors of HCC incidence. A Poisson regression method was used to estimate the incidence rate of HCC in NAFLD patients with a specified set of identified risk factors in the stepwise Cox regression analysis. Results. Among the 39,424 NAFLD patients, 57.8% were women, 44.5% were ever smokers, 27.3% had diabetes, 39.9% had dyslipidemia, 4.7% had Fibrosis-4 index (FIB-4)>2.67 (advanced fibrosis), and 3.7% had cirrhosis. The mean (standard deviation) age and BMI at first recorded diagnosis of NAFLD were 57.0 (11.4) years and 33.7 (7.4) kg/m2, respectively. The corresponding figures in 371 incident HCC cases were 65.1 (10.6) years of age, 31.9 (6.9) kg/m2 of BMI, 47.7% women, 52.8% ever smokers, 38.3% diabetes, 39.6% dyslipidemia, 17.8% FIB-4 >2.67, and 11.6% cirrhosis. All of these were independent factors for HCC risk. The estimated incidence rate of HCC for a male patient with NAFLD who was 65 years old, ever smoked, had BMI 30 kg/m3 and a history of diabetes and dyslipidemia, but had neither advanced fibrosis nor cirrhosis, was 3.02 (95% confidence interval [CI], 2.37-3.84) per 1000 person-years. The corresponding figures were 8.20 (95% CI, 5.78-11.62) for a male with advanced fibrosis but no cirrhosis and the same other characteristics as described above, and 18.05 (95% CI, 12.19-26.72) for the same patient with cirrhosis. On the other hand, the incidence of HCC for a male cirrhotic patient without a history of smoking or diabetes was 9.53 per 1000 person-years, a 47% reduction in risk. Conclusion. In this large cohort of NAFLD patients, we identified age, sex, BMI, smoking, diabetes, dyslipidemia, advanced fibrosis and cirrhosis as independent risk predictors for HCC. Although the effect of smoking and diabetes was relatively small in low-risk patients, their impact on high-risk NAFLD, especially those with advanced fibrosis or cirrhosis is discernable. Smoking cessation and treatment of diabetes may be potential strategies for reducing HCC risk in high-risk NAFLD patients. Citation Format: Jian-Min Yuan, Renwei Wang, Hung N. Luu, Jaideep Behari. Predictors of hepatocellular carcinoma development in nonalcoholic fatty liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2258.

Increased incidence of immune-mediated myocarditis in advanced skin malignancies treated with immune checkpoint inhibitors in the COVID-19 era.

2664 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results:A review of 361 patients that received ICI from 9/2014 – 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 – 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated AST:ALT ratio (median 1.58:1) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% pre-pandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and AST:ALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.

119-LB: Targeted IL-22 Improves Glucose Tolerance and Reduces Hepatic Steatosis and Hepatic Fibrosis in Murine Models of Diabetes and Liver Disease

The cytokine interleukin-22 (IL-22) is an inhibitor of cellular stress. In HFD murine models, systemic IL-22 is efficacious to restore glucose tolerance, reduce circulating triglycerides and hepatic steatosis, and improve AST:ALT ratio, but is also associated with gut and skin toxicity. As an approach to maintain efficacy without skin/gut adverse effects we have developed a prototype IL-22-based bispecific biologic drug candidate (IL-22-ScFv) which is targeted towards the pancreas and liver. In mouse models of T2D and NAFLD/NASH twice-weekly subcutaneous administration of IL-22-ScFv provides numerous therapeutic and metabolic benefits. After IL-22-ScFv administration for four weeks in HFD mice random glucose, glucose tolerance and insulin tolerance were normalised (c.f. chow fed controls) . Significant reduction in hepatic steatosis was also seen, evidenced by liver weight, histology, oil-red-O, and (normalisation of) key lipogenic gene expression patterns. In both Thioacetamide/HFD and Choline Deficient L-Amino acid defined/HFD mice IL-22-ScFv administration significantly reduced hepatic fibrosis (Masson’s trichrome, picrosirius red, and normalisation of hepatic expression of Col1a1&2, Col3a1, Timp2, Mmp2 and Cd68) . Effective targeting of IL-22 to liver and pancreas was observed with minimal IL-22 exposure to gut and skin. Following four weeks administration of a range of doses of IL-22-ScFv no adverse effects were observed. Histological analysis of gut and skin showed no features of hyperproliferation, consistent with effective targeting of IL-22 to liver and pancreas. Mechanism of action of IL-22-ScFv was again shown to be reduction in cellular stress via IL-22 receptor mediated STAT3 phosphorylation. In conclusion, liver/pancreas targeted IL-22 shows promise as a therapeutic approach to metabolic liver disease, with concomitant improvement in disorders of glucose homeostasis. Disclosure J. B. Prins: None. H. Sajiir: None. S. Keshvari: None. K. Wong: None. J. Lockett: Advisory Panel; Lilly Diabetes. M. Mcguckin: None. S. Z. Hasnain: None.

Increased Inflammatory Markers at AMPH-Addicts Are Related to Neurodegenerative Conditions: Alzheimer’s Disease

Amphetamine addiction is widespread worldwide despite causing severe physical and mental problems, including neurodegeneration. One of the most common neurodegenerative disorders is Alzheimer’s disease (AD). Several inflammatory markers have been linked to AD. Previous studies have also found these biomarkers in amphetamine-addicts (AMPH-add). This study thus seeks to understand how AD and AMPH-addiction are related. A case–control observational study was conducted. Seventeen AMPH-adds ranging in age from 23 to 40 were recruited from Al Amal Psychiatric Hospital. In addition, 19 healthy subjects matching their age and gender were also recruited. The Luminex technique was used to measure serum alpha 1 antichymotrypsin (ACT), pigment epithelium-derived factor (PEDF), and macrophage inflammatory protein-4 (MIP-4), after complying with ethical guidelines and obtaining informed consent. In addition, liver function enzymes were correlated to AD’s predictive biomarkers in AMPH-adds. AMPH-adds had significantly higher serum levels of ACT, PEDF, and MIP-4 when compared to healthy controls (p = 0.03, p = 0.001, and p = 0.012, respectively). Furthermore, there is a significant correlation between lower ALT levels and elevated AST to ALT ratios in AMPH-adds (r = 0.618, 0.651, and p = 0.0001). These changes in inflammatory biomarkers may be linked to the onset of AD at a young age in amphetamine-drug addicts.

Pancreatic Interleukin-22 Receptor Signaling is Critical in Maintaining Beta-Cell Insulin Production and is Hepatoprotective

Abstract We discovered that the cytokine interleukin-22 (IL-22) is an efficient natural inhibitor of cellular stress and exogenous IL-22 improved insulin quality in pancreatic β-cells in preclinical models of Type 2 diabetes. Importantly, IL-22 completely restored glucose tolerance, suppressed fasting hyperinsulinemia/hyperproinsulinemia, and restored insulin sensitivity in obese animals. Moreover, metabolic improvements were accompanied by significant improvements in circulating triglycerides, liver function (AST:ALT ratio) and a reduction in hepatic lipid accumulation. Whilst the IL-22 receptor, IL-22RA1 is highly expressed in the pancreas and liver, its endogenous role in these tissues remains elusive. To explore this, we generated tissue specific IL-22ra1 knockout mice lacking the receptor in pancreatic β-cells (Il-22ra1fl/fl x Ins2Cre: IL-22ra1β-cell−/−) and hepatocytes (Il-22ra1fl/fl x AlbCre: IL-22ra1Hep−/−). We assessed their metabolic phenotype including glycemic control, hepatic lipid accumulation, and hepatic markers of cellular stress, lipid, and glucose metabolism with age or with obesity. We discovered that IL-22ra1β-cell−/− animals developed hyperglycemia with age and had defective insulin secretion, which was exacerbated when on a high fat diet. Interestingly, they also had a significant increase in markers of hepatic inflammation and cellular stress. In conclusion we demonstrate, for the first time, that local endogenous IL-22 secretion in pancreatic β-cells maintains insulin biosynthesis. Moreover, our work highlights the importance of the pancreatic-β-cell-liver axis as the absence of pancreatic IL-22ra1 signaling leads to a marked increase in liver inflammation and cellular stress.

Fibroscan Compared to Aspartate Aminotransferase to Platelet Ratio Index (APRI) and Aspartate Aminotransferase to Alanine Aminotransferase Ratio (AST to ALT) in the Assessment of Liver Fibrosis in Patients with Non Alcoholic Fatty Liver Disease in a Terti

Objectives: To compare the extent of liver fibrosis using fibroscan and subsequently compare it with AST/ALT ratio and AST to platelet ratio index (APRI).
 Study Design: Comparative cross-sectional study.
 Place and Duration of Study: Chemical Pathology Department, Military Hospital Rawalpindi in collaboration with Armed forces institute of Radiology & Imaging and Gastroenterology Department, Military Hospital Rawalpindi from Jan to Apr 2021.
 Methodology: A total of 50 patients in group-1 and 24 healthy subject participants in group-2 as controls were studied. Serum AST, ALT, platelet count, APRI and AST to ALT ratio were assessed along with fibroscan results to determine stages of liver fibrosis and results were compared for the association.
 Results: There were 49 (66%) males and 25 (34%) females included in the study with the mean age of 49.77 ± 8.3 years. 11 (14.9%) patients had advanced fibrosis. There was a significant negative relationship (p-value <0.001 and r = -0.637) between platelet count and increasing fibroscan score (F1, F2) and a significant positive correlation between fibroscan score and AST (pvalue <0.001 and r=0.623), ALT (p-value <0.001 and r=0.596), fibroscan result and APRI (p-value < 0.001 and r=0.771) and fibroscan scores and AST/ALT ratio (p-value= 0.037 and r=0.243). One third of the study subjects had fibrosis in early and relatively advanced stages (F1, F2 respectively) correlating with serum and blood markers.
 Conclusion: Early fibro scan testing and serum markers can help in early diagnosis and timely initiation of treatment.

Association of the serum transaminase with mortality among the US elderly population.

Considering the inconsistent findings of research into the associations between serum levels of liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutamyltransferase [GGT]) and mortality among elderly people, we aimed to investigate the associations of ALT, AST, GGT, and De-Ritis ratio (DRR, defined as AST/ALT) and all-cause or cause-specific mortality among the US elderly people using National Health and Nutrition Examination Surveys data. We included 6415 elderly participants (≥65years). Exclusion criteria included positive test for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus infection at baseline. Multivariable-adjusted Cox regression models calculating hazard ratios (HR) and 95% confidence intervals were developed for each of the liver enzyme measures. All-cause cumulative mortality was 33.8%, of which 23.8% were cardiovascular disease (CVD) deaths, 15.6% were cancer deaths, and 60.6% were other cause deaths. Adjusted Cox models found increased all-cause mortality risk for low ALT (HR: 1.70), low AST (HR: 1.13), high GGT (HR: 1.25), and high DRR (HR: 1.68). Low ALT and high DRR predicted CVD mortality. Low ALT (HR: 1.91), low AST (HR: 1.16), high GGT (HR: 1.40), and high DRR (HR: 1.76) predicted other cause mortality. Low ALT and high DRR were associated with increased CVD and cancer mortality. All serum liver enzyme measures were associated with all-cause mortality and other cause mortality in the US elderly population. Further studies may validate these findings in other elderly populations.

Diagnosis of liver fibrosis in ageing patients with HIV at risk for non-alcoholic fatty liver disease in Italy and Canada: assessment of a two-tier pathway.

Since the introduction of effective antiretroviral therapy, liver-related mortality has increased ten-fold in ageing people with HIV. This trend is driven by ageing-related metabolic conditions that cause non-alcoholic fatty liver disease (NAFLD), which affects 35-65% of people with HIV. Clinically significant (stage 2-4) liver fibrosis develops in over 15% of people with HIV who have NAFLD. Strategies are needed to identify people with HIV at risk for significant liver fibrosis and reduce cirrhosis-related complications. Non-invasive tests to diagnose liver fibrosis include ultrasound-based transient elastography and serum biomarkers. Transient elastography is a feasible tool to assess liver fibrosis, but it is not largely accessible in HIV clinics. We aimed to determine whether a two-tier care pathway with assessment of simple serum biomarkers for fibrosis as first tier could reduce the need for the specialist transient elastography test (second tier). Patients were consecutively identified through a clinical programme for liver disease in people with HIV in Canada and Italy. We applied a two-tier care pathway to three prospective cohorts of people with HIV at risk for NAFLD, defined as those with elevated liver transaminases, body mass index (BMI) of 25 or greater, or diabetes. Patients with alcohol abuse or coinfection with hepatitis B or C viruses were excluded. Five simple serum biomarkers of fibrosis, based on liver transaminases, platelets, and BMI (fibrosis-4 index [FIB-4], BARD [BMI, AST to ALT ratio, diabetes] score, NAFLD fibrosis score, AST to ALT ratio, and AST-to-platelet ratio index [APRI]) were applied as a first-tier assessment to exclude significant liver fibrosis. All patients then received transient elastography. We assessed the decrease in referral for transient elastography that would have occurred based on biomarker assessment and discordance between high transient elastography (≥7·1 kPa), indicating significant liver fibrosis, and low serum fibrosis biomarkers (FIB-4 <1·3, BARD score 0-1, NAFLD fibrosis score less than -1·455, AST to ALT ratio <0·8, and APRI <0·5). We also assessed independent factors associated with that discordance by multivariable logistic regression analysis. We included 1202 people with HIV at risk for NAFLD (mean age 51·2 years [SD 10·1], 914 [76%] male and 288 [24%] female, mean HIV duration 16·3 years [SE 9·7], mean BMI 26·5 Kg/m2 [SD 4·5]; prevalence of diabetes 49·5%). 222 (18·5%) of these participants had significant liver fibrosis according to transient elastography. Assessment of simple fibrosis biomarkers would have decreased transient elastography referrals between 22·5% (BARD score) and 82·4% (APRI). Discordance rate ranged from 3·9% (NAFLD fibrosis score) to 11·1% (APRI). After adjustment for age, sex, presence of diabetes, level of HDL cholesterol, and CD4 cell count, BMI (odds ratio 1·12, 95% CI 1·07-1·17) and triglyceride level (1·25, 1·08-1·46) were independent predictors of discordance for low APRI and high transient elastography. Use of a two-tier pathway to identify liver fibrosis in ageing people with HIV at risk for NAFLD could reduce transient elastography examinations by a substantial proportion, reducing costs and helping to optimise use of resources in HIV care. GS is supported by a Senior Salary Award from Fonds de recherche du Québec-Santé (number 296306).

A220 THE IMPACT OF DIABETES AND AGE ON PERFORMANCE OF NON-INVASIVE SERUM-BASED TESTS FOR PREDICTION OF ADVANCED FIBROSIS IN BIOPSY-PROVEN NAFLD

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is now a leading cause of end-stage liver disease. Advanced stage F3-4 fibrosis predicts liver-related mortality in NAFLD patients. Simple non-invasive serum-based tests (NIT) for F3-4 are limited by indeterminate scores, necessitating secondary tests or liver biopsy. Diagnostic NIT cut-offs may vary in NAFLD patients with diabetes mellitus (DM) and the elderly. Identifying appropriate thresholds in populations in which these tests can be applied will reduce indeterminates and facilitate their broader use. Aims The aim of this study was to assess the impact of DM status and age on the performance of NIT for prediction of advanced fibrosis in patients with biopsy-proven NAFLD. Methods Patients presenting to two Canadian tertiary care centers between 2010–2018 for liver biopsy to diagnose NAFLD were included in this study. NIT including NFS, FIB4, BARD, AST-to-platelet ratio index (APRI), and AST to ALT ratio (AST/ALT) were calculated for each patient using validated cut-offs. Results 457 patients were included in this study. Mean age was 48.8±12.9 years, 56% male, mean BMI 32.3 ± 6.7kg/m2, 69% with DM, and F3-4 prevalence 48%. Indeterminate rates for NIT were generally higher for older patients, with or without DM (27–49% and 37–52%, vs. 33–42% and 20–37%, respectively). FIB-4 and NFS both had high specificity &amp;gt;0.9 in DM patients &amp;lt;60 years (Table 1). There were no differences in AUROC for individual NITs between patients with and without DM, and those &amp;lt; 60 vs. ≥ 60, nor between individual NIT within these groups. Conclusions DM status and age, ≥ 60 vs. &amp;lt; 60, do not appear to have a significant impact on diagnostic performance of serum-based NIT in our cohort. Older patients had higher indeterminate results and reduced specificity, but T2DM status and age did not appear to have an impact on rate of misclassified patients. Serum-based NIT thresholds need to be optimized for older patients to reduce indeterminates and improve specificity. Funding Agencies None

Two-Tier Care Pathways for Liver Fibrosis Associated to Non-Alcoholic Fatty Liver Disease in HIV Mono-Infected Patients.

(1) Background: Developing strategies to identify significant liver fibrosis in people with HIV (PWH) is crucial to prevent complications of non-alcoholic fatty liver disease (NAFLD). We aim to investigate if five simple serum biomarkers applied to PWH can optimize a care pathway to identify significant liver fibrosis defined by transient elastography (TE). (2) Methods: A two-tier fibrosis pathway was applied to three prospective cohorts of PWH undergoing TE with CAP. NAFLD was diagnosed as a controlled attenuation parameter ≥ 248 dB/m. Five simple fibrosis biomarkers (FIB-4 < 1.3, BARD score 0–1, NAFLD fibrosis score < −1.455, AST:ALT ratio < 0.8 and APRI < 0.5) were applied as first-tiers to exclude significant liver fibrosis. We determined the decrease in referral for TE that would have occurred based on biomarker assessment and the discordance between low simple fibrosis biomarkers and high TE (≥7.1 kPa), indicating significant liver fibrosis. (3) Results: Of the 1749 consecutive PWH, 15.1% had significant liver fibrosis by TE and 39.1% had NAFLD. The application of the fibrosis biomarkers as first tiers would have resulted in a decrease in TE referrals between 24.9% (BARD score) and 86.3% (APRI). The lowest discordance rate was with NAFLD fibrosis score (8.5%). After adjustments, BMI (odds ratio (OR) 1.12, 95% CI: 1.08–1.17) and triglycerides (OR 1.26, 95% CI: 1.11–1.44) were independent predictors of discordance for APRI < 0.5 and TE ≥ 7.1. The performance of the two-tier pathways was similar in PWH with and without NAFLD. (4) Conclusions: Implementing a two-tier pathway could save a substantial proportion up of TE examinations, reducing costs and helping resource optimization in HIV care. Patients with metabolic risk factors for NAFLD and low fibrosis biomarker may still be considered for TE referral.

Is AST/ALT Ratio a Predictor of In-hospital Mortality in Pulmonary Embolism Patients?

To document the association between serum transaminases and in-hospital mortality in pulmonary embolism (PE) patients. Analytical study. Patients treated with acute PE in hospital between January 2011 and December 2019 from Sakarya University Medical School Research and Teaching Hospital, Sakarya, Turkey. Patients with PE were included. Receiver operating characteristics (ROC) analysis was conducted to define a cut-off value for AST/ALT ratio to predict in-hospital death. Simplified pulmonary embolism severity index (sPESI) scores were calculated and the AST/ALT ratio were entered into binary logistic regression analysis with components of sPESI score to document the prognostic significance of as an independent predictor of in-hospital mortality. 164 acute PE patients were included; of those, 33 (20%) died in hospital. Deceased patients had higher AST/ALT ratio (median, 1.4; 25th-75th percentile, 1.1-1.8) comparing to patients with discharged home (median, 1.1; 25th-75th percentile, 0.84-1.4) (p=0.006). ROC analysis showed that AST/ALT ratio was an indicator of in-hospital mortality, and the calculated area under the curve was 0.655 (95% CI, 0.547-0.764). The cut-off value of 1.3 was associated with a prognostic sensitivity of 61% and specificity of 65%. Binary logistic regression analysis failed to show AST/ALT ratio as an independent predictor of in-hospital mortality. AST/ALT ratio predicts in-hospital mortality with acceptable sensitivity and specificity in patients with acute PE and might be used as a biomarker for risk stratification. Key Words: Pulmonary embolism, In-hospital mortality, Transaminases.

Macrofilaricidal Activity, Acute and Biochemical Effects of Three Lichen Species Found on Mount Cameroon.

Onchocerciasis is a parasitic infection affecting a relatively small population globally but has very devastating pathological outcomes. Ivermectin and recently moxidectin are the only drugs approved for clinical management of the disease, both of which have several limitations. In particular, they are efficacious against microfilariae (microfilaricidal) with no activity against adult worms (nonmacrofilaricidal). Promising anthelmintic activity has been reported in some lichens. This study investigated three lichens, Usnea articulata, Parmotrema tinctorum, and Heterodermia obscurata, found on Mount Cameroon, for potential macrofilaricidal activity. Organic extracts were screened for anti-Onchocerca activity against Onchocerca ochengi isolated from cattle skin using worm motility and MTT formazan assays. Toxicity of highly active extracts was investigated on monkey kidney epithelial (LLCMK2) cells and in BALB/c mice (2000 mg/kg body weight) including effects on liver enzymes. The methanol extract of P. tinctorum (Pammet) was the most active against adult male worms (IC50 = 8.1 μg/mL) with the highest selectivity index (SI = 21.3). U. articulata was the most active against the adult female (IC50 = 36.3 μg/mL) but had a low SI value (3.4). No mortality and no adverse effects were recorded in the acute toxicity test. These two most active extracts had no significant effect on liver enzymes, alanine aminotransferase, and aspartate (P values < 0.05), but a high AST : ALT ratio (2.59) for Pammet indicates likely reversible adverse hepatic toxicity. The high macrofilaricidal activity and selectivity of P. tinctorum suggest it is a potential source of new macrofilaricides which should be further investigated to identify its bioactive constituents.

Development and Validation of a Novel Nomogram for Predicting Vessels that Encapsulate Tumor Cluster in Hepatocellular Carcinoma.

BackgroundVessels that encapsulate tumor cluster (VETC) is associated with poor prognosis in hepatocellular carcinoma (HCC). Vessels that encapsulate tumor cluster estimation before initial treatment is helpful for clinical doctors. We aimed to construct a novel predictive model for VETC, using preoperatively accessible clinical parameters and imagine features.MethodsTotally, 365 HCC patients who received curative hepatectomy in the Sun Yat-Sen University Cancer Center from 2013 to 2014 were enrolled in this study. Vessels that encapsulate tumor cluster pattern was confirmed by immunochemistry staining. 243 were randomly assigned to the training cohort while the rest was assigned to the validation cohort. Independent predictive factors for VETC estimation were determined by univariate and multivariate logistic analysis. We further constructed a predictive nomogram for VETC in HCC. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curve, and calibration curve. Besides, the decision curve was plotted to evaluate the clinical usefulness. Ultimately, Kaplan–Meier survival curves were utilized to confirm the association between the nomogram and survival.ResultsImmunochemistry staining revealed VETC in 87 patients (23.8%). lymphocyte to monocyte ratio (>7.75, OR = 4.06), neutrophil (>7, OR = 4.48), AST to ALT ratio (AAR > .86, OR = 2.16), ALT to lymphocyte ratio index (BLRI > 21.73, OR = 2.57), alpha-fetoprotein (OR = 1.1), and tumor diameter (OR = 2.65) were independent predictive factors. The nomogram incorporating these predictive factors performed well with an area under the curve (AUC) of .746 and .707 in training and validation cohorts, respectively. Calibration curves indicated the predicted probabilities closely corresponded with the actual VETC status. Moreover, the decision curve proved our nomogram could provide clinical benefits with patients. Finally, low probability of VETC group had significantly longer recurrence free survival (RFS) and overall survival (OS) than the high probability of the VETC group (all P < .001).ConclusionA novel predictive nomogram integrating clinical indicators and image characteristics shows strong predictive VETC performance and might provide standardized net clinical benefits.

Comparison of toxic effects of iron-molybdenum polyoxometalates and mixture of their components

Introduction. The physicochemical properties and the impact on living organisms of nanoparticles and components that make up nanoparticles may differ radically, however, insufficient attention is paid to a comparative study of the toxicity of nanoparticles and constituents of nanoparticles. Material and methods. Biochemical and hematological parameters in the blood of 50 male Wistar rats were determined after a single, seven-fold and thirty-fold intramuscular injection of an aqueous solution of iron-molybdenum nanocluster polyoxometalates (POM) and a mixture of the POM components at a dose of 1.5 mg/kg. A solution of a POM components’ mixture was obtained by the destruction of POM with an increase in pH, followed by neutralization, since POM are unstable in an alkaline medium. Results. The introduction of POM did not cause deviations from the norm in the activity of AST, ALT, total alkaline phosphatase and its bone isoenzyme, α-amylase, protein content, urea and creatinine, which indicates the absence of cytolytic syndrome, including in the liver and myocardium, no damage to the acinar part of pancreas, changes in bone tissue, preservation of the protein-synthetic function of the liver and the filtering ability of the kidneys. The introduction of a solution of POM components (molybdenum, iron) was accompanied by an increase in the activity of AST, alkaline phosphatase, the AST / ALT ratio after 7 injections and an increase in the last two parameters after 30 injections. The impact of POM is characterized by an increase in the content of hemoglobin and erythrocytes in the blood and less pronounced leukopenia, in contrast to the mixture of POM components. Conclusion. A less pronounced deviation from the norm of biochemical parameters and a lower degree of leukopenia make it possible to assess the effect of POM nanoparticles as less toxic than the action of POM components not organized into nanoparticles.

PSX-A-3 Late-Breaking: Analysis of serum chemistry for metabolic function in GnRH-II receptor knockdown and littermate control boars

Abstract Pigs are the only livestock species encoding functional proteins for both the second form of gonadotropin-releasing hormone (GnRH-II) and its receptor (GnRHR-II), which are uniquely expressed in reproductive and non-reproductive tissues. To examine the physiological role of the GnRH-II/GnRHR-II system, we produced a swine line with reduced endogenous levels of GnRHR-II (GnRHR-II KD); males exhibit 70% diminished testicular GnRHR-II mRNA levels and 82% reduced circulating testosterone concentrations. Given that testosterone impacts metabolism, blood was collected from GnRHR-II KD (n = 5) and littermate control (n = 5) boars via indwelling jugular catheters, with serum isolated and subjected to veterinary diagnostic panels for metabolic analyte examination (PhysLab, Lincoln, NE). Statistical analyses utilized the MIXED procedure of SAS; the model included line as fixed and litter as random effects. Creatine kinase and blood urea nitrogen (BUN):creatinine ratios were elevated, creatinine was reduced (P &amp;lt; 0.01), and thyroxine tended to be decreased (P &amp;lt; 0.10) in GnRHR-II KD compared with control boars. Glucose, BUN, amylase, and lipase levels were not different. Liver products differed in transgenic versus control boars; levels of lactic dehydrogenase, aspartate and alanine aminotransferases (AST; ALT), and gamma-glutamyl transpeptidase were higher, whereas AST:ALT ratios, total protein, albumin, and globulin levels were lower (P &amp;lt; 0.05) in GnRHR-II KD boars. Albumin:globulin ratios and bilirubin (total and direct) did not differ. Additionally, serum cholesterol was decreased (P &amp;lt; 0.05), non-high density lipoproteins (HDLs) and low density lipoproteins (LDLs) tended to be decreased (P &amp;lt; 0.10), and triglycerides, HDLs, and cholesterol:HDL ratios did not differ between GnRHR-II KD and control males. These data suggest metabolic disruption in GnRHR-II KD boars, which may be due to suppressed gonadal steroidogenesis or ubiquitous knockdown of GnRHR-II expression. Supported by USDA/NIFA AFRI (2017-67015-26508) and Hatch Multistate (NEB-26–244) funds. USDA is an equal opportunity provider and employer.

Reduction of Effects of Dietary Aflatoxin B1 on Biochemical Parameters of the Fish Clarias Batrachus by Vitamin C

Aflatoxins are produced mainly by molds Aspergillus flavus and Aspergillus parasiticus. They cause toxicity called aflatoxicosis in animals and human beings which is of great concern in aquaculture also. Aflatoxin B1 is the most potent of all the known aflatoxins which mediates its effects by producing reactive oxygen species (ROS) and by irreversible damage to DNA and proteins leading to genotoxicity and cytotoxicity. Vitamin C is a potent antioxidant and reduces reactivity of ROS by donating electrons to them. Previous investigations suggest its role in alleviating aflatoxicosis in Nile tilapia. Present studies were conducted to determine the reduction in the negative effects of aflatoxin B1 on blood biochemical parameters and liver glycogen of fish Clarias batrachus by dietary supplementation of vitamin C. In the present investigation 60 fish were divided into four groups. Each group comprised fifteen fish. Four types of feed were prepared on the basis of presence of aflatoxin B1 and vitamin C. Feed I consists of a basal diet given to the first group of fish or control. Feed II consisted of aflatoxin B1 contaminated feed given to second group of fish. In feed III and IV 300 mg/kg and 600 mg/kg vitamin C was added to aflatoxin B1 contaminated feed The objective of the present investigation was to explore the role of Vitamin C in reduction of adverse effects of aflatoxin on plasma biochemical parameters and liver glycogen of the fish Clarias batrachus. The group of fish that was given the feed II showed a significant increase in serum level of ALT, AST, bilirubin, blood urea, glucose and albumin globulin ratio but significant decrease was observed in total serum proteins and liver glycogen as a result of dietary aflatoxin .Supplementation of Vitamin C in the feed significantly decreased the adverse effects of aflatoxin and the parameters showed significant improvement. The group of fish fed with 600 mg/kg vitamin C showed best results and were nearly similar to those of the control. The present investigation revealed that feed containing 600 mg/kg vitamin C diminishes the effect of aflatoxin B1 in the fish reducing the health risk in humans consuming the fish as aflatoxins has the potential to accumulate and stay in the tissues of animals for long period of time.

Aspartate aminotransferase to alanine aminotransferase ratio is associated with frailty and mortality in older patients with heart failure

Frailty is a common comorbidity associated with adverse events in patients with heart failure, and early recognition is key to improving its management. We hypothesized that the AST to ALT ratio (AAR) could be a marker of frailty in patients with heart failure. Data from the FRAGILE-HF study were analyzed. A total of 1327 patients aged ≥ 65 years hospitalized with heart failure were categorized into three groups based on their AAR at discharge: low AAR (AAR < 1.16, n = 434); middle AAR (1.16 ≤ AAR < 1.70, n = 487); high AAR (AAR ≥ 1.70, n = 406). The primary endpoint was one-year mortality. The association between AAR and physical function was also assessed. High AAR was associated with lower short physical performance battery and shorter 6-min walk distance, and these associations were independent of age and sex. Logistic regression analysis revealed that high AAR was an independent marker of physical frailty after adjustment for age, sex and body mass index. During follow-up, all-cause death occurred in 161 patients. After adjusting for confounding factors, high AAR was associated with all-cause death (low AAR vs. high AAR, hazard ratio: 1.57, 95% confidence interval, 1.02–2.42; P = 0.040). In conclusion, AAR is a marker of frailty and prognostic for all-cause mortality in older patients with heart failure.

Progression of Nonalcoholic Fatty Liver Disease-Associated Fibrosis in a Large Cohort of Patients with Type 2 Diabetes.

Nonalcoholic fatty liver disease (NAFLD) can progress to advanced fibrosis, especially in patients with type 2 diabetes. Small studies have shown that fibrosis can also regress. We aimed to provide large-scale data on progression and regression of fibrosis in diabetics with NAFLD. Adult diabetic patients with the diagnosis of NAFLD based on ICD-9 codes were identified. We used scores from noninvasive tests to identify patients with advanced fibrosis, calculated at first assessment and last follow-up visit. Cutoff values for advanced fibrosis were AST: ALT ratio > 1.4, AST to platelet ratio index > 1.5, FIB-4 score > 2.67, and NAFLD fibrosis score > 0.676. Our cohort included 50,695 diabetics with NAFLD (55.3% female; 71% Caucasian; mean age, 51.2 ± 11.6y). During median follow-up of 84.4months, 25.8% transitioned from no advanced fibrosis to advanced fibrosis (progression), 6.4% transitioned from advanced fibrosis to no advanced fibrosis (regression), and the rest remained stable. Factors associated with transition to advanced fibrosis were female sex, older age at first evaluation, African-American race, obesity, chronic kidney disease, or coronary artery disease. Use of insulin increased the risk of progression to advanced fibrosis (odds ratio,1.36; p < .001), whereas use of oral hypoglycemic agents, angiotensin 2 receptor blockers, and fibrates was associated with reduced risk (odds ratios, 0.92, 0.94 and 0.90, respectively; all p < .05). In a large cohort of patients with type 2 diabetes and NAFLD, more than a quarter progressed to advanced fibrosis. These findings indicate the need for early detection and staging of NAFLD in diabetics.

Baseline Values of Nonalcoholic Fatty Liver Disease Scores and Its Risk Assessment in Patients with Type 2 Diabetes Mellitus

Introduction: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing and is fueled by a twin-epidemic of obesity and diabetes mellitus in India. The objective of the study was to estimate various noninvasive NAFLD scores (NINS) for the baseline risk-assessment of NAFLD in patients with type 2 diabetes mellitus (T2DM). Methods: An observational, cross-sectional, open label, study of investigator-rated NINS was conducted ensuring adherence to relevant ethical standards. Results: In a 3-month period, 29 patients with T2DM were enrolled (age [mean ± SD]: 55.8 ± 9.72 years; men [n, %]: 18, 62%). One patient (3.45%) by fibrosis-4 index (cutoff for advanced fibrosis ≥2.67) and by AST to platelet ratio index (cutoff ≥0.98); 2 (6.90%) by NAFLD fibrosis score (cutoff ≥0.676); 20 (69%) by body mass index (BMI), AST to ALT ratio, and DM score (BARD; cuff-off ≥2); and 27 (93.10%) by BMI, age, ALT, triglyceride score (cutoff ≥1) indicated high risk for advanced hepatic fibrosis. Only the BARD score (median [min-max]: 3 [1–4]) was elevated above the cutoff values while other scores were below cutoff values. The study failed to demonstrate any correlation between age, gender, anthropometric and metabolic parameters, and NINS. Conclusion: While this study did not demonstrate significant elevation of NINS, scores were found be elevated in some T2DM patients and they may be at high risk of advanced liver fibrosis. Further well-designed studies in this domain are required for early detection, management, and reducing the burden of liver disease in Indian patients with diabetes.