Baseline ALT Levels Research Articles

Reactivation of Hepatitis B Virus among Malignancy Patients Undergoing Chemotherapy: A Prospective Cohort Study

Abstract Introduction: Reactivation of hepatitis B virus (HBV) can occur in patients receiving short-term chemotherapy, long-term immunosuppressive therapy, or disease-modifying antirheumatic agents for rheumatological diseases and is more common in hepatitis B surface antigen-positive patients. However, there is a lack of data for reactivation among malignant patients undergoing chemotherapy in resolved HBV patients. Methodology: A prospective cohort study of 200 oncological patients on chemotherapy was conducted for the reactivation of the HBV for a year. Patients underwent a thorough physical examination; baseline assessment and biochemical test and test were repeated at each follow-up. Results: The majority were females and in the 40–60-year age group. Age and serum albumin levels were significantly different (P < 0.05) among the reactivated versus the nonreactivated groups. Hepatitis B reactivation was seen in 14 (7%) patients with a maximum in the rituximab therapy group (11.26%). There was no statistically significant difference in baseline ALT levels between patients who experienced reactivation and those who did not. Conclusion: In the present study population, 7% had hepatitis B reactivation. The present study identifies old age, low serum albumin, and rituximab chemotherapy as significant risk factors for reactivation. Prophylactic antiviral therapy seems to be effective as no reactivation has occurred in this group.

Pemafibrate Reduced Liver Stiffness in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease Complicated with Hyperlipidemia and Liver Fibrosis with a Fibrosis-4 Index Above 1.3.

Aim To evaluate the effect of pemafibrate (PEM) on metabolic dysfunction-associated steatotic liver disease (MASLD). Method We retrospectively evaluated 43 patients with hyperlipidemia and MASLD to determine changes in clinical factors between the start of PEM treatment and 0.5 years later. Using FibroScan, 39 of 43 patients were evaluated for liver stiffness (LS; kPa) and controlled attenuation parameter (CAP; dB/m). None of the patients had decompensated cirrhosis. Result Thirty patients were women, the median age was 66 years old, the median fibrosis-4 (FIB-4) score was 2.52, the median LS was 8.05 kPa, and the median CAP was 280.5 dB/m at the start of PEM treatment. AST, ALT, ALP, γGTP, and triglyceride levels decreased 0.5 years after starting PEM treatment, but FIB-4, LS, and CAP values did not decrease. However, LS decreased in patients with a FIB-4 index ≥1.3 at the start of PEM treatment, whereas it did not change in patients with a FIB-4 index <1.3. Similarly, LS decreased in patients with a value ≥8 kPa at the start of treatment and did not change in those with <8 kPa. The decreased LS group had higher baseline ALT and LS levels and lower ALT levels during 0.5 years of follow-up than the increased LS group. Conclusion At the initiation of PEM treatment, the LS decreased in patients with MASLD complicated by hyperlipidemia and moderate LS (FIB-4>1.3 or LS >8 kPa). Although there is currently no approved treatment for MASLD, PEM may be a viable treatment option for MASLD with mild LS.

Incidence and Risk Factors of Veno-Occlusive Disease Are Different in Younger Versus Older Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic stem cell transplantation (allo-SCT). Improved transplant techniques and increased awareness of modifiable risk factors have reduced VOD incidence. However, the interaction of historic risk factors in the current era, particularly with the increasing use of calicheamicin-based therapies and post-transplant cyclophosphamide as GVHD prophylaxis, remains unclear. Methods: We conducted a retrospective, single center, chart-based study of consecutive adult patients (age ≥ 18 years) undergoing allo-SCT at MD Anderson Cancer Center between January 1 st, 2017 and December 31 st, 2021. VOD cases were defined using the classic VOD EBMT criteria or if patients received defibrotide treatment for VOD based on clinical judgment of the treating physician. Risk factors for VOD were evaluated in univariate analysis using Fine and Grey regression analysis. Multivariate analysis was performed using Classification and Regression Tree (CART) analysis to validate the findings of univariate analysis and evaluate independent effects accounting for potential interaction effects. Results: A total of 1561 patients were included in our analysis. Median age was 56 years and 60% were male. Patients primarily had acute myeloid leukemia/myelodysplastic syndrome (AML/MDS; 60%), acute lymphoblastic leukemia (ALL; 13%), or myeloproliferative neoplasms (13%). Most patients had matched related (28%) or unrelated donors (48%), and 21% underwent haploidentical transplantation. Forty-nine (3%) patients received inotuzumab ozogamicin (InO) containing regimens prior to allo-SCT, and 30 (2%) were exposed to gemtuzumab ozogamicin (GO). Post-transplant cyclophosphamide (PTCy) was used as GVHD prophylaxis in 72% of patients. Incidence of VOD in the entire study population was 4.8%. There was a significant difference in the median age of patients diagnosed with VOD compared to those without VOD (46 years vs 56 years, respectively, p=0.001). Further examination of the incidence of VOD within different age groups identified a VOD rate of 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those &amp;gt; 25 years (Table 1). Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD (Figure 1). Given these findings, risk factor analysis was stratified according to age. In patients ≤25 years of age, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with &amp;gt;1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Within the younger cohort of patients with AML/MDS, 2 of 3 patients (67%) who received gemtuzumab ozogamicin (GO) developed VOD compared to 10% who did not receive GO (p=0.05). In patients aged &amp;gt;25 years, elevated baseline bilirubin, AST, ALT, and GO exposure were associated with increased VOD rates. VOD incidence based on baseline bilirubin levels (WNL, &amp;gt;ULN to 1.5x ULN, and &amp;gt;1.5x ULN) was 3%, 14%, and 16%, respectively (p&amp;lt;0.001). For baseline ALT levels (WNL, &amp;gt;ULN to 2.5x ULN, and &amp;gt;2.5x ULN), VOD rates were 4%, 3%, and 8%, respectively (p=0.02). Similarly, VOD rates with baseline AST levels (WNL, &amp;gt;ULN to 2.5x ULN, and &amp;gt;2.5x ULN) were 3%, 4%, and 27%, respectively (p≤0.001). In patients aged &amp;gt;25 years with AML/MDS, those receiving GO had a higher incidence of VOD compared to AML/MDS patients not exposed to GO (15% vs. 3%; p=0.01). There was no significant difference in VOD rates between those receiving PTCy and those receiving alternate GVHD prophylaxis in either age cohort. Conclusion: In summary, our data highlight that young adults (age 18 - 25 years) represent a distinct adult population with increased rates of VOD compared to their older counterparts, which are exacerbated by disease and treatment related factors (DRI and number lines of therapy). In contrast, patients &amp;gt; 25 years of age had low rates of VOD even in the presence of historical predictors, with only hepatic risk factors identified as increasing baseline VOD risk. There was no observed increased incidence of VOD among those receiving PTCy as GVHD prophylaxis.

A novel approach for the treatment of advanced hepatocellular carcinoma (HCC).

35 Background: No established treatments for patients with advanced HCC and moderate hepatic dysfunction (Child-Pugh B; CPB) are available. Namodenoson is an A3 adenosine-receptor agonist currently under clinical development as a treatment for advanced HCC with CPB. Methods: Wereport the results of a prospective placebo-controlled randomized (2:1) phase 2 trial investigating namodenoson (25 mg BID) as a second-line therapy in HCC with CPB and focus on a case of a long-term complete response (CR). Results: The study included 78 patients (50 namodenoson-treated, 28 placebo-treated). Namodenoson was well-tolerated and no treatment-related deaths were reported. Median overall survival (OS, the primary endpoint) was not statistically significantly different between the namodenoson and placebo arms (4.1 and 4.3 months, respectively, hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.49‒1.38; p=.46). The difference in 12-month OS was statistically significant (44% vs 18%, respectively, p=.028). Pre-planned analysis of patients with CPB7 (34 namodenoson-treated, 22 placebo-treated) showed nonsignificant improvements in OS and progression-free survival (PFS). OS: 6.9 vs 4.3 months; HR, 0.81; 95% CI: 0.45‒1.43; p=.46. PFS: 3.5 vs 1.9 months; HR, 0.89; 95% CI: 0.51‒1.55; p=.67. Of the patients with ≥1 assessment post-baseline, partial response (PR) was reported in 3 of 34 (8.8%) namodenoson-treated patients and none of the 21 placebo-treated patients. One of 3 the patients who achieved a PR (a 61-year old woman with CPB7, Barcelona Clinic Liver Cancer stage C, and Eastern Cooperative Oncology Group performance status 2) continued treatment with namodenoson under an open-label extension program (treatment is ongoing for &gt;6 years). The patient achieved a CR (determined via CT scans) 4 years after treatment initiation. Furthermore, the patient's baseline ALT and AST levels which were elevated at baseline (68 U/L and 44 U/L, respectively) normalized after 4 weeks, and her serum α-fetoprotein level, which was 47 ng/ml at baseline, declined to normal levels after 20 weeks of treatment and reached 1.3 ng/mL at time of CR. The patient experienced no treatment-related adverse events. At present (6 years from treatment initiation), the response is ongoing as shown by liver function evaluation and imaging studies. Conclusions: Treatment with namodenoson can result in a complete and long-term response. The findings support the clinical development of namodenoson as a treatment for HCC with CPB7. Clinical trial information: NCT02128958 .

98-OR: Oral Insulin Alleviates Liver Fibrosis and Reduces Fat in Patients with NASH and Type 2 Diabetes—Results of Phase II Clinical Trial

NAFLD is the most common liver disorder in the USA. NASH is an advanced form of NAFLD and a leading cause of end-stage liver disease and indication for liver transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease. This double-blind, randomized, placebo-controlled, multicenter study aimed to determine the effect of oral insulin in patients with NASH and T2DM. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n=21) or placebo (n=11) capsule. Safety was monitored throughout the study. At screening and after 12 weeks of treatment, liver fat content was measured by MRI-PDFF and liver fibrosis and steatosis levels by FibroScan®. No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2±22.8% vs. -6.5±15.3%, respectively) and liver segment 3 (-11.7±21.1% vs. +0.1±17.3%, respectively) fat content were higher in the insulin as compared to the placebo arm. Patients receiving insulin showed a median -1.1 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively. In comparison, placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, HbA1c levels decreased by a mean -0.27±1.3% in the oral insulin cohort and increased by a mean 0.23±0.73% in the placebo cohort. Mean percent changes from baseline ALT and AST levels were -0.1±30.4% and -0.8±28.6%, respectively, in the oral insulin arm and 3.0±26.7% and 13.4±46.6%, respectively, in the placebo arm. Over the treatment period, mean total cholesterol, HDL, LDL, and triglycerides levels were consistently lower than baseline in the active arm and higher than baseline in the placebo arm. The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes. Disclosure Y.Ishay: None. J.M.Neutel: None. Y.Kolben: None. R.Gelman: None. O.Sneh arbib: None. O.Lopez: None. R.Sotolongo: None. Y.Ilan: None. M.Kidron: Employee; Oramed Pharmaceuticals.

A44 A 1000 PATIENT CANADIAN NETWORK FOR AUTOIMMUNE LIVER DISEASE EVALUATION OF CLINICAL AND DEMOGRAPHIC PATTERNS OF AUTOIMMUNE HEPATITIS

Abstract Background We sought to understand how the demographics of autoimmune hepatitis (AIH) have changed over time in Canada. Purpose Using a large multi-centre Canadian cohort of patients with AIH, we describe the trends in patient and disease characteristics at presentation across 30 years of clinical practice. Method Patients from the Canadian Network for Autoimmune Liver Disease with a confirmed diagnosis of AIH (simplified score ≥6) were included for analysis. Patients were grouped into five cohorts according to the year of diagnosis (i.e., &amp;lt;2000, 2000-2004, 2005-2009, 2010-2014, ≥2015). Patient demographics and baseline clinical and biochemistry features of disease activity were investigated using Chi-square tests and Kruskal-Wallis tests adjusted for multiple comparisons. Logistic and linear regression models with estimated means were utilized to further investigate relationships with time and to adjust for confounding. Result(s) 1016 patients followed across 10 Canadian health centres with AIH were diagnosed between November 1965 and December 2021. Overall, 76.4% (n=776) of patients were female, and the median age at diagnosis was 46 years (IQR 28.2 - 58.3). Cirrhosis at presentation was seen in 20.6% of patients (n=209). The median age at diagnosis increased significantly from 31.8 years [IQR 17.9 - 46.8] pre-2000 to 54 years [IQR 9.0 - 95.2] after 2014 (p&amp;lt;0.001; Figure 1a). This effect of time persisted after adjusting for sex and cirrhosis status at diagnosis. Female sex and the presence of cirrhosis at diagnosis were factors independently associated with older age at presentation (p&amp;lt;0.0001). The proportion of patients that presented with cirrhosis at diagnosis increased significantly over calendar time, from 13.7% (n=23) pre-2000 to 30.8% (n=69) after 2014 (p=0.003; Figure 1b). Male sex was independently associated with an increased odds of having cirrhosis at presentation (OR= 1.46, CI 1.02 - 2.07) and higher baseline ALT levels compared to females (p=0.036). The proportion of patients that identified as non-white ethnicity increased significantly from 15.2% (n= 24) pre-2000, to 32% (n= 86) after 2014 (p&amp;lt;0.001, Figure 1b). This effect of time on ethnicity was most pronounced after the year 2010 (OR= 2.32, CI 1.39 - 3.98) and persisted after adjusting for sex. There was no significant pattern of change in sex over calendar time. Image Conclusion(s) In Canada, patients with AIH at presentation are now older, have more advanced disease, and are more ethnically diverse than when compared to 30 years ago. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; industry Disclosure of Interest None Declared

Demographic characteristics and associated influencing factors in treated patients with chronic hepatitis B with hypoviremia : a single-center retrospective cross-sectional study

Objective: To investigate the demographic characteristics and clinical influencing factors which associates with the occurrence probability of persistent or intermittent hypoviremia (LLV) in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs). Methods: A single-center retrospective analysis was performed on patients with CHB who received outpatient NAs therapy for≥48 ± 2 weeks. According to the serum hepatitis B virus (HBV) DNA load at 48±2 weeks treatment, the study groups were divided into LLV (HBV DNA < 20 IU/ml and < 2 000 IU/ml) and MVR group (sustained virological response, HBV DNA < 20 IU/ml). Demographic characteristics and clinical data at the start of NAs treatment (considered as baseline) were retrospectively collected for both patient groups. The differences in the reduction of HBV DNA load during treatment was compared between the two groups. Correlation and multivariate analysis were further conducted to analyze the associated factors influencing the LLV occurrence. Statistical analysis was performed using the independent samples t-test, c2 test, Spearman analysis, multivariate logistic regression analysis, or area under the receiver operating characteristic curve. Results: A total of 509 cases were enrolled, with 189 and 320 in the LLV and MVR groups, respectively. Compared to patients with MVR group at baseline: (1) the demographics characteristics of patients showed that LLV group was younger in age (39.1 years, P = 0.027), had a stronger family history (60.3%, P = 0.001), 61.9% received ETV treatment, and higher proportion of compensated cirrhosis (20.6%, P = 0.025) at baseline; (2) the serum virological characteristics of patients showed that LLV group had higher HBV DNA load, qHBsAg level, qHBeAg level, HBeAg positive rate, and the proportion of genotype C HBV infection but decreased HBV DNA during treatment (P < 0.001) at baseline; (3) the biochemical characteristics of patients showed that LLV group had lower serum ALT levels (P = 0.007) at baseline; (4) the noninvasive fibrosis markers of patients showed that LLV group were characterized by high aspartate aminotransferase platelet ratio index (APRI) (P = 0.02) and FIB-4 (P = 0.027) at baseline. HBV DNA, qHBsAg and qHBeAg were positively correlated with LLV occurrence (r = 0.559, 0.344, 0.435, respectively), while age and HBV DNA reduction were negatively correlated (r = -0.098, -0.876, respectively). Logistic regression analysis showed that ETV treatment history, high HBV DNA load at baseline, high qHBsAg level, high qHBeAg level, HBeAg positive, low ALT and HBV DNA level were independent risk factors for patients with CHB who developed LLV with NAs treatment. Multivariate prediction model had a good predictive value for LLV occurrence [AUC 0.922 (95%CI: 0.897 ~ 0.946)]. Conclusion: In this study, 37.1% of CHB patients treated with first-line NAs has LLV. The formation of LLV is influenced by various factors. HBeAg positivity, genotype C HBV infection, high baseline HBV DNA load, high qHBsAg level, high qHBeAg level, high APRI or FIB-4 value, low baseline ALT level, reduced HBV DNA during treatment, concomitant family history, metabolic liver disease history, and age < 40 years old are potential risk factors for developing LLV in patients with CHB during the therapeutic process.

Chronic Hepatitis C Virus Infection Is Associated with an Increased Risk of Diabetes Mellitus in Thalassemia Major

Introduction. Hepatitis C virus (HCV) infection is associated with a number of important extrahepatic manifestations. The association between HCV infection and the occurrence of diabetes mellitus remains controversial. Aim. The aim of this multicentric study was to prospectively assess the relationship between HCV infection and diabetes mellitus in patients with thalassemia major (TM). Methods. We considered 1057 TM patients (539 females; 29.79±10.08 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT). Every 18±3 months the patients performed a magnetic resonance imaging (MRI) scan for iron overload assessment by the T2* technique. The disturbances of glucose metabolism were assessed within three months from each MRI by means of oral glucose tolerance test (OGTT). Results. On the basis of the presence of HCV antibodies and RNA, a categorization in 4 groups was performed: negative patients (group 1a, N=460), patients who spontaneously cleared the virus in the first 6 months of infection (group 1b, N=242), patients who eradicated the virus after the treatment with antiviral therapy obtaining a sustained virological response (SVR) (group 2, N=102), and patients with chronic HCV infection (group 3, N=254). The absolute first MRI was the baseline for patients in groups 1a, 1b and 3 while for patients in group 2 the baseline was represented by the first MRI performed after the virus eradication. The follow-up date coincided with the date of the last available MRI. Mean age was significantly lower in group 1a than in all the other 3 groups and in both groups 1b and 3 than in group 2. Group 1a and 1b were considered as a unique group (group 1, no chronic HCV infection). A match 1:1 for age and sex with group 2 was performed. At the baseline ALT and AST levels were significantly increased in group 3 versus both groups 1 and 2 (P<0.0001 for all comparison) and GGT was significantly higher in group 3 than in group 2 (P=0.024). No significant difference was detected in iron overload indices. The OGTT was not performed in 5 patients without known diabetes and frequency of diabetes was comparable among the three groups. Mean follow-up time was 66.27±39.23 months. Among the 253 (84.1%) patients free of diabetes at the baseline MRI, 8 did not perform the OGTT at the follow-up. So, we considered 245 patients: 85 in group 1, 83 in group 2, and 77 in group 3. During the follow-up, diabetes mellitus was recorded in the 2.4%, 6.0% and 7.8% of patients in group 1, 2 and 3, respectively. The chronic HCV group showed a significantly higher risk of diabetes than group 1 (hazard-ratio-HR=5.33, 95%CI=1.06-26.93; P=0.043). The Figure shows the Kaplan-Meier curve. Conclusion. Chronic HCV infection is associated with a significant higher risk of diabetes mellitus in TM patients and, as a consequence, it should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Liver involvement and mortality in COVID-19: A retrospective analysis from the CORACLE study group.

liver abnormalities are common in COVID-19 patients and associated with higher morbidity and mortality. We aimed to investigate clinical significance and effect on the mortality of abnormal liver function tests (ALFTs) in COVID-19 patients. we retrospectively evaluated in a multicentre study all patients admitted with confirmed diagnosis of COVID-19. 434 patients were included in this analysis. Among overall patients, 311 (71.6%) had normal baseline ALT levels. 123 patients showed overall abnormal liver function tests (ALFTs) at baseline [101 ALFTs <2x UNL and 22 ≥2 UNL]. Overall in-hospital mortality was 14% and mean duration of hospitalization was 10.5 days. Hypertension (50.5%), cardiovascular diseases (39.6%), diabetes (23%) were frequent comorbidities and 53.7% of patients had ARDS. At multivariate analysis, the presence of ARDS at baseline (OR=6.11; 95% CI: 3.03-12.32; p<0.000); cardiovascular diseases (OR=4; 95% CI: 2.05-7.81; p<0.000); dementia (OR=3.93; 95%CI:1.87-8.26; p<0.000) and no smoking (OR=4.6; 95% CI: 1.45-14.61; p=0.010) resulted significantly predictive of in-hospital mortality. The presence of ALFTs at baseline was not significantly associated with mortality (OR=3.44; 95% CI=0.81-14.58; p=0.094). ALFTs was frequently observed in COVID-19 patients, but the overall in-hospital mortality was mainly determined by the severity of illness, comorbidities and presence of ARDS.

Incidence and predictors of nevirapine and efavirenz-associated rash among Indonesian HIV patients

Many drugs used for the treatment of HIV disease can cause drug hypersensitivity reactions. Since 2002, World Health Organization (WHO) has recommended the use of nevirapine and efavirenz as part of first line antiretroviral therapies for several years. Both of the drugs had equivalent clinical efficacy but differences in toxicity profile. We aimed to determine the incidence and predictors of nevirapine and efavirenz-associated rash among Indonesian HIV-infected patients. A retrospective cohort study was conducted among Indonesian patients who were using nevirapine or efavirenz between January 2004 to December 2013. All eligible predictors were analyzed using bivariate and multivariate analysis. 2,071 patients received nevirapine and 1,212 received efavirenz as first line therapies. The cumulative incidence of nevirapine-associated rash was 14% (95%CI: 12.5-15.5%) and evafirenz-associated rash was 4.5% (95%CI: 3.4-5.8%). Severe reactions occurred 1% patients receiving NVP and 0.1% patients receiving EFV, but no patients died due to these conditions. Predictors independently related with nevirapine-associated rash were female gender (adjusted RR = 1.622; 95%CI: 1.196-2.199; p = 0.002), baseline absolute CD4 count above 200 cells/mm3 (adjusted RR = 1.387; 95%CI: 1.041-1.847; p = 0.025), and hepatitis C co-infection (adjusted RR = 1.507; 95%CI: 1.138-1.995; p = 0.004). Baseline ALT level > 1.25 times upper normal limit (adjusted RR = 1.508; 95%CI: 0.998-2.278; p = 0.051) had a tendency to be a good predictor. None of the risk factors investigated was associated with developing efavirenz-associated rash. Female, baseline absolute CD4 count above 200 cells/mm3, hepatitis C co-infection and baseline ALT levels more than 1.25 times upper normal limit were predictors for nevirapine-associated rash in HIV patients.

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors.

Simple SummaryHepatitis is a relatively frequent immune-related adverse event in patients with hepatocellular carcinoma receiving immunotherapy, but risk factors and clinical course are unclear. Herein, we show that the development of high-grade hepatitis is associated with increased baseline ALT levels and infectious etiology of hepatocellular carcinoma (related to prior hepatitis B or C virus exposure). In addition, when resolved, high-grade hepatitis does not preclude treatment resumption and does not affect subsequent time to treatment failure. Analysis of baseline tumor specimens, at a preliminary level, suggests that biological features reminiscent of the hepatocellular carcinoma “immune class” could protect against high-grade hepatitis development, thereby warranting further investigation.Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included—20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4–2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.

Effects of on-treatment ALT flares on serum HBsAg and HBV RNA in patients with chronic HBV infection.

As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5×ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4-12], 7.6×ULN [IQR 6.2-10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p<.001). On-treatment flares were significantly and independently associated with HBsAg and HBV RNA decline ≥1log10 at the final visit declines started shortly before the flare, progressing towards 24weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.

Clinical effect of entecavir antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase and mild liver histological abnormalities

Objective To investigate the clinical effect of entecavir antiviral therapy in chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (PNALT) and mild liver histological abnormalities. Methods A retrospective analysis was performed for 181 patients with hepatitis B virus (HBV) infection who were admitted to The First Affiliated Hospital of Guangxi Medical University from January 2008 to January 2018, and according to the baseline ALT level, they were divided into study group (61 patients with PNALT at baseline), control group 1 [62 patients with an ALT level of (1-2)×upper limit of normal (ULN)], and control group 2 (58 patients with an ALT level of > 2×ULN). Entecavir antiviral therapy was given for at least 1 year, and clinical outcome was compared between the three groups. The life-table method was used to calculate the cumulative progression rates and annual incidence rates of virologic response, HBeAg serological response, and virologic breakthrough. An analysis of variance was used for comparison of continuous data between groups, and the SNK method was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between groups. Results Among the 181 patients enrolled in this study, there were 124 male patients (68.5%) and 80 patients with positive HBeAg (44.2%), with a mean follow-up time of 3.63 years. The three groups had a mean annual incidence rate of virologic response of 74.37%, 71.89%, and 74.21%, respectively (χ2=2.91, P=0.371) and an annual incidence rate of virologic breakthrough of 3.48%, 5.17%, and 2.73%, respectively (χ2=1.72, P=0.097). For the patients with positive HBeAg, the three groups had a mean annual clearance rate of 9.79%, 37.16%, and 38.24%, respectively (χ2=1.37, P=0.01) and a mean annual HBeAg seroconversion rate of 9.10%, 31.35%, and 36.74%, respectively (χ2=5.61, P=0.021); the study group had significantly lower mean annual clearance rate and seroconversion rate of HBeAg than the control groups 1 and 2 (all P Conclusion CHB patients with PNALT level can obtain satisfactory virologic response after entecavir antiviral therapy, while immunological response needs to be further improved.

COVID-19-related abdominal pain is associated with elevated liver transaminases, which could predict poor clinical outcomes

ObjectiveAbdominal pain and liver injury have been frequently reported during Coronavirus Disease-2019 (COVID-19). In the setting of a systemic infection these features can induce misleading surgical diagnostics. Our aim was to investigate characteristics of abdominal pain in COVID-19 patients and its association with disease severity and liver injury.MethodsData of all COVID-19 hospitalized patients over 16 years old were retrieved from the beginning of the epidemic in Switzerland until end of June 2020. Patients admitted exclusively for other pathologies (including surgical abdominal conditions) and/or recovered from COVID-19, and pregnant women were excluded. Abdominal pain was linked to COVID-19 only after evident alternative diagnostic exclusion. Five times the upper limit of transaminases was considered as liver injury.ResultsAmong the 1026 patients who fulfill the inclusion/exclusion criteria, 199 (19.4%) exhibited spontaneous abdominal pain and 165 (16.2%) after abdomen palpation. Systematized abdominal pain was most frequently localized in the epigastric (39.8%) and upper right quadrant (23.7%). Considering baseline ALT levels, 7.14% of patients with epigastric pain had pathological ALT value versus 0.29% of patients without symptoms (p = 0.008). When taking the 30days maximal transaminases value, this reached respectively 16.3% versus 2.7% (p < 0.001) and 20% versus 3.8% (p < 0.001) for respectively AST and ALT.With logistic regression we demonstrated that baseline pathological AST value was associated with hospital mortality and/or admission to intensive/intermediate care unit with an odds ratio of 13.9 (CI 1.5-124.7, p = 0.019).ConclusionThese results suggest that COVID-19-induced abdominal pain is associated with liver injury which could predict poor evolution of disease.

Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA

Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.

Mild AST elevation as an early sign of COVID-19 severity in a multicenter Madrid cohort.

liver enzyme elevation has been reported in SARS-CoV-2 disease (COVID-19) in heterogeneous cohorts, mainly from China. Comprehensive reports from other countries are needed. In this study, we dissect the pattern, evolution, and predictive value of such abnormalities in a cohort from Madrid, Spain. a retrospective study with a prospective 14-day follow-up of 373 patients with confirmed COVID-19 in five Madrid hospitals, including 50 outpatients. A COVID-19 severe course was defined as the need for mechanical ventilation. a total of 33.1 % of hospitalized patients showed baseline AST elevation and 28.5 % showed ALT elevation, compared with 12 % and 8 % of outpatients (p ≤ 0.001). Baseline AST, ALT and GGT levels correlated with LDH and C-reactive protein (CRP) levels (r ≤ 0.598, p < 0.005). AST elevation was associated with other severity markers such as male sex, lymphopenia, and pneumonia on X-Ray (p < 0.05 for all). ALP and bilirubin levels were rarely increased. Patients with elevated baseline AST showed a progressive normalization of this enzyme and an increase in ALT and GGT levels. Patients with normal baseline AST showed a flattened evolution pattern with levels within the range. Patients with a severe course of COVID-19 more frequently showed elevated baseline AST than those with a milder evolution (54.2 % vs. 25.4 %, p < 0.001). Age, AST and CRP were independent risk factors for a severe course of COVID-19. mild liver enzyme elevation is associated with COVID-19 severity. Baseline AST is an independent predictor of severe COVID-19 course, and tends to normalize over time. ALT and GGT show a late elevation.

Sexual Dimorphism in Hepatocyte Xenograft Models

Humanized liver mouse models are crucial tools in liver research, specifically in the fields of liver cell biology, viral hepatitis and drug metabolism. The livers of these humanized mouse models are repopulated by 3-dimensional islands of fully functional primary human hepatocytes (PHH), which are notoriously difficult to maintain in vitro. As low efficiency and high cost hamper widespread use, optimization is of great importance. In the present study, we analyzed experimental factors associated with Hepatitis E virus (HEV) infection and PHH engraftment in 2 xenograft systems on a Nod-SCID-IL2Ry-/- background: the alb-urokinase plasminogen activator mouse model (uPA-NOG, n=399); and the alb-HSV thymidine kinase model (TK-NOG, n = 198). In a first analysis, HEV fecal shedding in liver humanized uPA-NOG and TK-NOG mice with comparable human albumin levels was found to be similar irrespective of the mouse genetic background. In a second analysis, sex, mouse age at transplantation and hepatocyte donor were the most determinant factors for xenograft success in both models. The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.

CYP2E1-DEPENDENT VARIATIONS IN HEPATOCYTES DAMAGE DURING TREATMENT OF TUBERCULOSIS

Relevance. Investigation of polymorphism in a locus of CYP2E1 as the prognostic factor of drug-induced hepatotoxicity at anti-TB therapy is significant due to the influence of CYP2E1 on drug metabolism.&#x0D; The objective of the investigation is to analyze the association of rs2070676 СYP2E1 gene polymorphism with drug-induced hepatotoxicity by means of the clinical-laboratory values of serum transaminases at anti-TB treatment.&#x0D; Materials and methods. The study involved 47 patients with drug-susceptible tuberculosis first time discovered. 58 healthy volunteers comprised a control group. Laboratory indices were determined in venous blood three times: before the treatment as baseline; in 2 months of intensive therapy (isoniazid, rifampicin, ethambutol, pyrazinamide), then in 4 months of maintenance therapy (isoniazid, rifampicin). Serum activities of enzymes ALT, AST, and GGT were measured by standard algorithm on automatic analyzer BS-300. Analysis of rs2070676 polymorphism of CYP2E1 gene was performed by polymerase chain reaction using standard PureLink® Genomic DNA Kit for Purification of Genomic DNA; Manufacturer of INVITROGEN (USA). For statistical processing, IBM SPSS Statistics 23 was applied.&#x0D; Results. Investigation of serum ALT and AST in patients with major genotype CYP2E1 (C/C) showed the lower baseline ALT and AST levels comparing to the control group, which might be caused by suppression of hepatocytes functions at the development of the disease. Anti-TB treatment caused an increase in ALT and AST levels comparing to the baseline in patients with major CYP2E1 (C/C) genotype. In the group with C/G polymorphism, the baseline ALT level didn’t differ much from the baseline of the control group; it showed a decrease after intensive therapy and returned back to the initial level at maintenance therapy. This might be related to the certain protective property of СYP2E1 gene polymorphism. The AST level was increased after intensive therapy (to a smaller extent than for the patients with major C/C genotype) and remained on the same level at maintenance therapy. A study of GGT showed a gradual increase regardless of genotype.&#x0D; Conclusion. According to the data of the experiment, the status of hepatocytes in patients with tuberculosis at baseline and during treatment was different depending on the CYP2E1 genotype. The results of the experiment indicate that the CYP2E1 gene polymorphism has a certain protecting role. It reduces the level of drug metabolites and hepatotoxicity which causes mitochondrial dysfunction.

P150 Risk of hepatitis flare in patients with previous hepatitis B virus exposure amongst inflammatory bowel disease patients: results from a territory-wide Hong Kong IBD Registry study

Abstract Background Biological therapies, thiopurines and steroid are commonly used in the treatment of inflammatory bowel disease (IBD) and may cause hepatitis B virus (HBV) reactivation. However, their exact risk of hepatitis B flare in patients with previous HBV exposure is poorly defined. We aim to study the risk of hepatitis flare in IBD patients with previous HBV exposure. Methods Patients were identified from a territory-wide Hong Kong IBD Registry. IBD patients who were negative for HBsAg and received biological therapies or thiopurines or steroids from 1 January 2000 to 30 June 2019 were included. Patients who were positive for total antibody to hepatitis B core antigen (anti-HBc) and/or hepatitis B surface antigen (anti-HBs) were defined to have previous HBV exposure. Primary endpoint was development of hepatitis flare (alanine Aminotransferase [ALT) &amp;gt;80U/L). Results Total 369 patients fulfilled the inclusion criteria and were classified into three groups: anti-HBs positive only (n = 246); anti-HBs and anti-HBc positive (n = 78) and anti-HBc positive only (n = 45). Median follow-up duration was 60 months (Interquartile range: 32.7–60 months). Seventy-six IBD patients (20.6%) developed hepatitis flare. Cumulative incidence of hepatitis flare were 13.2%, 18.3% and 22% at 12 months, 36 months and 60 months respectively. Use of thiopurine [adjusted hazard ratio (aHR) 2.56; 95% Confidence Interval (CI) 1.54 – 4.26, p &amp;lt; 0.001]and ever exposure to steroid [aHR 2.73; 95% CI 1.30–5.72; p = 0.008] were risk factors for hepatitis flare after adjustment of baseline ALT level. The use of biological therapy was not associated with risk of hepatitis flare [aHR 1.79; 95% CI 0.79–3.99; p = 0.14]. Ever exposure to steroid was associated with increased risk of hepatitis flare irrespective of the peak dose (&amp;lt;20mg prednisolone daily, 20-40mg daily or &amp;gt;40mg daily) [aHR: 2.34–4.18]. Fifteen patients (4.1%) developed severe icteric hepatitis flare (ALT &amp;gt; 120U/L and bilirubin &amp;gt;38 mmol/L). Cumulative incidence of severe icteric hepatitis flare were 2.7%, 7.2% and 8.4% at 12 months, 36 months and 60 months respectively. Conclusion Amongst IBD patients with previous HBV exposure who were treated with biological therapy, thiopurines or steroid, 20.6% developed hepatitis flare. The use of thiopurine and ever exposure to steroid were risk factors for hepatitis flare. The use of biological therapy was not associated with risk of hepatitis flare.

Effect of nucleos(t)ide analogue on serum HBsAg level in chronic hepatitis B patients: A 3-years study

AimWe aim to explore the effects of nucleos(t)ide analogues (NUCs) on the changes of HBsAg in chronic hepatitis B (CHB) patients. MethodsA total of 264 CHB patients were enrolled in our study. All of them were treated with NUCs for at least three years. Quantification of HBsAg levels were measured by Elecsys HBsAg II. ResultsAlthough HBsAg levels were significantly higher in HBeAg seropositive CHB patients at baseline than in HBeAg seronegative CHB patients (3.84 ± 0.82 vs 3.21 ± 0.59 IU/mL), HBsAg levels declined more rapidly in the HBeAg seropositive group (P < 0.001). In HBeAg-positive CHB patients, HBsAg level in the telbivudine (LDT)-treated group was 3.68 ± 0.56 IU/mL after 52-week of treatment, which was significantly higher than that in lamivudine (LAM)-treated group (P = 0.009). Multivariable analyses showed that baseline HBV DNA viral load (OR = 0.75, P = 0.018), baseline ALT level (OR = 0.99, P = 0.015), and baseline HBsAg level (OR = 0.188, P < 0.001) were independent factors that affected HBsAg decline in HBeAg seropositive CHB patients. For HBeAg seronegative CHB patients, the average of serum HBsAg levels in LAM-, LdT-, adefovir (ADV)-, and entecavir (ETV)-treated groups at baseline, 52 weeks, 104 weeks, and 156 weeks were similar. Multivariable analyses showed that only baseline HBV DNA level (OR = 0.56, P = 0.020) and baseline HBsAg level (OR = 0.57, P = 0.012) were independent factors that affected HBsAg decline in HBeAg seronegative patients with CHB. Baseline HBV DNA level (OR = 0.72, P = 0.010) and baseline HBsAg level (OR = 0.19, P < 0.001) were independent factors that affected all CHB patients. ConclusionsCHB Patients who had received NUCs antiviral treatment showed a slow but significant decrease in serum HBsAg level. Long-term monitoring and continuous antiviral treatment are necessary, especially for those patients with risk factors associated with HBsAg decline.