Hepatitis after gene therapy, what are the possible causes?

Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno-associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune-mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre-existing liver conditions. Liver biopsy data conducted years post-gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug-induced liver injury (DILI) based on Hy's Law criteria. Essential pre-therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non-invasive fibroscans, while novel blood-based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long-term effects on the liver, providing insights for optimising gene therapy for haemophilia.

Within-individual reproducibility of a dual sample oral cholate challenge test (DuO) and simplified versions of the HepQuant SHUNT test.

Current noninvasive liver tests measure fibrosis, inflammation, or steatosis and do not measure function. The HepQuant platform of noninvasive tests uniquely assesses both liver function and physiology through the hepatic uptake of stable isotopes of cholate. However, the prototypical HepQuant SHUNT test (SHUNT V1.0) is cumbersome to administer, requiring intravenous and oral administration of cholate and six peripheral venous blood samples over 90 min. To alleviate the burden of test administration, we explored whether an oral only (DuO) version, and other simplified versions, of the test could provide reproducible measurements of liver function. DuO requires only oral dosing and two blood samples over 60 min. The simplified SHUNT test versions were SHUNT V1.1 (oral and IV dosing but four blood samples) and SHUNT V2.0 (oral and IV dosing but only two blood samples over 60 min). In this paper, we describe the reproducibility of DuO and the simplified SHUNT tests relative to that of SHUNT V1.0; equivalency is described in a separate paper. Data from two studies comprising 236 SHUNT tests in 94 subjects were analyzed retrospectively by each method. All simplified methods were highly reproducible across test parameters with intraclass correlation coefficients >0.93 for test parameters Disease Severity Index (DSI) and Hepatic Reserve. DuO and SHUNT V2.0 improved reproducibility in measuring portal-systemic shunting (SHUNT%). These simplified tests, particularly DuO and SHUNT V2.0, are easier to administer and less invasive, thus, having the potential to be more widely accepted by care providers administering the test and by patients receiving the test.

Administration of silymarin in NAFLD/NASH: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide and poses serious harm to human health. There is growing evidence suggesting that the administration of specific supplements or nutrients may slow NAFLD progression. Silymarin is a hepatoprotective extract of milk thistle, but its efficacy in NAFLD remains unclear. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrails.gov, and China National Knowledge Infrastructure and were screened according to the eligibility criteria. Data were analyzed using Revman 5.3. Continuous values and dichotomous values were pooled using the standard mean difference (SMD) and odds ratio (OR). Heterogeneity was evaluated using the Cochran's Q test (I2 statistic). A P<0.05 was considered statistically significant. RESULTS: A total of 26 randomized controlled trials involving 2,375 patients were included in this study. Administration of silymarin significantly reduced the levels of TC (SMD[95%CI]=-0.85[-1.23, -0.47]), TG (SMD[95%CI]=-0.62[-1.14, -0.10]), LDL-C (SMD[95%CI]=-0.81[-1.31, -0.31]), FI (SMD[95%CI]=-0.59[-0.91, -0.28]) and HOMA-IR (SMD[95%CI]=-0.37[-0.77, 0.04]), and increased the level of HDL-C (SMD[95%CI]=0.46[0.03, 0.89]). In addition, silymarin attenuated liver injury as indicated by the decreased levels of ALT (SMD[95%CI]=-12.39[-19.69, -5.08]) and AST (SMD[95% CI]=-10.97[-15.51, -6.43]). The levels of fatty liver index (SMD[95%CI]=-6.64[-10.59, -2.69]) and fatty liver score (SMD[95%CI]=-0.51[-0.69, -0.33]) were also decreased. Liver histology of the intervention group revealed significantly improved hepatic steatosis (OR[95%CI]=3.25[1.80, 5.87]). CONCLUSIONS: Silymarin can regulate energy metabolism, attenuate liver damage, and improve liver histology in NAFLD patients. However, the effects of silymarin will need to be confirmed by further research.

Associating Liver Enzymes and Their Interactions with Metabolic Syndrome Prevalence in a Japanese Working Population.

Background: Serum gamma-glutamyltransferase (γ-GT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels often increase in metabolic diseases. Objective: This study was conducted to determine which liver enzymes are strongly associated with metabolic syndrome (MetS), how they interact to produce different probability estimates, and what cutoff levels should be used to guide clinical decision-making. Methods: The researchers examined the insurance-based medical checkup data of 293,610 employees ≥35 years years of age, who underwent medical checkups between April 1, 2016, and March 31, 2017. Liver enzyme levels were grouped into quartiles. The association and interaction of liver enzymes with MetS were examined using logistic regression, and receiver operating characteristic (ROC) analyses were used to determine the optimal cutoff values for each liver enzyme in detecting the prevalence of MetS. Results: High levels of γ-GT and ALT were more strongly associated with MetS than AST. At various levels, the tested liver enzymes were found interactive, and associated with the likelihood of MetS prevalence. ROC analysis underscored the significance of all liver enzymes in predicting the development of MetS. The cutoff values for each liver enzyme were determined. Conclusion: This findings of this study directly support the identification of MetS risks within the population, prioritize prevention strategies, and potentially inform policy formulation.

Effect of Liver Dysfunction on S-1 Therapy Induced Adverse Effects: A Retrospective Cohort Study.

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.

Evaluate the value of prolonging the duration of tiopronin for injection administration in preventing hepatotoxicity.

As part of supportive therapy, prophylaxis with tiopronin for injection (TI) against common hepatotoxicity complications has often been used. However, methods to prevent hepatotoxicity have not been established. Therefore, our study was aimed to find out the relationship between the periods of TI prophylaxis and post-treatment hepatotoxicity, and evaluated the value of prolonging the duration of TI administration in preventing hepatotoxicity. Hepatotoxicity was detected through liver transaminases, bilirubin, alkaline phosphatase, and clinical features of liver insufficiency. Multivariable logistic regressions were conducted to examine the association of the periods of TI prophylaxis and post-treatment hepatotoxicity. Between January 2022 and March 2023, a total of 452 patients with gynecological cancer were enrolled in the study, of which 93 (20.58%) participants were post-treatment hepatotoxicity positive. TI with different prevention days were no significant difference among participants with or without post-treatment hepatotoxicity in crude model (P > 0.05). The P-value, the odds ratios (OR) and 95% confidence intervals (CI) of participants with TI prophylaxis for 1 day for post-treatment hepatotoxicity were 0.040, 3.534 (1.061-11.765) in fully adjusted model. Past history of hepatotoxicity is a confounding variable, and there was no significant difference for post-treatment hepatotoxicity when stratified by past history of hepatotoxicity (P > 0.05). The study indicate that the periods of TI prophylaxis is not associated with post-treatment hepatotoxicity, suggesting that prolonged the periods of TI prophylaxis might be an invalid method for the prevention of post-treatment hepatotoxicity.

LASSO-derived model for the prediction of lean-non-alcoholic fatty liver disease in examinees attending a routine health check-up.

BACKGROUND: Lean individuals with non-alcohol fatty liver disease (NAFLD) often have normal body size but abnormal visceral fat. Therefore, an alternative to body mass index should be considered for prediction of lean-NAFLD. This study aimed to use representative visceral fat links with other laboratory parameters using the least absolute shrinkage and selection operator (LASSO) method to construct a predictive model for lean-NAFLD. METHODS: This retrospective cross-sectional analysis enrolled 2325 subjects with BMI < 24 kg/m2 from medical records of 51,271 examinees who underwent a routine health check-up. They were randomly divided into training and validation cohorts at a ratio of 1:1. The LASSO-derived prediction model used LASSO regression to select 23 clinical and laboratory factors. The discrimination and calibration abilities were evaluated using the Hosmer-Lemeshow test and calibration curves. The performance of the LASSO model was compared with the fatty liver index (FLI) model. RESULTS: The LASSO-derived model included four variables-visceral fat, triglyceride levels, HDL-C-C levels, and waist hip ratio-and demonstrated superior performance in predicting lean-NAFLD with high discriminatory ability (AUC, 0.8416; 95% CI: 0.811-0.872) that was comparable with the FLI model. Using a cut-off of 0.1484, moderate sensitivity (75.69%) and specificity (79.86%), as well as high negative predictive value (95.9%), were achieved in the LASSO model. In addition, with normal WC subgroup analysis, the LASSO model exhibits a trend of higher accuracy compared to FLI (cut-off 15.45). CONCLUSIONS: We developed a LASSO-derived predictive model with the potential for use as an alternative tool for predicting lean-NAFLD in clinical settings.

Researchers developed a model to predict a type of liver disease called non-alcoholic fatty liver disease (NAFLD) in lean individuals.The model accurately detects NAFLD in lean individuals using factors like visceral fat, triglyceride levels, and waist-to-hip ratio, aiding in identifying the disease in normal-weight people with abnormal fat distribution.

Spectrum of Liver Injury in Dengue Fever: Cause or Effect of Severe Dengue?

The study aimed to determine if deranged liver function tests (LFTs) can predict severe dengue or mortality. It included 135 dengue patients, with a mean age of 30.9 ± 12.09 years. Among the patients, 82 (60.7%) were under 30 years of age. Nearly half of the patients (64, 47. 4%) had some degree of liver damage indicated by deranged LFTs, 27 (42.1%) had elevated alanine transaminase (ALT), 7 (10.9%) had increased bilirubin, and 30 (46.9%) had high values of alkaline phosphatase (ALP). However, only elevated ALP levels were positively correlated with mortality (Pearson's R = 0.282, p = <0.05). The mean bilirubin was 11.711 ± 8.602 umol/l, and the mean values of ALT and ALP were 107 ± 240 and 113.571 ± 59.91 IU/L, respectively, which were higher than the normal. The study findings suggested that hepatic derangement is a common occurrence in dengue patients, and increased ALP levels could be an indicator of a higher risk of mortality. These findings can help improve patient care by identifying the potential risk factors for mortality. Key Words: Dengue, Liver function tests, Alanine transaminase, Alkaline phosphatase.

The Diversity of the Linguofacial Trunk.

Background and Objectives: Typically, the external carotid artery (ECA) sends off separate anterior branches: the superior thyroid, lingual, and facial arteries. These could, however, form common trunks: thyrolinguofacial, linguofacial (LFT), or thyrolingual. Although known, the LFT variant was poorly detailed previously, and most authors just counted the variant. We aimed to demonstrate the individual anatomical possibilities of the LFT on a case-by-case basis. Materials and Methods: 150 archived angioCT files were used. After applying inclusion and exclusion criteria, 147 files of 86 males and 61 females were kept for this study. Results: In 34/147 cases, LFTs were found (23.12%). Bilateral LFTs were found in 13/34 cases (38.24%) and unilateral LFTs in 21/34 (61.76%) cases. Forty-seven LFTs were thus identified and further studied for different variables. Regarding the vertical topography of LFT origin, type 1a (suprahyoid and infragonial) was found in 28 LFTs (59.57%), type 1b (suprahyoid and gonial) was found in eight LFTs (17.02%), type 3 (suprahyoid and supragonial) was found in two LFTs (4.25%), type 2 (hyoid level of origin) in eight LFTs (17.02%), and type 3 (infrahyoid origin) in just one LFT (2.12%). Types of the initial course of the LFT were determined: type I, ascending, was found in 22/47 LFTs; type II, descending, in 12/47 LFTs; and type III, transverse, in 13/47 LFTs. Regarding the orientation of the first loop of the LFT, 23/47 LFTs had no loop, 4/47 had anterior loops, 1/47 had a posterior loop, 5/47 had superior loops, 5/47 had inferior loops, and 9/47 had medial loops. The position of the LFT relative to the ECA was classified as medial, anterior, or antero-medial. An amount of 12/47 LFTs were anterior to the ECA, 22/47 were antero-medial, 10/47 were medial, 2/47 were inferior, and 1/47 was lateral. Regarding their general morphology, 23/47 LFTs had a rectilinear course, 22/47 had loops, and 2/47 were coiled. A case-by-case presentation of results further demonstrated the diversity of the LFT. Conclusions: In conclusion, the morphology and topography of the LFT are individually specific and unpredictable. It can be anticipated case-by-case by surgeons on CT or MR angiograms.

The link between high factor VIII to protein C ratio values and poor liver function after major hepatectomy.

Our goal was to assess the coagulation profile in the immediate postoperative time after major liver surgery and its association with the liver function. Our hypothesis is that a decreased synthesis of the coagulation factor levels reflects an impaired liver synthesis following hepatic resection and will be associated with poor outcomes. This is a prospective, observational study recruiting consecutive patients scheduled for major liver resection in a tertiary hospital. Coagulation profile was assessed by conventional assays, viscoelastic assays and coagulation factor levels preoperatively and, on postoperative days 1, 2 and 6. Factor VIII to protein C (FVIII/PC) ratio has been used as a surrogate marker of hemostatic imbalance. Liver function was measured with conventional and indocyanine green (ICG) clearance tests, which were obtained preoperatively and on postoperative days 1 and 2. Sixty patients were recruited and 51 were included in the study. There is a clear increase in FVIII/PC ratio after surgery, which was significantly associated with low liver function, being more pronounced beyond postoperative day 2 and in patients with poorer liver function ( P  < 0.001). High FVIII/PC ratio values were significantly associated with higher postoperative morbidity, prolonged ICU and hospital stay and less survival ( P  < 0.05). High FVIII/PC ratio on postoperative day 2 was found to be predictor of posthepatectomy liver failure (PHLF; area under the ROC curve = 0.8129). Early postoperative high FVIII/PC ratio values are associated with low liver function, PHLF and poorer outcomes in patients undergoing major hepatic resection.

Free mebrofenin clearance.

OBJECTIVES: To determine if three new simplified equations for measurement of free mebrofenin clearance give similar results to the equations defined by Ekman et. al ., and to evaluate the properties of all four methods. Regional mebrofenin clearance has been used to predict future remnant liver function and liver failure after regional liver therapy, such as partial hepatic resection. METHODS: The means, standard deviations, and correlations of the free mebrofenin clearance measured by the Ekman method and the three simplified methods were compared in a consecutive series of 26 studies in 20 patients. The fractional change in the blood and free mebrofenin activities were compared, and integrals of normalized blood and free mebrofenin ("effective times") were compared. RESULTS: The average percent free mebrofenin clearance for the Ekman and the first, second and third simplified methods were 13.62 ± 2.88%/min, 12.98 ± 2.97%/min, 12.52 ± 2.81%/min and 15.03 ± 2.27%/min, respectively. The correlations of the new methods with Ekman were 0.97, 0.93 and 0.93. The fractional changes during the measurement interval for the blood and free mebrofenin activities were 0.381 ± 0.065 and 0.329 ± 0.062, difference 0.052, P < 0.5. The integrals of normalized blood and free mebrofenin activities were 2.566 ± 0.160 min and 2.661 ± 0.158 min, difference of 0.094 min and P < 0.05. CONCLUSIONS: The results of the three new methods were similar to the Ekman method. The first simplified method was identified as the lead method for clinical validation in a larger population.

Advances in noninvasive measurement of liver function and physiology: The HepQuant DuO test.

Current noninvasive liver tests are surrogates for fibrosis and lack ability to directly measure liver function. HepQuant tests measure liver function and physiology through hepatic uptake of stable cholate isotopes. HepQuant SHUNT (V1.0) involves oral and intravenous dosing and six blood samples over 90 min. We developed simplified test versions: SHUNT V2.0 (oral and intravenous dosing, two blood samples over 60 min) and DuO (oral dosing only, two blood samples over 60 min). The aim of this study was to evaluate equivalency of the simplified tests to the original SHUNT test. Data from three studies comprising 930 SHUNT tests were retrospectively analysed by each method. Equivalence was evaluated in terms of proportion of tests in which the difference between methods was less than any clinically meaningful difference and additionally by two one-sided t-test and bioequivalence methods. DuO and SHUNT V2.0 were equivalent to the original SHUNT test for Disease Severity Index, with >99% and >96% of tests falling within equivalence bounds. DuO and SHUNT V2.0 met equivalency criteria by two one-sided t-tests and bioequivalence. DuO and SHUNT V2.0 are easier to administer, are less invasive than the original SHUNT test and have potential to be more accepted by patients and providers.

Drug-Induced Liver Injury in the Elderly: Consensus Statements and Recommendations from the IQ-DILI Initiative.

The elderly demographic is the fastest-growing segment of the world's population and is projected to exceed 1.5 billion people by 2050. With multimorbidity, polypharmacy, susceptibility to drug-drug interactions, and frailty as distinct risk factors, elderly patients are especially vulnerable to developing potentially life-threatening safety events such as serious forms of drug-induced liver injury (DILI). It has been a longstanding shortcoming that elderly individuals are often a vulnerable population underrepresented in clinical trials. As such, an improved understanding of DILI in the elderly is a high-priority, unmet need. This challenge is underscored by recent documents put forward by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) that encourage data collection in the elderly and recommend improved practices that will facilitate a more inclusive approach. To establish what is already known about DILI in the elderly and pinpoint key gaps of knowledge in this arena, a working definition of "elderly" is required that accounts for both chronologic and biologic ages and varying states of frailty. In addition, it is critical to characterize the biological role of aging on liver function, as well as the different epidemiological factors such as polypharmacy and inappropriate prescribing that are common practices. While data may not show that elderly people are more susceptible to DILI, DILI due to specific drugs might be more common in this population. Improved characterization of DILI in the elderly may enhance diagnostic and prognostic capabilities and improve the way in which liver safety is monitored during clinical trials. This summary of the published literature provides a framework to understand and evaluate the risk of DILI in the elderly. Consensus statements and recommendations can help to optimize medical care and catalyze collaborations between academic clinicians, drug manufacturers, and regulatory scientists to enable the generation of high-quality research data relevant to the elderly population.

Non-linear associations of circulating total bilirubin concentration with the risk of nonalcoholic fatty liver disease and all-cause mortality.

INTRODUCTION AND OBJECTIVES: Accumulating evidence has supported that mild elevated total bilirubin exerts antioxidant and anti-inflammatory properties in multiple metabolic diseases. We aimed to explore the association of circulating total bilirubin concentration with non-alcoholic fatty liver disease (NAFLD) risk and all-cause mortality and examine the potential nonlinear relationships between them. MATERIAL AND METHODS: We used nationally representative data from the National Health and Nutrition Examination Survey (NHANES). NAFLD was assessed using the fatty liver index (FLI) and United States fatty liver index (USFLI), respectively. RESULTS: A total of 35 912 and 17 329 participants were included in FLI-NAFLD (case with NAFLD was diagnosed by FLI) and USFLI-NAFLD (case with NAFLD was diagnosed by USFLI) groups, respectively. The mean age of total population was 46.25 years, and 48.51% were male. Compared to participants with lowest quintile of total bilirubin concentration, those with highest quintile had lower risk of NAFLD in both FLI-NAFLD (OR: 0.48, 95% CI: 0.40, 0.59) and USFLI-NAFLD (OR: 0.55, 95% CI: 0.43, 0.70) groups. Compared to participants with lowest quintile of total bilirubin concentration, the association between total bilirubin concentration and all-cause mortality was not significant among those with highest quintile of total bilirubin concentration (HR: 0.89, 95% CI: 0.66, 1.20). The restricted spline curves showed the nonlinear U-shaped association of total bilirubin concentration with NAFLD risk and all-cause mortality. The segmented linear regression analysis showed negative associations between total bilirubin concentration and risk of NAFLD in both FLI-NAFLD (OR: 0.94, 95% CI: 0.93, 0.95) and USFLI-NAFLD (OR: 0.95, 95% CI: 0.93, 0.96) groups when total bilirubin concentration was below the turning point (FLI-NAFLD: 18.81 µmol/L; USFLI-NAFLD: 15.39 µmol/L) and these associations were not significant when total bilirubin concentration was higher than the turning point. Furthermore, all-cause mortality decreased (OR: 0.97, 95%CI: 0.95, 1.00) with increased total bilirubin concentration up to the turning point (11.97 µmol/L), and then all-cause mortality increased with increasing total bilirubin concentration (OR: 1.03, 95%CI: 1.02, 1.04). CONCLUSIONS: We found that higher circulating total bilirubin concentration within the physiological range was associated with decreased risk of NAFLD and all-cause mortality among NAFLD patients.