Quantitative phase analysis and molecular structure of human gallstones using synchrotron radiation X-ray diffraction and FTIR spectroscopy.

Human gallstones are the most common disorder in the biliary system, affecting up to 20 % of the adult population. The formation of gallstones is primarily due to the supersaturating of cholesterol in bile. In order to comprehend gallstone disease in detail, it is necessary to have accurate information about phase identification and molecular structure. Different types of gallstone samples were collected from the Middle East area after surgical operations including; cholesterol, pigment, and mixed gallstones. To estimate the basic information about the stone formation and the pathophysiology of cholelithiasis as well as to classify the collected human gallstones, attenuated total reflection Fourier transform Infrared spectrometry (ATR-FTIR) was used to analyze the different gallstone structures in the wavenumber range from 400 to 4000 cm-1. Calcium bilirubinate was specified by the bands at 1662 cm-1, 1626 cm-1, and 1572 cm-1, while cholesterol rings were designated by the bands at 1464, 1438, 1055, and 1022 cm-1. It can be assumed that all samples consist of mixed gallstones based on the doublets at 1375 cm-1 and 1365 cm-1. The levels of calcium bilirubin and various minerals varied among the analyzed samples, indicating the heterogeneity in their composition and suggesting potential implications for gallstone formation. Based on the quantitative phase analysis using synchrotron radiation X-ray diffraction (SR-XRD), two phases of anhydrous cholesterol as a major content and one phase of monohydrate cholesterols as trace content represent the main components of most of the gallstones. Additional phases of calcium carbonate in the form of calcite, vaterite, aragonite, and bilirubinate were also quantified. According to the outcomes of the FTIR and the SR-XRD measurements, there exists a statistical correlation between the different types of chemical constituents of the gallstones.

Predictive factors in the differential diagnosis of benign and malignant causes in patients undergoing endoscopic retrograde cholangiopancreatography for extrahepatic cholestasis.

OBJECTIVE: Diagnosing benign vs. malignant extrahepatic cholestasis is challenging despite the currently available advanced imaging and endoscopic techniques. This study aims to determine the predictive accuracy of initial biochemical data and bile duct dilatation findings in transabdominal ultrasound (US) to differentiate between benign and malignant disease in patients with extrahepatic cholestasis. PATIENTS AND METHODS: We reviewed the case records of 814 patients who had undergone endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (in cases of unsuccessful ERCP) for extrahepatic cholestasis. The etiology of biliary obstruction was determined based on ERCP, endoscopic ultrasonography, radiology, cytology, biopsy, and/or clinical follow-up at one year. The patients were divided into benign and malignant groups according to the underlying etiology of biliary obstruction. A complete biochemical profile, transabdominal ultrasonography at presentation, and other demographic data were recorded. RESULTS: Alkaline phosphatase (p = 0.002), aspartate aminotransferase (p = 0.038), and bilirubin levels were significantly higher in malignant patients. The mean age of patients with malignancy was 69.5 years, vs. 60.6 years in benign patients (p < 0.001). The likelihood of malignancy increased with the increased bilirubin levels (> 200 µmol/l: 30.0% sensitivity, 97.6% specificity). The total bilirubin level predicting malignancy as the best cut-off value was 111 mmol/L with optimum sensitivity and specificity (61.8% and 83.8%, respectively) and area under the curve = 0.756, (p < 0.001). Intrahepatic bile duct (IHBD) dilatation was significantly higher in malignant patients (p < 0.001). CONCLUSIONS: A serum bilirubin level of 111 µmol/L or higher and the detection of IHBD dilatation on abdominal ultrasonography are important predictors in the differential diagnosis of benign and malignant causes of extrahepatic cholestasis.

Measuring and imaging of transcutaneous bilirubin, hemoglobin, and melanin based on diffuse reflectance spectroscopy.

Significance: Evaluation of biological chromophore levels is useful for detection of various skin diseases, including cancer, monitoring of health status and tissue metabolism, and assessment of clinical and physiological vascular functions. Clinically, it is useful to assess multiple different chromophores in vivo with a single technique or instrument. Aim: To investigate the possibility of estimating the concentration of four chromophores, bilirubin, oxygenated hemoglobin, deoxygenated hemoglobin, and melanin from diffuse reflectance spectra in the visible region. Approach: A new diffuse reflectance spectroscopic method based on the multiple regression analysis aided by Monte Carlo simulations for light transport was developed to quantify bilirubin, oxygenated hemoglobin, deoxygenated hemoglobin, and melanin. Three different experimental animal models were used to induce hyperbilirubinemia, hypoxemia, and melanogenesis in rats. Results: The estimated bilirubin concentration increased after ligation of the bile duct and reached around 18 mg/dl at 50 h after the onset of ligation, which corresponds to the reference value of bilirubin measured by a commercially available transcutaneous bilirubin meter. The concentration of oxygenated hemoglobin and that of deoxygenated hemoglobin decreased and increased, respectively, as the fraction of inspired oxygen decreased. Consequently, the tissue oxygen saturation dramatically decreased. The time course of melanin concentration after depilation of skin on the back of rats was indicative of the supply of melanosomes produced by melanocytes of hair follicles to the growing hair shaft. Conclusions: The results of our study showed that the proposed method is capable of the in vivo evaluation of percutaneous bilirubin level, skin hemodynamics, and melanogenesis in rats, and that it has potential as a tool for the diagnosis and management of hyperbilirubinemia, hypoxemia, and pigmented skin lesions.

A critical appraisal of the ISGLS definition of biliary leakage after liver resection.

PURPOSE: The International Study Group of Liver Surgery (ISGLS) defined post-hepatectomy biliary leakage as drain/serum bilirubin ratio > 3 at day 3 or the interventional/surgical revision due to biliary peritonitis. We investigated the definition's applicability. METHODS: A retrospective evaluation of all liver resections over a 6-year period was performed. ROC analyses were performed for drain/serum bilirubin ratios on days 1, 2, and 3 including grade A to C (analysis I) and grade B and C biliary leakages (analysis II) to test specific cutoff values. RESULTS: A total of 576 patients were included. One hundred nine (18.9%) postoperative bile leakages occurred (19.6% of the whole population grade A, 16.5% grade B/C). Areas under the curve (AUC) for analysis I were 0.841 (day 1), 0.846 (day 2), and 0.734 (day 3). The highest sensitivity (78% on day 1/77% on day 2) and specificity (78% on day 1/79% on day 2) in analysis I were obtained for a drain/serum bilirubin ratio of 2.0. AUCs for analysis II were similar: 0.788 (day 1), 0.791 (day 2), and 0.650 (day 3). The highest sensitivity (73% on day 1/71% on day 2) and specificity (74% on day 1/76% on day 2) in analysis II were detected for a drain/serum bilirubin ratio of 2.0 on postoperative day 2. CONCLUSION: Biliary leakages should be defined if the drain/serum bilirubin ratio is > 2.0 on postoperative day 2.

Clinical Utility of Albumin Bilirubin Grade as a Prognostic Marker in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: a Systematic Review and Meta-analysis.

PURPOSE: Hepatic function is a key prognostic marker in patients with hepatocellular cancer (HCC) and central to patient selection for transarterial chemoembolization (TACE). We investigated the clinical utility of the Albumin-Bilirubin (ALBI) grade, an emerging prognostic model, in this heterogenous cohort via a meta-analysis of published studies. METHODS: Publications including full text articles and abstracts regarding ALBI grade were sourced by two independent researchers from databases including PubMed, Embase, Medline and Cochrane Library. Studies analysing patients with HCC undergoing TACE treatment were systematically screened utilising the PRISMA tool for data extraction and synthesis, after exclusion of duplicates, irrelevant studies and overlapping cohorts. The primary outcome was overall survival (OS), as determined by ALBI grade and assessed by hazard ratio (HRs) with 95% confidence intervals (CIs), with analysis of collated data using comprehensive meta-analysis, version 3.0 software. RESULTS: Eight studies were included, with a pooled population of 6538 patients with HCC that underwent TACE treatment. Higher pre-treatment grade was associated with poor OS, with median OS of 12.0 months (P < 0.001) in ALBI grade 3, compared to 33.5 months in ALBI grade 1 (P < 0.001). Significant heterogeneity within each ALBI grade was associated with age and tumour size (P < 0.001) in ALBI grades 1 and 2. In contrast, age and alcohol-related liver disease were significant in the ALBI grade 3 group (P < 0.001). CONCLUSIONS: High pre-treatment ALBI grade is associated with poorer prognosis in patients with HCC undergoing TACE therapy. The ALBI grade demonstrates clinical utility for clinical prognostication and patient selection for TACE.

Effect of albumin measurement methods on the albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is an index of liver function based on total bilirubin (T-BIL) and albumin levels, and its usefulness has been widely reported. This study aimed to investigate the effect of different methods of measuring T-BIL and albumin levels on the ALBI grade in patients with liver disease. METHODS: In total, 170 patients from our hospital were included in this study. Correlations between T-BIL levels measured using the vanadate oxidation and enzymatic methods were analysed. Similarly, a correlation analysis of albumin levels between the bromocresol green (BCG) and modified bromocresol purple (BCP) methods was performed. Additionally, the ALBI grade was calculated for patients with liver disease, and the differences between each method of albumin measurement were compared. RESULTS: No differences were observed in the measured T-BIL values between the two methods. Contrastingly, the albumin levels of 100 random samples and 70 liver disease patients obtained using the modified BCP method were significantly lower than those measured using the BCG method. The rate of change in the modified ALBI grade between the BCG and BCP methods was 25.7%. CONCLUSIONS: Caution should be taken when comparing ALBI grades with those measured by other facilities because the method of albumin measurement can affect the ALBI grade. Standardization of albumin measurement is needed worldwide.

Feasibility for SERS-based discrimination of gallbladder cancer from polyp by indirect recognition of components in bile.

The aqueous solution extracted from raw bile juice is composed primarily of bile salts, with lower levels of bilirubin and its derivatives. Among them, the bilirubin and bilirubin-derived metabolites are the only surface-enhanced Raman scattering (SERS)-active components. An analytical scheme indirectly responsive and able to utilize all bile components, including SERS-inactive bile salts, was explored for SERS-based discrimination of gallbladder (GB) polyp and GB cancer. Initially, the surface of a SERS substrate (Au nanodendrite on Ni foil (AuND@NiF)) was covered with an alkanethiol molecule to generate a SERS signal and attract bile components by mutual interaction. For more effective recognition of bile components, 4 independent substrates covered with 4 different alkanethiols with various functional groups (SH(CH2)2CH3, SH(CH2)2NH2, SH(CH2)2COOH, and SH(CH2)2OH) were prepared. The SERS peaks of each substrate clearly varied on interaction with pure bile components as well as aqueous bile samples, and the SERS peaks in each substrate were individually characteristic. When the principal component (PC) scores of spectra obtained using the SH(CH2)2CH3- and SH(CH2)2OH-covered substrates were combined, the k-Nearest Neighbor-based discrimination accuracy was 100%, superior to those (90.6-96.9%) using individual substrates. The use of complementary bile component-induced spectral information provided by the two substrates was responsible for accurate discrimination. On the other hand, when bare AuND@NiF recognizing only SERS-active bilirubin derivatives was used, discrimination was unsatisfactory (accuracy: 75.0%).

Assessment of spent hemp biomass as a potential ingredient in ruminant diet: nutritional quality and effect on performance, meat and carcass quality, and hematological parameters in finishing lambs.

Spent hemp biomass (SHB), a byproduct of cannabinoid extraction from the production of industrial hemp has not been approved by FDA-CVM since its effects on animal health, performance, and product quality are unknown. Our objective was to investigate the effects of feeding two levels of SHB and a 4-wk withdrawal period on performance, carcass characteristic, meat quality, and hematological parameters in finishing lambs. A total of 35 weaned, Polypay male lambs kept in single pens were randomly assigned to five feeding treatments (n = 7) and fed diets containing either no SHB (CON) or SHB at 10% (LH1) or 20% (HH1) for 4 wk with 4 wk of clearing period from SHB, or SHB at 10% (LH2) or 20% (HH2) for 8 wk. Chemical analysis revealed SHB to have a nutritive quality similar to alfalfa with no mycotoxin, terpenes, or organic residuals as a result of the extraction process. Feed intake of lambs was negatively affected by 20% SHB in period 1 but not in period 2 where feed intake was the greatest in HH1 and LH2. In contrast, none of the performance data, including liveweight gains, were different across the groups and periods. In period 1, blood glucose, cholesterol, calcium, paraoxonase, and tocopherol were decreased by the level of SHB fed, while bilirubin and alkaline phosphatase (ALP) were increased. In period 2, the concentration in blood of urea, magnesium, bilirubin, ALP, and ferric reducing ability of the plasma (FRAP) were higher in LH2 and HH2 as compared with CON, while ß-hydroxybutyrate was lower in HH2. Blood parameters related to liver health, kidney function, immune status, and inflammation were unaffected by feeding SHB. Most carcass and meat quality parameters did not differ across feeding groups either. Except carcass purge loss and meat cook loss were larger in lambs that were fed 20% SHB. Although lower feed intake of lambs that were fed 20% SHB initially in period 1 suggested SHB was not palatable to the lambs, increased feed intake at a lower level of inclusion at 10% in period 2 may point to a positive long-term effect of feeding SHB.

The use of hemp by-products in livestock diets holds promise for reducing feed costs and achieving greater resource-use efficiency through integration of livestock production and rapidly growing hemp farming. Spent hemp biomass (SHB), the byproduct of the extraction process of cannabidiol from hemp can potentially be included in the ruminant diets due to its desirable nutritional properties. However, the potential accumulation of tetrahydrocannabinol­a psychotropic compound in animal tissues and its effect on animal health, production, and product quality are still unknown. Therefore, we conducted an indoor feeding study to investigate the effects of varying levels of SHB and a withdrawal period on feed intake, performance, health, and meat quality of lambs at Oregon State University. Our findings indicated that SHB can be included in lamb diets without causing any major detrimental effects on performance, meat quality, or health of the lambs.

Longitudinal increase in albumin-bilirubin score is associated with non-malignancy-related mortality and quality of life in patients with liver cirrhosis.

Due to the developments in the treatment for hepatitis, it is possible to prevent the progression of liver fibrosis and improve patients' prognosis even if it has already led to liver cirrhosis (LC). Consequently, a two-step study was conducted. To begin with, a retrospective study was conducted to identify the potential predictors of non-malignancy-related mortality from LC. Then, we prospectively analyzed the validity of these parameters as well as their association with patients' quality of life. In the retrospective study, 89 cases were included, and the multivariate Cox regression analysis indicated that age (P = 0.012), model for end-stage liver disease (MELD) score (P = 0.012), and annual rate of change of the albumin-bilirubin (ALBI) score (P < 0.001) were significantly associated with LC prognosis. In the prospective study, 70 patients were included, and the patients were divided into cirrhosis progression and non-progression groups. The univariate logistic regression analysis indicated the serum procollagen type III N-terminal peptide level (P = 0.040) and MELD score (P = 0.010) were significantly associated with the annual rate of change of the ALBI score. Furthermore, the mean Chronic Liver Disease Questionnaire score worsened from 5.3 to 4.9 in the cirrhosis progression group (P = 0.034). In conclusion, a longitudinal increase in the ALBI score is closely associated with non-malignancy-related mortality and quality of life.

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC. METHODS: Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as ≤ -2.60 score and a grade of 2 as a score of > -2.60 to ≤ -1.39. RESULTS: Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46-0.86] and 0.42 [0.32-0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66-1.06] and 0.46 [0.37-0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup. DISCUSSION: These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01908426.

Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

Comparación clínica y laboratorial de la fiebre amarilla severa versus dengue grave en Perú / Clinical and laboratory differences between severe yellow fever and severe dengue in emergency patients

En los centros de Emergencia con poco apoyo de laboratorio, es difícil diferenciar a los pacientes con dengue grave y fiebre amarilla severa. El objetivo fue comparar el perfil clínico y de laboratorio de los pacientes con dengue grave y fiebre amarilla severa en Urgencias. Se realizó un estudio observacional retrospectivo de pacientes con diagnóstico confirmado de dengue y fiebre amarilla en el período 2018 a 2020 atendidos en la Unidad de Emergencia del Hospital Carrión, Huancayo-Perú. Se evaluaron un total de 35 pacientes, 11 pacientes (31,4%) fueron diagnosticados con fiebre amarilla severa y 24 pacientes (68,5%) con dengue grave. La media de los resultados de laboratorio con fiebre amarilla severa fueron bilirrubina indirecta 4,7 ml/dL, aspartato transaminasa 4463 UI/L, transaminasa aminotransferasa 4329 UI/L, creatinina 4,9 mg/dl. En pacientes con dengue grave el hematocrito promedio fue 51,8, hemoglobina 17,6 g/dl, plaquetas 24 × 103/mm. En pacientes con síndrome ictérico-febril la presencia de bradicardia, bilirrubina indirecta elevada y transaminasas muy elevadas debe hacer sospechar de fiebre amarilla; mientras que los pacientes que acuden por ascitis, derrame pleural, aumento de hematocrito y deficiencia de plaquetas, se debe tratar como dengue grave sobre todo en Unidades de Emergencia con poco apoyo de laboratorio(AU)

In Emergency centers with little laboratory support, differentiating patients with dengue and yellow fever is difficult. The Aim was to compare the clinical and laboratory profile of patients with severe dengue and severe yellow fever in the Emergency unit. We conducted a retrospective observational study of patients with a confirmed diagnosis of dengue and yellow fever in the period 2018 to 2020 treated in the Emergency Unit of the Carrión hospital, Huancayo-Peru. A total of 35 patients were evaluated, 11 patients (31.4%) were diagnosed with severe yellow fever and 24 patients (68.5%) with severe dengue. The mean laboratory results in patients with severe yellow fever were indirect bilirubin 4.7 ml/dL, aspartate transaminase 4463 IU/L, transaminase aminotransferase 4329 IU/L, creatinine 4.9 mg / dl. In patients with severe dengue were hematocrit 51.8, hemoglobin 17.6 g / dl, platelets 24 × 103 / mm. In patients with syndrome jaundice and fever the presence of bradycardia, elevated indirect bilirubin, and very elevated transaminases should be suspicious for yellow fever; while in patients who come for ascites, pleural effusion, increased hematocrit and platelet deficiency, it should be treated as severe dengue especially in Emergency Units with little laboratory support(AU)

Biliary Atresia/Neonatal Cholestasis: What is in the Horizon?

"Biliary atresia (BA) is a common cause of jaundice in infancy. There is increasing evidence that newborn screening with direct or conjugated bilirubin leads to earlier diagnosis. Although the Kasai portoenterostomy is the primary treatment, there are scientific advances in adjuvant therapies. As pediatric patients transition to adult care, multidisciplinary care is essential, given the complexity of this patient population."

Fluorescent sensing of free bilirubin at nanomolar level using a Langmuir-Blodgett film of glucuronic acid-functionalized gold nanoclusters.

Serum bilirubin is an important indicator to assess liver function and diagnose various types of liver diseases. The level of serum bilirubin is also negatively correlated with the risk of cardiovascular disease and cancer. We had fabricated a fluorescent film sensor aiming at free bilirubin detection at the nanomolar level. Gold nanoclusters capped by human serum albumin (HSA-AuNCs) were utilized as a fluorescent platform for bilirubin biorecognition. HSA-AuNCs were functionalized with glucuronic acid to increase the binding sites for bilirubin. An ultrathin film of glucuronic acid-functionalized gold nanoclusters was obtained by the Langmuir-Blodgett (LB) technique. When exposed to bilirubin, the interaction between free bilirubin and the functionalized AuNCs resulted in fluorescent quenching of the film. Good linearity could be achieved for the quenching efficiency versus the logarithm of free bilirubin concentration over a concentration range of 1.00 nM~5.00 µM. The limit of detection (LOD) was calculated to be (2.70 ± 0.14) × 10-1 nM (S/N = 3). The film sensor presents a good anti-interference capability towards common substances coexisting with bilirubin in serum. Satisfactory results achieved in the tests of real serum samples indicate that the LB film sensor can be used for bilirubin determination in nanomolar concentration.

Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study.

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

Comparison of Modified Child-pugh (MCP), Albumin-bilirubin (ALBI), and Child-pugh (CP) score for predicting of survival in Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization.

BACKGROUND: Both modified Child-Pugh (MCP) and Albumin-bilirubin (ALBI) grade were reported that simpler, more objective and evidence-based alternative to the Child-Pugh (CP) class for assessing liver function. AIMS: To investigate whether the MCP and ALBI grade could better evaluate the liver reserve of Hepatocellular Carcinoma (HCC) patients treated with TACE (transcatheter arterial chemoembolization) than CP grade. METHODS: Three hundred seventy-six consecutive HCC patients treated with TACE between December 2007 and October 2011 were enrolled. The baseline characteristics and clinical information were collected. Homogeneity and discriminatory ability were compared between the MCP grade and ALBI class or CP grade. RESULTS: Compared with the CP and ALBI, the MCP grade had a higher predictive accuracy for overall survival (OS) in terms of homogeneity and discriminatory ability. Most of the HCC patients had CP class A disease (84.0%) at presentation, and within this CP class, although the ALBI grade revealed two clear and nonoverlapping groups, the MCP grade revealed three clearly different prognostic groups. Both in the ALBI grade 1 or ALBI grade 2 group, the MCP grade still showed a significant progressive decrease in OS from the smallest to the largest grades, but the CP class was unsatisfactory in stratifying these patients. CONCLUSIONS: The stratification ability and prognostic predictive power of the MCP grade for HCC patients treated with TACE may be better than that of the ALBI grade or CP class.

Case Study 6: Deconvoluting Hyperbilirubinemia-Differentiating Between Hepatotoxicity and Reversible Inhibition of UGT1A1, MRP2, or OATP1B1 in Drug Development.

New molecular entities (NMEs) are evaluated using a rigorous set of in vitro and in vivo studies to assess their safety and suitability for testing in humans. Regulatory health authorities require that therapeutic and supratherapeutic doses be administered, by the intended route of administration, to two nonclinical species prior to human testing. The purpose of these studies is to identify potential target organ toxicity and to determine if the effects are reversible. Liver is a potential site for toxicity caused by orally administered NMEs due to high exposure during first pass after oral administration. A range of clinical chemistry analytes are routinely measured in both nonclinical and clinical studies to evaluate and monitor for hepatotoxicity. While bilirubin itself circulates within a wide range of concentrations in many animal species and humans, without causing adverse effects and possibly providing benefits, bilirubin is one of the few readily monitored circulating biomarkers that can provide insight into liver function. Therefore, any changes in plasma or urine bilirubin levels must be carefully evaluated. Changes in bilirubin may occur as a result of adaptive nontoxic changes or severe toxicity. Examples of adaptive nontoxic changes in liver function, which may elevate direct (conjugated) and/or indirect (unconjugated) bilirubin above baseline levels, include reversible inhibition of UGT1A1-mediated bilirubin metabolism and OATP1B1-, OATP1B3-, or MRP2-mediated transport. Alternatively, hepatocellular necrosis, hypoalbuminuria, or cholestasis may also lead to elevation of bilirubin; in some cases, these effects may be irreversible.This chapter aims to demonstrate application of enzyme kinetic principles in understanding the risk of bilirubin elevation through inhibition of multiple processes-involving both enzymes and transporters. In the sections that follow, we first provide a brief summary of bilirubin formation and disposition. Two case examples are then provided to illustrate the enzyme kinetic studies needed for risk assessment and for identifying the mechanisms of bilirubin elevation. Caveats of methods and data interpretation are discussed in these case studies. The data presented in this chapter is unpublished at the time of compilation of this book. It has been incorporated in this chapter to provide a sense of complexities in enzyme kinetics to the reader.

A risk factor-based predictive model for linezolid-induced anaemia: A 7-year retrospective study.

WHAT IS KNOWN AND OBJECTIVE: The primary adverse reaction of linezolid is haematological toxicity, leading to thrombocytopenia and anaemia. This study aimed to investigate the risk factors of linezolid-induced anaemia (LI-AN) and establish a predictive model by multivariate logistic regression model analysis to predict LI-AN risks in Chinese adult patients. METHODS: Demographic and clinical data of patients who underwent linezolid therapy for more than three days between January 2014 and December 2020 in Zhongshan Hospital, Fudan University, were retrieved from the hospital's electronic medical record for analysis. Multivariate logistic regression analysis was employed to establish a predictive model, whose predictability was further evaluated by the area under the receiver operating characteristic (ROC) curve. RESULTS AND DISCUSSION: The study comprised 298 patients among the 2322 patients who underwent linezolid treatment between 2014 and 2020. Among the 298 patients, 32 (10.7%) developed anaemia with an average of 11.4 (SD 6.2) days after the initiation of linezolid therapy. Multivariate logistic analysis revealed that age ≥60 years (odds ratio [OR] 2.815, 95% confidence interval [CI] 1.242-6.379), higher total bilirubin (TBi) (OR 1.031, 95% CI 1.011-1.051), eGFR < 60 ml/(min·1.73 m2 ) (OR 2.537, 95% CI 1.054-6.106), duration of linezolid therapy (DLT) (OR 1.091, 95% CI 1.023-1.163) and intensive care unit (ICU) admittance (OR 2.664, 95% CI 1.150-6.174) were the independent risk factors for anaemia occurrence among patients receiving linezolid therapy. A logistic regression equation based on the five risk factors was subsequently established and transformed to obtain the calculation formula of the combined predictor: Y(Combined predictor)  = XTBi  + 34.5 × XAge≥60  + 31.1 × XeGFR<60  + 32.7 × XICU  + 2.9 × XDLT , (where Age ≥60 years, yes = 1, no = 0; eGFR < 60 ml/(min·1.73 m2 ), yes = 1, no = 0; ICU admittance, yes = 1, no = 0). The area under the ROC curve of the combined predictors equation was 0.773 with an optimal cut-off point value of 92.4, corresponding to a 75.0% sensitivity and 76.7% specificity. WHAT IS NEW AND CONCLUSION: LI-AN is associated with age (≥60 years), higher TBi, eGFR < 60 ml/(min·1.73 m2 ), DLT and ICU admittance. Physicians should thus calculate the combined predictor value at the beginning of linezolid treatment to predict and evaluate the risk of LI-AN. An optimal cut-off value larger than 92.4 indicates that the patient has a higher LI-AN risk. As such, Hb levels should be monitored regularly, and dosage regimens adjusted accordingly to prevent anaemia occurrence. This study provides an evidence-based logistic model that reduces LI-AN incidences and promotes the safe clinical use of linezolid.

Bilirubin: The yellow hormone?

Bilirubin is a tetrapyrrolic compound originating from heme catabolism. Although originally considered only a potentially dangerous waste product, it has become increasingly evident that this molecule represents an important modulator of various biological functions in the human body. Bilirubin appears to have versatile functions, from cell signaling (behaving almost like a "real" hormonal substance), modulation of metabolism, to immune regulation, affecting biological activities with apparent clinical and even therapeutic consequences. These activities may be the reason for the lower incidence of diseases of civilisation (cardiovascular diseases, arterial hypertension, diabetes, obesity, metabolic syndrome, certain cancers, autoimmune, and neurodegenerative diseases) observed in individuals with a chronic mild unconjugated hyperbilirubinemia, a typical sign of Gilbert's syndrome. While higher serum concentrations of unconjugated bilirubin may serve as an important protective factor against these diseases, low levels of bilirubin are associated with the opposite effect.

The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose-corrected trough concentration in the early period after liver transplantation.

PURPOSE: To explore the relationship between rs2291075 polymorphism in SLCO1B1 gene, which encodes an influx transmembrane protein transporter, and tacrolimus dose-corrected trough concentration (C/D, ng ml-1 mg-1 kg-1) in the early period after liver transplantation. METHODS: CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms of 210 liver transplantation patients and their corresponding donor livers were assessed by PCR amplification and DNA sequencing. The influence of gene polymorphisms on C/D values of tacrolimus was analyzed. The early postoperative period after liver transplantation was divided into the convalescence phase (1-14 days) and stationary phase (15-28 days) according to the change of liver function and tacrolimus C/D values. RESULTS: The combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of tacrolimus into three groups: fast elimination (FE), intermediate elimination (IE), and slow elimination (SE), which was entitled the FIS classification system. Tacrolimus C/D ratios of recipient SLCO1B1 rs2291075 CT and TT carriers were very close and were significantly lower than those of recipient SLCO1B1 rs2291075 CC genotype carriers in convalescence phase (p = 0.0195) and in stationary phase (p = 0.0152). There were no statistically significant differences between tacrolimus C/D ratios of patients carried with SLCO1B1 rs2291075 CT, TT genotype donors, and those carried with SLCO1B1 rs2291075 CC genotype donors. A model consisting of tacrolimus daily dose, total bilirubin, FIS classification, and recipient SLCO1B1 rs2291075 could predict tacrolimus C/D ratios in the convalescence phase by multivariate analysis. However, recipient SLCO1B1 rs2291075 genotype failed to enter forecast model for C/D ratios in stationary phase. Recipient SLCO1B1 rs2291075 genotype had significant effect on tacrolimus C/D ratios in convalescence phase (p = 0.0300) and stationary phase (p = 0.0400) in subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746. CONCLUSION: SLCO1B1 rs2291075 could be a novel genetic locus associated with tacrolimus metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes, could be helpful to guide the personalized administration of tacrolimus in early period after liver transplantation.