The Albumin-Bilirubin Score as a Predictor of Liver-Related Mortality in Primary Biliary Cholangitis with Compensated Cirrhosis.

BACKGROUND: Although several prognostic scores have been reported to correlate with the prognosis of primary biliary cholangitis (PBC) patients, there are limited tools to predict the prognosis of PBC with compensated cirrhosis. This study aimed to evaluate the prognostic performance of the albumin-bilirubin (ALBI) score in PBC patients with compensated cirrhosis. METHODS: We conducted a retrospective longitudinal study of 219 patients with compensated PBC cirrhosis to evaluate the prognostic performance of the ALBI using Cox regression model, receiver operating characteristic (ROC) curve, and Kaplan-Meier method. RESULTS: During follow-up, a total of 19 subjects (8.7%) met the primary endpoint of liver-related death or liver transplantation (LT). Patients who died/underwent LT have higher ALBI score (-1.06 vs. -2.06, p < 0.001) at baseline than those who survived. ALBI score (hazard ratio: 15.011, 95% confidence interval [CI]: 5.045-44.665, p < 0.001) was associated with an increase in liver-related mortality or LT. ALBI score had the best discriminative capacity to predict the 5-year liver-related mortality (area under the ROC curve: 0.871, 95% CI [0.820, 0.913]) compared with other prognostic scores. The ROC curve showed that the best cut-off value of ALBI score was -1.47, with 90.0% sensitivity and 76.6% specificity. Also, the probability of transplant-free survival decreased with increasing ALBI grade (log-rank p = 0.003). The 5-year transplant-free survival rates of patients in grade 1, grade 2, and grade 3 were 100.0%, 96.4%, and 89.4%, respectively. CONCLUSION: ALBI score is a simple and effective predictive factor estimating the clinical outcome of patients with compensated PBC cirrhosis and provides better prognostic performance compared with other prognostic scores.

TR score: A noninvasive model to predict histological stages in patients with primary biliary cholangitis.

Introduction: The aim of this study was to develop a noninvasive prediction model for histological stages in PBC that is simple, easy to implement, and highly accurate. Methods: A total of 114 patients with PBC were included in this study. Demographic, laboratory data and histological assessments were collected. The independent predictors of histological stages were selected to establish a noninvasive serological model. The scores of 22 noninvasive models were calculated and compared with the established model. Results: This study included 99 females (86.8%) and 15 males (13.2%). The number of patients in Scheuer's stage 1, 2, 3 and 4 was 33 (29.0%), 34 (29.8%), 16 (14.0%), and 31 (27.2%), respectively. TBA and RDW are independent predictors of PBC histological stages. The above indexes were used to establish a noninvasive model-TR score. When predicting early histological change (S1) or liver fibrosis and cirrhosis (S3-S4), the AUROC of TR score were 0.887 (95% CI, 0.809-0.965) and 0.893 (95% CI, 0.816-0.969), higher than all of the other 22 models included in this study. When predicting cirrhosis (S4), its AUROC is still as high as 0.921 (95% CI, 0.837-1.000). Conclusion: TR score is an easy, cheap and stable noninvasive model, without complex calculation formulas and tools, and shows good accuracy in diagnosing the histological stages of PBC.

The impact and role of hepatic hydrothorax in the prognosis of patients with decompensated cirrhosis: A retrospective propensity score-matched study.

Background and aims: Hepatic Hydrothorax (HH) is one of the complications in patients with decompensated cirrhosis and its impact and role in the prognosis of patients with decompensated cirrhosis are not yet clear. Thus, this study aimed to determine the role of HH in patients with decompensated cirrhosis and the long-term impact on their mortality. Materials and methods: A retrospective study analyzed 624 patients with ascites without pleural effusion in decompensated cirrhosis and 113 patients with HH. Propensity scores were calculated based on eight variables, and the HH and non-HH groups were matched in a 1:1 ratio. The effect and role of HH on the prognosis of patients with decompensated cirrhosis was analyzed using the Kaplan-Meier method and Cox proportional hazards regression model. Results: A total of 737 patients were included. Out of 113 HH patients, 106 could be matched to 106 non-HH patients. After matching, baseline characteristics were well-balanced. The multifactorial Cox proportional hazards model indicated that hepatic encephalopathy and HH were independent risk factors affecting prognostic survival in patients with decompensated cirrhosis (P < 0.01), with risk ratios and 95% confidence intervals (CI) of 2.073 (95% CI: 1.229-3.494, P < 0.01) and 4.724 (95% CI: 3.287-6.789, P < 0.01), respectively. Prognostic survival was significantly worse in the HH group compared to patients in the non-HH group, with mortality rates of 17.9, 30.1, and 59.4% at 6 months, 1 year, and 2 years in the HH group, compared to 0.9, 3.8, and 5.6% in the non-HH group, respectively. The estimated median survival time was 21 (95% CI: 18-25) months in the HH group and 49 (95% CI: 46-52) months in the non-HH group (P < 0.001). Conclusion: Hepatic hydrothorax is significantly associated with higher mortality in patients with decompensated cirrhosis and is a highly negligible independent decompensated event affecting their prognosis.

Analysis of clinical features and prognostic factors in patients with hepatic hydrothorax: a single-center study from China.

BACKGROUND: The clinical features and factors affecting the prognostic survival of hepatic hydrothorax (HH) are currently unknown. METHODS: We conducted a retrospective cohort study of 131 patients with HH using the Kaplan-Meier method and Cox proportional hazards regression analysis to assess factors influencing the prognosis of HH. RESULTS: A total of 131 patients were enrolled: the male to female ratio was 80:51 (1.59:1), and the mean age was 52.76 ± 11.88 years. Hepatitis B cirrhosis was the main cause of HH, and abdominal distention and dyspnea were the most common clinical signs. Ascites was present in varying amounts in all patients and was the most common decompensated complication, with pleural effusions mostly seen on the right side (107/131; 82%), followed by the left side (16/131; 12%) and bilateral effusions (8/131; 6%). For overall survival without transplantation, the estimated median survival time was 21 (95% confidence interval [CI]:18-25) months, and survival rates at 6 months, 1 year, and 2 years were 77.2%, 62.4%, and 29.7%, respectively. After controlling for covariates that were associated with liver-related mortality in the univariate analysis, males (hazard ratio [HR]: 1.721, 95% CI: 1.114-2.658, P = 0.005) and combined hepatic encephalopathy (HR: 2.016, 95% CI: 1.101-3.693, P = 0.001) were found to be associated with an increase in liver-related mortality. CONCLUSIONS: In this cohort of HH patients without liver transplantation, male sex and hepatic encephalopathy were associated with a higher risk of liver-related death.

A rare case report of iatrogenic Cushing syndrome caused by direct anti-hepatitis C virus therapy with sofosbuvir/velpatasvir.

RATIONALE: Sofosbuvir/velpatasvir (SOF/VEL) is a combination of direct-acting antivirals with pan-genotypic activity that is used to treat chronic hepatitis C virus infection. This was a fixed-dose regimen. SOF is a nucleotide nonstructural 5B polymerase inhibitor and VEL is an nonstructural 5A inhibitor. Side effects of this agent on the endocrine system, particularly iatrogenic Cushing syndrome (ICS), are uncommon. Here, we present a case of ICS with significantly low serum adrenocorticotropic hormone and cortisol levels caused by SOF/VEL. PATIENT CONCERNS: A 49-year-old Asian woman with chronic hepatitis C and cirrhosis presented with a round face, fat thickening at the clavicle and back of the neck, mild facial edema, facial congestion, skin ulceration on the hands, central obesity, acne, and general status changes after 3 months of treatment with SOF/VEL (400 mg/dose, 1/day). DIAGNOSES: The patient's serum adrenocorticotropic hormone and cortisol levels dropped significantly, and her normal rhythm vanished, with no visible aberrant lesions on computed tomography or across the abdomen. The patient was diagnosed with ICS. OUTCOMES: Symptoms improved after withdrawing SOF/VEL and taking low-dose oral hydrocortisone. Thus, the SOF/VEL was suspected to be an offender. To our knowledge, this is the first time that SOF/VEL has been linked to ICS. LESSONS: Hepatologists and primary care physicians treating hepatitis C virus should be more aware of this uncommon adverse event so that direct-acting antiviral therapy can be stopped sooner if it recurs. The findings of this study emphasize the importance of collaboration between hepatologists and endocrinologists in co-management of complications.

Does Depressive-Type Schizophrenia Exist? How Do We Prove It?: An Updated Review and Overview.

Depressive symptoms can occur at any point in the duration of schizophrenia. However, we are unable to predict if or when depression will occur in schizophrenic patients. Simultaneously, the standard treatment of depression in schizophrenic patients is the combination of antidepressants and antipsychotics, which has been minimally effective for most patients. Based on several studies, we hypothesized the existence of depressive-type schizophrenia and reviewed the substantial evidence supporting the hypothesis of depressive-type schizophrenia. Simultaneously, we propose technical methods to explore the neuropathology of depressive-type schizophrenia in order to identify the disease during its early stages and to predict how patients will respond to the standard treatment strategies. We believe that the new classification of depressive-type schizophrenia will differentiate it from other forms of depression. In return, this will aid in the discovery of new therapeutic strategies for combatting this disease.

Auditory verbal hallucination and the auditory network: From molecules to connectivity.

Auditory verbal hallucinations (AVHs) frequently occur across multiple psychiatric diseases especially in schizophrenia (SCZ) patients. Functional imaging studies have revealed the hyperactivity of the auditory cortex and disrupted auditory-verbal network activity underlying AVH etiology. This review will firstly summarize major findings from both human AVH patients and animal models, with focuses on the auditory cortex and associated cortical/sub-cortical areas. Besides mesoscale connectivity or activity data, structure and functions at synaptic level will be discussed, in conjunction with molecular mechanisms. We have summarized major findings for the pathogenesis of AVH in SCZ patients, with focuses in the auditory cortex and prefrontal cortex (PFC). Those discoveries provide explanations for AVH from different perspectives including inter-regional connectivity, local activity in specific areas, structure and functions of synapse, and potentially molecular targets. Due to the uniqueness of AVH in humans, full replica using animals seems impossible. However, we can still extract useful information from animal SCZ models based on the disruption of auditory pathway during AVH episodes. Therefore, we will further interpolate the synaptic structures and molecular targets, whose dysregulation in SCZ models may be highly related with AVH episodes. As the last part, implications for future development of treatment strategies will be discussed.

Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice.

Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.

Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using LC/MS/MS.

Tocopherols and tocotrienols are metabolized via hydroxylation and oxidation of their hydrophobic side chain to generate 13'-hydroxychromanols (13'-OHs) and various carboxychromanols, which can be further metabolized by conjugation including sulfation. Recent studies indicate that long-chain carboxychromanols, especially 13'-carboxychromanol (13'-COOH), appear to be more bioactive than tocopherols in anti-inflammatory and anticancer actions. To understand the potential contribution of metabolites to vitamin E-mediated effects, an accurate assay is needed to evaluate bioavailability of these metabolites. Here we describe an LC/MS/MS assay for quantifying vitamin E metabolites using negative polarity ESI. This assay includes a reliable sample extraction procedure with efficacy of ≥ 89% and interday/intraday variation of 3-11% for major metabolites. To ensure accurate quantification, short-chain, long-chain, and sulfated carboxychromanols are included as external/internal standards. Using this assay, we observed that sulfated carboxychromanols are the primary metabolites in the plasma of rodents fed with γ-tocopherol or δ-tocopherol. Although plasma levels of 13'-COOHs and 13'-OHs are low, high concentrations of these compounds are found in feces. Our study demonstrates an LC/MS/MS assay for quantitation of sulfated and unconjugated vitamin E metabolites, and this assay will be useful for evaluating the role of these metabolites in vivo.

Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice.

Inflammation can promote colon cancer. Mechanistic studies indicate that γ-tocopherol (γT), a major form of vitamin E in diets, has anti-inflammatory and anticancer properties. Here we investigated the effectiveness of γT and a mixture of tocopherols against colitis and colitis-promoted colon tumorigenesis in male BALB/c mice. γT or mixed tocopherols (at 0.1% diet) did not show any effect on colon tumorigenesis induced by azoxymethane (AOM, 10mg/kg) with three cycles of dextran sodium sulfate (DSS at 1.5-2.5%). γT failed to exhibit protection of severe colitis caused by three cycles of DSS at 2.5%. In contrast, when AOM-initiated carcinogenesis was promoted by relatively mild colitis induced by one-cycle DSS (1.5%), γT, but not mixed tocopherols, suppressed total multiplicity of macroscopic adenomas (P=0.06) and large adenomatous polyps (>2mm(2), P<0.05) by 60 and 85%, respectively. γT also significantly decreased tumor multiplicity (>2mm(2)) induced by AOM with two cycles of 1.5% DSS even when dietary supplementation was started after AOM injection. Consistently, γT but not mixed tocopherols attenuated DSS (1.5%)-induced colon inflammation and damage as well as formation of atypical glandular hyperplasia. Mice supplemented with tocopherols had high fecal excretion of 13'-carboxychromanol, a long-chain vitamin E metabolite shown to have potent anti-inflammatory activities. Our study demonstrates that γT is able to alleviate moderate but not severe colitis and its promoted tumorigenesis, and indicates that inflammation severity should be considered in evaluating anticancer effectiveness of chemoprevention agents.

Development and optimization of an LC-MS/MS-based method for simultaneous quantification of vitamin D2 , vitamin D3 , 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.

Simultaneous and accurate measurement of vitamin D and 25-hydroxyvitamin D in biological samples is a barrier limiting our ability to define "optimal" vitamin D status. Thus, our goal was to optimize conditions and evaluate an LC-MS method for simultaneous detection and quantification of vitamin D(2) , vitamin D(3) , 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) in serum. Extraction and separation of vitamin D forms were achieved using acetone liquid-liquid extraction and by a reversed phase C8 column, respectively. Detection was performed on a triple quadrupole tandem mass spectrometer (QQQ-MS/MS) equipped with atmospheric pressure photo ionization source. The LOQs for all analytes tested were 1 ng/mL for hydroxylated molecules and 2 ng/mL for the parent vitamin Ds. RSD at lower LOQ (2 ng/mL) and in medium (80 ng/mL) and high (200 ng/mL) quality control samples did not exceed 20 and 15% CV, respectively. Accuracy of the method for determination of hydroxylated molecules was also validated using National Institutes of Standards and Technology standard samples and found to be in the range of 90.9-111.2%. In summary, a sensitive and reproducible method is reported for simultaneous quantification of vitamin D(2) , vitamin D(3) , 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) molecules in biological samples.

Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases.

Cyclooxygenase (COX-1/COX-2)-catalyzed eicosanoid formation plays a key role in inflammation-associated diseases. Natural forms of vitamin E are recently shown to be metabolized to long-chain carboxychromanols and their sulfated counterparts. Here we find that vitamin E forms differentially inhibit COX-2-catalyzed prostaglandin E(2) in IL-1beta-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of gamma-tocotrienol approximately delta-tocopherol > gamma-tocopherol >> alpha- or beta-tocopherol. The cellular inhibition is partially diminished by sesamin, which blocks the metabolism of vitamin E, suggesting that their metabolites may be inhibitory. Consistently, conditioned media enriched with long-chain carboxychromanols, but not their sulfated counterparts or vitamin E, reduce COX-2 activity in COX-preinduced cells with 5 microM arachidonic acid as substrate. Under this condition, 9'- or 13'-carboxychromanol, the vitamin E metabolites that contain a chromanol linked with a 9- or 13-carbon-length carboxylated side chain, inhibits COX-2 with an IC(50) of 6 or 4 microM, respectively. But 13'-carboxychromanol inhibits purified COX-1 and COX-2 much more potently than shorter side-chain analogs or vitamin E forms by competitively inhibiting their cyclooxygenase activity with K(i) of 3.9 and 10.7 microM, respectively, without affecting the peroxidase activity. Computer simulation consistently indicates that 13'-carboxychromanol binds more strongly than 9'-carboxychromanol to the substrate-binding site of COX-1. Therefore, long-chain carboxychromanols, including 13'-carboxychromanol, are novel cyclooxygenase inhibitors, may serve as anti-inflammation and anticancer agents, and may contribute to the beneficial effects of certain forms of vitamin E.