Peripheral endocannabinoids in major depressive disorder and alcohol use disorder: a systematic review.

BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are two high-prevalent conditions where the Endocannabinoid system (ECS) is believed to play an important role. The ECS regulates how different neurotransmitters interact in both disorders, which is crucial for controlling emotions and responses to stress and reward stimuli. Measuring peripheral endocannabinoids (eCBs) in human serum and plasma can help overcome the limitations of detecting endocannabinoid levels in the brain. This systematic review aims to identify levels of peripheral eCBs in patients with MDD and/or AUD and find eCBs to use as diagnostic, prognostic biomarkers, and potential therapeutic targets. METHODS: We conducted a systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines from the earliest manuscript until October 22, 2023, in three electronic databases. We included studies of human adults who had a current diagnosis of AUD and/or MDD and evaluated plasma or serum endocannabinoids. We carefully considered known variables that may affect endocannabinoid levels. RESULTS: We included 17 articles in this systematic review, which measured peripheral eCBs in 170 AUD and 359 MDD patients. Stressors increase peripheral 2-arachidonyl-glycerol (2-AG) concentrations, and 2-AG may be a particular feature of depression severity and chronicity. Anxiety symptoms are negatively correlated with anandamide (AEA) concentrations, and AEA significantly increases during early abstinence in AUD. Studies suggest a negative correlation between Oleoylethanolamide (OEA) and length of abstinence in AUD patients. They also show a significant negative correlation between peripheral levels of AEA and OEA and fatty acid amide hydrolase (FAAH) activity. Eicosapentaenoylethanolamide (EPEA) is correlated to clinical remission rates in depression. Included studies show known variables such as gender, chronicity, symptom severity, comorbid psychiatric symptoms, length of abstinence in the case of AUD, and stress-inducibility that can affect peripheral eCBs. CONCLUSIONS: This systematic review highlights the important role that the ECS plays in MDD and AUD. Peripheral eCBs appear to be useful biomarkers for these disorders, and further research may identify potential therapeutic targets. Using accessible biological samples such as blood in well-designed clinical studies is crucial to develop novel therapies for these disorders.

AUDIT C compared to PEth in middle-aged volunteers.

AIMS: To compare Alcohol Use Disorders Identification Test (AUDIT C) to phosphatidylethanol (PEth) in middle-aged randomly selected volunteers. Apply previously suggested lower cut-offs for PEth using moderate alcohol intake according to AUDIT C as a reference. METHODS: Within the Swedish CardioPulmonary BioImage Study, 2255 middle-aged (50-64 years of age) volunteers in northern Sweden participated in comparing AUDIT C to PEth 16:0/18:1. RESULTS: There was a moderate correlation between PEth 16:0/18:1 and AUDIT C (r = 0.66). None of the participants with the AUDIT C-score 0 had a measurable PEth. Of moderate alcohol consumers, according to AUDIT C (AUDIT C 1-3 women, 1-4 men), 96% had a PEth below 0.3 µmol/L, 91% had a PEth below 0.16 µmol/L, and 84% had a PEth below 0.11 µmol/L. With PEth equivalent to excessive alcohol consumption (≥0.3 µmol/L), 26% had an AUDIT C-score below excessive alcohol consumption (<4 for women and <5 for men). Thirty percent of patients with a PEth ≥0.16 µmol/L had an AUDIT C-score below excessive alcohol consumption, and 37% had a PEth ≥0.11 µmol/L. We found no significant correlation between BMI and PEth or AUDIT C. CONCLUSIONS: There is a significant correlation between AUDIT C and PEth. Using AUDIT C alone, 26% of high-consumers, according to PEth, are not found in our cohort, but an AUDIT C-score of 0 will exclude high consumption, according to PEth. Our findings support the current cut-off for PEth of 0.3 µmol/L, but a lower cut-off seems reasonable.

Divergent Roles of APOAI and APOM in the Identification of Alcohol Use Disorder and Their Association With Inflammation and Cognitive Decline: A Pilot Study.

BACKGROUND: Alcohol use disorder (AUD) courses with inflammation and cognitive decline. Apolipoproteins have emerged as novel target compounds related to inflammatory processes and cognition. METHODS: A cross-sectional study was performed on abstinent AUD patients with at least 1 month of abstinence (n = 33; 72.7% men) and healthy controls (n = 34; 47.1% men). A battery of plasma apolipoproteins (APOAI, APOAII, APOB, APOCII, APOE, APOJ, and APOM), plasma inflammatory markers (LPS, LBP), and their influence on cognition and presence of the disorder were investigated. RESULTS: Higher levels of plasma APOAI, APOB, APOE, and APOJ, as well as the proinflammatory LPS, were observed in the AUD group, irrespective of sex, whereas APOM levels were lower vs controls. Hierarchical logistic regression analyses, adjusting for covariates (age, sex, education), associated APOM with the absence of cognitive impairment in AUD and identified APOAI and APOM as strong predictors of the presence or absence of the disorder, respectively. APOAI and APOM did not correlate with alcohol abuse variables or liver status markers, but they showed an opposite profile in their associations with LPS (positive for APOAI; negative for APOM) and cognition (negative for APOAI; positive for APOM) in the entire sample. CONCLUSIONS: The HDL constituents APOAI and APOM were differentially regulated in the plasma of AUD patients compared with controls, playing divergent roles in the disorder identification and associations with inflammation and cognitive decline.

Phosphatidylethanol in post-mortem brain: Correlation with blood alcohol concentration and alcohol use disorder.

Phosphatidylethanol (PEth) is an alcohol derivative that has been employed as a blood-based biomarker for regular alcohol use. This study investigates the utility of phosphatidylethanol (PEth) as a biomarker for assessing alcohol consumption in post-mortem brain tissue. Using samples from the New South Wales Brain Tissue Resource Centre, we analysed PEth(16:0/18:1) levels in the cerebellum and meninges of individuals with varying histories of alcohol use, including those diagnosed with alcohol use disorder (AUD) and controls. Our findings demonstrate a significant correlation between PEth levels and blood alcohol content (BAC) at the time of death, supporting the biomarker's sensitivity to recent alcohol intake. Furthermore, this study explores the potential of PEth levels in differentiating AUD cases from controls, taking into consideration the complexities of diagnosing AUD post-mortem. The study also examined the relationship between PEth levels and liver pathology, identifying a link with the severity of liver damage. These results underscore the value of PEth as a reliable indicator of alcohol consumption and its potential contributions to post-mortem diagnostics and consequently, research into alcohol-related brain damage.

Race explains substantial variance in whole blood thiamine diphosphate concentrations.

Deficiency for thiamine (vitamin B1), traditionally assessed via the activity of the thiamine-dependent enzyme erythrocyte transketolase, has been reported in individuals with alcohol use disorder (AUD) and in people with HIV; concentrations of the metabolically active diphosphate form, however, have yet to be reported in HIV cohorts and results in AUD are equivocal. In this cross-sectional study, samples from 170 AUD, 130 HIV, and 100 healthy control individuals were analyzed to test the hypothesis that AUD and HIV groups relative to healthy controls would show low whole blood thiamine diphosphate (TDP) concentrations related to peripheral neuropathy. TDP concentrations were not different in the 3 study groups (P = .6141) but were lower in Black (n = 172) relative to White (n = 155) individuals (P < .0001) regardless of group. In a multiple regression, race relative to diagnoses explained more than 10 times the variance in whole blood TDP concentrations (F4,395 = 3.5, P = .0086; r2 = 15.1]. Performance on a measure of peripheral neuropathy (2-point discrimination) was worse in the HIV and AUD cohorts relative to the healthy control group (P < .0001) but was not associated with TDP concentrations. These findings suggest that Black individuals carry a heightened vulnerability for low whole blood TDP concentrations, but the clinical significance and mechanisms underlying these results remain to be determined.

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

High-density lipoprotein (HDL) as an indicator for alcohol use in a psychiatrically ill population.

AIMS: To examine the cross sectional and longitudinal associations between the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) and differences in high-density lipoprotein (HDL) in a psychiatrically ill population. METHODS: Retrospective observational study using electronic health record data from a large healthcare system, of patients hospitalized for a mental health/substance use disorder (MH/SUD) from 1 July 2016 to 31 May 2023, who had a proximal AUDIT-C and HDL (N = 15 915) and the subset who had a repeat AUDIT-C and HDL 1 year later (N = 2915). Linear regression models examined the association between cross-sectional and longitudinal AUDIT-C scores and HDL, adjusting for demographic and clinical characteristics that affect HDL. RESULTS: Compared with AUDIT-C score = 0, HDL was higher among patients with greater AUDIT-C severity (e.g. moderate AUDIT-C score = 8.70[7.65, 9.75] mg/dl; severe AUDIT-C score = 13.02 [12.13, 13.90] mg/dL[95% confidence interval (CI)] mg/dl). The associations between cross-sectional HDL and AUDIT-C scores were similar with and without adjusting for patient demographic and clinical characteristics. HDL levels increased for patients with mild alcohol use at baseline and moderate or severe alcohol use at follow-up (15.06[2.77, 27.69] and 19.58[2.77, 36.39] mg/dL[95%CI] increase for moderate and severe, respectively). CONCLUSIONS: HDL levels correlate with AUDIT-C scores among patients with MH/SUD. Longitudinally, there were some (but not consistent) increases in HDL associated with increases in AUDIT-C. The increases were within range of typical year-to-year variation in HDL across the population independent of alcohol use, limiting the ability to use HDL as a longitudinal clinical indicator for alcohol use in routine care.

Vitamin D Deficiency Is Associated with Advanced Liver Fibrosis and Impaired Fasting Glucose in Alcohol Use Disorder.

BACKGROUND: Vitamin D deficiency is a risk factor for liver disease, insulin resistance, and beta cell dysfunction. Individuals with alcohol use disorder (AUD) have many comorbidities, with a heavy burden of liver disease and metabolic complications, including type 2 diabetes mellitus (T2DM). OBJECTIVE: We aimed to analyze the prevalence and associations of vitamin D deficiency in patients admitted for in-hospital treatment of AUD. METHODS: A cross-sectional study was conducted in patients consecutively admitted for the treatment of AUD between January 2017 and October 2023. Sociodemographic data, substance use characteristics, and blood parameters were available at admission. Vitamin D status was assessed through the serum concentrations of 25-hydroxyvitamin D [25(OH)D] levels using a direct competitive chemiluminescent immunoassay method. Deficiency of vitamin D was defined as a concentration less than 20 ng/mL; impaired fasting glucose (IFG) was defined by fasting blood glucose >100 mg/dL (5.6 mmol/L), and advanced liver fibrosis by an FIB-4 index >3.25. RESULTS: Two hundred and forty-three patients were included (75% male) with a mean age of 49 ± 10 years, mean BMI of 26.4 ± 7.3, mean alcohol consumption of 163 ± 81 g/day, and a mean duration of AUD of 18.1 ± 11.2 years. Mean 25(OH)D, fasting blood glucose, AST, ALT, and platelets were 14.4 ± 10.2 ng/mL, 103.4 ± 40.9 mg/dL, 55.1 ± 75.8 U/L, 44.8 ± 76.6 U/L, and 206.3 ± 84.8 × 109/L, respectively. The prevalence of vitamin D deficiency was 80.6%, and 41.1% of patients had levels less than 10 ng/mL. IFG was present in 32.3% of patients, and 20.5% had FIB-4 values >3.25. In the multivariable analysis, IFG (OR, 2.51; 95% CI: 1.02-6.17, p = 0.04) and advanced liver fibrosis (OR, 4.27; 95% CI: 1.21-15.0, p = 0.02) were the only factors associated with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency was very prevalent in this series of patients with AUD and was associated with impaired fasting glucose and advanced liver fibrosis.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Prevalence and associations of metabolic syndrome in patients with alcohol use disorder.

Excessive alcohol consumption has been associated with different components of the metabolic syndrome (MetS) such as arterial hypertension, dyslipidemia, type 2 diabetes or obesity. We aimed to analyze the prevalence and associations of MetS in patients with Alcohol Use Disorder (AUD). Cross-sectional study in heavy drinkers admitted for the treatment of AUD between 2013 and 2017. Medical comorbidity, anthropometric data, alcohol use and biological parameters were obtained. MetS was established according to the harmonized definition. A total of 728 patients (22% women) were included; median age was 47 years (IQR: 40-53.5), median alcohol consumption was 160 g/day (IQR: 115-240) and prevalence of MetS was 13.9%. The multivariate analysis showed a significant dose-response effect of estimated glomerular filtration (eGFR) and MetS: relative to patients with eGFR > 90 mL/min, those with eGFR (60-90 mL/min) and those with eGFR < 60 mL/min were 1.93 times (95% CI 1.18-3.15) and 5.61 times (95% CI 1.66-19.0) more likely to have MetS, respectively. MetS was significantly associated with hyperuricemia (OR 2.28, 95% CI 1.36-3.82) and elevated serum GGT (OR 3.67, 95% CI 1.80-7.46). Furthermore, for every increase of 1 year in age, the probability of MetS increased significantly (OR 1.03, 95% CI 1.01-1.05). MetS in heavy drinkers is independently associated with reduced kidney function and metabolic risk factors including hyperuricemia and elevated serum GGT.

Transdermal sensor features correlate with ecological momentary assessment drinking reports and predict alcohol-related consequences in young adults' natural settings.

BACKGROUND: Wearable transdermal alcohol concentration (TAC) sensors allow passive monitoring of alcohol concentration in natural settings and measurement of multiple features from drinking episodes, including peak intoxication level, speed of intoxication (absorption rate) and elimination, and duration. These passively collected features extend commonly used self-reported drink counts and may facilitate the prediction of alcohol-related consequences in natural settings, aiding risk stratification and prevention efforts. METHOD: A total of 222 young adults aged 21-29 (M age = 22.3, 64% female, 79% non-Hispanic white, 84% undergraduates) who regularly drink heavily participated in a 5-day study that included the ecological momentary assessment (EMA) of alcohol consumption (daily morning reports and participant-initiated episodic EMA sequences) and the wearing of TAC sensors (SCRAM-CAM anklets). The analytic sample contained 218 participants and 1274 days (including 554 self-reported drinking days). Five features-area under the curve (AUC), peak TAC, rise rate (rate of absorption), fall rate (rate of elimination), and duration-were extracted from TAC-positive trajectories for each drinking day. Day- and person-level associations of TAC features with drink counts (morning and episodic EMA) and alcohol-related consequences were tested using multilevel modeling. RESULTS: TAC features were strongly associated with morning drink reports (r = 0.6-0.7) but only moderately associated with episodic EMA drink counts (r = 0.3-0.5) at both day and person levels. Higher peaks, larger AUCs, faster rise rates, and faster fall rates were significantly predictive of day-level alcohol-related consequences after adjusting for both morning and episodic EMA drink counts in separate models. Person means of TAC features added little above daily scores to the prediction of alcohol-related consequences. CONCLUSIONS: These results support the utility of TAC sensors in studies of alcohol misuse among young adults in natural settings and outline the specific TAC features that contribute to the day-level prediction of alcohol-related consequences. TAC sensors provide a passive option for obtaining valid and unique information predictive of drinking risk in natural settings.

Determinants and Clinical Implications of Thyroid Peroxidase Antibodies in Middle-Aged and Elderly Individuals: The Rotterdam Study.

Background: Thyroid peroxidase antibodies (TPO-Abs) play an important role in autoimmune thyroid disease, but are also prevalent in healthy individuals. However, it is unclear what determinants may influence the occurrence of TPO-Abs in healthy individuals and how TPO-Abs may affect health outcomes in these individuals. We aimed to identify determinants of TPO-Abs in a large, prospective population-based cohort of middle-aged and elderly individuals and to subsequently assess the association between TPO-Abs and risk of overall and cause-specific mortality. Methods: We performed binomial and multinomial logistic regression analyses to obtain odds ratios (ORs) and 95% confidence intervals [95% CIs] for the association of potential determinants based on previous literature with TPO-Ab positivity (>35 kU/L), TPO-Ab detectability (>5 kU/L), and TPO-Ab categories. Cox proportional hazards regression analyses were performed to obtain hazard ratios (HRs) and CIs for the association between TPO-Abs and mortality risk. Results: In 9685 participants (57% women, median baseline age 63.3 years, median follow-up time 10.1 years), we identified female sex (OR = 2.47 [CI 2.13-2.86]) and current smoking (OR = 3.10 [CI 2.66-3.62]) as determinants of TPO-Ab positivity and TPO-Ab detectability, respectively. Higher age (OR = 0.98 [CI 0.97-0.98]) and all categories of alcohol consumption (ORs ranging from 0.71-0.78) were associated with lower odds of TPO-Ab detectability. TPO-Ab detectability was associated with a higher risk of overall (HR = 1.09 [CI 1.01-1.17]), cancer-related (HR = 1.18 [CI 1.01-1.38]), and cardiovascular mortality (HR = 1.21 [CI 1.01-1.45]). Interestingly, this was more prominent in men compared with women (HR for cardiovascular mortality 1.50 vs. 0.99, respectively). Conclusions: In community-dwelling middle-aged and elderly individuals, female sex and current smoking are the most important determinants associated with TPO-Ab levels in the detectable and positive range, whereas alcohol consumption is associated with lower odds of TPO-Abs. The clinical importance of detectable TPO-Ab levels is illustrated by the association with an increased mortality risk, mainly in men. Our results warrant further exploration of the clinical applicability of detectable TPO-Ab levels, potentially as a marker for low-grade inflammation. The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831.

Plasma calcium concentration during detoxification predicts neural cue-reactivity and craving during early abstinence in alcohol-dependent patients.

Recent studies on the pathophysiology of alcohol dependence suggest a link between peripheral calcium concentrations and alcohol craving. Here, we investigated the association between plasma calcium concentration, cue-induced brain activation, and alcohol craving. Plasma calcium concentrations were measured at the onset of inpatient detoxification in a sample of N = 115 alcohol-dependent patients. Alcohol cue-reactivity was assessed during early abstinence (mean 11.1 days) using a functional magnetic resonance imaging (fMRI) alcohol cue-reactivity task. Multiple regression analyses and bivariate correlations between plasma calcium concentrations, clinical craving measures and neural alcohol cue-reactivity (CR) were tested. Results show a significant negative correlation between plasma calcium concentrations and compulsive alcohol craving. Higher calcium levels predicted higher alcohol cue-induced brain response in a cluster of frontal brain areas, including the dorsolateral prefrontal cortex (dlPFC), the anterior prefrontal cortex (alPFC), and the inferior (IFG) and middle frontal gyri (MFG). In addition, functional brain activation in those areas correlated negatively with craving for alcohol during fMRI. Higher peripheral calcium concentrations during withdrawal predicted increased alcohol cue-induced brain activation in frontal brain areas, which are associated with craving inhibition and cognitive control functions. This might indicate that higher plasma calcium concentrations at onset of detoxification could modulate craving inhibition during early abstinence.Trial registration number: DRKS00003388; date of registration: 14.12.2011.

Circulating high density lipoprotein distinguishes alcoholic hepatitis from heavy drinkers and predicts 90-day outcome: lipoproteins in alcoholic hepatitis.

BACKGROUND: Alcohol-associated liver disease (ALD) and alcoholic hepatitis (AH) significantly impact the liver, an organ central to the lipid and lipoprotein metabolism. OBJECTIVE: To define changes in the lipid and lipoprotein profiles in subjects with alcoholic hepatitis (AH) versus heavy drinkers with normal liver function and to determine the association of the AH-mediated lipoprotein phenotype with AH severity and outcomes. METHODS: AH cases (n=196) and a heavy drinker control group (n=169) were identified in a multicenter, prospective cohort. The relationships between lipid panels and lipoprotein profiles among AH and heavy drinkers were interrogated using three common measurements: the conventional lipid panel, extended lipid panel by NMR, and NMR-based direct lipoprotein profiling. Predictive values for AH severity and mortality were determined using Harrell's C-Index. RESULTS: Lipid and lipoprotein profiles were significantly different in AH compared to heavy drinkers. Among them, high density lipoprotein (HDL) particle concentration exhibited the most significant reduction in AH compared to heavy drinkers (5.3 ± 3.4 vs 22.3 ± 5.4 µmol/L, p < 0.001). Within AH patients, HDL particle concentration was inversely associated with Maddrey's Discriminant Function (DF) (p < 0.001), and independently associated with mortality at both 90 and 365 days even after adjustment for DF (p = 0.02, p = 0.05 respectively). HDL particle concentration less than 3.5 µmol/L and total cholesterol ≤ 96 mg/dL identified AH patients with higher 90-day mortality. CONCLUSION: Lipid and lipoprotein profiles are profoundly altered in AH and can help in prognosticating disease severity and mortality.

Correlation of Antibodies to Neurotransmitters in the Sera of Women with Alcohol Dependence and Depressive Disorders.

Comparative analysis of blood sera from women with alcohol dependence and depressive disorders or from conditionally healthy women revealed reduced level of antibodies to dopamine, norepinephrine, serotonin, glutamate, and GABA in blood serum in women with dysthymic disorder and a depressive episode and their increased content in women with alcohol dependence in combination with depressive disorders.

Incidence, predictors and patterns of care of patients with very severe hypertriglyceridemia in Ontario, Canada: a population-based cohort study.

BACKGROUND: The incidence of severe (S-HTG) and very severe hypertriglyceridemia (VS-HTG) among Canadians is unknown. This study aimed to determine the incidence, characteristics, predictors and care patterns for individuals with VS-HTG. METHODS: Using linked administrative healthcare databases, a population-based cohort study of Ontario adults was conducted to determine incidence of new onset S-HTG (serum triglycerides (TG) > 10-20 mmol/L) and VS-HTG (TG > 20 mmol/L) between 2010 and 2015. Socio-demographic and clinical characteristics of those with VS-HTG were compared to those who had no measured TG value > 3 mmol/L. Univariable and multivariable logistic regression were used to determine predictors for VS-HTG. Healthcare patterns were evaluated for 2 years following first incidence of TG > 20 mmol/L. RESULTS: Incidence of S-HTG and VS-HTG in Ontario was 0.16 and 0.027% among 10,766,770 adults ≥18 years and 0.25 and 0.041% among 7,040,865 adults with at least one measured TG, respectively. Predictors of VS-HTG included younger age [odds ratios (OR) 0.64/decade, 95% confidence intervals (CI) 0.62-0.66], male sex (OR 3.83; 95% CI 3.5-4.1), diabetes (OR 5.38; 95% CI 4.93-5.88), hypertension (OR 1.69; 95% CI 1.54-1.86), chronic liver disease (OR 1.71; 95% CI 1.48-1.97), alcohol abuse (OR 2.47; 95% CI 1.90-3.19), obesity (OR 1.49; 95% CI 1.13-1.98), and chronic kidney disease (OR 1.39; 95% CI 1.19-1.63). CONCLUSION: The 5-year incidence of S-HTG and VS-HTG in Canadian adults was 1 in 400 and 1 in 2500, respectively. Males, those with diabetes, obese individuals and those with alcohol abuse are at highest risk for VS-HTG and may benefit from increased surveillance.

Evaluation of neurotrophic factors and education level as predictors of cognitive decline in alcohol use disorder.

Cognitive reserve (CR) is the capability of an individual to cope with a brain pathology through compensatory mechanisms developed through cognitive stimulation by mental and physical activity. Recently, it has been suggested that CR has a protective role against the initiation of substance use, substance consumption patterns and cognitive decline and can improve responses to treatment. However, CR has never been linked to cognitive function and neurotrophic factors in the context of alcohol consumption. The present cross-sectional study aims to evaluate the association between CR (evaluated by educational level), cognitive impairment (assessed using a frontal and memory loss assessment battery) and circulating levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in patients with alcohol use disorder (AUD). Our results indicated that lower educational levels were accompanied by earlier onset of alcohol consumption and earlier development of alcohol dependence, as well as impaired frontal cognitive function. They also suggest that CR, NT-3 and BDNF may act as compensatory mechanisms for cognitive decline in the early stages of AUD, but not in later phases. These parameters allow the identification of patients with AUD who are at risk of cognitive deterioration and the implementation of personalized interventions to preserve cognitive function.

Alcohol use and dysglycemia among people living with human immunodeficiency virus (HIV) in the Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions (ALIVE-Ex) study.

BACKGROUND: At-risk alcohol use is a common and costly form of substance misuse that is highly prevalent among people living with HIV (PLWH). The goal of the current analysis was to test the hypothesis that PLWH with at-risk alcohol use are more likely to meet the clinical criteria for prediabetes/diabetes than PLWH with low-risk alcohol use. METHODS: A cross-sectional analysis was performed on measures of alcohol and glycemic control in adult PLWH (n = 105) enrolled in a prospective, interventional study (the ALIVE-Ex Study (NCT03299205)) that investigated the effects of aerobic exercise on metabolic dysregulation in PLWH with at-risk alcohol use. The Alcohol Use Disorders Identification Test (AUDIT), Timeline Followback, and phosphatidylethanol (PEth) level were used to measure alcohol use. Participants were stratified into low-risk (AUDIT score < 5) and at-risk alcohol use (AUDIT  score ≥ 5). All participants underwent an oral glucose tolerance test and measures of glycemic control- the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and Matsuda Index - were correlated with alcohol measures and compared by AUDIT score group using mixed-effects linear and logistic regression models, adjusting for age, sex, race, body mass index (BMI), and viral load. RESULTS: In response to the glucose challenge, participants with at-risk alcohol use (n = 46) had higher glucose levels and were five times more likely to meet criteria for prediabetes/diabetes (OR: 5.3 (1.8, 15.9)) than participants with an AUDIT score < 5. Two-hour glucose values were positively associated with AUDIT score and PEth level and a higher percentage of PLWH with at-risk alcohol use had glucose values ≥140 mg/dl than those with low-risk alcohol use (34.8% vs. 10.2%, respectively). CONCLUSION: In this cohort of PLWH, at-risk alcohol use increased the likelihood of meeting the clinical criteria for prediabetes/diabetes (2-h glucose level ≥140 mg/dl). Established determinants of metabolic dysfunction (e.g., BMI, waist-hip ratio) were not associated with greater alcohol use and dysglycemia, suggesting that other mechanisms may contribute to the impaired glycemic control observed in this cohort.

Association of Plasma Pro-Brain-Derived Neurotrophic Factor (proBDNF)/Mature Brain-Derived Neurotrophic Factor (mBDNF) Levels with BDNF Gene Val66Met Polymorphism in Alcohol Dependence.

BACKGROUND In a previous study, we reported that pro-brain-derived neurotrophic factor (proBDNF) was involved in the pathology of alcohol dependence, and the single-nucleotide polymorphism (SNP) Val66Met was located at the prodomain of the brain-derived neurotrophic factor gene (BDNF). This polymorphism has been reported to affect intracellular trafficking and activity-dependent secretion of BDNF. Our present research investigated the relationships between the BDNF Val66Met polymorphism and the plasma levels of proBDNF and mature brain-derived neurotrophic factor (mBDNF) in patients with alcohol dependence. MATERIAL AND METHODS The BDNF gene Val66Met polymorphism was genotyped in 59 alcohol-dependent patients and 37 age- and sex-matched controls, and the plasma levels of proBDNF and mBDNF were assessed by enzyme-linked immunosorbent assay in all participants. RESULTS No association was found between the BDNF gene Val66Met polymorphism and alcohol dependence (P>0.05). In comparison with the control group, the level of plasma proBDNF in the alcohol-dependence group was notably increased (Z=-2.228, P=0.026), while the level of mBDNF was remarkedly decreased (Z=-2.014, P=0.044). In the alcohol-dependence group, significant associations were not found between the Val66Met polymorphisms and proBDNF and mBDNF plasma levels (P>0.05). The plasma level of proBDNF was positively correlated with the average daily alcohol consumption in the last month (r=0.344, P=0.008) and drinking history (r=0.317, P=0.014), while the plasma level of mBDNF had negative effects (r=-0.361, P=0.005, with the average daily alcohol consumption; r=-0.427, P=0.001, with drinking history). CONCLUSIONS The BDNF gene Val66Met polymorphism does not appear to affect the secretion of proBDNF and mBDNF in Chinese patients with alcohol dependence. Furthermore, this study reconfirmed that the plasma levels of proBDNF and mBDNF were correlated with the average daily alcohol consumption in the last month and with drinking history.

The prognostic significance of serum aspartate transaminase and gamma-glutamyl transferase in liver deceased donors.

The impact of aspartate transaminases (AST) and gamma-glutamyl transferase (GGT) in serum of deceased donors on outcomes after liver transplantation (LT) is unclear. This study aimed to explore the relationship between donor highest AST value or first donor GGT value and graft survival. All consecutive patients who underwent a primary LT in a single center with available donor AST (N = 1253) and GGT value (N = 1152) were included. There was no significant association between donor AST and 90-day graft survival. We found a moderate association between GGT and 90-day graft survival. We found a significant interaction with a donor history of alcohol abuse (HAA). The risk of graft loss was associated with AST and GGT in donors with an HAA but remains unchanged in donors without HAA. There was no difference in graft survival according to donor AST or GGT with a cutoff ≥95th percentile (475 UI/l for AST and 170 UI/l for GGT). However, graft survival was significantly decreased when donors combined GGT ≥ 170 UI/l and HAA (61% at one year). Hepatic grafts from donors with high AST or high GGT but without alcohol history and no additional risk factors can be transplanted in low-risk recipient.