210 results on '"Vatsalya, Vatsalya"'
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2. Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis
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Chalasani, Naga, Patidar, Kavish R., Vuppalanchi, Raj, Samala, Niha, Yoder, Lindsey, Nephew, Lauren, Shah, Vijay H., Simonetto, Douglas A., Kamath, Patrick, Vargas, Hugo E., Yang, Liu, Dasarathy, Srinivasan, Welch, Nicole, Bellar, Annette, Attaway, Amy, Dasarathy, Jaividhya, Growley, Ashley, Streem, David, Nagy, Laura E., Mitchell, Mack C., Herlong, H. Franklin, Kerr, Thomas, Cotter, Thomas, Sanyal, Arun, O'Connor, Sara, Luketic, Velimir, Asgharpour, Amon, Taylor, Stephanie, McClain, Craig J., Vatsalya, Vatsalya, Jophlin, Loretta, Cave, Matt, Jha, Suman Kumar, Marsano, Luis, Barve, Ashutosh, Frimodig, Jane, Bataller, Ramon, Ravi, Samhita, Behari, Jaideep, Shivanekar, Sharvari, Novelli, Paula, Duarte-Rojo, Andres, Jonassaint, Naudia, Szabo, Gyongyi, Curry, Jiang, Zhenghui G., Agarwal, Ushma, Hazel, Mia, Schnabl, Bernd, Gawrieh, Samer, Tu, Wanzhu, Kamath, Patrick S., Chalasani, Naga P., Tang, Qing, Radaeva, Svetlana, Barton, Bruce, and Sanyal, Arun J.
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- 2024
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3. Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes
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Leila Gobejishvili, Vatsalya Vatsalya, Diana V. Avila, Yana B. Feygin, Craig J. McClain, Sriprakash Mokshagundam, and Shirish Barve
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endotoxemia ,sCD14 ,sCD163 ,liver injury ,T2DM ,Biology (General) ,QH301-705.5 - Abstract
Background: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. Methods: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25–80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann–Whitney test to assess differences between study groups. Pearson’s correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. Results: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. Conclusions: These findings suggest that the pathogenic changes in the gut–liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.
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- 2024
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4. One-month assessment of Th-cell axis related inflammatory cytokines, IL-17 and IL-22 and their role in alcohol-associated liver disease
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Manasa Sagaram, Jane Frimodig, Danielle Jayanty, Huirong Hu, Amor J. Royer, Ryne Bruner, Maiying Kong, Melanie L. Schwandt, and Vatsalya Vatsalya
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alcohol use disorder ,alcohol-associated hepatitis ,audit ,IL-17 ,IL-22 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionChanges in the expression of cyto- and chemokines due to alcohol-associated liver disease (ALD) have been reported to be both protective and pathogenic. This study examined plasma levels of two key cytokines, Il-17 and Il-22, which construct the proinflammatory vs. anti-inflammatory axes across the spectrum of alcohol use disorder (AUD) and ALD including alcohol-associated hepatitis (AH) to determine the underlying status of the inflammation.MethodsForty-two males and females aged 25-63 yrs. were grouped as healthy controls (HV[n=8]), AUD with no liver injury (AUDNLI [n=8]), AUD with liver injury (AUDLI [n=8]), non-severe alcohol-associated hepatitis (NSAH [n=9]), and severe alcohol-associated hepatitis (SAH [n=9]). Demographic, drinking, and clinical data were collected. Blood samples were collected at baseline (BL, all subjects) and during week 4 (W4, only patients) for IL-17 and IL-22; and statistically analyzed.ResultsIL-17 was highly elevated in the SAH group both at BL and post-SOC. LTDH and BL IL-22 in non-severe AH patients were associated significantly. LTDH significantly predicted W4 IL-22 levels, positively (increasing) in NSAH and inversely (lowering) in SAH patients. BL and W4 IL-22 levels were significantly higher (4-fold, p≤0.001) in all AH patients compared to all AUD patients (AUROC=0.988, p≤0.001). IL-22 showed significant affinity with AST, AST: ALT ratio, total bilirubin, INR, and PT both at BL and W4. IL-22 was inversely associated with IL-1β; and positively with TNF-α and IL-8 both at BL, and W4. BL IL-17 showed a positive correlation with MELD (p=0.017) in all AH patients. In SAH, > 2-fold W4 IL-17 level compared to BL showed significant within subjects’ effects, p=0.006. In AUD patients without AH, the drop in IL-17 at W4 vs. BL showed a significant within subjects’ effect, p=0.031.DiscussionDrinking chronicity predicted opposite effects in IL-22 levels in NSAH (antiinflammatory) and SAH (pro-inflammatory) patients at post-SOC. BL IL-22 levels differentiated AH patients robustly from the AUD patients (with or without liver injury); and showed corresponding increases stepwise with the stages of ALD. IL-22 was closely associated with progression and injury markers of the liver; and response to the cytokines of pro-inflammatory nature. Pro-inflammatory indicator of IL-17 cell axis, IL-17 showed a strong positive association with MELD, a severity indicator of AH.
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- 2023
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5. Novel paradigms for the gut–brain axis during alcohol withdrawal, withdrawal-associated depression, and craving in patients with alcohol use disorder
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Vatsalya Vatsalya, Joris C. Verster, Manasa Sagaram, Amor J. Royer, Huirong Hu, Ranganathan Parthasarathy, Melanie L. Schwandt, Maiying Kong, Vijay A. Ramchandani, Wenke Feng, Ruchita Agrawal, Xiang Zhang, and Craig J. McClain
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alcohol dependence (AD) ,alcohol use disorder (AUD) ,craving ,cytokines ,depression ,gut–brain axis ,Psychiatry ,RC435-571 - Abstract
IntroductionPatients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms.MethodsForty-eight AUD patients [men (n = 34) and women (n = 14)] aged 23–63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score > 10] [n = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [n = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS).ResultsCS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-1β and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R2 = 0.955, p = 0.006) in the AUD patients, who had higher ratings for cravings (PACS > 5).DiscussionThe interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut–brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut–brain axis response to heavy drinking.Trial registrationClinicalTrials.gov, identifier: NCT# 00106106.
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- 2023
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6. Influence of age and sex on alcohol pharmacokinetics and subjective pharmacodynamic responses following intravenous alcohol exposure in humans
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Vatsalya, Vatsalya, Byrd, Nia D., Stangl, Bethany L., Momenan, Reza, and Ramchandani, Vijay A.
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- 2023
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7. Pharmacodynamic determinants of hangover: An intravenous alcohol self-administration study in non-dependent drinkers
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Stangl, Bethany L., Vogt, Emily L., Blau, Lauren E., Ester, Corbin D., Gogineni, Aruna, Diazgranados, Nancy, Vatsalya, Vatsalya, and Ramchandani, Vijay A.
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- 2022
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8. Linoleic Acid‐Derived Oxylipins Differentiate Early Stage Alcoholic Hepatitis From Mild Alcohol‐Associated Liver Injury
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Dennis Warner, Vatsalya Vatsalya, Kara H. Zirnheld, Jeffrey B. Warner, Josiah E. Hardesty, John C. Umhau, Craig J. McClain, Krishnarao Maddipati, and Irina A. Kirpich
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Alcohol‐associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol‐associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)‐derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA‐derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End‐Stage Liver Disease score
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- 2021
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9. Metabolic Profiling of Bile Acids in the Urine of Patients with Alcohol‐Associated Liver Disease
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Liqing He, Vatsalya Vatsalya, Xipeng Ma, Jiayang Zhang, Xinmin Yin, Seongho Kim, Wenke Feng, Craig J. McClain, and Xiang Zhang
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Bile acids (BAs) play important functions in the development of alcohol‐associated liver disease (ALD). In the current study, urine BA concentrations in 38 patients with well‐described alcohol‐associated hepatitis (AH) as characterized by Model for End‐Stage Liver Disease (MELD), 8 patients with alcohol‐use disorder (AUD), and 19 healthy controls (HCs) were analyzed using liquid chromatography–mass spectrometry. Forty‐three BAs were identified, and 22 BAs had significant changes in their abundance levels in patients with AH. The potential associations of clinical data were compared to candidate BAs in this pilot proof‐of‐concept study. MELD score showed positive correlations with several conjugated BAs and negative correlations with certain unconjugated BAs; taurine‐conjugated chenodeoxycholic acid (CDCA) and MELD score showed the highest association. Cholic acid, CDCA, and apocholic acid had nonsignificant abundance changes in patients with nonsevere ALD compared to HCs but were significantly increased in those with severe AH. Receiver operating characteristic analysis showed that the differences in these three compounds were sufficiently large to distinguish severe AH from nonsevere ALD. Notably, the abundance levels of primary BAs were significantly increased while most of the secondary BAs were markedly decreased in AH compared to AUD. Most importantly, the amount of total BAs and the ratio of primary to secondary BAs increased while the ratio of unconjugated to conjugated BAs decreased as disease severity increased. Conclusion: Abundance changes of specific BAs are closely correlated with the severity of AH in this pilot study. Urine BAs (individually or as a group) could be potential noninvasive laboratory biomarkers for detecting early stage ALD and may have prognostic value in AH morbidity.
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- 2021
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10. Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes.
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Gobejishvili, Leila, Vatsalya, Vatsalya, Avila, Diana V., Feygin, Yana B., McClain, Craig J., Mokshagundam, Sriprakash, and Barve, Shirish
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TYPE 2 diabetes ,LIVER injuries ,PEARSON correlation (Statistics) ,KUPFFER cells ,LIVER cells - Abstract
Background: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. Methods: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25–80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann–Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. Results: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. Conclusions: These findings suggest that the pathogenic changes in the gut–liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis
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Vatsalya, Vatsalya, Cave, Matthew C., Kong, Maiying, Gobejishvili, Leila, Falkner, K. Cameron, Craycroft, John, Mitchell, Mack, Szabo, Gyongi, McCullough, Arthur, Dasarathy, Srinivasan, Radaeva, Svetlana, Barton, Bruce, and McClain, Craig J.
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- 2020
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12. Metabolic Analysis of Nucleosides/Bases in the Urine and Serum of Patients with Alcohol-Associated Liver Disease
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Liqing He, Vatsalya Vatsalya, Xipeng Ma, Carolyn M. Klinge, Matthew C. Cave, Wenke Feng, Craig J. McClain, and Xiang Zhang
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modified nucleosides ,7,9-dimethylguanine ,ms2t6A ,epitranscriptomics ,alcohol-associated liver disease ,Microbiology ,QR1-502 - Abstract
Accumulating evidence supports the important role of RNA modifications in liver disease pathogenesis. However, RNA modifications in alcohol-associated liver disease (ALD) have not yet been reported. Modified ribonucleosides/bases are products of RNA degradation; therefore, we investigated whether modified ribonucleosides/bases in human urine and serum are changed and whether these changes are associated with the severity of ALD. Human urine and serum samples from patients with ALD and appropriate controls were collected. Free nucleosides/bases were extracted from these samples and quantified using untargeted and targeted metabolomic approaches. Thirty-nine and forty free nucleosides/bases were respectively detected in human urine and serum samples. Twelve and eleven modified nucleosides are significantly changed in patients’ urine and serum (q < 0.05 and fold-change > 20%). The abundance of modified nucleobase and ribonucleoside, 7,9-dimethylguanine in urine and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in serum are strongly associated with the severity of ALD. Spearman’s rank correlation coefficient of these two metabolites with the Model for End-stage Liver Disease (MELD) score are 0.66 and 0.74, respectively. Notably, the abundance changes in these two metabolites are sufficiently large to distinguish severe alcohol-associate hepatitis (AH) from non-severe ALD and non-severe ALD from healthy controls.
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- 2022
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13. Illustration of Gut–Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function
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Manasa Sagaram, Amor J. Royer, Huirong Hu, Abhas Rajhans, Ranganathan Parthasarathy, Sathya Sridevi Krishnasamy, Sri Prakash Mokshagundam, Maiying Kong, Melanie L. Schwandt, Dipendra Parajuli, Matthew C. Cave, and Vatsalya Vatsalya
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alcohol use disorder ,gut dysfunction ,gut–thyroid axis ,pro-inflammatory cytokines ,thyroid-associated hormones ,Cytology ,QH573-671 - Abstract
(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 β, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut–immune–thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut–thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut–brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD.
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- 2022
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14. Association of Hypomagnesemia and Liver Injury, Role of Gut-Barrier Dysfunction and Inflammation: Efficacy of Abstinence, and 2-Week Medical Management in Alcohol Use Disorder Patients
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Evan J. Winrich, Khushboo S. Gala, Abhas Rajhans, Christian D. Rios-Perez, Amor J. Royer, Zarlakhta Zamani, Ranganathan Parthasarathy, Luis S. Marsano-Obando, Ashutosh J. Barve, Melanie L. Schwandt, and Vatsalya Vatsalya
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alcoholic liver disease ,alcohol use disorder ,early-stage ALD ,heavy drinking ,hypomagnesemia ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients were sub-divided within each group into patients with normal magnesium (0.85 and more mmol/L) and deficient magnesium (less than 0.85 mmol/L) levels. All participants were assessed at baseline (BL) and received standard medical management for 2 weeks with reassessment at the treatment end (2w). (3) Female participants of this study showed a significantly lower baseline level of magnesium than their male counterparts. Gr.2 patients showed a greater propensity in the necrotic type of liver cell death, who reported higher chronic and recent heavy drinking. Magnesium level improved to the normal range in Gr.2 post-treatment, especially in the hypomagnesemia sub-group (0.77 ± 0.06 mmol/L (BL) vs. 0.85 ± 0.05 mmol/L (2w), p = 0.02). In Gr.2, both apoptotic (K18M30) and necrotic (K18M65) responses were significantly and independently associated with inflammasome activity comprising of LBP (Lipopolysaccharide binding-protein) and TNFα (Tumor necrosis factor -α), along with serum magnesium. (4) In AUD patients with liver injury, 2-week medical management seems to improve magnesium to a normal level. This group exhibited inflammatory activity (LBP and TNFα) contributing to clinically significant hypomagnesemia. In this group, the level of magnesium, along with the unique inflammatory activity, seems to significantly predict apoptotic and necrotic types of hepatocyte death.
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- 2022
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15. Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis
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Manasa Sagaram, Ranganathan Parthasarathy, Sally L. Condon, Charles F. Closson, Maiying Kong, Melanie L. Schwandt, Loretta L. Jophlin, Wenke Feng, Ashutosh J. Barve, and Vatsalya Vatsalya
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early-stage ALD ,AUD ,fibrosis ,IL-8 ,K18M65 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21–65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.
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- 2022
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16. Repurposing Treatment of Wernicke–Korsakoff Syndrome for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-Vitro Evidence and Pharmacokinetic Profile
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Vatsalya Vatsalya, Fengyuan Li, Jane Frimodig, Khushboo S. Gala, Shweta Srivastava, Maiying Kong, Vijay A. Ramchandani, Wenke Feng, Xiang Zhang, and Craig J. McClain
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cytokine storm ,COVID-19 ,IL-17 ,pandemic ,thiamine ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Coronavirus disease identified in 2019 (COVID-19) can be complicated by the Th17 cell-mediated IL-17 proinflammatory response. We tested if thiamine can effectively lower the Th17 response in a clinical study [Proinflammatory state in alcohol use disorder patients termed as disease controls (DC)] and corroborated the results using an in vitro study. We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19. Three-week 200 mg dose of thiamine was administered to sixteen DC patients. Eight healthy volunteers (HV) were also included in this investigation. A subsequent in vitro study was performed to validate the effectiveness of thiamine [100 mg/day equivalent (0.01 μg/ml)] treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19) and effective and safe dose ranges of thiamine. We developed a pharmacokinetic profile for thiamine dose range as a novel intervention strategy in COVID-19. DC group showed significantly elevated proinflammatory cytokines compared to HV. Thiamine-treated DC patients showed significant lowering in IL-17 and increase in the IL-22 levels. In humans, a range of 79–474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (∼45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the Th17 mediated IL-17 immune storm, and the subsequent neurological symptoms observed in COVID-19. Further studies using thiamine as an intervention/prevention strategy in COVID-19 patients could identify its precise anti-inflammatory role.
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- 2021
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17. Interaction of Heavy Drinking Patterns and Depression Severity Predicts Efficacy of Quetiapine Fumarate XR in Lowering Alcohol Intake in Alcohol Use Disorder Patients
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Vatsalya Vatsalya, Maiying Kong, Luis M Marsano, Zimple Kurlawala, Kan V Chandras, Melanie L Schwandt, Vijay A Ramchandani, and Craig J McClain
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Public aspects of medicine ,RA1-1270 - Abstract
Background: Shared etiological pathways of dopamine and serotonin neurotransmission play a central role in heavy alcohol intake and exacerbation in the symptoms of depression. We investigated the treatment efficacy of Quetiapine fumarate extended release (XR) in lowering alcohol intake in alcohol use disorder (AUD) patients indicated by the shared alleviation of depression ratings and patterns of heavy drinking. Methods: Hundred and eight male and female heavy drinking AUD patients in the age range of 18 to 64 years. participated in a randomized clinical trial (RCT) to receive 12 weeks of quetiapine XR or placebo (N = 115). Participants were sub-grouped by the severity grading of depression using Montgomery-Asberg Depression Rating Scale (MADRS) (clinically relevant ⩾8 [CR], clinically non-relevant ⩽7 [CNR]) at baseline in both the groups. Drinking history and depression ratings were assessed at the patients’ visits. Results: Heavy drinking days (HDD) and total drinks (TD) were significantly fewer in CR patients at the treatment end. A true positive response in AUROC analysis supported the lowering of TD in CR patients. The number of drinking days (NDD) and average drinks per drinking day (AvgD) were lower in the CNR patients at treatment-end. Significant associations with increasing effect sizes were observed for all the heavy drinking measures (HDD, TD, NDD, and AvgD) and MADRS scores by the end of the treatment course. Conclusions: Baseline elevated depressive symptoms could likely predict the course of heavy alcohol drinking during the treatment, and efficacy outcome of a treatment. AUD patients with baseline clinically significant depression had a progressive lowering in heavy drinking markers significantly corresponding to the lowering of depression symptoms by the end of treatment with Quetiapine fumarate XR. ClinicalTrials.gov: NCT#0049862 ( https://clinicaltrials.gov/ct2/show/NCT00498628?term=litten&draw=2&rank=3 )
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- 2020
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18. Dysregulation in Plasma ω3 Fatty Acids Concentration and Serum Zinc in Heavy Alcohol-Drinking HCV Patients
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Vatsalya Vatsalya, Ruchita Agrawal, Jane Frimodig, Shweta Srivastava, and Melanie L. Schwandt
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Microbiology ,QR1-502 - Abstract
Alcohol use disorder (AUD) patients comorbid with hepatitis C virus (HCV) infection (HCV + AUD) could have progressively severe clinical sequels of liver injury and inflammation. Serum zinc and several polyunsaturated fatty acids (PUFAs) get dysregulated in AUD as well as HCV. However, the extent of dysregulation of PUFAs and zinc deficiency and their interaction in HCV + AUD as a comorbid pathology has not been studied. We examined the role of dysregulation of FAs and low zinc in HCV + AUD patients. 138 male and female participants aged 21–67 years were grouped as HCV-only (Gr. 1; n = 13), HCV + AUD (Gr. 2; n = 25), AUD without liver injury (Gr. 3; n = 37), AUD with liver injury (Gr. 4; n = 51), and healthy volunteers (Gr. 5 or HV; n = 12). Drinking history, individual demographic measures, fasting fatty acids, liver function, and zinc were measured and analyzed. HCV + AUD patients showed the highest ALT level compared to the rest of the groups. Serum zinc concentrations were the lowest, and the proinflammatory shift was the highest (characterized by ω6 : ω3 ratio) in the HCV + AUD patients. Total ω3, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA5,3) were the lowest in HCV + AUD patients. Total ω3, α-linoleic acid (α-LA) along with covariable number of drinking days past 90 days (NDD90), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA5,3) independently showed significant association with low zinc in the HCV + AUD patients. Heavy drinking pattern showed that NDD90 has a significant mediating role in the representation of the relationship between candidate ω3 PUFAs and zinc uniquely in the HCV + AUD patients. Low serum zinc showed a distinctively stronger association with total and candidate ω3s in the HCV + AUD patients compared to the patients with HCV or AUD alone, supporting dual mechanism involved in the exacerbation of the proinflammatory response in this comorbid cohort. This trial is registered with NCT#00001673.
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- 2020
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19. Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis.
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Hassanein, Tarek, McClain, Craig J., Vatsalya, Vatsalya, Stein, Lance L., Flamm, Steven L., Martin, Paul, Cave, Matthew C., Mitchell Jr, Mack, Barton, Bruce, Nagy, Laura, Szabo, Gyongyi, McCullough, Arthur, Dasarathy, Srinivasin, Shah, Jaymin, Blevins, Christina, Scott, Deborah, Krebs, William, Brown, James E., and WeiQi Lin
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- 2024
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20. Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients
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Vatsalya Vatsalya, Khushboo S. Gala, Ammar Z. Hassan, Jane Frimodig, Maiying Kong, Nachiketa Sinha, and Melanie L. Schwandt
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ALD ,AUD ,heavy drinking markers ,hyperhomocysteinemia ,TLFB ,withdrawal ,Biology (General) ,QH301-705.5 - Abstract
Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal ≤ 13 µmol/L (Group 1 (Gr.1); n = 80), and elevated > 13 µmol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27; Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1β (IL-1β)), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)); 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-β, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients; AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-β, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD.
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- 2020
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21. Altered urinary tryptophan metabolites in alcohol‐associated liver disease.
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Xu, Raobo, Vatsalya, Vatsalya, He, Liqing, Ma, Xipeng, Feng, Wenke, McClain, Craig J., and Zhang, Xiang
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BIOMARKERS , *LIVER function tests , *PROTHROMBIN time , *STATISTICS , *ALCOHOLISM , *METABOLOMICS , *ALCOHOLIC liver diseases , *LIQUID chromatography , *ONE-way analysis of variance , *CASE-control method , *MANN Whitney U Test , *METABOLISM , *TRYPTOPHAN , *SEVERITY of illness index , *MASS spectrometry , *DESCRIPTIVE statistics , *RESEARCH funding , *INTERNATIONAL normalized ratio , *BLOOD cell count , *DATA analysis software , *DATA analysis , *RECEIVER operating characteristic curves , *MOLECULAR structure , *METABOLITES , *ASPARTATE aminotransferase , *ALANINE aminotransferase , *BILIRUBIN - Abstract
Background: Alcohol‐associated liver disease (ALD) leads to millions of deaths worldwide annually. A few potential biomarkers of ALD have been discovered through metabolomic or proteomic analysis. Tryptophan (Trp), one of nine essential amino acids, has been extensively studied and shown to play significant roles in many mammalian physiological processes. However, Trp metabolism changes in ALD are not yet fully understood. Whereas urine is an abundant and non‐invasive source for disease biomarker discovery the current study investigated whether the abundance of Trp metabolites in the urine of ALD patients differs from that of healthy subjects. We also examined whether, if present in ALD, changes in urinary Trp metabolites can serve as markers for differentiating between mild/moderate and severe ALD. Methods: We quantified the concentration of Trp and its metabolites in urine samples of healthy controls (n = 18), patients with mild or moderate alcohol‐related liver injury (non‐severe ALD; n = 21), and patients with severe alcohol‐associated hepatitis (severe AH; n = 25) using both untargeted and targeted metabolomics. Results: Eighteen Trp metabolites were identified and quantified from the untargeted metabolomics data. We developed a targeted metabolomics method to quantify the Trp and its metabolites and quantified 17 metabolites from the human urine samples. The data acquired in the untargeted and targeted platforms agreed and showed that the Trp concentration is not affected by the severity of ALD. However, the abundance of 10 Trp metabolites was correlated with the model for end‐stage liver disease (MELD) score, with the abundance of nine metabolites significantly different between the healthy control and ALD patient groups. Conclusion: We found that Trp metabolism differs between ALD patients and healthy controls even though the concentration of Trp was not affected. Two Trp metabolites, quinolinic acid and indoxyl sulfate, correlate highly with the severity of ALD. [ABSTRACT FROM AUTHOR]
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- 2023
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22. The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis.
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Vatsalya, Vatsalya, Wenke Feng, Maiying Kong, Huirong Hu, Gyongyi Szabo, McCullough, Arthur, Dasarathy, Srinivasan, Nagy, Laura E., Radaeva, Svetlana, Barton, Bruce, Mitchell, Mack, and McClain, Craig J.
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ALCOHOLISM , *HEPATITIS , *LACTOBACILLUS , *LACTOBACILLUS rhamnosus , *LIVER injuries - Abstract
INTRODUCTION: We investigated the effect of daily oral Lactobacillus rhamnosus GG (LGG) in reducing liver injury/severity and drinking in patients with alcohol use disorder and moderately severe alcohol-associated hepatitis. METHODS: Forty-six male and female individuals with alcohol use disorder and moderate alcohol-associated hepatitis (12 ≤ model for end-stage liver disease score < 20, aged 21-67 years) received either LGG (n = 24) or placebo (n = 22). Data were collected/assessed at baseline and at 1, 3, and 6 months. RESULTS: LGG treatment was associated with a significant reduction in liver injury after 1 month. Six months of LGG treatment reduced heavy drinking levels to social or abstinence levels. DISCUSSION: LGG treatment was associated with an improvement in both liver injury and drinking. [ABSTRACT FROM AUTHOR]
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- 2023
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23. Continued Education Webinar: Leveraging Novel Microbiome-related Therapies
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Leggio Lorenzo, Barb, Jennifer, and Vatsalya Vatsalya
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- 2023
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24. Role of Zinc in the Development/Progression of Alcoholic Liver Disease
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McClain, Craig, Vatsalya, Vatsalya, and Cave, Matthew
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- 2017
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25. Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope
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Khushboo S. Gala and Vatsalya Vatsalya
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alcohol ,novel biomarkers ,medical management ,alcoholic hepatitis ,noninvasive biomarkers ,alcoholic liver disease ,Cytology ,QH573-671 - Abstract
Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH.
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- 2020
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26. Safety Assessment of Liver Injury with Quetiapine Fumarate XR Management in Very Heavy Drinking Alcohol-Dependent Patients
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Vatsalya, Vatsalya, Pandey, Akash, Schwandt, Melanie L., Cave, Matthew C., Barve, Shirish S., Ramchandani, Vijay A., and McClain, Craig J.
- Published
- 2016
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27. Characterization of hangover following intravenous alcohol exposure in social drinkers: methodological and clinical implications
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Vatsalya, Vatsalya, Stangl, Bethany L., Schmidt, Veronica Y., and Ramchandani, Vijay A.
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- 2018
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28. Mo1506 ONE-MONTH NATURAL HISTORY ASSESSMENT OF TH-CELL AXIS RELATED INFLAMMATORY CYTOKINES, IL-17 AND IL-22 AND THEIR ROLE IN ALCOHOL-ASSOCIATED LIVER DISEASE.
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Jayanty, Danielle P., Sagaram, Manasa, Akter, Sharmin, Kong, Maiying, Schwandt, Melanie L., Singal, Ashwani K., and Vatsalya, Vatsalya
- Published
- 2024
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29. Mo1530 WAITLIST AND POST-TRANSPLANT OUTCOMES OF MET-ALD ARE POORER COMPARED TO THOSE WITH ALD PATIENTS
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Panneerselvam, Deepan, Jalil, Sajid, Elfeki, Mohamed A., Vatsalya, Vatsalya, Dunn, Winston, Wong, Robert, McClain, Craig J., Kuo, Yong-Fang, and Singal, Ashwani K.
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- 2024
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30. Mo1523 RESPONSE CHANGES IN SERUM MAGNESIUM LEVELS IN PATIENTS WITH SEVERE ALCOHOL-ASSOCIATED HEPATITIS CORRESPOND WITH SEVERITY-ASSOCIATED PROGNOSTIC OUTCOMES
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Tiwari, Harsh, Winrich, Evan, Royer, Amor, Singal, Ashwani K., Parajuli, Dipendra, and Vatsalya, Vatsalya
- Published
- 2024
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31. 854 FECAL EXTRACELLULAR VESICLES FROM ALD SUBJECTS EXACERBATED ALCOHOL-ASSCOCIATED LIVER DISEASE IN MICE
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Li, Fengyuan, Pan, Guihua, Lee, Jiyeon, Zhang, Lihua, Vatsalya, Vatsalya, McClain, Craig J., and Feng, Wenke
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- 2024
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32. Blood phosphatidylethanol (PEth) positivity associates with unfavorable waitlist-related outcomes for patients medically appropriate for liver transplant
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Faulkner, Claire S., White, Collin M., Manatsathit, Wuttiporn, Lamb, Bernadette, Vatsalya, Vatsalya, McClain, Craig J., and Jophlin, Loretta L.
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Alcohol Drinking ,Humans ,Glycerophospholipids ,Article ,Biomarkers ,Liver Transplantation ,Retrospective Studies - Abstract
Excessive alcohol use is a leading etiology of liver disease and indication for liver transplantation. Accurate measurement of alcohol use remains a challenge in the management of patients in the pre-, peri-, and post-liver transplant settings. Blood 16:0-18:1 phosphatidylethanol (PEth) concentration is a sensitive and specific biomarker of binge and moderate, chronic alcohol use. As PEth has the longest detection window of available blood-based direct alcohol biomarkers for moderate to heavy drinking, it shows promise as an indicator of patterns and chronicity of drinking. However, the utility of PEth in clinical liver transplantation is understudied. This study examines the association of PEth results with liver transplantation waitlist-focused patient outcomes.Retrospective data for all patients tested for PEth for a one-year period at a tertiary care medical center with an active liver transplantation program were abstracted. Indications for PEth testing, liver transplantation waitlist-related outcomes (e.g., listing and delisting) following testing and associations of PEth results with other parameters were analyzed.Over a one-year period, 153 PEth tests were performed on 109 individuals. The most frequent indications for PEth testing were as an objective indicator of alcohol use patterns (86.3%) and to assess alcohol as a putative etiology of liver injury (13.7%). Of the 109 patients, 56 were medically appropriate for liver transplantation. Medically acceptable candidates with unfavorable transplantation waitlist-related outcomes (delisting, deferment of transplant evaluation, deferment of listing until completion of recommended alcohol rehabilitation, and being deemed not a transplant candidate) were at least 3.41 times more likely to have a positive PEth test than those with favorable transplantation waitlist-related outcomes (odds ratio 3.41, confidence interval 3.41 to ∞, p = 0.001).This single-center study reporting a comprehensive account of PEth utilization at a liver transplant center demonstrates that liver transplantation waitlist-related outcomes are associated with PEth test results. Patients with positive PEth tests were more likely to have unfavorable transplant waitlist-related outcomes. PEth testing has not been validated as a predictor of relapse to drinking in post-transplant patients and because its utility in the pre-transplant setting is unclear its use could lead to disparities in the selection of patients for liver transplantation.
- Published
- 2022
33. Characterization of Hypomagnesemia in Alcoholic Hepatitis Patients and Its Association with Liver Injury and Severity Markers.
- Author
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Winrich, Evan J., Tiwari, Harsh, Gala, Khushboo S., Royer, Amor J., Parajuli, Dipendra, and Vatsalya, Vatsalya
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LIVER injuries ,HYPOMAGNESEMIA ,HEPATITIS ,CEREBRAL vasospasm ,PROGNOSIS ,LIVER diseases - Abstract
Introduction: Hypomagnesemia has been documented in alcohol-associated liver disease (ALD). This study aims to characterize hypomagnesemia in alcoholic hepatitis (AH) patients and identify its response with liver injury and severity markers. Materials and Methods: A total of 49 male and female AH patients with an age range of 27–66 years were enrolled in this study. Patients were grouped by MELD: MiAH (mild AH < 12 [n = 5]), MoAH (12 ≤ moderate AH ≤ 19 [n = 13]), and SAH (severe AH ≥ 20 [n = 31]). Patients were also evaluated by MELD grouping as non-severe (MELD ≤ 19 [n = 18]) and severe (MELD ≥ 20 [n = 31]). Data were collected on demographics (Age; BMI), drinking history (AUDIT; LTDH), liver injury (ALT; AST), and liver severity (Maddrey's DF; MELD; AST:ALT). Serum magnesium (SMg) levels were tested as SOC lab (normal ≥ 0.85 ≤ 1.10 mmol/L). Results: SMg was deficient in each group; the lowest in the MoAH patients. The true positivity of SMg values were at a good performance level when compared between severe and non-severe AH patients (AUROC: 0.695, p = 0.034). We found that the SMg level < 0.78 mmol/L could predict severe AH (sensitivity = 0.100 and 1-specificity = 0.000) at this true positivity, and subsequently analyzed patients with SMg < 0.78 mmol/L (Gr.4) and ≥0.78 mmol/L (Gr.5). Between Gr.4 and Gr.5, there were clinically as well as statistically significant differences in disease severity as defined by MELD, Maddrey's DF, and ABIC scores. Conclusions: This study demonstrates the utility of SMg levels to identify AH patients who may have progressed to severe status. The extent of magnesium response in AH patients also corresponded significantly with the prognosis of liver disease. Physicians suspecting AH in patients with recent heavy drinking may use SMg as an indicator to guide further testing, referrals, or treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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34. Probiotic‐derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation.
- Author
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Jiang, Mengwei, Li, Fengyuan, Liu, Yunhuan, Gu, Zelin, Zhang, Lihua, Lee, Jiyeon, He, Liqing, Vatsalya, Vatsalya, Zhang, Huang‐Ge, Deng, Zhongbin, Zhang, Xiang, Chen, Shao‐Yu, Guo, Grace L., Barve, Shirish, McClain, Craig J., and Feng, Wenke
- Published
- 2023
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35. Metabolomics analysis of urine from patients with alcohol-associated liver disease reveals dysregulated caffeine metabolism.
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Raobo Xu, Liqing He, Vatsalya, Vatsalya, Xipeng Ma, Seongho Kim, Mueller, Eugene G., Wenke Feng, McClain, Craig J., and Xiang Zhang
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LIVER diseases ,URINALYSIS ,METABOLOMICS ,CAFFEINE ,METABOLISM ,CHRONIC active hepatitis - Abstract
Excess alcohol intake causes millions of deaths annually worldwide. Asymptomatic early-stage, alcohol-associated liver disease (ALD) is easily overlooked, and ALD is usually only diagnosed in more advanced stages. We explored the possibility of using polar urine metabolites as biomarkers of ALD for early-stage diagnosis and functional assessment of disease severity by quantifying the abundance of polar metabolites in the urine samples of healthy controls (n = 18), patients with mild or moderate liver injury (n = 21), and patients with severe alcohol-associated hepatitis (n = 25). The polar metabolites in human urine were first analyzed by untargeted metabolomics, showing that 209 urine metabolites are significantly changed in patients, and 17 of these are highly correlated with patients' model for end-stage liver disease (MELD) score. Pathway enrichment analysis reveals that the caffeine metabolic pathway is the most affected in ALD. We then developed a targeted metabolomics method and measured the concentration of caffeine and its metabolites in urine using internal and external standard calibration, respectively. The described method can quantify caffeine and its 14 metabolites in 35 min. The results of targeted metabolomics analysis agree with the results of untargeted metabolomics, showing that 13 caffeine metabolites are significantly decreased in patients. In particular, the concentrations of 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil are markedly decreased with increased disease severity. We suggest that these three metabolites could serve as functional biomarkers for differentiating early-stage ALD from more advanced liver injury. NEW & NOTEWORTHY Our study using both untargeted and targeted metabolomics reveals the caffeine metabolic pathway is dysregulated in ALD. Three caffeine metabolites, 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil, can differentiate the severity of early-stage ALD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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36. The International Society for Biomedical Research on Alcoholism BULLETIN Volume 4 Issue 4
- Author
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Pautassi, Ricardo Marcos, Leeman, Robert F, Vatsalya Vatsalya, Camarini, Rosana, Winrich, Evan, Wang, Yan, Palma, Elena, Riva, Antonio, Ferreiro, Andrea Vásquez, Marengo, Leonardo, Salguero, Agustin, Warner, Jeffrey, and Verster, Joris
- Published
- 2022
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37. Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients
- Author
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Jane Frimodig, Melanie L. Schwandt, Maiying Kong, Vatsalya Vatsalya, Nachiketa Sinha, Khushboo Gala, and Ammar Z Hassan
- Subjects
0301 basic medicine ,Subset Analysis ,medicine.medical_specialty ,Hyperhomocysteinemia ,Alcoholic liver disease ,congenital, hereditary, and neonatal diseases and abnormalities ,AUD ,TLFB ,Medicine (miscellaneous) ,Inflammation ,Alcohol use disorder ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,hyperhomocysteinemia ,lcsh:QH301-705.5 ,Liver injury ,business.industry ,withdrawal ,Comprehensive metabolic panel ,nutritional and metabolic diseases ,medicine.disease ,030104 developmental biology ,lcsh:Biology (General) ,ALD ,heavy drinking markers ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal &le, 13 µ, mol/L (Group 1 (Gr.1), n = 80), and elevated >, mol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27, Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1&beta, (IL-1&beta, )), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)), 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-&beta, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients, AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-&beta, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD.
- Published
- 2021
38. The Effect of Varenicline on the Neural Processing of Fearful Faces and the Subjective Effects of Alcohol in Heavy Drinkers
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Gowin, Joshua L., Vatsalya, Vatsalya, Westman, Jonathan G., Schwandt, Melanie L., Bartlett, Selena, Heilig, Markus, Momenan, Reza, and Ramchandani, Vijay A.
- Published
- 2016
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39. Metabolic Analysis of Nucleosides/Bases in the Urine and Serum of Patients with Alcohol-Associated Liver Disease.
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He, Liqing, Vatsalya, Vatsalya, Ma, Xipeng, Klinge, Carolyn M., Cave, Matthew C., Feng, Wenke, McClain, Craig J., and Zhang, Xiang
- Subjects
NUCLEOSIDES ,LIVER diseases ,RIBONUCLEOSIDES ,RNA modification & restriction ,METABOLITES ,URINE - Abstract
Accumulating evidence supports the important role of RNA modifications in liver disease pathogenesis. However, RNA modifications in alcohol-associated liver disease (ALD) have not yet been reported. Modified ribonucleosides/bases are products of RNA degradation; therefore, we investigated whether modified ribonucleosides/bases in human urine and serum are changed and whether these changes are associated with the severity of ALD. Human urine and serum samples from patients with ALD and appropriate controls were collected. Free nucleosides/bases were extracted from these samples and quantified using untargeted and targeted metabolomic approaches. Thirty-nine and forty free nucleosides/bases were respectively detected in human urine and serum samples. Twelve and eleven modified nucleosides are significantly changed in patients' urine and serum (q < 0.05 and fold-change > 20%). The abundance of modified nucleobase and ribonucleoside, 7,9-dimethylguanine in urine and 2-methylthio-N
6 -threonylcarbamoyladenosine (ms2 t6 A) in serum are strongly associated with the severity of ALD. Spearman's rank correlation coefficient of these two metabolites with the Model for End-stage Liver Disease (MELD) score are 0.66 and 0.74, respectively. Notably, the abundance changes in these two metabolites are sufficiently large to distinguish severe alcohol-associate hepatitis (AH) from non-severe ALD and non-severe ALD from healthy controls. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
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40. 2263
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Corbin Daniel Ester, Bethany Stangl, Aruna Gogineni, Lauren Blau, Vatsalya Vatsalya, and Vijay Ramchandani
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Medicine - Abstract
OBJECTIVES/SPECIFIC AIMS: The current study examined hangover following IV alcohol self-administration (IV-ASA) using the Computer-Assisted Infusion System. The goal of the study was to identify predictors of hangover, including drinking history, alcohol sensitivity, family history, expectancies, and sex differences in nondependent drinkers. METHODS/STUDY POPULATION: The study sample included 89 healthy, nondependent drinkers aged 21–45 years. After a screening to exclude any medical illness or psychiatric disorders, participants completed an IV-ASA session. Each session consisted of a 25-minute priming phase, during which participants were prompted to press a button to receive individually standardized alcohol infusions, followed by a 2-hour “open bar” phase, during which they were instructed to recreate a typical drinking experience. Results from the IV-ASA included peak and average BrAC. Drinking patterns were assessed using the Alcohol Use Disorders Identification Test, which provided 3 subscales: consumption (AUDIT-C), dependence (AUDIT-D), and harmful drinking (AUDIT-H). Subjective response to alcohol was measured using the Drug Effects Questionnaire (DEQ). The Alcohol Hangover Scale (AHS) was used to assess hangover for the period between participants’ departure from the study unit and 10 am the next morning. The Alcohol Effects Questionnaire (AEFQ) is a measure which includes 40 true/false statements about how alcohol typically makes respondents feel, and was used to measure alcohol expectancies. RESULTS/ANTICIPATED RESULTS: Results showed that 78% of participants endorsed having at least 1 hangover symptom following IV-ASA. The most commonly reported items were tired, thirsty, headache, and hangover. There was no association between hangover scores and the AUDIT-C or IV-ASA. Because alcohol consumption was not related to hangover symptoms, risky drinking behavior was examined. Results indicated that participants endorsing 4 or more items on the AUDIT-D plus AUDIT-H subscales showed significantly higher average hangover scores. Linear regression analyses indicated that alcohol hangover scores were associated with DEQ items feel, high, and intoxicated. Ongoing analyses are examining additional predictors of hangover including family history, alcohol expectancies, sex differences, and other alcohol sensitivity measures. DISCUSSION/SIGNIFICANCE OF IMPACT: The results indicated that risky drinking patterns and alcohol response measures were positively associated with hangover symptoms in non-dependent drinks, while no correlation between consumption and hangover symptoms were found. Since previous research has shown than greater subjective response is associated with heavy drinking and predictive of alcohol use disorder, it is possible that hangover symptoms is a marker of this relationship. Since the role of hangover in the transition from heavy drinking to disorder still remains unclear, it will be important to characterize this relationship between alcohol sensitivity and hangover as a function of drinking patterns. This understanding may help to prevent this transition from at-risk drinking to alcohol dependent drinking.
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- 2017
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41. Illustration of Gut–Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.
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Sagaram, Manasa, Royer, Amor J., Hu, Huirong, Rajhans, Abhas, Parthasarathy, Ranganathan, Krishnasamy, Sathya Sridevi, Mokshagundam, Sri Prakash, Kong, Maiying, Schwandt, Melanie L., Parajuli, Dipendra, Cave, Matthew C., and Vatsalya, Vatsalya
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ALCOHOLISM ,THYROID gland ,ALCOHOL drinking ,PATIENTS ,PROTEIN hormones ,THYROTROPIN receptors ,INFLAMMATION - Abstract
(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 β, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut–immune–thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut–thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut–brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD. [ABSTRACT FROM AUTHOR]
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- 2022
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42. Association of Hypomagnesemia and Liver Injury, Role of Gut-Barrier Dysfunction and Inflammation: Efficacy of Abstinence, and 2-Week Medical Management in Alcohol Use Disorder Patients.
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Winrich, Evan J., Gala, Khushboo S., Rajhans, Abhas, Rios-Perez, Christian D., Royer, Amor J., Zamani, Zarlakhta, Parthasarathy, Ranganathan, Marsano-Obando, Luis S., Barve, Ashutosh J., Schwandt, Melanie L., and Vatsalya, Vatsalya
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ALCOHOLISM ,ALANINE aminotransferase ,HYPOMAGNESEMIA ,LIVER injuries ,TUMOR necrosis factors ,LIVER cells - Abstract
(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients were sub-divided within each group into patients with normal magnesium (0.85 and more mmol/L) and deficient magnesium (less than 0.85 mmol/L) levels. All participants were assessed at baseline (BL) and received standard medical management for 2 weeks with reassessment at the treatment end (2w). (3) Female participants of this study showed a significantly lower baseline level of magnesium than their male counterparts. Gr.2 patients showed a greater propensity in the necrotic type of liver cell death, who reported higher chronic and recent heavy drinking. Magnesium level improved to the normal range in Gr.2 post-treatment, especially in the hypomagnesemia sub-group (0.77 ± 0.06 mmol/L (BL) vs. 0.85 ± 0.05 mmol/L (2w), p = 0.02). In Gr.2, both apoptotic (K18M30) and necrotic (K18M65) responses were significantly and independently associated with inflammasome activity comprising of LBP (Lipopolysaccharide binding-protein) and TNFα (Tumor necrosis factor -α), along with serum magnesium. (4) In AUD patients with liver injury, 2-week medical management seems to improve magnesium to a normal level. This group exhibited inflammatory activity (LBP and TNFα) contributing to clinically significant hypomagnesemia. In this group, the level of magnesium, along with the unique inflammatory activity, seems to significantly predict apoptotic and necrotic types of hepatocyte death. [ABSTRACT FROM AUTHOR]
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- 2022
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43. Dilemma of Treating Psychosis Secondary to Stroke
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Ruchita Agrawal, Vatsalya Vatsalya, Shikha Verma, Monica Halappanavar, and Kosisochukwu Oraka
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Psychiatry ,medicine.medical_specialty ,Psychosis ,business.industry ,Daily function ,General Engineering ,030204 cardiovascular system & hematology ,post stroke psychosis ,medicine.disease ,stroke ,Dilemma ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,medicine ,psychosis ,Intensive care medicine ,business ,Stroke ,030217 neurology & neurosurgery ,long term neuropsychiatric sequelae - Abstract
Post-stroke psychosis is prevalent and disabling with increased mortality risk. Treatment for post-stroke psychosis is limited in this staggering medical concern. The most commonly used medications are antipsychotics, however, the risk for stroke increases further with the use of antipsychotics. Furthermore, interventional clinical studies have not been carried out to test the efficacy and safety of antipsychotics in the management of post-stroke psychosis. We present a case of post-stroke psychosis to highlight the risks faced by these patients in terms of daily function and safety concerns and the challenges encountered in treatment due to poor response to the conventional antipsychotics; and so calling attention to early diagnosis and improved treatment options. More clinical investigations are needed to address the pathology associated with the clinical presentation and exploring the pharmacotherapies to improve efficacy and safety of treatment for post-stroke psychosis.
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- 2021
44. Cardiac Reactivity During the Ascending Phase of Acute Intravenous Alcohol Exposure and Association with Subjective Perceptions of Intoxication in Social Drinkers
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Vatsalya, Vatsalya, Momenan, Reza, Hommer, Daniel W., and Ramchandani, Vijay A.
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- 2014
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45. Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis.
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Sagaram, Manasa, Parthasarathy, Ranganathan, Condon, Sally L., Closson, Charles F., Kong, Maiying, Schwandt, Melanie L., Jophlin, Loretta L., Feng, Wenke, Barve, Ashutosh J., and Vatsalya, Vatsalya
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ALCOHOLISM ,LIVER histology ,FIBROSIS ,LIVER cells ,BIOMARKERS ,SYMPTOMS ,CELL death - Abstract
(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21–65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8. [ABSTRACT FROM AUTHOR]
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- 2022
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46. Interaction of Heavy Drinking Patterns and Depression Severity Predicts Efficacy of Quetiapine Fumarate XR in Lowering Alcohol Intake in Alcohol Use Disorder Patients
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Kan V. Chandras, Luis M. Marsano, Maiying Kong, Craig J. McClain, Melanie L. Schwandt, Zimple Kurlawala, Vatsalya Vatsalya, and Vijay A. Ramchandani
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medicine.medical_specialty ,MADRS ,Exacerbation ,Alcohol ,Alcohol use disorder ,24 Current Developments in Substance Abuse Treatment ,alcohol use disorder ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dopamine ,Alcohol dependents ,Internal medicine ,Quetiapine Fumarate ,Medicine ,Depression (differential diagnoses) ,Original Research ,Heavy drinking ,business.industry ,lcsh:Public aspects of medicine ,lcsh:RA1-1270 ,medicine.disease ,030227 psychiatry ,quetiapine fumarate XR ,Psychiatry and Mental health ,Endocrinology ,chemistry ,drinking-markers ,Montgomery–Åsberg Depression Rating Scale ,depression ,Etiology ,Alcohol intake ,Serotonin ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
BackgroundShared etiological pathways of dopamine and serotonin neurotransmission play a central role in heavy alcohol intake and exacerbation in the symptoms of depression.We investigated the role of depression ratings and patterns of heavy drinking on the treatment efficacy of Quetiapine fumarate XR in lowering alcohol intake in alcohol use disorder (AUD) patients.MethodsOne hundred and eight male and female heavy drinking AUD patients in the age range of 18–64 yrs. received 12 weeks of active treatment. Participants were grouped by the severity grading of depression using Montgomery-Asberg Depression Rating Scale (MADRS) (clinically relevant≥8 [CR], clinically non-relevant≤7 [CNR]) at baseline. Drinking history and depression ratings were assessed at the patients visits.ResultsHeavy drinking days (HDD) and total drinks (TD) were significantly fewer in CR patients at the treatment end. A true positive response in AUROC analysis supported the lowering of TD in CR patients. The number of drinking days (NDD) and average drinks per drinking day (AvgD) were lower in the CNR patients at treatment-end. Significant associations with increasing effect sizes were observed for all the heavy drinking measures (HDD, TD, NDD and AvgD) and MADRS scores by the end of the treatment course.ConclusionsBaseline elevated depressive symptoms could likely predict the course of heavy alcohol drinking during the treatment, and efficacy outcome of a treatment. AUD patients with baseline clinically significant depression had a progressive lowering in heavy drinking markers significantly corresponding to the lowering of depression symptoms by the end of treatment with Quetiapine fumarate XR.ClinicalTrials.govNCT#0049862 (https://clinicaltrials.gov/ct2/show/NCT00498628?term=litten&draw=2&rank=3)
- Published
- 2020
47. Therapeutic Prospects for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-vitro Evidence and Pharmacokinetic Profile
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Fengyuan Li, Khushboo Gala, Maiying Kong, Wenke Feng, Vijay A. Ramchandani, Craig J. McClain, Xiang Zhang, Shweta Srivastava, Jane Frimodig, and Vatsalya Vatsalya
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business.industry ,Septic shock ,medicine.medical_treatment ,food and beverages ,Pharmacology ,medicine.disease ,Effective dose (pharmacology) ,Proinflammatory cytokine ,Cytokine ,Immune system ,Pharmacokinetics ,medicine ,Thiamine ,Cytokine storm ,business - Abstract
IntroductionEmerging infectious diseases, especially the coronavirus disease identified in 2019 (COVID-19), can be complicated by a severe exacerbation in the Th17 cell-mediated IL-17 proinflammatory immune storm. This enhanced immune response plays a major role in mortality and morbidity, including neurological symptoms. We hypothesized that countering the cytokine storm with thiamine may have therapeutic efficacy in lowering the Th17 cell proinflammatory response. We used anin vitrostudy and corroborated those results in disease controls (DC). We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19.Study Participants and MethodsWe investigated the effect of a three-week 200 mg dose of thiamine in lowering the Th17 response in sixteen DC (proinflammatory origin due to heavy alcohol drinking) patients; and eight healthy control/volunteers (HV) as a pilot clinical-translational investigation. To further investigate, we performed anin vitrostudy evaluating the effectiveness of thiamine treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. In thisin vitrostudy, 100 mg/day equivalent (0.01 µg/ml) thiamine was used. Based on recent publications, we compared the results of the IL-17 response from our clinical andin vitrostudy to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19), including symptoms, and dose ranges of effective and safe administration of thiamine. We developed a dose range and pharmacokinetic profile for thiamine as a novel intervention strategy in COVID-19 to alleviate the effects of the cytokine storm and neurological symptoms.ResultsThe DC group showed significantly elevated proinflammatory cytokines compared to HV. Three-week of 200 mg daily thiamine treatment significantly lowered the baseline IL-17 levels while increased IL-22 levels (anti-inflammatory response). This was validated by anin vitromacrophage response using a lower thiamine dose equivalent (100 mg), which resulted in attenuation of IL-17 and elevation of IL-22 at the mRNA level compared to the ethanol-only treated group. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (which exist in 45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment.DiscussionThe Th17 mediated IL-17 proinflammatory response can potentially be attenuated by thiamine. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the cytokine/immune storm of COVID-19 and the subsequent neurological symptoms observed in COVID-19 patients. Further studies using thiamine as an interventional/prevention strategy in severe COVID-19 patients could identify its precise anti-inflammatory role.
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- 2020
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48. Sensitivity to Experiencing Alcohol Hangovers: Reconsideration of the 0.11% Blood Alcohol Concentration (BAC) Threshold for Having a Hangover
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Verster, Joris C, Kruisselbrink, L Darren, Slot, Karin A, Anogeianaki, Aikaterini, Adams, Sally, Alford, Chris, Arnoldy, Lizanne, Ayre, Elisabeth, Balikji, Stephanie, Benson, Sarah, Bruce, Gillian, Devenney, Lydia E, Frone, Michael R, Gunn, Craig, Heffernan, Thomas, Hensel, Kai O, Hogewoning, Anna, Johnson, Sean J, van Lawick van Pabst, Albertine E, van de Loo, Aurora J A E, Mackus, Marlou, Merlo, Agnese, Murphy, René J L, Owen, Lauren, Palmer, Emily O C, van Rossum, Charmaine J I, Scholey, Andrew, Terpstra, Chantal, Vatsalya, Vatsalya, Vermeulen, Sterre A, van Wijk, Michelle, Stock, Ann-Kathrin, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, dIRAS RA-1, and IRAS OH Toxicology
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hangover ,subjective intoxication ,alcohol ,sensitivity ,blood alcohol concentration - Abstract
The 2010 Alcohol Hangover Research Group consensus paper defined a cutoff blood alcohol concentration (BAC) of 0.11% as a toxicological threshold indicating that sufficient alcohol had been consumed to develop a hangover. The cutoff was based on previous research and applied mostly in studies comprising student samples. Previously, we showed that sensitivity to hangovers depends on (estimated) BAC during acute intoxication, with a greater percentage of drinkers reporting hangovers at higher BAC levels. However, a substantial number of participants also reported hangovers at comparatively lower BAC levels. This calls the suitability of the 0.11% threshold into question. Recent research has shown that subjective intoxication, i.e., the level of severity of reported drunkenness, and not BAC, is the most important determinant of hangover severity. Non-student samples often have a much lower alcohol intake compared to student samples, and overall BACs often remain below 0.11%. Despite these lower BACs, many non-student participants report having a hangover, especially when their subjective intoxication levels are high. This may be the case when alcohol consumption on the drinking occasion that results in a hangover significantly exceeds their "normal" drinking level, irrespective of whether they meet the 0.11% threshold in any of these conditions. Whereas consumers may have relative tolerance to the adverse effects at their "regular" drinking level, considerably higher alcohol intake-irrespective of the absolute amount-may consequentially result in a next-day hangover. Taken together, these findings suggest that the 0.11% threshold value as a criterion for having a hangover should be abandoned.
- Published
- 2020
49. Dysregulation in Plasma ω3 Fatty Acids Concentration and Serum Zinc in Heavy Alcohol-Drinking HCV Patients
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Jane Frimodig, Melanie L. Schwandt, Vatsalya Vatsalya, Ruchita Agrawal, and Shweta Srivastava
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0301 basic medicine ,medicine.medical_specialty ,Article Subject ,Hepatitis C virus ,Alcohol use disorder ,medicine.disease_cause ,Gastroenterology ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Virology ,Internal medicine ,mental disorders ,medicine ,Liver injury ,chemistry.chemical_classification ,business.industry ,medicine.disease ,Eicosapentaenoic acid ,digestive system diseases ,QR1-502 ,030104 developmental biology ,Infectious Diseases ,chemistry ,Zinc deficiency ,030211 gastroenterology & hepatology ,Docosapentaenoic acid ,Liver function ,business ,Polyunsaturated fatty acid - Abstract
Alcohol use disorder (AUD) patients comorbid with hepatitis C virus (HCV) infection (HCV + AUD) could have progressively severe clinical sequels of liver injury and inflammation. Serum zinc and several polyunsaturated fatty acids (PUFAs) get dysregulated in AUD as well as HCV. However, the extent of dysregulation of PUFAs and zinc deficiency and their interaction in HCV + AUD as a comorbid pathology has not been studied. We examined the role of dysregulation of FAs and low zinc in HCV + AUD patients. 138 male and female participants aged 21–67 years were grouped as HCV-only (Gr. 1; n = 13), HCV + AUD (Gr. 2; n = 25), AUD without liver injury (Gr. 3; n = 37), AUD with liver injury (Gr. 4; n = 51), and healthy volunteers (Gr. 5 or HV; n = 12). Drinking history, individual demographic measures, fasting fatty acids, liver function, and zinc were measured and analyzed. HCV + AUD patients showed the highest ALT level compared to the rest of the groups. Serum zinc concentrations were the lowest, and the proinflammatory shift was the highest (characterized by ω6 : ω3 ratio) in the HCV + AUD patients. Total ω3, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA5,3) were the lowest in HCV + AUD patients. Total ω3, α-linoleic acid (α-LA) along with covariable number of drinking days past 90 days (NDD90), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA5,3) independently showed significant association with low zinc in the HCV + AUD patients. Heavy drinking pattern showed that NDD90 has a significant mediating role in the representation of the relationship between candidate ω3 PUFAs and zinc uniquely in the HCV + AUD patients. Low serum zinc showed a distinctively stronger association with total and candidate ω3s in the HCV + AUD patients compared to the patients with HCV or AUD alone, supporting dual mechanism involved in the exacerbation of the proinflammatory response in this comorbid cohort. This trial is registered with NCT#00001673.
- Published
- 2020
50. Positive blood phosphatidylethanol concentration is associated with unfavorable waitlist‐related outcomes for patients medically appropriate for liver transplantation.
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Faulkner, Claire S., White, Collin M., Manatsathit, Wuttiporn, Lamb, Bernadette, Vatsalya, Vatsalya, McClain, Craig J., and Jophlin, Loretta L.
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BIOMARKERS ,ACADEMIC medical centers ,LIVER ,BINGE drinking ,RETROSPECTIVE studies ,TERTIARY care ,TREATMENT effectiveness ,DESCRIPTIVE statistics ,LIVER transplantation ,PHOSPHOLIPIDS ,WOUNDS & injuries - Abstract
Background: Excessive alcohol use is a leading etiology of liver disease and indication for liver transplantation. Accurate measurement of alcohol use remains a challenge in the management of patients in the pre‐, peri‐, and post‐liver transplant settings. Blood 16:0‐18:1 phosphatidylethanol (PEth) concentration is a sensitive and specific biomarker of binge and moderate, chronic alcohol use. As PEth has the longest detection window of available blood‐based direct alcohol biomarkers for moderate to heavy drinking, it shows promise as an indicator of patterns and chronicity of drinking. However, the utility of PEth in clinical liver transplantation is understudied. This study examines the association of PEth results with liver transplantation waitlist‐focused patient outcomes. Methods: Retrospective data for all patients tested for PEth for a one‐year period at a tertiary care medical center with an active liver transplantation program were abstracted. Indications for PEth testing, liver transplantation waitlist‐related outcomes (e.g., listing and delisting) following testing and associations of PEth results with other parameters were analyzed. Results: Over a one‐year period, 153 PEth tests were performed on 109 individuals. The most frequent indications for PEth testing were as an objective indicator of alcohol use patterns (86.3%) and to assess alcohol as a putative etiology of liver injury (13.7%). Of the 109 patients, 56 were medically appropriate for liver transplantation. Medically acceptable candidates with unfavorable transplantation waitlist‐related outcomes (delisting, deferment of transplant evaluation, deferment of listing until completion of recommended alcohol rehabilitation, and being deemed not a transplant candidate) were at least 3.41 times more likely to have a positive PEth test than those with favorable transplantation waitlist‐related outcomes (odds ratio 3.41, confidence interval 3.41 to ∞, p = 0.001). Conclusion: This single‐center study reporting a comprehensive account of PEth utilization at a liver transplant center demonstrates that liver transplantation waitlist‐related outcomes are associated with PEth test results. Patients with positive PEth tests were more likely to have unfavorable transplant waitlist‐related outcomes. PEth testing has not been validated as a predictor of relapse to drinking in post‐transplant patients and because its utility in the pre‐transplant setting is unclear its use could lead to disparities in the selection of patients for liver transplantation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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