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Item Association of liver function markers and apolipoprotein E ε4 with pathogenesis and cognitive decline in Alzheimer's disease(Frontiers Media, 2024-07-24) Han, Sang-Won; Lee, Sang-Hwa; Kim, Jong Ho; Lee, Jae-Jun; Park, Young Ho; Kim, SangYun; Nho, Kwangsik; Sohn, Jong-Hee; Radiology and Imaging Sciences, School of MedicineBackground: Alzheimer's disease (AD) is a complex neurodegenerative disorder influenced by various factors, including liver function, which may impact the clearance of amyloid-β (Aβ) in the brain. This study aimed to explore how the apolipoprotein E (APOE) ε4 allele affects the relationship of liver function markers with AD pathology and cognition. Methods: We analyzed data from two independent cohorts, including 732 participants from the Hallym University Medical Center and 483 from the Alzheimer's Disease Neuroimaging Initiative, each group consisting of individuals with and without the APOE ε4 allele. Cross-sectional analyses evaluated the associations of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, total bilirubin, and albumin) with AD diagnosis, amyloid positron emission tomography (PET) burden, and cerebrospinal fluid biomarkers for AD (Aβ42, total tau, and phosphorylated tau181) at baseline. Longitudinally, we investigated the associations between these liver enzymes and changes in cognitive performance over the course of a year. Logistic and linear regression models were used to analyze these associations and mediation analyses were conducted to assess whether age and amyloid PET burden mediated these associations. Results: Only in the APOE ε4 carrier group, a high AST to ALT ratio and low ALT levels were significantly associated with AD diagnosis, increased amyloid PET burden, and faster longitudinal decline in cognitive function in both cohorts. In particular, the AST to ALT ratio was associated with cerebrospinal fluid Aβ42 levels exclusively in the APOE ε4 carrier group in the Alzheimer's Disease Neuroimaging Initiative cohort but not with phosphorylated tau181 or total tau levels. Moreover, mediation analyses from both cohorts revealed that in the APOE ε4 carriers group, age did not mediate the associations between liver enzymes and AD diagnosis or amyloid PET burden. However, amyloid PET burden partially mediated the association between liver enzymes and AD diagnosis exclusively in the APOE ε4 carriers group. Conclusion: This study provides valuable insights into the significant association of the APOE ε4 allele with liver enzymes and their potential role in Aβ-related pathogenesis and cognition in AD. Further research is required to elucidate the underlying mechanisms and potential therapeutic implications of these findings.Item Association of Serum Liver Enzymes with Brain Amyloidopathy and Cognitive Performance(IOS Press, 2023-12-29) Han, Sang-Won; Lee, Sang-Hwa; Kim, Jong Ho; Lee, Jae-Jun; Park, Young Ho; Kim, SangYun; Nho, Kwangsik; Sohn, Jong-Hee; Radiology and Imaging Sciences, School of MedicineBackground: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles in the brain. Emerging evidence has suggested potential interactions between the brain and periphery, particularly the liver, in regulating Aβ homeostasis. Objective: This study aimed to investigate the association of serum liver enzymes with brain amyloidopathy and cognitive performance in patients with complaints of cognitive decline. Methods: A total of 1,036 patients (mean age 74 years, 66.2% female) with subjective cognitive decline, mild cognitive impairment, AD dementia, and other neurodegenerative diseases were included using the Smart Clinical Data Warehouse. Amyloid positron emission tomography (PET) imaging, comprehensive neuropsychological evaluations, and measurements of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, and albumin, were assessed. After propensity score matching, logistic and linear regression analyses were used to investigate the associations between liver enzymes, amyloid status, and cognitive performance. Additionally, a machine learning approach was used to assess the classification performance of liver enzymes in predicting amyloid PET positivity. Results: Lower ALT levels and higher AST-to-ALT ratios were significantly associated with amyloid PET positivity and AD diagnosis. The AST-to-ALT ratio was also significantly associated with poor memory function. Machine learning analysis revealed that the classification performance of amyloid status (AUC = 0.642) for age, sex, and apolipoprotein E ɛ4 carrier status significantly improved by 6.2% by integrating the AST-to-ALT ratio. Conclusions: These findings highlight the potential association of liver function on AD and its potential as a diagnostic and therapeutic implications.Item Hepatitis B Virus Reactivation in Cancer Patients Receiving Direct-Acting Antivirals for Hepatitis C Virus Infection(Wiley, 2021) Pritchard, Haley; Hwang, Jessica P.; Angelidakis, Georgios; Yibirin, Marcel; Wang, Lan; Miller, Ethan; Torres, Harrys A.; Medicine, School of MedicineDirect-acting antivirals (DAAs) against hepatitis C virus (HCV) infection can cause hepatitis B virus (HBV) reactivation in HBV/HCV co-infected patients. Cancer patients undergoing immunosuppressant treatment or chemotherapy are at risk for HBV reactivation. To our knowledge, no prospective studies have examined the risk of HBV reactivation during DAA treatment for HCV infection in cancer patients with HBV/HCV co-infection. Here, we report the results of one such study. In a prospective observational study, we enrolled HCV-infected cancer patients undergoing DAA treatment at The University of Texas MD Anderson Cancer Center between January 2015 and March 2018. Data regarding demographics, cancer history, and prior HCV treatment history were collected. Patients were assessed for HBV status before DAA treatment and for HBV-related outcomes, including HBV reactivation, hepatitis flare, and HBV-associated hepatitis, during DAA treatment. Demographic and treatment variables were analyzed using descriptive statistics. One hundred sixty-six patients were analyzed. Forty-eight patients received systemic chemotherapy within 6 months before to 6 months after treatment with DAAs. Ledipasvir plus sofosbuvir was the most common DAA regimen, administered to 88 patients (53%). Fifty-one patients (31%) had past HBV infection, and 4 (2.4%) had chronic HBV infection. No patient experienced HBV reactivation, hepatitis flare, or HBV-associated hepatitis induced by DAA treatment. In HCV-infected cancer patients, DAA treatment is safe regardless of whether patients have past or chronic HBV infection. However, HBV screening is still recommended before the initiation of and during DAA treatment, as is anti-HBV prophylactic treatment in selected cases.Item Neonatal Graves Disease Masquerading as Hemochromatosis(Oxford University Press, 2024-07-24) Maggiotto, Liesbeth; Mittelman, Steven D.; Fallah, Roja; Pediatrics, School of MedicineThyroid autoimmunity is extremely common in the adult population and can affect pregnancy outcomes. Signs in the newborn can range from absent to severe, making the diagnosis easy to miss. We present an interesting case of neonatal Graves disease associated with intrauterine growth restriction, premature delivery, and liver failure with severely high ferritin, thought to be secondary to hemochromatosis. Treatment of the underlying hyperthyroidism caused a rapid resolution of the elevated ferritin and liver failure. This report highlights the importance of considering Graves disease in newborns with liver failure of unknown etiology.Item The utility of commonly used laboratory tests to screen for excessive alcohol use in clinical practice(Wiley, 2015-08) Gough, Gina; Heathers, Laura; Puckett, Deonna; Westerhold, Chi; Ren, Xiaowei; Yu, Zhangsheng; Crabb, David W.; Liangpunsakul, Suthat; Department of Medicine, IU School of MedicineBACKGROUND: This current study was undertaken to carefully assess the accuracy of routinely used laboratory tests in detecting excessive/recent alcohol use. We also determined the kinetics of these markers in subjects who underwent an intensive alcohol rehabilitation program. METHODS: The study cohort consisted of 210 nonexcessive drinkers, 272 excessive drinkers, and 76 with alcoholic cirrhosis. To determine the kinetics of these markers during alcohol abstinence, we followed 45 subjects with history of excessive alcohol use for 12 weeks during the intensive alcohol treatment program. RESULTS: Percentage of carbohydrate deficient transferrin (%CDT) provided the highest diagnostic performance (area under the curve [AUC] 0.77) followed by gamma-glutamyl transferase (GGT) (AUC 0.68) to detect excessive drinkers. The percentage of excessive drinkers with aspartate aminotransferase:alanine aminotransferase (AST:ALT) > 2 was only 2%, whereas 51% of subjects with alcoholic cirrhosis had AST:ALT > 2. In the multivariate analysis, the levels of GGT and %CDT were associated with the level of alcohol consumed during the past 30 days. The levels of GGT, mean corpuscular volume (MCV), and %CDT were significantly lower compared to those at baseline before alcohol rehabilitation, whereas the AST, ALT, and AST:ALT ratio were unchanged. The percent reduction was ~2.7% (for MCV), 19% (for GGT), and 43% (for %CDT) at the end of the 12-week follow-up compared to the baseline. CONCLUSIONS: %CDT are useful markers to screen for excessive alcohol use and for follow-up of abstinence. Most subjects with excessive alcohol use do not have a high AST:ALT ratio. Rather, the AST:ALT > 2 is suggestive of alcoholic cirrhosis. The performance of the %CDT to screen for heavy alcohol use is still not ideal. Further research to identify the noninvasive marker(s) (i.e., using proteomic or metabolomics approach) should be considered.