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Soni JR, Marrapu S, Kumar R. Hypochloremia is an underutilised prognostic marker in patients with advanced liver cirrhosis and liver failure. World J Hepatol 2025; 17:103807. [DOI: 10.4254/wjh.v17.i3.103807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/16/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
Patients with advanced liver cirrhosis and liver failure frequently experience abnormalities in their serum electrolyte levels. In such patients, hyponatremia has been identified as a predictor of poor outcomes. However, emerging evidence suggests that serum chloride may provide even better prognostic information in similar situations. Hypochloremia, characterised by low serum chloride levels, has been linked to increased mortality, exacerbated organ dysfunction, and higher requirements for renal replacement therapy and vasopressors in various critical conditions, including advanced liver diseases. The pathophysiological mechanisms underlying the association between low serum chloride levels and poor outcomes in liver disease appear to involve complex interactions among electrolyte imbalances, renal function, and systemic hemodynamics. Chloride dysregulation can influence renal salt-sensing mechanisms, disrupt acid-base homeostasis, and exacerbate complications such as hepatic encephalopathy and hepatorenal syndrome. This article aims to elucidate the prognostic significance of lower serum chloride levels in patients with advanced liver disease. By reviewing recent literature and analysing clinical data, we seek to establish serum chloride as an underutilised but valuable prognostic marker. Understanding the role of serum chloride in liver disease could enhance prognostic accuracy, refine treatment strategies, and ultimately improve patient outcomes.
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Affiliation(s)
- Jinit R Soni
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sudheer Marrapu
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Torre A, Córdova-Gallardo J, Martínez-Sánchez FD. Hepatic encephalopathy: risk identification and prophylaxis approaches. Metab Brain Dis 2025; 40:138. [PMID: 40053146 DOI: 10.1007/s11011-025-01531-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/08/2025] [Indexed: 03/26/2025]
Abstract
Hepatic encephalopathy (HE) is a debilitating neurological condition associated with cirrhosis, characterized by cognitive impairment ranging from minimal to overt symptoms. It significantly impacts patients' quality of life and substantially burdens healthcare systems. This review examines current prophylactic strategies for HE, focusing on established treatments, emerging therapies, and predictive tools to identify high-risk patients. Traditional treatments such as lactulose and rifaximin remain the cornerstone of HE management, effectively reducing ammonia levels and preventing recurrence. However, novel approaches like L-ornithine L-aspartate, albumin infusions, and antioxidants like resveratrol show promise in further improving outcomes by addressing underlying pathophysiological mechanisms, including systemic inflammation and gut dysbiosis. Developing predictive models, such as the AMMON-OHE score and clinical-genetic risk assessments, enhances the ability to tailor preventive interventions to individual patient profiles. These advancements are crucial in mitigating the incidence of overt HE, reducing hospital admissions, and improving patient survival rates. The future of HE management lies in personalized medicine, targeting specific inflammatory and metabolic pathways, with the potential integration of genetic manipulation. Continued research is essential to refine these strategies, ultimately aiming to improve the prognosis and quality of life for cirrhotic patients at risk of HE.
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Affiliation(s)
- Aldo Torre
- Metabolic Unit, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubiran", Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, Ciudad de México, 14080, Mexico.
- Department of Gastroenterology, Medical Center ABC, Sur 136 116, Las Américas, Álvaro Obregón, 01120, Ciudad de México, Mexico.
| | - Jacqueline Córdova-Gallardo
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Escolar 411A, Copilco Universidad, Coyoacán, Ciudad de México, 04360, Mexico.
- Department of Hepatology, Hospital General "Dr. Manuel Gea González", Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, Ciudad de México, 14080, Mexico.
| | - Froylan David Martínez-Sánchez
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Escolar 411A, Copilco Universidad, Coyoacán, Ciudad de México, 04360, Mexico
- Department of Internal Medicine, Hospital General "Dr. Manuel Gea González", 14080 Mexico City, Mexico. Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080, Ciudad de México, Mexico
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Wang J, Chen X, Qin C, Shi R, Huang Y, Gong J, Zeng X, Wang D. Lactate-to-albumin ratio as a potential prognostic predictor in patients with cirrhosis and sepsis: a retrospective cohort study. BMC Infect Dis 2025; 25:223. [PMID: 39953385 PMCID: PMC11829571 DOI: 10.1186/s12879-025-10601-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/04/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Patients with liver cirrhosis face high infection risks due to immune dysfunction and hospital-related factors, increasing mortality rates when sepsis occurs. While various biomarkers predict outcomes in cirrhosis, few are accessible and reliable. This study addresses the gap by evaluating the prognostic potential of the lactate-to-albumin ratio (LAR). METHODS We retrospectively analyzed data from patients with cirrhosis and sepsis who were admitted to the intensive care unit at Beth Israel Deaconess Medical Center between 2008 and 2022. LAR was calculated from the ratio obtained from the first measurement taken within 24 h of admission. The optimal LAR threshold was determined using R statistical software. Kaplan-Meier analysis was used to compare mortality risks between two patient groups, while multivariate Cox proportional hazards regression models were used to assess the association between LAR and mortality risk in patients with cirrhosis and concomitant sepsis. A restricted cubic spline (RCS) was used to explore potential dose-response relationships between LAR and mortality. Receiver operating characteristic (ROC) analyses were used to assess the predictive ability, sensitivity, and specificity of LAR for all-cause mortality in patients with cirrhosis and combined sepsis, and the area under the curve (AUC) was calculated. Finally, subgroup analyses were performed to assess the relationship between LAR and prognosis across different populations. RESULTS A total of 1731 patients were included in the study. The optimal LAR threshold was identified as 1.0 using R statistical software. Kaplan-Meier analysis indicated that patients with higher LAR levels had a higher risk of 14-day, 28-day, and 90-day all-cause mortality (all log-rank P < 0.001). Multivariate Cox proportional hazards models indicated independent associations between higher LAR levels and all-cause mortality at 14-day, 28-day, and 90-day before and after adjusting for confounders. RCS analysis revealed a nonlinear association between LAR and short- and long-term all-cause mortality in patients with cirrhosis and sepsis. ROC curve analysis showed that although the predictive value of LAR for the prognosis of patients with cirrhosis combined with sepsis was slightly inferior to that of the Model for End-Stage Liver Disease score, it was significantly better than that of lactate, albumin, and the Sequential Organ Failure Assessment. Subgroup analyses showed no significant interactions between LAR and any specific subgroup. CONCLUSION LAR has good predictive value for the prognosis of patients with cirrhosis and sepsis.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xi Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Chuan Qin
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Ruizi Shi
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Yu Huang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Jianping Gong
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
| | - Decai Wang
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
- Department of Urology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
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Wang J, Yang P, Zeng X, Chen S, Chen X, Deng L, Shi R, Qin C, Luo H, Gong J, Luo H, Wang D. Prognostic significance of albumin corrected anion gap in patients with acute pancreatitis: a novel perspective. Sci Rep 2025; 15:1318. [PMID: 39779808 PMCID: PMC11711654 DOI: 10.1038/s41598-025-85773-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 01/06/2025] [Indexed: 01/11/2025] Open
Abstract
This study aims to explore the relationship between the albumin-corrected anion gap (ACAG) and short- and long-term all-cause mortality (ACM) in patients with acute pancreatitis (AP) managed in the intensive care unit (ICU). We conducted a retrospective analysis utilizing data extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. This study sought to investigate the correlation between ACAG and ACM among patients diagnosed with AP across various disease stages. R statistical software was used to identify the optimal thresholds for ACAG. Kaplan-Meier survival curves and multivariate Cox proportional hazards regression models were employed to assess the association between ACAG and short- and long-term ACM of AP. The predictive ability, sensitivity, specificity, and area under the curve (AUC) of ACAG for short- and long-term ACM in AP were investigated using receiver operating characteristic analysis. Subgroup analyses were also conducted. A cohort comprising 605 participants was included in this study. The ideal threshold for ACAG identified by R statistical software was 21.5. Cox proportional hazards modeling revealed that there was an independent association between patients with AP with ACAG ≥ 21.5 and ACM at 3, 7, 10, 14, 28, 90, and 180 days and 1 year before and after adjustment for confounders. Survival curves demonstrated that patients with ACAG ≥ 21.5 had lower survival rates at 3, 7, 10, 14, 28, 90, and 180 days and 1 year. In addition, ACAG showed superior performance, with a larger AUC than the anion gap, albumin, and Systemic Inflammatory Response Syndrome score and Sequential Organ Failure Assessment at 3, 7, 10, 14, 28, 90, and 180 days and 1 year. Subgroup analysis revealed no significant interaction between ACAG and any subgroups Elevated levels of ACAG were found to be associated with increased short- and long-term ACM in patients with AP, and ACAG may be an independent predictor of ACM at different disease stages.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Pei Yang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Sirui Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xi Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Lan Deng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Ruizi Shi
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Chuan Qin
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Huiwen Luo
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Hua Luo
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
| | - Decai Wang
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
- Department of Urology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
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Gatz AE, Xiong C, Chen Y, Jiang S, Nguyen CM, Song Q, Li X, Zhang P, Eadon MT, Su J. Health disparities in the risk of severe acidosis: real-world evidence from the All of Us cohort. J Am Med Inform Assoc 2024; 31:2932-2939. [PMID: 39401251 PMCID: PMC11631078 DOI: 10.1093/jamia/ocae256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 09/11/2024] [Accepted: 10/09/2024] [Indexed: 12/12/2024] Open
Abstract
OBJECTIVE To assess the health disparities across social determinants of health (SDoH) domains for the risk of severe acidosis independent of demographical and clinical factors. MATERIALS AND METHODS A retrospective case-control study (n = 13 310, 1:4 matching) is performed using electronic health records (EHRs), SDoH surveys, and genomics data from the All of Us participants. The propensity score matching controls confounding effects due to EHR data availability. Conditional logistic regressions are used to estimate odds ratios describing associations between SDoHs and the risk of acidosis events, adjusted for demographic features, and clinical conditions. RESULTS Those with employer-provided insurance and those with Medicaid plans show dramatically different risks [adjusted odds ratio (AOR): 0.761 vs 1.41]. Low-income groups demonstrate higher risk (household income less than $25k, AOR: 1.3-1.57) than high-income groups ($100-$200k, AOR: 0.597-0.867). Other high-risk factors include impaired mobility (AOR: 1.32), unemployment (AOR: 1.32), renters (AOR: 1.41), other non-house-owners (AOR: 1.7), and house instability (AOR: 1.25). Education was negatively associated with acidosis risk. DISCUSSION Our work provides real-world evidence of the comprehensive health disparities due to socioeconomic and behavioral contributors in a cohort enriched in minority groups or underrepresented populations. CONCLUSIONS SDoHs are strongly associated with systematic health disparities in the risk of severe metabolic acidosis. Types of health insurance, household income levels, housing status and stability, employment status, educational level, and mobility disability play significant roles after being adjusted for demographic features and clinical conditions. Comprehensive solutions are needed to improve equity in healthcare and reduce the risk of severe acidosis.
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Affiliation(s)
- Allison E Gatz
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Chenxi Xiong
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Department of Computer and Information Technology, Purdue University, West Lafayette, IN 47907, United States
| | - Yao Chen
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Shihui Jiang
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Chi Mai Nguyen
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Qianqian Song
- Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL 32608, United States
| | - Xiaochun Li
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Pengyue Zhang
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Michael T Eadon
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jing Su
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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Oyelade T, Moore KP, Mani AR. Application of physiological network mapping in the prediction of survival in critically ill patients with acute liver failure. Sci Rep 2024; 14:23571. [PMID: 39384597 PMCID: PMC11464518 DOI: 10.1038/s41598-024-74351-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 09/25/2024] [Indexed: 10/11/2024] Open
Abstract
Reduced functional connectivity of physiological systems is associated with poor prognosis in critically ill patients. However, physiological network analysis is not commonly used in clinical practice and awaits quantitative evidence. Acute liver failure (ALF) is associated with multiorgan failure and mortality. Prognostication in ALF is highly important for clinical management but is currently dependent on models that do not consider the interaction between organ systems. This study aims to examine whether physiological network analysis can predict survival in patients with ALF. Data from 640 adult patients admitted to the ICU for paracetamol-induced ALF were extracted from the MIMIC-III database. Parenclitic network analysis was performed on the routine biomarkers using 28-day survivors as reference population and network clusters were identified for survivors and non-survivors using k-clique percolation method. Network analysis showed that liver function biomarkers were more clustered in survivors than in non-survivors. Arterial pH was also found to cluster with serum creatinine and bicarbonate in survivors compared with non-survivors, where it clustered with respiratory nodes indicating physiologically distinctive compensatory mechanism. Deviation along the pH-bicarbonate and pH-creatinine axes significantly predicts mortality independent of current prognostic indicators. These results demonstrate that network analysis can provide pathophysiologic insight and predict survival in critically ill patients with ALF.
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Affiliation(s)
- Tope Oyelade
- Division of Medicine, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
- Network Physiology Laboratory, Division of Medicine, UCL, London, UK
| | - Kevin P Moore
- Division of Medicine, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Ali R Mani
- Division of Medicine, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
- Network Physiology Laboratory, Division of Medicine, UCL, London, UK.
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Pan Z, Lin J, Huo C, Yin D, Guo Q. Increased serum albumin corrected anion gap levels are associated with poor prognosis in septic patients with liver cirrhosis. Sci Rep 2024; 14:21510. [PMID: 39277682 PMCID: PMC11401841 DOI: 10.1038/s41598-024-72703-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024] Open
Abstract
The prognosis of septic patients with cirrhosis is worse compared to septic patients without cirrhosis. Early and accurate prognosis determination in patients with cirrhosis and sepsis is pivotal for guiding treatment decisions. The aim of this study was to investigate the association between albumin-corrected anion gap (ACAG) and clinical prognosis of patients with sepsis and cirrhosis. This study extracted data of patients with sepsis and cirrhosis from the Medical Information Mart for Intensive Care (MIMIC-IV) database. A total of 1340 patients (64.6% male) were enrolled. After confounders adjusting, elevated ACAG had a significant association with 28-day mortality (HR1.604; 95% CI 1.258-2.048; P < 0.001). Restricted cubic spline revealed that a linear relationship between ACAG and 28-day mortality (P-nonlinear = 0.089, P-overall = 0.001). According to the ROC curve analysis, the ACAG demonstrated a higher area under the curve (AUC) of 0.703 compared to AG (0.675). Kaplan-Meier analysis revealed higher 28-day mortality in high ACAG group (log-rank test, χ^2 = 175.638, P < 0.001). Furthermore, subgroup analysis showed a significant interaction between ACAG and etiology of cirrhosis (P for interaction = 0.014). Therefore, ACAG could provide clinicians with valuable insights for guiding interventions in this high-risk population.
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Affiliation(s)
- Zetao Pan
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, China
| | - Jiancheng Lin
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, China
| | - Cunyang Huo
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, China
| | - Di Yin
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, China
| | - Qiang Guo
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, China.
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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Yao S, Chai H, Tao T, Zhang L, Yang X, Li X, Yi Z, Wang Y, An J, Wen G, Jin H, Tuo B. Role of lactate and lactate metabolism in liver diseases (Review). Int J Mol Med 2024; 54:59. [PMID: 38785162 PMCID: PMC11188982 DOI: 10.3892/ijmm.2024.5383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/22/2024] [Indexed: 05/25/2024] Open
Abstract
Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a post‑translational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolism‑related genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, non‑alcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.
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Affiliation(s)
- Shun Yao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hongyu Chai
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Ting Tao
- Department of Burns and Plastic Surgery, Fuling Hospital, Chongqing University, Chongqing 408099, P.R. China
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xingyue Yang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xin Li
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Zhiqiang Yi
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Yongfeng Wang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jiaxin An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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Amiri M, Jiang M, Salari A, Xiu R, Alper SL, Seidler UE. Reduced surface pH and upregulated AE2 anion exchange in SLC26A3-deleted polarized intestinal epithelial cells. Am J Physiol Cell Physiol 2024; 326:C829-C842. [PMID: 38223928 PMCID: PMC11193482 DOI: 10.1152/ajpcell.00590.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/21/2023] [Accepted: 01/02/2024] [Indexed: 01/16/2024]
Abstract
Loss of function mutations in the SLC26A3 gene cause chloride-losing diarrhea in mice and humans. Although systemic adaptive changes have been documented in these patients and in the corresponding knockout mice, how colonic enterocytes adapt to loss of this highly expressed and highly regulated luminal membrane anion exchanger remains unclear. To address this question, SLC26A3 was deleted in the self-differentiating Caco2BBe colonic cell line by the CRISPR/Cas9 technique. We selected a clone with loss of SLC26A3 protein expression and morphological features indistinguishable from those of the native cell line. Neither growth curves nor development of transepithelial electrical resistance (TEER) differed between wild-type (WT) and SLC26A3 knockout (KO) cells. Real-time qPCR and Western analysis in SLC26A3-KO cells revealed an increase in AE2 expression without significant change in NHE3 expression or localization. Steady-state pHi and apical and basolateral Cl-/HCO3- exchange activities were assessed fluorometrically in a dual perfusion chamber with independent perfusion of luminal and serosal baths. Apical Cl-/HCO3- exchange rates were strongly reduced in SLC26A3-KO cells, accompanied by a surface pH more acidic than that of WT cells. Steady-state pHi was not significantly different from that of WT cells, but basolateral Cl-/HCO3- exchange rates were higher in SLC26A3-KO than in WT cells. The data show that CRISPR/Cas9-mediated SLC26A3 deletion strongly reduced apical Cl-/HCO3- exchange rate and apical surface pH, but sustained a normal steady-state pHi due to increased expression and function of basolateral AE2. The low apical surface pH resulted in functional inhibition of NHE-mediated fluid absorption despite normal expression of NHE3 polypeptide.NEW & NOTEWORTHY SLC26A3 gene mutations cause chloride-losing diarrhea. To understand how colonic enterocytes adapt, SLC26A3 was deleted in Caco2BBe cells using CRISPR/Cas9. In comparison to the wild-type cells, SLC26A3 knockout cells showed similar growth and transepithelial resistance but substantially reduced apical Cl-/HCO3- exchange rates, and an acidic surface pH. Steady-state intracellular pH was comparable between the WT and KO cells due to increased basolateral AE2 expression and function.
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Affiliation(s)
- Mahdi Amiri
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Min Jiang
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Azam Salari
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Renjie Xiu
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Seth L Alper
- Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States
| | - Ursula E Seidler
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
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10
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Vaishnav B, Barla DR, Ruchitha P, Wadivkar AN, Tonde T, Mondkar S. Pulmonary Dysfunction in Patients with Cirrhosis of the Liver: A Study of Pulmonary Function Tests and Arterial Blood Gases. Int J Appl Basic Med Res 2024; 14:48-53. [PMID: 38504842 PMCID: PMC10947758 DOI: 10.4103/ijabmr.ijabmr_367_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 12/18/2023] [Accepted: 01/10/2024] [Indexed: 03/21/2024] Open
Abstract
Background and Aim Respiratory complications in liver cirrhosis can occur due to various mechanisms, such as ascites causing restricted lung expansion and opening of intrapulmonary vascular shunts due to high portal pressures. We aimed to study the effects of the liver dysfunction on the lungs by evaluating arterial blood gas (ABG) and pulmonary function test (PFT) of all study subjects. Subjects and Methods A cross-sectional study was done between August 2020 and September 2022. Diagnosed cases of the liver cirrhosis were enrolled in the study after informed consent and were subjected to the following investigations: chest X-ray, oximetry, spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), two-dimensional echocardiography, and ABG analysis (ABGA). The cases were divided into three groups based on their Child-Pugh staging, and statistical analysis was done on the collected data. Results A total of 64 (53 males and 11 females) patients with an average age of 49.82 ± 9.89 years were studied. Alcoholism was the most common cause of cirrhosis in males. Breathlessness (65.6%) and pleural effusion (26.6%) were the most common respiratory symptoms and signs, respectively. Seventeen patients had hepatic hydrothorax, eight patients had hepatopulmonary syndrome (HPS), and six patients had portopulmonary hypertension. Low pH (17.2%) and oxygen partial pressure (PaO2) (20.3%) were the most common ABGA findings. The pH, PaO2, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), and DLCO were significantly low in Child Pugh Stage C (P < 0.05). The pH, pO2, HCO3, FEV1, FVC, FEV1/FVC, and DLCO were significantly lower in patients with HPS (P < 0.05). Conclusion Metabolic acidosis and low FEV1/FVC and DLCO were the common findings in study subjects. Pulmonary dysfunction was common in advanced liver cirrhosis. Patients with HPS had worse ABG and PFT parameters than those without HPS.
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Affiliation(s)
- Bhumika Vaishnav
- Department of Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India
| | - Dasaradha Ramu Barla
- Department of Medicine, Gitam Institute of Medical Sciences and Research, Visakhapatnam, Andhra Pradesh, India
| | - Pailla Ruchitha
- Department of Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India
| | - Aniruddh N. Wadivkar
- Department of Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India
| | - Tushar Tonde
- Department of Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India
| | - Saish Mondkar
- Department of Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India
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11
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Lukomskyj AO, Partyka CL. Severe Multifactorial Metabolic Alkalosis in the Emergency Department: A Case Report. J Emerg Med 2024; 66:e33-e37. [PMID: 37867035 DOI: 10.1016/j.jemermed.2023.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/14/2023] [Accepted: 08/10/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND Metabolic alkalosis is an uncommon clinical entity resulting from a wide variety of underlying etiologies including gastrointestinal, renal, endocrine, and metabolic causes. It is a typically clinically silent condition; however, severe cases can be life-threatening, mandating both a systematic investigative approach and an early aggressive management strategy. CASE REPORT We present a case of a 58-year-old man with severe, multifactorial metabolic alkalosis (pH 7.72, HCO3- 42 mmol/L, pCO2 31 mm Hg) resulting from refractory vomiting, severe hypokalemia (2.0 mmol/L), and hypoalbuminemia (albumin 20 g/L). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Severe metabolic alkalosis is associated with significant morbidity and mortality. Clinicians need to be aware of the potential underlying causes in these cases, as well as how to delineate between chloride- and non-chloride-depleted states, which dictates initial treatment. We provide a pragmatic summary of the evaluation, pertinent investigations, and early management of these cases.
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Affiliation(s)
- Alissa O Lukomskyj
- Emergency Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Christopher L Partyka
- Emergency Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Aeromedical Operations, NSW Ambulance, Bankstown Airport, New South Wales, Australia
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12
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Kim Y, Kwon S, Kim SG, Lee J, Han CH, Yu S, Kim B, Paek JH, Park WY, Jin K, Han S, Kim DK, Lim CS, Kim YS, Lee JP. Impact of decreased levels of total CO2 on in-hospital mortality in patients with COVID-19. Sci Rep 2023; 13:16717. [PMID: 37794030 PMCID: PMC10550989 DOI: 10.1038/s41598-023-41988-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 09/04/2023] [Indexed: 10/06/2023] Open
Abstract
Decreased total CO2 (tCO2) is significantly associated with all-cause mortality in critically ill patients. Because of a lack of data to evaluate the impact of tCO2 in patients with COVID-19, we assessed the impact of tCO2 on all-cause mortality in this study. We retrospectively reviewed the data of hospitalized patients with COVID-19 in two Korean referral hospitals between February 2020 and September 2021. The primary outcome was in-hospital mortality. We assessed the impact of tCO2 as a continuous variable on mortality using the Cox-proportional hazard model. In addition, we evaluated the relative factors associated with tCO2 ≤ 22 mmol/L using logistic regression analysis. In 4,423 patients included, the mean tCO2 was 24.8 ± 3.0 mmol/L, and 17.9% of patients with tCO2 ≤ 22 mmol/L. An increase in mmol/L of tCO2 decreased the risk of all-cause mortality by 4.8% after adjustment for age, sex, comorbidities, and laboratory values. Based on 22 mmol/L of tCO2, the risk of mortality was 1.7 times higher than that in patients with lower tCO2. This result was maintained in the analysis using a cutoff value of tCO2 24 mmol/L. Higher white blood cell count; lower hemoglobin, serum calcium, and eGFR; and higher uric acid, and aspartate aminotransferase were significantly associated with a tCO2 value ≤ 22 mmol/L. Decreased tCO2 significantly increased the risk of all-cause mortality in patients with COVID-19. Monitoring of tCO2 could be a good indicator to predict prognosis and it needs to be appropriately managed in patients with specific conditions.
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Affiliation(s)
- Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Soie Kwon
- Department of Internal Medicine, Chung-Ang University Heukseok Hospital, Seoul, Korea
| | - Seong Geun Kim
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Jeonghwan Lee
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Chung-Hee Han
- Department of Obstetrics and Gynecology, Bagae Hospital, Pyeongtaek, Gyeonggi-Do, Korea
| | - Sungbong Yu
- Department of General Surgery, Bagae Hospital, Pyeongtaek, Gyeonggi-Do, Korea
| | - Byunggun Kim
- Department of Orthopedic Surgery, Bagae Hospital, Pyeongtaek, Gyeonggi-Do, Korea
| | - Jin Hyuk Paek
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Woo Yeong Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Kyubok Jin
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
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13
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Kou Y, Yang Y, Du S, Liu X, He K, Yuan W, Nie B. Risk factors for the development of sepsis in patients with cirrhosis in intensive care units. Clin Transl Sci 2023; 16:1748-1757. [PMID: 37226657 PMCID: PMC10582674 DOI: 10.1111/cts.13549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/28/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
Sepsis is a serious complication of liver cirrhosis. This study aimed to develop a risk prediction model for sepsis among patients with liver cirrhosis. A total of 3130 patients with liver cirrhosis were enrolled from the Medical Information Mart for Intensive Care IV database, and randomly assigned into training and validation cohorts in a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) regression was used to filter variables and select predictor variables. Multivariate logistic regression was used to establish the prediction model. Based on LASSO and multivariate logistic regression, gender, base excess, bicarbonate, white blood cells, potassium, fibrinogen, systolic blood pressure, mechanical ventilation, and vasopressor use were identified as independent risk variables, and then a nomogram was constructed and validated. The consistency index (C-index), receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA) were used to measure the predictive performance of the nomogram. As a result of the nomogram, good discrimination was achieved, with C-indexes of 0.814 and 0.828 for the training and validation cohorts, respectively, and an area under the curve of 0.849 in the training cohort and 0.821 in the validation cohort. The calibration curves demonstrated good agreement between the predictions and observations. The DCA curves showed the nomogram had significant clinical value. We developed and validated a risk-prediction model for sepsis in patients with liver cirrhosis. This model can assist clinicians in the early detection and prevention of sepsis in patients with liver cirrhosis.
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Affiliation(s)
- Yan‐qi Kou
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
| | - Yu‐ping Yang
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical UniversityGuangdong Medical UniversityZhanjiangChina
| | - Shen‐shen Du
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
| | - Xiongxiu Liu
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
| | - Kun He
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
| | - Wei‐nan Yuan
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
| | - Biao Nie
- Department of GastroenterologyThe First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhouChina
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14
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Serrano-Morillas N, González-Alayón C, Vastola-Mascolo A, Rodríguez-Rodríguez AE, Hernández G, Porrini E, Hernández-Guerra M, Alvarez de la Rosa D. Decaying kidney function during cirrhosis correlates with remodeling of distal colon aldosterone target gene expression. Am J Physiol Gastrointest Liver Physiol 2023; 325:G306-G317. [PMID: 37461846 DOI: 10.1152/ajpgi.00073.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/21/2023] [Accepted: 07/12/2023] [Indexed: 08/03/2023]
Abstract
Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K+ and Na+ homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K+ excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or patients with cirrhosis with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na+ channel β and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Patients with cirrhosis showed increased expression of 11-β-hydroxysteroid-dehydrogenase 2 (11βHSD2), which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. In summary, our data show that decaying kidney function during cirrhosis progression toward a decompensated state with hypovolemia correlates with remodeling of distal colon ion transporter expression, supporting a role for aldosterone in the process.NEW & NOTEWORTHY Liver cirrhosis progression significantly alters ion transporter subunit expression in the rat distal colon, a change that correlated well with declining kidney function and the severity of the disease. Our data suggest that the steroid hormone aldosterone participates in this homeostatic response to maintain electrolyte balance.
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Affiliation(s)
- Natalia Serrano-Morillas
- Departamento de Ciencias Médicas Básicas, Universidad de La Laguna, La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
| | | | - Arianna Vastola-Mascolo
- Departamento de Ciencias Médicas Básicas, Universidad de La Laguna, La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
| | - Ana E Rodríguez-Rodríguez
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
- Research Unit, Hospital Universitario de Canarias, La Laguna, Spain
| | - Guadalberto Hernández
- Departamento de Ciencias Médicas Básicas, Universidad de La Laguna, La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
| | - Esteban Porrini
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
- Research Unit, Hospital Universitario de Canarias, La Laguna, Spain
| | - Manuel Hernández-Guerra
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
- Research Unit, Hospital Universitario de Canarias, La Laguna, Spain
- Servicio de Aparato Digestivo, Hospital Universitario de Canarias, La Laguna, Spain
| | - Diego Alvarez de la Rosa
- Departamento de Ciencias Médicas Básicas, Universidad de La Laguna, La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain
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15
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Ito J, Lemus H, Wu T. Serum Phosphorus, Serum Bicarbonate, and Renal Function in Relation to Liver CYP1A2 Activity. Diagnostics (Basel) 2023; 13:2996. [PMID: 37761363 PMCID: PMC10529210 DOI: 10.3390/diagnostics13182996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
The liver plays an important role in normal metabolism and physiological functions such as acid-base balance; however, limited epidemiologic studies have investigated how the liver contributes toward acid-base balance using non-invasive biomarkers. We determined associations between serum biomarkers related to acid-base balance and renal function with liver CYP1A2 activity. We used data from 1381 participants of the 2009-2010 National Health and Nutrition Examination Survey (NHANES) with measurements of serum phosphorus, serum bicarbonate, caffeine intake, caffeine metabolites, and estimated glomerular filtration rate (eGFR). Liver CYP1A2 activity was estimated using urine caffeine metabolite indices, which were calculated as the ratio of one of the urine caffeine metabolites (i.e., paraxanthine and 1-methyluric acid) to caffeine intake. We analyzed associations in the whole data set and in different strata of hepatic steatosis index (HSI) based on different cut-points. We found that serum bicarbonate was positively associated with CYP1A2 activity in the whole data set when comparing persons with bicarbonate at Q4 to Q1 (β = 0.18, p = 0.10 for paraxanthine; β = 0.20, p = 0.02 for 1-methyluric acid). Furthermore, serum phosphorus was positively associated with CYP1A2 activity only in the stratum of 30 ≤ HSI < 36. Lastly, low eGFR was significantly associated with lower CYP1A2 activity measured with paraxanthine in the whole dataset and in all the strata with HSI < 42; when comparing eGFR < 60 to eGFR > 90, β estimates ranged from -0.41 to -1.38, p-values ranged from 0.0018 to 0.004. We observed an opposite trend in the highest stratum (HSI ≥ 42). Non-invasive measurements of serum bicarbonate, serum phosphorus, and eGFR have dynamic associations with CYP1A2 activity. These associations depend on the extent of liver damage and the caffeine metabolite used to assess CYP1A2 activity.
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Affiliation(s)
- Joy Ito
- Division of Epidemiology and Biostatistics, School of Public Health, San Diego State University, San Diego, CA 92182, USA; (J.I.); (H.L.)
| | - Hector Lemus
- Division of Epidemiology and Biostatistics, School of Public Health, San Diego State University, San Diego, CA 92182, USA; (J.I.); (H.L.)
| | - Tianying Wu
- Division of Epidemiology and Biostatistics, School of Public Health, San Diego State University, San Diego, CA 92182, USA; (J.I.); (H.L.)
- Moores Cancer Center, School of Medicine, University of California, San Diego, CA 92037, USA
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16
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Cao Y, Liu MC, Hanlon EL, Chen Y, Afzal MZ, Hayes CA, Hill JM. Clinical presentation of Warburg effect in aggressive lymphoma: a case report. J Med Case Rep 2023; 17:380. [PMID: 37608348 PMCID: PMC10464222 DOI: 10.1186/s13256-023-04079-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/14/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND The Warburg effect is a rare condition in tumor biology, illustrated by significant lactate production in the presence of oxygen. The Warburg effect is associated with very poor prognosis in patients with malignancy. CASE PRESENTATION We report a 76-year-old Caucasian woman with double-expressor diffuse large B cell lymphoma who presented with severe lactic acidosis and extreme hypoglycemia with normal mentation. Her lactic acidosis was initially controlled with a bicarbonate infusion, and the patient was started promptly on steroids, followed by chemotherapy, but her clinical course was complicated by tumor lysis syndrome, acute renal failure requiring hemodialysis, and progressive liver failure. She manifested a temporary clinical response to chemotherapy but eventually died of complications. CONCLUSIONS This case demonstrates the importance of prompt recognition of the Warburg effect, aggressive supportive measures, and early initiation of chemotherapy. Future studies are needed to characterize the role of hemodialysis in this setting.
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Affiliation(s)
- Yenong Cao
- Department of Hematology and Oncology, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
| | - Margaret C Liu
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA
| | - Emma L Hanlon
- Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA
| | - York Chen
- Department of Internal Medicine, Dartmouth Health, 1 Medical Center Drive, Lebanon, NH, 03756 , USA
| | - Muhammad Z Afzal
- Division of Hematology and Oncology, Dartmouth Cancer Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA
| | - Christi A Hayes
- Division of Hematology and Oncology, Dartmouth Cancer Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA
| | - John M Hill
- Division of Hematology and Oncology, Dartmouth Cancer Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA
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17
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Georgakopoulou VE, Asimakopoulou S, Cholongitas E. Pulmonary function testing in patients with liver cirrhosis (Review). MEDICINE INTERNATIONAL 2023; 3:36. [PMID: 37533800 PMCID: PMC10391595 DOI: 10.3892/mi.2023.96] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/29/2023] [Indexed: 08/04/2023]
Abstract
Liver cirrhosis is a common long-term outcome of chronic hepatic inflammation. Patients with liver cirrhosis may also have pulmonary complications. There are several reasons for pulmonary dysfunction in liver cirrhosis, including intrinsic cardiopulmonary dysfunction unrelated to liver disease and specific disorders related to the presence of liver cirrhosis and/or portal hypertension. The most prevalent and clinically significant pulmonary complications are hepatic hydrothorax, hepatopulmonary syndrome, spontaneous pulmonary empyema and portopulmonary hypertension. Pulmonary function tests (PFTs) have traditionally been used to assess the lung function of patients with liver cirrhosis. To the best of our knowledge, the present review is the first to detail all types of PFTs performed in patients with liver cirrhosis and discuss their clinical significance. Patients with liver cirrhosis have reduced values of spirometric parameters, diffusion capacity for carbon monoxide (DLCO), lung volumes, maximal inspiratory pressure and maximal expiratory pressure. Furthermore, they have a higher closing volume, a greater airway occlusion pressure 0.1 sec after the onset of inspiratory flow and greater exhaled nitric oxide values. In order to improve pulmonary function, patients with ascites may require therapeutic paracentesis. Such findings should be considered when evaluating individuals with liver disease, particularly those who may require surgery. Poor lung function, particularly restrictive lung disease, can have an impact on post-transplant outcomes, such as ventilator time, length of hospital duration and post-operative pulmonary complications; thus, the transplant care team needs to be aware of its prevalence and relevance.
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Affiliation(s)
- Vasiliki Epameinondas Georgakopoulou
- Department of Infectious Diseases and COVID-19 Unit, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Stavroula Asimakopoulou
- First Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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18
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Jeong JH, Lee SB, Sung A, Shin H, Kim DH. Factors predicting mortality in patients with alcoholic liver cirrhosis visiting the emergency department. Medicine (Baltimore) 2023; 102:e33074. [PMID: 36827072 PMCID: PMC11309678 DOI: 10.1097/md.0000000000033074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/25/2023] Open
Abstract
Liver cirrhosis (LC) is a major cause of morbidity and mortality worldwide and is becoming a regional and healthcare burden. South Korea is one of the 10 countries with the highest age standardized prevalence of decompensated LC. Moreover, the proportion of patients with alcoholic LC is increasing and there has been no decrease in the incidence of decompensated alcoholic LC. Patients with decompensated LC frequently visit the emergency department (ED). Several studies focused on patients with LC who visited the ED, but the studies about alcoholic LC were limited. This study aimed to identify predicting factors for mortality in alcoholic LC patients visiting the ED. This was a retrospective study of alcoholic LC patients who visited an ED between November 2017 and June 2021. The baseline characteristics, complications of LC, model for end-stage liver disease (MELD) score, and laboratory values including lactate were assessed. The primary outcome was in-hospital mortality. In total, 433 patients with alcoholic LC were included for analysis and the in hospital mortality rate was 15.9% (n = 69). Univariate regression analyses identified that MELD score, lactate, platelet, international normalized ratio, bilirubin, creatinine, albumin, and C-reactive protein (CRP) predicted in-hospital mortality. Multivariate regression analysis showed that MELD score, lactate, albumin, and CRP were significantly associated with in-hospital mortality. MELD score, lactate, albumin, and CRP predicted the mortality in alcoholic LC patients visiting the ED.
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Affiliation(s)
- Jin Hee Jeong
- Department of Emergency Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, Gyeongsangnam-do, Republic of Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju-si, Gyeongsangnam-do, Republic of Korea
| | - Sang Bong Lee
- Department of Emergency Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, Gyeongsangnam-do, Republic of Korea
| | - Aejin Sung
- Department of Emergency Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, Gyeongsangnam-do, Republic of Korea
| | - Hyuntack Shin
- Department of Emergency Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, Gyeongsangnam-do, Republic of Korea
| | - Dong Hoon Kim
- Department of Emergency Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, Gyeongsangnam-do, Republic of Korea
- Gyeongsang Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju-si, Gyeongsangnam-do, Republic of Korea
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19
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Naps MS, Leong SH, Hartwell EE, Rentsch CT, Kranzler HR. Effects of topiramate therapy on serum bicarbonate concentration in a sample of 10,279 veterans. Alcohol Clin Exp Res 2023; 47:438-447. [PMID: 36810985 DOI: 10.1111/acer.15011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/20/2022] [Accepted: 01/03/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND Topiramate, which is increasingly being used to treat alcohol use disorder (AUD), is commonly associated with reduced serum bicarbonate concentrations. However, estimates of the prevalence and magnitude of this effect are from small samples and do not address whether topiramate's effects on acid-base balance differ in the presence of an AUD or by topiramate dosage. METHODS Veterans Health Administration electronic health record (EHR) data were used to identify patients with a minimum of 180 days of topiramate prescription for any indication and a propensity score-matched control group. We differentiated patients into two subgroups based on the presence of a diagnosis of AUD in the EHR. Baseline alcohol consumption was determined using Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores in the EHR. Analysis also included a three-level measure representing mean daily dosage. The topiramate-associated changes in serum bicarbonate concentration were estimated in difference-in-differences linear regression models. A serum bicarbonate concentration <17 mEq/L was considered to represent possible clinically significant metabolic acidosis. RESULTS The cohort comprised 4287 topiramate-treated patients and 5992 propensity score-matched controls with a mean follow-up period of 417 days. The mean topiramate-associated reductions in serum bicarbonate concentration were <2 mEq/L in the low (≤88.75), medium (>88.75 and ≤141.70), and high (>141.70) mg/day dosage tertiles, irrespective of AUD history. Concentrations <17 mEq/L occurred in 1.1% of topiramate-treated patients and 0.3% of controls and were not associated with alcohol consumption or an AUD diagnosis. CONCLUSIONS The excess prevalence of metabolic acidosis associated with topiramate treatment does not differ with dosage, alcohol consumption, or the presence of an AUD. Baseline and periodic serum bicarbonate concentration measurements are recommended during topiramate therapy. Patients prescribed topiramate should be educated about the symptoms of metabolic acidosis and urged to report their occurrence promptly to a healthcare provider.
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Affiliation(s)
- Michelle S Naps
- Mental Illness Research, Education and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.,School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shirley H Leong
- Mental Illness Research, Education and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA
| | - Emily E Hartwell
- Mental Illness Research, Education and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.,Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Christopher T Rentsch
- VA Connecticut Healthcare System, US Department of Veterans Affairs, West Haven, Connecticut, USA.,Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.,Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK
| | - Henry R Kranzler
- Mental Illness Research, Education and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.,Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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20
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Shurubor YI, Rogozhin AE, Isakova EP, Deryabina YI, Krasnikov BF. Residual Amino Acid Imbalance in Rats during Recovery from Acute Thioacetamide-Induced Hepatic Encephalopathy Indicates Incomplete Healing. Int J Mol Sci 2023; 24:ijms24043647. [PMID: 36835059 PMCID: PMC9967446 DOI: 10.3390/ijms24043647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/16/2023] Open
Abstract
The delayed consequences of the influence of hepatic encephalopathy (HE) on the metabolism of animals have not been studied enough. We have previously shown that the development of acute HE under the influence of the thioacetamide (TAA) toxin is accompanied by pathological changes in the liver, an imbalance in CoA and acetyl CoA, as well as a number of metabolites of the TCA cycle. This paper discusses the change in the balance of amino acids (AAs) and related metabolites, as well as the activity of glutamine transaminase (GTK) and ω-amidase enzymes in the vital organs of animals 6 days after a single exposure to TAA. The balance of the main AAs in blood plasma, liver, kidney, and brain samples of control (n = 3) and TAA-induced groups (n = 13) of rats that received the toxin at doses of 200, 400, and 600 mg/kg was considered. Despite the apparent physiological recovery of the rats at the time of sampling, a residual imbalance in AA and associated enzymes persisted. The data obtained give an idea of the metabolic trends in the body of rats after their physiological recovery from TAA exposure and may be useful for prognostic purposes when choosing the necessary therapeutic agents.
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Affiliation(s)
| | - Alexander E. Rogozhin
- Valiev Institute of Physics and Technology of the Russian Academy of Sciences, Moscow 117218, Russia
| | - Elena P. Isakova
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia
| | - Yulia I. Deryabina
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia
| | - Boris F. Krasnikov
- Centre for Strategic Planning of FMBA of Russia, Moscow 119121, Russia
- Correspondence: ; Tel.: +7-(985)-095-5445
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21
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Chandra S, Ravula S, Errabelli P, Spencer H, Singh M. No Good Deed: Acidosis in Chronic Kidney and Liver Disease. J Ren Nutr 2023; 33:499-502. [PMID: 36736470 DOI: 10.1053/j.jrn.2022.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 11/09/2022] [Accepted: 12/13/2022] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis) are associated with increased all-cause mortality rates in moderate and advanced chronic kidney disease (CKD) cases. Correction of presumed acidosis using sodium bicarbonate, targeting serum levels around 22 mmol/L, has proven to be beneficial in delaying the progression of the disease and provided mortality benefit. A similar prognostic association may exist between uncorrected metabolic acidosis in chronic liver disease. Correcting it with sodium-containing salts may require more interventions due to increased sodium/fluid load. In patients with liver failure, a naturally alkalotic state, where sodium load is a concern, the impact of this intervention is unclear. DESIGN This study aims to generate proof of concept through a retrospective chart review in individuals with CKD-related metabolic acidosis and liver cirrhosis. RESULT Our analysis revealed a statistically significant association between the need for paracentesis and bicarbonate therapy. Our study has multiple drawbacks, including a retrospective chart review and limitation of data due to single-center patients. CONCLUSION We extrapolate that lowering bicarbonate targets in other clinical scenarios like liver failure, pregnancy, and cardiac failure may be prudent and will lead to a lower sodium load.
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Affiliation(s)
- Samira Chandra
- University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | | | | | - Horace Spencer
- University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Manisha Singh
- University of Arkansas for Medical Sciences, Little Rock, Arkansas.
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22
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Perez Ruiz de Garibay A, Kortgen A, Leonhardt J, Zipprich A, Bauer M. Critical care hepatology: definitions, incidence, prognosis and role of liver failure in critically ill patients. Crit Care 2022; 26:289. [PMID: 36163253 PMCID: PMC9511746 DOI: 10.1186/s13054-022-04163-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 09/10/2022] [Indexed: 01/11/2023] Open
Abstract
AbstractOrgan dysfunction or overt failure is a commonplace event in the critically ill affecting up to 70% of patients during their stay in the ICU. The outcome depends on the resolution of impaired organ function, while a domino-like deterioration of organs other than the primarily affected ones paves the way for increased mortality. “Acute Liver Failure” was defined in the 1970s as a rare and potentially reversible severe liver injury in the absence of prior liver disease with hepatic encephalopathy occurring within 8 weeks. Dysfunction of the liver in general reflects a critical event in “Multiple Organ Dysfunction Syndrome” due to immunologic, regulatory and metabolic functions of liver parenchymal and non-parenchymal cells. Dysregulation of the inflammatory response, persistent microcirculatory (hypoxic) impairment or drug-induced liver injury are leading problems that result in “secondary liver failure,” i.e., acquired liver injury without underlying liver disease or deterioration of preexisting (chronic) liver disease (“Acute-on-Chronic Liver Failure”). Conventional laboratory markers, such as transaminases or bilirubin, are limited to provide insight into the complex facets of metabolic and immunologic liver dysfunction. Furthermore, inhomogeneous definitions of these entities lead to widely ranging estimates of incidence. In the present work, we review the different definitions to improve the understanding of liver dysfunction as a perpetrator (and therapeutic target) of multiple organ dysfunction syndrome in critical care.
Graphic Abstract
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23
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Suresh MR. The Early Detection of Hypovolemic Shock and Shifting the Focus to Compensation. J Intensive Care Med 2022; 37:1673-1675. [PMID: 35850608 DOI: 10.1177/08850666221114267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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24
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Katopodis P, Pappas EM, Katopodis KP. Acid-base abnormalities and liver dysfunction. Ann Hepatol 2022; 27:100675. [PMID: 35074477 DOI: 10.1016/j.aohep.2022.100675] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/14/2022] [Accepted: 01/15/2022] [Indexed: 02/04/2023]
Abstract
In addition to the kidneys and lungs, the liver also plays an important role in the regulation of the Acid-Base Equilibrium (ABE). The involvement of the liver in the regulation of ABE is crucial because of its role in lactic acid metabolism, urea production and in protein homeostasis. The main acid-base imbalance that occurs in patients with liver cirrhosis is Respiratory Alkalosis (RAlk). Due to the fact that in these patients additional pathophysiological mechanisms that affect the ABE are present, other disorders may appear which compensate or enhance the primary disorder. Conventional ABE reading models fail to identify and assess the underlying disorders in patients with liver cirrhosis. This weakness of the classical models led to the creation of new physicochemical mathematical models that take into account all the known parameters that develop and affect the ABE. In addition to the RAlk, in patients with liver cirrhosis, metabolic alkalosis (due to hypoalbuminemia), hyponatremic metabolic acidosis, hyperchloremic metabolic acidosis, lactic acidosis and metabolic alkalosis due to urea metabolism are some of the pathophysiological mechanisms that affect the ABE.
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Affiliation(s)
- Periklis Katopodis
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
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25
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Nguyen D, Lawrence MM, Berg H, Lyons MA, Shreim S, Keating MT, Weidling J, Botvinick EL. Transcutaneous Flexible Sensor for In Vivo Photonic Detection of pH and Lactate. ACS Sens 2022; 7:441-452. [PMID: 35175733 PMCID: PMC8886565 DOI: 10.1021/acssensors.1c01720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
![]()
Clinical research
shows that frequent measurements of both pH and
lactate can help guide therapy and improve patient outcome. However,
current methods of sampling blood pH and lactate make it impractical
to take readings frequently (due to the heightened risk of blood infection
and anemia). As a solution, we have engineered a subcutaneous pH and
lactate sensor (PALS) that can provide continuous, physiologically
relevant measurements. To measure pH, a sheet containing a pH-sensitive
fluorescent dye is placed over 400 and 465 nm light-emitting diodes
(LEDs) and a filter-coated photodetector. The filter-coated photodetector
collects an emitted signal from the dye for each LED excitation, and
the ratio of the emitted signals is used to monitor pH. To measure
lactate, two sensing sheets comprising an oxygen-sensitive phosphorescent
dye are each mounted to a 625 nm LED. One sheet additionally comprises
the enzyme lactate oxidase. The LEDs are sequentially modulated to
excite the sensing sheets, and their phase shift at the LED drive
frequency is used to monitor lactate. In vitro results
indicate that PALS successfully records pH changes from 6.92 to 7.70,
allowing for discrimination between acidosis and alkalosis, and can
track lactate levels up to 9 mM. Both sensing strategies exhibit fast
rise times (< 5 min) and stable measurements. Multianalyte in vitro models of physiological disorders show that the
sensor measurements consistently quantify the expected pathophysiological
trends without cross talk; in vivo rabbit testing
further indicates usefulness in the clinical setting.
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Affiliation(s)
- Dat Nguyen
- Department of Biomedical Engineering, University of California Irvine, Irvine, California 92697-2730, United States
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
- Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, University of California Irvine, Irvine, California 92697, United States
| | - Micah M. Lawrence
- Department of Biomedical Engineering, University of California Irvine, Irvine, California 92697-2730, United States
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
- Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, University of California Irvine, Irvine, California 92697, United States
| | - Haley Berg
- Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, University of California Irvine, Irvine, California 92697, United States
| | - Monika Aya Lyons
- Department of Biomedical Engineering, University of California Irvine, Irvine, California 92697-2730, United States
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
- Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, University of California Irvine, Irvine, California 92697, United States
| | - Samir Shreim
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
| | - Mark T. Keating
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
| | - John Weidling
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
| | - Elliot L. Botvinick
- Department of Biomedical Engineering, University of California Irvine, Irvine, California 92697-2730, United States
- Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612, United States
- Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, University of California Irvine, Irvine, California 92697, United States
- Department of Surgery, University of California, Irvine, California 92697-2730, United States
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26
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Wang C, Ma C, Gong L, Dai S, Li Y. Preventive and therapeutic role of betaine in liver disease: A review on molecular mechanisms. Eur J Pharmacol 2021; 912:174604. [PMID: 34743980 DOI: 10.1016/j.ejphar.2021.174604] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/29/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022]
Abstract
Betaine is a kind of water-soluble quaternary amine-type alkaloid widely existing in food, such as wheat germ, beet, spinach, shrimp and wolfberry. As an important methyl donor and osmotic pressure regulator in human body, betaine plays an important role in a variety of physiological activities. In recent years, a large number of literatures have shown that betaine has good preventive and therapeutic effects on many liver diseases, including chemical or drug-induced liver injury, nonalcoholic fatty liver disease, alcoholic fatty liver disease, liver fibrosis, hepatitis B and hepatitis C. Therefore, by searching the databases of Web of Science, PubMed, SciFinder and CNKI, this paper has summarized the molecular mechanisms of betaine in improving liver diseases. The results show that the improvement of liver diseases by betaine is closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, improvement of insulin resistance, reduction of endoplasmic reticulum stress, alleviation of liver oxidative stress, increase of autophagy, remodeling of intestinal flora and regulation of epigenetic modification. More importantly, nuclear transcription factor kappa (NF-κB), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α/γ (PPAR-α/γ), liver X receptor α (LXRα), protein kinase B (Akt), toll-like receptor 4 (TLR4) and cysteinyl aspartate specific proteinase-3 (Caspase-3) signaling pathways are considered as important molecular targets for betaine to improve liver diseases. These important findings will provide a direction and basis for further exploring the pathogenesis of various liver diseases and tapping the potential of betaine in the clinical treatment.
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Affiliation(s)
- Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shu Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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27
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Zechner C, Adams-Huet B, Gregory B, Neyra JA, Rule JA, Li X, Rakela J, Moe OW, Lee WM. Hypophosphatemia in acute liver failure of a broad range of etiologies is associated with phosphaturia without kidney damage or phosphatonin elevation. Transl Res 2021; 238:1-11. [PMID: 34298149 PMCID: PMC8572166 DOI: 10.1016/j.trsl.2021.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/21/2021] [Accepted: 07/15/2021] [Indexed: 11/19/2022]
Abstract
Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R2 = 0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins.
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Affiliation(s)
- Christoph Zechner
- Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA; Department of Pharmacology. UT Southwestern Medical Center, Dallas, Texas, USA; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA.
| | - Beverley Adams-Huet
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA; Division of Biostatistics, Population and Data Sciences, Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Blake Gregory
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA; Division of Primary Care, Department of Internal Medicine, Alameda Health System, Oakland, California, USA
| | - Javier A Neyra
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA; Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA; Division of Nephrology, Bone and Mineral Metabolism, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Jody A Rule
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Xilong Li
- Division of Biostatistics, Population and Data Sciences, Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jorge Rakela
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA; Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA; Department of Physiology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
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28
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de Souza JR, Yokoyama AP, Magnus MM, Boin I, de Ataide EC, Munhoz DC, Pereira FB, Luzo A, Orsi FA. Association of acidosis with coagulopathy and transfusion requirements in liver transplantation. J Thromb Thrombolysis 2021; 53:887-897. [PMID: 34800258 DOI: 10.1007/s11239-021-02609-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2021] [Indexed: 11/26/2022]
Abstract
The relationship between acidosis and coagulopathy has long been described in vitro and in trauma patients, but not yet in orthotopic liver transplantation (OLT). The association of metabolic acidosis with coagulopathy and with transfusion requirements was evaluated in patients submitted to OLT. Changes in acid-base and coagulation parameters were analyzed by repeated measures. Regression analyses [adjusted for sex, age, model for end stage liver disease (MELD) score, and baseline values of hemoglobin, fibrinogen, international normalized ratio, platelets] determined the association of acid-base parameters with coagulation markers and transfusion requirement. We included 95 patients, 66% were male, 49.5% of the patients had hepatocellular carcinoma and the mean MELD score was 20.4 (SD 8.9). The values of all the coagulation and acid-base parameters significantly changed during OLT, particularly in the reperfusion phase. After adjustments for baseline parameters, the decrease in pH and base excess (BE) values were associated with a decrease in fibrinogen levels (mean decrease of fibrinogen level = 14.88 mg/dL per 0.1 unit reduction of pH values and 3.6 mg/dL per 1 mmol/L reduction of BE levels) and an increase in red blood cells transfusion (2.16 units of RBC per 0.1 unit reduction of pH and 0.38 units of RBC per 1 mmol/L reduction of BE levels). Among multiple factors potentially associated with adverse outcomes, decreasing pH levels were independently associated with the length of hospitalization but not with in-hospital mortality. Metabolic acidosis is independently associated with decreased fibrinogen levels and increased intraoperative transfusion requirement during OLT. Awareness of that association may improve treatment strategies to reduce intraoperative bleeding risk in OLT.
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Affiliation(s)
- Júlia Ruete de Souza
- Faculty of Medicine, Pontifical Catholic University of Campinas, Campinas, Brazil
| | - Ana Paula Yokoyama
- School of Medical Sciences, University of Campinas, Campinas, Brazil
- Hemotherapy and Cell Therapy Department, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | - Ilka Boin
- Department of Surgery, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | | | - Derli Conceição Munhoz
- Department of Anestiology, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | | | - Angela Luzo
- Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil
| | - Fernanda Andrade Orsi
- Department of Pathology, School of Medical Sciences, University of Campinas, Campinas R. Tessália Vieira de Camargo, 126 Cidade Universitária, Campinas, 13083-887, Brazil.
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29
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Delineation of the healthy rabbit liver by immunohistochemistry - A technical note. Acta Histochem 2021; 123:151795. [PMID: 34627038 DOI: 10.1016/j.acthis.2021.151795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/08/2021] [Accepted: 09/28/2021] [Indexed: 10/20/2022]
Abstract
Liver diseases pose a big global health problem and liver failure may result from viral infection, overnutrition or tumors. Studying pathologic liver tissue demands for accurate and specific histological stainings and immunohistochemical labellings, including chromogenic and fluorescent approaches. Moreover, a reliable set of healthy liver stainings and labellings are required, to provide a baseline or reference for the pathological situation. Here, we used the liver tissue of a healthy rabbit and compared different histological key steps, such as paraffin embedding after formalin fixation versus cryopreservation; or an antigen retrieval (AR) step in processing paraffin sections versus the same procedure without AR; or chromogenic with fluorescent detection system, respectively. Moreover, we provide images of serial sections, where we stained the same morphological structure with different markers, including collagen I, collagen III, fibronectin, α-SMA, elastin, protease-activated receptor-2 (PAR-2) which is an inflammation-related marker, ki67 for proliferating cells, and orcein (as negative control for pathological aberrations like Wilson disease). Differences between conditions were quantitatively assessed by measuring the colour intensity. Generally, we observed that cryosections exhibited a stronger signal intensity in immunohistochemically labelled sections than in paraffin sections; however, the strong staining got slurred, which sometimes hampered proper identification of morphological structures at higher magnifications. Moreover, there was a clear increase in signal intensity for paraffin sections when an AR step was performed compared to condition without AR. Results for mouse isotype staining as a negative control clearly supported those findings. Different stainings of the portal triad, the central vein and the bile ducts revealed a clear-cut distribution of extracellular matrix components, with prominent fibronectin and elastin around the lumen of the central vein as well as a patchy PAR-2 expression. As for the bile ducts, complete absence of α-SMA and PAR-2 was found at the margins, however, collagen I expression and elastin were positive and showed a strong signal. Like this, we provide useful and valuable reference images for researchers using the rabbit liver model. It may help to decide which of the immunohistochemical protocols are valuable to reach a certain aim and which protocols lead to the best visualization of the target structure.
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Lee DU, Fan GH, Hastie DJ, Addonizio EA, Karagozian R. The clinical impact of paroxysmal arrhythmias on the hospital outcomes of patients admitted with cirrhosis: propensity score matched analysis of 2011-2017 US hospitals. Expert Rev Cardiovasc Ther 2021; 19:947-956. [PMID: 34493127 DOI: 10.1080/14779072.2021.1978841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND We evaluate the effects of paroxysmal arrhythmia on the hospital outcomes of patients admitted with cirrhosis. RESEARCH DESIGN AND METHODS 2011-2017 National Inpatient Sample was used to isolate patients with decompensated/compensated cirrhosis, stratified by paroxysmal arrhythmia (supraventricular: PSVT and ventricular: PVT). The cohorts were matched using propensity-score matching and compared to mortality, length of stay, cost, and cardiac complications (cardioversion, cardiogenic shock, cardiac arrest, and ventricular fibrillation). RESULTS In compensated cirrhosis, 2,453 had PSVT with matched controls; 5,274 had PVT with matched controls. Those with PSVT had higher mortality (aOR 1.55 95%CI 1.23-1.95) and higher rates of cardioversion and cardiogenic shock; likewise, those with PVT had higher mortality (aOR 2.41 95%CI 2.09-2.78) and higher rates of all complications. In decompensated cirrhosis, 1,598 had PSVT with matched controls; 4,178 had PVT with matched controls. Those with PSVT had higher mortality (aOR 1.57 95%CI 1.28-1.93) and higher rates of cardioversion, cardiogenic shock, cardiac arrest; those with PVT had higher mortality (aOR 2.25 95%CI 1.98-2.56) and higher rates of all complications. CONCLUSION The findings from this study show that in either decompensated or compensated cohort, those with paroxysmal arrhythmias are at a higher risk of in-hospital mortality and adverse cardiac outcomes.
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Affiliation(s)
- David Uihwan Lee
- Liver Center, Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA
| | - Gregory Hongyuan Fan
- Liver Center, Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA
| | - David Jeffrey Hastie
- Liver Center, Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA
| | - Elyse Ann Addonizio
- Liver Center, Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA
| | - Raffi Karagozian
- Liver Center, Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA
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Gao Y, Zhang H, Zhong H, Yang S, Wang Q. Lactate and blood ammonia on admission as biomarkers to predict the prognosis of patients with acute mushroom poisoning and liver failure: a retrospective study. Toxicol Res (Camb) 2021; 10:850-855. [PMID: 34484676 DOI: 10.1093/toxres/tfab068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 06/22/2021] [Accepted: 07/04/2021] [Indexed: 11/14/2022] Open
Abstract
The diagnosis of liver damage induced by mushroom poisoning is still challenging. This study aims to screen the early biological indexes that could predict acute mushroom poisoning with liver damage. The patients with acute mushroom poisoning and liver damage admitted to The First Affiliated Hospital of Dalian Medical University，China from July 2007 to August 2017 were analyzed retrospectively. A total of 66 patients were enrolled in this study, with 44 and 22 patients in the liver injury group and liver failure group, respectively. Ten patients in the liver failure group died, with a mortality of 45.5% in this group. Multivariable Cox regression showed that the blood ammonia (NH3) and lactic acid (Lac) at the time of admission were independently associated with the in-hospital time to death for patients with liver failure induced by mushroom poisoning. Lactate and blood ammonia at the time of admission could be used to predict the prognosis of patients with acute mushroom poisoning and liver failure.
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Affiliation(s)
- Yanguo Gao
- Department of Neurology, Xinhua Hospital Affiliated to Dalian University, No. 156 Wansui Street, Shahekou District, Dalian, China
| | - Hongqiao Zhang
- Department of Emergency, the First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Xigang District Dalian, China
| | - Hua Zhong
- Department of Medical Record, the First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Xigang District Dalian, China
| | - Suosuo Yang
- Department of Emergency, the First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Xigang District Dalian, China
| | - Qiuyan Wang
- Department of Emergency, the First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Xigang District Dalian, China
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Rubin DM. Stewart’s approach to quantitative acid-base physiology should replace traditional bicarbonate-centered models. J Appl Physiol (1985) 2021; 130:2019-2021. [DOI: 10.1152/japplphysiol.00042.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- David M. Rubin
- Biomedical Engineering Research Group, University of the Witwatersrand, Johannesburg, South Africa
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Admission Serum Bicarbonate Predicts Adverse Clinical Outcomes in Hospitalized Cirrhotic Patients. Can J Gastroenterol Hepatol 2021; 2021:9915055. [PMID: 34055676 PMCID: PMC8149247 DOI: 10.1155/2021/9915055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/05/2021] [Indexed: 01/11/2023] Open
Abstract
A low serum bicarbonate (SB) level is predictive of adverse outcomes in kidney injury, infection, and aging. Because the liver plays an important role in acid-base homeostasis and lactic acid metabolism, we speculated that such a relationship would exist for patients with cirrhosis. To assess the prognostic value of admission SB on adverse hospital outcomes, clinical characteristics were extracted and analyzed from a large electronic health record system. Patients were categorized based on admission SB (mEq/L) into 7 groups based on the reference range (22-25) into mildly (18-21), moderately (14-17), and severely (<14) decreased groups and mildly (26-29), moderately (30-33), and severely (>30) increased groups, and the relationship of SB category with the frequency of complications (acute kidney injury/hepatorenal syndrome, portosystemic encephalopathy, gastrointestinal bleeding, ascites, and spontaneous bacterial peritonitis) and hospital metrics (length of stay [LOS], admission to an intensive care unit [ICU], and mortality) was assessed. A total of 2,693 patients were analyzed. Mean SB was 22.9 ± 4.5 mEq/L. SB was within the normal range (22-25 mEq/L) in 1,072 (39.8%) patients, and 955 patients (36%) had a low SB. As the SB category decreased, the incidence of complications progressively increased (p < 0.001). Increased MELD-Na score and low serum albumin also correlated with frequency of complications (p < 0.001). As the SB category decreased, LOS, ICU admission, and mortality progressively increased (p < 0.001). On multivariate analysis, the association of decreased SB with higher odds of complications, LOS, ICU admission, and mortality persisted. Conclusion. Low admission SB in patients with cirrhosis is associated with cirrhotic complications, longer LOS, increased ICU admissions, and increased hospital mortality.
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Wang T, Chen K, Yao W, Zheng R, He Q, Xia J, Li J, Shao Y, Zhang L, Huang L, Qin L, Xu M, Zhang Z, Pan D, Li Z, Huang F. Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance. J Hepatol 2021; 74:1038-1052. [PMID: 33248168 DOI: 10.1016/j.jhep.2020.11.028] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Lactate has recently been reported to accumulate in the livers of patients progressing from simple steatosis to non-alcoholic steatohepatitis (NASH). However, the underlying mechanism(s) of lactate accumulation and the role of lactate in the progression of non-alcoholic fatty liver disease (NAFLD) are essentially unknown. METHODS We compared the acetylome in liver samples taken from healthy individuals, patients with simple steatosis and patients with NASH to identify potential targets of acetylation with a role in lactate metabolism. Interactions between the acetylated target and acetyltransferases were measured in multiple cell lines. An acetyltransferase inhibitor was injected into high-fat diet (HFD)-fed mice to determine the role of lactate on NAFLD progression in vivo. RESULTS Hyperacetylation of lactate dehydrogenase B (LDHB) was found to be associated with lactate accumulation in NAFL and NASH livers in humans and mice. P300/CBP-associated factor (PCAF)-mediated acetylation of LDHB K82 was found to significantly decrease LDHB activity and impair hepatic lactate clearance, resulting in lactate accumulation. Acetylated LDHB induced lactate accumulation which exacerbated lipid deposition and inflammatory responses by activating histone hyperacetylation in HFD-induced NASH. The administration of embelin, a PCAF inhibitor, and the generation of an acetylation-deficient mutant of LDHB ameliorated NASH. CONCLUSION PCAF-dependent LDHB acetylation plays a key role in hepatic lipid accumulation and inflammatory responses by impairing lactate clearance; this process might be a potential therapeutic target for the treatment of NASH. LAY SUMMARY Lactate is known to accumulate in the livers of patients during the progression of non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanism(s) of this accumulation and its importance in disease progression are unknown. Herein, we show that the acetylation of an enzyme involved in lactate metabolism leads to impaired lactate clearance and exacerbates NAFLD progression.
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Affiliation(s)
- Tongxin Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Kai Chen
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Weilei Yao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Ruilong Zheng
- Animal Nutrition Group, Department of Animal Sciences, Wageningen University & Research, De Elst 1, 6708 WD, Wageningen, The Netherlands
| | - Qiongyu He
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Jun Xia
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Juan Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Yafei Shao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Li Zhang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Lu Huang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Longshan Qin
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Mingming Xu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Zheng Zhang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Dingyu Pan
- Department of hepatobiliary and pancreatic Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, China
| | - Zhen Li
- Department of hepatobiliary and pancreatic Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, China
| | - Feiruo Huang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China; Key laboratory of Environment Correlative Dietology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China.
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Saikrithika S, Kumar AS. A selective voltammetric pH sensor using graphitized mesoporous carbon/polyaniline hybrid system. J CHEM SCI 2021. [DOI: 10.1007/s12039-021-01908-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Lactate and Bilirubin Index: A New Indicator to Predict Critically Ill Cirrhotic Patients’ Prognosis. Can J Gastroenterol Hepatol 2021. [DOI: 10.1155/2021/6624177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objectives. We aimed to perform external validation of the prognostic value of the lactate and bilirubin (LB) index, a new indicator, and compare the ability of the LB index and other scoring systems to predict both short- and long-term mortality in critically ill cirrhotic patients. Materials and Methods. A number of 479 cirrhotic patients admitted into ICU were included in our research. We measured prognostic scores in the first 24 hours including LB index, Child–Pugh, SOFA, CLIF-SOFA, and MELD scores. The LB index was calculated as follows: ln [1000 × lactate (mmol/L) × bilirubin (µmol/L)]/2. The primary outcomes were 28-day and 3-year all-cause mortality. Multivariate logistic regression analyses were used to investigate the independent association between the LB index and the mortality in critically ill cirrhotic patients. The area under the receiver operating characteristic curve was used to assess the prediction accuracy of short- and long-term mortality of the clinical score. Calibration of the score was evaluated by Hosmer–Lemeshow goodness-of-fit test for significance. Results. Multivariate logistic regression analysis identified that the LB index (odds ratio: 5.487, 95% confidence interval: 3.542–8.501,
) was the strongest predictor for 28-day mortality. The LB index gave the highest area under the curve (0.791, 95% confidence interval: 0.747–0.836) in predicting 28-day mortality. For predicting 3-year mortality, the model for end-stage liver disease (MELD) score showed better discrimination ability with an area under the curve of 0.726 (95% confidence interval: 0.680–0.771). The risk of mortality significantly increased when the clinical scores were ≥ the optimal cutoff values. Conclusions. The LB index, a simple prognostic indicator, performs well in predicting critically ill cirrhotic patients’ short-term prognosis, while, for long-term prognosis, the MELD score is more appropriate.
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Trampert DC, van de Graaf SFJ, Jongejan A, Oude Elferink RPJ, Beuers U. Hepatobiliary acid-base homeostasis: Insights from analogous secretory epithelia. J Hepatol 2021; 74:428-441. [PMID: 33342564 DOI: 10.1016/j.jhep.2020.10.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/03/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022]
Abstract
Many epithelia secrete bicarbonate-rich fluid to generate flow, alter viscosity, control pH and potentially protect luminal and intracellular structures from chemical stress. Bicarbonate is a key component of human bile and impaired biliary bicarbonate secretion is associated with liver damage. Major efforts have been undertaken to gain insight into acid-base homeostasis in cholangiocytes and more can be learned from analogous secretory epithelia. Extrahepatic examples include salivary and pancreatic duct cells, duodenocytes, airway and renal epithelial cells. The cellular machinery involved in acid-base homeostasis includes carbonic anhydrase enzymes, transporters of the solute carrier family, and intra- and extracellular pH sensors. This pH-regulatory system is orchestrated by protein-protein interactions, the establishment of an electrochemical gradient across the plasma membrane and bicarbonate sensing of the intra- and extracellular compartment. In this review, we discuss conserved principles identified in analogous secretory epithelia in the light of current knowledge on cholangiocyte physiology. We present a framework for cholangiocellular acid-base homeostasis supported by expression analysis of publicly available single-cell RNA sequencing datasets from human cholangiocytes, which provide insights into the molecular basis of pH homeostasis and dysregulation in the biliary system.
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Affiliation(s)
- David C Trampert
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Meibergdreef 9, Amsterdam, the Netherlands
| | - Stan F J van de Graaf
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Meibergdreef 9, Amsterdam, the Netherlands
| | - Aldo Jongejan
- Amsterdam UMC, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Meibergdreef 9, Amsterdam, the Netherlands
| | - Ronald P J Oude Elferink
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Meibergdreef 9, Amsterdam, the Netherlands
| | - Ulrich Beuers
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Meibergdreef 9, Amsterdam, the Netherlands.
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Serum lactate level predicts 6-months mortality in patients with hepatitis B virus-related decompensated cirrhosis: a retrospective study. Epidemiol Infect 2021; 149:e26. [PMID: 33397544 PMCID: PMC8057512 DOI: 10.1017/s0950268820003143] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The prediction of prognosis is an important part of management in hepatitis B virus (HBV)-related decompensated cirrhosis patients with high long-term mortality. Lactate is a known predictor of outcome in critically ill patients. The aim of this study was to assess the prognostic value of lactate in HBV-related decompensated cirrhosis patients. We performed a single-centre, observational, retrospective study of 405 HBV-related decompensated cirrhosis patients. Individuals were evaluated within 24 h after admission and the primary outcome was evaluated at 6-months. Multivariable analyses were used to determine whether lactate was independently associated with the prognosis of HBV-related decompensated cirrhosis patients. The area under the ROC (AUROC) was calculated to assess the predictive accuracy compared with existing scores. Serum lactate level was significantly higher in non-surviving patients than in surviving patients. Multivariable analyses demonstrated that lactate was an independent risk factor of 6-months mortality (odds ratio: 2.076, P < 0.001). Receiver operating characteristic (ROC) curves were drawn to evaluate the discriminative ability of lactate for 6-months mortality (AUROC: 0.716, P < 0.001). Based on our patient cohort, the new scores (Model For End-Stage Liver Disease (MELD) + lactate score, Child–Pugh + lactate score) had good accuracy for predicting 6-months mortality (AUROC = 0.769, P < 0.001; AUROC = 0.766, P < 0.001). Additionally, the performance of the new scores was superior to those of existing scores (all P < 0.001). Serum lactate at admission may be useful for predicting 6-months mortality in HBV-related decompensated cirrhosis patients, and the predictive value of the MELD score and Child–Pugh score was improved by adjusting lactate. Serum lactate should be part of the rapid diagnosis and initiation of therapy to improve clinical outcome.
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Quade BN, Parker MD, Occhipinti R. The therapeutic importance of acid-base balance. Biochem Pharmacol 2021; 183:114278. [PMID: 33039418 PMCID: PMC7544731 DOI: 10.1016/j.bcp.2020.114278] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on the pharmacokinetic properties of drugs. Our review considers all major organ systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.
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Affiliation(s)
- Bianca N Quade
- Department of Physiology and Biophysics, The State University of New York, The University at Buffalo, Buffalo, NY 14203, USA
| | - Mark D Parker
- Department of Physiology and Biophysics, The State University of New York, The University at Buffalo, Buffalo, NY 14203, USA; Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; State University of New York Eye Institute, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Rossana Occhipinti
- Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
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Heimbach T, Chen Y, Chen J, Dixit V, Parrott N, Peters SA, Poggesi I, Sharma P, Snoeys J, Shebley M, Tai G, Tse S, Upreti VV, Wang YH, Tsai A, Xia B, Zheng M, Zhu AZX, Hall S. Physiologically-Based Pharmacokinetic Modeling in Renal and Hepatic Impairment Populations: A Pharmaceutical Industry Perspective. Clin Pharmacol Ther 2020; 110:297-310. [PMID: 33270249 PMCID: PMC8359227 DOI: 10.1002/cpt.2125] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 11/17/2020] [Indexed: 12/29/2022]
Abstract
The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.
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Affiliation(s)
- Tycho Heimbach
- Pharmaceutical Sciences, Merck & Co., Inc, Rahway, New Jersey, USA
| | - Yuan Chen
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, California, USA
| | - Jun Chen
- Clinical Pharmacology, Alkermes Inc, Waltham, Massachusetts, USA
| | - Vaishali Dixit
- Drug Metabolism and Pharmacokinetics, Kymera Therapeutics, Watertown, Massachusetts, USA
| | - Neil Parrott
- Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Italo Poggesi
- Clinical Pharmacology and Pharmacometrics, Janssen, Milan, Italy
| | - Pradeep Sharma
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Jan Snoeys
- Department of Drug Metabolism and Pharmacokinetics, Janssen R&D, Beerse, Belgium
| | - Mohamad Shebley
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, Illinois, USA
| | - Guoying Tai
- Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Plc, Collegeville, Pennsylvania, USA
| | - Susanna Tse
- Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA
| | - Vijay V Upreti
- Clinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, California, USA
| | - Ying-Hong Wang
- Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Inc, Kenilworth, New Jersey, USA
| | - Alice Tsai
- Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Inc, Boston, Massachusetts, USA
| | - Binfeng Xia
- PK/PD Group, Pharmacokinetics, Dynamics and Metabolism, Sanofi, Bridgewater, New Jersey, USA
| | - Ming Zheng
- Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA
| | - Andy Z X Zhu
- Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International, Co, Cambridge, Massachusetts, USA
| | - Stephen Hall
- Department of Drug Disposition, Lilly, Indianapolis, Indiana, USA
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Alkalemia and Hepatic Encephalopathy in a Chronic Dialysis Patient. Am J Med Sci 2020; 362:207-210. [PMID: 34092398 DOI: 10.1016/j.amjms.2020.12.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/16/2020] [Accepted: 12/21/2020] [Indexed: 11/23/2022]
Abstract
Hepatic encephalopathy (HE) includes cognitive, psychiatric and neuromotor abnormalities observed from brain dysfunction secondary to liver disease and/or porto-systemic shunting. HE can have a wide range of clinical manifestations ranging from trivial lack of awareness, decreased attention span, personality changes to confusion, seizures, coma, and death. The onset of HE in cirrhosis is a poor prognostic factor. While HE has a complex pathogenesis which is not completely understood, hyperammonemia plays an important role in neurotoxicity and brain dysfunction. Alkalemia facilitates the conversion of NH4+ to NH3, which is free to cross the blood-brain barrier exacerbating HE. Prompt recognition and correction of underlying risk factors is central to the management of HE.
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Palladini G, Ferrigno A, Di Pasqua LG, Berardo C, Rizzo V, Perlini S, Vairetti M. Associations between serum trace elements and inflammation in two animal models of nonalcoholic fatty liver disease. PLoS One 2020; 15:e0243179. [PMID: 33306695 PMCID: PMC7732075 DOI: 10.1371/journal.pone.0243179] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 11/16/2020] [Indexed: 01/14/2023] Open
Abstract
Background The comparison of hepatic steatosis animal models has allowed the understanding of mechanisms involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the progression to nonalcoholic steatohepatitis (NASH). We investigated the changes in serum levels of trace elements and inflammation markers in fatty livers using two rat models of NAFLD, the methionine and choline deficient (MCD) diet model and Obese-Zucker rats. Material and methods NAFLD was induced in male Wistar rats by 3-week MCD diet administration, after which, blood samples were collected. 12-week old Obese (fa/fa) and Lean (fa/-) male Zucker rats were also used. Serum levels of hepatic enzymes, Urea, Uric acid, Ca2+, Cl, Fe, K, Na, Mg and Zn were quantified, as well as the inflammation markers TNF-alpha, IL-1beta and IL-6. Results In MCD rats, a serum increase in Cl, Mg and Na and a decrease in Ca2+, Zn were detected in comparison with control rats. An increase in only serum Ca2+ was found in Obese-Zucker rats. In MCD rat serum, Zn was inversely correlated with IL-1beta, IL-6, TNF-alpha, Urea and Uric Acid; Ca2+ was inversely correlated with IL-1beta, IL-6 and Urea; Cl and Mg were directly correlated with Uric Acid and Urea, respectively. In Obese-Zucker rats, Cl and IL-1beta were inversely correlated, whereas Ca2+ and Urea where directly correlated, as well Fe and TNF-alpha. Conclusions The serum concentrations of trace elements change significantly only in MCD rats, which spontaneously progress to NASH. The causes of these changes may be a result of defense strategies of the organism, which is regulated by immunoregulatory cytokines. These results might suggest that the impairment of trace element status should be taken into account when the effectiveness of a pharmacological treatment is under evaluation.
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Affiliation(s)
- Giuseppina Palladini
- Dept of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Andrea Ferrigno
- Dept of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- * E-mail:
| | | | - Clarissa Berardo
- Dept of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Vittoria Rizzo
- Dept of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Stefano Perlini
- Dept of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Emergency Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mariapia Vairetti
- Dept of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
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43
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Nie Y, Zhang Y, Liu LX, Zhu X. Serum Lactate Level Predicts Short-Term and Long-Term Mortality of HBV-ACLF Patients: A Prospective Study. Ther Clin Risk Manag 2020; 16:849-860. [PMID: 32982257 PMCID: PMC7490053 DOI: 10.2147/tcrm.s272463] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 08/21/2020] [Indexed: 12/28/2022] Open
Abstract
Background Acute chronic liver failure (ACLF) is a high-mortality disease characterized by rapid deterioration of liver function and multiple organ failure. The aim of this study was to assess the short-term and long-term predictive values of serum lactate in HBV-ACLF patients to facilitate early treatment and thereby improve patient survival. Methods We conducted a single-center, observational prospective study of 108 hospitalized patients. Biochemical examination and demographic data were obtained within 24 hours of admission. Logistics analysis was used to determine whether serum levels were independently for prognosis of HBV-ACLF patients. The area under ROC curve evaluates the prediction accuracy compared to the existing score. Results Serum lactate levels in nonsurviving patients were significantly higher than those in surviving patients. Logistics analysis demonstrated that serum lactate was an independent risk factor for 28-day, 3-month, and 6-month mortality. ROC curve evaluates the prediction efficiencies of serum lactate for 28-day, 3-month, and 6-month mortality. The AUROCs of new scores by adding lactate (Child-Pugh+ lactate score, MELD+ lactate score, MELD-Na+ lactate score, CLIF-C OF+ lactate score, CLIF-SOFA+ lactate score, CLIF-C ACLF+ lactate score) were superior to those of existing scores, particularly the MELD score and MELD-Na score (P<0.05) at all time points. Conclusion Serum lactate can be used as an effective indicator to predict the short-term and long-term mortality in HBV-ACLF patients, and the predictive value of the MELD score and MELD-Na was improved by adjusting for lactate. Lactate testing at admission can be beneficial in prognostic assessment and clinical decision-making.
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Affiliation(s)
- Yuan Nie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Yue Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Lin-Xiang Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Xuan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
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44
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Lin X, Huang X, Wang L, Feng S, Chen X, Cai W, Huang Z. Prognostic Value of Acute-On-Chronic Liver Failure (ACLF) Score in Critically Ill Patients with Cirrhosis and ACLF. Med Sci Monit 2020; 26:e926574. [PMID: 32978936 PMCID: PMC7526342 DOI: 10.12659/msm.926574] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background In the intensive care unit (ICU), critically ill patients with cirrhosis and acute-on-chronic liver failure (ACLF) continue to have high mortality rates. The AARC ACLF score is a simple, newly-developed score based on Asian ACLF patients, which performs well in prognosis. The present study attempted to verify the prognostic ability of AARC ACLF in non-Asian critically ill patients with cirrhosis and ACLF. Material/Methods We enrolled 786 patients. Relevant clinical data were collected within 24 h after admission to compare the differences between survivors and non-survivors, and all the patients were followed up for at least 180 days. Results The 28-day, 90-day, and 180-day mortality rates were 28.9% (227/786), 36.4% (286/786), and 40.3% (317/786), respectively. Multivariate Cox regression analysis showed that AARC ACLF score (HR: 1.375, 95% CI: 1.247–1.516, P<0.001) was an independent predictive factor of 28-day mortality, and the AUROC of the predictive ability in 28-day mortality of the AARC ACLF score was 0.754. In addition, the AARC ACLF score was regraded into 3 classes (low risk: AARC ACLF <9, intermediate risk: 9≤ AARC ACLF <12, and high risk: AARC ACLF ≥12). The AARC ACLF score can be used for dynamic assessment by retest at days 4–7. Conclusions The AARC ACLF score has a good predictive value for 28-day, 90-day, and 180-day mortality in non-Asian critically ill patients with cirrhosis and ACLF, which is not inferior to CLIF-C ACLFsLact and other models. It is easy to use at bedside, and it is dynamic and reliable.
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Affiliation(s)
- Xinran Lin
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Xielin Huang
- Department of Gastroenterology Surgery, The Second Affiliated Hospital of Wenzhou Medical University,, Wenzhou, Zhejiang, China (mainland)
| | - Li Wang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Shuyi Feng
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Xiaofu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Weimin Cai
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
| | - Zhiming Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland)
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45
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Chen J, Hackett EP, Singh J, Kovács Z, Park JM. Simultaneous Assessment of Intracellular and Extracellular pH Using Hyperpolarized [1- 13C]Alanine Ethyl Ester. Anal Chem 2020; 92:11681-11686. [PMID: 32786486 DOI: 10.1021/acs.analchem.0c01568] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tissue pH is tightly regulated in vivo, being a sensitive physiological biomarker. Advent of dissolution dynamic nuclear polarization (DNP) and its translation to humans stimulated development of pH-sensitive agents. However, requirements of DNP probes such as biocompatibility, signal sensitivity, and spin-lattice relaxation time (T1) complicate in vivo translation of the agents. Here, we developed a 13C-labeled alanine derivative, [1-13C]-l-alanine ethyl ester, as a viable DNP probe whose chemical shift is sensitive to the physiological pH range, and demonstrated the feasibility in phantoms and rat livers in vivo. Alanine ethyl ester readily crosses cell membrane while simultaneously assessing extracellular and intracellular pH in vivo. Following cell transport, [1-13C]-l-alanine ethyl ester is instantaneously hydrolyzed to [1-13C]-l-alanine, and subsequently metabolized to [1-13C]lactate and [13C]bicarbonate. The pH-insensitive alanine resonance was used as a reference.
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Affiliation(s)
- Jun Chen
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States
| | - Edward P Hackett
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States
| | - Jaspal Singh
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States
| | - Zoltán Kovács
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States
| | - Jae Mo Park
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States.,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States.,Department of Electrical and Computer Engineering, University of Texas at Dallas, Richardson, Texas 75080, United States
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46
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Gholamipoor D, Nassiri-Toosi M, Azadi M, Asadi Gharabaghi M. The Relationship Between Airway Occlusion Pressure and Severity of liver Cirrhosis in Candidates for Liver Transplantation. Middle East J Dig Dis 2020; 12:111-115. [PMID: 32626564 PMCID: PMC7320985 DOI: 10.34172/mejdd.2020.170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND End-stage cirrhosis is an irreversible condition, and liver transplantation is the only treatment option in for the affected patients. Respiratory problems and abnormal breathing are common findings among these patients. In this study, for the first time, we examined the relationship between the severity of liver cirrhosis and respiratory drive measured by mouth occlusion pressure (P0.1). METHODS This was a cross-sectional study conducted on 50 candidates for liver transplantation who were referred to the pulmonary clinic of Imam Khomeini Hospital for pre-operative pulmonary evaluations. Arterial blood gas analysis (ABG), pulmonary function tests, and measurement of P0.1 were performed for all patients. The severity of liver disease was assessed using the Model for End-Stage Liver Disease (MELD) score. RESULTS The median P0.1 was 5 cm H2 O. P0.1 was negatively associated with PaCO2 (r = -0.466, p = 0.001) and HCO3 - (r = -0.384, p = 0.007), and was positively correlated with forced expiratory volume at 1s (FEV1 )/ forced vital capacity (FVC) (r = 0.282, p = 0.047). There was a strong correlation between P0.1 and MELD score (r = 0.750, p < 0.001). Backward multivariate linear regression revealed that a higher MELD score and lower PaCO2 were associated with increased P0.1. CONCLUSION High levels of P0.1 and strong direct correlation between P0.1 and MELD score observed in the present study are suggestive of the presence of abnormal increased respiratory drive in candidates for liver transplantation, which is closely related to their disease severity.
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Affiliation(s)
- Delara Gholamipoor
- Resident of Internal Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohssen Nassiri-Toosi
- Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masumeh Azadi
- Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Asadi Gharabaghi
- Thoracic Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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47
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Gao F, Lin MT, Yang XY, Cai MX, Nan H, Xie W, Huang ZM. Metabolic acidosis in critically ill patients with cirrhosis: Epidemiology and short-term mortality risk factors. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:883-891. [PMID: 31633484 DOI: 10.5152/tjg.2019.18813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Metabolic acidosis is a common complication in patients with cirrhosis at the intensive care units (ICUs) and associated with increased mortality. The aim of our research was to explore the epidemiology and risk factors of metabolic acidosis in critically ill patients with cirrhosis. MATERIALS AND METHODS A total of 975 patients with cirrhosis were selected into our study, and all participants were followed up for at least 28 days. Cox regression model and machine-learning algorithm were used to identify the importance of different risk factors, respectively. Finally, an improved prognostic model as Model for End-stage Liver Disease and metabolic acidosis (MELD-MA) was developed. RESULTS Among the 975 patients with liver cirrhosis, 506 had metabolic acidosis, including 257 patients who had decompensated metabolic acidosis at ICU admission. The 28-day mortality was 41% (206/506) in patients with metabolic acidosis. Bilirubin (hazard ratio (HR): 1.023, 95% confidence interval (CI): 1.011-1.036), international normalized ratio (HR: 1.527, 95% CI: 1.332-1.750), pH (HR: 0.173, 95% CI: 0.047-0.640), BE-Lac (HR: 0.907, 95% CI: 0.868-0.948), and BE-Na (HR: 0.923, 95% CI: 0.859-0.991) were considered as independent prognostic parameters for 28-day mortality. MELD-NA had significantly higher discrimination (area under the receiver operating characteristic curve 0.79) than MELD and Child-Pugh score. CONCLUSION Critically ill patients with cirrhosis have a high mortality rate and poor prognosis because of the high prevalence of metabolic acidosis. Lactic acidosis is the worst prognosis of all types of metabolic acidosis. MELD-MA performs well on the short-term mortality assessment in critically ill patients with cirrhosis and metabolic acidosis.
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Affiliation(s)
- Feng Gao
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Miao-Tong Lin
- Department of Emergency Medicine, Intensive Care, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xing-Yi Yang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Meng-Xing Cai
- Department of Cardiovascular Medicine, the Heart Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hao Nan
- Department of Respiratory Medicine, the Third People's Hospital of Yueqing, Wenzhou, China
| | - Wei Xie
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhi-Ming Huang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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48
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Smith FC, Stocker SL, Danta M, Carland JE, Kumar SS, Liu Z, Greenfield JR, Braithwaite HE, Cheng TS, Graham GG, Williams KM, Day RO. The safety and pharmacokinetics of metformin in patients with chronic liver disease. Aliment Pharmacol Ther 2020; 51:565-575. [PMID: 31960986 DOI: 10.1111/apt.15635] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/16/2019] [Accepted: 12/23/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. AIMS To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). METHODS Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. RESULTS All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CLMet /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P = 0.03). CONCLUSIONS The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145).
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Affiliation(s)
- Felicity C Smith
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
| | - Mark Danta
- St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia.,Gastroenterology and Hepatology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Jane E Carland
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
| | - Shaun S Kumar
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Zhixin Liu
- Stats Central, University of New South Wales, Kensington, NSW, Australia
| | - Jerry R Greenfield
- St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia.,Department of Diabetes and Endocrinology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,Diabetes and Metabolism, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Hannah E Braithwaite
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Tim S Cheng
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Garry G Graham
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Kenneth M Williams
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Richard O Day
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia.,St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
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49
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Munteanu C, ULUSOY Y, KİLİC B. Investigation of Healing Effects of Afyon Region Thermal Spring Water on Experimentally-Induced Gastritis in Mice. BALNEO RESEARCH JOURNAL 2020. [DOI: 10.12680/balneo.2020.347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
In this study, 40 Albino mice were induced with ethyl alcohol to form of gastritis. In the treatment stage, control group mice were given tap water, while study group mice were given fresh water of Süreyya I hot spring. Clinical, hematological, biochemical, blood gases measurements and histopathological examinations of the gastric tissue were performed on the 1st, 7th, 14th and 21th days after the initiation of the treatment. At the end of the study, no significant difference was found between the groups in terms of body temperature (p> 0.05), whereas heart and respiratory frequencies were significantly higher in the study group animals (p <0.05). Although mean WBC, NOTR, MON, EOS and MCV decreased significantly in both groups (p <0.05), it was found that the mean of these parameters were more significant in SG at all measurement times (p <0.05). It was determined that TP, ALB and GLU levels increased in SG contrast to CG, and statistically significant decreases in AST, ALT, CK, ALP, LDH, UREA, CREA and IgG levels after the treatment. Additionally, pH, partial CO2 pressure, base deficit, bicarbonate, Ca and K levels decreased after gastritis procedure, whereas lactate, Na and Cl levels increased. Consequently, the clinical, hematological, blood biochemical parameters, blood gases and histopathological findings were evaluated as a whole, it was concluded that Süreyya I hot spring water was very successful in the treatment of gastritis.
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Affiliation(s)
| | - Yavuz ULUSOY
- 2. Ministry of Agriculture and Forestry, Veterinary Control Central Research Institute, Pathology Laboratory, Ankara/ Turkey
| | - Bahadir KİLİC
- Ministry of Agriculture and Forestry, Veterinary Control Central Research Institute, Pathology Laboratory, Ankara/ Turkey
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50
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Henry KE, Chaney AM, Nagle VL, Cropper HC, Mozaffari S, Slaybaugh G, Parang K, Andreev OA, Reshetnyak YK, James ML, Lewis JS. Demarcation of Sepsis-Induced Peripheral and Central Acidosis with pH (Low) Insertion Cycle Peptide. J Nucl Med 2020; 61:1361-1368. [PMID: 32005774 DOI: 10.2967/jnumed.119.233072] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 01/22/2020] [Indexed: 01/04/2023] Open
Abstract
Acidosis is a key driver for many diseases, including cancer, sepsis, and stroke. The spatiotemporal dynamics of dysregulated pH across disease remain elusive, and current diagnostic strategies do not provide localization of pH alterations. We sought to explore if PET imaging using hydrophobic cyclic peptides that partition into the cellular membrane at low extracellular pH (denoted as pH [low] insertion cycles, or pHLIC) can permit accurate in vivo visualization of acidosis. Methods: Acid-sensitive cyclic peptide c[E4W5C] pHLIC was conjugated to bifunctional maleimide-NO2A and radiolabeled with 64Cu (half-life, 12.7 h). C57BL/6J mice were administered lipopolysaccharide (15 mg/kg) or saline (vehicle) and serially imaged with [64Cu]Cu-c[E4W5C] over 24 h. Ex vivo autoradiography was performed on resected brain slices and subsequently stained with cresyl violet to enable high-resolution spatial analysis of tracer accumulation. A non-pH-sensitive cell-penetrating control peptide (c[R4W5C]) was used to confirm specificity of [64Cu]Cu-c[E4W5C]. CD11b (macrophage/microglia) and TMEM119 (microglia) immunostaining was performed to correlate extent of neuroinflammation with [64Cu]Cu-c[E4W5C] PET signal. Results: [64Cu]Cu-c[E4W5C] radiochemical yield and purity were more than 95% and more than 99%, respectively, with molar activity of more than 0.925 MBq/nmol. Significantly increased [64Cu]Cu-c[E4W5C] uptake was observed in lipopolysaccharide-treated mice (vs. vehicle) within peripheral tissues, including blood, lungs, liver, and small intestines (P < 0.001-0.05). Additionally, there was significantly increased [64Cu]Cu-c[E4W5C] uptake in the brains of lipopolysaccharide-treated animals. Autoradiography confirmed increased uptake in the cerebellum, cortex, hippocampus, striatum, and hypothalamus of lipopolysaccharide-treated mice (vs. vehicle). Immunohistochemical analysis revealed microglial or macrophage infiltration, suggesting activation in brain regions containing increased tracer uptake. [64Cu]Cu-c[R4W5C] demonstrated significantly reduced uptake in the brain and periphery of lipopolysaccharide mice compared with the acid-mediated [64Cu]Cu-c[E4W5C] tracer. Conclusion: Here, we demonstrate that a pH-sensitive PET tracer specifically detects acidosis in regions associated with sepsis-driven proinflammatory responses. This study suggests that [64Cu]Cu-pHLIC is a valuable tool to noninvasively assess acidosis associated with both central and peripheral innate immune activation.
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Affiliation(s)
- Kelly E Henry
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Aisling M Chaney
- Department of Radiology, Stanford University, Stanford, California
| | - Veronica L Nagle
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.,Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.,Departments of Pharmacology and Radiology, Weill Cornell Medical College, New York, New York
| | - Haley C Cropper
- Department of Radiology, Stanford University, Stanford, California
| | - Saghar Mozaffari
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California
| | - Gregory Slaybaugh
- Department of Physics, University of Rhode Island, Kingston, Rhode Island
| | - Keykavous Parang
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California
| | - Oleg A Andreev
- Department of Physics, University of Rhode Island, Kingston, Rhode Island
| | - Yana K Reshetnyak
- Department of Physics, University of Rhode Island, Kingston, Rhode Island
| | - Michelle L James
- Department of Radiology, Stanford University, Stanford, California.,Department of Neurology and Neurological Science, Stanford University, Stanford, California; and
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York .,Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.,Departments of Pharmacology and Radiology, Weill Cornell Medical College, New York, New York.,Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York
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