|
1
|
Hayat MS, Shoaib MM, Sohail S, Ahmed S, Shahid F, Ahmad H, Naseer MR, Shoaib MM, Ahmed R. Evaluating the regional and demographic variables in alcoholic liver disease-related mortality trends in the United States from 1999 to 2020: A cross sectional study. Medicine (Baltimore) 2025; 104:e41988. [PMID: 40193677 PMCID: PMC11977744 DOI: 10.1097/md.0000000000041988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 04/09/2025] Open
Abstract
Alcoholism-related liver diseases are becoming one of the leading causes of cirrhosis- related deaths in the United States. Analyzing the temporal trends in alcoholic liver disease-related mortality among individuals, identifying the populations at high risk, and guiding the implementation of tailored interventions to address the escalating effects of alcoholic liver disease (ALD) on public health. Data extracted from death certificates via the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database was examined from 1999 to 2020 for ALD related age-adjusted mortality rates (AAMRs). The data was stratified by year, age, gender, race and geographical region. Annual percentage changes were calculated using Joinpoint Regression Program. A total of 373,302 deaths occurred due to ALD from 1999 to 2020. ALD related AAMRs declined from 1999 to 2006, followed by an initial slow rise till 2018, and then rising rapidly from 2018 to 2020. Individuals aged 55 to 64 had the highest mortality rates. Males had higher AAMRs than females. American Indians or Alaskans exhibited the highest AAMRs, and Asians or Pacific Islanders had the lowest. Western America having the highest mortality rate. New Mexico had the highest AAMR among states. Rural United States was a hotspot for ALD related mortality. There is an overall increase in ALD-related deaths in the United States from 1999 to 2020. The highest AAMRs were observed in American Indians or Alaskan, males, 55 to 64 years of age, in the Western region, in New Mexico state, and rural areas.
Collapse
Affiliation(s)
- Malik Saad Hayat
- Department of Medicine, King Edward Medical University, Nila Gumbad Chowk, Lahore, Punjab, Pakistan
| | - Muhammad Mukarram Shoaib
- Department of Medicine, King Edward Medical University, Nila Gumbad Chowk, Lahore, Punjab, Pakistan
| | - Sara Sohail
- Department of Medicine, King Edward Medical University, Nila Gumbad Chowk, Lahore, Punjab, Pakistan
| | - Shahzaib Ahmed
- Department of Medicine, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, Pakistan
| | - Fatima Shahid
- Department of Medicine, King Edward Medical University, Nila Gumbad Chowk, Lahore, Punjab, Pakistan
| | - Hadia Ahmad
- Department of Medicine, King Edward Medical University, Nila Gumbad Chowk, Lahore, Punjab, Pakistan
| | - Mohammad Rayyan Naseer
- Department of Medicine, King Edward Medical University, Nila Gumbad Chowk, Lahore, Punjab, Pakistan
| | | | - Raheel Ahmed
- Department of Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom
| |
Collapse
|
|
2
|
Xiao J, Wang F, Yuan Y, Gao J, Xiao L, Yan C, Guo F, Zhong J, Che Z, Li W, Lan T, Tacke F, Shah VH, Li C, Wang H, Dong E. Epidemiology of liver diseases: global disease burden and forecasted research trends. SCIENCE CHINA. LIFE SCIENCES 2025; 68:541-557. [PMID: 39425834 DOI: 10.1007/s11427-024-2722-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 09/02/2024] [Indexed: 10/21/2024]
Abstract
We assessed the global incidence, mortality, and disability-adjusted life years (DALYs) associated with various liver diseases, including alcohol-related liver disease (ALD), hepatitis B/C virus infections (HBV or HCV), liver cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), and other chronic liver diseases, from the 2019 Global Burden of Disease study. Additionally, we analyzed the global trends in hepatology research and drug development. From 2000 to 2019, prevalence rates increased for ALD, MASLD and other liver diseases, while they decreased for HBV, HCV, and liver cancer. Countries with a high socio-demographic index (SDI) exhibited the lowest mortality rates and DALYs. The burden of liver diseases varied due to factors like sex and region. In nine representative countries, MASLD, along with hepatobiliary cancer, showed highest increase in funding in hepatology research. Globally, the major research categories in hepatology papers from 2000 to 2019 were cancer, pathobiology, and MASLD. The United States (U.S.) was at the forefront of hepatology research, with China gradually increasing its influence over time. Hepatologists worldwide are increasingly focusing on studying the communication between the liver and other organs, while underestimating the research on ALD. Cancer, HCV, and MASLD were the primary diseases targeted for therapeutic development in clinical trials. However, the proportion of new drugs approved for the treatment of liver diseases was relatively low among all newly approved drugs in the U.S., China, Japan, and the European Union. Notably, there were no approved drug for the treatment of ALD in the world.
Collapse
Affiliation(s)
- Jia Xiao
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, China.
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, 510630, China.
| | - Fei Wang
- Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China
- School of Biological Sciences, Jinan University, Guangzhou, 519070, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, 410015, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lu Xiao
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Chao Yan
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Feifei Guo
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Jiajun Zhong
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Wei Li
- Faculty of Pharmaceutical Sciences, Toho University, Chiba Tokyo, 143-8540, Japan
| | - Tian Lan
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, 13353, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, 13353, Germany
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Cui Li
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, 100085, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266071, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
| |
Collapse
|
|
3
|
Li R, Prastein DJ. Patients with alcohol abuse have higher risks of complications after coronary artery bypass grafting: A population-based study of National Inpatient Sample from 2015 to 2020. Alcohol 2024; 120:51-57. [PMID: 38452863 DOI: 10.1016/j.alcohol.2024.03.002] [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: 02/12/2024] [Revised: 02/25/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND Alcohol abuse (AA) has s high prevalence, affecting 10 to 15 million Americans. While AA was demonstrated to negatively impact cardiovascular health, limited evidence from existing studies presents conflicting findings regarding the effects of AA on coronary artery bypass grafting (CABG) outcomes. This study aimed to compare the in-hospital outcomes after CABG between AA and non-AA patients. METHODS Patients who underwent CABG were identified in National Inpatient Sample from Q4 2015-2020. Exclusion criteria included age<18 years and concomitant procedures. A 1:3 propensity-score matching was used to address differences in demographics, socioeconomic status, primary payer status, hospital characteristics, comorbidities, and transfer/admission status between AA and non-AA patients. In-hospital outcomes after CABG were examined. RESULTS There were 5694 (3.39%) AA patients who underwent CABG. After matching, 17,315 from 162,488 non-AA patients were matched to all AA patients. AA and non-AA patients had comparable mortality (1.64% vs 1.55%, p = 0.67) and MACE (2.46% vs 2.56%, p = 0.73). However, AA patients had higher cardiogenic shock (8.31% vs 7.43%, p = 0.03), mechanical ventilation (11.51% vs 7.96%, p < 0.01), hemorrhage/hematoma (57.49% vs 54.75%, p < 0.01), superficial (0.99% vs 0.61%, p < 0.01) and deep wound complications (0.37% vs 0.18%, p = 0.02), reopen surgery for bleeding control (0.92% vs 0.63%, p = 0.03), transfer out (21.00% vs 16.38%, p < 0.01), longer time from admission to operation (p < 0.01), longer length of stay (p < 0.01), and higher hospital charge (p < 0.01). CONCLUSION While AA was not found to be linked with in-hospital mortality or MACE after CABG, it was independently associated with postoperative complications. These findings could enhance preoperative risk stratification for AA patients and inform postoperative management following CABG.
Collapse
Affiliation(s)
- Renxi Li
- The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
| | - Deyanira J Prastein
- The George Washington University Hospital, Department of Surgery, Washington, DC, USA
| |
Collapse
|
|
4
|
Battistella S, Grasso M, Catanzaro E, D’Arcangelo F, Corrà G, Germani G, Senzolo M, Zanetto A, Ferrarese A, Gambato M, Burra P, Russo FP. Evolution of Liver Transplantation Indications: Expanding Horizons. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:412. [PMID: 38541138 PMCID: PMC10972065 DOI: 10.3390/medicina60030412] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 01/03/2025]
Abstract
Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy; (S.B.); (E.C.); (F.D.); (G.C.); (G.G.); (M.S.); (A.Z.); (A.F.); (M.G.); (P.B.)
| |
Collapse
|
|
5
|
Bai Y, Liu F, Zheng L, Wan Y, Fan J, Deng J, Li Q, Xie Y, Guo P. "Yajieshaba" prevents acute alcoholic liver injury and repairs the intestinal mucosal barrier. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116921. [PMID: 37490990 DOI: 10.1016/j.jep.2023.116921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/12/2023] [Accepted: 07/13/2023] [Indexed: 07/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE An essential factor related to the acute alcoholic liver injury is damage to the intestinal mucosal barrier. Yajieshaba (YJSB) is a commonly used formulation of Dai people in China and protects the liver. AIM OF THE STUDY This study investigated whether YJSB can prevent acute alcoholic liver injury by regulating the intestinal mucosal barrier. MATERIALS AND METHODS The mice received 0.39 g/kg, 1.17 g/kg, and 3.51 g/kg dose YJSB for 7 days, a mouse model of acute alcoholic liver injury was established by a single instillation of 56% alcohol. Plasma biochemical markers were analyzed, liver injury was identified by histopathology, lipopolysaccharide (LPS), nuclear factor-k-gene binding (NF-κB), hepatic inflammatory factors, oxidative stress factors and reactive oxygen species (ROS) content was analyzed. The morphological changes of intestinal histology were observed by H&E staining, and the ultrastructure of ileal cells was observed by transmission electron microscopy. Immunofluorescence and Western blot was used to determine the expression levels of transporters and enzymes involved in Claudin 1, Occludin and zona occludens 1 (ZO-1) homeostasis in the liver and intestine. RESULTS The findings showed that YJSB reduced the levels of aspartate aminotr ansferase (AST), alanine aminotransferase (ALT) and total bile acid (TBA), both of which are indicators of liver function and had a protective effect against liver injury. In the liver homogenate, YJSB reduced the level of LPS, NF-κB, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), decreased the level of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-PX) and catalase (CAT) and ROS. The results of hematoxylin and eosin (H&E) staining and transmission electron microscopy analysis revealed that YJSB reduced the degree of damage to intestinal tissue and intracellular organelles, implying that YJSB can reduce the "attack factor" that causes intestinal barrier damage, increase the "defense factor" that protects the intestinal barrier. The results of immunohistochemistry and Western blotting analysis showed that YJSB could increase the expression of claudin 1, occludin, and ZO-1 proteins, suggesting that the mechanism of action of YJSB against acute alcohol liver injury involves the upregulation of the expression of the intestinal barrier-related proteins and the repair of the damaged intestinal barrier. CONCLUSIONS YJSB can block LPS, oxidative stress factors, and other harmful substances in the blood and protect the liver resisting acute alcoholic liver injury.
Collapse
Affiliation(s)
- Yuanmei Bai
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Feifan Liu
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Lijie Zheng
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Yan Wan
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Jiachen Fan
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Jiahao Deng
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Qiongchao Li
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Yuhuan Xie
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China.
| | - Peixin Guo
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, People's Republic of China; Yunnan Key Laboratory of Dai and Yi Medicines, Yunnan University of Chinese Medicine, Kunming, 650500, Yunnan, People's Republic of China.
| |
Collapse
|
|
6
|
Mac Gearailt C, Murphy C, McCaffrey J, Turk M, Murray K. A thematic analysis of alcohol use and culture amongst elite (intercounty) Gaelic Athletic Association (GAA) players. Ir J Med Sci 2023; 192:3169-3173. [PMID: 37150759 PMCID: PMC10692017 DOI: 10.1007/s11845-023-03394-7] [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: 04/03/2023] [Accepted: 04/27/2023] [Indexed: 05/09/2023]
Abstract
BACKGROUND There are limited studies examining alcohol consumption in Gaelic Athletic Association (GAA) players. In a previous paper, we reported excess alcohol consumption, alcohol-related harms and binge drinking amongst elite GAA players. In that survey, the players were provided with an opportunity to provide comments on alcohol. This current study analyses these comments. AIMS The aim of this study was to provide a qualitative analysis of elite GAA players opinions on alcohol consumption, harms, behaviours and culture. METHODS An anonymous, web-based e-questionnaire was distributed to all registered adult elite (inter-county) GAA players. This analysed demographics, alcohol consumption, alcohol culture and alcohol-related harms. This paper is a thematic analysis of the players comments on alcohol in the GAA. RESULTS Seven hundred seventy-three of 3592 (21%) players responded. One hundred fifty-two respondents (21%) commented in the free text section of the survey regarding alcohol. One hundred eleven comments (73%) were suitable for analysis. Relevant themes were a pattern of abstinence and bingeing (n = 44), excess alcohol consumption (n = 40) and drinking bans contributing to a binge drinking culture (n = 37). There was a mixed attitude to alcohol sponsorship. CONCLUSION These data show players recognise intermittent binge drinking with periods of abstinence and alcohol-related harms. Further initiatives regarding alcohol harm reduction merit consideration including prohibition of alcohol sponsorship, similar to the GAA's ban on gambling.
Collapse
Affiliation(s)
| | - Colm Murphy
- Washington Street Medical Centre, Cork, Ireland
| | - Jack McCaffrey
- Children's Health Ireland, Temple Street, Dublin, Ireland
| | | | - Kieran Murray
- University Hospital Limerick and University of Limerick, Limerick, Ireland.
| |
Collapse
|
|
7
|
Shetty A, Ibrahim B, Eskander B, Saab S. Management of Patients After Treatment of Severe Alcohol-associated Hepatitis. J Clin Gastroenterol 2023; 57:991-1000. [PMID: 37428091 DOI: 10.1097/mcg.0000000000001882] [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: 07/11/2023]
Abstract
Alcohol-associated liver disease is the leading indication for hospitalization among patients with chronic liver disease. Rates of hospitalization for alcohol-associated hepatitis have been rising over the last 2 decades. Patients with alcohol-associated hepatitis carry significant morbidity and mortality, but there is a lack of standardized postdischarge management strategies to care for this challenging group of patients. Patients warrant management of not only their liver disease but also their alcohol use disorder. In this review, we will discuss outpatient management strategies for patients who were recently hospitalized and discharged for alcohol-associated hepatitis. We will discuss short management of their liver disease, long-term follow-up, and review-available treatment options for alcohol use disorder and challenges associated with pursuing treatment for alcohol use disorder.
Collapse
Affiliation(s)
- Akshay Shetty
- Departments of Medicine
- Surgery, University of California at Los Angeles, Los Angeles, CA
| | | | - Benjamin Eskander
- Departments of Medicine
- Surgery, University of California at Los Angeles, Los Angeles, CA
| | - Sammy Saab
- Departments of Medicine
- Surgery, University of California at Los Angeles, Los Angeles, CA
| |
Collapse
|
|
8
|
Morales R, Bolarín JM, Muro M, Legaz I. Presence of KIR2DL2/S2, KIR2DL5, and KIR3DL1 Molecules in Liver Transplant Recipients with Alcoholic Cirrhosis Could Be Implicated in Death by Graft Failure. Diagnostics (Basel) 2023; 13:diagnostics13071217. [PMID: 37046435 PMCID: PMC10093628 DOI: 10.3390/diagnostics13071217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Background: The second-most frequent diagnosis among patients receiving liver transplants (LTs) is alcoholic liver disease. The multifactorial pathophysiology of alcoholic liver disease depends on the innate immune system and the inflammatory cascade. According to recent studies on these receptors, killer-cell immunoglobulin-like receptors (KIRs) may be involved in sepsis, liver rejection, and virus relapse. We aimed to investigate the impact of preclinical issues like ascites and encephalopathy and KIR genetic traits on death from sepsis, multiorgan failure (MF), and graft failure (GF) in AC patients undergoing LTs. Methods: We retrospectively reviewed 164 consecutive and deceased Caucasian AC patients who underwent LTs. Pre-transplant complications, cause of death, and patient survival were analyzed. Genomic DNA was taken from peripheral blood, and PCR-SSO was used for genotyping KIR. Results: Compared to GF patients, there was a statistically significant increase in the frequency of KIR2DL2+ (75.8% vs. 51.2%; p = 0.047). Another increase in frequency was also observed in KIR2DS2+ in sepsis compared to the GF group (51.2% vs. 43.7%; p = 0.018). In patients who passed away from MF, a decrease in KIR2DL5+ was observed in AC patients with and without encephalopathy (p = 0.018). The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.045), which was confirmed by multivariate logistic regression. The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.012) and was confirmed by multivariate logistic regression. KIR2DS1+ and KIR2DS4+ showed increased mortality due to GF compared to patients without these genes (p = 0.011 and 0.012, respectively). However, this fact was confirmed only for KIR2DS1+ by multivariate logistic Cox regression. Conclusions: The presence of the KIR2DL2/S2+, KIR2DL5+, and KIR3DL1+ genes increases the frequency of death from multiple organ failure or graft failure. Our findings highlight the AC patient’s vulnerability to a LT during hospitalization. Following the transplant and outside of it, we adopt essential preventive measures to create a routine healthcare screening to enhance and modify treatments to increase survival.
Collapse
Affiliation(s)
- Raquel Morales
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
| | - José Miguel Bolarín
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
| | - Manuel Muro
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
- Correspondence: (M.M.); (I.L.); Tel.: +34-968-369-599 (M.M.); +34-868-883-957 (I.L.); Fax: +34-968-349-678 (M.M.); +34-868-834-307 (I.L.)
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
- Correspondence: (M.M.); (I.L.); Tel.: +34-968-369-599 (M.M.); +34-868-883-957 (I.L.); Fax: +34-968-349-678 (M.M.); +34-868-834-307 (I.L.)
| |
Collapse
|
|
9
|
Neonatal Orally Administered Zingerone Attenuates Alcohol-Induced Fatty Liver Disease in Experimental Rat Models. Metabolites 2023; 13:metabo13020167. [PMID: 36837786 PMCID: PMC9966972 DOI: 10.3390/metabo13020167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Alcohol intake at different developmental stages can lead to the development of alcohol-induced fatty liver disease (AFLD). Zingerone (ZO) possess hepato-protective properties; thus, when administered neonatally, it could render protection against AFLD. This study aimed to evaluate the potential long-term protective effect of ZO against the development of AFLD. One hundred and twenty-three 10-day-old Sprague-Dawley rat pups (60 males; 63 females) were randomly assigned to four groups and orally administered the following treatment regimens daily during the pre-weaning period from postnatal day (PND) 12-21: group 1-nutritive milk (NM), group 2-NM +1 g/kg ethanol (Eth), group 3-NM + 40 mg/kg ZO, group 4-NM + Eth +ZO. From PND 46-100, each group from the neonatal stage was divided into two; subgroup I had tap water and subgroup II had ethanol solution as drinking fluid, respectively, for eight weeks. Mean daily ethanol intake, which ranged from 10 to 14.5 g/kg body mass/day, resulted in significant CYP2E1 elevation (p < 0.05). Both late single hit and double hit with alcohol increased liver fat content, caused hepatic macrosteatosis, dysregulated mRNA expression of SREBP1c and PPAR-α in male and female rats (p < 0.05). However, neonatal orally administered ZO protected against liver lipid accretion and SREBP1c upregulation in male rats only and attenuated the alcohol-induced hepatic PPAR-α downregulation and macrosteatosis in both sexes. This data suggests that neonatal orally administered zingerone can be a potential prophylactic agent against the development of AFLD.
Collapse
|
|
10
|
Zhou Y, Hua J, Huang Z. Effects of beer, wine, and baijiu consumption on non-alcoholic fatty liver disease: Potential implications of the flavor compounds in the alcoholic beverages. Front Nutr 2023; 9:1022977. [PMID: 36687705 PMCID: PMC9852916 DOI: 10.3389/fnut.2022.1022977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/07/2022] [Indexed: 01/09/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and its global incidence is estimated to be 24%. Beer, wine, and Chinese baijiu have been consumed worldwide including by the NAFLD population. A better understanding of the effects of these alcoholic beverages on NAFLD would potentially improve management of patients with NAFLD and reduce the risks for progression to fibrosis, cirrhosis, and hepatocellular carcinoma. There is evidence suggesting some positive effects, such as the antioxidative effects of bioactive flavor compounds in beer, wine, and baijiu. These effects could potentially counteract the oxidative stress caused by the metabolism of ethanol contained in the beverages. In the current review, the aim is to evaluate and discuss the current human-based and laboratory-based study evidence of effects on hepatic lipid metabolism and NAFLD from ingested ethanol, the polyphenols in beer and wine, and the bioactive flavor compounds in baijiu, and their potential mechanism. It is concluded that for the potential beneficial effects of wine and beer on NAFLD, inconsistence and contrasting data exist suggesting the need for further studies. There is insufficient baijiu specific human-based study for the effects on NAFLD. Although laboratory-based studies on baijiu showed the antioxidative effects of the bioactive flavor compounds on the liver, it remains elusive whether the antioxidative effect from the relatively low abundance of the bioactivate compounds could outweigh the oxidative stress and toxic effects from the ethanol component of the beverages.
Collapse
Affiliation(s)
- Yabin Zhou
- School of Biological Engineering, Sichuan University of Science and Engineering (SUSE), Zigong, Sichuan, China,Liquor-Making Biotechnology and Application Key Laboratory of Sichuan Province, Sichuan University of Science and Engineering (SUSE), Zigong, Sichuan, China,College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Jin Hua
- School of Biological Engineering, Sichuan University of Science and Engineering (SUSE), Zigong, Sichuan, China,College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Zhiguo Huang
- School of Biological Engineering, Sichuan University of Science and Engineering (SUSE), Zigong, Sichuan, China,Liquor-Making Biotechnology and Application Key Laboratory of Sichuan Province, Sichuan University of Science and Engineering (SUSE), Zigong, Sichuan, China,*Correspondence: Zhiguo Huang,
| |
Collapse
|
|
11
|
Sedki M, Ahmed A, Goel A. Ethical and allocation issues in liver transplant candidates with alcohol related liver disease. Transl Gastroenterol Hepatol 2022; 7:26. [PMID: 35892052 PMCID: PMC9257533 DOI: 10.21037/tgh-2020-13] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 09/17/2020] [Indexed: 09/01/2024] Open
Abstract
In the past decade, alcohol-related liver disease (ALD) has become the leading indication for liver transplantation (LT) in the United States. Despite this major development, there still remains some controversy in a distinct subset of this patient population, those presenting with alcoholic hepatitis (AH). There is significant debate within the transplant community regarding acceptance criteria for patients with AH requiring LT, especially those with less than 6 months of sobriety. With that being said, LT in the setting of ALD and AH has shown an improvement in survival rates; additionally, many studies have reported that careful selection of patients with ALD has produced excellent post-transplant outcomes even if transplant occurred with less than 6 months of sobriety. In this review, we aim to discuss the ethical and allocation-associated issues that arise when considering ALD and/or AH for LT; furthermore, we delve into the history, controversies, current guidelines, and future directions of LT in this subgroup.
Collapse
Affiliation(s)
- Mai Sedki
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aparna Goel
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
12
|
Riaz F, Wei P, Pan F. Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review. Front Cell Dev Biol 2022; 10:949603. [PMID: 35912096 PMCID: PMC9337771 DOI: 10.3389/fcell.2022.949603] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
The majority of chronic hepatic diseases are caused by nutritional imbalance. These nutritional inequities include excessive intake of alcohol and fat, which causes alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), respectively. The pathogenesis of hepatic diseases is mainly dependent on oxidative stress, autophagy, DNA damage, and gut microbiota and their metabolites. These factors influence the normal physiology of the liver and impact the hepatic microenvironment. The hepatic microenvironment contains several immune cells and inflammatory cytokines which interact with each other and contribute to the progression of chronic hepatic diseases. Among these immune cells, Foxp3+ CD4+ regulatory T cells (Tregs) are the crucial subset of CD4+ T cells that create an immunosuppressive environment. This review emphasizes the function of Tregs in the pathogenesis of ALD and NAFLD and their role in the progression of NAFLD-associated hepatocellular carcinoma (HCC). Briefly, Tregs establish an immunosuppressive landscape in the liver by interacting with the innate immune cells and gut microbiota and their metabolites. Meanwhile, with the advancement of steatosis, these Tregs inhibit the proliferation, activation and functions of other cytotoxic T cells and support the progression of simple steatosis to HCC. Briefly, it can be suggested that targeting Tregs can act as a favourable prognostic indicator by modulating steatosis and insulin resistance during the pathogenesis of hepatic steatosis and NAFLD-associated HCC.
Collapse
Affiliation(s)
- Farooq Riaz
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Ping Wei
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Chongqing Key Laboratory of Pediatrics, Department of otolaryngology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Fan Pan
- Center for Cancer Immunology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- *Correspondence: Fan Pan,
| |
Collapse
|
|
13
|
Chintakindi S, Boateng BA, Vodkin I, Herrick N, Moceri M, Raleigh D, Wang E, El-Said H, Reeves R, Sepulveda JS, Alshawabkeh L. Alcohol use is prevalent among adults with the fontan circulation but does not correlate with liver disease. INTERNATIONAL JOURNAL OF CARDIOLOGY CONGENITAL HEART DISEASE 2022; 7:100339. [PMID: 39712264 PMCID: PMC11657169 DOI: 10.1016/j.ijcchd.2022.100339] [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: 12/01/2021] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
Background Alcohol consumption is associated with an increased risk of liver disease. There are limited studies on the epidemiology of alcohol use and its effects on Fontan-associated liver disease (FALD) in adulthood. Methods In this single-center prospective cohort study, patients were enrolled from the Fontan clinic between November 2019 and November 2020, excluding those with chronic hepatitis C or B. Alcohol consumption was quantified by Alcohol Use Disorders Identification Test (AUDIT) questionnaire and a supplementary questionnaire. Participants were stratified into alcohol consumers and non-consumers. Alcohol consumption was correlated to the magnitude of fibrosis on liver biopsy and the varices, ascites, splenomegaly, and thrombocytopenia (VAST) score. Results Forty-three patients (age 30 ± 6.5 years) were enrolled, and most were in NYHA FC 1 or 2. Twenty-six (60.5%) participants consumed alcohol regularly in the past year (twenty with low-risk consumption and six with hazardous consumption). Alcohol consumers were more likely to have better NYHA FC. Of those, half reported alcohol consumption for longer than one year before enrollment. Eleven (25.6%) participants reported underage drinking. After multivariable adjustment, male sex was associated with increased severity of liver fibrosis (OR 3.7 [1.0 to 13.6]). Alcohol consumption was not associated with liver fibrosis (OR 1.2 [0.3 to 4.9]) or VAST scores (OR 1.2 [0.01 to 2.2]). Conclusions Alcohol consumption is prevalent among adults with the Fontan circulation but does not correlate with FALD. However, further studies are required to validate the results in cohorts with heavier alcohol consumption. Underage drinking was prevalent and warrants screening in pediatrics.
Collapse
Affiliation(s)
| | | | | | - Nicole Herrick
- Division of Cardiovascular Medicine, Department of Medicine, United States
| | - Maria Moceri
- Division of Cardiovascular Medicine, Department of Medicine, United States
| | - Deborah Raleigh
- Division of Cardiovascular Medicine, Department of Medicine, United States
| | - Edward Wang
- Division of Cardiovascular Medicine, Department of Medicine, United States
| | - Howaida El-Said
- Division of Pediatric Cardiology, Department of Pediatrics, University of California, San Diego, United States
| | - Ryan Reeves
- Division of Cardiovascular Medicine, Department of Medicine, United States
| | - Jose Silva Sepulveda
- Division of Pediatric Cardiology, Department of Pediatrics, University of California, San Diego, United States
| | - Laith Alshawabkeh
- Division of Cardiovascular Medicine, Department of Medicine, United States
| |
Collapse
|
|
14
|
Fenollal-Maldonado G, Brown D, Hoffman H, Kahlon C, Grossberg G. Alcohol Use Disorder in Older Adults. Clin Geriatr Med 2021; 38:1-22. [PMID: 34794695 DOI: 10.1016/j.cger.2021.07.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
As the number of older adults worldwide continues to grow, we observe a proportional growth of substance use. Despite the myriad of complications alcohol use disorder (AUD) has on the body with regards to organ systems and mental health, the topic has been underresearched in the older adult population. Thus, it is important to create awareness about the growing problem of AUD among older adults. In this way, we can mitigate the long-term complications and side effects observed with alcohol abuse in this vulnerable population.
Collapse
Affiliation(s)
- Gabriela Fenollal-Maldonado
- Department of Psychiatry and Behavioral Neuroscience, Division of Geriatric Psychiatry, St. Louis University School of Medicine, 1438 South Grand Boulevard, St Louis, MO 63104, US.
| | - Derek Brown
- Department of Psychiatry and Behavioral Neuroscience, Division of Geriatric Psychiatry, St. Louis University School of Medicine, 1438 South Grand Boulevard, St Louis, MO 63104, US
| | - Heidi Hoffman
- Saint Louis University School of Medicine, St. Louis University, 1438 South Grand Boulevard, St Louis, MO 63104, US
| | - Chanchal Kahlon
- Saint Louis University School of Medicine, St. Louis University, 1438 South Grand Boulevard, St Louis, MO 63104, US
| | - George Grossberg
- Department of Psychiatry and Behavioral Neuroscience, Division of Geriatric Psychiatry, St. Louis University School of Medicine, 1438 South Grand Boulevard, St Louis, MO 63104, USA
| |
Collapse
|
|
15
|
Liu M, Cao S, He L, Gao J, Arab JP, Cui H, Xuan W, Gao Y, Sehrawat TS, Hamdan FH, Ventura-Cots M, Argemi J, Pomerantz WCK, Johnsen SA, Lee JH, Gao F, Ordog T, Mathurin P, Revzin A, Bataller R, Yan H, Shah VH. Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis. Nat Commun 2021; 12:4560. [PMID: 34315876 PMCID: PMC8316465 DOI: 10.1038/s41467-021-24843-w] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 07/01/2021] [Indexed: 02/08/2023] Open
Abstract
Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.
Collapse
Affiliation(s)
- Mengfei Liu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sheng Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Li He
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Juan P Arab
- Department of Gastroenterology and Hepatology, School of Medicine of the Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Huarui Cui
- Department of Chemistry, University of Minnesota, Minneapolis, MN, USA
| | - Weixia Xuan
- Department of Respiratory and Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Yandong Gao
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Feda H Hamdan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Meritxell Ventura-Cots
- Department of Gastroenterology Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
| | - Josepmaria Argemi
- Department of Gastroenterology Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Steven A Johnsen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jeong-Heon Lee
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Fei Gao
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Tamas Ordog
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Alexander Revzin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Ramon Bataller
- Department of Gastroenterology Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
| | - Huihuang Yan
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
16
|
Causes of Death and Survival in Alcoholic Cirrhosis Patients Undergoing Liver Transplantation: Influence of the Patient's Clinical Variables and Transplant Outcome Complications. Diagnostics (Basel) 2021; 11:diagnostics11060968. [PMID: 34072173 PMCID: PMC8227029 DOI: 10.3390/diagnostics11060968] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 11/17/2022] Open
Abstract
Background. Clinical and molecular mechanisms involved in the cause and time of death of alcoholic cirrhosis (AC) patients undergoing liver transplantation (LT) are not entirely understood. In sudden death cases, judicial autopsy practice is mandatory for determining the cause and circumstances of death. The medico-legal autopsy data are essential for helping health authorities to guide future public health activities, assess the effectiveness of health systems, and adopt the necessary preventive measures to improve and adapt the treatments in order to increase these patients’ survival. Objective. Our study aimed to determine the different clinical and sociodemographic causes that influence the different causes of death and the short- and long-term survival of AC patients undergoing liver transplantation. Methods. A total of 122 deceased AC patients undergoing LT were analyzed at different times post-transplantation. The main pre- and post-transplant complications were analyzed in relation to the cause of death and the patient’s survival, as well as the causes and time at which the patient’s death occurred. Results. A total of 53.3% of non-sudden death was observed. A large number of the deaths of AC patients undergoing transplantation were due to non-sudden death, sepsis, and graft failure (GF), the main causes of death in the sample being similar in both sexes. In non-sudden deaths, there were no significant differences between the death rates either related or not related to the liver transplant. Sepsis was the main cause, with the highest percentage (21.3%) of mortality, followed by GF (18.9%) and multiorgan failure (15.6%) at ten years. Furthermore, our results showed how pre-transplant clinical complications, such as viral infections and encephalopathy, influence the age at which multiorgan failure occurs in the transplanted patient. Conclusion. Multiorgan failure is the leading cause of sudden death, with higher mortality during the first year after transplantation, followed by sepsis and GF. Our results show the vulnerability of AC patients, both in the hospital period after the transplant and outside.
Collapse
|
|
17
|
Thomes PG, Rasineni K, Saraswathi V, Kharbanda KK, Clemens DL, Sweeney SA, Kubik JL, Donohue TM, Casey CA. Natural Recovery by the Liver and Other Organs after Chronic Alcohol Use. Alcohol Res 2021; 41:05. [PMID: 33868869 PMCID: PMC8041137 DOI: 10.35946/arcr.v41.1.05] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Chronic, heavy alcohol consumption disrupts normal organ function and causes structural damage in virtually every tissue of the body. Current diagnostic terminology states that a person who drinks alcohol excessively has alcohol use disorder. The liver is especially susceptible to alcohol-induced damage. This review summarizes and describes the effects of chronic alcohol use not only on the liver, but also on other selected organs and systems affected by continual heavy drinking—including the gastrointestinal tract, pancreas, heart, and bone. Most significantly, the recovery process after cessation of alcohol consumption (abstinence) is explored. Depending on the organ and whether there is relapse, functional recovery is possible. Even after years of heavy alcohol use, the liver has a remarkable regenerative capacity and, following alcohol removal, can recover a significant portion of its original mass and function. Other organs show recovery after abstinence as well. Data on studies of both heavy alcohol use among humans and animal models of chronic ethanol feeding are discussed. This review describes how (or whether) each organ/tissue metabolizes ethanol, as metabolism influences the organ’s degree of injury. Damage sustained by the organ/tissue is reviewed, and evidence for recovery during abstinence is presented.
Collapse
Affiliation(s)
- Paul G Thomes
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Karuna Rasineni
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Viswanathan Saraswathi
- Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska.,Department of Internal Medicine, Section of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska
| | - Kusum K Kharbanda
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Dahn L Clemens
- Department of Internal Medicine, Section of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, Nebraska.,Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Sarah A Sweeney
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Jacy L Kubik
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Terrence M Donohue
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Carol A Casey
- Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.,Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| |
Collapse
|
|
18
|
Rasineni K, Jordan CW, Thomes PG, Kubik JL, Staab EM, Sweeney SA, Talmon GA, Donohue TM, McNiven MA, Kharbanda KK, Casey CA. Contrasting Effects of Fasting on Liver-Adipose Axis in Alcohol-Associated and Non-alcoholic Fatty Liver. Front Physiol 2021; 12:625352. [PMID: 33746771 PMCID: PMC7966527 DOI: 10.3389/fphys.2021.625352] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/02/2021] [Indexed: 01/15/2023] Open
Abstract
Background: Fatty liver, a major health problem worldwide, is the earliest pathological change in the progression of alcohol-associated (AFL) and non-alcoholic fatty liver disease (NAFL). Though the causes of AFL and NAFL differ, both share similar histological and some common pathophysiological characteristics. In this study, we sought to examine mechanisms responsible for lipid dynamics in liver and adipose tissue in the setting of AFL and NAFL in response to 48 h of fasting. Methods: Male rats were fed Lieber-DeCarli liquid control or alcohol-containing diet (AFL model), chow or high-fat pellet diet (NAFL model). After 6-8 weeks of feeding, half of the rats from each group were fasted for 48 h while the other half remained on their respective diets. Following sacrifice, blood, adipose, and the liver were collected for analysis. Results: Though rats fed AFL and NAFL diets both showed fatty liver, the physiological mechanisms involved in the development of each was different. Here, we show that increased hepatic de novo fatty acid synthesis, increased uptake of adipose-derived free fatty acids, and impaired triglyceride breakdown contribute to the development of AFL. In the case of NAFL, however, increased dietary fatty acid uptake is the major contributor to hepatic steatosis. Likewise, the response to starvation in the two fatty liver disease models also varied. While there was a decrease in hepatic steatosis after fasting in ethanol-fed rats, the control, chow and high-fat diet-fed rats showed higher levels of hepatic steatosis than pair-fed counterparts. This diverse response was a result of increased adipose lipolysis in all experimental groups except fasted ethanol-fed rats. Conclusion: Even though AFL and NAFL are nearly histologically indistinguishable, the physiological mechanisms that cause hepatic fat accumulation are different as are their responses to starvation.
Collapse
Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Clayton W. Jordan
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Paul G. Thomes
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Jacy L. Kubik
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Elizabeth M. Staab
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Sarah A. Sweeney
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Terrence M. Donohue
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Mark A. McNiven
- Department of Biochemistry and Molecular Biology and the Center for Digestive Diseases, Mayo Clinic, Rochester, MN, United States
| | - Kusum K. Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol A. Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| |
Collapse
|
|
19
|
Asiedu B, Nyakudya TT, Lembede BW, Chivandi E. Early-life exposure to alcohol and the risk of alcohol-induced liver disease in adulthood. Birth Defects Res 2021; 113:451-468. [PMID: 33577143 DOI: 10.1002/bdr2.1881] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 11/10/2022]
Abstract
Alcohol consumption remains prevalent among pregnant and nursing mothers despite the well-documented adverse effects this may have on the offspring. Moderate-to-high levels of alcohol consumption in pregnancy result in fetal alcohol syndrome (FAS) disorders, with brain defects being chief among the abnormalities. Recent findings indicate that while light-to-moderate levels may not cause FAS, it may contribute to epigenetic changes that make the offspring prone to adverse health outcomes including metabolic disorders and an increased propensity in the adolescent-onset of drinking alcohol. On the one hand, prenatal alcohol exposure (PAE) causes epigenetic changes that affect lipid and glucose transcript regulating genes resulting in metabolic abnormalities. On the other hand, it can program offspring for increased alcohol intake, enhance its palatability, and increase acceptance of alcohol's flavor through associative learning, making alcohol a plausible second hit for the development of alcohol-induced liver disease. Adolescent drinking results in alcohol dependence and abuse in adulthood. Adolescent drinking results in alcohol dependence and abuse in adulthood. Alterations on the opioid system, particularly, the mu-opioid system, has been implicated in the mechanism that induces increased alcohol consumption and acceptance. This review proposes a mechanism that links PAE to the development of alcoholism and eventually to alcoholic liver disease (ALD), which results from prolonged alcohol consumption. While PAE may not lead to ALD development in childhood, there are chances that it may lead to ALD in adulthood.
Collapse
Affiliation(s)
- Bernice Asiedu
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa
| | - Trevor Tapiwa Nyakudya
- Department of Physiology, Faculty of Health Sciences, School of Medicine, University of Pretoria, Gezina, South Africa
| | - Busisani Wiseman Lembede
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa
| | - Eliton Chivandi
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa
| |
Collapse
|
|
20
|
Jain P, Shasthry SM, Choudhury AK, Maiwall R, Kumar G, Bharadwaj A, Arora V, Vijayaraghavan R, Jindal A, Sharma MK, Bhatia V, Sarin SK. Alcohol associated liver cirrhotics have higher mortality after index hospitalization: Long-term data of 5,138 patients. Clin Mol Hepatol 2021; 27:175-185. [PMID: 33317256 PMCID: PMC7820216 DOI: 10.3350/cmh.2020.0068] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/01/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Liver cirrhosis is an important cause of morbidity and mortality globally. Every episode of decompensation and hospitalization reduces survival. We studied the clinical profile and long-term outcomes comparing alcohol-related cirrhosis (ALC) and non-ALC. METHODS Cirrhosis patients at index hospitalisation (from January 2010 to June 2017), with ≥1 year follow-up were included. RESULTS Five thousand and one hundred thirty-eight cirrhosis patients (age, 49.8±14.6 years; male, 79.5%; alcohol, 39.5%; Child-A:B:C, 11.7%:41.6%:46.8%) from their index hospitalization were analysed. The median time from diagnosis of cirrhosis to index hospitalization was 2 years (0.2-10). One thousand and seven hundred seven patients (33.2%) died within a year; 1,248 (24.3%) during index hospitalization. 59.5% (2,316/3,890) of the survivors, required at least one readmission, with additional mortality of 19.8% (459/2,316). ALC compared to non-ALC were more often (P<0.001) male (97.7% vs. 67.7%), younger (40-50 group, 36.2% vs. 20.2%; P<0.001) with higher liver related complications at baseline, (P<0.001 for each), sepsis: 20.3% vs. 14.9%; ascites: 82.2% vs. 65.9%; spontaneous bacterial peritonitis: 21.8% vs. 15.7%; hepatic encephalopathy: 41.0% vs. 25.0%; acute variceal bleeding: 32.0% vs. 23.7%; and acute kidney injury 30.5% vs. 19.6%. ALC patients had higher Child-Pugh (10.6±2.0 vs. 9.0±2.3), model for end-stage liver-disease scores (21.49±8.47 vs. 16.85±7.79), and higher mortality (42.3% vs. 27.3%, P<0.001) compared to non-ALC. CONCLUSION One-third of cirrhosis patients die in index hospitalization. 60% of the survivors require at least one rehospitalization within a year. ALC patients present with higher morbidity and mortality and at a younger age.
Collapse
Affiliation(s)
- Priyanka Jain
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | | | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankit Bharadwaj
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajan Vijayaraghavan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikram Bhatia
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| |
Collapse
|
|
21
|
Waleed M, Abdallah MA, Kuo YF, Arab JP, Wong R, Singal AK. Higher Frequency of Hospital-Acquired Infections but Similar In-Hospital Mortality Among Admissions With Alcoholic Hepatitis at Academic vs. Non-academic Centers. Front Physiol 2020; 11:594138. [PMID: 33343391 PMCID: PMC7744884 DOI: 10.3389/fphys.2020.594138] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022] Open
Abstract
Background Alcoholic hepatitis (AH) is a unique syndrome characterized by high short-term mortality. The impact of the academic status of a hospital (urban and teaching) on outcomes in AH is unknown. Methods National Inpatient Sample dataset (2006–2014) on AH admissions stratified to academic center (AC) or non-academic center (NAC) and analyzed for in-hospital mortality (IHM), hospital resource use, length of stay in days (d), and total charges (TC) in United States dollars (USD). Admission year was stratified to 2006–2008 (TMI), 2009–2011 (TM2), and 2012–2014 (TM3). Results Of 62,136 AH admissions, the proportion at AC increased from 46% in TM1 to 57% in TM3, Armitage trend, p < 0.001. On logistic regression, TM3, younger age, black race, Medicaid and private insurance, and development of acute on chronic liver failure (ACLF) were associated with admission to an AC. Of 53,264 admissions propensity score matched for demographics, pay status, and disease severity, admissions to AC vs. NAC (26,622 each) were more likely to have liver disease complications (esophageal varices, ascites, and hepatic encephalopathy) and hospital-acquired infections (HAI), especially Clostridioides difficile and ventilator-associated pneumonia. Admissions to AC were more likely transfers from outside hospital (1.6% vs. 1.3%) and seen by palliative care (4.8% vs. 3.3%), p < 0.001. Use of endoscopy, dialysis, and mechanical ventilation were similar. With similar IHM comparing AC vs. NAC (7.7% vs. 7.8%, p = 0.93), average LOS and number of procedures were higher at AC (7.7 vs. 7.1 d and 2.3 vs. 1.9, respectively, p < 0.001) without difference on total charges ($52,821 vs. $52,067 USD, p = 0.28). On multivariable logistic regression model after controlling for demographics, ACLF grade, and calendar year, IHM was similar irrespective of academic status of the hospital, HR (95% CI): 1.01 (0.93–1.08, p = 0.70). IHM decreased over time, with ACLF as strongest predictor. A total of 63 and 22% were discharged to home and skilled nursing facility, respectively, without differences on academic status of the hospital. Conclusion Admissions with AH to AC compared to NAC have higher frequency of liver disease complications and HAI, with longer duration of hospitalization. Prospective studies are needed to reduce HAI among hospitalized patients with AH.
Collapse
Affiliation(s)
- Muhammad Waleed
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, United States
| | - Mohamed A Abdallah
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, United States
| | - Yong-Fang Kuo
- Department of Biostatistics, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Juan P Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Robert Wong
- Division of Gastroenterology and Hepatology, Alameda Health System Highland Hospital, Oakland, CA, United States
| | - Ashwani K Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, United States.,Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, SD, United States
| |
Collapse
|
|
22
|
Lim YL, Eom YW, Park SJ, Hong T, Kang SH, Baik SK, Park KS, Kim MY. Bone Marrow-Derived Mesenchymal Stem Cells Isolated from Patients with Cirrhosis and Healthy Volunteers Show Comparable Characteristics. Int J Stem Cells 2020; 13:394-403. [PMID: 32840228 PMCID: PMC7691862 DOI: 10.15283/ijsc20072] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022] Open
Abstract
Background and Objectives Autologous or allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) have been applied in clinical trials to treat liver disease. However, only a few studies are comparing the characteristics of autologous MSCs from patients and allogeneic MSCs from normal subjects. Methods and Results We compared the characteristics of BMSCs (BCs and BPs, respectively) isolated from six healthy volunteers and six patients with cirrhosis. In passage 3 (P3), senescent population and expression of p53 and p21 were slightly higher in BPs, but the average population doubling time for P3–P5 in BPs was approximately 65.3±11.1 h, which is 18.4 h shorter than that in BCs (83.7±9.2 h). No difference was observed in the expression of CD73, CD90, or CD105 between BCs and BPs. Adipogenic differentiation slightly increased in BCs, but the expression levels of leptin, peroxisome proliferator-activated receptor γ, and CCAAT-enhancer-binding protein α did not vary between differentiated BCs and BPs. While ATP and reactive oxygen species levels were slightly lower in BPs, mitochondrial membrane potential, oxygen consumption rate, and expression of mitochondria-related genes such as cytochrome c oxidase 1 were not significantly different between BCs and BPs. Conclusions Taken together, there are marginal differences in the proliferation, differentiation, and mitochondrial activities of BCs and BPs, but both BMSCs from patients with cirrhosis and healthy volunteers show comparable characteristics.
Collapse
Affiliation(s)
- Yoo Li Lim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Su Jung Park
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Taeui Hong
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| |
Collapse
|
|
23
|
Yoon YH, Chen CM, Slater ME, Jung MK, White AM. Trends in Premature Deaths From Alcoholic Liver Disease in the U.S., 1999-2018. Am J Prev Med 2020; 59:469-480. [PMID: 32863077 PMCID: PMC7508789 DOI: 10.1016/j.amepre.2020.04.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/17/2020] [Accepted: 04/23/2020] [Indexed: 12/18/2022]
Abstract
INTRODUCTION So-called deaths of despair-those involving drug overdoses, alcohol-related liver disease, and suicide-have been rising in the U.S. among middle-aged white, non-Hispanic adults without a college degree. Premature deaths (ages 25-69) from alcoholic liver disease were examined specifically in this study from 1999 to 2018, by sex, race/Hispanic origin, and age group. METHODS Data were drawn from the 1999-2018 Multiple Cause of Death database and bridged-race estimates of the U.S. resident population, including 281,243 alcoholic liver disease deaths or an average of 8 deaths per 100,000 population. Analyses examined alcoholic liver disease death rates for sex differences among 3 age groups (25-49, 50-59, and 60-69 years), by race and Hispanic origin, from 1999 to 2018; age-adjusted and age-specific annual percentage changes (accounted for cohorts); years of potential life lost; and age of death for sociodemographic backgrounds, alcoholic liver disease clinical courses, and comortalities. RESULTS White non-Hispanics increasingly experienced greater alcoholic liver disease mortality than black non-Hispanics and Hispanics, confirming the racial and ethnic crossover observed in previous studies. Although men consistently had higher rates of mortality, male-to-female ratios decreased in the past 2 decades and were the lowest among ages 25-49 years and especially among ages 25-34 years. Although women generally had longer life expectancies, women died of alcoholic liver disease on average about 2-3 years earlier than men. CONCLUSIONS Prevention and intervention efforts are imperative to address the narrowing sex gap and widening racial disparities in alcoholic liver disease premature deaths.
Collapse
Affiliation(s)
| | | | | | - M Katherine Jung
- National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland
| | - Aaron M White
- National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland
| |
Collapse
|
|
24
|
Finkelhor D. Trends in Adverse Childhood Experiences (ACEs) in the United States. CHILD ABUSE & NEGLECT 2020; 108:104641. [PMID: 32739600 DOI: 10.1016/j.chiabu.2020.104641] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 05/11/2023]
Abstract
BACKGROUND It is important for those called upon to discuss major social determinants of health such as adverse childhood experiences (ACEs) to have accurate knowledge about generational trends in their prevalence. OBJECTIVE To review available trend data on major forms of ACEs. METHODS A search of academic data bases was conducted by combining the term "trend" with a variety of terms referring to childhood adversities. RESULTS Available trend data on ACEs from the 20th century show multi-decade declines in parental death, parental illness, sibling death, and poverty, but multi-decade increases in parental divorce, parental drug abuse and parental incarceration. More recent trend data on ACEs for the first fifteen to eighteen years of the 21st century show declines in parental illness, sibling death, exposure to domestic violence, childhood poverty, parental divorce, serious childhood illness, physical abuse, sexual abuse, physical and emotional bullying and exposure to community violence. Two 21st century ACE increases were for parental alcohol and drug abuse. Overall, there appear to have been more historical and recent improvements in ACEs than deteriorations. But the US still lags conspicuously behind other developed countries on many of these indicators. CONCLUSION Awareness of improvements, as well as persistent challenges, are important to motivate policy makers and practitioners and to prompt them to recognize the feasibility of success in the prevention of ACEs.
Collapse
Affiliation(s)
- David Finkelhor
- Crimes Against Children Research Center, University of New Hampshire, 125 McConnell Hall, 15 Academic Way, Durham, NH, 03824, United States.
| |
Collapse
|
|
25
|
Julien J, Ayer T, Bethea ED, Tapper EB, Chhatwal J. Projected prevalence and mortality associated with alcohol-related liver disease in the USA, 2019-40: a modelling study. LANCET PUBLIC HEALTH 2020; 5:e316-e323. [PMID: 32504584 DOI: 10.1016/s2468-2667(20)30062-1] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 02/09/2023]
Abstract
BACKGROUND Alcohol-related liver disease is the leading indication for liver transplantation in the USA. After remaining stable for over three decades, the number of deaths due to alcohol-related liver disease has been increasing as a result of increased high-risk drinking. We aimed to project trends in alcohol-related cirrhosis and deaths in the USA up to 2040 and assess the effect of potential changes in alcohol consumption on those trends. METHODS In this modelling study, we developed a multicohort state-transition (Markov) model of high-risk alcohol drinking patterns and alcohol-related liver disease in high-risk drinking populations born in 1900-2016 in the USA projected up to 2040. We used data from the National Epidemiologic Survey on Alcohol and Related Conditions, National Institute of Alcohol Abuse and Alcoholism, US National Death Index, National Vital Statistics System, and published studies. We modelled trends in alcohol-related liver disease under three projected scenarios: the status quo scenario, in which current trends continued; a moderate intervention scenario, in which trends in high-risk drinking reduced to 2001 levels under some hypothetical moderate intervention; and a strong intervention, in which trends in high-risk drinking decreased by 3·5% per year under some hypothetical strong intervention. The primary outcome was to project deaths associated with alcohol-related liver disease from 2019 to 2040 for each pattern of alcohol consumption under the different scenarios. FINDINGS Our model closely reproduced the observed trends in deaths due to alcohol-related liver disease from 2005 to 2018. Under the status quo scenario, age-standardised deaths due to alcohol-related liver disease are expected to increase from 8·23 (95% uncertainty interval [UI] 7·92-9·29) per 100 000 person-years in 2019 to 15·20 (13·93-16·19) per 100 000 person-years in 2040, and from 2019 to 2040, 1 003 400 (95% CI 896 800-1 036 200) people are projected to die from alcohol-related liver disease, resulting in 1 128 400 (1 113 200-1 308 400) DALYs by 2040. Under the moderate intervention scenario, age-standardised deaths due to alcohol-related liver disease would increase to 14·49 (95% UI 12·55-14·57) per 100 000 person-years by 2040, with 968 100 (95% UI 845 600-975 900) individuals projected to die between 2019 and 2040-35 300 fewer deaths than under the status quo scenario (a 3·5% decrease). Whereas, under the strong intervention scenario, age-standardised deaths due to alcohol-related liver disease would peak at 8·65 (95% UI 8·12-9·51) per 100 000 person-years in 2024 and decrease to 7·60 (6·96-8·10) per 100 000 person-years in 2040, with 704 300 (95% CI 632 700-731 500) individuals projected to die from alcohol-related liver disease in the USA between 2019 and 2040-299 100 fewer deaths than under the status quo scenario (a 29·8% decrease). INTERPRETATION Without substantial changes in drinking culture or interventions to address high-risk drinking, the disease burden and deaths due to alcohol-related liver disease will worsen in the USA. Additional interventions are urgently needed to reduce mortality and morbidity associated with alcohol-related liver disease. FUNDING American Cancer Society and the Robert Wood Johnson Health Policy Research Fellowship.
Collapse
Affiliation(s)
- Jovan Julien
- Department of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA
| | - Turgay Ayer
- Department of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Emily D Bethea
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Jagpreet Chhatwal
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, USA.
| |
Collapse
|
|
26
|
Roles of peroxisome proliferator-activated receptor α in the pathogenesis of ethanol-induced liver disease. Chem Biol Interact 2020; 327:109176. [PMID: 32534989 DOI: 10.1016/j.cbi.2020.109176] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/02/2020] [Accepted: 06/09/2020] [Indexed: 12/18/2022]
Abstract
Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.
Collapse
|
|
27
|
Rasineni K, Kubik JL, Knight KL, Hall L, Casey CA, Kharbanda KK. Ghrelin regulates adipose tissue metabolism: Role in hepatic steatosis. Chem Biol Interact 2020; 322:109059. [PMID: 32171850 PMCID: PMC7716754 DOI: 10.1016/j.cbi.2020.109059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 03/10/2020] [Indexed: 02/09/2023]
Abstract
Fatty liver is the earliest and most common response of the liver to consumption of excessive alcohol. Steatosis can predispose the fatty liver to develop progressive liver damage. Chief among the many mechanisms involved in development of hepatic steatosis is dysregulation of insulin-mediated adipose tissue metabolism. Particularly, it is the enhanced adipose lipolysis-derived free fatty acids and their delivery to the liver that ultimately results in hepatic steatosis. The adipose-liver axis is modulated by hormones, particularly insulin and adiponectin. In recent studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from pancreatic β-cells. The consequent reduction in circulating insulin levels promotes adipose lipolysis and mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Because many tissues, including adipose tissue, express ghrelin receptor we hypothesized that ghrelin may directly affect energy metabolism in adipocytes. We have exciting new preliminary data which shows that treatment of premature 3T3-L1 adipocytes with ghrelin impairs adipocyte differentiation and inhibits lipid accumulation in the tissue designed to store energy in the form of fat. We further observed that ghrelin treatment of differentiated adipocytes significantly inhibited secretion of adiponectin, a hepatoprotective hormone that reduces lipid synthesis and promotes lipid oxidation. These results were corroborated by our observations of a significant increase in serum adiponectin levels in ethanol-fed rats treated with a ghrelin receptor antagonist verses the un-treated ethanol-fed rats. Interestingly, in adipocytes, ghrelin also increases secretion of interleukin-6 (IL-6) and CCL2 (chemokine [C-C motif] ligand 2), cytokines which promote hepatic inflammation and progression of liver disease. To summarize, the alcohol-induced increase in serum ghrelin levels dysregulates adipose-liver interaction and promotes hepatic steatosis by increasing the free fatty acid released from adipose for hepatic uptake, and by altering adiponectin and cytokine secretion. Taken together, our data indicates that targeting the activity of ghrelin may be a powerful treatment strategy.
Collapse
Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA.
| | - Jacy L Kubik
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
| | - Kurt L Knight
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
| | - Lukas Hall
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| |
Collapse
|
|
28
|
Glahn A, Proskynitopoulos PJ, Bleich S, Hillemacher T. Pharmacotherapeutic management of acute alcohol withdrawal syndrome in critically Ill patients. Expert Opin Pharmacother 2020; 21:1083-1092. [PMID: 32281894 DOI: 10.1080/14656566.2020.1746271] [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] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Alcohol withdrawal syndrome is a common and life-threatening condition in patients suffering from alcohol use disorder. Treatment of this syndrome is challenging, especially in patients that are critically ill, either because of withdrawal symptoms or underlying conditions. For the treatment, several pharmacological agents exist, such as benzodiazepines, barbiturates, or dexmedetomidine. Nonetheless, as alcohol withdrawal syndromes can occur in every clinical setting, it is necessary to provide a guideline for clinicians confronted with this syndrome in varying clinical contexts. AREAS COVERED The authors provide a systematic review of the literature found in PubMed and Embase following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. EXPERT OPINION For the treatment of alcohol withdrawal syndrome, medications targeting the GABA system are preferred. Benzodiazepines are regarded as the gold standard. However, as many adjunct therapeutic options exist, it is essential to find symptom-triggered approaches and treatment protocols for the variety of clinical contexts. Apart from that, it is necessary to compare protocols toward clinical variables rather than investigating medications that are in use for the treatment of alcohol withdrawal syndrome.
Collapse
Affiliation(s)
- A Glahn
- Department of Psychiatry, Psychotherapy and Social Psychiatry, Hannover Medical School , Hannover, Germany
| | - P J Proskynitopoulos
- Department of Psychiatry, Psychotherapy and Social Psychiatry, Hannover Medical School , Hannover, Germany
| | - S Bleich
- Department of Psychiatry, Psychotherapy and Social Psychiatry, Hannover Medical School , Hannover, Germany
| | - T Hillemacher
- Department of Psychiatry, Psychotherapy and Social Psychiatry, Hannover Medical School , Hannover, Germany.,Department of Psychiatry and Psychotherapy, Paracelcus Medical University , Nuremberg, Germany
| |
Collapse
|
|
29
|
Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Transl Gastroenterol Hepatol 2020; 5:16. [PMID: 32258520 PMCID: PMC7063528 DOI: 10.21037/tgh.2019.09.08] [Citation(s) in RCA: 322] [Impact Index Per Article: 64.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/05/2019] [Indexed: 12/12/2022] Open
Abstract
Liver diseases are fast emerging as global health priorities. Fatty liver is described in the setting of non-alcoholic fatty liver disease (NAFLD) as well as alcoholic liver disease (ALD), the pathogenesis of excess fat being different in the two conditions while both are important components of the changing face of burden of liver diseases worldwide. They are intimately associated with a globalized economy and an increasingly homogenous socio- cultural order with a westernized lifestyle. The accompanying adoption of a progressively sedentary life, consumption of diet dense in calories facilitate development of NAFLD while a spiraling upward trend in alcohol use along with earlier age of drinking as well as increased amount of per capita alcohol consumption increases the prevalence of ALD globally. Adverse health outcomes in NAFLD as well as ALD are caused not only by progressive liver fibrosis that is the most significant factor for liver related and all-cause mortality in both but also by non-liver (cardiovascular, cancer, accidents, neurological) clinical outcomes that calls for a multidisciplinary and social approach to these conditions. We present here an outline of facets of epidemiology of both NAFLD as well as ALD along with its' public health implications. A broad-based integrated approach that incorporates social, behavioral as well as biological targets need to be undertaken at a health system level in a planned manner for these evolving liver health priorities that disproportionately challenges the low- and middle-income countries of Asia, South America and Africa.
Collapse
Affiliation(s)
- Souveek Mitra
- Indian Institute of Liver and Digestive Sciences Sitala (east), Jagadishpur, Sonarpur, Kolkata, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research Chandigarh, Chandigarh, India
| | - Abhijit Chowdhury
- Indian Institute of Liver and Digestive Sciences Sitala (east), Jagadishpur, Sonarpur, Kolkata, India
- Department of Hepatology School of Digestive and Liver Diseases Institute of Post Graduate Medical Education & Research Kolkata, India
| |
Collapse
|
|
30
|
Adejumo AC, Cholankeril G, Iqbal U, Yoo ER, Boursiquot BC, Concepcion WC, Kim D, Ahmed A. Readmission Rates and Associated Outcomes for Alcoholic Hepatitis: A Nationwide Cohort Study. Dig Dis Sci 2020; 65:990-1002. [PMID: 31372912 DOI: 10.1007/s10620-019-05759-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Alcoholic hepatitis (AH) can lead to sudden and severe hepatic decompensation necessitating recurrent hospitalizations. We evaluated the trends, predictors, and healthcare cost burden of AH-related readmissions in the USA. METHODS Utilizing the National Readmissions Database 2010-2014, we performed a retrospective longitudinal analysis to identify the index readmission with AH for up to 90 days after discharge. Annual trends of 30- and 90-day AH-related readmissions were calculated. Predictors of 30- and 90-day readmission were determined by multivariate logistic regression. Annual healthcare cost burden associated with AH-linked readmissions was estimated. RESULTS Of the 21,572 (unweighted: 50,769) AH-related hospitalizations, 4917 (22.8%) and 7890 (36.6%) were readmitted in 30 and 90 day, respectively, with rates that were statistically unchanged from 2010 to 2014. Predictors of 30-day readmissions included female gender, hepatitis C virus infection, cirrhosis, ascites, acute kidney injury, urinary tract infection, history of bariatric surgery, chronic pancreatitis, and high medical comorbidity index. Acute pancreatitis and palliative care consultation were associated with a lower risk of 30-day readmission. Predictors of 90-day readmission were similar to risk factors for 30-day readmission. From 2010 to 2014, the annual cost (and total hospitalization days) burden increased in 2014 to $164 million (22,244 days) and $321 million (42,772 days) for 30- and 90-day AH-related readmissions, respectively. CONCLUSION Despite relatively stable trends in AH-related readmission, the total LOS and cost has been rising. A target-directed approach with a focus on high-risk subpopulations may help understand the unique challenges associated with the rising cost of AH-related readmissions.
Collapse
Affiliation(s)
- Adeyinka C Adejumo
- Department of Medicine, North Shore Medical Center, 81 Highland Ave., Salem, MA, 01970, USA.
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA.
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Umair Iqbal
- Department of Medicine, Geisinger Medical Center, Danville, PA, USA
| | - Eric R Yoo
- Department of Internal Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA
| | - Brian C Boursiquot
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Waldo C Concepcion
- Department of Surgery, Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
31
|
da Silva Morais A, Oliveira JM, Reis RL. Biomaterials and Microfluidics for Liver Models. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1230:65-86. [DOI: 10.1007/978-3-030-36588-2_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
32
|
Testino G, Vignoli T, Patussi V, Scafato E, Caputo F. Management of end-stage alcohol-related liver disease and severe acute alcohol-related hepatitis: position paper of the Italian Society on Alcohol (SIA). Dig Liver Dis 2020; 52:21-32. [PMID: 31757596 DOI: 10.1016/j.dld.2019.09.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 08/28/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023]
Abstract
Worldwide, the prevalence of alcohol use disorder (AUD) is 20-30% in men and 10-15% in women, and cirrhosis due to alcohol-related liver disease (ALD) is responsible for 0.9% of global deaths and 47.9% of cirrhosis-related deaths. End-stage ALD (ESALD) is the final condition of alcohol-related cirrhosis, and severe acute alcohol-related hepatitis (SAAH) is a distinct clinical syndrome associated with the consumption of large amounts of alcohol. In some cases, ESALD, and SAAH may need liver transplantation (LT). Thus, the management of ESALD and SAAH in patients affected by AUD may be an essential part of the clinical skills for hepatologists. For these reasons, the national board of the Italian Society on Alcohol have reviewed the most recent data on the management of ESALD, SAAH and LT for ALD in patients with AUD, formulating a position paper with related recommendations regarding four issues of specific clinical interest in this field: (a) the management of hepatic encephalopathy in patients with AUD, and LT in patients with ESALD; (b) the management of SAAH; (c) the management of AUD in patients with ESALD and SAAH; (d) special populations: polydrug addicts.
Collapse
Affiliation(s)
- Gianni Testino
- Unit of Addiction and Hepatology ASL3 Liguria, San Martino Hospital, Genova, Italy
| | - Teo Vignoli
- Unit of Addiction Treatment, Lugo, Ravenna, Italy
| | | | - Emanuele Scafato
- National Observatory on Alcohol, National Institute of Health, Roma, Italy
| | - Fabio Caputo
- Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara, Italy; "G. Fontana" Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Medical and Surgical Sciences, University of Bologna, Italy.
| | | |
Collapse
|
|
33
|
Rasineni K, Kubik JL, Casey CA, Kharbanda KK. Inhibition of Ghrelin Activity by Receptor Antagonist [d-Lys-3] GHRP-6 Attenuates Alcohol-Induced Hepatic Steatosis by Regulating Hepatic Lipid Metabolism. Biomolecules 2019; 9:517. [PMID: 31546643 PMCID: PMC6843513 DOI: 10.3390/biom9100517] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 01/13/2023] Open
Abstract
Alcoholic steatosis, characterized by an accumulation of triglycerides in hepatocytes, is one of the earliest pathological changes in the progression of alcoholic liver disease. In our previous study, we showed that alcohol-induced increase in serum ghrelin levels impair insulin secretion from pancreatic β-cells. The consequent reduction in the circulating insulin levels promote adipose-derived fatty acid mobilization to ultimately contribute to hepatic steatosis. In this study, we determined whether inhibition of ghrelin activity in chronic alcohol-fed rats could improve hepatic lipid homeostasis at the pancreas-adipose-liver axis. Adult Wistar rats were fed Lieber-DeCarli control or an ethanol liquid diet for 7 weeks. At 6 weeks, a subset of rats in each group were injected with either saline or ghrelin receptor antagonist, [d-Lys-3] GHRP-6 (DLys; 9 mg/kg body weight) for 5 days and all rats were sacrificed 2 days later. DLys treatment of ethanol rats improved pancreatic insulin secretion, normalized serum insulin levels, and the adipose lipid metabolism, as evidenced by the decreased serum free fatty acids (FFA). DLys treatment of ethanol rats also significantly decreased the circulating FFA uptake, de novo hepatic fatty acid synthesis ultimately attenuating alcoholic steatosis. To summarize, inhibition of ghrelin activity reduced alcoholic steatosis by improving insulin secretion, normalizing serum insulin levels, inhibiting adipose lipolysis, and preventing fatty acid uptake and synthesis in the liver. Our studies provided new insights on the important role of ghrelin in modulating the pancreas-adipose-liver, and promoting adipocyte lipolysis and hepatic steatosis. The findings offer a therapeutic approach of not only preventing alcoholic liver injury but also treating it.
Collapse
Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| | - Jacy L Kubik
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Research Service, Veterans' Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
| |
Collapse
|
|
34
|
Yuan Q, Hou S, Zhai J, Tian T, Wu Y, Wu Z, He J, Chen Z, Zhang J. S100A4 promotes inflammation but suppresses lipid accumulation via the STAT3 pathway in chronic ethanol-induced fatty liver. J Mol Med (Berl) 2019; 97:1399-1412. [PMID: 31321478 DOI: 10.1007/s00109-019-01808-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 05/24/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023]
Abstract
S100A4, a member of the S100 calcium-binding protein family, has been identified in a subpopulation of liver macrophages and promotes liver fibrosis via hepatic stellate cell activation. However, the specific role of S100A4 in alcoholic liver disease (ALD) has not been well investigated. Here, S100A4 knockout (S100A4-/-) mice were used in a chronic-binge ethanol model for studying the role of S100A4 and its related molecular mechanism in ALD. S100A4 expression was increased in ethanol-induced liver tissues of wild-type (WT) mice. Macrophage-derived S100A4 promoted liver inflammation but suppressed lipid accumulation under the ethanol feeding condition. S100A4 deficiency promoted ethanol-induced liver injury and hepatic fat accumulation. Further mechanistic studies found that S100A4 inhibited liver fat accumulation mainly by activating the STAT3 pathway and downregulating lipogenic gene expression, especially that of SREBP-1c. In AML-12 cells, a STAT3 inhibitor abolished STAT3 levels and decreased the expression of SREBP1c. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly promoted ethanol-induced liver injury and fatty accumulation. Thus, S100A4 may represent a potential candidate target for the prevention and treatment of ethanol-induced fatty liver. In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c. KEY MESSAGES: In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.
Collapse
Affiliation(s)
- Qi Yuan
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Shasha Hou
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Junfeng Zhai
- The Chinese Academy of Inspection and Quarantine, Beijing, People's Republic of China
| | - Tian Tian
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Yingjie Wu
- The State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, People's Republic of China
| | - Zhenlong Wu
- The State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, People's Republic of China
| | - Jinsheng He
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Zhinan Chen
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China.,The Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jinhua Zhang
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China.
| |
Collapse
|
|
35
|
Santos SGRD, Mattos AA, Guimarães MM, Boger BDS, Coral GP. Alcohol Consumption Influences Clinical Outcome in Patients Admitted to a Referral Center for Liver Disease. Ann Hepatol 2019; 17:470-475. [PMID: 29735785 DOI: 10.5604/01.3001.0011.7391] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Excessive alcohol consumption is a public health concern worldwide and has been associated with high mortality rates. This study aimed to determine the prevalence of alcohol consumption and its influence on the prognosis of hospitalized cirrhotic patients in a tertiary care hospital. MATERIAL AND METHODS We reviewed the medical records of all patients with hepatic cirrosis admitted between January 2009 and December 2014, in a referral center for liver disease in southern Brazil. Data on clinical outcomes, associated conditions, infections, and mortality were collected and compared between alcoholic and nonalcoholic patients. RESULTS The sample consisted of 388 patients; 259 (66.7%) were men. One hundred fifty-two (39.2%) were classified as heavy use of alcohol. Most alcoholic patients were men (n = 144; 94.7%). Mean age was 55.6 ± 8.9 years. Hepatic decompensations and infections were more prevalent in alcoholic patient. Spontaneous bacterial peritonitis and respiratory tract infection accounted for most of the infections. Excessive alcohol consumption was associated with mortality (P = 0.009) in multivariate analysis. CONCLUSION On the present study, the prevalence of heavy use of alcohol was high and associated with a poorer prognosis in hospitalized cirrhotic patients, increasing the risk of infection and death.
Collapse
Affiliation(s)
- Suyan G R Dos Santos
- Postgraduate Program in Medicine: Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Angelo A Mattos
- Federal University of Health Sciences of Porto Alegre (UFCSPA), Brazil
| | - Marcela M Guimarães
- Postgraduate Program in Medicine: Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Bibiana de S Boger
- Postgraduate Program in Medicine: Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Gabriela P Coral
- Postgraduate Program in Medicine: Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| |
Collapse
|
|
36
|
Legaz I, Bolarín JM, Navarro E, Campillo JA, Moya R, Pérez-Cárceles MD, Luna A, Osuna E, Miras M, Muro M, Minguela A, Alvarez López R. KIR2DL2/S2 and KIR2DS5 in alcoholic cirrhotic patients undergoing liver transplantation. Arch Med Sci 2019; 17:764-774. [PMID: 34025847 PMCID: PMC8130473 DOI: 10.5114/aoms.2019.84410] [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] [Received: 12/12/2018] [Accepted: 03/23/2019] [Indexed: 11/30/2022] Open
Abstract
INTRODUCTION The molecular mechanisms underlying alcoholic liver fibrosis and cirrhosis are not completely understood. Hepatic fibrosis involves the interplay of diverse cells and factors, including hepatic stellate cells (HSCs), Kupffer, NK cells, and T-lymphocyte subsets. Killer-cell immunoglobulin-like receptors (KIR) are membrane receptors involved in mediation between NK and activated HSCs, regulating NK cell function through their interaction with HLA-I molecules. The aim of this study was to analyse the genetic association between KIR genes and the susceptibility to or protection from alcoholic cirrhosis (AC) in a cohort of male AC patients undergoing liver transplantation (LT) with and without concomitant viral infections. MATERIAL AND METHODS KIR genotyping was performed in nuclear DNA extracted from 281 AC patients and compared with 319 male controls. RESULTS Significant differences between total AC patients and healthy controls were only found in the case of KIR2DL2 and KIR2DS5. KIR2DL2 was significantly underrepresented in non-viral AC patients (52.6% vs. 63.3%; p = 0.015), while patients heterozygous for KIR2DL2 were also underrepresented in the non-viral AC group compared with controls (p = 0.034). KIR2DS5 was overrepresented in this group compared with healthy controls (p = 0.002). All these observations were only evident in AC patients older than 54 years old. CONCLUSIONS Our data suggest a contrary effect of KIR2DL2 and KIR2DS5 in AC patients older than 54 years, in whom the presence of KIR2DL2 appears to be protective against AC, whereas the presence of KIR2DS5 seems to promote the fibrotic process, particularly in patients with no associated viral infection.
Collapse
Affiliation(s)
- Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, Murcia, Spain
- Research Institute on Ageing, University of Murcia, Murcia, Spain
| | - Jose Miguel Bolarín
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - Elena Navarro
- Digestive Medicine Service, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| | - Jose Antonio Campillo
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| | - Rosa Moya
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| | - María Dolores Pérez-Cárceles
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, Murcia, Spain
- Research Institute on Ageing, University of Murcia, Murcia, Spain
| | - Aurelio Luna
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - Eduardo Osuna
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, Murcia, Spain
- Research Institute on Ageing, University of Murcia, Murcia, Spain
| | - Manuel Miras
- Digestive Medicine Service, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| | - Manuel Muro
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| | - Alfredo Minguela
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| | - Rocio Alvarez López
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain
| |
Collapse
|
|
37
|
Rasineni K, Thomes PG, Kubik JL, Harris EN, Kharbanda KK, Casey CA. Chronic alcohol exposure alters circulating insulin and ghrelin levels: role of ghrelin in hepatic steatosis. Am J Physiol Gastrointest Liver Physiol 2019; 316:G453-G461. [PMID: 30702902 PMCID: PMC6483023 DOI: 10.1152/ajpgi.00334.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/07/2019] [Accepted: 01/16/2019] [Indexed: 01/31/2023]
Abstract
Fatty liver is the earliest response of the liver to excessive ethanol consumption. Central in the development of alcoholic steatosis is increased mobilization of nonesterified free fatty acids (NEFAs) to the liver from the adipose tissue. In this study, we hypothesized that ethanol-induced increase in ghrelin by impairing insulin secretion, could be responsible for the altered lipid metabolism observed in adipose and liver tissue. Male Wistar rats were fed for 5-8 wk with control or ethanol Lieber-DeCarli diet, followed by biochemical analyses in serum and liver tissues. In addition, in vitro studies were conducted on pancreatic islets isolated from experimental rats. We found that ethanol increased serum ghrelin and decreased serum insulin levels in both fed and fasting conditions. These results were corroborated by our observations of a significant accumulation of insulin in pancreatic islets of ethanol-fed rats, indicating that its secretion was impaired. Furthermore, ethanol-induced reduction in circulating insulin was associated with lower adipose weight and increased NEFA levels observed in these rats. Additionally, we found that increased concentration of serum ghrelin was due to increased synthesis and maturation in the stomach of the ethanol-fed rats. We also report that in addition to its effect on the pancreas, ghrelin can also directly act on hepatocytes via the ghrelin receptors and promote fat accumulation. In conclusion, alcohol-induced elevation of circulating ghrelin levels impairs insulin secretion. Consequently, reduced circulating insulin levels likely contribute to increased free fatty acid mobilization from adipose tissue to liver, thereby contributing to hepatic steatosis. NEW & NOTEWORTHY Our studies are the first to report that ethanol-induced increases in ghrelin contribute to impaired insulin secretion, which results in the altered lipid metabolism observed in adipose and liver tissue in the setting of alcoholic fatty liver disease.
Collapse
Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Paul G Thomes
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Jacy L Kubik
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska-Lincoln , Lincoln, Nebraska
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| |
Collapse
|
|
38
|
Patel J, Lucas CJ, Margalit M, Martin JH. Laxative Use in Inpatients on Oxycodone/Naloxone Prolonged Release and Oxycodone Prolonged Release for Cancer and Non-cancer Pain. J Pain Palliat Care Pharmacother 2019; 32:116-123. [DOI: 10.1080/15360288.2018.1545725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
39
|
Epidemiology of Alcohol Consumption and Societal Burden of Alcoholism and Alcoholic Liver Disease. Clin Liver Dis 2019; 23:39-50. [PMID: 30454831 DOI: 10.1016/j.cld.2018.09.011] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcohol abuse is a major determinant of public health outcomes. Worldwide data from 2016 indicate that alcohol is the seventh leading risk factor in terms of disability-adjusted life years, an increase of more than 25% from 1990 to 2016. Understanding the epidemiology of alcoholic liver disease, including the regional variations in consumption and public policy, is an area of active research. In countries where the per capita consumption of alcohol decreases, there appears to be an associated decrease in disease burden. Given alcohol's health burden, an increased focus on alcohol control policies is needed.
Collapse
|
|
40
|
Abstract
With the discovery of direct-acting antivirals and the prospective of viral hepatitis becoming curable, alcohol liver disease (ALD) is back to primetime. In the last 20 years, there have been many advances in the understanding of the biology, the psychology and the social and environmental factors associated with this long-known medical problem. Recent information about regional, ethnic, cultural and genetic factors seem to be relevant for the Latin American (LA) population. New approaches based on the new concepts and current information will render better results in the overall management of patients with this problem. Considering alcohol use disorder and ALD as part of the same entity managing it in a multidisciplinary approach seems to be best way to deal with this disease.
Collapse
Affiliation(s)
- Octavio Campollo
- Center of Studies on Alcohol and Addictions, Hospital Civil de Guadalajara FAA, Universidad de Guadalajara. Guadalajara, Jalisco, Mexico.
| |
Collapse
|
|
41
|
Méndez-Sánchez N, Zamarripa-Dorsey F, Panduro A, Purón-González E, Coronado-Alejandro EU, Cortez-Hernández CA, Higuera de la Tijera F, Pérez-Hernández JL, Cerda-Reyes E, Rodríguez-Hernández H, Cruz-Ramón VC, Ramírez-Pérez OL, Aguilar-Olivos NE, Rodríguez-Martínez OF, Cabrera-Palma S, Cabrera-Álvarez G. Current trends of liver cirrhosis in Mexico: Similitudes and differences with other world regions. World J Clin Cases 2018; 6:922-930. [PMID: 30568947 PMCID: PMC6288506 DOI: 10.12998/wjcc.v6.i15.922] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/19/2018] [Accepted: 11/14/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the main current etiologies of cirrhosis in Mexico. METHODS We performed a cross-sectional retrospective multicenter study that included eight hospitals in different areas of Mexico. These hospitals provide health care to people of diverse social classes. The inclusion criteria were a histological, clinical, biochemical, endoscopic, or imaging diagnosis of liver cirrhosis. Data were obtained during a 5-year period (January 2012-December 2017). RESULTS A total of 1210 patients were included. The mean age was 62.5 years (SD = 12.1), and the percentages of men and women were similar (52.0% vs 48.0%). The most frequent causes of liver cirrhosis were hepatitis C virus (HCV) (36.2%), alcoholic liver disease (ALD) (31.2%), and nonalcoholic steatohepatitis (23.2%), and the least frequent were hepatitis B virus (1.1%), autoimmune disorders (7.3%), and other conditions (1.0%). CONCLUSION HCV and ALD are the most frequent causes of cirrhosis in Mexico. However, we note that non-alcoholic fatty liver disease (NAFLD) as an etiology of cirrhosis increased by 100% compared with the rate noted previously. We conclude that NAFLD will soon become one of the most frequent etiologies of liver cirrhosis in Mexico.
Collapse
Affiliation(s)
- Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City 14050, Mexico
| | | | - Arturo Panduro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara “Fray Antonio Alcalde”, Guadalajara 44280, Jalisco, Mexico
| | - Emma Purón-González
- Department of Internal Medicine, “Christus Muguerza “Super Specialty” Hospital” Monterrey, Monterrey 64060, Nuevo León, Mexico
| | - Edgar Ulises Coronado-Alejandro
- Department of Internal Medicine, “Christus Muguerza “Super Specialty” Hospital” Monterrey, Monterrey 64060, Nuevo León, Mexico
| | | | - Fátima Higuera de la Tijera
- Department of Gastroenterology, “General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
| | - José Luis Pérez-Hernández
- Department of Gastroenterology, “General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
| | - Eira Cerda-Reyes
- Department of Gastroenterology, “Central Military Hospital”, Mexico City 11200, Mexico
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Sujan R, Cruz-Lemini M, Altamirano J, Simonetto DA, Maiwall R, Axley P, Richardson T, Desai V, Cabezas J, Vargas V, Kamath PS, Shah VH, Sarin SK, Bataller R, Singal AK. A Validated Score Predicts Acute Kidney Injury and Survival in Patients With Alcoholic Hepatitis. Liver Transpl 2018; 24:1655-1664. [PMID: 30153377 DOI: 10.1002/lt.25328] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 08/07/2018] [Indexed: 02/07/2023]
Abstract
Identifying patients at high risk for acute kidney injury (AKI) during hospitalization among patients admitted with severe alcoholic hepatitis (AH) is an unmet clinical need. We performed a multicentric prospective cohort study using data from 4 different cohorts on well-characterized patients hospitalized with severe AH. Data collected on 773 AH patients from 4 cohorts across the globe were randomly split into test (n = 390) and validation (n = 383) cohorts. We found that 32% of the patients developed inpatient AKI in the test cohort. Approximately 60% of patients met criteria for systemic inflammatory response syndrome (SIRS) at admission. Hepatic encephalopathy, SIRS, and Model for End-Stage Liver Disease score at admission predicted inpatient AKI with odds ratios of 3.86, 2.24, and 1.14, respectively. The AKI risk score developed using these predictors stratified risk of inpatient AKI to low (score <3), moderate (3-4), and high (>4). These findings were replicated in the validation cohort. In the whole study cohort, patients with AKI had a lower 90-day survival (53% versus 77%; P < 0.001). Those with AKI risk score of >4 had significantly lower 90-day survival as compared with those with risk scores between 3 and 4 and <3 (47% versus 68% versus 88%; P < 0.001). In conclusion, AKI occurs frequently in AH patients and negatively impacts short-term mortality. The AKI risk score is useful in identifying patients at high risk for inpatient AKI and may be useful for developing new therapeutic strategies to prevent AKI in patients with AH.
Collapse
Affiliation(s)
- Ravi Sujan
- University of Alabama at Birmingham, Birmingham, AL
| | - Monica Cruz-Lemini
- Unidad de Investigación en Neurodesarrollo, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Queretaro, Mexico
| | - Jose Altamirano
- Liver Unit, Internal Medicine Department, Vall d'Hebrón University Hospital, Vall d'Hebrón Institut de Recerca, Barcelona, Spain
| | | | - Rakhi Maiwall
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Page Axley
- University of Alabama at Birmingham, Birmingham, AL
| | | | | | - Joaquin Cabezas
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Victor Vargas
- Liver Unit, Internal Medicine Department, Vall d'Hebrón University Hospital, Vall d'Hebrón Institut de Recerca, Barcelona, Spain
| | | | | | - Shiv K Sarin
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ramon Bataller
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA
| | | |
Collapse
|
|
43
|
Yang R, Guan MJ, Zhao N, Li MJ, Zeng T. Roles of extrahepatic lipolysis and the disturbance of hepatic fatty acid metabolism in TNF-α -induced hepatic steatosis. Toxicology 2018; 411:172-180. [PMID: 30359672 DOI: 10.1016/j.tox.2018.10.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 09/16/2018] [Accepted: 10/20/2018] [Indexed: 12/20/2022]
Abstract
Our previous study showed that both Kupffer cell eliminator (GdCl3) and tumor necrosis factor α (TNF-α) receptor antagonist (etanercept) could partially attenuate binge drinking-induced liver steatosis. Herein, we extended the study by directly investigating the roles of TNF-α on the hepatic fat levels in mice and in HepG2 cells, and explored the underlying mechanisms. SPF male ICR mice were exposed to TNF-α (0.166 mg/kg body weight) with or without phenylisopropyl adenosine (PIA, an anti-lipolytic drug) for 1.5, 3, 6, and 24 h. We found that TNF-α treatment resulted in hepatic triglyceride (TG) elevation at 6 h time point, which was blocked by PIA. TNF-α led to the activation of extrahepatic lipolysis demonstrated by the increase of serum free fatty acid (FFA) level, and the increased protein levels of adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase (HSL) in mice epididymal adipose tissues, but had no significant effects on the protein levels of sterol regulatory element binding protein 1c (SREBP-1c) and peroxisomal proliferator activation receptor α (PPAR-α) in mice liver. The in vitro study showed TNF-α treatment could not result in elevation of TG in HepG2 cells, although it indeed brought about a slight activation of SREBP-1c. These results support the hypothesis that TNF-α might make a small contribution to ethanol-induced fatty liver by stimulating extrahepatic lipolysis.
Collapse
Affiliation(s)
- Rui Yang
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Shandong Province, Jinan City, 250012, PR China
| | - Min-Jie Guan
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Shandong Province, Jinan City, 250012, PR China
| | - Ning Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Shandong Province, Jinan City, 250012, PR China
| | - Ming-Jun Li
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Shandong Province, Jinan City, 250012, PR China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Shandong Province, Jinan City, 250012, PR China.
| |
Collapse
|
|
44
|
T. Krishnareddy N, Thomas JV, Nair SS, N. Mulakal J, Maliakel BP, Krishnakumar IM. A Novel Curcumin-Galactomannoside Complex Delivery System Improves Hepatic Function Markers in Chronic Alcoholics: A Double-Blinded, randomized, Placebo-Controlled Study. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9159281. [PMID: 30345312 PMCID: PMC6174784 DOI: 10.1155/2018/9159281] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/26/2018] [Accepted: 07/24/2018] [Indexed: 01/05/2023]
Abstract
Considering the recent interest in free (unconjugated) curcuminoids delivery, the present study investigated the efficacy of a novel food-grade free-curcuminoids delivery system (curcumin-galactomannoside complex; CGM) in improving the hepatic function markers (inflammation and oxidative stress) in chronic alcoholics. The double-blinded, placebo-controlled study randomized 48 subjects with elevated serum transaminases and gamma-glutamyl transferase (GGT) levels, who were allocated to two groups (n=24) and to receive either placebo or CGM at (250 mg × 2)/day for 8 weeks. While liver function markers (transaminases and GGT) in the placebo group showed an increase (~ 9.5%), CGM group indicated a significant decrease in transaminases (31%) and GGT (29%) from the baseline levels. The beneficial effect of CGM was also clear from the significant increase (p <0.001) in endogenous antioxidants (GSH, SOD, and GPx) and decrease in inflammatory markers (IL-6 and CRP) levels (p <0.001) as compared to both the baseline and placebo group. To summarize, the nutritional intervention of CGM-curcumin was found to offer a significant hepatoprotective effect to attenuate the alcohol induced alterations to hepatic function markers. The Indian Medical Council and Drug Controller General of India approved Clinical Trial Registry No. CTRI/2018/03/012385.
Collapse
Affiliation(s)
| | - Jestin V. Thomas
- Leads Clinical Research & Bio Services Pvt. Ltd., Bangalore, India
| | | | | | | | | |
Collapse
|
|
45
|
Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci 2018; 75:3143-3157. [PMID: 29947925 PMCID: PMC11105722 DOI: 10.1007/s00018-018-2852-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/18/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate-cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.
Collapse
Affiliation(s)
- Ning Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital of Shandong University, 107 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China.
| |
Collapse
|
|
46
|
Wahlang B, McClain C, Barve S, Gobejishvili L. Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 2018; 49:105-115. [PMID: 29902522 PMCID: PMC6445381 DOI: 10.1016/j.cellsig.2018.06.005] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023]
Abstract
Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.
Collapse
Affiliation(s)
- Banrida Wahlang
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA
| | - Craig McClain
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA; Robley Rex Louisville VAMC, Louisville, KY, USA
| | - Shirish Barve
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA
| | - Leila Gobejishvili
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA.
| |
Collapse
|
|
47
|
The emergency medicine evaluation and management of the patient with cirrhosis. Am J Emerg Med 2018; 36:689-698. [PMID: 29290508 DOI: 10.1016/j.ajem.2017.12.047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 12/21/2017] [Accepted: 12/22/2017] [Indexed: 12/12/2022] Open
|
|
48
|
Woodhouse CA, Patel VC, Singanayagam A, Shawcross DL. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease. Aliment Pharmacol Ther 2018; 47:192-202. [PMID: 29083037 DOI: 10.1111/apt.14397] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 06/06/2017] [Accepted: 10/03/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target. AIM To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver. METHODS We conducted a PubMed search using search terms including 'microbiome', 'liver' and 'cirrhosis' as well as 'non-alcoholic fatty liver disease', 'steatohepatitis', 'alcohol' and 'primary sclerosing cholangitis'. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website. RESULTS Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non-alcoholic fatty liver disease, alcohol-related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune-mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation. CONCLUSIONS Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of "healthy" bacteria may ameliorate the dysbiosis and alter prognosis.
Collapse
Affiliation(s)
- C A Woodhouse
- Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, UK
| | - V C Patel
- Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, UK
| | - A Singanayagam
- Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, UK
| | - D L Shawcross
- Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, London, UK
| |
Collapse
|
|
49
|
Guan MJ, Zhao N, Xie KQ, Zeng T. Hepatoprotective effects of garlic against ethanol-induced liver injury: A mini-review. Food Chem Toxicol 2018; 111:467-473. [DOI: 10.1016/j.fct.2017.11.059] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 11/01/2017] [Accepted: 11/30/2017] [Indexed: 02/07/2023]
|
|
50
|
Kim A, McCullough RL, Poulsen KL, Sanz-Garcia C, Sheehan M, Stavitsky AB, Nagy LE. Hepatic Immune System: Adaptations to Alcohol. Handb Exp Pharmacol 2018; 248:347-367. [PMID: 29374837 DOI: 10.1007/164_2017_88] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Both the innate and adaptive immune systems are critical for the maintenance of healthy liver function. Immune activity maintains the tolerogenic capacity of the liver, modulates hepatocellular response to various stresses, and orchestrates appropriate cellular repair and turnover. However, in response to heavy, chronic alcohol exposure, the finely tuned balance of pro- and anti-inflammatory functions in the liver is disrupted, leading to a state of chronic inflammation in the liver. Over time, this non-resolving inflammatory response contributes to the progression of alcoholic liver disease (ALD). Here we review the contributions of the cellular components of the immune system to the progression of ALD, as well as the pathophysiological roles for soluble and circulating mediators of immunity, including cytokines, chemokines, complement, and extracellular vesicles, in ALD. Finally, we compare the role of the innate immune response in health and disease in the liver to our growing understanding of the role of neuroimmunity in the development and maintenance of a healthy central nervous system, as well as the progression of neuroinflammation.
Collapse
Affiliation(s)
- Adam Kim
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Rebecca L McCullough
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Kyle L Poulsen
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Carlos Sanz-Garcia
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Megan Sheehan
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Abram B Stavitsky
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
| | - Laura E Nagy
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA.
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA.
- Department of Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA.
- Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
| |
Collapse
|