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1
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Eun JR, Kim SU. Repurposing of Antiplatelet Agent: Cilostazol for the Treatment of Alcohol-Related Liver Disease. Gut Liver 2025; 19:318-326. [PMID: 39774120 PMCID: PMC12070207 DOI: 10.5009/gnl240295] [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: 07/02/2024] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 01/11/2025] Open
Abstract
Alcohol-related liver disease (ALD) is a serious global health concern, characterized by liver inflammation and progressive fibrosis. There are no Food and Drug Administration-approved drugs, thus effective treatments are needed. Severe alcoholic hepatitis (AH) is the most severe manifestation of ALD, with a 28-day mortality rate ranging from 20% to 50%. For decades, pentoxifylline, an antiplatelet agent, has been used off-label for the treatment of severe AH owing to its tumor necrosis factor-α inhibition properties. However, the STOPAH trial did not reveal the survival benefit of pentoxifylline. Consequently, pentoxifylline is no longer recommended as the first-line therapy for severe AH. In contrast, cilostazol is widely used as an antiplatelet agent in cardiovascular medicine and demonstrates promising results. Cilostazol is a selective phosphodiesterase type 3 inhibitor, whereas pentoxifylline is non-selective. Recent studies using experimental models of alcohol-induced liver injury and other liver diseases have yielded promising results. Although cilostazol shows promise for hepatoprotective effects, it has not yet been evaluated in human clinical trials. In this review, we will explore the mechanism underlying the hepatoprotective effects of cilostazol, along with the pathophysiology of alcohol-induced liver injury, addressing the pressing need for effective therapeutic options for patients with ALD.
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Affiliation(s)
- Jong Ryeol Eun
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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2
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Zhu Y, Jia Y, Zhang E. Oxidative stress modulation in alcohol-related liver disease: From chinese botanical drugs to exercise-based interventions. Front Pharmacol 2025; 16:1516603. [PMID: 40351443 PMCID: PMC12062749 DOI: 10.3389/fphar.2025.1516603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/10/2025] [Indexed: 05/14/2025] Open
Abstract
Alcohol-related liver disease (ALD) is a chronic liver injury caused by long-term excessive alcohol consumption, with complex and multifaceted pathological mechanisms. Research indicates that oxidative stress (OS), inflammatory responses, and lipid metabolic disturbances induced by alcohol and its metabolites are primary contributors to hepatocyte injury, positioning OS as a key target in ALD treatment. The main non-pharmacological treatment for ALD is alcohol abstinence, while medical treatment primarily relies on Western pharmacological interventions. However, recent research has increasingly highlighted the potential of Chinese botanical drugs in improving histological features and modulating signaling pathways associated with OS in ALD, underscoring the therapeutic potential of traditional Chinese herb medicine. Despite these promising findings, the precise mechanisms and effects of these extracts remain incompletely understood, and potential side effects must be considered. Therefore, a comprehensive analysis of herbal extracts with therapeutic effects is essential to optimize clinical administration and ensure safe, effective treatment. This review focuses on OS as a central theme, categorizing Chinese botanical drugs into six major groups-flavonoids, polyphenols, terpenoids, alkaloids, saponins, and anthraquinones-all widely used in traditional Chinese herb medicine. The review provides an overview of their botanical characteristics and therapeutic actions in the context of ALD, offering insights into OS regulation and exploring their potential as treatments for ALD. Notably, physical exercise shares overlapping mechanisms with botanical drugs in regulating OS. Combining two strategies could offer a promising integrative treatment for ALD, though further research is needed to confirm their synergistic benefits and optimize clinical applications.
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Affiliation(s)
| | | | - Enming Zhang
- School of Sports Medicine and Physical Therapy, Beijing Sport University, Beijing, China
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3
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Enciu VT, Ologeanu PM, Constantinescu A, Fierbinteanu-Braticevici C. Latest Insights in Alcohol-Related Liver Disease and Alcoholic Hepatitis. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MEDECINE INTERNE 2025:rjim-2025-0007. [PMID: 40245287 DOI: 10.2478/rjim-2025-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Indexed: 04/19/2025]
Abstract
Alcohol-related liver disease (ALD) is still to this date one of the leading causes of chronic liver disease globally. ALD comprises a wide disease spectrum, from the benign liver steatosis, to the life-threatening inflammatory acute phenotype of alcoholic hepatitis (AH) and ultimately, advanced liver fibrosis and cirrhosis. AH represents an acute inflammatory liver condition caused by prolonged high quantities of alcohol intake. Disease outcome varies from mild to severe, with systemic implication and high mortality. Although the pathogenesis has been extensively studied over the years, little progress has been made regarding therapeutic options. In over 50 years, steroid treatment is still the cornerstone therapeutic option, albeit having multiple limitations and a low success rate. On the other hand, important progress has been made regarding disease management and severity stratification with the implementation of different prognostic score. Although highly prevalent, AH still has many unmet needs, with a growing necessity for novel non-invasive diagnosis, prognosis biomarkers and impactful treatment options.
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Affiliation(s)
- Vlad-Teodor Enciu
- 1Internal Medicine II and Gastroenterology Department, Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- 2Emergency University Hospital, 050098 Bucharest, Romania
| | - Priscila Madalina Ologeanu
- 1Internal Medicine II and Gastroenterology Department, Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- 2Emergency University Hospital, 050098 Bucharest, Romania
| | - Alexandru Constantinescu
- 2Emergency University Hospital, 050098 Bucharest, Romania
- 3Internal Medicine I and Gastroenterology Department, Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 050474, Bucharest, Romania
| | - Carmen Fierbinteanu-Braticevici
- 1Internal Medicine II and Gastroenterology Department, Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- 2Emergency University Hospital, 050098 Bucharest, Romania
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4
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Wan H, Zhou X, Su J, Xia T, Zhang D. Comparative Efficacy and Safety of Different Regimens of Current JAK Inhibitors in Psoriatic Arthritis: A Network Meta-analysis. J Clin Rheumatol 2025:00124743-990000000-00336. [PMID: 40184480 DOI: 10.1097/rhu.0000000000002232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2025]
Abstract
BACKGROUND Janus kinase (JAK) inhibitors have been approved for treating psoriatic arthritis (PsA); however, the comparative efficacy of different JAK inhibitors remains unclear. This study aimed to investigate the comparative efficacy and safety of different JAK inhibitors in treating PsA. METHODS This network meta-analysis was conducted in strict accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Network Meta-Analyses and Cochrane methods. RESULTS Five studies involving 2757 patients were included. Pairwise meta-analysis revealed that JAK inhibitors significantly increased the American College of Rheumatology 20 score and Psoriasis Area and Severity Index 75 responses, which were confirmed by the network meta-analysis. The network meta-analysis further suggested that filgotinib 200 mg once daily (OD) (odds ratio [OR] = 3.17, 95% credible interval [CrI] = 1.07-9.88) and upadacitinib 30 mg OD (OR = 2.34, 95% CrI = 1.13-4.78) had higher American College of Rheumatology 20 score responses compared with tofacitinib 5 mg twice a day. However, upadacitinib 30 mg OD was associated with a higher risk of adverse events (placebo: OR = 1.80, 95% CrI = 1.14-2.87) and serious adverse events compared with filgotinib 200 mg OD (OR = 0.05, 95% CrI = 0.00-0.82). Upadacitinib 15 mg OD, the currently recommended therapy, is comparable in both efficacy and safety to other treatment regimens. CONCLUSIONS Filgotinib 200 mg OD is the safest and most effective JAK inhibitor for PsA, followed by upadacitinib 30 mg OD. However, upadacitinib 30 mg OD carries the highest risk of adverse events. Upadacitinib 15 mg OD, the currently recommended therapy, is not superior in efficacy and safety compared with other treatment options. More high-quality studies are needed to confirm these findings due to the limited number of included studies.
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Affiliation(s)
- Huiying Wan
- From the Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China
| | - Xiyuan Zhou
- From the Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China
| | - Jia Su
- From the Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China
| | - Tian Xia
- Department of Pathology, Western Theater Command Air Force Hospital
| | - Dingding Zhang
- Sichuan Provincial Key Laboratory for Genetic Disease, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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5
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Goran LG, Liţă (Cofaru) FA, Fierbinţeanu-Braticevici C. Acute-on-Chronic Liver Failure: Steps Towards Consensus. Diagnostics (Basel) 2025; 15:751. [PMID: 40150093 PMCID: PMC11941433 DOI: 10.3390/diagnostics15060751] [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: 02/16/2025] [Revised: 03/09/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by organ failure and high short-term mortality. Since its first definition in 2013, many international organizations have defined this syndrome and, till now, there has been no agreement regarding definitions and diagnostic criteria. Although the precise mechanism of ACLF is unknown, precipitant factors and the systemic inflammation response play a major role. Specific management of this high-mortality syndrome is still under development, but a general consensus in the diagnosis and management of ACLF is needed.
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Affiliation(s)
- Loredana Gabriela Goran
- Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (F.A.L.); (C.F.-B.)
- Internal Medicine II and Gastroenterology Department, University Emergency Hospital Bucharest, 050098 Bucharest, Romania
| | - Florina Alexandra Liţă (Cofaru)
- Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (F.A.L.); (C.F.-B.)
- Emergency Department, University Emergency Hospital Bucharest, 050098 Bucharest, Romania
| | - Carmen Fierbinţeanu-Braticevici
- Emergency University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (F.A.L.); (C.F.-B.)
- Internal Medicine II and Gastroenterology Department, University Emergency Hospital Bucharest, 050098 Bucharest, Romania
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Schulz MS, Angeli P, Trebicka J. Acute and non-acute decompensation of liver cirrhosis (47/130). Liver Int 2025; 45:e15861. [PMID: 38426268 PMCID: PMC11815624 DOI: 10.1111/liv.15861] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 12/18/2023] [Accepted: 01/19/2024] [Indexed: 03/02/2024]
Abstract
In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.
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Affiliation(s)
- Martin S. Schulz
- Department of Internal Medicine BUniversity of MünsterMünsterGermany
| | - Paolo Angeli
- European Foundation for Study of Chronic Liver FailureBarcelonaSpain
| | - Jonel Trebicka
- Department of Internal Medicine BUniversity of MünsterMünsterGermany
- European Foundation for Study of Chronic Liver FailureBarcelonaSpain
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Yamazaki T, Schnabl B. Acute alcohol-associated hepatitis: Latest findings in non-invasive biomarkers and treatment. Liver Int 2025; 45:e15608. [PMID: 37183549 PMCID: PMC10646153 DOI: 10.1111/liv.15608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/15/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023]
Abstract
Acute alcohol-associated hepatitis (AH) is a syndrome that occurs in heavy and long-term drinkers and results in severe jaundice and liver failure. The mortality rate in severe cases is 20%-50% at 28 days, and in cases that do not improve despite appropriately timed corticosteroid therapy, the mortality rate reaches 70% at 6 months. The only curative treatment is early liver transplantation, but less than 2% of patients with severe AH are eligible. In order to improve the prognosis, diagnostic tools are needed to detect appropriate cases at risk of severe conditions, and new therapies need to be developed that can replace corticosteroids. Recent research has revealed that the pathogenesis of AH involves a complex of factors, including changes in the gut microbiota, inflammatory and cytokine signalling, oxidative stress and mitochondrial dysfunction, and abnormalities in the hepatic regenerative capacity. Non-invasive diagnostic tools focusing on these specific pathologies have been reported in recent years. In addition, several novel agents targeting specific pathways are currently being developed and tested in clinical trials. This review will provide an overview of alcohol-associated hepatitis and focus on the latest diagnostic tools, particularly non-invasive biomarkers, and novel therapies.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Nagano, Matsumoto, Japan
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, California, San Diego, USA
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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Durkin C, Schaubel DE, Kaplan DE, Mahmud N, Bittermann T. Survival Benefit From Corticosteroids in Severe Alcohol-associated Hepatitis Attributed to Clinical and Treatment Differences in a Large Multicenter Cohort. Clin Transl Gastroenterol 2025; 16:e00791. [PMID: 39620604 PMCID: PMC11756888 DOI: 10.14309/ctg.0000000000000791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/01/2024] [Indexed: 12/13/2024] Open
Abstract
INTRODUCTION Corticosteroids are recommended by multiple society guidelines for the treatment of severe alcohol-associated hepatitis (AH). However, their use remains controversial due to inconsistent studies regarding their survival benefit. METHODS This was a retrospective cohort study of first-time hospitalizations for severe AH (Maddrey discriminant function ≥ 32) admitted to the Veterans Health Administration between January 3, 2005, and December 5, 2020, (i) evaluating the effect of corticosteroid therapy on all-cause survival, (ii) characterizing the clinical and psychosocial factors associated with corticosteroid use, and (iii) determining the effect of duration of corticosteroid therapy on all-cause survival among treatment-responsive patients (Lille score < 0.45). RESULTS During the study period, 2,618 patients were admitted with severe AH, of whom 1,083 (41.37%) received corticosteroids. Although corticosteroids were significantly associated with improved all-cause survival in the unadjusted model ( P = 0.022), no survival benefit was observed in the adjusted model after accounting for baseline and admission characteristics (adjusted hazard ratio [aHR] = 1.01, P = 0.818). Psychiatry consultation was the only factor evaluated that was protective against mortality (aHR = 0.67, P < 0.001). Among the 428 patients (49.7%) responsive to corticosteroids, duration of therapy was not associated with overall survival on unadjusted ( P = 0.696) or adjusted models (aHR = 1.12, P = 0.710 for a ≥28-day course compared with a ≤7-day reference). DISCUSSION Despite being recommended by clinical guidelines for severe AH, corticosteroids have low utilization with no survival benefit after accounting for differences in patient characteristics and practice patterns. Among patients with treatment response per the Lille score, no difference was observed in overall survival between shorter and longer durations of corticosteroid therapy.
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Affiliation(s)
- Claire Durkin
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Douglas E. Schaubel
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - David E. Kaplan
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Section of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Nadim Mahmud
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Section of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Therese Bittermann
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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De La Torre SA, Morcos M, Saab S, Shetty A. Alcohol-Associated Hepatitis: Short- and Long-Term Management. Dig Dis Sci 2025; 70:74-84. [PMID: 39576428 PMCID: PMC11761462 DOI: 10.1007/s10620-024-08705-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 10/19/2024] [Indexed: 01/25/2025]
Abstract
Alcohol-associated hepatitis, considered a severe form of alcohol-associated liver disease, carries with it multiple negative health outcomes ranging not only to increased hospitalizations but also increased rates of mortality. While the inpatient management remains critical in optimizing clinical outcomes, a shift in focus to the outpatient management of alcohol-associated hepatitis is warranted as a long-term solution to this emerging health pandemic. Here, we review the clinical presentation, diagnosis, and current prognostication scoring systems for alcohol-associated hepatitis. We then offer a multimodal approach to the continued management of alcohol-associated hepatitis in the outpatient setting encompassing not only nutritional optimization, alcohol use disorder treatment, and the medical management of chronic liver disease, but also briefly review the current trend of the use of liver transplantation.
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Affiliation(s)
| | - Marco Morcos
- Department of Surgery, Pfleger Liver Institute, UCLA Medical Center, 100 Medical Plaza, Suite 700, Los Angeles, CA, 90095, USA
| | - Sammy Saab
- Department of Medicine, University of California, Los Angeles, CA, USA
- Department of Surgery, Pfleger Liver Institute, UCLA Medical Center, 100 Medical Plaza, Suite 700, Los Angeles, CA, 90095, USA
| | - Akshay Shetty
- Department of Medicine, University of California, Los Angeles, CA, USA.
- Department of Surgery, Pfleger Liver Institute, UCLA Medical Center, 100 Medical Plaza, Suite 700, Los Angeles, CA, 90095, USA.
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12
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Song DS, Yang JM, Jung YK, Yim HJ, Kim HY, Kim CW, Kim SS, Cheong JY, Lee HL, Lee SW, Yoo JJ, Kim SG, Kim YS. Rifaximin treatment in patients with severe alcoholic hepatitis: A multicenter, randomized controlled, open-label, pilot trial. Ann Hepatol 2024; 30:101749. [PMID: 39662593 DOI: 10.1016/j.aohep.2024.101749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/10/2024] [Accepted: 09/30/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION AND OBJECTIVES The short-term mortality of severe alcoholic-associated hepatitis (SAH) is high, but there are no effective treatments to improve short-term mortality other than corticosteroids. This study investigated the effects of adding rifaximin to standard treatment in patients with SAH. MATERIAL AND METHODS In this randomized controlled open-label trial, patients with SAH (Maddrey's discriminant function≥32) were randomized to the rifaximin or control group. Patients were simultaneously treated with corticosteroid or pentoxifylline as standard treatment for 4 weeks. Randomization was stratified by SAH treatment. RESULTS A total of 50 patients were enrolled in this study (29 in the control group and 21 in the rifaximin group). The mean Model for End-stage Liver Disease (MELD) scores were 24.4 and 27.5 in the control and rifaximin groups, respectively (P = 0.106). There were no significant differences in 6-month Liver Transplantation (LT)-free survival rate between the two groups (P = 0.502). When stratified by SAH treatment, there was no significant difference in 6-month LT-free survival rate between the control and rifaximin treatment groups (P = 0.186 in the corticosteroid group and P = 0.548 in the pentoxifylline group). There were no significant differences in the occurrence of liver-related complications between the two groups (all Ps>0.05). The MELD score was the only independent factor for 6-month LT-free survival (hazard ratio 1.188, 95 % confidence interval 1.094-1.289, P<0.001), and rifaximin was not. CONCLUSIONS In patients with SAH, adding rifaximin to corticosteroid or pentoxifylline had no survival benefit and no preventive effect on the development of liver-related complications. The MELD score was the only significant factor for short-term mortality. CLINICAL TRIAL REGISTRATION The study was registered on ClinicalTrials.gov (number: NCT02485106).
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Affiliation(s)
- Do Seon Song
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jin Mo Yang
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea.
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea
| | - Hee Yeon Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Chang Wook Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Soon Sun Kim
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Jae Youn Cheong
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Hae Lim Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Sung Won Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Young Seok Kim
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
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Flemming JA, Djerboua M, Chapman O, Ayonrinde O, Terrault NA. Epidemiology and Outcomes of Alcohol-Associated Hepatitis in Adolescents and Young Adults. JAMA Netw Open 2024; 7:e2452459. [PMID: 39729318 DOI: 10.1001/jamanetworkopen.2024.52459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Importance Alcohol-associated hepatitis (AH) has high mortality, and rates are increasing among adolescents and young adults (AYAs). Objective To define the sex-specific epidemiology of AH in AYAs and the association between female sex and liver-related outcomes after a first presentation of AH. Design, Setting, and Participants A retrospective, population-based cohort study of routinely collected health care data held at ICES from Ontario, Canada, was conducted. Data on AYAs (age, 13-39 years) with first presentation of AH without a history of cirrhosis and/or decompensation from January 1 to December 31, 2022, were included in the analysis. Exposures Study year and female sex. Main Outcome and Measures Overall and sex-specific yearly rates of AH were compared using Poisson regression and rate ratios (RRs). Associations between female sex and incident cirrhosis and/or decompensation were evaluated using competing risks regression, and liver-related mortality by sex was evaluated with cumulative incidence functions. Results A total of 3340 AYAs with AH were identified. Median age was 33 (IQR, 28-36) years, and the population included 1190 (36%) females and 2150 (64%) males. Rates of AH increased by 8% per year (RR, 1.08; 95% CI, 1.07-1.09), with yearly rates increasing faster among females (RR, 1.11; 95% CI, 1.09-1.12) than males (RR, 1.07; 95% CI, 1.06-1.07). A total of 2374 individuals (71%) were alive without cirrhosis 6 months after AH presentation. Of those, 527 (22%) developed incident cirrhosis and/or decompensation after a median follow-up of 4 (IQR, 2-9) years (37% females vs 29% males; P < .001). After adjustment, female sex was associated with a 47% higher subhazard of cirrhosis and/or decompensation compared with male sex (38%) (subhazard, 1.47; 95% CI, 1.23-1.76; P < .001). The cumulative incidence of liver-related mortality at 10 years was higher among females (11.0%; 95% CI, 8.3%-14.2%) than males (6.9%; 95% CI, 5.4%-8.6%) (P = .01). Conclusions and Relevance Over the past 2 decades, the rates of AH among AYAs increased significantly, with the greatest increase observed among females. The findings of this study suggest sex-specific interventions to prevent the development of AH and the progression to cirrhosis after an episode of AH are needed.
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Affiliation(s)
- Jennifer A Flemming
- Department of Medicine, Queen's University Ontario, Ontario, Canada
- Department of Public Health Sciences, Queen's University Ontario, Ontario, Canada
- ICES-Queen's, Ontario, Canada
| | | | - Orli Chapman
- Department of Medicine, Queen's University Ontario, Ontario, Canada
| | - Oyedeji Ayonrinde
- Department of Psychiatry, Queen's University Ontario, Ontario, Canada
| | - Norah A Terrault
- Department of Medicine, University of Southern California, Los Angeles
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14
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Philips CA. A comprehensive review of diagnosis and management of alcohol-associated hepatitis. SAGE Open Med 2024; 12:20503121241297000. [PMID: 39526098 PMCID: PMC11549690 DOI: 10.1177/20503121241297000] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Alcohol-associated hepatitis is an extreme form of alcohol-related liver disease associated with high short-term mortality. Currently, there are no authorized therapies for the treatment of severe alcohol-associated hepatitis. Important diagnostic steps for alcohol-associated hepatitis include recognizing the presence of an alcohol use disorder, distinguishing alcohol-related liver disease from metabolic-dysfunction-associated steatotic liver disease, ruling out alternative causes of acute hepatitis, confirming the diagnosis with validated criteria or a liver biopsy, and using the model for end-stage liver disease score to predict clinical outcome and initiate therapy. Due to the lack of other effective therapy options, corticosteroids continue to be used as initial treatment for patients with severe alcohol-associated hepatitis. Patients who do not improve while on steroid treatment and are ideal candidates should be considered for curative liver transplantation as soon as possible. Avoiding unnecessary and ineffective pharmacological and interventional therapy can help to keep costs down. If a patient is not a good candidate for a transplant or is rapidly deteriorating in health due to a condition such as acute or chronic liver failure, a salvage/bridge to transplant should be pursued through enrolment in a clinical trial program. The role of healthy donor stool transplant and targeted bacteriophage therapy seems promising, pending prospective controlled trials.
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Affiliation(s)
- Cyriac Abby Philips
- Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
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15
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Torres S, Hardesty J, Barrios M, Garcia-Ruiz C, Fernandez-Checa JC, Singal AK. Mitochondria and Alcohol-Associated Liver Disease: Pathogenic Role and Target for Therapy. Semin Liver Dis 2024. [PMID: 39317216 DOI: 10.1055/a-2421-5658] [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: 09/26/2024]
Abstract
Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease and a major cause of liver-related death. ALD is a multifactorial disease triggered by the oxidative metabolism of alcohol which leads to the activation of multiple factors that promote the progression from steatosis to more advanced stages like alcohol-associated steatohepatitis (AH) that culminate in alcohol-associated cirrhosis and hepatocellular carcinoma. Poor understanding of the complex heterogeneous pathology of ALD has limited drug development for this disease. Alterations in mitochondrial performance are considered a crucial event in paving the progression of ALD due to the crucial role of mitochondria in energy production, intermediate metabolism, calcium homeostasis, and cell fate decisions. Therefore, understanding the role of mitochondria in eliciting steatosis and progression toward AH may open the door to new opportunities for treatment. In this review, we will cover the physiological function of mitochondria, its contribution to ALD in experimental models and human disease, and explore whether targeting mitochondria may represent a game changer in the treatment of ALD.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Josiah Hardesty
- Division of Gastroenterology and Hepatology, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Monica Barrios
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Ashwani K Singal
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Division of Gastroenterology and Hepatology, University of Louisville, Louisville, Kentucky
- Transplant Hepatology, Trager Transplant Center and Jewish Hospital, University of Health, Louisville, Kentucky
- Department of Clinical Research, Robley Rex VA Medical Center, Louisville, Kentucky
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16
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Verma N, Vinod AP, Singal AK. The pharmacological management of alcohol-related cirrhosis: what's new? Expert Opin Pharmacother 2024; 25:1923-1941. [PMID: 39360770 DOI: 10.1080/14656566.2024.2409941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwin P Vinod
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani K Singal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Louisville School of Medicine, Louisville, KY, USA
- Department of Transplant Hepatology, Jewish Hospital and Trager Transplant Center, Louisville, Kentucky, USA
- Department of Research, Veteran Affairs Medical Center, Sioux Falls, SD, USA
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17
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Gawrieh S, Dasarathy S, Tu W, Kamath PS, Chalasani NP, McClain CJ, Bataller R, Szabo G, Tang Q, Radaeva S, Barton B, Nagy LE, Shah VH, Sanyal AJ, Mitchell MC. Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis. J Hepatol 2024; 80:684-693. [PMID: 38342441 PMCID: PMC11214682 DOI: 10.1016/j.jhep.2024.01.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 01/18/2024] [Accepted: 01/21/2024] [Indexed: 02/13/2024]
Abstract
BACKGROUND & AIMS Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. METHODS In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. RESULTS Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14-0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13-0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). CONCLUSIONS Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. IMPACT AND IMPLICATIONS There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. TRIAL REGISTRATION NCT04072822.
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Affiliation(s)
- Samer Gawrieh
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Srinivasan Dasarathy
- Division of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Wanzhu Tu
- Department of Biostatistics and Health Data Science, Indiana University, Indianapolis, IN, United States
| | - Patrick S Kamath
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Craig J McClain
- Division of Gastroenterology and Hepatology, University of Louisville, Louisville, KY, United States
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; Division of Hepatology, Hospital Clinic, Barcelona, Spain
| | - Gyongyi Szabo
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Qing Tang
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, United States
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, United States
| | - Laura E Nagy
- Division of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Vijay H Shah
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, United States
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, TX, United States.
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18
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Huai Q, Zhu C, Zhang X, Dai H, Li X, Wang H. Mesenchymal stem/stromal cells armored by FGF21 ameliorate alcohol-induced liver injury through modulating polarization of macrophages. Hepatol Commun 2024; 8:e0410. [PMID: 38551384 PMCID: PMC10984668 DOI: 10.1097/hc9.0000000000000410] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/01/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) is a major health care challenge worldwide with limited therapeutic options. Although mesenchymal stem/stromal cells (MSCs) represent a newly emerging therapeutic approach to treat ALD, thus far, there have been extensive efforts to try and enhance their efficacy, including genetically engineering MSCs. FGF21, an endocrine stress-responsive hormone, has been shown to regulate energy balance, glucose, and lipid metabolism and to enhance the homing of MSCs toward injured sites. Therefore, the purpose of this study was to investigate whether MSCs that overexpress FGF21 (FGF21-MSCs) improve the therapeutic effect of MSCs in treating ALD. METHODS Human umbilical cord-derived MSCs served as the gene delivery vehicle for the FGF21 gene. Human umbilical cord-derived MSCs were transduced with the FGF21 gene using lentiviral vectors to mediate FGF21 overexpression. We utilized both chronic Lieber-DeCarli and Gao-binge models of ethanol-induced liver injury to observe the therapeutic effect of FGF21-MSCs. Liver injury was phenotypically evaluated by performing biochemical methods, histology, and inflammatory cytokine levels. RESULTS Compared with MSCs alone, administration of MSCs overexpressing FGF21(FGF21-MSCs) treatment significantly enhanced the therapeutic effect of ALD in mice, as indicated by the alleviation of liver injury with reduced steatosis, inflammatory infiltration, oxidative stress, and hepatic apoptosis, and the promotion of liver regeneration. Mechanistically, FGF21 could facilitate the immunomodulatory function of MSCs on macrophages by setting metabolic commitment for oxidative phosphorylation, which enables macrophages to exhibit anti-inflammatory inclination. CONCLUSIONS Our data elucidate that MSC modification by FGF21 could enhance their therapeutic effect in ALD and may help in the exploration of effective MSCs-based cell therapies for the treatment of ALD.
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Affiliation(s)
- Qian Huai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Cheng Zhu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xu Zhang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Hanren Dai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xiaolei Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Inflammation and Immune-mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
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19
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Duan F, Liu C, Chang C, Song S, Zhai H, Cheng J, Yang S. Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2024; 50:191-206. [PMID: 38011683 DOI: 10.1080/00952990.2023.2266117] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 11/29/2023]
Abstract
Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.
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Affiliation(s)
- Fangfang Duan
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chen Liu
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chunyan Chang
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shanshan Song
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hang Zhai
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jun Cheng
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Song Yang
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Division 2, Department of Hepatology, The Fourth People's Hospital of Qinghai Province, Xining, China
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Singeap AM, Minea H, Petrea O, Robea MA, Balmuș IM, Duta R, Ilie OD, Cimpoesu CD, Stanciu C, Trifan A. Real-World Utilization of Corticosteroids in Severe Alcoholic Hepatitis: Eligibility, Response, and Outcomes. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:311. [PMID: 38399598 PMCID: PMC10890054 DOI: 10.3390/medicina60020311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024]
Abstract
Background and Objectives: Alcoholic hepatitis (AH) poses a medical challenge, causing moderately severe to life-threatening episodes with high short- and long-term mortality. This study aimed to explore real-world corticosteroid utilization in severe AH, response predictors, and patient outcomes. Materials and Methods: We conducted a retrospective study on patients admitted for severe AH, defined as a Maddrey Discriminant Function score equal to or above 32, at a tertiary care center. We reviewed patients' medical observation charts to identify corticosteroid prescriptions, reasons for ineligibility, and response rates. Responders were defined based on the Lille score, and predictors of non-response were identified. Short-term (one-month) and long-term (one-year) mortality rates were calculated according to treatment and response. Results: Out of 310 patients enrolled with severe AH, 59% received corticosteroids, achieving a response rate of 75.4%. The reasons for not administering corticosteroids were as follows: uncontrolled infections (27.6%), renal dysfunction (20.4%), gastrointestinal bleeding (18.9%), acute pancreatitis (7.1%), uncontrolled diabetes (3.1%), and other or unknown causes (22.8%). The overall 1-month mortality rate was 12.2%, higher in non-responders (35.3%) and patients who did not receive corticosteroids (13.4%) compared to responders (3.6%). The overall 1-year mortality rate was 62.5%, similar between patients who did not receive corticosteroids (78.7%) and non-responders (77.7%) and higher compared to responders (42.8%). Predictive factors for non-response included older age (OR = 1.05, 95%CI: 1.01-1.08), concomitant cirrhosis (OR= 2.11, 95% CI: 1.064-4.20), MELD scores exceeding 30 (OR = 2.42, 95% CI: 1.21-4.80), severe hypoalbuminemia (OR = 2.46, 95%CI: 1.12-5.37), and increased serum creatinine (OR = 1.5, 95% CI: 1.1-2.03). Among the prognostic scores, MELD 3.0 score exhibited superior efficacy for short-term (AUC = 0.734, 95% CI 0.656-0.811) and long-term mortality (AUC = 0.777, 95% CI: 0.724-0.830) compared to alternative scoring systems. Conclusions: Low eligibility rate and poor prognosis underscore the need for effective therapies. Our findings contribute to refining risk stratification and early prediction of non-response, aiding clinicians in identifying more beneficial therapies.
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Affiliation(s)
- Ana-Maria Singeap
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (A.-M.S.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
| | - Horia Minea
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (A.-M.S.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Oana Petrea
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (A.-M.S.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Madalina-Andreea Robea
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, 700057 Iasi, Romania
| | - Ioana-Miruna Balmuș
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, 700057 Iasi, Romania
| | - Raluca Duta
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, 700057 Iasi, Romania
| | - Ovidiu-Dumitru Ilie
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
- Department of Mother and Child, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, No. 16, 700115 Iasi, Romania
| | - Carmen Diana Cimpoesu
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
- Department of Emergency Medicine, “St. Spiridon” University Hospital, 700111 Iasi, Romania
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, Iasi, Blvd. Independentei 1, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (A.-M.S.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (A.-M.S.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
- CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (M.-A.R.); (I.-M.B.); (R.D.); (O.-D.I.); (C.D.C.)
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania
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Miller A, Carney B, Shah S, Chen HW, Gougol A, Borhani A, Bataller R, Malik S, Rachakonda V. Liver surface nodularity and ascites are associated with mortality risk in acute alcohol-associated hepatitis. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:273-282. [PMID: 38123167 DOI: 10.1111/acer.15248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/16/2023] [Accepted: 12/11/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Acute alcohol-associated hepatitis (AH) is associated with high mortality. CT-derived liver surface nodularity (LSN) is a robust prognostic biomarker in other chronic liver diseases. The aim of this study was to determine relationships between LSN, disease severity, and mortality in AH. METHODS Adults hospitalized with AH from January 2016 to March 2020 were included if an abdominal CT was performed between 8 weeks prior to 72 h after hospitalization. LSN was measured using quantitative methods (Liver Surface Nodularity Software version 0.88, Birmingham, AL, USA). Cox proportional hazards models, logistic regression and AUROC analysis were used to examine relationships between LSN and 180-day transplant-free survival. RESULTS Of 386 patients hospitalized with AH during the study period, 230 had CT scans performed, and 205 met inclusion criteria. Mean transplant-free survival was 127 days (95% CI 118-137). Within each cohort, patients were grouped into low [LSN-LOW, N = 109 (53.2%)] and high [LSN-HIGH, N = 96 (46.8%)] LSN strata based on an optimal cutoff of 2.86 derived from unadjusted ROC curves. Patients with high LSN had features of portal hypertension, which included encephalopathy [53 (55.2%) vs. 43 (39.4%), p = 0.017], ascites on CT [81 (84.4%) vs. 69 (63.3%), p = 0.001] and portosystemic shunts [78 (81.2%) vs. 69 (63.3%), p = 0.003]. High LSN, ascites and MELD were independently associated with lower likelihood of 180-day transplant-free survival, and inclusion of a score assigning 1 point each for high LSN or ascites on CT (AHRADS score) to MELD enhanced diagnostic accuracy of AUROC for 180-day survival compared to MELD alone [AUROC 0.782 (95% CI 0.719-0.845) vs. 0.735 (0.667-0.802), p = 0.023]. CONCLUSIONS CT-derived factors that include LSN and ascites are radiographic biomarkers associated with 180-day transplant-free survival in alcohol-associated hepatitis.
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Affiliation(s)
- Alex Miller
- Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Benjamin Carney
- Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Shivani Shah
- Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Hui-Wei Chen
- Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Amir Gougol
- University of California San Francisco School of Medicine, San Francisco, California, USA
| | - Amir Borhani
- Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Ramon Bataller
- Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain
| | - Shahid Malik
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Vikrant Rachakonda
- Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
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22
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Jophlin LL, Singal AK, Bataller R, Wong RJ, Sauer BG, Terrault NA, Shah VH. ACG Clinical Guideline: Alcohol-Associated Liver Disease. Am J Gastroenterol 2024; 119:30-54. [PMID: 38174913 PMCID: PMC11040545 DOI: 10.14309/ajg.0000000000002572] [Citation(s) in RCA: 70] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 10/04/2023] [Indexed: 01/05/2024]
Abstract
ABSTRACT Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%-50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%-60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.
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Affiliation(s)
- Loretta L. Jophlin
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville Health, Louisville, Kentucky, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of South Dakota, Sioux Falls, South Dakota, USA
| | - Ramon Bataller
- Liver Unit, Department of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain
| | - Robert J. Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | - Bryan G. Sauer
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA
| | - Norah A. Terrault
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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23
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Condon S, Jophlin LL. Past, Present, and Future Therapies for Alcohol-associated Hepatitis. Clin Ther 2023; 45:1171-1176. [PMID: 37980219 PMCID: PMC10842010 DOI: 10.1016/j.clinthera.2023.10.013] [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: 07/13/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 11/20/2023]
Abstract
PURPOSE Alcohol-associated hepatitis (AH) is a unique presentation of cholestatic steatohepatitis with liver dysfunction and malaise preceded by heavy alcohol intake. Although AH exists on a spectrum, in its most severe form, 28-day mortality approaches 50%. Clinical trials of therapeutic interventions over the last 50 years have yielded few durable therapies, none of which convey benefit beyond the short term. METHODS A qualitative systematic review was performed via searches of PubMed, the International Clinical Trials Registry Platform, and ClinicalTrials.gov for therapeutic interventions for AH. FINDINGS Prior to 2005, clinical trial results for AH were identified within PubMed. From 2005 to the present, trials were well catalogued within online registries and included information regarding trial status (eg, complete, terminated, actively enrolling). Most clinical trials for AH have used existing medications broadly targeting pathogenic themes of AH (eg, inflammation, cell death) in an off-label manner. The trend of initially promising pilot studies answered by larger trials showing lack of efficacy or safety signals have ended the hopes of many new therapeutics. The emergence of theragnostics to identify patients who may benefit from existing therapies and trials of agents with novel mechanisms of action, including epigenetic modifications and hyaluronic acid signaling targeted to AH pathogenesis, are currently under investigation. IMPLICATIONS This review of AH treatments details the historical interventions and clinical trials that have led to the current treatment algorithm and active studies shaping the therapeutic pipeline for AH.
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Affiliation(s)
- Sally Condon
- Department of Medicine, Division of Gastroenterology Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA
| | - Loretta L Jophlin
- Department of Medicine, Division of Gastroenterology Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA.
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24
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Ding L, Sun L, Zhou X. Network meta-analysis comparing efficacy and safety of different protocols of corneal cross-linking for the treatment of progressive keratoconus. Graefes Arch Clin Exp Ophthalmol 2023; 261:2743-2753. [PMID: 36944752 DOI: 10.1007/s00417-023-06026-z] [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: 05/27/2022] [Revised: 02/13/2023] [Accepted: 02/25/2023] [Indexed: 03/23/2023] Open
Abstract
PURPOSE This study aimed to determine the preferred protocol of corneal collagen cross-linking (CXL) in the treatment of progressive keratoconus. METHODS Relevant studies were retrieved in PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL). Maximum keratometry value (Kmax), best spectacle-corrected visual acuity (BSCVA), manifest refraction spherical equivalent (MRSE), and endothelial cell density (ECD) were evaluated in network meta-analysis. RESULTS Eight randomized controlled trials (RCTs) were included. Low-level evidence suggested that aCXL with 30mW/cm2 for 3 min (aCXL-3) might be the best protocol for reducing BSCVA (65.22%) but worst protocol for reducing MRSE (51.53%). aCXL with 18mW/cm2 for 5 min (aCXL-5) might be the best protocol for reducing Kmax (39.58%) and MRSE (77.85%) but might be the worst for preserving ECD (50.98%). aCXL with 9mW/cm2 for 10 min (aCXL-10) might be the best protocol for preserving ECD (31.53%). CONCLUSION Overall, three protocols of aCXL are comparable in therapeutic efficacy and safety for treating progressive keratoconus. Despite no direct data comparing the efficacy of each technique according to different patients' profiles, it is reasonable to state that aCXL-5 may be the best for patients at early-stage to reduce Kmax and MRSE, aCXL-3 may be the best for patients at mid-stage to improve BSCVA, and aCXL-10 may be the best for patients at late-stage to preserve DEC.
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Affiliation(s)
- Lan Ding
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China
- Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Ling Sun
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China
- Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Xingtao Zhou
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China.
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China.
- Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
- Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China.
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25
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Kasper P, Lang S, Steffen HM, Demir M. Management of alcoholic hepatitis: A clinical perspective. Liver Int 2023; 43:2078-2095. [PMID: 37605624 DOI: 10.1111/liv.15701] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/11/2023] [Accepted: 08/07/2023] [Indexed: 08/23/2023]
Abstract
Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.
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Affiliation(s)
- Philipp Kasper
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sonja Lang
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hans-Michael Steffen
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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26
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Kasper P, Demir M. [Alcoholic hepatitis - current and future treatment approaches]. Dtsch Med Wochenschr 2023; 148:1095-1101. [PMID: 37611573 DOI: 10.1055/a-1941-7187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Acute severe alcoholic hepatitis is a serious disease with poor prognosis. As a result of an improved understanding of the underlying pathomechanisms, a variety of new, innovative therapeutic modalities are currently being investigated that may help to improve prognosis. New approaches include the application of anti-inflammatory agents (e.g., interleukin-1 inhibitors), modifications of the gut-liver axis via fecal microbiome transfer or the administration of non-absorbable antibiotics (e.g., rifaximin), and drugs to enhance hepatocellular regeneration (e.g., interleukin-22 agonists). This article describes current management concepts of alcoholic hepatitis and provides an overview of new potential treatment approaches.
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Affiliation(s)
- Philipp Kasper
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Köln, Köln, Deutschland
| | - Münevver Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte
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27
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Germani G, D’Arcangelo F, Grasso M, Burra P. Advances and Controversies in Acute Alcohol-Related Hepatitis: From Medical Therapy to Liver Transplantation. Life (Basel) 2023; 13:1802. [PMID: 37763206 PMCID: PMC10532507 DOI: 10.3390/life13091802] [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: 07/11/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Alcohol-related hepatitis (AH) is a clinical syndrome characterized by recent-onset jaundice in the context of alcohol consumption. In patients with severe AH "unresponsive" to steroid therapy, mortality rates exceed 70% within six months. According to European and American guidelines, liver transplantation (LT) may be considered in highly selected patients who do not respond to medical therapy. The aim of this narrative review is to summarize current knowledge from medical therapy to liver transplantation in acute alcohol-related hepatitis. Due to the impossibility to guarantee six-month abstinence, LT for AH is controversial. Principal concerns are related to organ scarcity in the subset of stigma of "alcohol use disorder" (AUD) and the risk of relapse to alcohol use after LT. Return to alcohol use after LT is a complex issue that cannot be assessed as a yes/no variable with heterogeneous results among studies. In conclusion, present data indicate that well-selected patients have excellent outcomes, with survival rates of up to 100% at 24 and 36 months after LT. Behavioral therapy, ongoing psychological support, and strong family support seem essential to improve long-term outcomes after LT and reduce the risk in relapse of alcohol use.
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Affiliation(s)
- Giacomo Germani
- Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
| | - Francesca D’Arcangelo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Marco Grasso
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
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Vannier AGL, Przybyszewski EM, Shay J, Patel SJ, Schaefer E, Goodman RP, Luther J. Psychotherapy for Alcohol Use Disorder Is Associated With Reduced Risk of Incident Alcohol-Associated Liver Disease. Clin Gastroenterol Hepatol 2023; 21:1571-1580.e7. [PMID: 35964893 PMCID: PMC9918606 DOI: 10.1016/j.cgh.2022.08.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alcohol-associated liver disease (ALD) is a devastating complication of alcohol use disorder (AUD). Once it develops, ALD is exceedingly difficult to treat; it therefore is critical to identify ways to prevent ALD. By treating the causes of increased alcohol consumption, psychotherapy may offer prophylactic benefit against the development of ALD for patients with AUD. METHODS In this retrospective cohort study, we used International Classification of Diseases, 9th and 10th revision, codes to identify 9635 patients with AUD in the Mass General Brigham Biobank. The mean follow-up period from AUD diagnosis was 9.2 years. We used Cox regression models to generate hazard ratios (HR) for the development of ALD given the receipt or nonreceipt of psychotherapy, adjusting for a range of other contributors including the receipt of medication-assisted treatment. RESULTS In our cohort, 60.4% of patients were men, 83.5% of patients were white, the median age was 57.0 years, and 3544 patients (36.8%) received psychotherapy. ALD developed in 1135 patients (11.8%). In multivariable analysis, psychotherapy was associated with a reduced rate of ALD (HR, 0.59; 95% CI, 0.50-0.71; P < .001). This association held for both individual psychotherapy (HR, 0.70; 95% CI, 0.56-0.86; P < .001) and group psychotherapy (HR, 0.76; 95% CI, 0.61-0.94; P = .01). Among patients with cirrhosis, psychotherapy was associated with a lower rate of hepatic decompensation (HR, 0.68; 95% CI, 0.48-0.95; P = .03). CONCLUSIONS The receipt of psychotherapy in the setting of AUD is associated with reduced incidence and progression of ALD. Given the safety and potential benefit of psychotherapy, clinicians should consider using it to prevent the development of ALD.
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Affiliation(s)
- Augustin G L Vannier
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Jessica Shay
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Suraj J Patel
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Esperance Schaefer
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Russell P Goodman
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Jay Luther
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts.
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Maurice JB, Tribich S, Zamani A, Ryan J. How to manage alcohol-related liver disease: A case-based review. Frontline Gastroenterol 2023; 14:435-441. [PMID: 37581189 PMCID: PMC10423597 DOI: 10.1136/flgastro-2022-102270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 05/02/2023] [Indexed: 08/16/2023] Open
Affiliation(s)
- James B Maurice
- Department of Gastroenterology and Hepatology, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
| | - Samuel Tribich
- Department of Hepatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Ava Zamani
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Jennifer Ryan
- Department of Hepatology and Liver Transplantation, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK
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Tu W, Gawrieh S, Dasarathy S, Mitchell MC, Simonetto DA, Patidar KR, McClain CJ, Bataller R, Szabo G, Tang Q, Barton BA, Radaeva S, Sanyal AJ, Shah V, for the Alcoholic Hepatitis Network (AlcHepNet) Investigators. Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis. Contemp Clin Trials Commun 2023; 32:101074. [PMID: 36698742 PMCID: PMC9869411 DOI: 10.1016/j.conctc.2023.101074] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/04/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Background Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.
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Affiliation(s)
- Wanzhu Tu
- Indiana University School of Medicine, USA
| | | | | | | | | | | | | | | | | | - Qing Tang
- Indiana University School of Medicine, USA
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31
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Alcohol-Related Liver Disease Including New Developments. Clin Liver Dis 2023; 27:157-172. [PMID: 36400463 DOI: 10.1016/j.cld.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The prevalence of alcohol consumption, alcohol use disorder (AUD), and alcohol-related liver disease (ALD) has exponentially increased over the last several years and rates continue to increase. Significant alcohol use can cause progression from steatosis in the liver to inflammation, fibrosis, and eventually cirrhosis. Additional risk factors for the progression of ALD disease include gender, race, and genetic predisposition. As such, it is essential for clinicians to understand and implement screening tools for early diagnosis of both AUD and ALD and be aware of emerging novel treatment options.
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32
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Thakral N, Deutsch-Link S, Singal AK. Therapeutic Pipeline in Alcohol-Associated Liver Disease. Semin Liver Dis 2023; 43:60-76. [PMID: 36572032 PMCID: PMC11503467 DOI: 10.1055/s-0042-1759614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.
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Affiliation(s)
- Nimish Thakral
- Division of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky
| | - Sasha Deutsch-Link
- Department of Medicine, University of North Carolina at Chapel Hill, North Carolina
| | - Ashwani K. Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
- Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
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33
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Alcoholic Hepatitis. Med Clin North Am 2023; 107:533-554. [PMID: 37001952 DOI: 10.1016/j.mcna.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Alcoholic hepatitis (AH) is a unique clinical syndrome on the spectrum of alcohol-associated liver disease (ALD). It constitutes a rising epidemic with increasing incidence and major public health implications. In severe AH, 30-day mortality approaches 30%, yet therapeutic options remain limited. Survival benefit from corticosteroids, the mainstay of medical treatment, is short-lived. Among corticosteroid nonresponders, the use of early liver transplantation is heterogeneous across centers and remains limited by significant barriers. Long-term prognosis is largely dictated by abstinence; however, comorbid alcohol use disorder remains undertreated. Efforts to address these challenges are required to curb the AH epidemic.
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Parker R. Reply. Clin Gastroenterol Hepatol 2023; 21:237. [PMID: 35378293 DOI: 10.1016/j.cgh.2022.03.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 03/20/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Richard Parker
- Leeds Liver Unit, St James's University Hospital, Leeds, United Kingdom
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35
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Adekunle AD, Adejumo A, Singal AK. Therapeutic targets in alcohol-associated liver disease: progress and challenges. Therap Adv Gastroenterol 2023; 16:17562848231170946. [PMID: 37187673 PMCID: PMC10176580 DOI: 10.1177/17562848231170946] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, none of the newer targets is currently close to an Food and Drug Administration approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and alcoholic hepatitis. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of early liver transplantation still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of alcohol use disorder and of liver disease for improving the long-term outcomes of patients with ALD.
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Affiliation(s)
- Ayooluwatomiwa Deborah Adekunle
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
| | - Adeyinka Adejumo
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
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36
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Philips CA, Tharakan A, Augustine P. Shallow Waters, Deep Secret: Trajectory of Serum Bilirubin to Predict Spontaneous Recovery in Alcohol-Associated Hepatitis. Clin Gastroenterol Hepatol 2023; 21:236-237. [PMID: 35151864 DOI: 10.1016/j.cgh.2022.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Cyriac Abby Philips
- Clinical and Translational Hepatology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
| | - Ajit Tharakan
- Department of Gastroenterology and Clinical Research, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
| | - Philip Augustine
- Department of Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Kerala, India
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37
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Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022; 10:biomedicines10102530. [PMID: 36289791 PMCID: PMC9599689 DOI: 10.3390/biomedicines10102530] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.
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Szabo G, Mitchell M, McClain CJ, Dasarathy S, Barton B, McCullough AJ, Nagy LE, Kroll-Desrosiers A, Tornai D, Min HA, Radaeva S, Holbein MEB, Casey L, Cuthbert J. IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis. Hepatology 2022; 76:1058-1068. [PMID: 35340032 PMCID: PMC10062003 DOI: 10.1002/hep.32478] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival. APPROACH AND RESULTS Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. CONCLUSIONS A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Mack Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Srinivasan Dasarathy
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Arthur J. McCullough
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Nagy
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Aimee Kroll-Desrosiers
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
- VA Central Western Massachusetts, Leeds, Massachusetts, USA
| | - David Tornai
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Hyesung Alice Min
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - M. E. Blair Holbein
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lisa Casey
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jennifer Cuthbert
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Kaur B, Rosenblatt R, Sundaram V. Infections in Alcoholic Hepatitis. J Clin Transl Hepatol 2022; 10:718-725. [PMID: 36062291 PMCID: PMC9396323 DOI: 10.14218/jcth.2022.00024] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/11/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Severe alcoholic hepatitis (sAH) is defined by a modified discriminant function ≥32 or model for end-stage liver disease (MELD) >20. Patients with sAH are in an immunocompromised state attributed to cirrhosis-related immunoparesis and corticosteroid use. Individuals with sAH often develop severe infections that adversely impact short-term prognosis. Currently, the corticosteroid prednisolone is the only treatment with proven efficacy in sAH; however, the combination of corticosteroid treatment and altered host defense in sAH has been thought to increase the risk of acquiring of bacterial, opportunistic fungal, and viral infections. Newer studies have shown that corticosteroids do not increase occurrence of infections in those with sAH; unfortunately, the lack of response to corticosteroids may instead predispose to infection development. Prompt and appropriate antibiotic treatment is therefore essential to improving patient outcomes. This review highlights common infections and risk factors in patients with sAH. Additionally, current diagnostic, therapeutic, and prophylactic strategies in these patients are discussed.
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Affiliation(s)
- Bhupinder Kaur
- Internal Medicine Department, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Russell Rosenblatt
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Vinay Sundaram
- Department of Gastroenterology and Hepatology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Correspondence to: Vinay Sundaram, Department of Gastroenterology and Hepatology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8635W. Third Street, Suite 1060W, Los Angeles, CA 90048, USA. ORCID: https://orcid.org/0000-0002-1450-7756. Tel: +1-310-423-6000, Fax: +1-310-423-6086, E-mail:
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Shu L, Fu Y, Sun H. The association between common serum adipokines levels and postmenopausal osteoporosis: A meta‐analysis. J Cell Mol Med 2022; 26:4333-4342. [PMID: 35791510 PMCID: PMC9344814 DOI: 10.1111/jcmm.17457] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/09/2022] [Accepted: 05/12/2022] [Indexed: 11/09/2022] Open
Abstract
The clinical relevance of blood levels of adipokines in individuals with postmenopausal osteoporosis (PMOP) has not been previously clarified. We performed this meta‐analysis to clarify the association between three common adipokines levels and the occurrence of PMOP. PubMed, Embase, Cochrane library, and China National Knowledgement Infrastructure (CNKI) were searched for collecting articles published before 31 October 2021, without language and status restrictions. Fourteen studies met the selection criteria. Meta‐analysis revealed that blood leptin level was remarkably lower (mean difference [MD], −1.94; 95% confidence interval [CI], −3.83 to −0.06; I2 = 96%) and adiponectin level was remarkably higher (MD, 3.48; 95% CI, 2.36 to 4.60; I2 = 90%) in individuals with PMOP than healthy individuals with normal bone mineral density (BMD). However, the statistical difference in leptin level was changed after eliminating the confounding influence of leptin sources and assay approaches. Furthermore, a positive association (r = 0.28) between leptin level and body mass index (BMI) as well as a negative association (r = −0.33) between adiponectin level and BMD was found. Moreover, adiponectin had the highest probability of predicting PMOP (84%). Current evidence suggests that leptin positively affects BMI and adiponectin negatively affects BMD, and adiponectin is the most relevant adipokine negatively associated with PMOP.
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Affiliation(s)
- Linyuan Shu
- Department of Emergency Medicine Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai China
| | - Yimu Fu
- Department of Emergency Medicine Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai China
| | - Hui Sun
- Department of Orthopaedic Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai China
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41
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Rattan P, Shah VH. Review article: current and emerging therapies for acute alcohol-associated hepatitis. Aliment Pharmacol Ther 2022; 56:28-40. [PMID: 35567372 DOI: 10.1111/apt.16969] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/20/2022] [Accepted: 04/28/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Alcohol-associated hepatitis is an acute manifestation of alcohol-associated liver disease (ALD) and is associated with 30%-40% mortality at 28 days. Abstinence and corticosteroids are the mainstays of treatment, but the latter only improves short-term mortality, so new and improved therapies remain an unmet need. AIMS The aim was to review the pathophysiology of alcohol-associated hepatitis and how various targets can be used by current and emerging therapies as treatment. METHODS A thorough literature review was conducted on acute alcohol-associated hepatitis, current therapies and therapies under investigation. RESULTS With the increasing prevalence of alcohol use disorder and ALD, the burden of alcohol-associated hepatitis is also expected to rise. The current understanding of alcohol-associated hepatitis pathophysiology has led to clinical trials of several therapies involving IL-1 antagonism, modification of the gut microbiome and liver regeneration. CONCLUSIONS Corticosteroid therapy for alcohol-associated hepatitis is restricted in its applicability and has limited efficacy. Developing multidisciplinary, patient-centred care models based on digital health technologies, in combination with continued discovery of novel therapies using multiomics data and computational biology techniques will be necessary to tackle the increasing burden of alcohol-associated hepatitis.
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Affiliation(s)
- Puru Rattan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Singal AK, Kwo P, Kwong A, Liangpunsakul S, Louvet A, Mandrekar P, McClain C, Mellinger J, Szabo G, Terrault N, Thursz M, Winder GS, Kim WR, Shah VH. Research methodologies to address clinical unmet needs and challenges in alcohol-associated liver disease. Hepatology 2022; 75:1026-1037. [PMID: 34496071 PMCID: PMC9235468 DOI: 10.1002/hep.32143] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022]
Abstract
Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol-associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient-selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD.
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Affiliation(s)
- Ashwani K. Singal
- Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA
- Division of Gastroenterology and Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota, USA
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Allison Kwong
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
| | | | - Pranoti Mandrekar
- Graduate School of Biomedical Sciences, UMass Medical School, Worcester, Massachusetts, USA
| | - Craig McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, USA
| | - Jessica Mellinger
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Gyongyi Szabo
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Norah Terrault
- Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, California, USA
| | - Mark Thursz
- Division of Digestive Diseases, Imperial College London, London, UK
| | - Gerald S. Winder
- Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA
| | - W. Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Gholami R, Khan R, Ramkissoon A, Alabdulqader A, Gimpaya N, Bansal R, Scaffidi MA, Prasad V, Detsky AS, Baker JP, Grover SC. Recommendation Reversals in Gastroenterology Clinical Practice Guidelines. J Can Assoc Gastroenterol 2022; 5:98-99. [PMID: 35368318 PMCID: PMC8972276 DOI: 10.1093/jcag/gwab040] [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: 05/06/2021] [Accepted: 09/28/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Recommendations in clinical practice guidelines (CPGs) may be reversed when evidence emerges to show they are futile or unsafe. In this study, we identified and characterized recommendation reversals in gastroenterology CPGs. METHODS We searched CPGs published by 20 gastroenterology societies from January 1990 to December 2019. We included guidelines which had at least two iterations of the same topic. We defined reversals as when (a) the more recent iteration of a CPG recommends against a specific practice that was previously recommend in an earlier iteration of a CPG from the same body, and (b) the recommendation in the previous iteration of the CPG is not replaced by a new diagnostic or therapeutic recommendation in the more recent iteration of the CPG. The primary outcome was the number of recommendation reversals. Secondary outcomes included the strength of recommendations and quality of evidence cited for reversals. RESULTS Twenty societies published 1022 CPGs from 1990 to 2019. Our sample for analysis included 129 unique CPGs. There were 11 recommendation reversals from 10 guidelines. New evidence was presented for 10 recommendation reversals. Meta-analyses were cited for two reversals, and randomized controlled trials (RCTs) for seven reversals. Recommendations were stronger after the reversal for three cases, weaker in two cases, and of similar strength in three cases. We were unable to compare recommendation strengths for three reversals. CONCLUSION Recommendation reversals in gastroenterology CPGs are uncommon but highlight low value or harmful practices.
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Affiliation(s)
- Reza Gholami
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Rishad Khan
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Anushka Ramkissoon
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | | | - Nikko Gimpaya
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Rishi Bansal
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Michael A Scaffidi
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Vinay Prasad
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California,USA
| | - Allan S Detsky
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada
| | - Jeffrey P Baker
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Samir C Grover
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
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Xu H, Wang H. Immune cells in alcohol-related liver disease. LIVER RESEARCH 2022; 6:1-9. [PMID: 39959807 PMCID: PMC11791833 DOI: 10.1016/j.livres.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/18/2021] [Accepted: 01/07/2022] [Indexed: 11/24/2022]
Abstract
Alcohol-related liver disease (ALD), which is caused by excessive alcohol consumption, is one of the most common types of liver disease and a primary cause of hepatic injury, with a disease spectrum that includes steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Various lines of evidence have indicated that immune cells play a significant role in the inflammatory processes of ALD. On the one hand, the liver contains various resident immune cells that have been proven to perform different functions in ALD. For example, in the progression of the disease, Kupffer cells (KCs) are activated by lipopolysaccharide-Toll-like receptor 4 signaling and release various proinflammatory cytokines. Moreover, alcohol intake has been shown to depress the function of natural killer cells. Additionally, two types of unconventional T cells (natural killer T cells and mucosal-associated invariant T cells) are involved in the development of ALD. On the other hand, alcohol and many different cytokines stimulate the recruitment and infiltration of circulating immune cells (neutrophils, T cells, macrophages, and mast cells) into the liver. The neutrophils can produce proinflammatory mediators and cause the dysfunction of anti-infection processes. Additionally, alcohol intake can change the phenotype of T cells, resulting in their increased production of interleukin-17. Aside from KCs, infiltrating macrophages have also been observed in patients with ALD, but the roles of all of these cells in the progression of the disease have shown both similarities and differences. Additionally, the activated mast cells are also associated with the development of ALD. Herein, we review the diverse roles of the various immune cells in the progression of ALD.
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Affiliation(s)
- Honghai Xu
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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Parker R, Cabezas J, Altamirano J, Arab JP, Ventura-Cots M, Sinha A, Dhanda A, Arrese M, McCune CA, Rowe IA, Schnabl B, Mathurin P, Shawcross D, Abraldes JG, Lucey MR, Garcia-Tsao G, Verna E, Brown RS, Bosques-Padilla F, Vargas V, Louvet A, Holt AP, Bataller R. Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients With Alcoholic Hepatitis. Clin Gastroenterol Hepatol 2022; 20:e289-e297. [PMID: 33516950 PMCID: PMC9188123 DOI: 10.1016/j.cgh.2021.01.042] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/20/2021] [Accepted: 01/24/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.
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Affiliation(s)
- Richard Parker
- Leeds Liver Unit, St James's University Hospital, Leeds, United Kingdom.
| | - Joaquin Cabezas
- Department of Gastroenterology and Hepatology, University Hospital Marques de Valdecilla, Valdecilla Research Institute, Santander, Spain; Liver Center, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jose Altamirano
- Internal Medicine Department, Hospital Quirónsalud, Barcelona, Spain
| | - Juan Pablo Arab
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Meritxell Ventura-Cots
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Ashish Sinha
- Department of Liver Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom
| | - Ashwin Dhanda
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - C Anne McCune
- Department of Liver Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom
| | - Ian A Rowe
- Leeds Liver Unit, St James's University Hospital, Leeds, United Kingdom
| | - Bernd Schnabl
- Department of Medicine, VA San Diego Healthcare System, University of California, San Diego, La Jolla, California
| | - Phillipe Mathurin
- Service des Maladies de l'Appareil Digestif et Unité, French Institute of Health and Medical Research, Hôpital Huriez, Lille, France
| | - Debbie Shawcross
- Liver Sciences, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Juan G Abraldes
- Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), Centre of Excellence Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada
| | - Michael R Lucey
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University, New Haven, Connecticut; Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, Connecticut
| | - Elizabeth Verna
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York
| | | | - Victor Vargas
- Liver Unit, Hospital Vall d'Hebron, Universitat Autònoma Barcelona, CIBEREHD, Barcelona, Spain
| | - Alexandre Louvet
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, New York
| | - Andrew P Holt
- Liver and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Ramon Bataller
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Morales-Arráez D, Ventura-Cots M, Altamirano J, Abraldes JG, Cruz-Lemini M, Thursz MR, Atkinson SR, Sarin SK, Kim W, Chavez-Araujo R, Higuera-de la Tijera MF, Singal AK, Shah VH, Kamath PS, Duarte-Rojo A, Charles EA, Vargas V, Jager M, Rautou PE, Rincon D, Zamarripa F, Restrepo-Gutiérrez JC, Torre A, Lucey MR, Arab JP, Mathurin P, Louvet A, García-Tsao G, González JA, Verna EC, Brown RS, Argemi J, Fernández-Carrillo C, Clemente A, Alvarado-Tapias E, Forrest E, Allison M, Bataller R. The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study. Am J Gastroenterol 2022; 117:301-310. [PMID: 34962498 PMCID: PMC8999152 DOI: 10.14309/ajg.0000000000001596] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 10/27/2021] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.
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Affiliation(s)
- D Morales-Arráez
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Department of Gastroenterology and Hepatology, Hospital Universitario de Canarias, Canarias, Spain
| | - M Ventura-Cots
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - J Altamirano
- Department of Internal Medicine, Hospital Quironsalud, Barcelona, Spain
| | - J G Abraldes
- Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Canada
| | - M Cruz-Lemini
- Women and Perinatal Research Group, Obstetrics and Gynecology Department, Sant Pau University Hospital, Barcelona, Spain, and Maternal and Child Health and Development Network (SAMID, RD16/0022/0015), Instituto de Salud Carlos III, Spanish Ministry of Health, Spain
| | - M R Thursz
- Department of Metabolism, Digestive disease and Reproduction, Imperial College London, UK
| | - S R Atkinson
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Department of Metabolism, Digestive disease and Reproduction, Imperial College London, UK
| | - S K Sarin
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - W Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - R Chavez-Araujo
- Hospital das Clinicas, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - A K Singal
- Division of Gastroenterology and Hepatology, the University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - V H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - P S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - A Duarte-Rojo
- Division of Gastroenterology and Hepatology, Department of Medicine, the University of Arkansas for Medical Science, Little Rock, Arkansas, USA
| | - E A Charles
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - V Vargas
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universidad Autónoma, Barcelona, CIBERehd, Barcelona, Spain
| | - M Jager
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - P E Rautou
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
- Inserm, UMR-970, Paris Cardiovascular Research Center, PARCC, Paris, France
| | - D Rincon
- Hepatology Department, Hospital General Universitario Gregorio Marañón, CIBERehd and Universidad Complutense, Madrid, Spain
| | - F Zamarripa
- Gastroenterology, Juarez Hospital, Mexico City, Mexico
| | - J C Restrepo-Gutiérrez
- Liver Transplant Program, Hospital Pablo Tobon Uribe, University of Antioquia, Medellin, Colombia
| | - A Torre
- Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - M R Lucey
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - J P Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - P Mathurin
- Service des Maladies de l'Appareil Digestif et de la Nutrition, CHU Lille, Lille, France
- LIRIC-Lille Inflammation Research International Center-U995, Univ. Lille, Inserm, CHU Lille, Lille, France
| | - A Louvet
- Service des Maladies de l'Appareil Digestif et de la Nutrition, CHU Lille, Lille, France
| | - G García-Tsao
- Section of Digestive Diseases, Yale University School of Medicine/VA-CT Healthcare System, New Haven/West Haven, Connecticut¸ USA
| | - J A González
- Gastroenterology Department, Hospital Universitario "Dr. José E González" Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - E C Verna
- Division of Digestive and Liver Diseases, Department of Medicine and Center for Liver Disease and Transplantation, Columbia University Irving Medical Center, New York, New York, USA
| | - R S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA
| | - J Argemi
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Liver Unit, Clinica Universidad de Navarra, IdisNA. Pamplona, Spain
| | - C Fernández-Carrillo
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - A Clemente
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Liver Unit and Digestive Department H.G.U. Gregorio Marañón, Madrid, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - E Alvarado-Tapias
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - E Forrest
- Glasgow Royal Infirmary, Glasgow, UK
| | - M Allison
- Liver Unit, Cambridge Biomedical Research Centre, Cambridge, UK
| | - R Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
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Abstract
In patients with cirrhosis and chronic liver disease, acute-on-chronic liver failure is emerging as a major cause of mortality. These guidelines indicate the preferred approach to the management of patients with acute-on-chronic liver failure and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.
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Jophlin L, Singal AK. Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure. J Clin Exp Hepatol 2022; 12:544-550. [PMID: 35535109 PMCID: PMC9077173 DOI: 10.1016/j.jceh.2021.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/09/2021] [Indexed: 01/11/2023] Open
Abstract
Patients with alcohol-associated liver disease may develop severe forms of presentation of acute-on-chronic liver failure, with a high risk for short-term mortality. Alcoholic hepatitis should be suspected among patients with alcohol-associated liver disease who present with acute-on-chronic liver failure. In this review, we discuss the need and feasibility of liver biopsy in the diagnosis of alcoholic hepatitis and predicting its prognosis among decompensated patients with alcohol-associated liver disease and acute-on-chronic liver failure.
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Key Words
- AARC, Asia-Pacific ACLF Research Consortium
- ACLF
- ACLF, acute-on-chronic liver failure
- AH
- AH, alcoholic hepatitis
- AHHS, alcoholic hepatitis histologic score
- ALD
- ALD, alcohol-associated liver disease
- AUD, alcohol use disorder
- DF, discriminant function
- EUS, endoscopic ultrasound
- EtG, ethyl glucuronide
- NIAAA, National Institute on Alcoholism and Alcohol Abuse
- PEth, phosphatidylethanol
- SALVE, Study of Alcohol-related LiVer disease in Europe
- histology
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Affiliation(s)
- Loretta Jophlin
- Department of Gastroenterology and Hepatology, University of Louisville, Louisville, KY, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, Department of Medicine, University of South Dakota Sanford School of Medicine, South Dakota, USA,Address for correspondence:. Ashwani K. Singal, Professor of Medicine, University of South Dakota Sanford School of Medicine, Transplant Hepatologist and Chief Clinical Research Affairs, Avera McKennan University Hospital Transplant Institute, Sioux Falls, SD, 57105, USA. Tel.: +605 322-8545; fax: +605 322 8536.
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Liu Y, Wu Y, Pan Z, Jiang F, Lu Y, Meng Y. Single-Dose Versus Multiple-Dose GnRH Agonist for Luteal-Phase Support in Women Undergoing IVF/ICSI Cycles: A Network Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2022; 13:802688. [PMID: 35432219 PMCID: PMC9008129 DOI: 10.3389/fendo.2022.802688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 03/02/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Although gonadotropin-releasing hormone (GnRH) agonist has been introduced as a beneficial luteal phase support (LPS), the optimal strategy of GnRH agonist remains unclear. This network meta-analysis was therefore performed to determine the comparative efficacy and safety of multiple-dose versus single-dose GnRH agonist protocol for LPS in patients undergoing IVF/ICSI cycles. METHODS We searched relevant studies in PubMed, Embase and the Cochrane Registry of Controlled Trials (CENTRAL) from their inception util to September 2021. Live birth, clinical pregnancy rate, multiple pregnancy rate, and clinical abortion rate was evaluated. Pairwise and network meta-analysis were conducted using RevMan and ADDIS based on random-effects model, respectively. Moreover, the prioritization of protocols based on ranking probabilities for different outcomes were performed. RESULTS Sixteen RCTs met our eligibility criteria. Pairwise meta-analysis showed that multiple-dose protocol of GnRH agonist was effective for increasing live birth rate (OR 1.80, 95% CI 1.15 to 2.83, p=0.01) and clinical pregnancy rate (OR 1.89, 95% CI 1.01 to 3.56, p=0.05) as well as decreasing clinical abortion rate (OR 0.55, 95% CI 0.34 to 0.90, p=0.02). Meanwhile, single-dose protocol of GnRH agonist was effective for increasing clinical pregnancy rate (OR 1.45, 95% CI 1.11 to 1.89, p=0.007) and multiple pregnancy rate (OR 2.55, 95% CI 1.12 to 5.78, p=0.03). However, network meta-analysis only confirmed that multiple-dose protocol of GnRH agonist was the best efficacious strategy for live birth rate (OR 2.04, 95% CrI 1.19 to 3.93) and clinical pregnancy rate (OR 2.10, 95% CrI 1.26 to 3.54). CONCLUSION Based on the results of NMA, multiple-dose protocol may be the optimal strategy for patients undergoing IVF/ICSI cycles owing to its advantage in increasing live birth and clinical pregnancy rate. Moreover, single-dose protocol may be the optimal strategy for improving multiple pregnancy rate. However, with the limitations, more RCTs are required to confirm our findings.
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Affiliation(s)
| | | | | | | | - Youhui Lu
- *Correspondence: Yushi Meng, ; Youhui Lu,
| | - Yushi Meng
- *Correspondence: Yushi Meng, ; Youhui Lu,
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Elfeki MA, Singal AK. Early Liver Transplantation: An Evolving Therapeutic Option for Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:3-5. [PMID: 35068777 PMCID: PMC8766704 DOI: 10.1016/j.jceh.2021.10.144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 01/03/2023] Open
Affiliation(s)
- Mohamed A. Elfeki
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
- Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, SD, USA
| | - Ashwani K. Singal
- Address for correspondence. Ashwani K. Singal, Professor of Medicine and Director Hepatology Elective, University of South Dakota Sanford School of Medicine, Transplant Hepatologist and Chief Clinical Research Affairs, Avera McKennan University Hospital and Transplant Institute, Sioux Falls, SD 57105, USA. Tel.: +605-322-8535.
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