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Farsi N, Sanchez-Avila M, Duarte M, Requena DO, Alkathery T, Ronquillo NR, Garcia-Buitrago M, Stoll LM, Montgomery EA, Byrnes K. Hepatic segmental atrophy: a diagnostic challenge with variable clinicopathologic features and an association with cardiovascular disease. Virchows Arch 2025:10.1007/s00428-025-04094-6. [PMID: 40232381 DOI: 10.1007/s00428-025-04094-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/04/2025] [Accepted: 03/27/2025] [Indexed: 04/16/2025]
Abstract
Hepatic segmental atrophy is an underrecognized pseudotumor that can cause diagnostic challenges. These lesions can be mass-forming and demonstrate a range of pathologic features that can lead to diagnostic errors on both imaging studies, on frozen section, and in biopsy material. The aim of this study was to better understand the clinicopathologic features of this condition as well as its association with cardiovascular disease. A retrospective computerized search of the files of two institutions was conducted spanning 2012 to 2024. All surgical slides were reviewed, and clinical and demographic information was collected. There were 45 patients, including 23 men and 22 women with median age of 63 years. Most (35/45, 78%) patients had a history of hypertension or cardiovascular disease. Thirty patients had a history of malignant neoplasm, and seven had cirrhosis. Histologically, the cases showed variable histologic features, ranging from nodular elastosis to more subtle lesions featuring degenerative hepatocytes with relative preservation of bile ducts between them. Association of these lesions with remote vascular injury might be explained by cardiovascular disease, most commonly hypertension. The current case series emphasizes the importance of recognizing this lesion and its association with cardiovascular diseases. While lobular or segmental atrophy of the liver has been recognized as a complication of many benign and malignant conditions, pathologists should be aware that this can present as a mass lesion.
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Affiliation(s)
- Negin Farsi
- Department of pathology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| | - Monica Sanchez-Avila
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Melissa Duarte
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Domenika Ortiz Requena
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Turky Alkathery
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Nemencio R Ronquillo
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Monica Garcia-Buitrago
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Lisa M Stoll
- Department of Pathology and Laboratory Medicine, Luke University Health Network, Bethlehem, StPA, 18015, USA
| | - Elizabeth A Montgomery
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Kathleen Byrnes
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63310, USA
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2
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Skladaný Ĺ, Žilinčanová D, Žilinčan M, Okapec S, Danček F, Adamcová-Selčanová S, Kukla M, Koller T. Hepatic venous pressure gradient in patients with (compensated and decompensated) advanced chronic liver disease - A comparison of metabolic dysfunction-associated steatotic liver disease with alcohol-associated liver disease: A retrospective view. PLoS One 2025; 20:e0317287. [PMID: 40043074 PMCID: PMC11882044 DOI: 10.1371/journal.pone.0317287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 12/25/2024] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND AND AIMS Hepatic venous pressure gradient (HVPG) is a strong surrogate of severity and outcome but its relative prognostic value in metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) is yet to be clarified. We compared HVPG in MASLD with ALD and other etiologies according to cirrhosis complications. PATIENTS AND METHODS In our cirrhosis registry RH7, we identified patients with data on HVPG and scrutinized them against the etiology of advanced chronic liver disease (ACLD) (MASLD, ALD, Other) and specific complications of ACLD such as variceal bleeding or ascites. We excluded patients with advanced malignancies and less than 6 months of follow-up. RESULTS We enrolled 220 patients with ALD, MASLD, and Other etiology in 128, 52, and 40 cases, respectively; te median age was 57, 60, and 52 years (P = 0.09); the proportion of females was 31, 67, and 55%, respectively (P < 0.01). Median MELD scores in ALD, MASLD, and Other etiologies were 16.0, 13.0, and 12.0 (P < 0.01), and the median HVPG was 18.0, 14.0, and 11.5 mmHg (P < 0.001). In 19, 30, and 25 compensated patients, the median HVPG was 10.0, 11.5, and 11.0 mmHg (P = 0.97). In 109, 22, and 15 decompensated patients, the median HVPG was 19.0, 15.5 and 14 mmHg (P = 0.01 for trend, difference ALD vs. other P < 0.01, ALD vs. MASLD, P = 0.295). Between decompensated MASLD and ALD patients, we observed no differences in the proportion of clinically significant portal hypertension (CSPH) (>10 mmHg). CONCLUSION In our cirrhosis registry study of hospitalized patients with ACLD, baseline HVPG measured for accepted indications differed according to the etiology of dACLD: patients with ALD had the highest values followed by MASLD and Other etiologies. Importantly, when looked at from the point of view of complications, the treshold for clinically significant portal hypertension remained fixed at the level recommended by BAVENO Consensus - 10 mm Hg irrespective of etiology.
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Affiliation(s)
- Ĺubomír Skladaný
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Daniela Žilinčanová
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Michal Žilinčan
- Department of Radiology, FD Roosevelt Hospital, Banská Bystrica, Slovakia
| | - Stanislav Okapec
- Department of Radiology, FD Roosevelt Hospital, Banská Bystrica, Slovakia
| | - Filip Danček
- Department of Radiology, FD Roosevelt Hospital, Banská Bystrica, Slovakia
| | - Svetlana Adamcová-Selčanová
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Michal Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
- Department of Endoscopy, University Hospital in Kraków, Kraków, Poland
| | - Tomáš Koller
- Subdivision of Gastroenterology and Hepatology, 5th Department of Medicine, Comenius University Faculty of Medicine, University Hospital Bratislava, Bratislava, Slovakia
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Shasthry SM, Sarin SK. Alcohol-Associated Liver Diseases: Spectrum, Nomenclature, and Definitions. Clin Liver Dis 2024; 28:621-631. [PMID: 39362711 DOI: 10.1016/j.cld.2024.06.003] [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] [Indexed: 10/05/2024]
Abstract
Alcohol-associated liver disease (AALD) is a global health problem with increasing incidence with associated high morbidity and mortality. Patients with AALD have varied clinical presentation encompassing a spectrum ranging from alcoholic steatosis, alcoholic steatohepatitis to alcohol-associated fibrosis/cirrhosis, which can be either compensated or decompensated. We need uniformity in defining each of the stages of AALD, which will help in both research and patient care. Algorithmic approach using noninvasive tests like enhanced liver fibrosis score, elastography, and fibrosis-4 scores can help in early diagnosis in addition to the presence of any red flags (low albumin, low platelet count, and raised transaminases).
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Affiliation(s)
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Sector D1, Vasantkunj, New Delhi 110070, India.
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4
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Yokoyama T, Iwadare T, Yamashita Y, Momose A, Ikeuchi H, Kondo S, Hashigami K, Iwaya M, Kimura T, Umemura T. Case of severe alcoholic hepatitis following acute pancreatitis. Clin J Gastroenterol 2024; 17:915-921. [PMID: 38809500 DOI: 10.1007/s12328-024-01988-x] [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: 03/16/2024] [Accepted: 05/18/2024] [Indexed: 05/30/2024]
Abstract
This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5-7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory-Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient's hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis.
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Affiliation(s)
- Takeru Yokoyama
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Takanobu Iwadare
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
| | - Akari Momose
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Hiroshi Ikeuchi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Shohei Kondo
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Kenta Hashigami
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
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5
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Lucitti JL, Laudermilk LT, Amato GS, Maitra R. The Monoacylglycerol Lipase Inhibitor ABX-1431 Does Not Improve Alcoholic Liver Disease. Cannabis Cannabinoid Res 2024; 9:e1179-e1183. [PMID: 37253145 DOI: 10.1089/can.2023.0003] [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] [Indexed: 06/01/2023] Open
Abstract
Introduction: Excessive alcohol consumption can result in alcoholic liver disease (ALD). There is no FDA-approved drug to specifically treat ALD and current management approaches have limited efficacy. Past studies indicate that monoacylglycerol lipase (MAGL) inhibition can have a positive impact on nonalcoholic fatty liver disease. However, the effect of MAGL inhibition in ALD has not been reported. Materials and Methods: We tested the highly selective and clinically evaluated MAGL inhibitor ABX-1431 in the Lieber-DeCarli liquid alcohol diet-induced model of ALD in C57BL/6 mice. Results: ABX-1431 failed to reduce ALD-associated steatosis and elevated levels of liver enzymes associated with hepatic injury. Furthermore, survival rate declined with increasing doses of ABX-1431 when compared with mice administered vehicle only. Conclusion: These data suggest that MAGL inhibition does not improve ALD and is unlikely to be a good strategy for this condition.
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Affiliation(s)
- Jennifer L Lucitti
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - Lucas T Laudermilk
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - George S Amato
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
| | - Rangan Maitra
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina, USA
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6
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Ali NAM, Abdelhamid AM, El-Sayed NM, Radwan A. Alpha-Asarone attenuates alcohol-induced hepatotoxicity in a murine model by ameliorating oxidative stress, inflammation, and modulating apoptotic-Autophagic cell death. Toxicol Appl Pharmacol 2024; 490:117041. [PMID: 39059505 DOI: 10.1016/j.taap.2024.117041] [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: 04/22/2024] [Revised: 07/01/2024] [Accepted: 07/21/2024] [Indexed: 07/28/2024]
Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver injury characterized by steatosis, inflammation, and fibrosis. This study explored the hepatoprotective mechanisms of alpha-asarone in a mouse model of chronic-binge alcohol feeding. Adult male mice were randomized into control, alcohol, and alcohol plus alpha-asarone groups. Serum aminotransferases and histopathology assessed liver injury. Oxidative stress was evaluated via malondialdehyde content, glutathione, superoxide dismutase, and catalase activities. Pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified by ELISA. P53-mediated apoptosis was determined by immunohistochemistry. Key autophagy markers phospho-AMPK, AMPK, Beclin-1, LC3-I/LC3-II ratio, and LC3 were examined by immunoblotting. Alcohol administration increased serum ALT, AST and ALP, indicating hepatocellular damage. This liver dysfunction was associated with increased oxidative stress, inflammation, p53 expression and altered autophagy. Alpha-asarone treatment significantly decreased ALT, AST and ALP levels and improved histological architecture versus alcohol alone. Alpha-asarone also mitigated oxidative stress, reduced TNF-α, IL-1β and IL-6 levels, ameliorated p53 overexpression and favorably modulated autophagy markers. Our findings demonstrate that alpha-asarone confers protective effects against ALD by enhancing antioxidant defenses, suppressing hepatic inflammation, regulating apoptotic signaling, and restoring autophagic flux. This preclinical study provides compelling evidence for the therapeutic potential of alpha-asarone in attenuating alcohol-induced liver injury and warrants further evaluation as a pharmacotherapy for ALD.
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Affiliation(s)
- Nada A M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Amir Mohamed Abdelhamid
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Norhan M El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Asmaa Radwan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
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7
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Mukhopadhyay B, Marietta C, Shen PH, Oiseni A, Mirshahi F, Mazzu M, Hodgkinson C, Winkler E, Yuan Q, Miranda D, Kunos G, Sanyal AJ, Goldman D. A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis. Nat Commun 2024; 15:2869. [PMID: 38693144 PMCID: PMC11063145 DOI: 10.1038/s41467-024-47085-y] [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: 05/28/2023] [Accepted: 03/15/2024] [Indexed: 05/03/2024] Open
Abstract
Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.
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Affiliation(s)
- Bani Mukhopadhyay
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Cheryl Marietta
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Pei-Hong Shen
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Abdul Oiseni
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Faridoddin Mirshahi
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Maria Mazzu
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Colin Hodgkinson
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Eli Winkler
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Qiaoping Yuan
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Daniel Miranda
- Aivia Machine Learning Team, Leica Microsystems, Inc, Deerfield, IL, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - David Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA.
- Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA.
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8
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Cooper KM, Colletta A, Hebda N, Devuni D. Alcohol associated liver disease and bariatric surgery: Current perspectives and future directions. World J Gastrointest Surg 2024; 16:650-657. [PMID: 38577096 PMCID: PMC10989338 DOI: 10.4240/wjgs.v16.i3.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/27/2024] [Accepted: 02/26/2024] [Indexed: 03/22/2024] Open
Abstract
Bariatric surgery is a routinely performed procedure and is associated with a reduction in all-cause mortality in patients with obesity. However, bariatric surgery has also been linked to increased alcohol use with up to 30% of these patients developing alcohol use disorder (AUD). The mechanism of AUD after bariatric surgery is multifactorial and includes anatomic, metabolic, and neurohumoral changes associated with post-surgical anatomy. These patients are at increased risk of alcohol associated liver disease and, in some cases, require liver transplantation. In this article, we provide a scoping review of epidemiology, pathophysiology, and clinical outcomes of alcohol-related health conditions after bariatric surgery.
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Affiliation(s)
- Katherine M Cooper
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
| | - Alessandro Colletta
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
| | - Nicholas Hebda
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
| | - Deepika Devuni
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
- Division of Gastroenterology, UMass Chan Medical School, Worcester, MA 01655, United States
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9
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Tsoneva DK, Ivanov MN, Vinciguerra M. Liquid Liver Biopsy for Disease Diagnosis and Prognosis. J Clin Transl Hepatol 2023; 11:1520-1541. [PMID: 38161500 PMCID: PMC10752811 DOI: 10.14218/jcth.2023.00040] [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: 02/05/2023] [Revised: 05/24/2023] [Accepted: 06/07/2023] [Indexed: 01/03/2024] Open
Abstract
Liver diseases are a major burden worldwide, the scope of which is expected to further grow in the upcoming years. Clinically relevant liver dysfunction-related blood markers such as alanine aminotransferase and aspartate aminotransferase have limited accuracy. Nowadays, liver biopsy remains the gold standard for several liver-related pathologies, posing a risk of complication due to its invasive nature. Liquid biopsy is a minimally invasive approach, which has shown substantial potential in the diagnosis, prognosis, and monitoring of liver diseases by detecting disease-associated particles such as proteins and RNA molecules in biological fluids. Histones are the core components of the nucleosomes, regulating essential cellular processes, including gene expression and DNA repair. Following cell death or activation of immune cells, histones are released in the extracellular space and can be detected in circulation. Histones are stable in circulation, have a long half-life, and retain their post-translational modifications. Here, we provide an overview of the current research on histone-mediated liquid biopsy methods for liver diseases, with a focus on the most common detection methods.
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Affiliation(s)
- Desislava K. Tsoneva
- Department of Medical Genetics, Medical University of Varna, Varna, Bulgaria
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Martin N. Ivanov
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Department of Anatomy and Cell Biology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Manlio Vinciguerra
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Faculty of Health, Liverpool John Moores University, Liverpool, United Kingdom
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10
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Yang HX, Guo FY, Lin YC, Wu YL, Nan JX, Jin CH, Lian LH. Synthesis of and anti-fibrotic effect of pyrazole derivative J-1048: Inhibition of ALK5 as a novel approach to liver fibrosis targeting inflammation. Bioorg Chem 2023; 139:106723. [PMID: 37459824 DOI: 10.1016/j.bioorg.2023.106723] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 06/24/2023] [Accepted: 07/06/2023] [Indexed: 08/13/2023]
Abstract
Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-β stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-β/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1β (IL-1β) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.
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Affiliation(s)
- Hong-Xu Yang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Fang-Yan Guo
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yong-Ce Lin
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Cheng-Hua Jin
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China.
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11
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Li D, Janmey PA, Wells RG. Local fat content determines global and local stiffness in livers with simple steatosis. FASEB Bioadv 2023; 5:251-261. [PMID: 37287868 PMCID: PMC10242205 DOI: 10.1096/fba.2022-00134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/09/2023] [Accepted: 04/04/2023] [Indexed: 06/09/2023] Open
Abstract
Fat accumulation during liver steatosis precedes inflammation and fibrosis in fatty liver diseases, and is associated with disease progression. Despite a large body of evidence that liver mechanics play a major role in liver disease progression, the effect of fat accumulation by itself on liver mechanics remains unclear. Thus, we conducted ex vivo studies of liver mechanics in rodent models of simple steatosis to isolate and examine the mechanical effects of intrahepatic fat accumulation, and found that fat accumulation softens the liver. Using a novel adaptation of microindentation to permit association of local mechanics with microarchitectural features, we found evidence that the softening of fatty liver results from local softening of fatty regions rather than uniform softening of the liver. These results suggest that fat accumulation itself exerts a softening effect on liver tissue. This, along with the localized heterogeneity of softening within the liver, has implications in what mechanical mechanisms are involved in the progression of liver steatosis to more severe pathologies and disease. Finally, the ability to examine and associate local mechanics with microarchitectural features is potentially applicable to the study of the role of heterogeneous mechanical microenvironments in both other liver pathologies and other organ systems.
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Affiliation(s)
- David Li
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Paul A. Janmey
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Institute for Medicine and EngineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PhysiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Rebecca G. Wells
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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12
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McLean Diaz P, Vannier A, Joshi AD, Mahle RE, Przybyszewski EM, Corey K, Chung RT, Luther J, Goodman RP, Schaefer EA. Serum Fibroblast Growth Factor-21 Discriminates Between Decompensated Alcohol-Associated Cirrhosis and Severe Alcohol-Associated Hepatitis. Clin Transl Gastroenterol 2023; 14:e00585. [PMID: 36972232 PMCID: PMC10299775 DOI: 10.14309/ctg.0000000000000585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/14/2023] [Indexed: 06/18/2023] Open
Abstract
INTRODUCTION We hypothesized that fibroblast growth factor-21 (FGF-21) would be highly expressed in patients with alcohol-associated hepatitis (AH) and could be a novel and biologically relevant predictive biomarker to reliably distinguish severe AH and decompensated alcohol-associated cirrhosis (AC). METHODS We identified a discovery cohort of 88 subjects with alcohol-associated liver disease (ALD) of varying disease severity from our ALD repository. Our validation cohort consisted of 37 patients with a biopsy-proven diagnosis of AH, AC, or absence of ALD with Model for End-Stage Liver Disease scores ≥10. Serum from both groups during index hospitalization was assayed for FGF-21 by ELISA. We performed receiver operating characteristic analysis and prediction modeling in both cohorts to discriminate between AH and AC in high Model for End-Stage Liver Disease (≥20) patients. RESULTS In both cohorts, FGF-21 concentrations were highest in subjects with moderate to severe AH compared with those having alcohol use disorder or AC (mean: 2,609 pg/mL, P < 0.0001). The discovery cohort area under the curve of FGF-21 between AH and AC was 0.81 (95% confidence interval: 0.65-0.98, P < 0.01). In the validation cohort, FGF-21 levels were higher in severe AH compared with AC (3,052 vs 1,235 pg/mL, P = 0.03), and the area under the curve was 0.76 (95% confidence interval: 0.56-0.96, P < 0.03). A survival analysis showed that patients with FGF-21 serum levels in the second interquartile had the highest survival compared with all other quartiles. DISCUSSION FGF-21 performs well as a predictive biomarker to distinguish severe AH from AC and may be helpful in the management and clinical investigation of patients with severe alcohol-associated liver diseases.
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Affiliation(s)
- Paige McLean Diaz
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Augustin Vannier
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Amit D. Joshi
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rachael E. Mahle
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Eric M. Przybyszewski
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kathleen Corey
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Raymond T. Chung
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jay Luther
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Russell P. Goodman
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Esperance A.K. Schaefer
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
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13
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Chaudhry H, Sohal A, Iqbal H, Roytman M. Alcohol-related hepatitis: A review article. World J Gastroenterol 2023; 29:2551-2570. [PMID: 37213401 PMCID: PMC10198060 DOI: 10.3748/wjg.v29.i17.2551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/10/2023] [Accepted: 04/13/2023] [Indexed: 05/23/2023] Open
Abstract
Alcohol-related hepatitis (ARH) is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by significant alcohol use. It ranges in severity from mild to severe and carries significant morbidity and mortality. The refinement of scoring systems has enhanced prognostication and guidance of clinical decision-making in the treatment of this complex disease. Although treatment focuses on supportive care, steroids have shown benefit in select circumstances. There has been a recent interest in this disease process, as coronavirus disease 2019 pandemic led to substantial rise in cases. Although much is known regarding the pathogenesis, prognosis remains grim due to limited treatment options. This article summarizes the epidemiology, genetics, pathogenesis, diagnosis and treatment of ARH.
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Affiliation(s)
- Hunza Chaudhry
- Department of Internal Medicine, University of California, San Francisco, Fresno, CA 93701, United States
| | - Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA 98105, United States
| | - Humzah Iqbal
- Department of Internal Medicine, University of California, San Francisco, Fresno, CA 93701, United States
| | - Marina Roytman
- Department of Gastroenterology and Hepatology, University of California, San Francisco, Fresno, CA 93701, United States
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14
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Solís-Muñoz P, de la Flor-Robledo M, García-Ruíz I, Fernández-García CE, González-Rodríguez Á, Shah N, Bataller R, Heneghan M, García-Monzón C, Solís-Herruzo JA. Mitochondrial respiratory chain activity is associated with severity, corticosteroid response and prognosis of alcoholic hepatitis. Aliment Pharmacol Ther 2023; 57:1131-1142. [PMID: 36864659 DOI: 10.1111/apt.17434] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 11/27/2022] [Accepted: 02/13/2023] [Indexed: 03/04/2023]
Abstract
BACKGROUND AND AIMS Little is known about the extent of mitochondrial respiratory chain (MRC) activity dysfunction in patients with alcoholic hepatitis (AH). We aimed to assess the hepatic MRC activity in AH patients and its potential impact on the severity and prognosis of this life-threatening liver disease. METHODS MRC complexes were measured in liver biopsies of 98 AH patients (non-severe, 17; severe, 81) and in 12 histologically normal livers (NL). Severity was assessed according to Maddrey's Index and MELD score. Corticosteroid response rate and cumulative mortality were also evaluated. RESULTS The activity of the five MRC complexes was markedly decreased in the liver of AH patients compared with that of NL subjects, being significantly lower in patients with severe AH than in those with non-severe AH. There was a negative correlation between the activity of all MRC complexes and the severity of AH. Interestingly, only complex I and III activities showed a significant positive correlation with the corticosteroid response rate and a significant negative correlation with the mortality rate at all-time points studied. In a multivariate regression analysis, besides the MELD score and the corticosteroid response rate, complex I activity was significantly associated with 3-month mortality (OR = 6.03; p = 0.034) and complex III activity with 6-month mortality (OR = 4.70; p = 0.041) in AH patients. CONCLUSION Our results indicate that MRC activity is markedly decreased in the liver of AH patients, and, particularly, the impairment of MRC complexes I and III activity appears to have a significant impact on the clinical outcomes of patients with AH.
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Affiliation(s)
- Pablo Solís-Muñoz
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain.,Unidad Médica Angloamericana, Madrid, Spain.,Gastroenterology and Hepatology Unit, Hospital Universitario Santa Cristina, Madrid, Spain.,Facultad de Medicina, Universidad Francisco de Vitoria, Madrid, Spain
| | | | - Inmaculada García-Ruíz
- Gastroenterology and Hepatology Laboratory, Research Institute, University Hospital "12 de Octubre". Universidad Complutense, Madrid, Spain
| | - Carlos E Fernández-García
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain
| | - Águeda González-Rodríguez
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain
| | - Naina Shah
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Ramón Bataller
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.,Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Departamento de Medicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
| | | | - Carmelo García-Monzón
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - José A Solís-Herruzo
- Gastroenterology and Hepatology Laboratory, Research Institute, University Hospital "12 de Octubre". Universidad Complutense, Madrid, Spain.,Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
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15
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Neonatal Orally Administered Zingerone Attenuates Alcohol-Induced Fatty Liver Disease in Experimental Rat Models. Metabolites 2023; 13:metabo13020167. [PMID: 36837786 PMCID: PMC9966972 DOI: 10.3390/metabo13020167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Alcohol intake at different developmental stages can lead to the development of alcohol-induced fatty liver disease (AFLD). Zingerone (ZO) possess hepato-protective properties; thus, when administered neonatally, it could render protection against AFLD. This study aimed to evaluate the potential long-term protective effect of ZO against the development of AFLD. One hundred and twenty-three 10-day-old Sprague-Dawley rat pups (60 males; 63 females) were randomly assigned to four groups and orally administered the following treatment regimens daily during the pre-weaning period from postnatal day (PND) 12-21: group 1-nutritive milk (NM), group 2-NM +1 g/kg ethanol (Eth), group 3-NM + 40 mg/kg ZO, group 4-NM + Eth +ZO. From PND 46-100, each group from the neonatal stage was divided into two; subgroup I had tap water and subgroup II had ethanol solution as drinking fluid, respectively, for eight weeks. Mean daily ethanol intake, which ranged from 10 to 14.5 g/kg body mass/day, resulted in significant CYP2E1 elevation (p < 0.05). Both late single hit and double hit with alcohol increased liver fat content, caused hepatic macrosteatosis, dysregulated mRNA expression of SREBP1c and PPAR-α in male and female rats (p < 0.05). However, neonatal orally administered ZO protected against liver lipid accretion and SREBP1c upregulation in male rats only and attenuated the alcohol-induced hepatic PPAR-α downregulation and macrosteatosis in both sexes. This data suggests that neonatal orally administered zingerone can be a potential prophylactic agent against the development of AFLD.
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16
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Han Y, Zee S, Cho KH. Beeswax Alcohol and Fermented Black Rice Bran Synergistically Ameliorated Hepatic Injury and Dyslipidemia to Exert Antioxidant and Anti-Inflammatory Activity in Ethanol-Supplemented Zebrafish. Biomolecules 2023; 13:136. [PMID: 36671520 PMCID: PMC9855622 DOI: 10.3390/biom13010136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/24/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Alcohol abuse, a global health problem, is closely associated with many pathological processes, such as dyslipidemia and cardiovascular disease. In particular, excessive alcohol consumption promotes dyslipidemia and liver damage, such as hepatic steatosis, fibrosis, and cirrhosis. Beeswax alcohol (BWA) is a natural product used for its antioxidant properties that has not been evaluated for its efficacy in alcohol-induced liver injury. In the present study, zebrafish were exposed to 1% ethanol with supplementation of 10% fermented black rice bran (BRB-F), 10% BWA, or 10% mixtures of BWA+BRB-F (MIX). The BRB-F, BWA, and MIX supplementation increased the survival rate dramatically without affecting the body weight changes. In histology of hepatic tissue, alcoholic foamy degeneration was ameliorated by the BWA or MIX supplements. Moreover, dihydroethidium (DHE) and immunohistochemistry staining suggested that the MIX supplement decreased the hepatic ROS production and interleukin-6 expression significantly owing to the enhanced antioxidant properties, such as paraoxonase. Furthermore, the MIX supplement improved alcohol-induced dyslipidemia and oxidative stress. The BWA and MIX groups showed lower blood total cholesterol (TC) and triglyceride (TG) levels with higher high-density lipoprotein-cholesterol (HDL-C) than the alcohol-alone group. The MIX group showed the highest HDL-C/TC ratio and HDL-C/TG ratio with the lowest low-density lipoprotein (LDL)-C/HDL-C ratio. In conclusion, BWA and BRB-F showed efficacy to treat alcohol-related metabolic disorders, but the MIX supplement was more effective in ameliorating the liver damage and dyslipidemia, which agrees with an enhanced antioxidant and anti-inflammatory activity exhibited by BWA/BRB-F in a synergistic manner.
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Affiliation(s)
- Youngji Han
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Seonggeun Zee
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Kyung-Hyun Cho
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
- LipoLab, Yeungnam University, Gyeongsan 38541, Republic of Korea
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17
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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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18
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Königshofer P, Hofer BS, Brusilovskaya K, Simbrunner B, Petrenko O, Wöran K, Herac M, Stift J, Lampichler K, Timelthaler G, Bauer D, Hartl L, Robl B, Sibila M, Podesser BK, Oberhuber G, Schwabl P, Mandorfer M, Trauner M, Reiberger T. Distinct structural and dynamic components of portal hypertension in different animal models and human liver disease etiologies. Hepatology 2022; 75:610-622. [PMID: 34716927 PMCID: PMC9299647 DOI: 10.1002/hep.32220] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 10/17/2021] [Accepted: 10/28/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Liver fibrosis is the static and main (70%-80%) component of portal hypertension (PH). We investigated dynamic components of PH by a three-dimensional analysis based on correlation of hepatic collagen proportionate area (CPA) with portal pressure (PP) in animals or HVPG in patients. APPROACH AND RESULTS Different animal models (bile duct ligation: n = 31, carbon tetrachloride: n = 12, thioacetamide: n = 12, choline-deficient high-fat diet: n = 12) and patients with a confirmed single etiology of cholestatic (primary biliary cholangitis/primary sclerosing cholangitis: n = 16), alcohol-associated (n = 22), and metabolic (NASH: n = 19) liver disease underwent CPA quantification on liver specimens/biopsies. Based on CPA-to-PP/HVPG correlation, potential dynamic components were identified in subgroups of animals/patients with lower-than-expected and higher-than-expected PP/HVPG. Dynamic PH components were validated in a patient cohort (n = 245) using liver stiffness measurement (LSM) instead of CPA. CPA significantly correlated with PP in animal models (Rho = 0.531; p < 0.001) and HVPG in patients (Rho = 0.439; p < 0.001). Correlation of CPA with PP/HVPG varied across different animal models and etiologies in patients. In models, severity of hyperdynamic circulation and specific fibrosis pattern (portal fibrosis: p = 0.02; septa width: p = 0.03) were associated with PH severity. In patients, hyperdynamic circulation (p = 0.04), vascular dysfunction/angiogenesis (VWF-Ag: p = 0.03; soluble vascular endothelial growth factor receptor 1: p = 0.03), and bile acids (p = 0.04) were dynamic modulators of PH. The LSM-HVPG validation cohort confirmed these and also indicated IL-6 (p = 0.008) and hyaluronic acid (HA: p < 0.001) as dynamic PH components. CONCLUSIONS The relative contribution of "static" fibrosis on PH severity varies by type of liver injury. Next to hyperdynamic circulation, increased bile acids, VWF-Ag, IL-6, and HA seem to indicate a pronounced dynamic component of PH in patients.
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Affiliation(s)
- Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria,Vienna Hepatic Hemodynamic Laboratoy, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Katharina Wöran
- Department of PathologyMedical University of ViennaViennaAustria
| | - Merima Herac
- Department of PathologyMedical University of ViennaViennaAustria
| | - Judith Stift
- Department of PathologyMedical University of ViennaViennaAustria
| | - Katharina Lampichler
- Department of Radiology and Nuclear MedicineMedical University of ViennaViennaAustria
| | - Gerald Timelthaler
- The Institute of Cancer ResearchDepartment of Medicine IMedical University of ViennaViennaAustria
| | - David Bauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic Laboratoy, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic Laboratoy, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Bernhard Robl
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer CenterMedical University of ViennaViennaAustria
| | - Maria Sibila
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer CenterMedical University of ViennaViennaAustria
| | - Bruno K. Podesser
- Center for Biomedical ResearchMedical University of ViennaViennaAustria
| | - Georg Oberhuber
- INNPATHInstitute of Pathology, University Hospital of InnsbruckInnsbruckAustria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria,Vienna Hepatic Hemodynamic Laboratoy, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic Laboratoy, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Experimental Hepatic Hemodynamic Lab (HEPEX)Medical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria,Vienna Hepatic Hemodynamic Laboratoy, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
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19
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Xie Y, Chang J, Pan Y, Hao W, Li J. Toxicological effects of acute prothioconazole and prothioconazole-desthio administration on liver in male Chinese lizards (Eremias argus). CHEMOSPHERE 2022; 291:132825. [PMID: 34762875 DOI: 10.1016/j.chemosphere.2021.132825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 06/13/2023]
Abstract
Prothioconazole (PTC) is a high effective systemic fungicide, and one of its major metabolites is prothioconazole-desthio (PTC-d). Because of its wildly use in the farmland of China, the local eco-toxicological effects of PTC as well as PTC-d are needed to be concerned. This study investigated hepatoxicity of Chinese lizards (Eremias argus), a local non-target organism, after single dose oral treated (100 mg kg-1 BW) through pathological, enzyme activity and gene expression analysis. PTC treatment caused ballooning and PTC-d treatment led to macrovesicular steatosis of hepatocyte. The elevation of serum indexes, including the activities of aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT), further confirmed the hepatic injury. PTC and PTC-d treatments altered oxidative status reflected by the inhibition of superoxide dismutase (SOD) activity , meanwhile, the stimulation of catalase (CAT) activity, glutathione peroxidase (GPx) activity and malondialdehyde (MDA) content. The mRNA expression changes of apoptosis-related factors and cytokines genes, including Bax, Bcl-2, TNF-α, NF-κB, Caspase-3 and Nrf2, deeply uncovered the potential mechanism of hepatotoxicity caused by PTC and PTC-d. In brief, the results indicated that both of these two compounds altered oxidative status, then were likely to trigger caspase-3 by affecting the ratio of pro- and anti-apoptotic factors which belong to intrinsic apoptosis pathway. Specifically, more serious impacts were induced by PTC-d than its parent compound. This study is the first to provide specific insight into potential hepatotoxicity resulted from PTC and PTC-d in male Chinese lizards.
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Affiliation(s)
- Yun Xie
- Institute of Food Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China; Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing RD 18, Beijing, 100085, China.
| | - Jing Chang
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing RD 18, Beijing, 100085, China
| | - Yifan Pan
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing RD 18, Beijing, 100085, China
| | - Weiyu Hao
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing RD 18, Beijing, 100085, China
| | - Jianzhong Li
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing RD 18, Beijing, 100085, China
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20
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Budelmann D, Laue H, Weiss N, Dahmen U, D’Alessandro LA, Biermayer I, Klingmüller U, Ghallab A, Hassan R, Begher-Tibbe B, Hengstler JG, Schwen LO. Automated Detection of Portal Fields and Central Veins in Whole-Slide Images of Liver Tissue. J Pathol Inform 2022; 13:100001. [PMID: 35242441 PMCID: PMC8860737 DOI: 10.1016/j.jpi.2022.100001] [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: 05/06/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Many physiological processes and pathological phenomena in the liver tissue are spatially heterogeneous. At a local scale, biomarkers can be quantified along the axis of the blood flow, from portal fields (PFs) to central veins (CVs), i.e., in zonated form. This requires detecting PFs and CVs. However, manually annotating these structures in multiple whole-slide images is a tedious task. We describe and evaluate a fully automated method, based on a convolutional neural network, for simultaneously detecting PFs and CVs in a single stained section. Trained on scans of hematoxylin and eosin-stained liver tissue, the detector performed well with an F1 score of 0.81 compared to annotation by a human expert. It does, however, not generalize well to previously unseen scans of steatotic liver tissue with an F1 score of 0.59. Automated PF and CV detection eliminates the bottleneck of manual annotation for subsequent automated analyses, as illustrated by two proof-of-concept applications: We computed lobulus sizes based on the detected PF and CV positions, where results agreed with published lobulus sizes. Moreover, we demonstrate the feasibility of zonated quantification of biomarkers detected in different stainings based on lobuli and zones obtained from the detected PF and CV positions. A negative control (hematoxylin and eosin) showed the expected homogeneity, a positive control (glutamine synthetase) was quantified to be strictly pericentral, and a plausible zonation for a heterogeneous F4/80 staining was obtained. Automated detection of PFs and CVs is one building block for automatically quantifying physiologically relevant heterogeneity of liver tissue biomarkers. Perspectively, a more robust and automated assessment of zonation from whole-slide images will be valuable for parameterizing spatially resolved models of liver metabolism and to provide diagnostic information.
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Affiliation(s)
| | | | | | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany
| | - Lorenza A. D’Alessandro
- Deutsches Krebsforschungszentrum, Systems Biology of Signal Transduction, Heidelberg, Germany
| | - Ina Biermayer
- Deutsches Krebsforschungszentrum, Systems Biology of Signal Transduction, Heidelberg, Germany
| | - Ursula Klingmüller
- Deutsches Krebsforschungszentrum, Systems Biology of Signal Transduction, Heidelberg, Germany
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Brigitte Begher-Tibbe
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
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21
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Reed TJ, D'Ambrosio D, Knollmann-Ritschel BE. Educational Case: Evaluating a patient with cirrhosis. Acad Pathol 2022; 9:100031. [PMID: 35813091 PMCID: PMC9257346 DOI: 10.1016/j.acpath.2022.100031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/02/2022] [Accepted: 01/22/2022] [Indexed: 11/15/2022] Open
Affiliation(s)
| | - Danielle D'Ambrosio
- Corresponding author. Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
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22
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Schroeder SM, Matsukuma KE, Medici V. Wilson disease and the differential diagnosis of its hepatic manifestations: a narrative review of clinical, laboratory, and liver histological features. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1394. [PMID: 34733946 PMCID: PMC8506558 DOI: 10.21037/atm-21-2264] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/25/2021] [Indexed: 01/05/2023]
Abstract
Objective The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease. Background Wilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied. Methods We conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition. Conclusions Aside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.
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Affiliation(s)
- Shannon M Schroeder
- Department of Internal Medicine, University of California Davis, Sacramento, CA, USA
| | - Karen E Matsukuma
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
| | - Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
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23
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Ting PS, Gurakar A, Wheatley J, Chander G, Cameron AM, Chen PH. Approaching Alcohol Use Disorder After Liver Transplantation for Acute Alcoholic Hepatitis. Clin Liver Dis 2021; 25:645-671. [PMID: 34229846 PMCID: PMC8264137 DOI: 10.1016/j.cld.2021.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Severe alcoholic hepatitis portends a high risk of mortality without liver transplantation. Transplant outcomes in patients with severe alcoholic hepatitis exhibit a strong inverse association with post-transplant alcohol relapse. The ingredients most central to ameliorating alcohol relapse risk may include destigmatized post-transplant alcohol monitoring, a nonpunitive clinician-patient partnership, and multimodal therapies to maintain abstinence and mitigate high-risk drinking. We here review the core principles of post-liver transplant management specific to alcohol use disorder.
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Affiliation(s)
- Peng-Sheng Ting
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 431, Baltimore, MD 21287, USA
| | - Ahmet Gurakar
- Liver Transplant, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Suite 918, Baltimore, MD 21205, USA.
| | - Jason Wheatley
- Department of Social Work, Johns Hopkins Hospital, 600 North Wolfe Street, Carnegie Suite 100, Baltimore, MD 21287, USA
| | - Geetanjali Chander
- Division of General Internal Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 8047A, Baltimore, MD 21287, USA
| | - Andrew M Cameron
- Division of Liver Transplant Surgery, Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 765, Baltimore, MD 21205, USA
| | - Po-Hung Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 429, Baltimore, MD 21287, USA
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24
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Abstract
The natural history of moderate alcoholic hepatitis (AH) is not well known. It is a frequent disease with a probable underestimated incidence compared with its severe form. Among the different prognostic scores predicting short-term mortality in AH, MELD seems to be the most accurate. The mortality of moderate AH is 3% to 7% in the short to medium term and 13% to 20% at 1 year, mainly because of liver-related complications, including severe infections. Long-term abstinence is the main goal of the treatment. There is still need for the development of new therapies for AH, including the less severe forms.
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Affiliation(s)
- Ana Clemente-Sánchez
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center (UPMC), BST West 11th Floor, Suite 1116-17, 200 Lothrop Street, Pittsburgh, PA 15213, USA; CIBERehd, Instituto de Salud Carlos III, Avenida Monforte de Lemos, 3-5, Pavilion 11th, Floor 0, Madrid 28029, Spain
| | - Aline Oliveira-Mello
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center (UPMC), BST West 11th Floor, Suite 1116-17, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Ramón Bataller
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Kaufmann Medical Building, 3471 Fifth Avenue, Suite 201.19, Pittsburgh, PA 15213, USA.
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25
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Rorat M, Hałoń A, Jurek T. Histology of Liver of the Deceased Due to Harmful Use of Alcohol. Alcohol Alcohol 2021; 55:518-523. [PMID: 32626893 DOI: 10.1093/alcalc/agaa059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/04/2020] [Accepted: 06/02/2020] [Indexed: 11/13/2022] Open
Abstract
AIM To study types and incidence of histological changes in liver of people deceased due to harmful use of alcohol. METHODS A retrospective review of medico-legal autopsy of 236 adults who died in the years 2015-2016 due to harmful use of alcohol was done. Histopathological liver samples taken during autopsies were evaluated. Blood alcohol content was analyzed. Serological tests for hepatitis B surface antigen and anti-hepatitis C virus (HCV) were performed. RESULTS The most common liver pathology (83.1%) was steatosis, mainly mixed type (50%); 66.9% had high-grade steatosis. Liver fibrosis was detected in 39.4% of cases, with fibrosis of higher than or equal to third grade in 14%, hepatitis in 44.5% and steatohepatitis in 19.1%. Toxic hepatocyte injury features (ballooning degeneration, Mallory-Denk bodies) were found in 20.8% cases and degenerative-damage changes in 41.1%. The correlation between the grade of steatosis and fibrosis (P = 0.0005), toxic injury (0.00000101) and degenerative-traumatic changes (P = 0.00000741) was found. The correlation was found between hepatitis and higher than or equal to third grade steatosis (P = 0.037), cholestasis (P = 0.0139), toxic injury features (P = 2.58 × 10-13), degenerative-damage changes (P = 7.9 × 10-12) and presence of anti-HCV (P = 0.00723) and between progression of fibrosis and presence of toxic injury features (2.28 × 10-19), degenerative-damage changes (P = 4.25 × 10-11) and anti-HCV (P = 0.0263). CONCLUSIONS Spectrum of histopathological liver changes is broad regardless of sex, and various traits are present in various patterns. Comorbidities have strong influence on the picture of changes in the liver. Exact evaluation how often and what histopathological changes will develop in alcohol liver disease is not possible by reason of variability of external factors.
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Affiliation(s)
- Marta Rorat
- Department of Forensic Medicine, Wroclaw Medical University, J. Mikulicza-Radeckiego 4 Str., 50-345 Wrocław, Poland
| | - Agnieszka Hałoń
- Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, Borowska 213 Str., 50-556 Wrocław, Poland
| | - Tomasz Jurek
- Department of Forensic Medicine, Wroclaw Medical University, J. Mikulicza-Radeckiego 4 Str., 50-345 Wrocław, Poland
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26
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Khanam A, Kottilil S. Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics. Front Immunol 2020; 11:2013. [PMID: 33117329 PMCID: PMC7578249 DOI: 10.3389/fimmu.2020.02013] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a severe life-threatening condition with high risk of multiorgan failure, sepsis, and mortality. ACLF activates a multifaceted interplay of both innate and adaptive immune response in the host which governs the overall outcome. Innate immune cells recognize the conserved elements of microbial and viral origin, both to extort instant defense by transforming into diverse modules of effector responses and to generate long-lasting immunity but can also trigger a massive intrahepatic immune inflammatory response. Acute insult results in the activation of innate immune cells which provokes cytokine and chemokine cascade and subsequently initiates aggressive systemic inflammatory response syndrome, hepatic damage, and high mortality in ACLF. Dysregulated innate immune response not only plays a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh, a model for end-stage liver disease, and sequential organ failure assessment score. A better understanding of the pathophysiological basis of the disease and precise immune mechanisms associated with liver injury offers a novel approach for the development of new and efficient therapies to treat this severely ill entity. Immunotherapies could be helpful in targeting immune-mediated organ damage which may constrain progression toward liver failure and eventually reduce the requirement for liver transplantation. Here, in this review we discuss the defects of different innate immune cells in ACLF which updates the current knowledge of innate immune response and provide potential targets for new therapeutic interventions.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
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27
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Valcin JA, Udoh US, Swain TM, Andringa KK, Patel CR, Al Diffalha S, Baker PRS, Gamble KL, Bailey SM. Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver. Front Physiol 2020; 11:1048. [PMID: 33013449 PMCID: PMC7504911 DOI: 10.3389/fphys.2020.01048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
Heavy alcohol drinking dysregulates lipid metabolism, promoting hepatic steatosis – the first stage of alcohol-related liver disease (ALD). The molecular circadian clock plays a major role in synchronizing daily rhythms in behavior and metabolism and clock disruption can cause pathology, including liver disease. Previous studies indicate that alcohol consumption alters liver clock function, but the impact alcohol or clock disruption, or both have on the temporal control of hepatic lipid metabolism and injury remains unclear. Here, we undertook studies to determine whether genetic disruption of the liver clock exacerbates alterations in lipid metabolism and worsens steatosis in alcohol-fed mice. To address this question, male liver-specific Bmal1 knockout (LKO) and flox/flox (Fl/Fl) control mice were fed a control or alcohol-containing diet for 5 weeks. Alcohol significantly dampened diurnal rhythms of mRNA levels in clock genes Bmal1 and Dbp, phase advanced Nr1d1/REV-ERBα, and induced arrhythmicity in Clock, Noct, and Nfil3/E4BP4, with further disruption in livers of LKO mice. Alcohol-fed LKO mice exhibited higher plasma triglyceride (TG) and different time-of-day patterns of hepatic TG and macrosteatosis, with elevated levels of small droplet macrosteatosis compared to alcohol-fed Fl/Fl mice. Diurnal rhythms in mRNA levels of lipid metabolism transcription factors (Srebf1, Nr1h2, and Ppara) were significantly altered by alcohol and clock disruption. Alcohol and/or clock disruption significantly altered diurnal rhythms in mRNA levels of fatty acid (FA) synthesis and oxidation (Acaca/b, Mlycd, Cpt1a, Fasn, Elovl5/6, and Fads1/2), TG turnover (Gpat1, Agpat1/2, Lpin1/2, Dgat2, and Pnpla2/3), and lipid droplet (Plin2/5, Lipe, Mgll, and Abdh5) genes, along with protein abundances of p-ACC, MCD, and FASN. Lipidomics analyses showed that alcohol, clock disruption, or both significantly altered FA saturation and remodeled the FA composition of the hepatic TG pool, with higher percentages of several long and very long chain FA in livers of alcohol-fed LKO mice. In conclusion, these results show that the liver clock is important for maintaining temporal control of hepatic lipid metabolism and that disrupting the liver clock exacerbates alcohol-related hepatic steatosis.
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Affiliation(s)
- Jennifer A Valcin
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Uduak S Udoh
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Telisha M Swain
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kelly K Andringa
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Chirag R Patel
- Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Sameer Al Diffalha
- Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | | | - Karen L Gamble
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Shannon M Bailey
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
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28
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Sehrawat TS, Liu M, Shah VH. The knowns and unknowns of treatment for alcoholic hepatitis. Lancet Gastroenterol Hepatol 2020; 5:494-506. [PMID: 32277902 DOI: 10.1016/s2468-1253(19)30326-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 02/06/2023]
Abstract
Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often arises in patients with a background of chronic liver disease and it is characterised by the rapid onset of jaundice and the development of myriad complications. Medical therapy for severe alcoholic hepatitis relies on corticosteroids, which have modest effectiveness. Abstinence from alcohol is critically important in patients with alcoholic hepatitis, but recidivism is high. Because of the absence of effective medical treatments for alcoholic hepatitis and alcohol dependency, there is a pressing need to develop new and effective therapeutics. Supported by promising preliminary and preclinical studies, many ongoing clinical trials of new therapies for alcoholic hepatitis are currently underway and are discussed further in this Series paper.
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Affiliation(s)
- Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mengfei Liu
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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29
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Philips CA, Augustine P, Yerol PK, Rajesh S, Mahadevan P. Severe alcoholic hepatitis: current perspectives. Hepat Med 2019; 11:97-108. [PMID: 31496843 PMCID: PMC6691395 DOI: 10.2147/hmer.s197933] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 07/18/2019] [Indexed: 12/12/2022] Open
Abstract
Severe acute alcoholic hepatitis (AH) is a catastrophic disease in the natural history of alcoholic liver disease with a very high 180-day mortality. It can present as acute on chronic liver failure with worse prognosis in the presence of infections and higher grades of liver disease severity. The clinical scenario involves a patient with a recent history of heavy alcohol consumption within three months of presentation with jaundice and characteristic liver enzyme elevation pattern with coagulopathy, hepatic encephalopathy, variceal bleeding and sepsis that results in extrahepatic organ failures. Several liver disease severities and therapy response indicators are in clinical use. Even though not approved, the only recommended treatment option for patients with severe AH is corticosteroids, which is without long term survival benefit. Novel efficacious treatment options awaiting high-quality multi-center studies include liver transplantation (involves strict selection criteria), growth factor therapy and fecal microbiota transplantation. In this exhaustive review, we discuss the definitions, disease severity, histopathology, and treatment options – past, present, and future, in patients with severe alcoholic hepatitis.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Philip Augustine
- Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Praveen Kumar Yerol
- Department of Gastroenterology, Government Medical College and Hospital, Thrissur, Kerala, India
| | - Sasidharan Rajesh
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Pushpa Mahadevan
- Clinical Pathology, VPS Lakeshore Hospital, Nettoor, Kerala, India
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30
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Elshaarawy O, Mueller J, Guha IN, Chalmers J, Harris R, Krag A, Madsen BS, Stefanescu H, Farcau O, Ardelean A, Procopet B, Thiele M, Mueller S. Spleen stiffness to liver stiffness ratio significantly differs between ALD and HCV and predicts disease-specific complications. JHEP Rep 2019; 1:99-106. [PMID: 32039357 PMCID: PMC7001583 DOI: 10.1016/j.jhepr.2019.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/01/2019] [Accepted: 05/12/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND & AIMS Both liver stiffness (LS) and spleen stiffness (SS) are widely used to non-invasively assess liver fibrosis and portal hypertension, respectively. We aimed to identify the impact of disease etiology, namely the localization of inflammation (portal vs. lobular), on the SS/LS ratio. METHODS In this multicenter study, LS and SS were prospectively assessed in 411 patients with alcohol-related liver disease (ALD) or hepatitis C virus (HCV) using FibroScan® (Echosens, Paris); changes in these parameters were also studied in response to treatment (alcohol withdrawal, HCV therapy). LS and spleen length (SL) were further analyzed in a retrospective cohort of 449 patients with long-term data on decompensation/death. RESULTS Both, SS and SL were significantly higher in HCV compared to ALD (42.0 vs. 32.6 kPa, p≪0.0001, 15.6 vs. 11.9 cm, p≪0.0001) despite a lower mean LS in HCV. Consequently, the SS to LS ratio and the SL to LS ratio were significantly higher in HCV (3.8 vs. 1.72 and 1.46 vs. 0.86, p≪0.0001) through all fibrosis stages. Notably, SL linearly increased with SS and the relation between SS and SL was identical in HCV and ALD. In contrast, livers were much larger in ALD at comparable LS. After treatment, LS significantly decreased in both diseases without significant changes to the SS/LS ratio. In the prognostic cohort, patients with ALD had higher LS values (30.5 vs. 21.3 kPa) and predominantly presented with jaundice (65.2%); liver failure was the major cause of death (p≪0.01). In contrast, in HCV, spleens were larger (17.6 vs. 12.1 cm) while variceal bleeding was the major cause of decompensation (73.2%) and death (p≪0.001). CONCLUSION Both SS/LS and SL/LS ratios are significantly higher in patients with portal HCV compared to lobular ALD. Thus, combined LS and SS or SL measurements provide additional information about disease etiology and disease-specific complications. LAY SUMMARY Herein, we show that patients with hepatitis C virus infection (HCV) have higher spleen stiffness and portal pressure than patients with alcohol-related liver disease (ALD), within the same fibrosis stage and matched to liver stiffness. Thus, the spleen stiffness to liver stiffness ratio is significantly higher in patients with HCV compared to ALD. Additionally, patients with HCV more commonly progress to portal hypertension-related complications (e.g. variceal bleeding), while patients with ALD more commonly progress to liver failure (e.g. jaundice). The spleen stiffness to liver stiffness ratio is a useful tool to confirm disease etiology and predict disease-specific complications.
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Affiliation(s)
- Omar Elshaarawy
- Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
| | - Johannes Mueller
- Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
| | - Indra Neil Guha
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Jane Chalmers
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Rebecca Harris
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology and Odense Patient data Exploratory Network, OPEN, Odense University Hospital, Odense, Denmark
| | - Bjørn Stæhr Madsen
- Department of Gastroenterology and Hepatology and Odense Patient data Exploratory Network, OPEN, Odense University Hospital, Odense, Denmark
| | - Horia Stefanescu
- Department of Hepatology and Liver Research Club, Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Oana Farcau
- Department of Hepatology and Liver Research Club, Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Andreea Ardelean
- Department of Hepatology and Liver Research Club, Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Bogdan Procopet
- Department of Hepatology and Liver Research Club, Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Maja Thiele
- Department of Gastroenterology and Hepatology and Odense Patient data Exploratory Network, OPEN, Odense University Hospital, Odense, Denmark
| | - Sebastian Mueller
- Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
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31
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Calvente CJ, Tameda M, Johnson CD, del Pilar H, Lin YC, Adronikou N, De Mollerat Du Jeu X, Llorente C, Boyer J, Feldstein AE. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J Clin Invest 2019; 129:4091-4109. [PMID: 31295147 PMCID: PMC6763256 DOI: 10.1172/jci122258] [Citation(s) in RCA: 190] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated pro-inflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we have identified a novel role for neutrophils as key contributors to resolving the inflammatory response in the liver. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery and early fibrosis. These findings were associated with an impairment of the phenotypic switch of pro-inflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3 / miR-223 ratio. Mice with a deletion of the granulocyte specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by restoring miR-223 levels using a miR-223 3p mimic or infusing neutrophils from wildtype animals. Collectively, our findings reveal a novel role for neutrophils in the liver as resolving effector cells that induce pro-inflammatory macrophages into a restorative phenotype, potentially via miR-223.
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Affiliation(s)
| | - Masahiko Tameda
- Department of Pediatrics, School of Medicine, UCSD, San Diego, California, USA
| | - Casey D. Johnson
- Department of Pediatrics, School of Medicine, UCSD, San Diego, California, USA
| | - Hana del Pilar
- Department of Pediatrics, School of Medicine, UCSD, San Diego, California, USA
| | - Yun Chin Lin
- Department of Pediatrics, School of Medicine, UCSD, San Diego, California, USA
| | | | | | - Cristina Llorente
- Department of Medicine, School of Medicine, UCSD, San Diego, California, USA
| | - Josh Boyer
- Department of Medicine, School of Medicine, UCSD, San Diego, California, USA
| | - Ariel E. Feldstein
- Department of Pediatrics, School of Medicine, UCSD, San Diego, California, USA
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Philips CA, Paramaguru R, Rajesh S, George T, Ahamed R, Augustine P. An unusual cause of acute-on-chronic liver failure. Indian J Gastroenterol 2019; 38:278-279. [PMID: 31264044 DOI: 10.1007/s12664-019-00963-6] [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] [Indexed: 02/04/2023]
Affiliation(s)
- Cyriac Abby Philips
- Gastroenterology and The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682 028, India.
- Philip Augustine Associates, Symphony, Automobile Road, Palarivattom, Kochi, 682 025, India.
| | | | - Sasidharan Rajesh
- Gastroenterology and The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682 028, India
| | - Tom George
- Gastroenterology and The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682 028, India
| | - Rizwan Ahamed
- Gastroenterology and The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682 028, India
| | - Philip Augustine
- Gastroenterology and The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682 028, India
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Teschke R. Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects. Biomedicines 2018; 6:E106. [PMID: 30424581 PMCID: PMC6316574 DOI: 10.3390/biomedicines6040106] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/13/2018] [Accepted: 10/20/2018] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Leimenstrasse 20, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Frankfurt/Main, Germany.
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Königshofer P, Brusilovskaya K, Schwabl P, Reiberger T. Animal models of portal hypertension. Biochim Biophys Acta Mol Basis Dis 2018; 1865:1019-1030. [PMID: 30055295 DOI: 10.1016/j.bbadis.2018.07.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 07/14/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
Chronic liver diseases ultimately lead to cirrhosis and portal hypertension (PHT). Indeed, PHT is a major cause of severe complications, while medical treatment is limited to non-selective beta blockers. Sophisticated animal models are needed to investigate novel treatment options for different etiologies of liver disease, effective anti-fibrotic agents as well as vasoactive drugs against PHT. In this review, we present some of the most common animal models of liver disease and PHT - including pre-hepatic, intra-hepatic and post-hepatic PHT in rodents. Methodology for induction, considerations for disease etiology, advantages and limitations and practical issues of these animal models are discussed. The appropriate and sensible use of animal models in preclinical research supporting the 3R concept of replacement, reduction and refinement is highlighted.
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Affiliation(s)
- P Königshofer
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - K Brusilovskaya
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - P Schwabl
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - T Reiberger
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.
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Mik P, Tonar Z, Malečková A, Eberlová L, Liška V, Pálek R, Rosendorf J, Jiřík M, Mírka H, Králíčková M, Witter K. Distribution of Connective Tissue in the Male and Female Porcine Liver: Histological Mapping and Recommendations for Sampling. J Comp Pathol 2018; 162:1-13. [PMID: 30060837 DOI: 10.1016/j.jcpa.2018.05.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 05/17/2018] [Accepted: 05/25/2018] [Indexed: 02/07/2023]
Abstract
The pig is a large animal model that is often used in experimental medicine. The aim of this study was to assess, in normal pig livers, sexual dimorphism in the normal fraction of hepatic interlobular and intralobular connective tissue (CT) in six hepatic lobes and in three macroscopical regions of interest (ROIs) with different positions relative to the liver vasculature. Using stereological point grids, the fractions of CT were quantified in histological sections stained with aniline blue and nuclear fast red. Samples (415 tissue blocks) were collected from healthy piglets, representing paracaval, paraportal and peripheral ROIs. There was considerable variability in the CT fraction at all sampling levels. In males the mean fraction of interlobular CT was 4.7 ± 2.4% (mean ± SD) and ranged from 0% to 11.4%. In females the mean fraction of the interlobular CT was 3.6 ± 2.2% and ranged from 0% to 12.3%. The mean fraction of intralobular (perisinusoidal summed with pericentral) CT was <0.2% in both sexes. The interlobular CT represented >99.8% of the total hepatic CT and the fractions were highly correlated (Spearman r = 0.998, P <0.05). The smallest CT fraction was observed in the left medial lobe and in the paracaval ROI and the largest CT fraction was detected in the quadrate lobe and in the peripheral ROI. For planning experiments involving the histological quantification of liver fibrosis and requiring comparison between the liver lobes, these data facilitate the power analysis for sample size needed to detect the expected relative increase or decrease in the fraction of CT.
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Affiliation(s)
- P Mik
- Department of Anatomy, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, Pilsen, Czech Republic
| | - Z Tonar
- Department of Histology and Embryology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, Pilsen, Czech Republic.
| | - A Malečková
- European Centre of Excellence NTIS, Faculty of Applied Sciences, University of West Bohemia, Univerzitní 22, Pilsen, Czech Republic
| | - L Eberlová
- Department of Anatomy, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, Pilsen, Czech Republic
| | - V Liška
- Department of Surgery and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, Pilsen, Czech Republic
| | - R Pálek
- Department of Surgery and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, Pilsen, Czech Republic
| | - J Rosendorf
- Department of Surgery and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 80, Pilsen, Czech Republic
| | - M Jiřík
- European Centre of Excellence NTIS, Faculty of Applied Sciences, University of West Bohemia, Univerzitní 22, Pilsen, Czech Republic
| | - H Mírka
- Department of Imaging Methods and Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, University Hospital in Pilsen, Czech Republic
| | - M Králíčková
- Department of Histology and Embryology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, Pilsen, Czech Republic
| | - K Witter
- Institute of Anatomy, Histology and Embryology, Department for Pathobiology, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, Austria
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Butler DC, Lewin DN, Batalis NI. Differential Diagnosis of Hepatic Necrosis Encountered at Autopsy. Acad Forensic Pathol 2018; 8:256-295. [PMID: 31240042 DOI: 10.1177/1925362118782056] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 04/13/2018] [Indexed: 12/13/2022]
Abstract
The liver is subject to a variety of extrinsic and intrinsic insults that manifest with both specific and nonspecific patterns of necrosis. In the autopsy setting, these patterns are often encountered as incidental findings or even causes of death. There are several etiologies of hepatic necrosis, including toxins, drug injuries, viral infections, ischemic injuries, and metabolic disease, all of which possess overlapping gross and histologic presentations. Nonetheless, patterned necrosis in the context of clinical and demographic history allows for the forensic pathologist to develop a differential diagnosis, which may then be pruned into a specific or likely cause. The aim of the following review is to elucidate these patterns in the context of the liver diseases from which they arise with the goal developing a differential diagnosis and ultimate determination of etiology. Acad Forensic Pathol. 2018 8(2): 256-295.
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Teschke R. Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options. Expert Opin Pharmacother 2018; 19:779-793. [PMID: 29708448 DOI: 10.1080/14656566.2018.1465929] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. AREAS COVERED This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. EXPERT OPINION Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.
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Affiliation(s)
- Rolf Teschke
- a Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty , Goethe University Frankfurt/Main , Frankfurt/Main , Germany
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Yang SS. Alcoholic Liver Disease in the Asian–Pacific Region with High Prevalence of Chronic Viral Hepatitis. J Med Ultrasound 2016. [DOI: 10.1016/j.jmu.2016.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Quaglia A, Alves VA, Balabaud C, Bhathal PS, Bioulac-Sage P, Crawford JM, Dhillon AP, Ferrell L, Guido M, Hytiroglou P, Nakanuma Y, Paradis V, Snover DC, Theise ND, Thung SN, Tsui WMS, van Leeuwen DJ. Role of aetiology in the progression, regression, and parenchymal remodelling of liver disease: implications for liver biopsy interpretation. Histopathology 2016; 68:953-67. [DOI: 10.1111/his.12957] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Alberto Quaglia
- Institute of Liver Studies; King's College Hospital and King's College; London UK
| | - Venancio A Alves
- Department of Pathology; University of São Paulo School of Medicine; São Paulo Brazil
| | | | - Prithi S Bhathal
- Department of Pathology; University of Melbourne; Melbourne VIC Australia
| | | | - James M Crawford
- Department of Pathology and Laboratory Medicine; Hofstra Northwell School of Medicine; Hempstead NY USA
| | - Amar P Dhillon
- Department of Cellular Pathology; UCL Medical School; London UK
| | - Linda Ferrell
- Department of Pathology; University of California; San Francisco CA USA
| | - Maria Guido
- Department of Medicine-DIMED; Pathology Unit; University of Padova; Padova Italy
| | - Prodromos Hytiroglou
- Department of Pathology; Aristotle University Medical School; Thessaloniki Greece
| | - Yasuni Nakanuma
- Department of Diagnostic Pathology; Shizuoka Cancer Center; Shizuoka Japan
| | | | - Dale C Snover
- Department of Pathology; Fairview Southdale Hospital; Edina MN USA
| | - Neil D Theise
- Departments of Pathology and Medicine (Division of Digestive Diseases); Beth Israel Medical Center of Albert Einstein College of Medicine; New York NY USA
| | - Swan N Thung
- Department of Pathology; Icahn School of Medicine at Mount Sinai; New York NY USA
| | - Wilson M S Tsui
- Department of Pathology; Caritas Medical Centre; Hong Kong China
| | - Dirk J van Leeuwen
- Section of Gastroenterology and Hepatology; Dartmouth Medical School; Hanover NH USA
- Onze Lieve Vrouwe Gasthuis; Amsterdam the Netherlands
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Iwakiri Y, Kim MY. Nitric oxide in liver diseases. Trends Pharmacol Sci 2015; 36:524-36. [PMID: 26027855 PMCID: PMC4532625 DOI: 10.1016/j.tips.2015.05.001] [Citation(s) in RCA: 199] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 05/05/2015] [Accepted: 05/06/2015] [Indexed: 02/06/2023]
Abstract
Nitric oxide (NO) and its derivatives play important roles in the physiology and pathophysiology of the liver. Despite its diverse and complicated roles, certain patterns of the effect of NO on the pathogenesis and progression of liver diseases are observed. In general, NO derived from endothelial NO synthase (eNOS) in liver sinusoidal endothelial cells (LSECs) is protective against disease development, while inducible NOS (iNOS)-derived NO contributes to pathological processes. This review addresses the roles of NO in the development of various liver diseases with a focus on recently published articles. We present here two recent advances in understanding NO-mediated signaling - nitrated fatty acids (NO2-FAs) and S-guanylation - and conclude with suggestions for future directions in NO-related studies on the liver.
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
| | - Moon Young Kim
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Lin JN, Chang LL, Lai CH, Lin KJ, Lin MF, Yang CH, Lin HH, Chen YH. Development of an Animal Model for Alcoholic Liver Disease in Zebrafish. Zebrafish 2015; 12:271-80. [PMID: 25923904 DOI: 10.1089/zeb.2014.1054] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) continues to be a major cause of liver-related morbidity and mortality worldwide. To date, no zebrafish animal model has demonstrated the characteristic manifestations of ALD in the setting of chronic alcohol exposure. The aim of this study was to develop a zebrafish animal model for ALD. Male adult zebrafish were housed in a 1% (v/v) ethanol solution up to 3 months. A histopathological study showed the characteristic features of alcoholic liver steatosis and steatohepatitis in the early stages of alcohol exposure, including fat droplet accumulation, ballooning degeneration of the hepatocytes, and Mallory body formation. As the exposure time increased, collagen deposition in the extracellular matrix was observed by Sirius red staining and immunofluorescence staining. Finally, anaplastic hepatocytes with pleomorphic nuclei were arranged in trabecular patterns and formed nodules in the zebrafish liver. Over the time course of 1% ethanol exposure, upregulations of lipogenesis, fibrosis, and tumor-related genes were also revealed by semiquantitative and quantitative real-time reverse transcription-polymerase chain reaction. As these data reflect characteristic liver damage by alcohol in humans, this zebrafish animal model may serve as a powerful tool to study the pathogenesis and treatment of ALD and its related disorders in humans.
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Affiliation(s)
- Jiun-Nong Lin
- 1 Department of Critical Care Medicine, E-Da Hospital, I-Shou University , Kaohsiung, Taiwan .,2 School of Medicine, College of Medicine, I-Shou University , Kaohsiung, Taiwan .,3 Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, I-Shou University , Kaohsiung, Taiwan
| | - Lin-Li Chang
- 4 Department of Microbiology, Faculty of Medicine, Kaohsiung Medical University , Kaohsiung, Taiwan
| | - Chung-Hsu Lai
- 3 Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, I-Shou University , Kaohsiung, Taiwan
| | - Kai-Jen Lin
- 5 Department of Pathology, I-Shou University , Kaohsiung, Taiwan
| | - Mei-Fang Lin
- 6 Department of Pharmacy, E-Da Hospital, I-Shou University , Kaohsiung, Taiwan
| | - Chih-Hui Yang
- 7 General Education Center, Meiho University , Pingtung, Taiwan
| | - Hsi-Hsun Lin
- 3 Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, I-Shou University , Kaohsiung, Taiwan
| | - Yen-Hsu Chen
- 8 School of Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung, Taiwan .,9 Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung, Taiwan .,10 Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan
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Sakhuja P. Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis? World J Gastroenterol 2014; 20:16474-9. [PMID: 25469015 PMCID: PMC4248190 DOI: 10.3748/wjg.v20.i44.16474] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/28/2014] [Accepted: 09/12/2014] [Indexed: 02/06/2023] Open
Abstract
The liver involvement in alcoholic liver disease (ALD) classically ranges from alcoholic steatosis, alcoholic hepatitis or steatohepatitis, alcoholic cirrhosis and even hepatocellular carcinoma. The more commonly seen histologic features include macrovesicular steatosis, neutrophilic lobular inflammation, ballooning degeneration, Mallory-Denk bodies, portal and pericellular fibrosis. Nonalcoholic steatohepatitis (NASH) is a condition with similar histology in the absence of a history of alcohol intake. Although the distinction is essentially based on presence or absence of a history of significant alcohol intake, certain histologic features favour one or the other diagnosis. This review aims at describing the histologic spectrum of alcoholic liver disease and at highlighting the histologic differences between ALD and NASH.
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