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Bokan G, Kovacevic M, Zdravkovic N, Bokonjic D, Kovacevic M, Prodanovic V, Mavija Z. Significance of Laboratory Findings and Esophageal Varices in Male Patients With Decompensated Alcoholic Liver Cirrhosis: A Single-Center Experience. Cureus 2025; 17:e78274. [PMID: 40027007 PMCID: PMC11872042 DOI: 10.7759/cureus.78274] [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] [Accepted: 01/31/2025] [Indexed: 03/05/2025] Open
Abstract
Introduction Alcoholic liver disease represents a growing global pandemic, particularly among younger men, and is one of the leading causes of premature death worldwide. Observing complications during the decompensation stage and monitoring disease progression dynamics using scoring systems are particularly important. Materials and methods This retrospective-prospective, descriptive, and analytical study included 123 male patients with a confirmed diagnosis of alcoholic liver cirrhosis, hospitalized at the Internal Medicine Clinic, University Clinical Centre of the Republic of Srpska in Banja Luka, Department of Gastroenterology and Hepatology. The study period spanned from January 2023 to January 2025, with the note that patient selection and monitoring began much earlier, in June 2021. After hospitalization, patients were followed monthly through a program of outpatient control examinations, with disease outcomes recorded. The study included all male patients over 18 years of age with a confirmed diagnosis of alcoholic liver cirrhosis and signed informed consent. Female patients and those with cirrhosis or other etiologies were excluded. For statistical data analysis, the Statistical Package for the Social Sciences (SPSS) version 29 (IBM Corp., Armonk, NY, USA) was used. The statistical analyses performed included median, standard deviation, analysis of variance, Student's t-test, chi-square test, and survival analysis. Results The mean age of the patients was 59.09±9.316 years. Most of them had anemia: 113 patients (91.86%) with decreased erythrocytes and 109 patients (88.62%) with decreased hemoglobin. Thrombocytopenia was observed in 104 patients (84.55%), while an increased mean corpuscular volume (MCV) was recorded in 68 patients (55.28%). Among biochemical parameters, the most common findings were increased bilirubin in 98 patients (79.67%), aspartate aminotransferase (AST) in 111 patients (90.24%), gamma-glutamyl transferase (GGT) in 109 patients (88.61%), and D-dimer in 110 patients (89.44%), while albumin levels were decreased in 107 patients (87.00%). Hyponatremia (decreased sodium) was observed in 63 patients (51.21%), and hypercalcemia (increased calcium) in 116 patients (94.30%). Jaundice was the most common external sign, present in 98 patients (79.67%), while ascites were noted in 86 patients (69.91%). Death during the first decompensation occurred in 31 patients (25.20%), of whom 17 (54.83%) died in the hospital. The leading cause of mortality is bleeding from esophageal varices. Conclusion Although a healthy liver performs over 200 distinct functions in the human body, a cirrhotic liver leads, one might say, to an even greater number of dysfunctions. This pathology is extremely complex, characterized by numerous complications and high treatment costs, which, despite all applied measures, do not ensure a favorable long-term prognosis without liver transplantation.
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Affiliation(s)
- Goran Bokan
- Gastroenterology and Hepatology, University Clinical Centre of the Republika Srpska, Banja Luka, BIH
| | | | - Natasa Zdravkovic
- Gastroenterology and Hepatology, University Clinical Center of Kragujevac, Kragujevac, SRB
| | - Dejan Bokonjic
- Pediatrics and Neonatology, Foca University Hospital, Foca, BIH
| | | | | | - Zoran Mavija
- Gastroenterology, University Clinical Centre of the Republika Srpska, Banja Luka, BIH
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Rattanasupar A, Prateepchaiboon T, Akarapatima K, Songjamrat A, Pakdeejit S, Chang A. Impact of pre-sarcopenia on outcomes of transarterial chemoembolization in unresectable hepatocellular carcinoma. Sci Rep 2024; 14:19249. [PMID: 39164379 PMCID: PMC11336115 DOI: 10.1038/s41598-024-70266-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/14/2024] [Indexed: 08/22/2024] Open
Abstract
Sarcopenia's impact on hepatocellular carcinoma (HCC) outcomes is well-documented, but the effects of pre-sarcopenia remain unclear. This study investigates the impact of pre-sarcopenia on tumor response and survival in patients with unresectable HCC undergoing transarterial chemoembolization (TACE). We retrospectively evaluated muscle volume using the SliceOmatic software in patients with unresectable HCC treated with TACE. Pre-sarcopenia was defined by Japan Society of Hepatology standards (men: 42 cm2/m2; women: 38 cm2/m2). Pre-sarcopenia and non-pre-sarcopenia groups were compared, and Cox proportional hazards model was used to identify survival-influencing variables. Subgroup analysis was conducted stratified by the tumor burden, using serum alpha-fetoprotein (AFP) levels at a diagnostic cutoff value of 200 ng/mL. Of the 100 patients, 39 had pre-sarcopenia. The presence of pre-sarcopenia was not associated with tumor complete response achievement. The median overall survival (OS) was significantly lower in the pre-sarcopenia group (18 months) than in the non-pre-sarcopenia group (30 months; log-rank P = 0.039). Subgroup analysis among 77 patients with AFP < 200 ng/mL revealed that OS was particularly poor in the pre-sarcopenia group (16 vs. 34 months; log-rank P < 0.001). Multivariate analysis identified increased AFP (adjusted hazard ratio [HR] per 10-unit increase 1.142; P < 0.001), higher Model for End-Stage Liver Disease score (adjusted HR per 1-unit increase 1.176; P < 0.001), and pre-sarcopenia (adjusted HR 2.965; P < 0.001) as predictors of shorter OS. Pre-sarcopenia is a significant predictor of increased mortality in patients with unresectable HCC undergoing TACE, especially in those with AFP < 200 ng/mL, suggesting its potential as a target for early intervention.
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Affiliation(s)
- Attapon Rattanasupar
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand
| | - Tanaporn Prateepchaiboon
- Division of Medical Oncology, Department of Internal Medicine, Hatyai Hospital, Songkhla, Thailand
| | - Keerati Akarapatima
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand
| | - Apiradee Songjamrat
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Songkhla, Thailand
| | - Songklod Pakdeejit
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Songkhla, Thailand
| | - Arunchai Chang
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand.
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Swanson GR, Garg K, Shaikh M, Keshavarzian A. Increased Intestinal Permeability and Decreased Resiliency of the Intestinal Barrier in Alcoholic Liver Disease. Clin Transl Gastroenterol 2024; 15:e00689. [PMID: 38334953 PMCID: PMC11042778 DOI: 10.14309/ctg.0000000000000689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 01/31/2024] [Indexed: 02/10/2024] Open
Abstract
INTRODUCTION Only 20%-30% of individuals with alcohol use disorder (AUD) develop alcoholic liver disease (ALD). While the development of gut-derived endotoxemia is understood to be a required cofactor, increased intestinal permeability in ALD is not completely understood. METHODS We recruited 178 subjects-58 healthy controls (HCs), 32 with ALD, 53 with AUD but no liver disease (ALC), and 35 with metabolic dysfunction-associated steatotic liver disease (MASLD). Intestinal permeability was assessed by a sugar cocktail as a percentage of oral dose. The permeability test was repeated after an aspirin challenge in a subset. RESULTS Five-hour urinary lactulose/mannitol ratio (primarily representing small intestinal permeability) was not statistically different in HC, ALC, ALD, and MASLD groups ( P = 0.40). Twenty-four-hour urinary sucralose (representing whole gut permeability) was increased in ALD ( F = 5.3, P < 0.01) and distinguished ALD from ALC; 24-hour sucralose/lactulose ratio (primarily representing colon permeability) separated the ALD group ( F = 10.2, P < 0.01) from the MASLD group. After aspirin challenge, intestinal permeability increased in all groups and ALD had the largest increase. DISCUSSION In a group of patients, we confirmed that (i) the ALD group has increased intestinal permeability compared with the HC, ALC, or MASLD group. In addition, because small bowel permeability (lactulose/mannitol ratio) is normal, the disruption of intestinal barrier seems to be primarily in the large intestine; (ii) decreased resiliency of intestinal barrier to injurious agents (such as NSAID) might be the mechanism for gut leak in subset of AUD who develop ALD.
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Affiliation(s)
- Garth R. Swanson
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, USA;
- Rush Center for Integrated Microbiome and Chronobiology, Rush University Medical Center, Chicago, Illinois, USA;
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois, USA;
| | - Kanika Garg
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois, USA;
| | - Maliha Shaikh
- Rush Center for Integrated Microbiome and Chronobiology, Rush University Medical Center, Chicago, Illinois, USA;
| | - Ali Keshavarzian
- Rush Center for Integrated Microbiome and Chronobiology, Rush University Medical Center, Chicago, Illinois, USA;
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois, USA;
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois, USA;
- Department of Physiology, Rush University Medical Center, Chicago, Illinois, USA.
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Aasarey R, Yadav K, Kashyap BK, Prabha S, Kumar P, Kumar A, Ruokolainen J, Kesari KK. Role of Immunological Cells in Hepatocellular Carcinoma Disease and Associated Pathways. ACS Pharmacol Transl Sci 2023; 6:1801-1816. [PMID: 38093838 PMCID: PMC10714437 DOI: 10.1021/acsptsci.3c00216] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 03/28/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the predominant causes of cancer-related mortality across the globe. It is attributed to obesity, excessive alcohol consumption, smoking, and infection by the hepatitis virus. Early diagnosis of HCC is essential, and local treatments such as surgical excision and percutaneous ablation are effective. Palliative systemic therapy, primarily with the tyrosine kinase inhibitor Sorafenib, is used in advanced cases. However, the prognosis for advanced HCC remains poor. This Review additionally describes the pathophysiological mechanisms of HCC, which include aberrant molecular signaling, genomic instability, persistent inflammation, and the paradoxical position of the immune system in promoting and suppressing HCC. The paper concludes by discussing the growing body of research on the relationship between mitochondria and HCC, suggesting that mitochondrial dysfunction may contribute to the progression of HCC. This Review focuses on immunological interactions between different mechanisms of HCC progression, including obesity, viral infection, and alcohol consumption.
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Affiliation(s)
- Ram Aasarey
- Department
of Laboratory Medicine, All India Institute
of Medical Science, New Delhi-11029, India
| | - Kajal Yadav
- Department
of Biotechnology, All India Institute of
Medical Science, New Delhi-11029, India
| | - Brijendra Kumar Kashyap
- Department
of Biotechnology Engineering, Institute of Engineering and Technology, Bundelkhand University, Jhansi-284128, Uttar Pradesh, India
| | - Sarit Prabha
- Department
of Biological Science and Engineering, Maulana
Azad National Institute of Technology, Bhopal-462003, Madhya Pradesh,India
| | - Pramod Kumar
- Indian
Council of Medical Research, National Institute
of Cancer Prevention and Research (NICPR), l-7, Sector-39, Noida-201301, National Capital Region, India
| | - Anil Kumar
- Department
of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Karmre, Kanke-835222, Ranchi, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
- Research
and Development Cell, Lovely Professional
University, Phagwara-144411, Punjab, India
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Malone D, Costin BN, MacElroy D, Al‐Hegelan M, Thompson J, Bronshteyn Y. Phenobarbital versus benzodiazepines in alcohol withdrawal syndrome. Neuropsychopharmacol Rep 2023; 43:532-541. [PMID: 37368937 PMCID: PMC10739082 DOI: 10.1002/npr2.12347] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 04/26/2023] [Accepted: 04/26/2023] [Indexed: 06/29/2023] Open
Abstract
AIM Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment for alcohol withdrawal syndrome (AWS). Currently, existing research offers only modest guidance on the safety and effectiveness of phenobarbital in managing AWS in hospital settings. The study objective was to assess if a phenobarbital protocol for the treatment of AWS reduces respiratory complications when compared to a more traditionally used benzodiazepine protocol. METHODS A retrospective cohort study analyzing adults who received either phenobarbital or benzodiazepine-based treatment for AWS over a 4-year period, 2015-2019, in a community teaching hospital in a large academic medical system. RESULTS A total of 147 patient encounters were included (76 phenobarbital and 71 benzodiazepine). Phenobarbital was associated with a significantly decreased risk of respiratory complications, defined by the occurrence of intubation (15/76 phenobarbital [20%] vs. 36/71 benzodiazepine [51%]) and decreased incidence of the requirement of six or greater liters of oxygen when compared with benzodiazepines (10/76 [13%] vs. 28/71 [39%]). There was a significantly higher incidence of pneumonia in benzodiazepine patients (15/76 [20%] vs. 33/71 [47%]). Mode Richmond Agitation Sedation Scale (RASS) scores were more frequently at goal (0 to -1) between 9 and 48 h after the loading dose of study medication for phenobarbital patients. Median hospital and ICU length of stay were significantly shorter for phenobarbital patients when compared with benzodiazepine patients (5 vs. 10 days and 2 vs. 4 days, respectively). CONCLUSION Parenteral phenobarbital loading doses with an oral phenobarbital tapered protocol for AWS resulted in decreased risk of respiratory complications when compared to standard treatment with benzodiazepines.
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Affiliation(s)
| | - Blair N. Costin
- Duke Regional HospitalDurhamNorth CarolinaUSA
- Duke University HospitalDurhamNorth CarolinaUSA
| | | | - Mashael Al‐Hegelan
- Duke Regional HospitalDurhamNorth CarolinaUSA
- Duke University HospitalDurhamNorth CarolinaUSA
| | - Julie Thompson
- Duke University School of NursingDurhamNorth CarolinaUSA
| | - Yuriy Bronshteyn
- Duke University HospitalDurhamNorth CarolinaUSA
- Durham Veterans Health AdministrationDurhamNorth CarolinaUSA
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Song Q, Chen Y, Ding Q, Griffiths A, Liu L, Park J, Liew CW, Nieto N, Li S, Dou X, Jiang Y, Song Z. mTORC1 inhibition uncouples lipolysis and thermogenesis in white adipose tissue to contribute to alcoholic liver disease. Hepatol Commun 2023; 7:e0059. [PMID: 36757400 PMCID: PMC9915967 DOI: 10.1097/hc9.0000000000000059] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 12/21/2022] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Adipose tissue thermogenic activities use fatty acids from lipolysis for heat generation. Therefore, a tight coupling between lipolysis and thermogenesis is physiologically imperative in maintaining not only body temperature but also lipids homeostasis. Adipose tissue dysfunction contributes to alcoholic liver disease (ALD). Here, studies were conducted to examine how alcohol intake affects adipose tissue thermogenic activities and whether altered adipose tissue thermogenesis contributes to ALD. METHODS Both the Lieber-DeCarli and the NIAAA mouse models of ALD were used. Denervation surgery in epididymal fat pads was performed. CL316,243, a selective β3-adrenoceptor agonist, SR59230A, a selective β3 adrenoceptor (ADRB3) antagonist, and rapamycin, a selective mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, were administrated through i.p. injection. Adipocyte-specific Prdm16 knockout mice were subjected to alcohol-containing diet chronically. RESULTS Chronic alcohol consumption, which enhances adipose tissue lipolysis, inhibits thermogenic activities of beige adipocytes in inguinal white adipose tissue (WAT), leading to an uncoupling status between lipolysis and thermogenesis in WAT at both basal and ADRB3 stimulation states. CL316,243 administration exacerbates liver pathologies of ALD. Alcohol intake inhibits mTORC1 activities in WAT. In mice, mTORC1 inhibition by rapamycin inhibits the thermogenesis of iWAT, whereas enhancing WAT lipolysis. Further investigations using adipocyte-specific Prdm16 knockout mice revealed that functional deficiency of beige adipocytes aggravates liver pathologies of ALD, suggesting that the inhibitory effect of alcohol on WAT browning/thermogenesis contributes to ALD pathogenesis. CONCLUSION Chronic alcohol consumption induces an "uncoupling status" between lipolysis and browning/thermogenesis in WAT by inhibiting mTORC1 activation. Diminished WAT browning/thermogenesis, concomitant with enhanced lipolysis, contributes to ALD pathogenesis.
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Affiliation(s)
- Qing Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Yingli Chen
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Qinchao Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Alexandra Griffiths
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Lifeng Liu
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jooman Park
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Chong Wee Liew
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Songtao Li
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaobing Dou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuwei Jiang
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA
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Akarapatima K, Chang A, Prateepchaiboon T, Pungpipattrakul N, Songjamrat A, Pakdeejit S, Rattanasupar A, Piratvisuth T. Predictive Outcomes Using Child-Turcotte-Pugh and Albumin-Bilirubin Scores in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization. J Gastrointest Cancer 2022; 53:1006-1013. [PMID: 34761340 DOI: 10.1007/s12029-021-00743-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2021] [Indexed: 02/08/2023]
Abstract
INTRODUCTION We assessed the ability of the Child-Turcotte-Pugh score and the albumin-bilirubin grade to predict the outcomes of hepatocellular carcinoma (HCC) in patients treated with transarterial chemoembolization. METHODS We retrospectively assessed 158 patients with HCC who underwent transarterial chemoembolization. The ability of the Child-Turcotte-Pugh score and the albumin-bilirubin grade to predict patient survival was assessed using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate survival-predictive variables and the relationship between the obtained score and overall survival. RESULTS Child-Turcotte-Pugh A (n = 102 (64.6%)) patients showed better overall survival than Child-Turcotte-Pugh B (n = 56 (35.4%)) patients (log-rank P = 0.017), while no significant difference in the overall survival between albumin-bilirubin ≤ 1 (n = 37 (23.4%)) and albumin-bilirubin > 1 (n = 121 (76.6%)) was detected (log-rank P = 0.140). Multivariate analysis identified alcoholic liver disease (P = 0.029), tumor size > 5 cm (P = 0.004), and serum alpha-fetoprotein > 200 ng/mL (P < 0.001) as independent predictive factors of mortality risk. A higher Child-Turcotte-Pugh score was positively associated with decreased overall survival (P = 0.031); however, a higher albumin-bilirubin grade showed marginally significant association (P = 0.088). CONCLUSIONS The Child-Turcotte-Pugh score precisely categorized the outcomes of HCC in patients undergoing transarterial chemoembolization, and cirrhotic patients with Child-Turcotte-Pugh A will have a better overall survival than those with Child-Turcotte-Pugh B, regardless of HCC status. These results suggest that the Child-Turcotte-Pugh classification system is a more powerful tool to predict patient outcomes than the albumin-bilirubin grading system.
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Affiliation(s)
- Keerati Akarapatima
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand
| | - Arunchai Chang
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand.
| | | | | | - Apiradee Songjamrat
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Songkhla, Thailand
| | - Songklod Pakdeejit
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Songkhla, Thailand
| | - Attapon Rattanasupar
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Songklanagarind Hospital, Prince of Songkhla University, Songkhla, Thailand
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Efficacy and safety of direct-acting antivirals for HCV in patients with extrahepatic malignancies: real-life experience. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00213-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Outcome of HCV treatment with direct antiviral agents in malignant patients is questionable. The aim is to assess the safety and efficacy of DAAs in treatment of chronic HCV patients who received chemotherapy for malignancies.
Materials
Retrospective cohort study of 83 patients with HCV post chemotherapy receiving DAAs treatment compared to a matched group of 88 chronic HCV patients without cancer. Demographic, laboratory and abdominal ultrasound data, and SVR were taken for all patients.
Results
Patients’ data revealed mean age (52 years) and BMI (29). A total of 52% of HCV patients were females, and 83.6% were treatment naïve. Patients with cancer had higher FIB4 values and more cirrhosis (20.5% vs. 13.6%) with no statistical significance. Total bilirubin and HbA1C levels were significantly higher in HCV patients without cancer. All patients in either groups received SOF-based DAAs except 2 cases received PAR/OMP/RBV. SVR rate was very high and comparable between the two groups (100% and 97.7% in post chemotherapy and control groups) with no statistical difference. Mortality was represented in 23% in patients post chemotherapy with FIB4 score considered the only predictor for mortality.
Conclusion
DAAs have excellent efficacy in patients post chemotherapy. Further studies should be conducted for their concomitant use with chemotherapy.
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Prateepchaiboon T, Chang A, Pungpipattrakul N, Akarapatima K, Rattanasupar A, Songjamrat A, Pakdeejit S, Piratvisuth T. Factors affecting prognosis in hepatocellular carcinoma patients post-transarterial chemoembolization. Indian J Gastroenterol 2022; 41:352-361. [PMID: 36029371 DOI: 10.1007/s12664-021-01227-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/08/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND To evaluate the factors influencing the achievement of a sustained complete response (CR) and overall survival (OS) in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). METHODS We retrospectively reviewed the records of HCC patients who underwent TACE as the first modality of treatment between 2014 and 2019. We investigated the factors affecting sustained CR (no recurrence within 6 months) and OS (time from diagnosis until either death or last follow-up). RESULTS The study enrolled 161 patients; 159 (98.8%) had cirrhosis. Post-TACE, 19.9% (32/161) achieved sustained CR. In the multivariate analysis, a tumor size < 5 cm was a positive factor for achieving sustained CR (odds ratio, 5.012; p = 0.006). In the proportional hazards model, the factors associated with decreased survival included alcohol-related liver disease (hazards ratio [HR] 1.683; p = 0.036), presence of symptoms (HR 1.816; p = 0.005) and portal hypertension (HR 1.608; p = 0.038) at initial diagnosis, serum alpha-fetoprotein (AFP) > 100 ng/mL (HR 2.082; p < 0.001), and higher Child-Pugh classification (HR 1.1.639; p = 0.024). Achievement of sustained CR (HR, 0.355; p = 0.002) was independently associated with increased survival. CONCLUSIONS The tumor size was a predictive factor for sustained CR. Alcohol-related liver disease, presence of symptoms and portal hypertension at initial diagnosis, elevated serum AFP, liver reserve status, and achieved sustained CR were independent factors affecting survival. We demonstrated the effect of alcohol-related liver disease on survival after TACE. Our results will aid physicians in the management and prognostication of HCC.
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Affiliation(s)
| | - Arunchai Chang
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand.
| | | | - Keerati Akarapatima
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand
| | - Attapon Rattanasupar
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Songkhla, 90110, Thailand
| | - Apiradee Songjamrat
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Songkhla, Thailand
| | - Songklod Pakdeejit
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Songkhla, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Songklanagarind Hospital, Prince of Songkhla University, Songkhla, Thailand
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Rattanasupar A, Chang A, Prateepchaiboon T, Pungpipattrakul N, Akarapatima K, Songjamrat A, Pakdeejit S, Prachayakul V, Piratvisuth T. Impact of alcohol consumption on treatment outcome of hepatocellular carcinoma patients with viral hepatitis who underwent transarterial chemoembolization. World J Hepatol 2022; 14:1162-1172. [PMID: 35978671 PMCID: PMC9258258 DOI: 10.4254/wjh.v14.i6.1162] [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: 02/04/2022] [Revised: 04/24/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alcohol consumption increases the risk of hepatocellular carcinoma (HCC) in patients with pre-existing liver disease, including viral hepatitis. However, studies on the impact of alcohol consumption on the outcomes of HCC are limited. We hypothesized that alcohol had an additional effect with chronic viral hepatitis infection on treatment outcomes after transarterial chemoembolization (TACE) in patients with intermediate-stage HCC (Barcelona Clinical Liver Cancer [BCLC] -B). AIM To evaluate the additional effect of alcohol on treatment outcomes of TACE among HCC patients with viral hepatitis. METHODS This study, conducted at Hatyai Hospital in Thailand, included HCC patients over 18 years of age with chronic viral hepatitis. Records of HCC patients with viral hepatitis classified as BCLC-B who underwent TACE as the first treatment modality between 2014 and 2019 were retrospectively reviewed. Patients with chronic viral hepatitis only were categorized under group A, and those with chronic viral hepatitis and concurrent alcohol consumption were categorized under group B. Both groups were compared, and the Cox proportional-hazards model was used to identify the survival-influencing variables. RESULTS Of the 69 patients, 53 were categorized in group A and 16 in group B. There were no statistically significant differences in tumor characteristics between the two patient groups. However, Group A had a statistically significantly higher proportion of complete response (24.5% vs 0%, P = 0.030) and a higher median survival rate (26.2 mo vs 8.4 mo; log-rank P = 0.012) compared to group B. Factors associated with decreased survival in the proportional-hazards model included alcohol consumption (hazards ratio [HR], 2.377; 95% confidence interval [CI], 1.109-5.095; P = 0.026), presence of portal hypertension (HR, 2.578; 95%CI, 1.320-5.037; P = 0.006), largest tumor size > 5 cm (HR, 3.558; 95%CI, 1.824-6.939; P < 0.001), and serum alpha-fetoprotein level > 100 ng/mL (HR, 2.536; 95%CI, 1.377-4.670; P = 0.003). CONCLUSION In HCC BCLC B patients with chronic viral hepatitis, alcohol consumption is an independent risk factor for increased mortality and decreases the rate of complete response and survival after TACE.
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Affiliation(s)
- Attapon Rattanasupar
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Arunchai Chang
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand.
| | | | | | - Keerati Akarapatima
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Apiradee Songjamrat
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Songklod Pakdeejit
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Varayu Prachayakul
- Siriraj Gastrointestinal Endoscopy Center, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkoknoi 10700, Bangkok, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Hatyai 90110, Songkhla, Thailand
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11
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Balakrishnan R, Mohammed V, Veerabathiran R. The role of genetic mutation in alcoholic liver disease. EGYPTIAN LIVER JOURNAL 2022; 12:14. [DOI: 10.1186/s43066-022-00175-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 01/26/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Alcoholic liver disease (ALD) is the world’s most common type of liver disease caused due to overconsumption of alcohol. The liver supports the best level of tissue damage by hefty drinking since it is the binding site of ethanol digestion. This disease can progress to alcoholic steatohepatitis from alcoholic fatty liver, which implies steatosis has become the most punctual reaction to hefty drinking and is portrayed by the deposition of fat hepatocytes. In addition, steatosis can advance to steatohepatitis, a more extreme, provocative sort of liver damage described by hepatic inflammation. Constant and unnecessary liquor utilization delivers a wide range of hepatic sores, fibrosis and cirrhosis, and sometimes hepatocellular carcinoma. Most people consuming > 40 g of liquor each day create alcoholic fatty liver (AFL); notwithstanding, just a subset of people will grow further developed infection. Hereditary, epigenetic, and non-hereditary components may clarify the impressive interindividual variety in the ALD phenotype.
Main body
This systematic review is to classify new candidate genes associated with alcoholic liver disorders, such as RASGRF2, ALDH2, NFE2L2, ADH1B, PNPLA3, DRD2, MTHFR, TM6SF2, IL1B, and CYP2E1, MBOAT7 as well as to revise the functions of each gene in its polymorphic sequence. The information obtained from the previously published articles revealed the crucial relationship between the genes and ALD and discussed each selected gene’s mechanism.
Conclusion
The aim of this review is to highlight the candidate genes associated with the ALD, and the evidence of this study is to deliberate the part of genetic alterations and modifications that can serve as an excellent biological maker, risk predictors, and therapeutic targets for this disease.
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12
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Zelber-Sagi S, Noureddin M, Shibolet O. Lifestyle and Hepatocellular Carcinoma What Is the Evidence and Prevention Recommendations. Cancers (Basel) 2021; 14:cancers14010103. [PMID: 35008267 PMCID: PMC8750465 DOI: 10.3390/cancers14010103] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The increasing public health burden of Hepatocellular carcinoma (HCC) emphasizes the importance of defining important modifiable risk factors. In the following review, we will discuss the evidence for the relation of major lifestyle risk factors, mostly from large population-based studies. Generally, it is has been shown that healthy lifestyle habits, including minimizing obesity, eating a healthy diet, avoidance of smoking and alcohol, and increasing physical activity, have the potential to prevent HCC. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, vegetables and fiber, are inversely associated with HCC, while red meat, saturated fat, cholesterol and sugar are related to increased risk. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. Smoking and alcohol can lead to liver fibrosis and liver cancer and jointly lead to an even greater risk. Abstract The increasing burden of hepatocellular carcinoma (HCC) emphasizes the unmet need for primary prevention. Lifestyle measures appear to be important modifiable risk factors for HCC regardless of its etiology. Lifestyle patterns, as a whole and each component separately, are related to HCC risk. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, are inversely associated with HCC, while red meat, saturated fat, and cholesterol are related to increased risk. Sugar consumption is associated with HCC risk, while fiber and vegetable intake is protective. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. However, the duration, mode and intensity of physical activity needed are yet to be determined. There is evidence that smoking can lead to liver fibrosis and liver cancer and has a synergistic effect with alcohol drinking. On the other hand, an excessive amount of alcohol by itself has been associated with increased risk of HCC directly (carcinogenic effect) or indirectly (liver fibrosis and cirrhosis progression. Large-scale intervention studies testing the effect of comprehensive lifestyle interventions on HCC prevention among diverse cohorts of liver disease patients are greatly warranted.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Correspondence: ; Tel.: +972-54-4634440; Fax: +972-3-5446086
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Oren Shibolet
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6697801, Israel
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13
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Watson C, Hassan M, Breeland G. Multifactorial jaundice and pigmented choledocholithiasis secondary to warm autoimmune hemolytic anemia and alcoholic cirrhosis. Proc AMIA Symp 2021; 35:229-231. [DOI: 10.1080/08998280.2021.1995107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Affiliation(s)
- Colten Watson
- Texas A&M Medical School Dallas Campus, Dallas, Texas
| | - Mazen Hassan
- Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas
| | - Grant Breeland
- Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas
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14
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Warner D, Vatsalya V, Zirnheld KH, Warner JB, Hardesty JE, Umhau JC, McClain CJ, Maddipati K, Kirpich IA. Linoleic Acid-Derived Oxylipins Differentiate Early Stage Alcoholic Hepatitis From Mild Alcohol-Associated Liver Injury. Hepatol Commun 2021; 5:947-960. [PMID: 34141982 PMCID: PMC8183177 DOI: 10.1002/hep4.1686] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/05/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)-derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA-derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End-Stage Liver Disease score <20). Lipoxygenase-derived LA metabolites (13-hydroxy-octadecadienoic acid [13-HODE] and 13-oxo-octadecadienoic acid) were markedly elevated only in patients with mAH. The cytochrome P450-derived LA epoxides 9,10-epoxy-octadecenoic acid (9,10-EpOME) and 12,13-EpOME were decreased in all patients regardless of the presence or absence of liver injury. LA-derived diols 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME) and 12,13-DiHOME as well as the corresponding diol/epoxide ratio were elevated in the mAH group, specifically compared to patients with mild liver injury. We found that 13-HODE and 12,13-EpOME (elevated and decreased, respectively) in combination with elevated interleukin-1β as independent predictors can effectively predict altered liver function as defined by elevated bilirubin levels. Conclusion: Specific changes in LA metabolites in individuals who are heavy drinkers can distinguish individuals with mAH from those with mild ALD.
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Affiliation(s)
- Dennis Warner
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA
| | - Vatsalya Vatsalya
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Robley Rex Veterans Medical CenterLouisvilleKYUSA
| | - Kara H Zirnheld
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA
| | - Jeffrey B Warner
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA
| | - Josiah E Hardesty
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA
| | | | - Craig J McClain
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Robley Rex Veterans Medical CenterLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA.,University of Louisville Alcohol CenterLouisvilleKYUSA.,Hepatobiology and Toxicology CenterUniversity of Louisville School of MedicineLouisvilleKYUSA
| | | | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.,Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineKYUSA.,University of Louisville Alcohol CenterLouisvilleKYUSA.,Hepatobiology and Toxicology CenterUniversity of Louisville School of MedicineLouisvilleKYUSA
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15
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Tu SM. Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies. Cancers (Basel) 2021; 13:cancers13112738. [PMID: 34205851 PMCID: PMC8199000 DOI: 10.3390/cancers13112738] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 02/04/2023] Open
Abstract
Simple Summary We postulate that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We propose that the virus may turn out to be a surreptitious agent and a serendipitous model in our quest to investigate the origin of cancer. When it pertains, oncology recapitulates ontogeny, although genetic makeup is king. Cellular context may be the key to elucidating a stem cell origin of cancer. Abstract In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontogeny; although genetic makeup is pivotal, cellular context may be paramount to elucidating a stem cell origin of cancer.
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Affiliation(s)
- Shi-Ming Tu
- Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas, MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA
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16
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Ho SY, Hsu CY, Liu PH, Lee RC, Ko CC, Huang YH, Su CW, Hou MC, Huo TI. Albumin-Bilirubin (ALBI) Grade-Based Nomogram for Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization. Dig Dis Sci 2021; 66:1730-1738. [PMID: 32548811 DOI: 10.1007/s10620-020-06384-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 06/01/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is highly heterogeneous because of variable characteristics of tumor burden and liver dysfunction. We aimed to propose and validate an albumin-bilirubin (ALBI) grade-based prognostic nomogram for HCC patients undergoing TACE. METHODS A total of 1051 patients with HCC undergoing TACE were randomly assigned to derivation (n = 525) and validation (n = 526) set in this retrospective study based on prospective data. The multivariate Cox proportional hazards model in derivation set was used to generate the nomogram. The predictive accuracy of the nomogram was evaluated by discrimination and calibration tests. RESULTS In multivariate analysis, presence of ascites, ALBI grade 2-3, serum ɑ-fetoprotein level ≥ 400 ng/mL, total tumor volume ≥ 396 cm3, presence of vascular invasion, and poor performance status were independently associated with decreased survival of patients in the derivation set. Each patient had an individualized score from 0 to 41 by adding up the points from these six prognostic predictors. The nomogram generated from the derivation set had a concordance index of 0.72 (95% confidence interval [CI] 0.63-0.82). Discrimination test in the validation set provided a good concordance index 0.72 (95% CI 0.62-0.81), and the calibration plots consistently matched the ideal 45-degree reference line for 3- and 5-year survival prediction. CONCLUSIONS The ALBI grade-based prognostic model can well discriminate the survival in HCC patients undergoing TACE. The proposed easy-to-use nomogram may accurately predict the survival at 3 and 5 years for individual HCC patient in the precision medicine era.
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Affiliation(s)
- Shu-Yein Ho
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chia-Yang Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Po-Hong Liu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rheun-Chuan Lee
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chih-Chieh Ko
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chien-Wei Su
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Teh-Ia Huo
- Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Taipei, 11217, Taiwan. .,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. .,Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
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17
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Jeon MY, Kim BK, Lee JS, Lee HW, Park JY, Kim DY, Ahn SH, Han KH, Kim SU. Negligible risks of hepatocellular carcinoma during biomarker-defined immune-tolerant phase for patients with chronic hepatitis B. Clin Mol Hepatol 2021; 27:295-304. [PMID: 33317247 PMCID: PMC8046628 DOI: 10.3350/cmh.2020.0216] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS The immune-tolerant (IT) phase of chronic hepatitis B (CHB) patients is not generally indicative of antiviral therapy (AVT). We assessed and compared the risk of hepatocellular carcinoma (HCC) during the IT-phase stringently defined by a low fibrosis-4 (FIB-4) index, compared to that in patients undergoing AVT. METHODS Among 125 untreated patients that were hepatitis B e-antigen positive, hepatitis B virus-DNA >20,000 IU/mL, with normal alanine aminotransferase level from 2012 to 2018, those with a FIB-4 index of <1.45 were classified into the IT-group. The cumulative probability of HCC was estimated using Kaplan-Meier analysis. All patients were assessed until HCC development (intention-to-treat [ITT] analysis), whereas those suspected of experiencing CHB phase switch were assessed using the per-protocol (PP) and censored at the time of phase switch. RESULTS The cumulative probability of HCC at 1-, 3-, and 5-years among the IT-group was zero, compared to AVT-treated patients with FIB-4 indices <1.45 during the same period: 0.2%, 0.6%, and 1.4%, respectively (P=0.264 for ITT and P=0.533 for PP). Among the initially screened 125 untreated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to the IT-group (P=0.005). Furthermore, among AVT-treated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to their counterpart (P<0.001). CONCLUSION The risk of HCC was negligible in the IT-group stringently defined by a low FIB-4 index. However, given that a higher HCC risk exists among untreated patients with higher FIB-4, appropriate criteria for AVT should be established.
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Affiliation(s)
- Mi Young Jeon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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18
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Q P, KC W, CL E. Common genetic substrates of alcohol and substance use disorder severity revealed by pleiotropy detection against GWAS catalog in two populations. Addict Biol 2021; 26:e12877. [PMID: 32027075 PMCID: PMC7415504 DOI: 10.1111/adb.12877] [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] [Received: 07/21/2019] [Revised: 11/15/2019] [Accepted: 01/11/2020] [Indexed: 12/01/2022]
Abstract
Alcohol and other substance use disorders (AUD and SUD) are complex diseases that are postulated to have a polygenic inheritance and are often comorbid with other disorders. The comorbidities may arise partially through genetic pleiotropy. Identification of specific gene variants accounting for large parts of the variance in these disorders has yet to be accomplished. We describe a flexible strategy that takes a variant-trait association database and determines if a subset of disease/straits are potentially pleiotropic with the disorder under study. We demonstrate its usage in a study of use disorders in two independent cohorts: alcohol, stimulants, cannabis (CUD), and multi-substance use disorders (MSUD) in American Indians (AI) and AUD and CUD in Mexican Americans (MA). Using a machine learning method with variants in GWAS catalog, we identified 229 to 246 pleiotropic variants for AI and 153 to 160 for MA for each SUD. Inflammation was the most enriched for MSUD and AUD in AIs. Neurological disorder was the most significantly enriched for CUD in both cohorts, and for AUD and stimulants in AIs. Of the select pleiotropic genes shared among substances-cohorts, multiple biological pathways implicated in SUD and other psychiatric disorders were enriched, including neurotrophic factors, immune responses, extracellular matrix, and circadian regulation. Shared pleiotropic genes were significantly up-regulated in brain regions playing important roles in SUD, down-regulated in esophagus mucosa, and differentially regulated in adrenal gland. This study fills a gap for pleiotropy detection in understudied admixed populations and identifies pleiotropic variants that may be potential targets of interest for SUD.
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Affiliation(s)
- Peng Q
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037 USA
| | - Wilhelmsen KC
- Department of Genetics and Neurology, University of North Carolina, Chapel Hill, NC 27599 USA
| | - Ehlers CL
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037 USA
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19
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Kim YS, Kim SG. Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases. Clin Mol Hepatol 2020; 26:715-727. [PMID: 32951410 PMCID: PMC7641579 DOI: 10.3350/cmh.2020.0173] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/31/2020] [Indexed: 12/15/2022] Open
Abstract
Alcoholic and non-alcoholic liver diseases begin from an imbalance in lipid metabolism in hepatocytes as the earliest response. Both liver diseases share common disease features and stages (i.e., steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma). However, the two diseases have differential pathogenesis and clinical symptoms. Studies have elucidated the molecular basis underlying similarities and differences in the pathogenesis of the diseases; the factors contributing to the progression of liver diseases include depletion of sulfhydryl pools, enhanced levels of reactive oxygen and nitrogen intermediates, increased sensitivity of hepatocytes to toxic cytokines, mitochondrial dysfunction, and insulin resistance. Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins and calcium depletion, contributes to the pathogenesis, often causing catastrophic cell death. Several studies have demonstrated a mechanism by which ER stress triggers liver disease progression. Autophagy is an evolutionarily conserved process that regulates organelle turnover and cellular energy balance through decomposing damaged organelles including mitochondria, misfolded proteins, and lipid droplets. Autophagy dysregulation also exacerbates liver diseases. Thus, autophagy-related molecules can be potential therapeutic targets for liver diseases. Since ER stress and autophagy are closely linked to each other, an understanding of the molecules, gene clusters, and networks engaged in these processes would be of help to find new remedies for alcoholic and non-alcoholic liver diseases. In this review, we summarize the recent findings and perspectives in the context of the molecular pathogenesis of the liver diseases.
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Affiliation(s)
- Yun Seok Kim
- College of Pharmacy, Seoul National University, Seoul, Korea
| | - Sang Geon Kim
- College of Pharmacy, Seoul National University, Seoul, Korea.,College of Pharmacy, Dongguk University, Goyang, Korea
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20
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Malnick S, Maor Y. The Interplay between Alcoholic Liver Disease, Obesity, and the Metabolic Syndrome. Visc Med 2020; 36:198-205. [PMID: 32775350 PMCID: PMC7383260 DOI: 10.1159/000507233] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/11/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Fatty liver may be the result of several factors. The two main contributors are nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). SUMMARY NAFLD is the hepatic manifestation of the metabolic syndrome (MetS) and is the major cause of chronic liver disease worldwide as a result of the obesity epidemic. ALD is also a common cause of chronic liver disease. Obesity is a major contributory factor to MetS and is also common in individuals who consume large amounts of alcohol. There is a similar hepatic pathology and both can result in severe fibrosis, cirrhosis, and its complications including hepatocellular carcinoma. This review discusses the etiology, pathogenesis, and genetics of both NAFLD and ALD and their interaction. It is necessary to understand this better in order to prevent and treat these important causes of liver disease worldwide. KEY MESSAGE Obesity, MetS, and alcohol consumption are linked to the development and progression of fatty liver disease. The coexistence of these factors in many patients requires a reassessment of many aspects of treatment of fatty liver disease.
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Affiliation(s)
- Stephen Malnick
- Department of Internal Medicine C, Kaplan Medical Center, Rehovot, Israel
| | - Yaakov Maor
- Institute of Gastroenterology and Hepatology, Kaplan Medical Center, Rehovot, Israel
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González-Regueiro JA, Ruiz-Margáin A, Cruz-Contreras M, Montaña-Duclaud AM, Cavazos-Gómez A, Demichelis-Gómez R, Macías-Rodríguez RU. Clinical characteristics and treatment outcomes in patients with liver cirrhosis and lymphoma. World J Hepatol 2020; 12:34-45. [PMID: 32184940 PMCID: PMC7061265 DOI: 10.4254/wjh.v12.i2.34] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/21/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND A significant number of patients with liver cirrhosis concomitantly develop some type of solid or hematological cancer, including lymphoma. Treatment of patients with lymphoma and cirrhosis is challenging for physicians due to the clinical characteristics related to cirrhosis, including biochemical and functional abnormalities, as well as portal hypertension and lack of scientific evidence, limiting the use of chemotherapy. Currently, experts recommend only offering oncological treatment to patients with compensated cirrhosis. AIM To evaluate the clinical characteristics and treatment outcomes in patients with cirrhosis and lymphoma treated with chemotherapy. METHODS This was a case-control study conducted at a tertiary care center in Mexico. Data was recorded from medical files and from 8658 possible candidates with cirrhosis and/or lymphoma (2000 to 2018). Only 23 cases had both diseases concomitantly; 10 patients with cirrhosis and lymphoma (cases) met the selection criteria and were included, and 20 patients with lymphoma (controls) were included and matched according to age, sex, and date of diagnosis, type and clinical stage of lymphoma. All patients received treatment with chemotherapy. For statistical analysis, descriptive statistics, Shapiro-Wilk test, Mann-Whitney U test, chi-square test and Fisher's exact test were used. Survival was evaluated using Kaplan-Meier curves and Log-rank test. RESULTS There were differences in biochemical variables inherent to liver disease and portal hypertension in patients with cirrhosis. The most frequent etiology of cirrhosis was hepatitis C virus (50%); 80% were decompensated, the median Child-Turcotte-Pugh score was 7.5 (6.75-9.25), and mean Model for End-stage Liver Disease was 11.5 ± 4.50. Regarding lymphomas, non-Hodgkin's were the most common (90%), and diffuse large B cell subtype was the most frequent, with a higher International Prognostic Index in the cases (3 vs 2, P = 0.049). The chemotherapy regimens had to be adjusted more frequently in the case group (50% vs 5%, P = 0.009). The complications derived from chemotherapy were similar between both groups (80% vs 90%, P = 0.407); however, non-hematological toxicities were more common in the case group (30% vs 0%, P = 0.030). There was no difference in the response to treatment between groups. Survival was higher in the control group (56 wk vs 30 wk, P = 0.269), although it was not statistically significant. CONCLUSION It may be possible to administer chemotherapy in selected cirrhotic patients, regardless of their severity, obtaining satisfactory clinical outcomes. Prospective clinical trials are needed to generate stronger recommendations.
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Affiliation(s)
- José A González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Mariana Cruz-Contreras
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Ana M Montaña-Duclaud
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Andrea Cavazos-Gómez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Roberta Demichelis-Gómez
- Department of Hematology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Ricardo U Macías-Rodríguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, Mexico City 14080, Mexico.
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Gala KS, Vatsalya V. Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope. Cells 2020; 9:E524. [PMID: 32106390 PMCID: PMC7140524 DOI: 10.3390/cells9030524] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 02/16/2020] [Accepted: 02/19/2020] [Indexed: 12/12/2022] Open
Abstract
Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH.
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Affiliation(s)
- Khushboo S. Gala
- Division of Internal Medicine, University of Louisville, Louisville, KY 40202; USA
| | - Vatsalya Vatsalya
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, Louisville, KY 40292, USA
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23
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Ho SY, Hsu CY, Liu PH, Hsia CY, Lei HJ, Huang YH, Ko CC, Su CW, Lee RC, Hou MC, Huo TI. Albumin-bilirubin grade-based nomogram of the BCLC system for personalized prognostic prediction in hepatocellular carcinoma. Liver Int 2020; 40:205-214. [PMID: 31505104 DOI: 10.1111/liv.14249] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/19/2019] [Accepted: 09/02/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS The prognostic accuracy of individual hepatocellular carcinoma (HCC) patient in each Barcelona Clinic Liver Cancer (BCLC) stage is unclear. We aimed to develop and validate an albumin-bilirubin (ALBI) grade-based nomogram of BCLC to estimate survival for individual HCC patient. METHODS Between 2002 and 2016, 3690 patients with newly diagnosed HCC were prospectively enrolled and retrospectively analysed. Patients were randomly split into derivation and validation cohort by 1:1 ratio. Multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, ALBI grade and performance status (PS). The concordance index and calibration plot were determined to evaluate the performance of this nomogram. RESULTS Beta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, ALBI grade and PS. The scores of the nomogram ranged from 0 to 24, and were used to predict 3- and 5-year patient survival. The concordance index of this nomogram was 0.77 (95% confidence interval [CI]: 0.71-0.81) in the derivation cohort and 0.76 (95% CI: 0.71-0.81) in the validation cohort. The calibration plots to predict both 3- and 5-year survival rate well matched with the 45-degree ideal line for both cohorts, except for ALBI-based BCLC stage 0 in the validation cohort. CONCLUSIONS The proposed ALBI-based nomogram of BCLC system is a simple and feasible strategy in the precision medicine era. Our data indicate it is a straightforward and user-friendly prognostic tool to estimate the survival of individual HCC patient except for very early stage patients.
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Affiliation(s)
- Shu-Yein Ho
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chia-Yang Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Po-Hong Liu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Cheng-Yuan Hsia
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hao-Jan Lei
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chih-Chieh Ko
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chien-Wei Su
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Rheun-Chuan Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Teh-Ia Huo
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Kępka A, Zwierz P, Chojnowska S, Ochocińska A, Skorupa E, Szczepański M, Szajda SD, Waszkiewicz N. Relation of plasma carnitine and aminotransferases to alcohol dose and time of dependence. Alcohol 2019; 81:62-69. [PMID: 31029632 DOI: 10.1016/j.alcohol.2019.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 04/18/2019] [Accepted: 04/19/2019] [Indexed: 01/27/2023]
Abstract
BACKGROUND Serum aspartate, alanine aminotransferases (AST, ALT), and plasma carnitine are all indirect biomarkers of alcohol abuse. Carnitine transfers long-chain fatty acids from cytoplasm to mitochondria for β-oxidation. The aim of the study was to determine the relationship between daily alcohol intake, time of alcohol dependence, plasma carnitine, and serum aminotransferases. PATIENTS We studied 26 men who were addicted for 2-30 years, consuming ethanol from 75 to 700 g/day (alcoholic group), as well as 17 healthy men (control group). RESULTS In alcoholics, compared to the controls, we found: a significant increase in serum: AST (p = 0.0014), ALT (p = 0.0071), AST/ALT ratio (p < 0.000); significantly lower plasma free carnitine (FC) (p = 0.0316) and total carnitine (TC) (p = 0.0349); and a significant negative correlation between FC (r = -0.6200; R2 = 0.3844; p = 0.0007), TC (r = -0.4365; R2 = 0.1905; p = 0.0258), and time of alcohol dependence, suggesting carnitine as an indirect marker of alcohol abuse. We did not find any significant correlation between FC, TC, and levels of alcohol or aminotransferase activity. CONCLUSION In the alcoholic group, there was an increase in serum activity of AST, ALT, and AST/ALT ratio that confirms liver injury. In addition, we found low plasma FC and TC, which may indicate damage to mitochondrial β-oxidation caused by alcohol metabolites. The significantly higher plasma FC and TC in patients consuming the most, compared to patients consuming smaller doses of alcohol, may be caused by a lower carnitine demand of injured liver cells, decreased urinary carnitine excretion by impaired renal tubules, and leakage of carnitine into the blood from damaged muscles by the higher quantities of alcohol. The negative correlation between carnitine concentration and time of alcohol dependence may suggest the potential use of carnitine for treatment of alcohol abuse.
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25
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Matsushita H, Takaki A. Alcohol and hepatocellular carcinoma. BMJ Open Gastroenterol 2019; 6:e000260. [PMID: 31139422 PMCID: PMC6505979 DOI: 10.1136/bmjgast-2018-000260] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/04/2019] [Accepted: 01/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer because it induces hepatocellular carcinoma (among other cancers) in humans. An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, and cirrhosis and eventually lead to hepatocellular carcinoma. It has been reported that alcohol abuse increases the relative risk of hepatocellular carcinoma by 3- to 10-fold. AIM AND METHODS To clarify the known mechanisms of alcohol-related carcinogenesis, we searched Pubmed using the terms alcohol and immune mechanism, alcohol and cancer, and immune mechanism and cancer and summarized the articles as a qualitative review. RESULTS From a clinical perspective, it is well known that alcohol interacts with other factors, such as smoking, viral hepatitis, and diabetes, leading to an increased risk of hepatocellular carcinoma. There are several possible mechanisms through which alcohol may induce liver carcinogenicity, including the mutagenic effects of acetaldehyde and the production of ROS due to the excessive hepatic deposition of iron. Furthermore, it has been reported that alcohol accelerates hepatitis C virus-induced liver tumorigenesis through TLR4 signaling. Despite intense investigations to elucidate the mechanisms, they remain poorly understood. CONCLUSION This review summarizes the recent findings of clinical and pathological studies that have investigated the carcinogenic effects of alcohol in the liver.
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Affiliation(s)
- Hiroshi Matsushita
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Abstract
Alcoholic liver disease, which ranges from mild disease to alcoholic hepatitis and cirrhosis, is a leading cause of morbidity and mortality worldwide. Alcohol intake can lead to changes in gut microbiota composition, even before liver disease development. These alterations worsen with advancing disease and could be complicit in disease progression. Microbial function, especially related to bile acid metabolism, can modulate alcohol-associated injury even in the presence of cirrhosis and alcoholic hepatitis. Microbiota changes might also alter brain function, and the gut-brain axis might be a potential target to reduce alcoholic relapse risk. Gut microbiota manipulation including probiotics, faecal microbial transplant and antibiotics has been studied in alcoholic liver disease with varying success. Further investigation of the modulation of the gut-liver axis is relevant, as most of these patients are not candidates for liver transplantation. This Review focuses on clinical studies involving the gut microbiota in patients with alcoholic liver disease across the spectrum from alcoholic fatty liver to cirrhosis and alcoholic hepatitis. Specific alterations in the gut-liver-brain axis that are complicit in the interactions between the gut microbiota and alcohol addiction are also reviewed.
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27
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Whitfield JB, Zhu G, Madden PAF, Montgomery GW, Heath AC, Martin NG. Biomarker and Genomic Risk Factors for Liver Function Test Abnormality in Hazardous Drinkers. Alcohol Clin Exp Res 2019; 43:473-482. [PMID: 30589442 PMCID: PMC6445646 DOI: 10.1111/acer.13949] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 12/21/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alcohol dependence and long-term excessive alcohol use may cause liver damage, but only some patients develop cirrhosis. Similarly, high alcohol intake without evident liver disease often but not always produces abnormal enzymatic liver function tests (LFTs), particularly gamma-glutamyl transferase (GGT). We postulate that the factors predisposing to cirrhosis in alcoholics and to liver enzyme abnormality in drinkers are similar, and that biochemical LFTs could therefore be useful as markers of risk of alcoholic liver disease in excessive drinkers. METHODS Data from participants in twin and twin-family studies on alcohol use and dependence were used to identify 1,003 people who had reported excessive alcohol intake (28 drinks or more per week). A total of 962 of these provided blood for biochemical tests at the same time. Body mass index (BMI) and biomarkers of metabolic syndrome, inflammation, and iron stores were used in logistic regression with abnormality in serum GGT, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) as outcomes. We conducted genome-wide association analyses for GGT, ALT, and AST separately in the group reporting excessive alcohol intake (N = 951) and a low-intake group reporting 14 drinks or fewer per week (N = 8,716), and compared results. RESULTS Abnormal GGT and ALT among excessive drinkers were associated with higher BMI, triglycerides, insulin, uric acid, C-reactive protein, ferritin, and transferrin saturation; and with lower high-density-lipoprotein cholesterol. Abnormal AST was associated with triglycerides, ferritin, and transferrin saturation. ALT was significantly associated with variants at reported genetic loci for alcoholic liver disease (PNPLA3, rs738409, p = 0.0076; TM6SF2, rs10401969, p = 0.0076; HSD17B13, rs10433879, p = 0.0024). CONCLUSIONS Known risk factors for alcoholic cirrhosis including obesity and markers of metabolic syndrome, iron overload and inflammation are associated with liver enzyme abnormality in excessive drinkers.
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Affiliation(s)
- John B Whitfield
- QIMR Berghofer Medical Research Institute , Brisbane, Queensland
| | - Gu Zhu
- QIMR Berghofer Medical Research Institute , Brisbane, Queensland
| | - Pamela A F Madden
- Department of Psychiatry , Washington University School of Medicine, St. Louis, Missouri
| | - Grant W Montgomery
- Institute for Molecular Bioscience , The University of Queensland, St. Lucia, Queensland
| | - Andrew C Heath
- Department of Psychiatry , Washington University School of Medicine, St. Louis, Missouri
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di Bello G, Vendemiale G, Bellanti F. Redox cell signaling and hepatic progenitor cells. Eur J Cell Biol 2018; 97:546-556. [PMID: 30278988 DOI: 10.1016/j.ejcb.2018.09.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 09/20/2018] [Accepted: 09/20/2018] [Indexed: 02/08/2023] Open
Abstract
Hepatic diseases are widespread in the world and organ transplantation is currently the only treatment for liver failure. New cell-based approaches have been considered, since stem cells may represent a possible source to treat liver diseases. Acute and chronic liver diseases are characterized by high production of reactive oxygen and nitrogen species, with consequent oxidative modifications of cellular macromolecules and alteration of signaling pathways, metabolism and cell cycle. Although considered harmful molecules, reactive species are involved in cell growth and differentiation processes, modulating the activity of transcription factors, which take part in stemness/proliferation. It is conceivable that redox balance may regulate the development of hepatic progenitor cells, function and survival in synchrony with metabolism during chronic liver diseases. This review aims to summarize diverse redox-sensitive signaling pathways involved in stem cell fate, highlighting the important role of hepatic progenitor cells as a possible source to treat end-stage liver disease for organ regeneration.
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Affiliation(s)
- Giorgia di Bello
- Centre for Experimental and Regenerative Medicine, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Gianluigi Vendemiale
- Centre for Experimental and Regenerative Medicine, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Francesco Bellanti
- Centre for Experimental and Regenerative Medicine, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Italy.
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Kim NH, Heo JD, Rho JR, Yang MH, Jeong EJ. The Standardized Extract of Limonium tetragonum Alleviates Chronic Alcoholic Liver Injury in C57Bl/6J Mice. Pharmacogn Mag 2018; 14:58-63. [PMID: 29576702 PMCID: PMC5858243 DOI: 10.4103/pm.pm_44_17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 03/14/2017] [Indexed: 11/06/2022] Open
Abstract
Background: In traditional folk medicine, Limonium tetragonum is used in the treatment of uterine hemorrhage, tinnitus, and oligomenorrhea. Objective: This study aimed to identify the therapeutic effect of L. tetragonum EtOAc extract (EALT) on liver of mice with chronic alcohol poisoning. Materials and Methods: C57BL/6J mice were administered 100 mg/kg of EALT with a single binge ethanol/Lieber-DeCarli liquid diet for 8 weeks. Results: The chronic-binge ethanol diet induced a significant increase in liver marker enzyme activities. Coadministration of EALT reversed the elevation of serum total cholesterol and triglyceride as well as aspartate aminotransferase and alanine aminotransferase due to chronic alcohol consumption. Histologic findings including markedly attenuated fat accumulation in hepatocytes were observed in EALT-treated mice. EALT supplementation prevented alcoholic liver injury through attenuation of inflammatory mediators such as toll-like receptor-4, cytochrome P4502E1, and cyclooxygenase-2, and inflammatory cytokine interleukin-6. Conclusion: Results provided direct experimental evidence for the hepatoprotective effect of EALT in the NIAAA mouse model. Therapeutic attempts with the L. tetragonum extract might be useful in the management of alcoholic liver disease. SUMMARY
Halophyte Limonium tetragonum has recently been of interest in Korea for its nutritional value and salty taste which made it an ideal vegetable Phytochemical analysis of L. tetragonum EtOAc extract (EALT) resulted in nine compounds including catechins and myricetin glycosides as main components Administration of EALT for 8 weeks showed hepatoprotective effect on Lieber-DeCarli diet-fed mouse model A significant decrease in liver marker enzymes and inflammatory mediators was also detected. Abbreviations used: EALT: L. tetragonum EtOAc extract; TC: Total cholesterol; TG: Triglyceride; ROS: Reactive oxygen species; CYP2E1: Cytochrome P4502E1; TLR-4: Toll-like receptor-4; COX-2: Cyclooxygenase-2.
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Affiliation(s)
- Na-Hyun Kim
- Gyeongnam Department of Environment and Toxicology, Korea Institute of Toxicology, Gyeongnam 52834, Republic of Korea
| | - Jeong-Doo Heo
- Gyeongnam Department of Environment and Toxicology, Korea Institute of Toxicology, Gyeongnam 52834, Republic of Korea
| | - Jung-Rae Rho
- Department of Oceanography, Kunsan National University, Jeonbuk 54150, Republic of Korea
| | - Min Hye Yang
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Eun Ju Jeong
- Department of Agronomy and Medicinal Plant Resources, Gyeongnam National University of Science and Technology, Jinju 52725, Republic of Korea
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Majc D, Tepes B. The Impact of Outpatient Clinical Care on the Survival and Hospitalisation Rate in Patients with Alcoholic Liver Cirrhosis. Radiol Oncol 2017. [PMID: 29520208 PMCID: PMC5839084 DOI: 10.1515/raon-2017-0056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background In the study, we aimed to determine whether regular outpatient controls in patients with alcoholic liver cirrhosis have an impact on their survival and hospitalisation rates. Patients and methods We included patients with liver cirrhosis and regular outpatient controls as a prospective study group and patients with liver cirrhosis who were admitted to hospital only in cases of complications as a retrospective control group. The study was conducted between 2006 and 2011. Results We included 98 patients in the study group and 101 patients in the control group. There were more outpatient controls in the study group than in the control group (5.54 examinations vs. 2.27 examinations, p = 0.000). Patients in the study group had 25 fewer hospitalisations (10.2%; p = 0.612). The median survival rate was 4.6 years in the study group and 2.9 years in the control group (p = 0.021). Patients with Child A classification had an average survival of one year longer in the study group (p = 0.035). No significant difference was found for Child B patients. Patients with Child C classification had longer survival by 1.6 years in the study group (p = 0.006). Alcohol consumption was lower in the study group than in the control group (p = 0.018). Conclusions We confirmed that patients with regular outpatient controls had lower alcohol consumption, a lower hospitalisation rate and significantly prolonged survival time. We confirmed the necessity for the establishment of regular outpatient controls in patients with alcoholic liver cirrhosis.
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Affiliation(s)
- Dejan Majc
- General Hospital Murska Sobota, Murska Sobota, Slovenia
| | - Bojan Tepes
- AM DC Rogaška, Rogaška Slatina, Slovenija
- Bojan Tepeš, M.D., Ph.D., FEBGH, AM DC Rogaška, Prvomajska 29 A, 3250 Rogaška Slatina
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Nielsen JK, Olafsson S, Bergmann OM, Runarsdottir V, Hansdottir I, Sigurdardottir R, Björnsson ES. Lifetime drinking history in patients with alcoholic liver disease and patients with alcohol use disorder without liver disease. Scand J Gastroenterol 2017; 52:762-767. [PMID: 28276826 DOI: 10.1080/00365521.2017.1295466] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To determine the differences in lifetime alcohol intake (LAI) and drinking patterns between patients with alcoholic liver disease (ALD) and alcohol use disorder (AUD) without notable liver injury and between males and females with ALD. METHODS Alcohol drinking patterns were assessed using the Lifetime Drinking History (LDH) a validated questionnaire, during an outpatient visit. Patients with AUD, currently in addiction treatment, were matched for gender and age (±5 years) with the ALD group. RESULTS A total of 39 patients with ALD (26 males and 13 females; median age 58) and equal number of AUD patients were included (median age 56 years). The onset age for alcohol drinking and duration of alcohol consumption was similar in ALD and AUD. The number of drinking days was higher in women with ALD than in women with AUD: 4075 [(3224-6504) versus 2092 (1296-3661), p = .0253]. The LAI and drinks per drinking day (DDD) were not significantly different between patients with ALD and AUD. Females with ALD had lower LAI than males with ALD: 32,934 (3224-6504) versus 50,923 (30,360-82,195), p = .0385, fewer DDD (p = .0112), and lower proportion of binge drinking as compared to males with ALD (p = .0274). CONCLUSIONS The total LAI was similar in patients with ALD and AUD. The number of drinking days over the lifetime was associated with the development of ALD in females. Females with ALD had significantly lower alcohol consumption than men with ALD despite similar duration in years of alcohol intake which supports the concept of female propensity of ALD.
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Affiliation(s)
- Jon Kristinn Nielsen
- a Department of Surgery , The National University Hospital of Iceland , Reykjavik , Iceland
| | - Sigurdur Olafsson
- b Department of Gastroenterology and Hepatology , Landspitali University Hospital , Reykjavik , Iceland
| | - Ottar M Bergmann
- b Department of Gastroenterology and Hepatology , Landspitali University Hospital , Reykjavik , Iceland
| | - Valgerdur Runarsdottir
- d Department of Internal Medicine , The National Center for Addiction Medicine, Vogur Hospital , Reykjavik , Iceland
| | - Ingunn Hansdottir
- d Department of Internal Medicine , The National Center for Addiction Medicine, Vogur Hospital , Reykjavik , Iceland.,e Department of Psychology , The National University Hospital of Iceland, University of Iceland , Reykjavik , Iceland
| | - Ragna Sigurdardottir
- c Department of Internal Medicine , The National University Hospital of Iceland , Reykjavik , Iceland
| | - Einar S Björnsson
- b Department of Gastroenterology and Hepatology , Landspitali University Hospital , Reykjavik , Iceland.,c Department of Internal Medicine , The National University Hospital of Iceland , Reykjavik , Iceland
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Greuter T, Malhi H, Gores GJ, Shah VH. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight 2017; 2:95354. [PMID: 28878132 DOI: 10.1172/jci.insight.95354] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are among the most frequent causes of chronic liver disease in the United States. Although the two entities are triggered by different etiologies - chronic alcohol consumption (ASH) and obesity-associated lipotoxicity (NASH) - they share overlapping histological and clinical features owing to common pathogenic mechanisms. These pathogenic processes include altered hepatocyte lipid metabolism, organelle dysfunction (i.e., ER stress), hepatocyte apoptosis, innate immune system activation, and hepatic stellate cell activation. Nonetheless, there are several disease-specific molecular signaling pathways, such as differential pathway activation downstream of TLR4 (MyD88-dependence in NASH versus MyD88-independence in ASH), inflammasome activation and IL-1β signaling in ASH, insulin resistance and lipotoxicity in NASH, and dysregulation of different microRNAs, which clearly highlight that ASH and NASH are two distinct biological entities. Both pathogenic similarities and differences have therapeutic implications. In this Review, we discuss these pathogenic mechanisms and their therapeutic implications for each disease, focusing on both shared and distinct targets.
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Affiliation(s)
- Thomas Greuter
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gregory J Gores
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Li W, Amet T, Xing Y, Yang D, Liangpunsakul S, Puri P, Kamath P, Sanyal A, Shah V, Katz B, Radaeva S, Crabb D, Chalasani N, Yu Q. Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study. Hepatology 2017; 66:575-590. [PMID: 28466561 PMCID: PMC5548491 DOI: 10.1002/hep.29242] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/27/2017] [Accepted: 04/24/2017] [Indexed: 12/13/2022]
Abstract
Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Tohti Amet
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yanyan Xing
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Dennis Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Puneet Puri
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Barry Katz
- Department of Biostatistics, Indiana University School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202
| | - Svetlana Radaeva
- National Institute of Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD
| | - David Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Internal Medicine, Eskenazi Health, Indianapolis, IN 46202
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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Abstract
This article will focus on the two areas of alcohol injury: first, the gastrointestinal system, primarily liver toxicity and cirrhosis, and second, the human toll in injury, examining injury epidemiology information that estimates alcohol's involvement in trauma. Any pharmacist consulting in any capacity, especially related to gastrointestinal disorders, will need to understand the significant sociological, pathological, pharmacological, and psychological impact of alcohol. Pharmacists providing care, including dispensing many different drugs to patients, should be cognizant of the interacting effects of alcohol and the need to warn patients. Finally, the reader will learn of a case in which a pharmacist was sued for not warning about the use of alcohol with a central nervous system depressant, and the resultant litigation after that lawsuit.
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Pinter M, Trauner M, Peck-Radosavljevic M, Sieghart W. Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open 2016; 1:e000042. [PMID: 27843598 PMCID: PMC5070280 DOI: 10.1136/esmoopen-2016-000042] [Citation(s) in RCA: 196] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 02/06/2016] [Indexed: 12/11/2022] Open
Abstract
Liver cirrhosis, the end-stage of every chronic liver disease, is not only the major risk factor for the development of hepatocellular carcinoma but also a limiting factor for anticancer therapy of liver and non-hepatic malignancies. Liver cirrhosis may limit surgical and interventional approaches to cancer treatment, influence pharmacokinetics of anticancer drugs, increase side effects of chemotherapy, render patients susceptible for hepatotoxicity, and ultimately result in a competitive risk for morbidity and mortality. In this review, we provide a concise overview about the impact of liver cirrhosis on the management and prognosis of patients with primary liver cancer or non-hepatic malignancies.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, USA
| | - Michael Trauner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III , Medical University of Vienna , Vienna , Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Department of Gastroenterology & Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Wolfgang Sieghart
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Austrian Society of Gastroenterology & Hepatology, Working Group GI-Oncology
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Wang ZG, Dou XB, Zhou ZX, Song ZY. Adipose tissue-liver axis in alcoholic liver disease. World J Gastrointest Pathophysiol 2016; 7:17-26. [PMID: 26909225 PMCID: PMC4753183 DOI: 10.4291/wjgp.v7.i1.17] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 09/07/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) remains an important health problem worldwide. The disease spectrum is featured by early steatosis, steatohepatitis (steatosis with inflammatory cells infiltration and necrosis), with some individuals ultimately progressing to fibrosis/cirrhosis. Although the disease progression is well characterized, no effective therapies are currently available for the treatment in humans. The mechanisms underlying the initiation and progression of ALD are multifactorial and complex. Emerging evidence supports that adipose tissue dysfunction contributes to the pathogenesis of ALD. In the first part of this review, we discuss the mechanisms whereby chronic alcohol exposure contributed to adipose tissue dysfunction, including cell death, inflammation and insulin resistance. It has been long known that aberrant hepatic methionine metabolism is a major metabolic abnormality induced by chronic alcohol exposure and plays an etiological role in the pathogenesis of ALD. The recent studies in our group documented the similar metabolic effect of chronic alcohol drinking on methionine in adipose tissue. In the second part of this review, we also briefly discuss the recent research progress in the field with a focus on how abnormal methionine metabolism in adipose tissue contributes to adipose tissue dysfunction and liver damage.
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Chiu WC, Huang YL, Chen YL, Peng HC, Liao WH, Chuang HL, Chen JR, Yang SC. Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats. Food Funct 2016; 6:1692-700. [PMID: 25910227 DOI: 10.1039/c5fo00104h] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Clinical and animal experiments indicated that gut-derived endotoxin and imbalanced intestinal microbiota contribute to the pathogenesis of alcoholic liver disease (ALD). In this study, we investigated whether synbiotic supplementation could improve ALD in rats by altering the intestinal microbial composition and improving the intestinal integrity. Male Wistar rats were divided into four groups according to plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and subjected to either a normal liquid diet (C), a normal liquid diet with synbiotic supplementation (C + S), an ethanol liquid diet (E), or an ethanol liquid diet with synbiotic supplementation (E + S) for 12 weeks. Results revealed that the ethanol-fed group showed increases in plasma AST and ALT activities, the endotoxin level, the hepatic triglyceride (TG) level, and hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels, and a decrease in the hepatic IL-10 level. Ethanol-feeding also contributed to increased intestinal permeability and decreased fecal bifidobacteria and lactobacilli amounts. However, synbiotic supplementation effectively attenuated the plasma endotoxin, hepatic TG and TNF-α levels, and increased the hepatic IL-10 level. Furthermore, synbiotic supplementation protected the rats against ethanol-induced hyperpermeability of the intestine, and significantly increased amounts of bifidobacteria and lactobacilli in the feces. This study demonstrated that synbiotics possess a novel hepatoprotective function by improving the intestinal permeability and microbiota in rats with ethanol-induced liver injury.
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Affiliation(s)
- Wan-Chun Chiu
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110, Taiwan.
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Ress C, Kaser S. Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol 2016; 22:1664-1673. [PMID: 26819531 PMCID: PMC4721997 DOI: 10.3748/wjg.v22.i4.1664] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/20/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents in the Western World. Etiologically, obesity and associated insulin resistance or excess alcohol intake are the most frequent causes of hepatic steatosis. However, steatosis also often occurs with chronic hepatitis C virus (HCV) infection and is also found in rare but potentially life-threatening liver diseases of pregnancy. Clinical significance and outcome of hepatic triglyceride accumulation are highly dependent on etiology and histological pattern of steatosis. This review summarizes current concepts of pathophysiology of common causes of hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, chronic HCV infections, drug-induced forms of hepatic steatosis, and acute fatty liver of pregnancy. Regarding the pathophysiology of NAFLD, this work focuses on the close correlation between insulin resistance and hepatic triglyceride accumulation, highlighting the potential harmful effects of systemic insulin resistance on hepatic metabolism of fatty acids on the one side and the role of lipid intermediates on insulin signalling on the other side. Current studies on lipid droplet morphogenesis have identified novel candidate proteins and enzymes in NAFLD.
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40
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Alcohol and the Intestine. Biomolecules 2015; 5:2573-88. [PMID: 26501334 PMCID: PMC4693248 DOI: 10.3390/biom5042573] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 09/24/2015] [Accepted: 10/05/2015] [Indexed: 02/07/2023] Open
Abstract
Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol-induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol-induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches.
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Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology. Biomolecules 2015; 5:2477-503. [PMID: 26437442 PMCID: PMC4693244 DOI: 10.3390/biom5042477] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/11/2015] [Accepted: 09/21/2015] [Indexed: 01/01/2023] Open
Abstract
Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis.
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Summa KC, Jiang P, Fitzpatrick K, Voigt RM, Bowers SJ, Forsyth CB, Vitaterna MH, Keshavarzian A, Turek FW. Chronic Alcohol Exposure and the Circadian Clock Mutation Exert Tissue-Specific Effects on Gene Expression in Mouse Hippocampus, Liver, and Proximal Colon. Alcohol Clin Exp Res 2015; 39:1917-29. [PMID: 26332085 DOI: 10.1111/acer.12834] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 06/30/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND Chronic alcohol exposure exerts numerous adverse effects, although the specific mechanisms underlying these negative effects on different tissues are not completely understood. Alcohol also affects core properties of the circadian clock system, and it has been shown that disruption of circadian rhythms confers vulnerability to alcohol-induced pathology of the gastrointestinal barrier and liver. Despite these findings, little is known of the molecular interactions between alcohol and the circadian clock system, especially regarding implications for tissue-specific susceptibility to alcohol pathologies. The aim of this study was to identify changes in expression of genes relevant to alcohol pathologies and circadian clock function in different tissues in response to chronic alcohol intake. METHODS Wild-type and circadian Clock(Δ19) mutant mice were subjected to a 10-week chronic alcohol protocol, after which hippocampal, liver, and proximal colon tissues were harvested for gene expression analysis using a custom-designed multiplex magnetic bead hybridization assay that provided quantitative assessment of 80 mRNA targets of interest, including 5 housekeeping genes and a predetermined set of 75 genes relevant for alcohol pathology and circadian clock function. RESULTS Significant alterations in expression levels attributable to genotype, alcohol, and/or a genotype by alcohol interaction were observed in all 3 tissues, with distinct patterns of expression changes observed in each. Of particular interest was the finding that a high proportion of genes involved in inflammation and metabolism on the array was significantly affected by alcohol and the Clock(Δ19) mutation in the hippocampus, suggesting a suite of molecular changes that may contribute to pathological change. CONCLUSIONS These results reveal the tissue-specific nature of gene expression responses to chronic alcohol exposure and the Clock(Δ19) mutation and identify specific expression profiles that may contribute to tissue-specific vulnerability to alcohol-induced injury in the brain, colon, and liver.
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Affiliation(s)
- Keith C Summa
- Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois
| | - Peng Jiang
- Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois
| | - Karrie Fitzpatrick
- Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois
| | - Robin M Voigt
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Samuel J Bowers
- Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois
| | - Christopher B Forsyth
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.,Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Martha H Vitaterna
- Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.,Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.,Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.,Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois.,Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, the Netherlands
| | - Fred W Turek
- Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois
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Costardi JVV, Nampo RAT, Silva GL, Ribeiro MAF, Stella HJ, Stella MB, Malheiros SVP. A review on alcohol: from the central action mechanism to chemical dependency. Rev Assoc Med Bras (1992) 2015; 61:381-7. [DOI: 10.1590/1806-9282.61.04.381] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 10/22/2014] [Indexed: 11/22/2022] Open
Abstract
SummaryIntroduction:alcohol is a psychotropic depressant of the central nervous system (CNS) that promotes simultaneous changes in several neuronal pathways, exerting a profound neurological impact that leads to various behavioral and biological alterations.Objectives:to describe the effects of alcohol on the CNS, identifying the signaling pathways that are modified and the biological effects resulting from its consumption.Methods:a literature review was conducted and articles published in different languages over the last 15 years were retrieved.Results:the studies reviewed describe the direct effect of alcohol on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids AEA and 2-AG, among others), the indirect effect of alcohol on the limbic and opioid systems, and the effect on calcium and potassium channels and on proteins regulated by GABA in the hippocampus.Discussion and conclusion:the multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction. Knowledge on the neuronal signaling pathways that are altered by alcohol allows the identification of effectors which could reduce its central action, thus, offering new therapeutic perspectives for the rehabilitation of alcohol addicts.
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Tang Y, Zhang L, Forsyth CB, Shaikh M, Song S, Keshavarzian A. The Role of miR-212 and iNOS in Alcohol-Induced Intestinal Barrier Dysfunction and Steatohepatitis. Alcohol Clin Exp Res 2015. [PMID: 26207424 DOI: 10.1111/acer.12813] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Alcoholic liver disease is commonly associated with intestinal barrier dysfunction. Alcohol-induced dysregulation of intestinal tight junction proteins, such as Zonula Occludens-1 (ZO-1), plays an important role in alcohol-induced gut leakiness. However, the mechanism of alcohol-induced disruption of tight junction proteins is not well established. The goal of this study was to elucidate this mechanism by studying the role of microRNA 212 (miR-212) and inducible nitric oxide synthase (iNOS) in alcohol-induced gut leakiness. METHODS The permeability of the Caco-2 monolayer was assessed by transepithelial electrical resistance and flux of fluorescein sulfonic acid. miR-212 was measured by real-time polymerase chain reaction. The wild-type, iNOS knockout, and miR-212 knockdown mice were fed with alcohol diet (29% of total calories, 4.5% v/v) for 8 weeks. The LNA-anti-miR-212 was used to inhibit miR-212 expression in mice. The alcohol-induced intestinal permeability, miR-212 expression, and liver injuries in mice were measured. RESULTS Our in vitro monolayer and in vivo mice studies showed that: (i) alcohol-induced overexpression of the intestinal miR-212 and intestinal hyperpermeability is prevented using miR-212 knockdown techniques; and (ii) iNOS is up-regulated in the intestine by alcohol and that iNOS signaling is required for alcohol-induced miR-212 overexpression, ZO-1 disruption, gut leakiness, and steatohepatitis. CONCLUSIONS These studies thus support a novel miR-212 mechanism for alcohol-induced gut leakiness and a potential target that could be exploited for therapeutic intervention to prevent leaky gut and liver injury in alcoholics.
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Affiliation(s)
- Yueming Tang
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois
| | - Lijuan Zhang
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois
| | - Christopher B Forsyth
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois
| | - Maliha Shaikh
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois
| | - Shiwen Song
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois
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Dusingize JC, Hoover DR, Shi Q, Mutimura E, Rudakemwa E, Ndacyayisenga V, Gakindi L, Mulvihill M, Sinayobye JD, Musabeyezu E, Anastos K. Association of Abnormal Liver Function Parameters with HIV Serostatus and CD4 Count in Antiretroviral-Naive Rwandan Women. AIDS Res Hum Retroviruses 2015; 31:723-30. [PMID: 25924728 PMCID: PMC4505765 DOI: 10.1089/aid.2014.0170] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We determined the associations of HIV infection/CD4 count with markers of hepatocellular damage [elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and liver synthetic function (decreased albumin) in HIV-infected (HIV(+)) antiretroviral therapy (ART)-naive and uninfected (HIV(-)) Rwandan women. In 2005, 710 HIV(+) ART-naive and 226 HIV(-) women enrolled in the Rwanda Women's Interassociation Study and Assessment. Liver enzymes were measured with abnormality defined as either AST or ALT ≥1.25 times the upper limit of normal. Low serum albumin level was defined as <3.5 g/dl. Multivariable logistic regression analysis identified independent predictors of elevated AST/ALT and low serum albumin. HIV(-) women had the lowest prevalence (6.6%) of abnormal AST/ALT, with the highest prevalence (16.4%) in HIV(+) women with CD4 <200 cells/μl (p=0.01). The odds of having serum albumin <3.5 g/dl was 5.7-fold higher in HIV(+) than HIV(-) women (OR=5.68, 95% CI: 3.32-9.71). The risk of low albumin decreased from low to high CD4 count, with OR=2.62, 95% CI: 1.66, 4.14 and OR=1.57, 95% CI: 1.01, 2.43 in HIV(+) women with a CD4 count <200 and 200-350 cells/μl, respectively vs. HIV(+) with CD4 >350 (p<0.001 and p<0.05 for all comparisons). Our findings suggest that HIV-associated liver damage may occur in ART-naive patients. Although liver abnormality prevalences in this cohort of HIV-infected Rwandan women are less than reported in developed countries, caution is needed for risk assessment measures to monitor and screen HIV-infected patients pre- and post-ART initiation in African clinical settings to curtail potential risks associated with HIV infection.
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Affiliation(s)
| | | | - Qiuhu Shi
- School of Health Sciences and Practice, New York Medical College, New York, New York
| | - Eugene Mutimura
- Regional Alliance for Sustainable Development (RASD Rwanda), Kigali, Rwanda
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Forsyth CB, Voigt RM, Burgess HJ, Swanson GR, Keshavarzian A. Circadian rhythms, alcohol and gut interactions. Alcohol 2015; 49:389-98. [PMID: 25499101 DOI: 10.1016/j.alcohol.2014.07.021] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 07/09/2014] [Accepted: 07/17/2014] [Indexed: 12/14/2022]
Abstract
The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20-30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyperpermeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in Clock(▵19) mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our data support circadian mechanisms for alcohol-induced gut leakiness that could provide new therapeutic targets for ALD.
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Affiliation(s)
- Christopher B Forsyth
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA; Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
| | - Robin M Voigt
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - Helen J Burgess
- Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL USA
| | - Garth R Swanson
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - Ali Keshavarzian
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA; Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Department of Molecular Biophysics & Physiology, Rush University Medical Center, Chicago, IL, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
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Couch RD, Dailey A, Zaidi F, Navarro K, Forsyth CB, Mutlu E, Engen PA, Keshavarzian A. Alcohol induced alterations to the human fecal VOC metabolome. PLoS One 2015; 10:e0119362. [PMID: 25751150 PMCID: PMC4353727 DOI: 10.1371/journal.pone.0119362] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 01/13/2015] [Indexed: 12/15/2022] Open
Abstract
Studies have shown that excessive alcohol consumption impacts the intestinal microbiota composition, causing disruption of homeostasis (dysbiosis). However, this observed change is not indicative of the dysbiotic intestinal microbiota function that could result in the production of injurious and toxic products. Thus, knowledge of the effects of alcohol on the intestinal microbiota function and their metabolites is warranted, in order to better understand the role of the intestinal microbiota in alcohol associated organ failure. Here, we report the results of a differential metabolomic analysis comparing volatile organic compounds (VOC) detected in the stool of alcoholics and non-alcoholic healthy controls. We performed the analysis with fecal samples collected after passage as well as with samples collected directly from the sigmoid lumen. Regardless of the approach to fecal collection, we found a stool VOC metabolomic signature in alcoholics that is different from healthy controls. The most notable metabolite alterations in the alcoholic samples include: (1) an elevation in the oxidative stress biomarker tetradecane; (2) a decrease in five fatty alcohols with anti-oxidant property; (3) a decrease in the short chain fatty acids propionate and isobutyrate, important in maintaining intestinal epithelial cell health and barrier integrity; (4) a decrease in alcohol consumption natural suppressant caryophyllene; (5) a decrease in natural product and hepatic steatosis attenuator camphene; and (6) decreased dimethyl disulfide and dimethyl trisulfide, microbial products of decomposition. Our results showed that intestinal microbiota function is altered in alcoholics which might promote alcohol associated pathologies.
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Affiliation(s)
- Robin D. Couch
- Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia, United States of America
- * E-mail:
| | - Allyson Dailey
- Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia, United States of America
| | - Fatima Zaidi
- Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia, United States of America
| | - Karl Navarro
- Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia, United States of America
| | - Christopher B. Forsyth
- Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Ece Mutlu
- Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Phillip A. Engen
- Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Ali Keshavarzian
- Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Pharmacology, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, United States of America
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
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Radiofrequency ablation is better than surgical resection in patients with hepatocellular carcinoma within the Milan criteria and preserved liver function: a retrospective study using propensity score analyses. J Clin Gastroenterol 2015; 49:242-9. [PMID: 24714185 DOI: 10.1097/mcg.0000000000000133] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
GOALS/BACKGROUND Radiofrequency ablation (RFA) and surgical resection (SR) are effective therapies for hepatocellular carcinoma (HCC) within the Milan criteria. We aimed to compare the treatment efficacy according to the liver functional reserve using propensity score analysis. STUDY There were 330 and 369 HCC patients within the Milan criteria undergoing SR and RFA, respectively. A total of 147 and 48 pairs of patients with Child-Turcotte-Pugh (CTP) scores=5 and >5, respectively, were matched for analyses. RESULTS Overall, the 3- and the 5-year survivals were 88% and 76% in the SR group and 80% and 66% in the RFA group, respectively (P=0.006). The SR group had significantly younger patients, a higher male-to-female ratio and hepatitis B infection rate, with a better liver functional reserve and performance status, and a larger tumor burden. In patients with a CTP score of 5, no survival difference was noted between the SR and the RFA groups (P=0.564). In patients with CTP score >5, the SR group had a better long-term survival than the RFA group (P=0.016). After propensity score analysis, the RFA group had a better long-term survival than the SR group in patients with CTP score=5 in the univariate (P=0.024) and the Cox proportional hazards models (hazard ratio: 0.47, P=0.031). Comparable survival results were noted between SR and RFA in patients with CTP score >5 (P=0.15). CONCLUSIONS RFA is a safe procedure with better treatment efficacy than SR in patients with small HCC and a CTP score of 5, and provides effects comparable to SR in patients with CTP score >5. The baseline liver functional reserve may enhance treatment selection for outcome prediction.
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Liu PH, Hsia CY, Lee YH, Hsu CY, Huang YH, Su CW, Lee RC, Lin HC, Huo TI. Surgical resection versus transarterial chemoembolization for BCLC stage C hepatocellular carcinoma. J Surg Oncol 2015; 111:404-9. [PMID: 25643842 DOI: 10.1002/jso.23854] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 11/08/2014] [Indexed: 01/03/2023]
Abstract
BACKGROUND Sorafenib is the only recommended treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). We aimed to compare surgical resection (SR) and transarterial chemoembolization (TACE) for advanced (BCLC stage C) HCC patients. METHODS A total of 264 and 389 advanced HCC patients received SR and TACE, respectively. Among them, 163 matched pairs of patients were identified from each treatment arm by propensity score matching analysis to compare long-term survival. RESULTS Of all patients, the SR group had better liver functional reserve than the TACE group. In the matched propensity model, the baseline characteristics were similar between patients receiving SR and TACE. SR provided significantly better long-term survival than TACE in all patients and in patients selected in the propensity model (both P < 0.001). In the Cox proportional hazards model, patients receiving TACE had a 2.393-fold increased risk of mortality compared with patients receiving SR (95% confidence interval: 1.610-3.556, P < 0.001). CONCLUSIONS SR provides significantly better long-term survival than TACE in patients with BCLC stage C HCC, and should be an integral part in the management of advanced HCC. Multidisciplinary approaches for these patients and further amendment to the BCLC classification scheme are required.
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Affiliation(s)
- Po-Hong Liu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Chen CF, Liu PH, Lee YH, Tsai YJ, Hsu CY, Huang YH, Chiou YY, Huo TI. Impact of renal insufficiency on patients with hepatocellular carcinoma undergoing radiofrequency ablation. J Gastroenterol Hepatol 2015; 30:192-8. [PMID: 25039567 DOI: 10.1111/jgh.12669] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIM Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). We aimed to investigate the impact of RI on the long-term survival of HCC patients undergoing radiofrequency ablation (RFA) and to determine the optimal staging strategy for these patients. METHODS RI was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) . A total of 123 and 344 patients with and without RI undergoing RFA, respectively, were enrolled. A one-to-one propensity score matching analysis with preset caliper width was performed. The prognostic ability of four currently used staging systems was compared by the Akaike information criterion (AIC). RESULTS HCC patients with RI undergoing RFA were older (P < 0.001) and had significantly different baseline characteristics. Of all patients, RI was significantly associated with a decreased long-term survival (P = 0.03). After matching in the propensity model, the baseline characteristics were similar between patients with (n = 92) and without (n = 92) RI. In the propensity model, RI was not significantly associated with a shortened survival (P = 0.273). In the Cox multivariate analysis, Child-Turcotte-Pugh class B or C was identified as the only independent predictor of poor prognosis. Among patients with RI undergoing RFA, the Taipei Integrated Scoring (TIS) system provided the highest homogeneity and lowest AIC value among the currently used staging systems. CONCLUSIONS The long-term survival of HCC patients undergoing RFA is not affected by RI. The TIS staging system may provide a better prognostic prediction for HCC patients with RI undergoing RFA.
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Affiliation(s)
- Chuan-Fu Chen
- Division of Gastroenterology, Wei Gong Memorial Hospital, Miaoli, Taiwan
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