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Hardesty JE, McClain CJ. Current Pharmacotherapy and Nutrition Therapy of Alcohol-Associated Liver Disease. Clin Liver Dis 2024; 28:731-745. [PMID: 39362718 PMCID: PMC11529778 DOI: 10.1016/j.cld.2024.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Patients with alcohol-associated liver disease (ALD) consume large amounts of empty calories and are at risk for malnutrition. Malnutrition can present with micro- or macro-nutrient deficiencies. The standard-of-care drug treatment for severe alcohol-associated hepatitis (AH) is corticosteroids. While still in the standard treatment there are limitations in efficacy and certain patients do not respond to treatment (Lille score ≥.45). This article will focus on important concepts related to nutrition and ALD and on recent findings on predicting corticosteroid response and prognosis for AH patients.
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Affiliation(s)
- Josiah E Hardesty
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; University of Louisville Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA.
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Harshal R. Severe Alcoholic Hepatitis-optimizing Medical Management: Whether we need a Liver Transplant. ANNALS OF CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2024; 8:006-016. [DOI: 10.29328/journal.acgh.1001045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Severe alcoholic hepatitis is an ethical and clinical conundrum, wherein a liver transplant is often recommended. The adequacy of medical treatment versus the risk of recidivism after transplant is often debated. Complete recovery in 26 of 27 patients with severe alcoholic hepatitis was observed, and hence the data was retrospectively analysed. Methods: 27 patients, with severe alcoholic hepatitis, with Maddrey's discriminant function between 59.7 to 165.2 (mean 107.53), from June 2017 to May 2022, were followed up for between 11 months to 6 years. INR ranged from 1.99 to 3.7 (mean 2.709), and bilirubin was between 7.6 to 37.01, (mean 20.859). 8 patients had pre-existing liver cirrhosis. All patients received probiotics, nutritional support, physical rehabilitation, saturated fat (clarified butter/ desi ghee) supplementation, and anti-oxidant support. At 90 days, total bilirubin improved to between 1.0 to 6.8 (mean 2.625). ALT (Alanine Transaminase/ SGPT) ranged from 65 to 550 (mean ALT – 197); and AST (Aspartate Transaminase / SGOT) ranged from 58 to 810 (mean AST – 271.51). Both the AST and ALT were near normal after 90 days. One patient died due to bacterial pneumonia and sepsis; the remaining 26 patients made a complete recovery. All patients including those with diagnosed liver cirrhosis, had complete resolution of their ascites, and near-normal liver function. At the last outpatient visit, none had ascites, edema, or encephalopathy, and had normal albumin levels and INR values. Conclusion: Probiotics, nutrition, a saturated fat diet, and exercise; all have shown benefits in patients with severe alcoholic hepatitis when tested individually. Concomitant use of all the above has not been reported in the treatment of alcoholic hepatitis. The role of nutrition alone versus the contribution of nutritional deficiencies and the role of gut-derived endotoxemia need to be studied in detail. How to identify patients who need a transplant, if it is needed at all, remains a challenge.
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Duan F, Liu C, Chang C, Song S, Zhai H, Cheng J, Yang S. Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2024; 50:191-206. [PMID: 38011683 DOI: 10.1080/00952990.2023.2266117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 11/29/2023]
Abstract
Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.
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Affiliation(s)
- Fangfang Duan
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chen Liu
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chunyan Chang
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shanshan Song
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hang Zhai
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jun Cheng
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Song Yang
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Division 2, Department of Hepatology, The Fourth People's Hospital of Qinghai Province, Xining, China
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Tu W, Gawrieh S, Dasarathy S, Mitchell MC, Simonetto DA, Patidar KR, McClain CJ, Bataller R, Szabo G, Tang Q, Barton BA, Radaeva S, Sanyal AJ, Shah V. Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis. Contemp Clin Trials Commun 2023; 32:101074. [PMID: 36698742 PMCID: PMC9869411 DOI: 10.1016/j.conctc.2023.101074] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/04/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Background Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.
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Affiliation(s)
- Wanzhu Tu
- Indiana University School of Medicine, USA
| | | | | | | | | | | | | | | | | | - Qing Tang
- Indiana University School of Medicine, USA
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Szabo G, Mitchell M, McClain CJ, Dasarathy S, Barton B, McCullough AJ, Nagy LE, Kroll-Desrosiers A, Tornai D, Min HA, Radaeva S, Holbein MEB, Casey L, Cuthbert J. IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis. Hepatology 2022; 76:1058-1068. [PMID: 35340032 PMCID: PMC10062003 DOI: 10.1002/hep.32478] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival. APPROACH AND RESULTS Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. CONCLUSIONS A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Mack Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Srinivasan Dasarathy
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Arthur J. McCullough
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Nagy
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Aimee Kroll-Desrosiers
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
- VA Central Western Massachusetts, Leeds, Massachusetts, USA
| | - David Tornai
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Hyesung Alice Min
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - M. E. Blair Holbein
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lisa Casey
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jennifer Cuthbert
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Nassar A, Azab AN. Effects of Dexamethasone and Pentoxifylline on Mania-like and Depression-like Behaviors in Rats. Pharmaceuticals (Basel) 2022; 15:ph15091063. [PMID: 36145284 PMCID: PMC9503945 DOI: 10.3390/ph15091063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/16/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Several studies support the notion that inflammation plays a role in the pathophysiology and treatment approaches of psychiatric illnesses, particularly mood disorders. Congruently, classic anti-inflammatory drugs were found efficacious in randomized clinical trials of patients with mood disorders. Moreover, accumulating data indicate that psychotropic drugs exhibit some anti-inflammatory effects. This study was undertaken to examine the efficacy of dexamethasone (a potent corticosteroid) and pentoxifylline (a methylxanthine drug with proven anti-tumor necrosis factor-α inhibitory activity) in behavioral models in rats, which were treated intraperitoneally with either dexamethasone or pentoxifylline for two weeks and then subjected to a battery of behavioral tests. Treatment with pentoxifylline, but not dexamethasone, was associated with antidepressant-like and anti-manic-like effects. The beneficial behavioral effects of pentoxifylline were accompanied by a prominent reduction in pro-inflammatory mediator levels in the brain. For the first time, the current work proves the efficacy of pentoxifylline against both mania-like and depressive-like behaviors. These results suggest that pentoxifylline may be a promising therapeutic intervention for patients with mood disorders. Taking into account the excellent tolerability profile of pentoxifylline in humans, it is warranted to conduct randomized clinical trials to investigate its therapeutic efficacy in patients with psychiatric disorders.
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Affiliation(s)
- Ahmad Nassar
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel
| | - Abed N. Azab
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel
- Department of Nursing, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel
- Correspondence:
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Gholami R, Khan R, Ramkissoon A, Alabdulqader A, Gimpaya N, Bansal R, Scaffidi MA, Prasad V, Detsky AS, Baker JP, Grover SC. Recommendation Reversals in Gastroenterology Clinical Practice Guidelines. J Can Assoc Gastroenterol 2022; 5:98-99. [PMID: 35368318 PMCID: PMC8972276 DOI: 10.1093/jcag/gwab040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/28/2021] [Indexed: 11/23/2022] Open
Abstract
Background Recommendations in clinical practice guidelines (CPGs) may be reversed when evidence emerges to show they are futile or unsafe. In this study, we identified and characterized recommendation reversals in gastroenterology CPGs. Methods We searched CPGs published by 20 gastroenterology societies from January 1990 to December 2019. We included guidelines which had at least two iterations of the same topic. We defined reversals as when (a) the more recent iteration of a CPG recommends against a specific practice that was previously recommend in an earlier iteration of a CPG from the same body, and (b) the recommendation in the previous iteration of the CPG is not replaced by a new diagnostic or therapeutic recommendation in the more recent iteration of the CPG. The primary outcome was the number of recommendation reversals. Secondary outcomes included the strength of recommendations and quality of evidence cited for reversals. Results Twenty societies published 1022 CPGs from 1990 to 2019. Our sample for analysis included 129 unique CPGs. There were 11 recommendation reversals from 10 guidelines. New evidence was presented for 10 recommendation reversals. Meta-analyses were cited for two reversals, and randomized controlled trials (RCTs) for seven reversals. Recommendations were stronger after the reversal for three cases, weaker in two cases, and of similar strength in three cases. We were unable to compare recommendation strengths for three reversals. Conclusion Recommendation reversals in gastroenterology CPGs are uncommon but highlight low value or harmful practices.
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Affiliation(s)
- Reza Gholami
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Rishad Khan
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Anushka Ramkissoon
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | | | - Nikko Gimpaya
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Rishi Bansal
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Michael A Scaffidi
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Vinay Prasad
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California,USA
| | - Allan S Detsky
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada
| | - Jeffrey P Baker
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Samir C Grover
- Division of Gastroenterology, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
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Pentoxifylline effects on hospitalized patients with COVID19: A randomized, double-blind clinical trial. Int Immunopharmacol 2021; 101:108227. [PMID: 34666302 PMCID: PMC8492603 DOI: 10.1016/j.intimp.2021.108227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/24/2021] [Accepted: 10/03/2021] [Indexed: 12/27/2022]
Abstract
Pentoxifylline (PTX) has broad-spectrum properties such as anti-inflammatory, anticoagulant, and antiviral effects. The aim of this study was to evaluate the efficacy and safety of PTX in hospitalized patients with COVID-19. This double-blind, placebo-controlled randomized clinical trial was conducted on hospitalized patients with COVID-19. The recruited patients were randomly (1:1) assigned to the PTX group and the placebo group. The intervention group received PTX capsules at a dose of 400 mg three times a day for 10 days along with the national regimen, including interferon plus lopinavir/ritonavir and hydroxychloroquine. The primary outcome was the improvement of clinical scores. The secondary outcomes, on the other hand, were improvement in inflammatory and oxidative stress factors and hospital complications. From a total of 102 patients who met the inclusion criteria, 72 individuals completed the study and were analyzed. No significant differences were shown in demographics and baseline clinical characteristics. Clinical scores was not significant between the two groups (P = 0.31 and 0.07 for day 5 and 11, respectively). Although the mean serum levels of interleukin-6 (IL-6) and glutathione changed significantly after 5 days in the PTX group (P = 0.03 and p = 0.04), ICU admission, intubation, and hospital stay did not differ between the two groups. The results of our study did not show any superiority of PTX over placebo in improving the clinical outcomes of patients with COVID-19. Although PTX had a beneficial effect on IL-6 and showed an acceptable safety profile, it did not offer any clinical benefit for COVID-19 complications.
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Van Melkebeke L, Korf H, Tsochatzis EA, van der Merwe S, Nevens F, Verbeek J. Treatment of severe alcoholic hepatitis: A systematic review. Curr Opin Pharmacol 2021; 60:91-101. [PMID: 34365226 DOI: 10.1016/j.coph.2021.06.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/16/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022]
Abstract
Severe alcoholic hepatitis is the most severe form of alcohol-related liver disease. Corticosteroids remain the first choice of treatment. However, they are only effective in a subset of patients and are associated with an increased infection risk. Furthermore, nonresponders to corticosteroids have a poor prognosis with a mortality of 70% over 6 months. As such, there is a high need for a more personalized use of corticosteroids and the development and identification of alternative therapeutic strategies. In this review, we summarize the recent and ongoing randomized controlled trials concerning the treatment of severe alcoholic hepatitis.
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Affiliation(s)
- Lukas Van Melkebeke
- Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Hannelie Korf
- Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom
| | - Schalk van der Merwe
- Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Frederik Nevens
- Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Jef Verbeek
- Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium.
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Gadour E, Mohamed T, Hassan Z, Hassan A. Meta-Analysis and Systematic Review of Primary Renal Tubular Acidosis in Patients With Autoimmune Hepatitis and Alcoholic Hepatitis. Cureus 2021; 13:e15287. [PMID: 34079685 PMCID: PMC8161551 DOI: 10.7759/cureus.15287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Renal and hepatic functions are often mingled through both the existence of associated primary organ diseases and hemodynamic co-relationship. The primary objective of this study was to sum up the relationship between autoimmune hepatitis (AIH) on renal tubular acidosis (RTA) and the stages of the disease. A systematic review was performed for 24 trials. A total of 3687 patients were included. The incidence of RTA occurring and short-term mortality reduction was seen in two groups; for an overall effect: Z = 2.85 (P = 0.004) a total 95% CI of 0.53 [0.34, 0.82]. Only one patient with alcoholic liver cirrhosis was found to have an incomplete type of RTA. Test for overall effect: Z = 2.28 (P = 0.02) 95% CI of 2.83 [1.16, 6.95]. A reduction in fatal infections with dual therapy of corticosteroid plus N-acetylcysteine (NAC) test for overall effect: Z = 3.07 (P = 0.002) with 95% CI of 0.45 [0.27, 0.75]. Autoimmune diseases are the most frequent underlying cause of secondary RTA in adults. The primary renal disease must be actively excluded in all patients with hepatic failure by aggressive clinical and laboratory evaluations.
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Affiliation(s)
- Eyad Gadour
- Gastroenterology and Hepatology, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, GBR
| | - Tamer Mohamed
- Acute Internal Medicine, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, GBR
| | - Zeinab Hassan
- Faculty of Medicine, The National Ribat University, Khartoum, SDN.,Medicine, Stockport Hospital NHS Foundation Trust, Manchester, GBR
| | - Abdalla Hassan
- Gastroenterology and Hepatology, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, GBR
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Uzzan S, Azab AN. Anti-TNF-α Compounds as a Treatment for Depression. Molecules 2021; 26:molecules26082368. [PMID: 33921721 PMCID: PMC8073844 DOI: 10.3390/molecules26082368] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/14/2021] [Accepted: 04/17/2021] [Indexed: 12/13/2022] Open
Abstract
Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating evidence suggests that inflammation may contribute to the pathophysiology of psychiatric disorders such as major depression and bipolar disorder. Copious studies have consistently shown that patients with mood disorders have increased levels of plasma tumor necrosis factor (TNF)-α. Given these findings, selective anti-TNF-α compounds were tested as a potential therapeutic strategy for mood disorders. This mini-review summarizes the results of studies that examined the mood-modulating effects of anti-TNF-α drugs.
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Affiliation(s)
- Sarit Uzzan
- Department of Clinical Biochemistry and Pharmacology, School for Community Health Professions—Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel;
| | - Abed N. Azab
- Department of Clinical Biochemistry and Pharmacology, School for Community Health Professions—Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel;
- Department of Nursing, School for Community Health Professions—Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel
- Correspondence: ; Tel.: +972-8-6479880; Fax: +972-8-6477683
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Ahearn OC, Watson MN, Rawls SM. Chemokines, cytokines and substance use disorders. Drug Alcohol Depend 2021; 220:108511. [PMID: 33465606 PMCID: PMC7889725 DOI: 10.1016/j.drugalcdep.2021.108511] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/30/2020] [Accepted: 12/14/2020] [Indexed: 12/18/2022]
Abstract
Efficacious pharmacotherapies for the treatment of substance use disorders need to be expanded and improved. Non-neuronal cells, particularly astrocytes and microglia, have emerged as therapeutic targets for the development of pharmacotherapies to treat dependence and relapse that accompanies chronic drug use. Cytokines and chemokines are neuroimmune factors expressed in neurons, astrocytes, and microglia that demonstrate promising clinical utility as therapeutic targets for substance use disorders. In this review, we describe a role for cytokines and chemokines in the rewarding and reinforcing effects of alcohol, opioids, and psychostimulants. We also discuss emerging cytokine- and chemokine-based therapeutic strategies that differ from conventional strategies directed toward transporters and receptors within the dopamine, glutamate, GABA, serotonin, and GABA systems.
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Affiliation(s)
- Olivia C. Ahearn
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA
| | - Mia N. Watson
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA
| | - Scott M. Rawls
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA,Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
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13
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Dasarathy S, Mitchell MC, Barton B, McClain CJ, Szabo G, Nagy LE, Radaeva S, McCullough AJ. Design and rationale of a multicenter defeat alcoholic steatohepatitis trial: (DASH) randomized clinical trial to treat alcohol-associated hepatitis. Contemp Clin Trials 2020; 96:106094. [PMID: 32739495 DOI: 10.1016/j.cct.2020.106094] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/26/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS Despite high mortality of alcohol-associated hepatitis, there has been limited advancement in treatment strategies. Defeat Alcoholic Steatohepatitis (DASH) is a multicenter, randomized, double-blind controlled trial whose primary objective was to evaluate the safety and efficacy of a novel combination of 3 drugs targeting different perturbations in AH. METHODS Severe AH was diagnosed by liver biopsy or clinical and biochemical criteria and model for end stage liver disease (MELD) score ≥ 20 stratified by MELD scores (20-25 and ≥ 26) and randomized to a combination of an interleukin receptor 1 antagonist, Anakinra(100 mg daily for 14 days) to suppress acute inflammation, pentoxifylline (400 mg three times a day for 28 days) to prevent hepatorenal syndrome, and zinc sulfate (220 mg orally once daily for 6 months) or the standard of care therapy including methylprednisolone 32 mg orally once daily for 28 days. The primary efficacy outcome was the unadjusted log-rank test of the Kaplan-Meier survival estimates for the two treatment groups at 180 days. RESULTS Between July 2012 to March 2018, 500 subjects with severe AH were screened of which 104 subjects were enrolled with MELD score of 25.6 ± 3.2 (20.0-35.0) in the investigational arm and 25.8 ± 4.5 (20.0-40.0) in the standard of care arm. Causes of screen failures included not meeting eligibility criteria (n = 347), declining to participate (n = 39), and other reasons (n = 10). CONCLUSIONS Data from the DASH consortium studies will determine if a combination of drugs targeting multiple mechanisms of injury in the severe AH will improve clinical outcomes.
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Affiliation(s)
| | | | | | | | - Gyongyi Szabo
- Harvard Medical School & Beth Israel Deaconess Medical Center, USA
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14
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Mitchell MC, Kerr T, Herlong HF. Current Management and Future Treatment of Alcoholic Hepatitis. Gastroenterol Hepatol (N Y) 2020; 16:178-189. [PMID: 34035720 PMCID: PMC8132686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Excessive alcohol consumption is responsible for approximately 50% of all deaths due to cirrhosis. Although the duration and amount of alcohol consumption are the primary factors responsible for the liver injury caused by consuming alcohol, the pathogenesis of the 3 stages of alcohol-associated liver disease (ALD)-fatty liver, alcoholic hepatitis (AH), and cirrhosis- is likely multifactorial. Preexisting obesity, dysbiosis of the gut microbiome, activation of proinflammatory cytokines, and genetic factors can all contribute to the risk of developing ALD. The cornerstone of therapy for all stages of ALD is abstinence from drinking alcoholic beverages. Severe AH, defined by a Maddrey discriminant function greater than 32, warrants additional therapy. The results of multiple studies evaluating the use of glucocorticoids in the treatment of severe AH led to guidelines from international societies that recommend glucocorticoid therapy in patients with severe AH without active infection. Liver transplantation provides an effective treatment option for patients who fail glucocorticoid therapy. Recent advances in understanding the pathogenesis of AH have led to the investigation of potential therapies directed at preventing the development of steatosis, inhibiting the innate immune response, modifying the gut microbiome, and stimulating liver regeneration.
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Affiliation(s)
- Mack C Mitchell
- Dr Mitchell is the Nancy S. and Jeremy L. Halbreich Professor of Gastroenterology and vice president of medical affairs at the University of Texas Southwestern Medical Center in Dallas, Texas. Dr Kerr is an associate professor and Dr Herlong is a professor in the Division of Digestive and Liver Diseases at the University of Texas Southwestern Medical Center
| | - Thomas Kerr
- Dr Mitchell is the Nancy S. and Jeremy L. Halbreich Professor of Gastroenterology and vice president of medical affairs at the University of Texas Southwestern Medical Center in Dallas, Texas. Dr Kerr is an associate professor and Dr Herlong is a professor in the Division of Digestive and Liver Diseases at the University of Texas Southwestern Medical Center
| | - H Franklin Herlong
- Dr Mitchell is the Nancy S. and Jeremy L. Halbreich Professor of Gastroenterology and vice president of medical affairs at the University of Texas Southwestern Medical Center in Dallas, Texas. Dr Kerr is an associate professor and Dr Herlong is a professor in the Division of Digestive and Liver Diseases at the University of Texas Southwestern Medical Center
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15
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Hyun J, Sun Z, Ahmadi AR, Bangru S, Chembazhi UV, Du K, Chen T, Tsukamoto H, Rusyn I, Kalsotra A, Diehl AM. Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis. J Clin Invest 2020; 130:2129-2145. [PMID: 31945016 PMCID: PMC7108908 DOI: 10.1172/jci132691] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 01/14/2020] [Indexed: 12/21/2022] Open
Abstract
Severe alcoholic hepatitis (SAH) is a deadly liver disease without an effective medical therapy. Although SAH mortality is known to correlate with hepatic accumulation of immature liver cells, why this occurs and how it causes death are unclear. Here, we demonstrate that expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA-splicing factor that maintains the nonproliferative, mature phenotype of adult hepatocytes, was suppressed in both human SAH and various mouse models of SAH in parallel with the severity of alcohol consumption and liver damage. Inflammatory cytokines released by excessive alcohol ingestion reprogrammed adult hepatocytes into proliferative, fetal-like cells by suppressing ESRP2. Sustained loss of ESRP2 permitted reemergence of a fetal RNA-splicing program that attenuates the Hippo signaling pathway and thus allows fetal transcriptional regulators to accumulate in adult liver. We further showed that depleting ESRP2 in mice exacerbated alcohol-induced steatohepatitis, enabling surviving hepatocytes to shed adult hepatocyte functions and become more regenerative, but threatening overall survival by populating the liver with functionally immature hepatocytes. Our findings revealed a mechanism that explains why liver failure develops in patients with the clinical syndrome of SAH, suggesting that recovery from SAH might be improved by limiting adult-to-fetal reprogramming in hepatocytes.
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Affiliation(s)
- Jeongeun Hyun
- Department of Medicine, Duke University Health System, Durham, North Carolina, USA
- Regeneration Next, Duke University School of Medicine, Durham, North Carolina, USA
- Institute of Tissue Regeneration Engineering (ITREN) and College of Science and Technology, Dankook University, Cheonan, South Korea
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ali Reza Ahmadi
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sushant Bangru
- Department of Biochemistry, School of Molecular and Cellular Biology, and
- Cancer Center at Illinois, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Ullas V. Chembazhi
- Department of Biochemistry, School of Molecular and Cellular Biology, and
| | - Kuo Du
- Department of Medicine, Duke University Health System, Durham, North Carolina, USA
| | - Tianyi Chen
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, USA
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Auinash Kalsotra
- Department of Biochemistry, School of Molecular and Cellular Biology, and
- Cancer Center at Illinois, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Anna Mae Diehl
- Department of Medicine, Duke University Health System, Durham, North Carolina, USA
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16
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Singh L, Joshi T, Tewari D, Echeverría J, Mocan A, Sah AN, Parvanov E, Tzvetkov NT, Ma ZF, Lee YY, Poznański P, Huminiecki L, Sacharczuk M, Jóźwik A, Horbańczuk JO, Feder-Kubis J, Atanasov AG. Ethnopharmacological Applications Targeting Alcohol Abuse: Overview and Outlook. Front Pharmacol 2020; 10:1593. [PMID: 32116660 PMCID: PMC7034411 DOI: 10.3389/fphar.2019.01593] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 12/09/2019] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is the cause of several diseases and thus is of a major concern for society. Worldwide alcohol consumption has increased by many folds over the past decades. This urgently calls for intervention and relapse counteract measures. Modern pharmacological solutions induce complete alcohol self-restraint and prevent relapse, but they have many side effects. Natural products are most promising as they cause fewer adverse effects. Here we discuss in detail the medicinal plants used in various traditional/folklore medicine systems for targeting alcohol abuse. We also comprehensively describe preclinical and clinical studies done on some of these plants along with the possible mechanisms of action.
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Affiliation(s)
- Laxman Singh
- Centre for Biodiversity Conservation & Management, G.B. Pant National Institute of Himalayan Environment & Sustainable Development, Almora, India
| | - Tanuj Joshi
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University Bhimtal Campus, Nainital, India
| | - Devesh Tewari
- Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Javier Echeverría
- Department of Environmental Sciences, Faculty of Chemistry and Biology, Universidad de Santiago de Chile, Santiago, Chile
| | - Andrei Mocan
- Department of Pharmaceutical Botany, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Archana N. Sah
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University Bhimtal Campus, Nainital, India
| | - Emil Parvanov
- Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Division BIOCEV, Prague, Czechia
| | - Nikolay T. Tzvetkov
- Institute of Molecular Biology “Roumen Tsanev”, Department of Biochemical Pharmacology and Drug Design, Bulgarian Academy of Sciences, Sofia, Bulgaria
- Department Global R&D, NTZ Lab Ltd., Sofia, Bulgaria
| | - Zheng Feei Ma
- Department of Public Health, Xi’an Jiaotong-Liverpool University, Suzhou, China
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Piotr Poznański
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Lukasz Huminiecki
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Mariusz Sacharczuk
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Artur Jóźwik
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Jarosław O. Horbańczuk
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Joanna Feder-Kubis
- Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego, Wrocław, Poland
| | - Atanas G. Atanasov
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
- Department of Pharmacognosy, University of Vienna, Vienna, Austria
- Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
- Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Vienna, Austria
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17
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Rodriguez WE, Wahlang B, Wang Y, Zhang J, Vadhanam MV, Joshi-Barve S, Bauer P, Cannon R, Ahmadi AR, Sun Z, Cameron A, Barve S, Maldonado C, McClain C, Gobejishvili L. Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench. Hepatology 2019; 70:1958-1971. [PMID: 31081957 PMCID: PMC6851418 DOI: 10.1002/hep.30761] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 04/30/2019] [Indexed: 12/11/2022]
Abstract
Alcoholic liver disease (ALD) is a major cause of liver-related mortality. There is still no US Food and Drug Administration-approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up-regulation of cAMP-degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol-induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up-regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti-inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin-inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol-mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol-induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.
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Affiliation(s)
- Walter E. Rodriguez
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA
| | - Banrida Wahlang
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA
| | - Yali Wang
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA
| | - Jingwen Zhang
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA
| | - Manicka V. Vadhanam
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA
| | - Swati Joshi-Barve
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA,,Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Kentucky, USA
| | - Philip Bauer
- Department of Physiology, School of Medicine, University of Louisville, Kentucky, USA,,EndoProtech, Inc., Louisville, Kentucky, USA
| | - Robert Cannon
- Department of Surgery, School of Medicine, University of Louisville, Kentucky, USA
| | - Ali Reza Ahmadi
- Department of Surgery and Transplant Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Zhaoli Sun
- Department of Surgery and Transplant Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andrew Cameron
- Department of Surgery and Transplant Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shirish Barve
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA,,Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Kentucky, USA
| | - Claudio Maldonado
- Department of Physiology, School of Medicine, University of Louisville, Kentucky, USA,,EndoProtech, Inc., Louisville, Kentucky, USA
| | - Craig McClain
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA,,Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Kentucky, USA,,Robley Rex VA Medical Center, Louisville, Kentucky, USA
| | - Leila Gobejishvili
- University of Louisville Alcohol Research Center, University of Louisville, Kentucky, USA,,Hepatobiology and Toxicology Center, University of Louisville, Kentucky, USA,,Department of Medicine, School of Medicine, University of Louisville, Kentucky, USA,,Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Kentucky, USA
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18
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Philips CA, Augustine P, Yerol PK, Rajesh S, Mahadevan P. Severe alcoholic hepatitis: current perspectives. Hepat Med 2019; 11:97-108. [PMID: 31496843 PMCID: PMC6691395 DOI: 10.2147/hmer.s197933] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 07/18/2019] [Indexed: 12/12/2022] Open
Abstract
Severe acute alcoholic hepatitis (AH) is a catastrophic disease in the natural history of alcoholic liver disease with a very high 180-day mortality. It can present as acute on chronic liver failure with worse prognosis in the presence of infections and higher grades of liver disease severity. The clinical scenario involves a patient with a recent history of heavy alcohol consumption within three months of presentation with jaundice and characteristic liver enzyme elevation pattern with coagulopathy, hepatic encephalopathy, variceal bleeding and sepsis that results in extrahepatic organ failures. Several liver disease severities and therapy response indicators are in clinical use. Even though not approved, the only recommended treatment option for patients with severe AH is corticosteroids, which is without long term survival benefit. Novel efficacious treatment options awaiting high-quality multi-center studies include liver transplantation (involves strict selection criteria), growth factor therapy and fecal microbiota transplantation. In this exhaustive review, we discuss the definitions, disease severity, histopathology, and treatment options – past, present, and future, in patients with severe alcoholic hepatitis.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Philip Augustine
- Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Praveen Kumar Yerol
- Department of Gastroenterology, Government Medical College and Hospital, Thrissur, Kerala, India
| | - Sasidharan Rajesh
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Cochin, Kerala, India
| | - Pushpa Mahadevan
- Clinical Pathology, VPS Lakeshore Hospital, Nettoor, Kerala, India
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19
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Tu Y, Zhu S, Wang J, Burstein E, Jia D. Natural compounds in the chemoprevention of alcoholic liver disease. Phytother Res 2019; 33:2192-2212. [PMID: 31264302 DOI: 10.1002/ptr.6410] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/29/2019] [Accepted: 05/21/2019] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD), caused by excessive consumption of alcohol, is a major cause of chronic liver disease worldwide. Much effort has been expended to explore the pathogenesis of ALD. Hepatic cell injury, oxidative stress, inflammation, regeneration, and bacterial translocation are all involved in the pathogenesis of ALD. Immediate abstinence is the most important therapeutic treatment for affected individuals. However, the medical treatment for ALD had not advanced in a long period. Intriguingly, an increasing body of research indicates the potential of natural compounds in the targeted therapy of ALD. A plethora of dietary natural products such as flavonoids, resveratrol, saponins, and β-carotene are found to exert protective effects on ALD. This occurs through various mechanisms composed of antioxidative, anti-inflammatory, iron chelation, pro-apoptosis, and/or antiproliferation of hepatic stellate cells and hepatocellular carcinoma cells. In this review, we will summarize current knowledge about the pathogenesis and treatments of ALD and focus on the potential of natural compounds in ALD therapies and underlying mechanisms.
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Affiliation(s)
- Yingfeng Tu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Shu Zhu
- Chinese Academy of Science and Technology for Development, Ministry of Science and Technology, Institute of Foresight and Evaluation Research, Beijing, China
| | - Jing Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ezra Burstein
- Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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20
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Louvet A, Thursz MR, Kim DJ, Labreuche J, Atkinson SR, Sidhu SS, O'Grady JG, Akriviadis E, Sinakos E, Carithers RL, Ramond MJ, Maddrey WC, Morgan TR, Duhamel A, Mathurin P. Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo-a Meta-analysis of Individual Data From Controlled Trials. Gastroenterology 2018; 155:458-468.e8. [PMID: 29738698 DOI: 10.1053/j.gastro.2018.05.011] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 04/25/2018] [Accepted: 05/01/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. METHODS We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. RESULTS Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48-0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43-0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P = .04) but not in multiple-imputation analysis (HR 0.71; P = .08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10-1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. CONCLUSIONS In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.
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Affiliation(s)
- Alexandre Louvet
- Service des maladies de l'appareil digestif, CHU Lille, Université de Lille and INSERM U995, Lille, France
| | - Mark R Thursz
- Department of Hepatology, Imperial College, Norfolk Place, London, United Kingdom
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | | | - Stephen R Atkinson
- Department of Hepatology, Imperial College, Norfolk Place, London, United Kingdom
| | - Sandeep Singh Sidhu
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - John G O'Grady
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, United Kingdom
| | - Evangelos Akriviadis
- 4th Department of Internal Medicine, Aristotle University of Thessaloniki, Greece
| | - Emmanouil Sinakos
- 4th Department of Internal Medicine, Aristotle University of Thessaloniki, Greece
| | | | | | - Willis C Maddrey
- Department of Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas
| | - Timothy R Morgan
- Gastroenterology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Alain Duhamel
- Université de Lille, CHU de Lille, EA 2694, Lille, France
| | - Philippe Mathurin
- Service des maladies de l'appareil digestif, CHU Lille, Université de Lille and INSERM U995, Lille, France.
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21
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Teschke R. Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options. Expert Opin Pharmacother 2018; 19:779-793. [PMID: 29708448 DOI: 10.1080/14656566.2018.1465929] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. AREAS COVERED This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. EXPERT OPINION Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.
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Affiliation(s)
- Rolf Teschke
- a Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty , Goethe University Frankfurt/Main , Frankfurt/Main , Germany
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Predictors of 90-day mortality in patients with severe alcoholic hepatitis: Experience with 183 patients at a tertiary care center from India. Indian J Gastroenterol 2018; 37:141-152. [PMID: 29704174 DOI: 10.1007/s12664-018-0842-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 03/04/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Severe alcoholic hepatitis (AH) is not an uncommon indication for hospital admission in India. However, there is limited data from India on predictors of mortality in patients of severe AH. We analyzed the data on patients with severe AH admitted to our institute and compared various parameters and severity scores in predicting 90-day mortality. METHODS In this prospective study, we analyzed patients with severe AH (defined as discriminant function ≥ 32) admitted from January 2015 to February 2017 to our institute. All patients were administered standard treatment according to various guidelines, and their 90-day mortality was determined. Various hematologic, biochemical factors, and severity scores were compared between survivors and patients who died. RESULTS A total of 183 patients (98% males, median age 41 years [range 20-70 years]) were included in our study. The median model for end-stage liver disease (MELD) was 26 (15-40). Ascites were present in 83% and hepatic encephalopathy in 38%. Only 21 (12%) could be offered steroid therapy, due to contraindications in the remaining. By 90 days, only 103 (56%) patients survived while 80 (44%) died. All patients died due to progressive liver failure and its complications. On multivariate analysis, presence of ascites, hepatic encephalopathy, high bilirubin, low albumin, high creatinine, high INR, and low potassium independently predicted 90-day mortality. All the scores performed significantly in predicting 90-day mortality with no statistically significant difference between them. MELD score had a maximum area under the curve 0.76 for 90-day mortality. A combination of Child class and presence of acute kidney injury (creatinine ≥ 1.35) was good in predicting 90-day mortality. CONCLUSION Our patients had severe AH characterized by a median MELD score of 26 and had a 90-day mortality of 44%. Most patients were not eligible to receive corticosteroids. Presence of Child C status and high serum creatinine value (≥ 1.35 mg/dL) accurately predicted mortality. Newer treatment options need to be explored for these patients.
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Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG Clinical Guideline: Alcoholic Liver Disease. Am J Gastroenterol 2018; 113:175-194. [PMID: 29336434 PMCID: PMC6524956 DOI: 10.1038/ajg.2017.469] [Citation(s) in RCA: 543] [Impact Index Per Article: 77.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 11/08/2017] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.
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Affiliation(s)
- Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham School of Medicine , Birmingham , Alabama , USA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Liver Research Center , Pittsburgh , Pennsylvania , USA
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health and Science University , Portland , Oregon , USA
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , Minnesota ,USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , Minnesota ,USA
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Pentoxifylline and Methylprednisolone Additively Alleviate Kidney Failure and Prolong Survival of Rats after Renal Warm Ischemia-Reperfusion. Int J Mol Sci 2018; 19:ijms19010221. [PMID: 29324683 PMCID: PMC5796170 DOI: 10.3390/ijms19010221] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/27/2017] [Accepted: 01/07/2018] [Indexed: 12/20/2022] Open
Abstract
Renal ischemia-reperfusion injury (IRI) induces local inflammation leading to kidney damage. Since pentoxifylline (PTX) and steroids have distinct immunomodulatory properties, we aimed to evaluate for the first time their combined use in IRI-induced acute kidney injury (AKI) and chronic kidney disease (CKD) in rats. In two experiments, PTX (100 mg/kg body weight subcutaneously) was administered 90 min prior to renal IRI or/and methylprednisolone (MP; 100 mg/kg body weight intramuscularly) was infused 60 min after reperfusion of a solitary kidney (AKI model: 45 min ischemia, 48 male Sprague-Dawley rats) or one kidney with excision of contralateral kidney 2 weeks later (CKD model: 90 min ischemia, 38 rats). Saline was infused in place of PTX or/and MP depending on the group. Renal function (diuresis, serum creatinine, creatinine clearance, sodium and potassium excretion, and urine protein/creatinine) was assessed at 48 h and 120 h post-IRI (AKI model) or 4, 16 and 24 weeks after IRI, along with survival analysis (CKD model). More evidently at early stages of AKI or CKD, treated animals showed higher glomerular filtration and diminished tubular loss of electrolytes, more so with PTX + MP than PTX or MP (serum creatinine (μmol/L) at 48 h of AKI: 60.9 ± 19.1 vs. 131.1 ± 94.4 vs. 233.4 ± 137.0, respectively, vs. 451.5 ± 114.4 in controls, all p < 0.05; and at 4 weeks of CKD: 89.0 ± 31.9 vs. 118.1 ± 64.5 vs. 156.9 ± 72.6, respectively, vs. 222.9 ± 91.4 in controls, p < 0.05 for PTX or PTX + MP vs. controls and PTX + MP vs. MP). Survival was better by >2-fold with PTX + MP (89%) vs. controls (40%; p < 0.05). PTX + MP largely protect from IRI-induced AKI and CKD and subsequent mortality in rats. This calls for clinical investigations, especially in kidney transplantation.
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25
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Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol 2017; 23:6549-6570. [PMID: 29085205 PMCID: PMC5643281 DOI: 10.3748/wjg.v23.i36.6549] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/25/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.
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Affiliation(s)
- Sukhpreet Singh
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, Nebraska Medical Center, Omaha, NE 68198, United States
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26
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Avila DV, Barker DF, Zhang J, McClain CJ, Barve S, Gobejishvili L. Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis. J Pathol 2017; 240:96-107. [PMID: 27287961 DOI: 10.1002/path.4760] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 05/06/2016] [Accepted: 05/31/2016] [Indexed: 12/15/2022]
Abstract
Alcohol-induced hepatic steatosis is a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signalling has been shown to significantly regulate lipid metabolism; however, the role of altered cAMP homeostasis in alcohol-mediated hepatic steatosis has never been studied. Our previous work demonstrated that increased expression of hepatic phosphodiesterase 4 (Pde4), which specifically hydrolyses and decreases cAMP levels, plays a pathogenic role in the development of liver inflammation/injury. The aim of this study was to examine the role of PDE4 in alcohol-induced hepatic steatosis. C57BL/6 wild-type and Pde4b knockout (Pde4b(-/-) ) mice were pair-fed control or ethanol liquid diets. One group of wild-type mice received rolipram, a PDE4-specific inhibitor, during alcohol feeding. We demonstrate for the first time that an early increase in PDE4 enzyme expression and a resultant decrease in hepatic cAMP levels are associated with the significant reduction in carnitine palmitoyltransferase 1A (Cpt1a) expression. Notably, alcohol-fed (AF) Pde4b(-/-) mice and AF wild-type mice treated with rolipram had significantly lower hepatic free fatty acid content compared with AF wild-type mice. Importantly, PDE4 inhibition in alcohol-fed mice prevented the decrease in hepatic Cpt1a expression via the Pparα/Sirt1/Pgc1α pathway. These results demonstrate that the alcohol- induced increase in hepatic Pde4, specifically Pde4b expression, and compromised cAMP signalling predispose the liver to impaired fatty acid oxidation and the development of steatosis. Moreover, these data also suggest that hepatic PDE4 may be a clinically relevant therapeutic target for the treatment of alcohol-induced hepatic steatosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Diana V Avila
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA
| | - David F Barker
- Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA
| | - JingWen Zhang
- Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA
| | - Craig J McClain
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.,Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA.,Robley Rex VA Medical Center, Louisville, Kentucky, USA
| | - Shirish Barve
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.,Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA
| | - Leila Gobejishvili
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.,Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA
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Abstract
PURPOSE OF REVIEW Alcohol consumption is increasing globally, as are complications of alcohol-related liver disease, including the most severe manifestation, alcoholic hepatitis. Despite the increased prevalence, many patients hospitalized with alcoholic hepatitis are either not diagnosed or inadequately treated leading to significant morbidity and high mortality rates. The purpose of this review is to discuss current challenges in the diagnosis and management of this frequently fatal condition. RECENT FINDINGS Recent studies and meta-analyses have improved our understanding of both the evaluation and treatment of alcoholic hepatitis including the diagnostic criteria, appropriate use of glucocorticoids and other therapeutic modalities including novel disease-specific therapeutic agents and indications for considering liver transplantation. SUMMARY Glucocorticoid therapy and enteral nutrition represent the best options for reducing short-term mortality in patients with the severe form of acute alcoholic hepatitis. The efficacy of other medications such as pentoxifylline as currently used does not support a role for use outside clinical trials. While the current management options for alcoholic hepatitis remain insufficient, improvements in diagnosis, determining prognosis and severity and the potential role of novel treatments provides encouragement that outcomes from this devastating condition will improve.
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28
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Fung P, Pyrsopoulos N. Emerging concepts in alcoholic hepatitis. World J Hepatol 2017; 9:567-585. [PMID: 28515843 PMCID: PMC5411952 DOI: 10.4254/wjh.v9.i12.567] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/21/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
Severe alcoholic hepatitis is implicated as a costly, worldwide public health issue with high morbidity and mortality. The one-month survival for severe alcoholic hepatitis is low with mortality rates high as 30%-50%. Abstinence from alcohol is the recommended first-line treatment. Although corticosteroids remain as the current evidence based option for selected patients with discriminant function > 32, improvement of short-term survival rate may be the only benefit. Identification of individuals with risk factors for the development of severe alcoholic hepatitis may provide insight to the diverse clinical spectrum and prognosis of the disease. The understanding of the complex pathophysiologic processes of alcoholic hepatitis is the key to elucidating new therapeutic treatments. Newer research describes the use of gut microbiota modification, immune modulation, stimulation of liver regeneration, caspase inhibitors, farnesoid X receptors, and the extracorporeal liver assist device to aid in hepatocellular recovery. Liver transplantation can be considered as the last medical option for patients failing conventional medical interventions. Although the preliminary data is promising in patients with low risk of recividism, controversy remains due to organ scarcity. This review article comprehensively summarizes the epidemiology, pathophysiology, risk factors, and prognostic indicators of severe alcoholic hepatitis with a focus on the current and emerging therapeutics.
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Affiliation(s)
- Phoenix Fung
- Phoenix Fung, Nikolaos Pyrsopoulos, Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Phoenix Fung, Nikolaos Pyrsopoulos, Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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29
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Treatment of Severe Alcoholic Hepatitis With Corticosteroid, Pentoxifylline, or Dual Therapy: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2017; 51:364-377. [PMID: 27636406 DOI: 10.1097/mcg.0000000000000674] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Although both corticosteroids and pentoxifylline are currently recommended drugs for the treatment of patients with severe alcoholic hepatitis, their effectiveness in reducing mortality remains unclear. In this systematic review, we aimed to evaluate the therapeutic and adverse effects of corticosteroids, pentoxifylline, and combination by using Cochrane methodology and therefore determine optimal treatment for severe alcoholic hepatitis. METHODS We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from their inauguration until October 2015. Combinations of the following keywords and controlled vocabularies were searched: alcoholic hepatitis, corticosteroid, and pentoxifylline. RESULTS A total of 2639 patients from 25 studies were included. The treatment groups did not differ significantly in terms of overall mortality. Analysis of 1-month mortality revealed corticosteroid monotherapy reduced mortality compared with placebo (OR=0.58; 95% CI, 0.34-0.98; P=0.04), but pentoxifylline monotherapy did not. The mortality with dual therapy was similar to corticosteroid monotherapy (OR=0.91; 95% CI, 0.62-1.34; P=0.63). However, dual therapy decreased the incidences of hepatorenal syndrome or acute kidney injury (OR=0.47; 95% CI, 0.26-0.86; P=0.01) and the infection risk (OR=0.63; 95% CI, 0.41-0.97; P=0.04) significantly more than corticosteroid monotherapy did. None of the treatments conferred any medium-term or long-term survival benefits in the present study. CONCLUSIONS Dual therapy was not inferior to corticosteroid monotherapy and could reduce the incidence of hepatorenal syndrome or acute kidney injury and risk of infection. Therefore, dual therapy might be considered in treatment of patients with severe alcoholic hepatitis.
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30
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Buzzetti E, Kalafateli M, Thorburn D, Davidson BR, Thiele M, Gluud LL, Del Giovane C, Askgaard G, Krag A, Tsochatzis E, Gurusamy KS. Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease): an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011646. [PMID: 28368093 PMCID: PMC6464309 DOI: 10.1002/14651858.cd011646.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol-related liver disease remains controversial. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol-related liver disease through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta-analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol-related liver diseases. SELECTION CRITERIA Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol-related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co-existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes. Alcoholic hepatitisFifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow-up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta-analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health-related quality of life or incidence of hepatocellular carcinoma. Severe alcoholic hepatitisOf the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow-up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis. SOURCE OF FUNDING Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials. Other alcohol-related liver diseasesThirty-one randomised clinical trials included 3695 participants with other alcohol-related liver diseases (with a wide spectrum of alcohol-related liver diseases). The period of follow-up ranged from one to 48 months. The mortality at maximal follow-up was lower in the propylthiouracil group versus the no intervention group (OR 0.45, 95% CI 0.26 to 0.78; 423 participants; 2 trials; low-quality evidence). However, this result is based on two small trials at high risk of bias and further confirmation in larger trials of low risk of bias is necessary to recommend propylthiouracil routinely in people with other alcohol-related liver diseases. The mortality at maximal follow-up was higher in the ursodeoxycholic acid group versus the no intervention group (OR 2.09, 95% CI 1.12 to 3.90; 226 participants; 1 trial; low-quality evidence). SOURCE OF FUNDING Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials. AUTHORS' CONCLUSIONS Because of very low-quality evidence, there is uncertainty in the effectiveness of any pharmacological intervention versus no intervention in people with alcoholic hepatitis or severe alcoholic hepatitis. Based on low-quality evidence, propylthiouracil may decrease mortality in people with other alcohol-related liver diseases. However, these results must be confirmed by adequately powered trials with low risk of bias before propylthiouracil can be considered effective.Future randomised clinical trials should be conducted with approximately 200 participants in each group and follow-up of one to two years in order to compare the benefits and harms of different treatments in people with alcoholic hepatitis. Randomised clinical trials should include health-related quality of life and report serious adverse events separately from adverse events. Future randomised clinical trials should have a low risk of bias and low risk of random errors.
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Affiliation(s)
- Elena Buzzetti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Maria Kalafateli
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Maja Thiele
- Odense University HospitalDepartment of Gastroenterology and HepatologySdr. Boulevard 29, Entrance 126OdenseDenmark5000
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards AlleHvidovreDenmark2650
| | - Cinzia Del Giovane
- University of Modena and Reggio EmiliaCochrane Italy, Department of Diagnostic, Clinical and Public Health MedicineVia del Pozzo 71ModenaItaly41124
| | - Gro Askgaard
- RigshospitaletDepartment of HepatologyBlegdamsvej 9København ØDenmark2100
| | - Aleksander Krag
- Odense University HospitalDepartment of Gastroenterology and HepatologySdr. Boulevard 29, indgang 126Odense CDenmark5000
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
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Mitchell MC, McClain CJ, McClain CJ. Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol 2017; 15:5-12. [PMID: 27979049 PMCID: PMC5172399 DOI: 10.1016/j.cgh.2016.08.047] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/28/2016] [Accepted: 08/30/2016] [Indexed: 02/07/2023]
Abstract
The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management. Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH). Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever. Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections. Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI). Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate. Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment. Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate. Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF. Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest. Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting. Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high. Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid.
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Affiliation(s)
| | | | - Craig J McClain
- Division of Gastroenterology, University of Louisville, Louisville, Kentucky
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32
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Owens RE, Snyder HS, Twilla JD, Satapathy SK. Pharmacologic Treatment of Alcoholic Hepatitis: Examining Outcomes Based on Disease Severity Stratification. J Clin Exp Hepatol 2016; 6:275-281. [PMID: 28003716 PMCID: PMC5157883 DOI: 10.1016/j.jceh.2016.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 07/12/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Maddrey discriminant function (MDF) score is a measure of disease prognosis in alcoholic hepatitis (AH) used to identify patients at highest risk of mortality and determine the need for initiation of pharmacologic treatment. The purpose of this study was to evaluate the effects of pharmacologic therapy for hospitalized AH patients as stratified by MDF score. METHODS A retrospective review of patients with an AH diagnosis admitted to a Methodist LeBonheur Healthcare adult hospital between 06/2009 and 06/2014 was conducted. Patients ≥18 years of age with an ICD-9 code for AH were evaluated. RESULTS Of the 493 patients screened, 234 met the inclusion criteria, comprised of 62 patients with an MDF ≥ 32 (treatment, n = 42 vs. no treatment, n = 20) and 172 patients with an MDF < 32 (treatment, n = 15 vs. no treatment, n = 157). For the patients with an MDF ≥ 32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (31% vs. 11%, respectively; P = 0.18) and 6-month mortality (45% treatment vs. 38% non-treatment; P = 0.75). For the patients with an MDF <32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (0% vs. 7%, respectively; P > 0.99) and 6-month mortality (11% treatment vs. 13% non-treatment; P > 0.99). There was no difference in incidence of acute kidney injury, hepatorenal syndrome, development of infection or hepatic encephalopathy between the treatment vs. non-treatment groups. CONCLUSIONS Pharmacologic treatment showed no survival benefit, regardless of disease severity. Given the mortality risk seen in mild-moderate AH patients not receiving treatment and concern for a possible treatment ceiling effect in severe AH patients, more data are needed to adequately assess the utility of MDF in selecting appropriate candidates for AH treatment.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- AH, alcoholic hepatitis
- AKI, acute kidney injury
- ALD, alcoholic liver disease
- ARR, absolute risk reduction
- GI, gastrointestinal
- HRS, hepatorenal syndrome
- INR, international normalized ratio
- MDF, Maddrey discriminant function
- MELD, Model for End-Stage Liver Disease
- Maddrey discriminant function
- PT, prothrombin time
- SCr, serum creatinine
- SD, standard deviation
- eGFR, estimated glomerular filtration rate
- pentoxifylline
- prednisolone
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Affiliation(s)
- Ryan E. Owens
- University of Oklahoma College of Pharmacy, Department of Pharmacy, Clinical and Administrative Sciences, 1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA,Address for correspondence: Ryan E. Owens, Department of Pharmacy, Clinical and Administrative Sciences, 1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA.Department of Pharmacy, Clinical and Administrative Sciences1110 North Stonewall AvenueOklahoma CityOK73117USA
| | - Heather S. Snyder
- Methodist University Hospital, Department of Pharmacy, 1265 Union Avenue, Memphis, TN 38104, USA
| | - Jennifer D. Twilla
- Methodist University Hospital, Department of Pharmacy, 1265 Union Avenue, Memphis, TN 38104, USA
| | - Sanjaya K. Satapathy
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Division of Surgery, Transplant Hepatology, 1265 Union Avenue, Memphis, TN 38104, USA
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Zeng T, Zhang CL, Xiao M, Yang R, Xie KQ. Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials. Front Immunol 2016; 7:538. [PMID: 27965666 PMCID: PMC5126119 DOI: 10.3389/fimmu.2016.00538] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 11/15/2016] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) encompasses a spectrum of liver injury ranging from steatosis to steatohepatitis, fibrosis, and finally cirrhosis. Accumulating evidences have demonstrated that Kupffer cells (KCs) play critical roles in the pathogenesis of both chronic and acute ALD. It has become clear that alcohol exposure can result in increased hepatic translocation of gut-sourced endotoxin/lipopolysaccharide, which is a strong M1 polarization inducer of KCs. The activated KCs then produce a large amount of reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, which finally lead to liver injury. The critical roles of KCs and related inflammatory cascade in the pathogenesis of ALD make it a promising target in pharmaceutical drug developments for ALD treatment. Several drugs (such as rifaximin, pentoxifylline, and infliximab) have been evaluated or are under evaluation for ALD treatment in randomized clinical trials. Furthermore, screening pharmacological regulators for KCs toward M2 polarization may provide additional therapeutic agents. The combination of these potentially therapeutic drugs with hepatoprotective agents (such as zinc, melatonin, and silymarin) may bring encouraging results.
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Affiliation(s)
- Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University , Jinan , China
| | - Cui-Li Zhang
- Institute of Toxicology, School of Public Health, Shandong University , Jinan , China
| | - Mo Xiao
- Institute of Toxicology, School of Public Health, Shandong University , Jinan , China
| | - Rui Yang
- Institute of Toxicology, School of Public Health, Shandong University , Jinan , China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University , Jinan , China
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Karakike E, Moreno C, Gustot T. Infections in severe alcoholic hepatitis. Ann Gastroenterol 2016; 30:152-160. [PMID: 28243035 PMCID: PMC5320027 DOI: 10.20524/aog.2016.0101] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 10/02/2016] [Indexed: 12/12/2022] Open
Abstract
Severe alcoholic hepatitis (sAH), defined by a modified discriminant function ≥32, is the most severe form of alcohol-induced liver disease and is associated with a 1-month mortality rate of around 30%. Corticosteroid treatment remains the only therapeutic option that improves short-term survival. Infectious complications, occurring in approximately 50% of patients, are the main causes of death, even in patients who benefit from corticosteroids. Liver failure, recent alcohol consumption and immunosuppressive drugs contribute to this infectious risk. Although infection is a well-described feature of cirrhosis, little is known about the characteristics of infections in sAH. Infection is mainly of bacterial origin and frequently affects the respiratory tract. Pathogens classically observed in cirrhosis, such as gram-negative bacilli, are frequently involved, but opportunistic pathogens, such as fungi (Aspergillus fumigatus, Pneumocystis jirovecii) or viruses (Cytomegalovirus, Herpes simplex) may appear, mainly related to corticosteroid treatment. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic strategies in this high-risk population should be assessed in well-designed trials.
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Affiliation(s)
- Eleni Karakike
- Department of Infectious Diseases, CHU Brugmann (Eleni Karakike)
| | - Christophe Moreno
- Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme, Université Libre de Bruxelles (Christophe Moreno, Thierry Gustot); Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (Christophe Moreno, Thierry Gustot), Brussels, Belgium
| | - Thierry Gustot
- Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme, Université Libre de Bruxelles (Christophe Moreno, Thierry Gustot); Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (Christophe Moreno, Thierry Gustot), Brussels, Belgium; Inserm Unité 1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France (Thierry Gustot)
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Yeluru A, Cuthbert JA, Casey L, Mitchell MC. Alcoholic Hepatitis: Risk Factors, Pathogenesis, and Approach to Treatment. Alcohol Clin Exp Res 2016; 40:246-55. [PMID: 26842243 DOI: 10.1111/acer.12956] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 11/02/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is an inflammatory disorder of the liver characterized clinically by jaundice, hepatomegaly, and abdominal pain, and histologically by macrovesicular steatosis and necroinflammation. METHODS This clinical review will cover what is known about the pathogenesis, clinical presentation, current treatments, and novel therapies for AH. RESULTS The pathogenesis and treatment of AH remain areas of active research. Although abstinence is the cornerstone of therapy for all stages of alcoholic liver disease, corticosteroids have shown modest short-term benefits in treatment of severe AH. CONCLUSIONS Improved understanding of the pathogenesis of AH has expanded the range of potential treatments for this devastating disease. Several novel therapies are also currently in various stages of testing through clinical trials.
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Affiliation(s)
| | - Jennifer A Cuthbert
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Lisa Casey
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
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Im GY, Lucey MR. Practical Concerns and Controversies in the Management of Alcoholic Hepatitis. Gastroenterol Hepatol (N Y) 2016; 12:478-489. [PMID: 27917083 PMCID: PMC5114494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Recent advances in the treatment of alcoholic hepatitis (AH) have reinforced the utility of glucocorticoids, a treatment that has been in use for nearly 4 decades, to enhance short-term survival. As multi-institutional consortia research new therapeutic advances, this orphan disease, which afflicts younger patients and has poor outcomes, continues to be difficult to manage. AH has a protean clinical presentation and course, with various prediction models and treatment approaches that can challenge even experienced providers. This review addresses 4 key controversies and other practical issues associated with the diagnosis, prognosis, management, and treatment of patients with AH.
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Affiliation(s)
- Gene Y Im
- Dr Im is an assistant professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai and the Recanati/Miller Transplantation Institute in New York, New York. Dr Lucey is a professor of medicine and chief of the Division of Gastroenterology and Hepatology at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin
| | - Michael R Lucey
- Dr Im is an assistant professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai and the Recanati/Miller Transplantation Institute in New York, New York. Dr Lucey is a professor of medicine and chief of the Division of Gastroenterology and Hepatology at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin
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37
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Singal AK, Kodali S, Vucovich LA, Darley-Usmar V, Schiano TD. Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review. Alcohol Clin Exp Res 2016; 40:1390-402. [PMID: 27254289 PMCID: PMC4930399 DOI: 10.1111/acer.13108] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 04/24/2016] [Indexed: 12/16/2022]
Abstract
Alcoholic hepatitis (AH) occurs in about one-third of individuals reporting long-term heavy alcohol use. It is associated with high short-term mortality, economic burden, and hospital resources utilization. We performed this systematic review to (i) describe clinical characteristics and genomics associated with the risk of AH; (ii) discuss role and limitations of liver biopsy and prognostic scoring systems; (iii) summarize evidence regarding the currently available therapies including liver transplantation; and (iv) outline emerging therapies with areas of unmet need. Literature search was performed for studies published in English language (January 1971 through March 2016). The following search engines were used: PubMed, Elsevier Embase, PsycINFO, and Cochrane Library. For the treatment section, only randomized controlled studies were included for this review. A total of 138 studies (59 randomized, 22 systematic reviews or meta-analyses, 7 surveys or guidelines, 7 population-based, and 43 prospective cohorts) were cited. There are over 325,000 annual admissions with AH contributing to about 0.8% of all hospitalizations in the United States. Liver biopsy may be required in about 25 to 30% cases for uncertain clinical diagnosis. Corticosteroids with or without N-acetylcysteine remains the only available therapy for severe episodes. Data are emerging on the role of liver transplantation as salvage therapy for select patients. Abstinence remains the most important factor impacting long-term prognosis. Results from the ongoing clinical trials within the National Institute on Alcohol Abuse and Alcoholism-funded consortia are awaited for more effective and safer therapies. AH is a potentially lethal condition with a significant short-term mortality. A high index of suspicion is required. There remains an unmet need for noninvasive biomarkers for the diagnosis, and predicting prognosis and response to therapy.
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Affiliation(s)
- Ashwani K Singal
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Sudha Kodali
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Lee A Vucovich
- UAB Lister Hill Library of the Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | - Victor Darley-Usmar
- Department of Pathology and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Thomas D Schiano
- Division of Liver Diseases, Mount Sinai School of Medicine, New York City, New York
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Saberi B, Dadabhai AS, Jang YY, Gurakar A, Mezey E. Current Management of Alcoholic Hepatitis and Future Therapies. J Clin Transl Hepatol 2016; 4:113-22. [PMID: 27350941 PMCID: PMC4913072 DOI: 10.14218/jcth.2016.00006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/27/2016] [Accepted: 03/28/2016] [Indexed: 12/12/2022] Open
Abstract
Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. It encompasses a spectrum of disease, including fatty liver disease, alcoholic hepatitis (AH), and alcoholic cirrhosis. AH can range from mild to severe disease, with severe disease being defined as: Discriminant Function (DF) ≥ 32, or Model for End-stage Liver Disease (MELD) ≥ 21, or presence of hepatic encephalopathy. Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. Besides alcohol cessation, corticosteroids have been used with conflicting results and are associated with an inherent risk of infection. Overall steroids have shown short term benefit when compared to placebo, but they have no obvious long term benefits. Pentoxifylline does not improve survival in patients with severe AH and is no longer recommended based on the results of the STOPAH (Steroid Or Pentoxifylline for Alcoholic Hepatitis) trial. Anti-tumor necrosis factor (TNF) agents are associated with increased risk of life threatening infections and death. Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). Future treatment may lie in human induced pluripotent stem cell (iPSC) technology, which is currently under investigation for the study of pathogenesis, drug discovery, and stem cell transplantation. Liver transplantation has been reported with good results in highly selected patients but is controversial due to limited organ supply.
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Affiliation(s)
- Behnam Saberi
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- *Correspondence to: Behnam Saberi, Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Tel: +1-410-614-2543, Fax: +1-410-614-7340, E-mail:
| | - Alia S. Dadabhai
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yoon-Young Jang
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Esteban Mezey
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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39
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Thursz M, Morgan TR. Treatment of Severe Alcoholic Hepatitis. Gastroenterology 2016; 150:1823-34. [PMID: 26948886 PMCID: PMC5828019 DOI: 10.1053/j.gastro.2016.02.074] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/22/2016] [Accepted: 02/24/2016] [Indexed: 12/18/2022]
Abstract
Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.
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Affiliation(s)
- Mark Thursz
- Division of Digestive Diseases, Imperial College, St Mary's Hospital Campus, London, United Kingdom.
| | - Timothy R Morgan
- Gastroenterology Services, VA Long Beach Healthcare, VA Long Beach Healthcare System, Long Beach, California.
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40
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Pal P, Ray S. Alcoholic Liver Disease: A Comprehensive Review. EUROPEAN MEDICAL JOURNAL 2016. [DOI: 10.33590/emj/10312346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Alcoholic liver disease, a leading cause of morbidity, mortality, and cirrhosis, can range from simple steatosis to hepatocellular carcinoma. Multiple mechanisms such as oxidative stress, mitochondrial dysfunction, and alteration in gut-liver axis have been proposed for the pathogenesis of alcoholic liver disease. Based on different prognostic models, alcoholic hepatitis patients can be stratified into sub-groups and specific pharmacological therapy can be started. Alcohol abstinence has a clear cut mortality benefit and nutritional support is very important as most of the patients are malnourished and in a hypercatabolic state. Other than conventional glucocorticoids and pentoxifylline, newer agents and combination therapy can be used in severe alcoholic hepatitis in patients not responsive to conventional glucocorticoid therapy. Liver transplantation improves survival in advanced alcoholic cirrhosis and it can be an option in severe alcoholic hepatitis patients who are not responding to other medical therapies. Whether early transplantation can improve the survival compared with the conventional waiting period of 6 months is an active area of investigation. This is due to the fact that most of the disease-related mortality occurs in the first 2 months.
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Affiliation(s)
- Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Sayantan Ray
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research (IPGMER) and SSKM Hospital, Kolkata, India
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41
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Lam P, Cheung F, Tan HY, Wang N, Yuen MF, Feng Y. Hepatoprotective Effects of Chinese Medicinal Herbs: A Focus on Anti-Inflammatory and Anti-Oxidative Activities. Int J Mol Sci 2016; 17:465. [PMID: 27043533 PMCID: PMC4848921 DOI: 10.3390/ijms17040465] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/21/2016] [Accepted: 03/21/2016] [Indexed: 12/12/2022] Open
Abstract
The liver is intimately connected to inflammation, which is the innate defense system of the body for removing harmful stimuli and participates in the hepatic wound-healing response. Sustained inflammation and the corresponding regenerative wound-healing response can induce the development of fibrosis, cirrhosis and eventually hepatocellular carcinoma. Oxidative stress is associated with the activation of inflammatory pathways, while chronic inflammation is found associated with some human cancers. Inflammation and cancer may be connected by the effect of the inflammation-fibrosis-cancer (IFC) axis. Chinese medicinal herbs display abilities in protecting the liver compared to conventional therapies, as many herbal medicines have been shown as effective anti-inflammatory and anti-oxidative agents. We review the relationship between oxidative stress and inflammation, the development of hepatic diseases, and the hepatoprotective effects of Chinese medicinal herbs via anti-inflammatory and anti-oxidative mechanisms. Moreover, several Chinese medicinal herbs and composite formulae, which have been commonly used for preventing and treating hepatic diseases, including Andrographis Herba, Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, Lycii Fructus, Coptidis Rhizoma, curcumin, xiao-cha-hu-tang and shi-quan-da-bu-tang, were selected for reviewing their hepatoprotective effects with focus on their anti-oxidative and ant-inflammatory activities. This review aims to provide new insight into how Chinese medicinal herbs work in therapeutic strategies for liver diseases.
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Affiliation(s)
- Puiyan Lam
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Fan Cheung
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Hor Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Man Fung Yuen
- Division of Gastroenterology and Hepatology, Queen Mary Hospital and Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
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Sarin SK, Choudhury A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol 2016; 13:131-49. [PMID: 26837712 DOI: 10.1038/nrgastro.2015.219] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of disease and potential for unaided recovery. The definition involves outlining the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune dysregulation with initial wide-spread immune activation, a state of systematic inflammatory response syndrome and subsequent sepsis due to immune paresis. The disease severity and outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic regeneration during ongoing liver failure, although challenging, is possible through the use of growth factors. Liver transplantation remains the definitive treatment with a good outcome. Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.
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Affiliation(s)
- Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
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Kim MS, Ong M, Qu X. Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination? World J Gastroenterol 2016; 22:8-23. [PMID: 26755857 PMCID: PMC4698510 DOI: 10.3748/wjg.v22.i1.8] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/07/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is the principal factor in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and liver failure. As one of the oldest forms of liver injury known to humans, ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide. Although the biological mechanisms, including increasing of acetaldehyde, oxidative stress with induction of cytochrome p450 2E1, inflammatory cytokine release, abnormal lipid metabolism and induction of hepatocyte apoptosis, by which chronic alcohol consumption triggers serious complex progression of ALD is well established, there is no universally accepted therapy to prevent or reverse. In this article, we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies. This review is focused on current therapeutic strategies for ALD, including lifestyle modification with nutrition supplements, available pharmacological drugs and new agents that are under development, liver transplantation, application of complementary medicines, and their combination. The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature. We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD. Through a system review, this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications. It is worthwhile to conduct large-scale, multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD.
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Corticosteroids Versus Pentoxifylline for Severe Alcoholic Hepatitis: A Sequential Analysis of Randomized Controlled Trials. J Clin Gastroenterol 2016; 50:871-881. [PMID: 27404293 PMCID: PMC5065367 DOI: 10.1097/mcg.0000000000000585] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Despite the significant morbidity and mortality associated with alcoholic hepatitis, a consensus or generally accepted therapeutic strategy has not yet been reached. The purpose of this analysis was to evaluate the effects of corticosteroids and pentoxifylline on short-term mortality, incidence of hepatorenal syndrome, and sepsis in patients with severe alcoholic hepatitis. MATERIALS AND METHODS We conducted a comprehensive search of the Cochrane library, PUBMED, Scopus, EMBASE, and published proceedings from major hepatology and gastrointestinal meetings from January 1970 to June 2015. All relevant articles irrespective of language, year of publication, type of publication, or publication status were included. Two independent reviewers extracted data and scored publications; a third investigator adjudicated discrepancies. The κ scores were measured to assess the agreement between the 2 initial reviewers. The review and meta-analyses were performed following the recommendations of The Cochrane Collaboration. Conventional meta-analysis and Trial sequential analysis were performed. GRADEpro version 3.6 was used to appraise the quality of epidemiologic evidence. RESULTS A total of 14 studies satisfied inclusion criteria comparing corticosteroids, pentoxifylline, or placebo. Compared with placebo, corticosteroids reduced 28-day mortality (RR=0.53; 95% CI, 0.33-0.84; P=0.006). There was no statistically significant difference in short-term mortality between pentoxifylline and placebo (RR=0.74; 95% CI, 0.46-1.18; P=0.21). Neither corticosteroids nor pentoxifylline impacted the incidence of hepatorenal syndrome or sepsis. Trial sequential analysis confirmed the results of our conventional meta-analysis. CONCLUSIONS AND RELEVANCE Corticosteroids demonstrated a decrease in 28-day mortality in patients with severe alcoholic hepatitis. The evidence from this study is insufficient to support any recommendations regarding the mortality benefit of pentoxifylline in severe alcoholic hepatitis.
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Thursz M, Forrest E, Roderick P, Day C, Austin A, O'Grady J, Ryder S, Allison M, Gleeson D, McCune A, Patch D, Wright M, Masson S, Richardson P, Vale L, Mellor J, Stanton L, Bowers M, Ratcliffe I, Downs N, Kirkman S, Homer T, Ternent L. The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial. Health Technol Assess 2015; 19:1-104. [PMID: 26691209 PMCID: PMC4781103 DOI: 10.3310/hta191020] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Alcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit. OBJECTIVES The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX. DESIGN The trial was a randomised, double-blind, 2 × 2 factorial, multicentre design. SETTING Sixty-five gastroenterology and hepatology inpatient units across the UK. PARTICIPANTS Patients with a clinical diagnosis of AH who had a Maddrey's discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis. INTERVENTIONS Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days. OUTCOMES The primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed. RESULTS At 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40; p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01; p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91; p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year. CONCLUSIONS We conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection. TRIAL REGISTRATION This trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.
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Affiliation(s)
- Mark Thursz
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Ewan Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - Paul Roderick
- Primary Care & Population Sciences, University of Southampton, Southampton, UK
| | - Christopher Day
- Institute of Cellular Medicine, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Andrew Austin
- Department of Gastroenterology, Derby Royal Hospital, Derby, UK
| | - John O'Grady
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Stephen Ryder
- Department of Hepatology, Nottingham University Hospitals NHS Trust and National Institute for Health Research Biomedical Research Unit, Queens Medical Centre, Nottingham, UK
| | - Michael Allison
- Department of Hepatology, Addenbrookes Hospital, Cambridge, UK
| | - Dermot Gleeson
- Department of Hepatology, Sheffield Teaching Hospitals Foundation Trust, Sheffield, UK
| | - Anne McCune
- Department of Hepatology, Bristol Royal Infirmary, Bristol, UK
| | - David Patch
- Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Mark Wright
- Department of Hepatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Steven Masson
- Institute of Cellular Medicine, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Paul Richardson
- Department of Hepatology, Royal Liverpool Hospital, Liverpool, UK
| | - Luke Vale
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Jane Mellor
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Louise Stanton
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Megan Bowers
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Ian Ratcliffe
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Nichola Downs
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Scott Kirkman
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Tara Homer
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Laura Ternent
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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46
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Caballeria J. [Is there a role for pentoxifylline in the treatment of alcoholic hepatitis?]. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 39:560-5. [PMID: 26589540 DOI: 10.1016/j.gastrohep.2015.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 09/30/2015] [Accepted: 10/03/2015] [Indexed: 11/16/2022]
Abstract
Despite better knowledge of the pathogenesis of severe alcoholic hepatitis (AH), corticosteroids are still the treatment recommended by clinical guidelines, pentoxifylline being the second-line option for non-responders to corticosteriods and for patients with contraindications. Pentoxifylline is a phosphodiesterase inhibitor with an anti-TNF effect and has been reported to reduce mortality and the incidence of hepatorenal syndrome in severe AH. After the first report, several studies, of distinct quality, have tested the efficacy of pentoxifylline in different scenarios. The conclusions of these studies are that pentoxifylline seems to improve survival in comparison to placebo but has lower efficacy than corticosteroids, with no improvement in survival when added to corticosteroids or in non-responders to steroid therapy. The role of pentoxifylline in severe alcoholic hepatitis is even more doubtful after the results of a very recent controlled study that showed no beneficial effect on survival at 1, 3 and 12 months of follow up, although a very recent network meta-analysis reported a beneficial effect of pentoxifylline alone or with corticosteroids on short-term survival. In conclusion, pentoxifylline has no clear beneficial effects in severe AH but could perhaps be used in patients with a contraindication to corticosteroids. However, the recommendations of clinical guidelines should be reconsidered and it is essential to search for new therapeutic targets for this disease.
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Affiliation(s)
- Juan Caballeria
- Unidad de Hepatología, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, España.
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Williams JA, Ding WX. A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease. Biomolecules 2015; 5:2619-42. [PMID: 26501336 PMCID: PMC4693250 DOI: 10.3390/biom5042619] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 09/23/2015] [Accepted: 09/25/2015] [Indexed: 12/15/2022] Open
Abstract
Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease is needed for future development of better therapeutic options for ALD. Mitophagy is a key mechanism for maintaining mitochondrial homeostasis by removing damaged mitochondria, and mitophagy protects against alcohol-induced liver injury. Parkin, an E3 ubiquitin ligase, is well-known to induce mitophagy in in vitro models although Parkin-independent mechanisms for mitophagy induction also exist. In this review, we discuss the roles of Parkin and mitophagy in protection against alcohol-induced liver injury and steatosis. We also discuss Parkin-independent mechanisms for mitophagy induction, which have not yet been evaluated in the liver but may also potentially have a protective role against ALD. In addition to mitophagy, mitochondrial spheroid formation may also provide a novel mechanism of protection against ALD, but the role of mitochondrial spheroids in protection against ALD progression needs to be further explored. Targeting removal of damaged mitochondria by mitophagy or inducing formation of mitochondrial spheroids may be promising therapeutic options for treatment of ALD.
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Affiliation(s)
- Jessica A Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
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48
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Acute kidney injury in acute on chronic liver failure. Hepatol Int 2015; 10:245-57. [DOI: 10.1007/s12072-015-9652-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 07/13/2015] [Indexed: 12/11/2022]
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49
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Singh S, Murad MH, Chandar AK, Bongiorno CM, Singal AK, Atkinson SR, Thursz MR, Loomba R, Shah VH. Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis. Gastroenterology 2015; 149:958-70.e12. [PMID: 26091937 DOI: 10.1053/j.gastro.2015.06.006] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 06/01/2015] [Accepted: 06/02/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons. METHODS We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function ≥32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. RESULTS We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons. CONCLUSIONS In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California.
| | - Mohammad Hassan Murad
- Knowledge and Evaluation Research Unit, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
| | - Apoorva K Chandar
- Division of Gastroenterology and Liver Diseases, Case Western Reserve University, Cleveland, Ohio
| | - Connie M Bongiorno
- Department of Library Services, Mayo Clinic-St. Mary's Hospital Library, Rochester, Minnesota
| | - Ashwani K Singal
- Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama
| | | | - Mark R Thursz
- Division of Hepatology, Imperial College, London, United Kingdom
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, and Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, California
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
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50
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Tijera FHDL, Servín-Caamaño AI, Serralde-Zúñiga AE, Cruz-Herrera J, Pérez-Torres E, Abdo-Francis JM, Salas-Gordillo F, Pérez-Hernández JL. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis. World J Gastroenterol 2015; 21:4975-4985. [PMID: 25945012 PMCID: PMC4408471 DOI: 10.3748/wjg.v21.i16.4975] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/16/2015] [Accepted: 02/13/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the impact of metadoxine (MTD) on the 3- and 6-mo survival of patients with severe alcoholic hepatitis (AH).
METHODS: This study was an open-label clinical trial, performed at the “Hospital General de México, Dr. Eduardo Liceaga”. We randomized 135 patients who met the criteria for severe AH into the following groups: 35 patients received prednisone (PDN) 40 mg/d, 35 patients received PDN+MTD 500 mg three times daily, 33 patients received pentoxifylline (PTX) 400 mg three times daily, and 32 patients received PTX+MTD 500 mg three times daily. The duration of the treatment for all of the groups was 30 d.
RESULTS: In the groups treated with the MTD, the survival rate was higher at 3 mo (PTX+MTD 59.4% vs PTX 33.3%, P = 0.04; PDN+MTD 68.6% vs PDN 20%, P = 0.0001) and at 6 mo (PTX+MTD 50% vs PTX 18.2%, P = 0.01; PDN+MTD 48.6% vs PDN 20%, P = 0.003) than in the groups not treated with MTD. A relapse in alcohol intake was the primary independent factor predicting mortality at 6 mo. The patients receiving MTD maintained greater abstinence than those who did not receive it (74.5% vs 59.4%, P = 0.02).
CONCLUSION: MTD improves the 3- and 6-mo survival rates in patients with severe AH. Alcohol abstinence is a key factor for survival in these patients. The patients who received the combination therapy with MTD were more likely to maintain abstinence than those who received monotherapy with either PDN or PTX.
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