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Kasuga R, Chu PS, Taniki N, Yoshida A, Morikawa R, Tabuchi T, Noguchi F, Yamataka K, Nakadai Y, Kondo M, Ebinuma H, Kanai T, Nakamoto N. Granulocyte-monocyte/macrophage apheresis for steroid-nonresponsive or steroid-intolerant severe alcohol-associated hepatitis: A pilot study. Hepatol Commun 2024; 8:e0371. [PMID: 38285891 PMCID: PMC10830070 DOI: 10.1097/hc9.0000000000000371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/22/2023] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Patients with severe alcohol-associated hepatitis (SAH) have a high short-term mortality rate. Unmet needs exist in patients who are refractory to corticosteroids (CS) or are ineligible for early liver transplantation. METHODS This was a prospective, open-label, nonrandomized pilot study conducted at a liver transplant center in Tokyo, Japan, starting in October 2015. Lille model and Model for End-stage Liver Disease (MELD) score-defined CS nonresponsive or CS-intolerant patients with SAH who fulfilled the inclusion criteria (leukocytosis over 10,000/μL, etc.) were considered for enrollment. The median duration from admission to enrollment was 23 days (IQR, 14-31 days), after standard of care. Granulocyte-monocyte/macrophage apheresis (GMA) performed with Adacolumn twice per week, up to 10 times per treatment course, was evaluated. RESULTS 13 GMA treatments were conducted through December 2021. Maddrey Discriminant Function was 53.217.7 at admission. The overall survival rate was 90.9% at 90 and 180 days. MELD scores significantly improved, from median (IQRs) of 23 (20-25) to 15 (13-21) after GMA (p<0.0001). Estimated mortality risks using the Lille model and MELD scores significantly improved from 20.9%±16.5% to 7.4%±7.3% at 2 months and from 30.4%±21.3% to 11.6%±10.8% at 6 months, respectively (both p<0.01), and were internally validated. The cumulative rate of alcohol relapse was 35.9% per year. No severe adverse events were observed. In exploratory analysis, granulocyte colony-stimulating factor levels were significantly correlated with prognostic systems such as MELD-Sodium scores after GMA (correlation coefficient= -0.9943, p<0.0001) but not before GMA (p=0.62). CONCLUSIONS Compared to published studies, GMA is associated with a lower-than-expected 90- and 180-day mortality in patients with CS-nonresponsive or CS-intolerant SAH. GMA may meet the needs as a salvage anti-inflammatory therapy for SAH. (Trial registration: UMIN000019351 and jRCTs No.032180221) (274 words).
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Affiliation(s)
- Ryosuke Kasuga
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Po-Sung Chu
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Nobuhito Taniki
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Aya Yoshida
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Rei Morikawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takaya Tabuchi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Fumie Noguchi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Karin Yamataka
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Yukie Nakadai
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Mayuko Kondo
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hirotoshi Ebinuma
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
- Department of Gastroenterology, International University of Health and Welfare, School of Medicine, 4Narita City, Chiba, Japan
| | - Takanori Kanai
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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Lai X, Wang S, Hu M, Sun Y, Chen M, Liu M, Li G, Deng Y. Dual targeting single arrow: Neutrophil-targeted sialic acid-modified nanoplatform for treating comorbid tumors and rheumatoid arthritis. Int J Pharm 2021; 607:121022. [PMID: 34416328 DOI: 10.1016/j.ijpharm.2021.121022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/27/2021] [Accepted: 08/15/2021] [Indexed: 10/20/2022]
Abstract
Clinically, rheumatoid arthritis (RA) is frequently accompanied by multi-system diseases. Among them, the incidence of comorbid tumors in RA is relatively high, resulting in a gradual increase in mortality; this poses a considerable challenge to clinical treatment. To date, no effective treatment plan for simultaneous tumor and RA therapy is available. Accordingly, we reported a sialic acid-modified doxorubicin hydrochloride liposome (DOX-SAL) that targets peripheral blood neutrophils (PBNs), which play an important role in tumors and RA. Furthermore, the prepared liposome induced PBN apoptosis by binding to L-selectin, which is highly expressed on the surface of PBNs activated by inflammation. This liposome, in turn, reduced the accumulation of inflammatory neutrophils at the disease site. In the first successfully established mouse model of RA comorbidity, induced by employing S180 sarcoma cells and collagen, DOX-SAL effectively inhibited tumor growth while simultaneously alleviating systemic RA symptoms without side effects. Additionally, the animals demonstrated adequate growth during the 48 days of treatment. This treatment strategy encompasses the best of both worlds, breaking the deadlock that tumors and RA cannot be effectively treated in parallel, highlighting a new concept and reference for the clinical treatment of comorbid tumors and RA.
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Affiliation(s)
- Xiaoxue Lai
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Shuo Wang
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Miao Hu
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Yiming Sun
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Meng Chen
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Mengyang Liu
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Gang Li
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Yihui Deng
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China.
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Sarin SK, Sharma S. Predictors of steroid non-response and new approaches in severe alcoholic hepatitis. Clin Mol Hepatol 2020; 26:639-651. [PMID: 33053936 PMCID: PMC7641572 DOI: 10.3350/cmh.2020.0196] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/14/2020] [Accepted: 08/21/2020] [Indexed: 12/15/2022] Open
Abstract
Severe alcoholic hepatitis (SAH) remains a disease with high mortality. Steroid is the main stay and has been shown to give modest 28-day survival benefit in carefully selected patients, but no 90-day survival benefit. Since non-responders have high incidence of infections and increased mortality, it would be worthwhile to identify them before starting steroid therapy. A high and rising bilirubin, urinary acetyl carnitine >2,500 ng/mL, high asiloglycoprotein positive microparticles, and specific features in liver biopsy could predict steroid non-response at baseline. There is an ever-growing need to find new and effective therapies for SAH patients. Besides aggressive nutrition, granulocyte colony stimulating factor, fecal microbiota transplantation, and plasma exchange appear promising therapies and provide a hope for steroid ineligible or steroid non-responsive patients. Suppression of hepatic inflammation, preventing new bacterial or fungal infections, and enhancing liver regeneration will remain the key targets for next generation therapies.
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Affiliation(s)
- Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shvetank Sharma
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Németh T, Sperandio M, Mócsai A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov 2020; 19:253-275. [PMID: 31969717 DOI: 10.1038/s41573-019-0054-z] [Citation(s) in RCA: 457] [Impact Index Per Article: 91.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2019] [Indexed: 12/13/2022]
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Wang W, Xu Y, Jiang C, Gao Y. Advances in the treatment of severe alcoholic hepatitis. Curr Med Res Opin 2019; 35:261-273. [PMID: 29781336 DOI: 10.1080/03007995.2018.1479247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Severe alcoholic hepatitis (SAH) is a costly and worldwide public health issue with high morbidity and mortality. Specific effective treatments for SAH have yet to be established. The aim of the present article is to review the current knowledge of the pathogenesis, assessment and treatment options in patients with SAH. To date, alcohol abstinence and enteral nutrition are the recommended first-line treatments. Although corticosteroids remain the preferred therapy for certain patients with a modified Maddrey discriminant function level greater than 54, they only improve short-term survival rates. New research focuses on liver inflammation, liver regeneration, the gut-liver axis, human induced pluripotent stem cells and extracorporeal albumin dialysis. Liver transplantation is considered the last medical option for patients with SAH who are nonresponsive to other medical treatments.
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Affiliation(s)
- Wenjun Wang
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| | - Ying Xu
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| | - Chang Jiang
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
| | - Yanhang Gao
- a Department of Hepatology , First Hospital of Jilin University, Jilin University , Jilin , China
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Chen BY, Jiang LX, Hao K, Wang L, Wang Y, Xie YW, Shen J, Zhu MH, Tong XM, Li KQ, Wang Z. Protection of plasma transfusion against lipopolysaccharide/ D-galactosamine-induced fulminant hepatic failure through inhibiting apoptosis of hepatic cells in mice *. J Zhejiang Univ Sci B 2018; 19:436-444. [PMCID: PMC6011027 DOI: 10.1631/jzus.b1700277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 07/12/2017] [Accepted: 07/12/2017] [Indexed: 01/03/2025]
Abstract
Fulminant hepatic failure is a severe clinical condition associated with extremely poor outcomes and high mortality. A number of studies have demonstrated the ability of plasma transfusion to successfully treat fulminant hepatic failure, but the underlying mechanisms are not well understood. The aim of the present study is to define the mechanisms of plasma transfusion treatment in lipopolysaccharide/D -galactosamine (LPS/D -GalN)-induced mice. LPS/D -GalN treatment in mice causes significant hepatic failure, including increasing serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, histopathological changes in centrilobular necrosis and inflammatory cells, and the up-regulation of inflammation (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). When LPS/D -GaIN-induced mice were treated with plasma, these changes were halted. Results showed that plasma transfusion significantly reduced mortality, and decreased the levels of AST, ALT, and inflammation factors such as TNF-α and IL-6. The expression levels of cleaved Caspase-3, BAX, and p53 were down-regulated and Bcl-2 was up-regulated, suggesting that plasma can reduce LPS/D -GalN-induced apoptosis. The protective mechanism of plasma against LPS/D -GalN-induced fulminant hepatic failure is related to the inhibition of the inflammatory response and the reduction in apoptosis through the down-regulation of the p53-induced apoptotic pathway.
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Affiliation(s)
- Bing-yu Chen
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Lu-xi Jiang
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Ke Hao
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Lu Wang
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Ying Wang
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Yi-wei Xie
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Jian Shen
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Meng-hua Zhu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
- Department of Nephrology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Xiang-ming Tong
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Kai-qiang Li
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Zhen Wang
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
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Watanabe K, Uchida Y, Sugawara K, Naiki K, Inao M, Nakayama N, Mochida S. Sequential therapy consisting of glucocorticoid infusions followed by granulocyte-monocyte absorptive apheresis in patients with severe alcoholic hepatitis. J Gastroenterol 2017; 52:830-837. [PMID: 27858246 DOI: 10.1007/s00535-016-1287-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 11/07/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Activated leukocytes infiltrating the liver contribute to the provocation of alcoholic hepatitis. Glucocorticoid induces the demargination of leukocytes from the hepatic sinusoids, whereas granulocyte-monocyte absorptive apheresis (GMA) removes leukocytes from the circulation. Thus, the usefulness of a sequential therapy consisting of glucocorticoid infusions followed by GMA was evaluated in patients with severe alcoholic hepatitis. METHODS Patients with severe alcoholic hepatitis received intravenous injections of methylprednisolone (1,000 mg/day) for 3 or 4 days, and then GMA was performed every day for 3 days. Responders were defined as those with attenuated serum C-reactive protein (CRP) levels during the GMA procedures. RESULTS Ten consecutive patients were enrolled. At the baseline, the Japan alcoholic hepatitis scores were 9 in two patients and 10 or more in eight patients, and the Model for End-Stage Liver Disease scores ranged from 22 to 43. In all the patients, the peripheral neutrophil counts increased and the serum levels of CRP, aspartate aminotransferase, IL-6, IL-8, TNF-α, and intercellular adhesion molecule 1 decreased immediately after the glucocorticoid infusions. However, a rebound increase in the serum CRP levels was observed in all patients after discontinuation of glucocorticoid infusions, but the maximal values during the GMA procedures were lower than the baseline values. Six patients were rescued, whereas the remaining four patients died because of sepsis, pneumonia, pancreatitis, and renal failure. CONCLUSIONS Sequential therapy combining glucocorticoid infusion and GMA was useful for attenuating liver injuries in patients with severe alcoholic hepatitis by preventing rebound increases in inflammatory reactions after discontinuation of glucocorticoid infusions, except in patients with bacterial infections and/or multiple organ failure.
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Affiliation(s)
- Kazuhiro Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Yoshihito Uchida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Kayoko Sugawara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Kayoko Naiki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Mie Inao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.
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Watanabe Y, Kamimura K, Iwasaki T, Abe H, Takahashi S, Mizuno KI, Takeuchi M, Eino A, Narita I, Terai S. Case of severe alcoholic hepatitis treated with granulocytapheresis. World J Clin Cases 2016; 4:369-374. [PMID: 27900326 PMCID: PMC5112357 DOI: 10.12998/wjcc.v4.i11.369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/06/2016] [Accepted: 08/27/2016] [Indexed: 02/05/2023] Open
Abstract
Severe alcoholic hepatitis (AH) has a high mortality, and it is associated with encephalopathy, acute renal failure, sepsis, gastrointestinal bleeding, and endotoxemia. The 28-d mortality remains poor (34%-40%), because no effective treatment has been established. Recently, corticosteroids (CS) have been considered effective for significantly improving the prognosis of those with AH, as it prevents the production of pro-inflammatory cytokines. However, CS are not always appropriate as an initial therapeutic option, such as in cases with an infection or resistance to CS. We describe a patient with severe AH complicated by a severe infection caused by the multidrug resistance bacteria (Pseudomonas aeruginosa), and was successfully treated with granulocytapheresis monotherapy without using CS. The experience of this case will provide understanding of the disease and information treating cases without using CS.
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Shasthry SM, Sarin SK. New treatment options for alcoholic hepatitis. World J Gastroenterol 2016; 22:3892-3906. [PMID: 27099434 PMCID: PMC4823241 DOI: 10.3748/wjg.v22.i15.3892] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/07/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using “Omics” platforms, newer options for patients with alcoholic hepatitis are expected soon.
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Suraweera DB, Weeratunga AN, Hu RW, Pandol SJ, Hu R. Alcoholic hepatitis: The pivotal role of Kupffer cells. World J Gastrointest Pathophysiol 2015; 6:90-98. [PMID: 26600966 PMCID: PMC4644891 DOI: 10.4291/wjgp.v6.i4.90] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/27/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.
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