Treatment of Alcoholic Liver Disease Including Emerging Therapies, Novel Targets, and Liver Transplantation

Petrášek, Jan; Szabó, Gyöngyi

doi:10.1007/978-3-319-20538-0_15

Cited by 4 publications

(7 citation statements)

References 142 publications

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“…Given the massive activation of pro-inflammatory cytokines in severe alcoholic hepatitis, anti-TNF therapies were used in experimental settings however showed no early benefit. All of the studies involving TNFα or TNF receptor blockade had to be discontinued due to the increased rate of infections (Petrasek and Szabo, 2016). This is not unexpected as chronic excessive alcohol users are immunocompromised and have poor anti-bacterial and anti-viral host defense mechanisms.…”

Section: Treatment Of Alcoholic Liver Disease and Moderate Alcoholic mentioning

confidence: 99%

“…Development of multi-organ involvement, most frequently hepatorenal syndrome and ARDS requiring mechanical ventilation, is associated with poor clinical outcome. Standard of care in the US in patients with acute alcoholic hepatitis (MDF > 32) is prednisolone 40 g for 28 days, shown to improve 6 month mortality (Petrasek and Szabo, 2016). Several studies have evaluated pentoxifylline alone in severe alcoholic hepatitis however results were controversial (Petrasek and Szabo, 2016).…”

Section: Treatment Of Severe Alcoholic Hepatitismentioning

confidence: 99%

“…Standard of care in the US in patients with acute alcoholic hepatitis (MDF > 32) is prednisolone 40 g for 28 days, shown to improve 6 month mortality (Petrasek and Szabo, 2016). Several studies have evaluated pentoxifylline alone in severe alcoholic hepatitis however results were controversial (Petrasek and Szabo, 2016). Co-administration of prednisolone and pentoxifylline failed to provide added benefit over steroids alone, with the exception of reduction in hepatorenal syndrome (Thursz et al, 2015).…”

Section: Treatment Of Severe Alcoholic Hepatitismentioning

confidence: 99%

“…Patients with acute severe alcoholic hepatitis are managed by active supportive therapy. Intake of at least 3,000 daily calories is associated with improved survival (Petrasek and Szabo, 2016). If steroids were started, evaluation of the Lille score on day 7 has good prognostic value (Louvet et al, 2007).…”

Section: Treatment Of Severe Alcoholic Hepatitismentioning

confidence: 99%

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Alcoholic Hepatitis: A Review

Hosseini

Shor

Szabó

2019

Alcohol and Alcoholism

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121

117

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Alcoholic liver disease (ALD) represents a spectrum of injury, ranging from simple steatosis to alcoholic hepatitis to cirrhosis. Regular alcohol use results in fatty changes in the liver which can develop into inflammation, fibrosis and ultimately cirrhosis with continued, excessive drinking. Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality that can occur in patients with steatosis or underlying cirrhosis. The pathogenesis of ALD is multifactorial and in addition to genetic factors, alcohol-induced hepatocyte damage, reactive oxygen species, gut-derived microbial components result in steatosis and inflammatory cell (macrophage and neutrophil leukocyte) recruitment and activation in the liver. Continued alcohol and pro-inflammatory cytokines induce stellate cell activation and result in progressive fibrosis. Other than cessation of alcohol use, medical therapy of AH is limited to prednisolone in a subset of patients. Given the high mortality of AH and the progressive nature of ALD, there is a major need for new therapeutic intervention for this underserved patient population.

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Section: Treatment Of Alcoholic Liver Disease and Moderate Alcoholic mentioning

confidence: 99%

Section: Treatment Of Severe Alcoholic Hepatitismentioning

confidence: 99%

Section: Treatment Of Severe Alcoholic Hepatitismentioning

confidence: 99%

Section: Treatment Of Severe Alcoholic Hepatitismentioning

confidence: 99%

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Alcoholic Hepatitis: A Review

Hosseini

Shor

Szabó

2019

Alcohol and Alcoholism

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121

117

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“…Despite significant advances in understanding the pathogenesis of ALD, very few treatment options are currently available. ( ) Here, we have tested the therapeutic potential of BA receptor agonists in two mouse models of alcoholic liver injury. Our data show that FXR and TGR5 agonists inhibit liver CYP7A1 expression, which is increased in ALD, reduce liver damage, and blunt hepatic steatosis through FASN downregulation.…”

Section: Discussionmentioning

confidence: 99%

FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice

Iracheta-Vellve

Calenda

Petrášek

et al. 2018

Hepatology Communications

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Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein‐coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT‐777, and INT‐767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3‐day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real‐time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT‐777 decreased hepatic macrovesicular steatosis and protected from ethanol‐induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT‐767, or INT‐777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin‐1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate–induced activation of protein kinase A. Conclusion: OCA, INT‐767, or INT‐777 administration is effective in reducing acute and chronic ethanol‐induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.

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Clinical Trial Design for Alcoholic Hepatitis

Szabó

2017

Semin Liver Dis

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Alcoholic hepatitis (AH) is an acute and clinically distinct manifestation of alcoholic liver disease. While severe AH causes 30% or higher mortality in 3 months, treatment options are limited and ineffective. Recent advances on the understanding of the pathomechanisms of AH have identified numerous potential targets for new therapeutic interventions. Many of those targets are currently under preclinical testing and/or in human clinical trials for nonalcoholic steatohepatitis. Thus, the field of AH should be ready to launch new efforts and targeted clinical trials for this underserved patient population. There are remaining challenges in designing clinical trials in AH that include definition of the severity of disease, common data elements in clinical trial design, and selection of clinically meaningful endpoints. Future efforts and consensus meetings between regulatory agencies, academic and clinical experts, and industry will be instrumental to advance this emerging and greatly needed field of clinical investigations.

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Treatment of Alcoholic Liver Disease Including Emerging Therapies, Novel Targets, and Liver Transplantation

Cited by 4 publications

References 142 publications

Alcoholic Hepatitis: A Review

Alcoholic Hepatitis: A Review

FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice

Clinical Trial Design for Alcoholic Hepatitis

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