Recurrent severe alcoholic hepatitis

Potts, Jonathan R.; Howard, Mark; Verma, Sumita

doi:10.1097/meg.0b013e32835d83d9

Cited by 27 publications

(11 citation statements)

References 33 publications

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“…In addition to the observation that sex/gender strongly influences immune function and the inflammatory response (Fish, 2008), previous reports have demonstrated that sex influences the biological response to EtOH (Ceylan-Isik et al, 2010). Compared to males, females exhibit: decreased risk for the development of ethanol dependence and addiction; increased ethanol sensitivity and ethanol consumption; reduced withdrawal severity; and increased risk of recidivism and relapse (Brady and Randall, 1999, Devaud and Chadda, 2001, Sershen et al, 2002, Wang et al, 2003, Carroll et al, 2004, Prescott et al, 2005, Becker and Hu, 2008, Potts et al, 2013). Evidence also indicates that ethanol is more rewarding in females (Blanchard et al, 1993, Torres et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

Wilhelm¹,

Hashimoto²,

Roberts³

et al. 2015

Brain Research

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Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.

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Section: Discussionmentioning

confidence: 99%

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

Wilhelm¹,

Hashimoto²,

Roberts³

et al. 2015

Brain Research

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“…In addition, females have reduced levels of alcohol dehydrogenase, a key liver enzyme involved in alcohol metabolism and removal (Baraona et al, 2001). Most notably, sex differences have been characterized in numerous alcohol-related behaviors in which females show: reduced risk for the development of ethanol dependence and addiction; increased ethanol sensitivity; increased ethanol consumption; reduced withdrawal severity; and increased risk of recidivism and relapse (Brady and Randall, 1999, Devaud and Chadda, 2001, Sershen et al, 2002, Wang et al, 2003, Carroll et al, 2004, Prescott et al, 2005, Becker and Hu, 2008, Potts et al, 2013). Alcohol may also be more rewarding in females (Blanchard et al, 1993, Torres et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Wilhelm

Hashimoto

Roberts³

et al. 2014

Neuroscience

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Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety.

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“…(Mathurin et al, 2007, Pares et al, 1986) Among patients surviving the initial AH episode, patient behavior and maintenance of abstinence determines the medium- and long- term mortality. (Thursz et al, 2015, Potts et al, 2013b, Potts et al, 2013a) Recurrent AH occurs in about two thirds of survivors of the initial episode with an estimated 5 year survival of only about 32%. (Potts et al, 2013a) Recurrent AH and recidivism is more common among women, is more severe than the initial episode, and significantly impacts long-term survival.…”

Section: Resultsmentioning

confidence: 99%

“…(Potts et al, 2013a) Recurrent AH and recidivism is more common among women, is more severe than the initial episode, and significantly impacts long-term survival. (Potts et al, 2013b, Potts et al, 2013a) Studies are needed to examine reliable and accurate models predictive of recidivism so as to identify high risk groups for intervention aiming to prevent recidivism and recurrent AH.…”

Section: Resultsmentioning

confidence: 99%

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Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review

Singal

Kodali

Vucovich

et al. 2016

Alcohol Clin Exp Res

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Alcoholic hepatitis 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 a) describe clinical characteristics and genomics associated with the risk of alcoholic hepatitis; b) discuss role and limitations of liver biopsy and prognostic scoring systems; c) summarize evidence regarding the currently available therapies including liver transplantation; and d) outline emerging therapies with areas of unmet need. Literature search was performed for studies published in English language (January 1971 through - March 2016). Following search engines were used: Pubmed, Elsevier Embase, PsychINFO, 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 cohort) were cited. There are over 325,000 annual admissions with alcoholic hepatitis contributing to about 0.8% of all hospitalizations in the US. Liver biopsy may be required in about 25–30% cases for uncertain clinical diagnosis. Corticosteroids with or without N-acetylcysteine remains the only available therapy for severe episode. 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. Alcoholic hepatitis is a potentially lethal condition with a significant short-term mortality. A high index of suspicion is required. There remains an unmet need for non-invasive biomarkers for diagnosis, and predicting prognosis and response to therapy.

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Recurrent severe alcoholic hepatitis

Cited by 27 publications

References 33 publications

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review

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