ACG Clinical Guideline: Alcoholic Liver Disease Singal, Ashwani K; Bataller, Ramon; Ahn, Joseph ...
The American journal of gastroenterology,
02/2018, Letnik:
113, Številka:
2
Journal Article
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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.
Background: Acute ethanol intoxication has the potential to alter immune reactivity by various pathways. The aim of this study was to investigate T-helper cell subsets transcription factors and ...cytokines in human peripheral blood mononuclear cells (PBMCs) following a single dose of lipopolysaccharide (LPS) with or without ethanol exposure. Methods: Human PBMCs were cultured in the presence of 100mM ethanol and/or 100ng/ml LPS for various time periods (1, 3, 8, and 24hours) and analyzed for the kinetics of gene expression by quantitative real-time PCR of selected transcription factors (T-bet, GATA3, Foxp3, and ROR gamma t) and cytokines (TNF- alpha , IL-6, IL-10, and IFN- gamma ). The proportion of Th17 and Treg cells was identified 24hours after treatment with ethanol and LPS by multiparameter flow cytometry. Viability and amount of dead cells were analyzed after 24 and 48hours by MTT assay and flow cytometry. Results: Following LPS challenge, gene expression of Foxp3 increased, whereas ROR gamma t decreased after 3hours, GATA3 decreased within 1hour, whereas expression of T-bet did not change at any time. Gene expression of TNF- alpha , interferon- gamma (IFN- gamma ), and IL-6 peaked after 3hours, expression of IL-10 peaked after 8hours. Ethanol suppressed the LPS-induced gene expression of Foxp3, ROR gamma t, and T-bet after 8hours, expression of TNF- alpha and IFN- gamma was also suppressed after 3 and 8hours. Markers of inflammation including TNF- alpha and IL-1 beta in supernatant of PBMCs were significantly decreased, while levels of IL-10 and IL-6 remained unchanged following ethanol exposure. Furthermore, ethanol-treated cells alone or in combination with LPS had significantly fewer IL-17- and IFN- gamma -secreting CD4+ T cells but constant proportion of Treg cells when compared to control cells. Proliferation and viability of the cells were not influenced under these conditions. Conclusions: Alcohol interferes with the kinetics of Foxp3, ROR gamma t, and T-bet gene expression and the production of TNF- alpha and IL-1s and influences the balance of Treg/Th17 cells following LPS exposure.
Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These ...animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.
Assessments of lysergic acid diethylamide (LSD) in the treatment of alcoholism have not been based on quantitative meta-analysis. Hence, we performed a meta-analysis of randomized controlled trials ...in order to evaluate the clinical efficacy of LSD in the treatment of alcoholism. Two reviewers independently extracted the data, pooling the effects using odds ratios (ORs) by a generic inverse variance, random effects model. We identified six eligible trials, including 536 participants. There was evidence for a beneficial effect of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36–2.84; p = 0.0003). Between-trial heterogeneity for the treatment effects was negligible (I2 = 0%). Secondary outcomes, risk of bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.
Abstract Alcohol is a leading cause of liver disease worldwide. Although alcohol abstinence is the crucial therapeutic goal for patients with alcoholic liver disease, these patients have less access ...to psychosocial, behavioral and/or pharmacological treatments for alcohol use disorder. Psychosocial and behavioral therapies include 12-step facilitation, brief interventions, cognitive behavioral therapy, and motivational enhancement therapy. In addition to medications approved by the Food and Drug Administration (FDA) for alcohol use disorder (disulfiram, naltrexone and acamprosate), recent efforts to identify potential new treatments have yielded promising candidate pharmacotherapies. Finally, more efforts are needed to integrate treatments across disciplines toward patient-centered approaches in the management of patients with alcohol use disorder and alcoholic liver disease.
Neuroimmune signaling in alcohol use disorder Erickson, Emma K.; Grantham, Emily K.; Warden, Anna S. ...
Pharmacology, biochemistry and behavior,
02/2019, Letnik:
177
Journal Article
Recenzirano
Odprti dostop
Alcohol use disorder (AUD) is a widespread disease with limited treatment options. Targeting the neuroimmune system is a new avenue for developing or repurposing effective pharmacotherapies. Alcohol ...modulates innate immune signaling in different cell types in the brain by altering gene expression and the molecular pathways that regulate neuroinflammation. Chronic alcohol abuse may cause an imbalance in neuroimmune function, resulting in prolonged perturbations in brain function. Likewise, manipulating the neuroimmune system may change alcohol-related behaviors. Psychiatric disorders that are comorbid with AUD, such as post-traumatic stress disorder, major depressive disorder, and other substance use disorders, may also have underlying neuroimmune mechanisms; current evidence suggests that convergent immune pathways may be involved in AUD and in these comorbid disorders. In this review, we provide an overview of major neuroimmune cell-types and pathways involved in mediating alcohol behaviors, discuss potential mechanisms of alcohol-induced neuroimmune activation, and present recent clinical evidence for candidate immune-related drugs to treat AUD.
•Alcohol exposure perturbs innate immune signaling in brain.•A wide array of neuroimmune molecules regulate behavioral responses to alcohol.•Microglia and astrocyte dysfunction may contribute to addictive behaviors.•Neuroimmune imbalance may confer vulnerability to psychiatric disorders.•Immunomodulatory drugs are new candidates for treating alcohol use disorder.
Background
Alcohol use disorder (AUD) confers a prodigious burden of disease, disability, premature mortality, and high economic costs from lost productivity, accidents, violence, incarceration, and ...increased healthcare utilization. For over 80 years, Alcoholics Anonymous (AA) has been a widespread AUD recovery organization, with millions of members and treatment free at the point of access, but it is only recently that rigorous research on its effectiveness has been conducted.
Objectives
To evaluate whether peer‐led AA and professionally‐delivered treatments that facilitate AA involvement (Twelve‐Step Facilitation (TSF) interventions) achieve important outcomes, specifically: abstinence, reduced drinking intensity, reduced alcohol‐related consequences, alcohol addiction severity, and healthcare cost offsets.
Search methods
We searched the Cochrane Drugs and Alcohol Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, CINAHL and PsycINFO from inception to 2 August 2019. We searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 15 November 2018. All searches included non‐English language literature. We handsearched references of topic‐related systematic reviews and bibliographies of included studies.
Selection criteria
We included randomized controlled trials (RCTs), quasi‐RCTs and non‐randomized studies that compared AA or TSF (AA/TSF) with other interventions, such as motivational enhancement therapy (MET) or cognitive behavioral therapy (CBT), TSF treatment variants, or no treatment. We also included healthcare cost offset studies. Participants were non‐coerced adults with AUD.
Data collection and analysis
We categorized studies by: study design (RCT/quasi‐RCT; non‐randomized; economic); degree of standardized manualization (all interventions manualized versus some/none); and comparison intervention type (i.e. whether AA/TSF was compared to an intervention with a different theoretical orientation or an AA/TSF intervention that varied in style or intensity). For analyses, we followed Cochrane methodology calculating the standard mean difference (SMD) for continuous variables (e.g. percent days abstinent (PDA)) or the relative risk (risk ratios (RRs)) for dichotomous variables. We conducted random‐effects meta‐analyses to pool effects wherever possible.
Main results
We included 27 studies containing 10,565 participants (21 RCTs/quasi‐RCTs, 5 non‐randomized, and 1 purely economic study). The average age of participants within studies ranged from 34.2 to 51.0 years. AA/TSF was compared with psychological clinical interventions, such as MET and CBT, and other 12‐step program variants.
We rated selection bias as being at high risk in 11 of the 27 included studies, unclear in three, and as low risk in 13. We rated risk of attrition bias as high risk in nine studies, unclear in 14, and low in four, due to moderate (> 20%) attrition rates in the study overall (8 studies), or in study treatment group (1 study). Risk of bias due to inadequate researcher blinding was high in one study, unclear in 22, and low in four. Risks of bias arising from the remaining domains were predominantly low or unclear.
AA/TSF (manualized) compared to treatments with a different theoretical orientation (e.g. CBT) (randomized/quasi‐randomized evidence)
RCTs comparing manualized AA/TSF to other clinical interventions (e.g. CBT), showed AA/TSF improves rates of continuous abstinence at 12 months (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.03 to 1.42; 2 studies, 1936 participants; high‐certainty evidence). This effect remained consistent at both 24 and 36 months.
For percentage days abstinent (PDA), AA/TSF appears to perform as well as other clinical interventions at 12 months (mean difference (MD) 3.03, 95% CI ‐4.36 to 10.43; 4 studies, 1999 participants; very low‐certainty evidence), and better at 24 months (MD 12.91, 95% CI 7.55 to 18.29; 2 studies, 302 participants; very low‐certainty evidence) and 36 months (MD 6.64, 95% CI 1.54 to 11.75; 1 study, 806 participants; very low‐certainty evidence).
For longest period of abstinence (LPA), AA/TSF may perform as well as comparison interventions at six months (MD 0.60, 95% CI ‐0.30 to 1.50; 2 studies, 136 participants; low‐certainty evidence).
For drinking intensity, AA/TSF may perform as well as other clinical interventions at 12 months, as measured by drinks per drinking day (DDD) (MD ‐0.17, 95% CI ‐1.11 to 0.77; 1 study, 1516 participants; moderate‐certainty evidence) and percentage days heavy drinking (PDHD) (MD ‐5.51, 95% CI ‐14.15 to 3.13; 1 study, 91 participants; low‐certainty evidence).
For alcohol‐related consequences, AA/TSF probably performs as well as other clinical interventions at 12 months (MD ‐2.88, 95% CI ‐6.81 to 1.04; 3 studies, 1762 participants; moderate‐certainty evidence).
For alcohol addiction severity, one study found evidence of a difference in favor of AA/TSF at 12 months (P < 0.05; low‐certainty evidence).
AA/TSF (non‐manualized) compared to treatments with a different theoretical orientation (e.g. CBT) (randomized/quasi‐randomized evidence)
For the proportion of participants completely abstinent, non‐manualized AA/TSF may perform as well as other clinical interventions at three to nine months follow‐up (RR 1.71, 95% CI 0.70 to 4.18; 1 study, 93 participants; low‐certainty evidence).
Non‐manualized AA/TSF may also perform slightly better than other clinical interventions for PDA (MD 3.00, 95% CI 0.31 to 5.69; 1 study, 93 participants; low‐certainty evidence).
For drinking intensity, AA/TSF may perform as well as other clinical interventions at nine months, as measured by DDD (MD ‐1.76, 95% CI ‐2.23 to ‐1.29; 1 study, 93 participants; very low‐certainty evidence) and PDHD (MD 2.09, 95% CI ‐1.24 to 5.42; 1 study, 286 participants; low‐certainty evidence).
None of the RCTs comparing non‐manualized AA/TSF to other clinical interventions assessed LPA, alcohol‐related consequences, or alcohol addiction severity.
Cost‐effectiveness studies
In three studies, AA/TSF had higher healthcare cost savings than outpatient treatment, CBT, and no AA/TSF treatment. The fourth study found that total medical care costs decreased for participants attending CBT, MET, and AA/TSF treatment, but that among participants with worse prognostic characteristics AA/TSF had higher potential cost savings than MET (moderate‐certainty evidence).
Authors' conclusions
There is high quality evidence that manualized AA/TSF interventions are more effective than other established treatments, such as CBT, for increasing abstinence. Non‐manualized AA/TSF may perform as well as these other established treatments. AA/TSF interventions, both manualized and non‐manualized, may be at least as effective as other treatments for other alcohol‐related outcomes. AA/TSF probably produces substantial healthcare cost savings among people with alcohol use disorder.
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