Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

Hepatology, Journal Year: 2019, Volume and Issue: 71(1), P. 306 - 333

Published: July 17, 2019

Supported by the American Association for Study of Liver Diseases. Potential conflict interest: Dr. Lucey received grants from Gilead, AbbVie and Pharmasolutions. Szabo consults Allergan. She Terra Firma, Glympse, Quest, Arrow, GLG, Salix Tobira. Genfit, Intercept, Verlyx, Novartis, SignaBlok Shire. holds intellectual property rights with Up to Date. Purpose Scope Guidance Alcohol‐associated liver disease (ALD) represents a spectrum injury resulting alcohol use, ranging hepatic steatosis more advanced forms including alcoholic hepatitis (AH), alcohol‐associated cirrhosis (AC), acute AH presenting as acute‐on‐chronic failure. ALD is major cause worldwide, both on its own co‐factor in progression chronic viral hepatitis, nonalcoholic fatty (NAFLD), iron overload, other diseases. develops through several stages, beginning steatosis, and, some individuals, gradually progressing (the histological correlate which steatohepatitis), culminating (Fig. 1).1 Progression these various stages dependent continued heavy use risk factors, female sex, genetic susceptibility, diet, comorbid disease. carries significant stigma society. It increasingly recognized providers that patients their families seek reduce ALD, change term "alcoholic" "alcohol‐associated" will help; thus, disease, steatohepatitis, are suggested, retaining familiar abbreviations (ALD, ASH, AC, respectively). Due longstanding usage, "alcoholic hepatitis" likely persist.Figure 1: Natural history Images courtesy M. Isabel Fiel.This 2019 provides data‐supported approach prevalence, clinical spectrum, diagnosis, management disorders (AUDs). The was developed consensus an expert panel guidance statements based formal review analysis published literature topics. quality (level) evidence strength each statement not formally rated. Updates 2010 Guideline include emphasis AUD definition, screening, treatment; new biomarkers; additional environmental susceptibility factors; definition AH, recent studies corticosteroids role transplantation AH. Prevalence Burden Alcohol‐Associated Disease includes variety disorders: varying degrees severity, AC complicated hepatocellular carcinoma (HCC). comprises substantial portion overall burden, United States responsible rising rates liver‐related mortality States, especially among younger patients.3 In due all estimated at 5.5 per 100,000 2012; relative contribution predicted increase proportion deaths C virus (HCV) declines.3 More recently, shown have increased 2008 2016, particularly ages 25‐34 years old.4 Cirrhotic noncirrhotic prevalence has been approximately 2% general US population, whereas Veterans' population 327 enrollees.7 privately insured patients, 100 enrollees, overall, projected rise over time.3 Worldwide, account about 10% alcohol‐attributable deaths, nearly half those loss 22.2 million disability‐adjusted life annually.10 competes HCV leading indication (LT).12 Medical costs high driven part higher number admissions patients.9 addition, related frequently underestimated lack candor reporting.10 women, may be increasing faster rate than men, mirroring women States.9 incidence difficult estimate, diagnostic accuracy administrative coding less reliable AH.15 varies worldwide. were found 0.83% 2010.13 Denmark, period 1999‐2008 rose 37 46 persons year men 24 34 women.17 A similar study Finland reported 65 cases 13 27 women.18 cases, estimates coding, accurate highlights difficulty estimating burden Accurate assessment full challenging, given identifying earlier, asymptomatic such ASH or moderate challenges overcome broader noninvasive fibrosis tools awareness need diagnose early‐stage Many underestimate true counting only without diseases HCV, spite fact concomitant 61% diseases, particular steatohepatitis (NASH), hemochromatosis.14 These factors result much 2‐fold ALD‐related mortality.11 Diagnosis Alcohol Use Disorders Since publication Diagnostic Statistical Manual (Fifth Edition), former categories abuse dependence replaced "alcohol disorder," characterized mild, moderate, severe accumulation negative consequences symptoms (Table 1).20 common many people drinking amounts consequences.21 However, AUD, defined escalating consumption despite attempts cut back, personal consequences, appearance craving, also rise.21 Rates high‐risk risen dramatically, two nationally representative surveys adults 50% between 2001 2013, even greater increases minorities, lower socioeconomic status.22 type consumed binge (five drinks occurring monthly often) changed same time (2000‐2013) observed distilled spirits (+11.5%), wine (+7.7%), drinking.22 geographically, highest capita northern eastern European countries Russia.14 Table 1 - Criteria Disorder Your Experience Past Year 1. often taken larger longer intended. presence least 2 indicates AUD: Mild: 2‐3 Moderate: 4‐5 Severe: 6 2. There persistent desire unsuccessful efforts down control use. 3. great deal spent activities necessary obtain alcohol, recover effects. 4. Craving, strong urge alcohol. 5. Recurrent failure fulfill obligations work, school, home. 6. Continued having recurrent social interpersonal problems caused exacerbated effects 7. Important social, occupational, recreational up reduced because 8. situations it physically hazardous. 9. knowledge physical psychological problem 10. Tolerance, either following: Need markedly achieve intoxication desired effect; Markedly diminished effect amount 11. Withdrawal, manifested characteristic withdrawal syndrome; (or closely substance, benzodiazepine) relieve avoid symptoms. Screening, Brief Intervention, Referral Treatment public health termed "screening, brief intervention, referral treatment." This process begins screening assessing level Discussion can off‐putting who feel stigmatized judged.23 As such, nonjudgmental, open, accepting interview style help maintain therapeutic alliance, limit underreporting denial AUDs.24 readily apparent, early ALD. National Institute Abuse Alcoholism (NIAAA) guide clinicians assess (including AUDs), provide pharmacotherapy, refer treatment.25 Of note, NIAAA guidelines limits apply populations rather (i.e., there no known safe ALD). Similarly, Preventive Services Task Force (USPSTF) recently recommendations regarding "Unhealthy Adolescents Adults: Screening Behavioral Counseling Interventions." summary recommended unhealthy primary care settings 18 older, pregnant providing engaged risky hazardous behavioral counseling interventions use.26 Efforts uncover harmful aided structured, validated tools. recommends one‐question initial screen: "How times past you had 5 day (for men) 4 women)?" men; four hours). If patient reports single episode, performing Inventory Test (AUDIT) recommended.27 AUDIT used widely USPSTF. Its original form included 10 questions (Q1‐Q3), (Q4‐Q6), any (Q7‐Q10), score 8 being predictive scores 20 suggestive (now moderate/severe AUD).27 Questions 1‐3 alone "AUDIT‐C") efficient means but this shorter does information problems.29 AUDIT‐C brief, convenient, performs better CAGE questionnaires misuse.30 indicate tests do diagnosis point assessment. Clinicians' Guide outlines intervention treatment public; space limitations prevent thorough discussion interventions.31 medicine specialty clinics identify early, coupling implications motivational reduction.32 Mandatory inpatients emergency department effectively identifies users, assists improves connection AUD.33 Importantly, improve detection well ability predict long‐term outcomes, hospitalization diagnoses.34 Biomarkers moieties urine, blood, hair, metabolites surrogates timeframe drinking. Society Addiction Medicine Psychiatric suggest biomarkers aid support recovery, catalysts patient, "catch" punish patients.36 Principles discussing biomarker before testing, alliance disclosure. Each described subsequently limitations. They should confirm refute combined lab testing biomarkers), exam, interview. Liver‐related enzymes, bilirubin, gamma‐glutamyl transferase (GGT) macrocytic anemia inadequate establish ALD.38 GGT enzyme cell membranes body tissues, spleen. Although elevated sensitivity AST, specific use.40 Carbohydrate‐deficient transferrin (CDT) generated inhibition glycosylation. Typically percentage CDT (%CDT) total transferrin, differences levels, half‐life weeks.41 utility limited low 25%‐50% false‐positive results arising absence use.42 posttransplant %CDT appears accurate, improved function.45 small (about 0.1%) metabolized uridine diphosphoglucuronate–glucuronosyltransferase diphosphoglucuronate–sulfotransferase, producing ethyl glucuronide (EtG) sulfate (EtS).47 Both excreted blood hair. false positives negatives reported, specificity urinary EtG 89% 99%, respectively, after LT.48 Other mixed etiology cirrhosis, sensitivities 76% 82% within 3 days test EtS, specificities 93% 86%, respectively.49 Urinary EtS prolonged renal failure, window positive ingestion kidney Phosphatidylethanol (PEth) phospholipid formed reaction phosphatidylcholine ethanol catalyzed phospholipase D erythrocyte membrane.50 PEth 10‐14 days, although chronic, repeated appear influenced age, mass index (BMI), disease.51 Women levels compared men.58 interindividual variations metabolism, undergone LT cutoff 80 ng/mL 91% (95% confidence interval [CI], 82%‐100%) 77% CI, 70%‐83%).59 Another revealed 100% (CI, 79%‐100%) 96% 91%‐99%) ng/mL.50 performance current best Tables Performance Alcoholic Disease. Detection Time, Cutoff Values, Individual Tests Source Time Values Sensitivity Specificity PPV NPV Clinical CDT/%CDT* Blood weeks 1.7%‐2.6% 21%‐50% 50%‐100% 64%‐100% 86%‐93% Lower Urine 500 76%‐89% 93%‐99% 81%‐90% 91%‐99% False Hair Months 30 pg/mg 81%‐100% 83%‐98% 68%‐95% 86%‐100% Costly, requires hair sample, availability 75 86% 70% Often + 97%‐100% 66%‐96% 85% costly urine *Not preferred disialotransferrin glycoform correlates intake. Some conducted show pretransplant patients.Abbreviations: NPV, value; PPV, value. Direct Comparison Characteristics Patients Before After Transplantation Andresen‐Streichert42 21% (6‐45) (96‐100) (39‐100) — 71% (41‐91) 98% (94‐100) 90% (58‐99) 95% (89‐98) 84% (54‐98) 92% (82‐97) 68% (41‐89) (88‐99) (79‐100) (91‐99) (62‐96) Staufer43 25% 64% 99% Abbreviations: Statements All receiving gastroenterology/hepatology outpatient clinics, departments, inpatient screened routinely using questionnaires. offered (AUDIT‐C ≥4, >8, drinkers). recovery. glucuronide, sulfate, affected therefore preferable. Because abstinence most important factor improving survival multidisciplinary addiction specialists AUDs clinically evident mandatory. We present different types treatment, focus treatments studied however, reluctant see professional mental provider. For ambivalent cessation, interviewing behaviors, use.60 online resource now available recognize find high‐quality easily accessible user‐friendly web‐based system, Navigator.61 Psychosocial Approaches wide disorder relatively few Major rehabilitation, group therapies, individual therapy, family/couples counseling, mutual societies (such Alcoholics Anonymous). Within sessions, modalities target mechanisms behavior change. cognitive‐behavior therapy (CBT), interviewing, enhancement (MET), contingency management, 12‐step facilitation, network couples/family counseling.24 fashion systematic trials integrating alongside medical clinic produced usual care, typically provider outside center.62 Types evaluated randomized observational CBT, MET, psycho‐education, ways trial. Five controlled (RCTs) three enrolled exclusively one showed statistically benefit integrated combining care.63 psychosocial modest improvement again outcomes.66 data modality consistently superior another across populations.70 Based findings, integrated, remains option practical settings.71 Relapse Prevention Medications Pharmacotherapy Food Drug Administration (FDA) non‐FDA approved medications provided FDA‐approved medications: disulfiram, naltrexone, acamprosate. needed treat return 12 acamprosate naltrexone. Disulfiram naltrexone undergo metabolism damage, metabolism. none AC. relapse prevention treatment. agents gabapentin, baclofen, topiramate, ondansetron, varenicline.72 Baclofen, gamma‐aminobutyric acid–B (GABA‐B) receptor agonist, pharmacotherapy tested RCT small, uncontrolled studies.71 trial consisting compensated decompensated 12‐week course baclofen (10 mg daily) resulted decreased during observation while exhibiting acceptable safety profile.71 Notably, encephalopathy excluded trial, impair mentation, side data, demonstrating efficacy, toxic probably safe. Medication Dosing Metabolism (M) Excretion (E) Mechanism Action Considerations Naltrexone* 50 mg/d orally 380 sq M: Hepatic Opioid antagonist Not Hepatotoxicity concerns E: Mostly renal, fecal 2%‐3% Acamprosate* 666 tid None NMDA No instances hepatotoxicity Renal Gabapentin 600‐1,800 Modulates GABA activity action presynaptic calcium channels Monitor dysfunction worsening status/sedation 75%, Baclofen 30‐60 Hepatic, GABA‐B agonist Single Topiramate 75‐400 extensively augmentation, glutamate antagonism Adapted Winder et al.237*FDA‐approved list ALD.Abbreviations: GABA, acid; NMDA, N‐methyl‐D‐aspartate; sq, subcutaneous; tid, day. professionals and/or ensure access range options. Multidisciplinary, considered Pathophysiology Risk Factors Given widespread clear minority drinkers develop injurious linearly dose‐dependent, threshold beyond serious consumption.79 According "Dietary Guidelines Americans 2015‐2020," Department Health Human Agriculture, upper standard drink men.80 Furthermore, defines pattern brings concentration 0.08 g/dL, occurs five hours.81 Substance Mental Administration, conducts annual Survey Health, uses almost identical adding "on month."82 By contains 14 g (equivalent oz. beer [5% alcohol], 8‐9 malt liquor, table wine, 1.5 spirits). simplification would adopt measure constituted g. continues reviewed, suggesting adverse consequences.83 pathophysiology complex. Heavy fat redox state transcription regulate pathways involved acid synthesis (increased) oxidation (decreased). changes gut permeability lead portal vein endotoxin, activation innate immune response, inflammation, injury, apoptosis necrosis, cytokine oxidative stress cascades. cascades involve interactions resident macrophages (Kupffer cells), myofibroblasts, endothelial cells, hepatocytes.85 Interruption explain anti‐inflammatory anti‐oxidant agents. ongoing examining anti‐cytokine gut‐directed therapies. lists influence injury.86 drinking.88 Wine associated beverages.89 Daily conferred smoking independently cirrhosis.90 meta‐analysis confirmed women.83 ALD.92 Coffee protects against causes, AH.93 Affecting Implicated dose above drink/day (women), drinks/day (men) Pattern consumption: daily drinking; fasting, Smoking cigarettes Genetics*: PNPLA3, TM6SF2, MBOAT7, HSD17B13 Increased BMI Presence conditions: hemochromatosis, NAFLD, NASH ameliorating Equivocal Type Moderate *Typically predisposition, allele

Language: Английский

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Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(7), P. 969 - 977.e2

Published: June 3, 2022

Language: Английский

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Gut microbiome, liver immunology, and liver diseases

Cellular and Molecular Immunology, Journal Year: 2020, Volume and Issue: 18(1), P. 4 - 17

Published: Dec. 14, 2020

Language: Английский

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Hepatocellular carcinoma in the setting of alcohol-related liver disease

Journal of Hepatology, Journal Year: 2019, Volume and Issue: 70(2), P. 284 - 293

Published: Jan. 15, 2019

Language: Английский

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Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2022, Volume and Issue: 20(1), P. 37 - 49

Published: Oct. 18, 2022

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, per-capita rose from 5.5 litres in 2005 to 6.4 2016 projected increase further 7.6 2030. In 2019, an estimated 25% global cirrhosis deaths were associated with alcohol. The age-standardized death rate (ASDR) alcohol-associated was 4.5 per 100,000 population, the highest lowest ASDR Africa Western Pacific, respectively. annual incidence hepatocellular carcinoma (HCC) among patients ranged 0.9% 5.6%. Alcohol approximately one-fifth HCC-related 2019. Between 2012 2017, for declined, but liver cancer increased. Measures are required curb heavy reduce burden HCC. Degree intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis genetic variants key factors development this Review, we discuss epidemiology, projections risk

Language: Английский

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Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury

Experimental & Molecular Medicine, Journal Year: 2021, Volume and Issue: 53(2), P. 168 - 188

Published: Feb. 1, 2021

Abstract Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs ascribed to their ability promote oxidative stress, inflammation, apoptosis. Recent studies in basic translational research have revealed the contributing roles development progression various aging-related conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, cancer. Excessive chronic and/or acute binge consumption alcohol (ethanol), a widely consumed addictive substance, is known cause more than 200 including use disorder (addiction), alcoholic disease, brain damage. However, despite considerable amount this area, underlying molecular mechanisms by which abuse causes cellular toxicity organ damage remain be further characterized. In review, we first briefly describe properties AGEs: formation, accumulation, receptor interactions. We then focus on causative functions that impact diseases. also highlight biological connection AGE–alcohol–adduct formations alcohol-mediated tissue injury. Finally, potential opportunities for treatment AGE- alcohol-related adduct-associated disorders according mechanistic insights presented.

Language: Английский

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Changing epidemiology of hepatocellular carcinoma in Asia

Liver International, Journal Year: 2022, Volume and Issue: 42(9), P. 2029 - 2041

Published: March 23, 2022

Liver cancer is the fifth most common and second leading cause of malignant death in Asia, Asia reports 72.5% world's cases 2020. As histological type, hepatocellular carcinoma (HCC) accounts for majority incidence mortality liver cases. This review presents changing epidemiology HCC Asian countries recent years. Globally, aged, male populations remain group with highest risk HCC. Hepatitis B virus (HBV) hepatitis C (HCV) are still factors a slight decline countries, which mainly attributed to HBV vaccination newborns, prevention HCV horizontal transmission treatment chronic hepatitis. However, prevalence caused by metabolic factors, including syndrome, obesity non-alcoholic fatty diseases, increasing rapidly may eventually become major Excessive alcohol consumption continues be an important factor as average growing. Hopefully, great effort has been made better regions, significantly prolongs survival patients. tend use more aggressive intervention than European American but it remains unclear whether this preference related prognosis. In conclusion, disease burden management should adjusted dynamically based on epidemiology.

Language: Английский

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Health Benefits and Side Effects of Short-Chain Fatty Acids

Foods, Journal Year: 2022, Volume and Issue: 11(18), P. 2863 - 2863

Published: Sept. 15, 2022

The gut microbiota and their metabolites could play an important role in health diseases of human beings. Short-chain fatty acids (SCFAs) are mainly produced by microbiome fermentation dietary fiber also be bacteria the skin vagina. Acetate, propionate, butyrate three major SCFAs, bioactivities have been widely studied. SCFAs many benefits, such as anti-inflammatory, immunoregulatory, anti-obesity, anti-diabetes, anticancer, cardiovascular protective, hepatoprotective, neuroprotective activities. This paper summarizes benefits side effects with a special attention paid to mechanisms action. provides better support for people eating well ways developed into functional food prevent diseases.

Language: Английский

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Mitochondrial alterations in fatty liver diseases

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 78(2), P. 415 - 429

Published: Oct. 7, 2022

Fatty liver diseases can result from common metabolic diseases, as well xenobiotic exposure and excessive alcohol use, all of which have been shown to exert toxic effects on hepatic mitochondrial functionality dynamics. Invasive or complex methodology limits large-scale investigations mitochondria in human livers. Nevertheless, abnormal function, such impaired fatty acid oxidation oxidative phosphorylation, drives stress has identified an important feature steatohepatitis. On the other hand, be flexible adapt ambient condition prevent triglyceride lipotoxin accumulation obesity. Experience studies xenobiotics provided insights into regulation mitochondria. Increasing awareness joint presence disease-related (lipotoxic) alcohol-related further highlights need better understand their mutual interaction potentiation disease progression. Recent clinical assessed diets bariatric surgery mitochondria, are also evolving interesting therapeutic target non-alcoholic disease. This review summarises current knowledge with a focus linked obesity, type 2 diabetes xenobiotics.

Language: Английский

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Beneficial Effects of Betaine: A Comprehensive Review

Biology, Journal Year: 2021, Volume and Issue: 10(6), P. 456 - 456

Published: May 22, 2021

Medicinal herbs and many food ingredients possess favorable biological properties that contribute to their therapeutic activities. One such natural product is betaine, a stable, nontoxic substance present in animals, plants, microorganisms. Betaine also endogenously synthesized through the metabolism of choline or exogenously consumed dietary intake. mainly functions as (i) an osmolyte (ii) methyl-group donor. This review describes major physiological effects betaine whole-body health its ability protect against both liver- well non-liver-related diseases conditions. Betaine's role preventing/attenuating alcohol-induced metabolic-associated liver has been studied extensively reviewed here. Several studies show protects development hepatic steatosis, apoptosis, accumulation damaged proteins. Additionally, it can significantly prevent/attenuate progressive injury by preserving gut integrity adipose function. The protective are primarily associated with regulation methionine removing homocysteine maintaining cellular SAM:SAH ratios. Similarly, prevents fatty disease progression. In addition, neuroprotective role, preserves myocardial function, pancreatic steatosis. attenuates oxidant stress, endoplasmic reticulum inflammation, cancer development. To conclude, exerts significant potentially beneficial for alleviating diverse number human

Language: Английский

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