The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases

Hepatology, Journal Year: 2017, Volume and Issue: 67(1), P. 328 - 357

Published: July 17, 2017

Potential conflict of interest: Dr. Chalasani consults for and received grants from Eli Lilly. He NuSirt, AbbVie, Afimmune, Tobira, Madrigal, Shire, Cempra, Ardelyx, Axovant, Amarin. Intercept, Gilead, Galectin, Cumberland. Younossi Bristol‐Myers Squibb, Allergan, GlaxoSmithKline. advises Vertex Janssen. Brunt Gilead. Charlton NGM Bio, Genfit, Novartis. Conatus. Cusi Novo Nordisk. Tobira. Cirius, Novartis, Janssen, Zydus, Nordic, Rinella Nusirt. She Fibrogen, Immuron, Enanta, AbbVie. Harrison Echosens, Prometheus, Perspectum, HistoIndex. Garland, Pfizer. is on the speakers' bureau Alexion. Sanyal Salix, Conatus, malinckrodt, Echosens‐Sandhill, Sequana. employed by Bio. owns stock in GenFit, Hemoshear, Durect, Indalo. Pfizer, Boehringer Ingleheim, Nimbus, Nitto Denko, Lilly, Nordisk, Fractyl, Chemomab, Affimmune, Teva, Ardelyx. Squibb Merck. royalties UptoDate. Exhalenz, Arkana, NewCo LLC. The funding development this Practice Guidance was provided American Association Study Liver Diseases. This practice guidance approved Diseases June 15, 2017. Preamble provides a data‐supported approach to diagnostic, therapeutic, preventive aspects nonalcoholic fatty liver disease (NAFLD) care. A "Guidance" document different "Guideline." Guidelines are developed multidisciplinary panel experts rate quality (level) evidence strength each recommendation using Grading Recommendations, Assessment Development, Evaluation system. topic, statements, not recommendations, put forward help clinicians understand implement most recent evidence. commissioned (AASLD) an update Guideline published 2012 conjunction with Gastroenterology College (ACG).1 Sections where there have been no notable newer publications modified, so some paragraphs remain unchanged. narrative review statements based following: (1) formal analysis recently world literature topic (Medline search up August 2016); (2) Physicians' Manual Assessing Health Practices Designing Guidelines2; (3) guideline policies AASLD; (4) experience authors independent reviewers regard NAFLD. intended use physicians other health professionals. As clinically appropriate, should be tailored individual patients. Specific whenever possible, and, when such available or inconsistent, made consensus opinion authors.3 rather than article, interested readers can refer several comprehensive reviews.4 Because lengthy, make it easier reader, list all recommendations tabular form as Supporting Table S1. Definitions For defining NAFLD, must hepatic steatosis (HS), either imaging histology, lack secondary causes fat accumulation significant alcohol consumption, long‐term steatogenic medication, monogenic hereditary disorders (Table 1). In majority patients, NAFLD commonly associated metabolic comorbidities obesity, diabetes mellitus, dyslipidemia. categorized histologically into (NAFL) steatohepatitis (NASH; 2). NAFL defined presence ≥5% HS without hepatocellular injury hepatocyte ballooning. NASH inflammation (e.g., ballooning), any fibrosis. "advanced" fibrosis, will referring specifically stages 3 4, that is, bridging fibrosis cirrhosis. 1 - Common Causes Secondary Macrovesicular ‐ Excessive consumption Hepatitis C (genotype 3) WD Lipodystrophy Starvation Parenteral nutrition Abetalipoproteinemia Medications mipomersen, lomitapide, amiodarone, methotrexate, tamoxifen, corticosteroids) Microvesicular Reye's syndrome (valproate, antiretroviral medicines) Acute pregnancy HELLP Inborn errors metabolism lecithin‐cholesterol acyltransferase deficiency, cholesterol ester storage disease, Wolman's disease) 2 Related Encompasses entire spectrum FLD individuals ranging SH cirrhosis Presence ballooning hepatocytes risk progression failure considered minimal. (ballooning) progress cirrhosis, failure, rarely cancer. current previous histological Cryptogenic obvious etiology. Patients cryptogenic heavily enriched factors obesity MetS. NAS An unweighted composite steatosis, lobular inflammation, scores. useful tool measure changes histology patients clinical trials. Fibrosis scored separately.126 SAF score semiquantitative consisting amount, activity (lobular plus fibrosis.130 Incidence Prevalence General Population INCIDENCE OF There paucity data regarding incidence general population. few studies reported Asian countries, which briefly summarized below: study followed 11,448 subjects 5 years, documented ultrasound 12% (n = 1,418).10 635 Nagasaki atomic bomb survivors who were 11.6 19.9 per 1,000 person‐years.11 565 subjects, at 3‐5 diagnosed magnetic resonance (MR) (MRI) transient elastography (TE), estimated 13.5% (34 person‐years).12 cohort study, 77,425 free baseline average 4.5 years. During 348,193.5 person‐years follow‐up, 10,340 participants ultrasound, translating 29.7 person‐years.13 rates population Western countries even less reported: England International Classification Diseases, Tenth Revision (ICD‐10) codes 29 100,000 person‐years. Given inaccuracy administrative coding ICD‐10, likely underestimates true NAFLD.14 Israel 28 person‐years.15 meta‐analysis pooled regional Asia 52.34 (95% confidence interval [CI], 28.31‐96.77) whereas West around CI, 19.34‐40.57).16 PREVALENCE contrast data, significantly higher number describing prevalence These epidemiology NAFLD: overall global 25.24% 22.10‐28.65).16 highest Middle East (31.79% [95% 13.48‐58.23]) South America (30.45% 22.74‐39.440]) lowest Africa (13.48% [5.69‐28.69]).16 described elsewhere, gold standard diagnosing remains biopsy. biopsy feasible population, direct assessment NASH. Nevertheless, attempts estimate indirect means.16 following paragraphs: among had "clinical indication" 59.10% 47.55‐69.73).16 specific (random living‐related donors, etc.) 6.67% 2.17‐18.73) 29.85% 22.72‐38.12).16 these estimates, one estimates ranges between 1.5% 6.45%.16 High‐Risk Groups Features (MetS) only highly prevalent but components MetS also increase developing NAFLD.16 bidirectional association has strongly established. context, established conditions (obesity, type diabetes, hypertension, dyslipidemia) emerging (sleep apnea, colorectal cancer, osteoporosis, psoriasis, endocrinopathies, polycystic ovary obesity) NAFLD.21 Obesity (excessive body mass index [BMI] visceral common well‐documented factor fact, overweight obese severely obese, (>95%) severe undergoing bariatric surgery NAFLD.23 Type mellitus (T2DM): very high T2DM. suggested third two thirds diabetic NAFLD.18 It important remember importance T2DM develop almost simultaneously patient, confounds its causal relationship require additional investigation.28 Dyslipidemia: High serum triglyceride (TG) levels low high‐density lipoprotein (HDL) dyslipidemia attending lipid clinics 50%.29 large, cross‐sectional conducted 44,767 Taiwanese attended single clinic, enrollees stratified four subgroups their total HDL‐cholesterol TG ratios. 53.76%; however, those ratios 33.41%, group 78.04%. Age, sex, ethnicity: may vary according age, ethnicity.31 both stage appear age.34 Risk Factors Associated With Conditions Established Other Hypothyroidism Obstructive sleep apnea Dyslipidemia Hypopituitarism MetSa Hypogonadism Polycystic Pancreatoduodenal resection Psoriasis aThe Adult Treatment Panel III definition requires three more features: waist circumference greater 102 cm men 88 women; level 150 mg/dL greater; HDL 40 50 systolic blood pressure 130 mm Hg diastolic 85 (5) fasting plasma glucose 110 greater.287 Although controversial, male sex Furthermore, times women.33 issues ethnicity impact evolved over initial reports compared non‐Hispanic whites, Hispanic blacks lower NAFLD.39 American‐Indian Alaskan‐Native populations seem (0.6%‐2.2%), need confirmed.31 intriguing suggest ethnic differences explained genetic variation related patatin‐like phospholipase domain‐containing protein (PNPLA‐3) gene.40 summary, varies across world, 28.01 19.34‐40.57) 28.31‐96.77). Natural History Outcomes Over past decades, natural history NAFLD.1 growing NASH, especially degree adverse outcomes liver‐related mortality.1 shown increased mortality matched control NAFLD.53 cause death cardiovascular (CVD), comorbidities. 12th leading second NAFLD.55 Cancer‐related top rate.56 meta‐analysis, liver‐specific determined 0.77 (range, 0.33‐1.77) 11.77 7.10‐19.53) 15.44 11.72‐20.34) 25.56 6.29‐103.80), respectively.16 1.94 1.28‐2.92) 1.05 0.70‐1.56), feature fibrosis; specifically, zone sinusoidal periportal (stage 2) advanced (bridging [stage 3] 4]). independently predictive mortality.44 now third‐most carcinoma (HCC) United States, attributed enormous condition.60 epidemic NAFLD‐related HCC 9% annual rate.61 older, shorter survival time, often heart die primary cancer patients.60 Around 13% Veteran Administration did Among factors, having absence confirms small cirrhosis.62 recognize what "burned out" NAFLD.63 particular disproportionately (T2DM, MetS) resemble pathological seldom features consistent cirrhosis.63 Important One surrogates documentation progressive (HF). HF showed mean 0.09 0.06‐0.12).16 Several investigated comparison hepatitis cirrhosis.9 prospective, U.S.‐based observed decompensation cirrhosis.65 However, international 247 cirrhosis) duration 85.6 ± 54.5 months 10‐year 81.5%—a cirrhosis.1 confirmed increasing numbers presenting requiring transplantation (LT). ranked second‐most LT overtake future, virus (HCV) treated curative antiviral regimens.9 noted previously, another important, outcome HCC. 0.44 0.29‐0.66) person‐years.16 HCC, 54.9% cases HCV, 16.4% alcoholic 14.1% 9.5% B virus. given extremely large within population.61 Alcohol Consumption Definition By definition, indicates ongoing amounts alcohol. precise suspected uncertain. meeting recommended that, trials candidate eligibility purposes, >21 drinks week >14 women 2‐year period preceding histology.68 According National Institute Abuse Alcoholism (NIAAA), drink contains about 14 g pure alcohol.69 Unfortunately, inconsistent.70 Statement: 1. Ongoing reasonable threshold evaluating Incidentally Discovered HEPATIC STEATOSIS (HS) Some thoracic abdominal reasons symptoms, signs, abnormal biochemistry demonstrate unsuspected HS. 11% incidentally discovered calculated (NFS).71 optimal diagnostic management strategies patient investigated. Statements: 2. detected symptoms signs attributable chemistries evaluated though they worked accordingly. 3. incidental normal biochemistries assessed alternate medications. Screening Primary Care, Diabetes, Clinics argued systematic screening least higher‐risk obesity. example, do suggests patients.72 gaps our knowledge diagnosis, history, treatment recent, cost‐effective Markov model present, because disutility treatment.75 sufficiently sensitive serve tests, TE potentially sensitive, utility tools unproven. called "vigilance" chronic (CLD) routine screening.76 4. Routine high‐risk groups care, advised time uncertainties surrounding tests options, along benefits cost‐effectiveness screening. 5. suspicion diabetes. Clinical decision aids NFS fibrosis‐4 (FIB‐4) vibration controlled (VCTE) used identify cirrhosis). Family Members familial clustering NAFLD.77 retrospective Willner et al. 18% similarly affected first‐degree relative.80 aggregation children after adjusting race, BMI, heritability MR‐measured fraction 0.386, present family members elevated alanine aminotransferase (ALT) obesity.81 Data reporting variable, detectable heritability, Hungarian twin cohort, nearly universal adolescents.77 ongoing, well‐characterized community‐dwelling twins California, MRI quantify correlated monozygotic, dizygotic, pairs, multivariable adjustment, 0.52 0.31‐0.73; P < 1.1 × 10–11) 0.50 0.28‐0.72; 6.1 10–1), respectively.84 6. Systematic currently. Initial Patient Suspected diagnosis competing etiologies HS, coexisting CLD. alternative C, medications, parenteral nutrition, Wilson's (WD), malnutrition When newly exclude CLD, including hemochromatosis, autoimmune viral hepatitis, alpha‐1 antitrypsin WD, drug‐induced injury. Serological evaluation uncover laboratory abnormalities always reflect disease. Two examples ferritin antibodies. Mildly does necessarily indicate iron overload, progression. somewhat conflicting, >1.5 upper limit (ULN) 628 adults.85 If transferrin saturation hemochromatosis excluded. Mutations HFE gene occur variable frequency significance unclear.86 setting determine extent Low titers autoantibodies, particularly antismooth muscle antinuclear antibodies, generally epiphenomenon consequence, 864 Research Network (NASH CRN), elevations autoantibodies (antinuclear antibodies >1:160 >1:40) 21% atypical features.87 While diseases being excluded, carefully taken comorbidities, central dyslipidemia, insulin resistance (IR), hypothyroidism, syndrome, obstructive apnea. 7. essential 8. persistently ferritin, saturation, context homozygote heterozygote C282Y mutation, considered. 9. suggestive (>5 ULN aminotransferases, globulins, albumin ratio) prompt work‐up 10. consider IR Noninvasive Steatohepatitis Advanced fairly dichotomous—NAFL benign, currently reliable identifying (SH) acknowledged limited cost, sampling error, procedure‐related morbidity mortality. Serum computed tomography (CT), MR, reliably Therefore, interest prediction rules noninvasive biomarkers detailed discussion beyond scope guidance.47 NONINVASIVE QUANTIFICATION IN predict severity SH)88 NAFLD.89 MR imaging, spectroscopy92 proton density fraction,93 excellent modality quantifying widely trials.95 obtain continuous attenuation parameters promising ambulatory setting.74 noninvasively qua

Language: Английский

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Mechanisms of NAFLD development and therapeutic strategies

Nature Medicine, Journal Year: 2018, Volume and Issue: 24(7), P. 908 - 922

Published: June 29, 2018

Language: Английский

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Mechanisms of hepatic stellate cell activation

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2017, Volume and Issue: 14(7), P. 397 - 411

Published: May 10, 2017

Language: Английский

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Molecular and cellular mechanisms of liver fibrosis and its regression

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2020, Volume and Issue: 18(3), P. 151 - 166

Published: Oct. 30, 2020

Language: Английский

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Hepatic stellate cells as key target in liver fibrosis

Advanced Drug Delivery Reviews, Journal Year: 2017, Volume and Issue: 121, P. 27 - 42

Published: May 12, 2017

Language: Английский

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EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update

Journal of Hepatology, Journal Year: 2021, Volume and Issue: 75(3), P. 659 - 689

Published: June 22, 2021

Language: Английский

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Liver inflammation and fibrosis

Journal of Clinical Investigation, Journal Year: 2017, Volume and Issue: 127(1), P. 55 - 64

Published: Jan. 2, 2017

Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in United States. Hepatocyte steatosis a component metabolic syndrome insulin resistance. Hepatic may be benign or progress hepatocyte injury initiation inflammation, activates immune cells. While Kupffer cells are resident macrophage liver, inflammatory such as infiltrating macrophages, T lymphocytes, neutrophils, DCs all contribute inflammation. The activate hepatic stellate cells, major source myofibroblasts liver. Here we review their crosstalk with myofibroblasts.

Language: Английский

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Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues

Molecular Aspects of Medicine, Journal Year: 2018, Volume and Issue: 65, P. 37 - 55

Published: Sept. 13, 2018

Language: Английский

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Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus

Annals of Internal Medicine, Journal Year: 2016, Volume and Issue: 165(5), P. 305 - 305

Published: June 20, 2016

The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited.To determine the efficacy safety pioglitazone treatment patients with NASH T2DM.Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682).University hospital.Patients (n = 101) T2DM biopsy-proven were recruited from general outpatient clinics.All prescribed a hypocaloric diet (500-kcal/d deficit weight-maintaining caloric intake) then randomly assigned pioglitazone, 45 mg/d, placebo for 18 months, followed an 18-month open-label phase treatment.The primary outcome was reduction at least points fatty liver disease activity score histologic categories without worsening fibrosis. Secondary outcomes included other outcomes, hepatic triglyceride content measured magnetic resonance proton spectroscopy, parameters.Among 58% achieved (treatment difference, 41 percentage [95% CI, 23 59 points]) 51% had resolution 32 [CI, 13 51 (P < 0.001 each). Pioglitazone also associated improvement individual scores, including fibrosis -0.5 -0.9 0.0]; P 0.039); reduced 19% 7% -7 -10 -4 points]; 0.001); improved adipose tissue, hepatic, muscle insulin sensitivity vs. all). All improvements persisted over 36 months therapy. overall rate adverse events did not differ between groups, although weight gain greater (2.5 kg placebo).Single-center study.Long-term safe effective NASH.Burroughs Wellcome Fund American Diabetes Association.

Language: Английский

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NAFLD and diabetes mellitus

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2016, Volume and Issue: 14(1), P. 32 - 42

Published: Oct. 12, 2016

Language: Английский

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