Lippincott Williams & Wilkins (LWW): Hepatology Journal: Published on May, 2023

This new American Association for the Study of Liver Diseases (AASLD) Guidance document reflects many advances in the field pertinent to any practitioner caring for patients with NAFLD and emphasizes advances in noninvasive risk stratification and therapeutics.

The most profound advances in NAFLD relevant to clinical practice are in biomarkers and therapeutics. Biomarkers and noninvasive tests (NITs) can be used clinically to either exclude advanced diseases or identify those with a high probability of cirrhosis.

DEFINITIONS

NAFLD is an overarching term that includes all disease grades and stages and refers to a population in which ≥5% of hepatocytes display macrovesicular steatosis in the absence of a readily identified alternative cause of steatosis (eg, medications, starvation, monogenic disorders) in individuals who drink little or no alcohol (defined as < 20 g/d for women and <30 g/d for men).

The spectrum of disease includes NAFL, characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation, and NASH, which is additionally characterized by the presence of inflammation and cellular injury (ballooning), with or without fibrosis, and finally Cirrhosis, which is characterized by bands of fibrous septa leading to the formation of cirrhotic nodules, in which the earlier features of NASH may no longer be fully appreciated on a liver biopsy.

Association between disease stage and adverse outcomes

Key points:

Patients with NASH and F2–4 fibrosis are at higher risk for liver-related events and mortality and are considered to have “at-risk” NASH.

The rates of fibrosis progression and hepatic decompensation vary depending on baseline disease severity, genetic, individual environmental, and comorbid disease determinants.

CVD and nonhepatic malignancies are the most common causes of mortality in patients with NAFLD without advanced fibrosis; death from liver disease predominates in patients with advanced fibrosis.

Prevalence and incidence of CKD is higher among patients with NASH and advanced fibrosis.

Death from nonhepatic malignancies is a common cause of death in patients with NAFLD, and thus, adherence to age-appropriate cancer screening has the potential to improve survival.

Patients with “at-risk” NASH (NASH with at least stage 2 fibrosis) are at increased risk of developing cirrhosis and liver-related complications.

Highly elevated liver stiffness, FIB-4, and ELF scores can predict an increased risk of hepatic decompensation and mortality.

Summary of key concepts to guide clinical practice

Screening for advanced fibrosis and risk stratification

• General population-based screening for NAFLD is not advised

• High-risk individuals, such as those with T2DM, medically complicated obesity, family history of cirrhosis, or more than mild alcohol consumption, should be screened for advanced fibrosis

• All patients with hepatic steatosis or clinically suspected NAFLD based on the presence of obesity and metabolic risk factors should undergo primary risk assessment with FIB-4

• In patients with pre-DM, T2DM, or 2 or more metabolic risk factors (or imaging evidence of hepatic steatosis) primary risk assessment with FIB-4 should be repeated every 1–2 y, due to limitations in the performance of FIB-4 in the context of T2DM. When available, a secondary assessment of liver fibrosis severity may be considered

• If FIB-4 ≥1.3, VCTE, MRE, or ELF may be used to exclude advanced fibrosis

• An elevated FIB-4 followed by elevated liver stiffness or an increased ELF can be used as a sequential strategy to identify advanced fibrosis

• In the nongastroenterology/hepatology setting, patients with suspected advanced NASH or discordant NITs should be referred to a specialist for evaluation, management, and/or further diagnostic evaluation

• Patients with NASH cirrhosis are at highest risk for liver-related outcomes and require routine surveillance for HCC, esophageal varices, and monitoring for decompensation

• ELF >11.3 has been linked to hepatic decompensation in the setting of advanced fibrosis and should prompt screening accordingly

Pearls for the assessment of NAFLD

• Aminotransferase levels are frequently normal in patients with advanced liver disease due to NASH and should not be used in isolation to exclude the presence of NASH with clinically significant fibrosis

• Normative values for ALT reported by most laboratories exceed what is considered a true normal. As a general rule, ALT >30 U/L should be considered abnormal

• Although standard ultrasound can detect hepatic steatosis, it is not recommended as a tool to identify hepatic steatosis due to low sensitivity across the NAFLD spectrum

• CAP as a point-of-care technique may be used to identify steatosis. MRI-PDFF can additionally quantify steatosis

Disease modifying interventions in patients with NAFLD

• Patients with NAFLD who are overweight or obese should be prescribed a diet that leads to a caloric deficit.

• When possible, diets with limited carbohydrates and saturated fat and enriched with high fiber and unsaturated fats (eg, Mediterranean diet) should be encouraged due to their additional cardiovascular benefits

• Coffee consumption (caffeinated or not) of at least 3 cups daily is associated with less advanced liver disease.

• Patients with NAFLD should be strongly encouraged to increase their activity level to the extent possible. Individualized prescriptive exercise recommendations may increase sustainability and have benefits independent of weight loss

• Bariatric surgery should be considered as a therapeutic option in patients who meet criteria for metabolic weight loss surgery as it effectively resolves NAFLD or NASH in the majority of patients without cirrhosis and reduces mortality from CVD and malignancy

Off-label use of approved medications for comorbid conditions

• There are currently no FDA-approved medications for the treatment of NAFLD, but drugs approved to treat associated comorbidities with potential benefit in NAFLD may be considered in the appropriate clinical setting

• Semaglutide can be considered for its approved indications (T2DM/obesity) in patients with NASH as it confers a cardiovascular benefit and improves NASH

• Pioglitazone improves NASH and can be considered for patients with NASH in the context of patients with T2DM

• Vitamin E can be considered in select individuals as it improves NASH in some patients without diabetes

• Available data on semaglutide, pioglitazone, and vitamin E do not demonstrate an antifibrotic benefit, and these compounds have not been carefully studied in patients with cirrhosis

• Metformin, UDCA, DPP-4, statins, and silymarin are well studied in NASH and should not be used as a treatment for NASH as they do not offer a meaningful histological benefit

• Statins are safe and recommended for CVD risk reduction in patients with NAFLD across the disease spectrum, including compensated cirrhosis

• Limited data exist on the safety and efficacy of statins in patients with decompensated cirrhosis, although statin use could be considered in patients with high CVD risk with careful monitoring

• Hypertriglyceridemia can be managed through lifestyle changes and supplementation with omega-3 fatty acids, icosapent ethyl, or fibrates

Role of alcohol

• In patients with NAFLD, alcohol can be a cofactor for liver disease progression, and intake should be assessed on a regular basis

• Patients with clinically significant hepatic fibrosis (≥F2) should abstain from alcohol use completely

Other considerations

• Improvement in ALT or reduction in liver fat content by imaging in response to an intervention may indicate histological improvement in disease activity

• First-degree relatives of patients with NASH cirrhosis should be counseled regarding their increased individual risk and offered screening for advanced hepatic fibrosis

Abbreviations: ALT, alanine aminotransferase; CAP, controlled attenuation parameter; CVD, cardiovascular disease; DM, diabetes mellitus; DPP-4, dipeptidyl peptidase-4; ELF, Enhanced Liver Fibrosis; FDA, US Food and Drug Administration; FIB-4, fibrosis-4 index; GI, gastrointestinal; MRE, magnetic resonance elastography; MRI-PDFF, MRI–proton density fat fraction; NIT, noninvasive test; T2DM, type 2 diabetes mellitus; UDCA, ursodeoxycholic acid; VCTE, vibration-controlled elastography.

Doctors Liked to Read More