PREAMBLE
The study of NAFLD has intensified significantly, with more than 1400 publications since 2018, when the last American Association for the Study of Liver Diseases (AASLD) Guidance document was published. This new 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. A separate guideline focused on the management of patients with NAFLD in the context of diabetes has been written jointly by the American Association of Clinical Endocrinology and AASLD. Given the significant growth in pediatric NAFLD, it will not be covered here to allow for a more robust discussion of the diagnosis and management of pediatric NAFLD in the upcoming AASLD Pediatric NAFLD Guidance. A “Guidance” differs from a “Guideline” in that it is not bound by the Grading of Recommendations, Assessment Development and Evaluation system. Thus, actionable statements rather than formal recommendations are provided herein. The highest available level of evidence was used to develop these statements, and, where high-level evidence was not available, expert opinion was used to develop guidance statements to inform clinical practice. Key points highlight important concepts relevant to understanding the disease and its management.
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. NIT “cut points” vary with the populations studied, underlying disease severity, and clinical setting. Those proposed in this guidance are meant to aid decision-making in the clinic and are not meant to be interpreted in isolation. Identifying patients with “at-risk” NASH (biopsy-proven NASH with stage 2 or higher fibrosis) is a more recent area of interest. Although the definitive diagnosis and staging of NASH remain linked to histology, noninvasive tools can now be used to assess the likelihood of significant fibrosis, predict risk of disease progression and decompensation, make management decisions, and, to some degree, assess response to treatment.
There is an ongoing debate over the nomenclature of fatty liver disease, which had not been finalized at the time this guidance was published. At the culmination of a rigorous consensus process, it is intended that any formal change in nomenclature will advance the field without a negative impact on disease awareness, clinical trial endpoints, or the drug development/approval process. Furthermore, it should allow for the emergence of newly recognized disease subtypes to address the impact of disease heterogeneity, including the role of alcohol, on disease progression and response to therapy. Input from patients has been central to all stages of the consensus process to ensure the minimization of nomenclature-related stigma.
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.
UPDATE ON EPIDEMIOLOGY AND NATURAL HISTORY
The prevalence of NAFLD and NASH is rising worldwide in parallel with increases in the prevalence of obesity and metabolic comorbid disease (insulin resistance, dyslipidemia, central obesity, and hypertension). The prevalence of NAFLD in adults is estimated to be 25%–30% in the general population and varies with the clinical setting, race/ethnicity, and geographic region studied but often remains undiagnosed. The associated economic burden attributable to NASH is substantial. The prevalence of NASH in the general population is challenging to determine with certainty; however, NASH was identified in 14% of asymptomatic patients undergoing colon cancer screening. This study also highlights that since the publication of a prior prospective prevalence study, the prevalence of clinically significant fibrosis (stage 2 or higher fibrosis) has increased >2-fold. This is supported by the projected rise in NAFLD prevalence by 2030, when patients with advanced hepatic fibrosis, defined as bridging fibrosis (F3) or compensated cirrhosis (F4), will increase disproportionately, mirroring the projected doubling of NASH. As such, the incidence of hepatic decompensation, HCC, and death related to NASH cirrhosis are likewise expected to increase 2- to 3-fold by 2030. Although expected to increase further, NASH-related cirrhosis is already the leading indication for liver transplantation in women and those >65 years of age and is on par with alcohol as the leading indication overall.
Natural history of disease progression
Data from meta-analyses and pooled studies demonstrate that fibrosis and the presence of steatohepatitis are the primary predictors of disease progression. The collinearity between NASH and the fibrosis it induces makes it challenging to demonstrate the independent contribution of NASH to fibrosis and adverse outcomes in multivariable analyses. Although fibrosis is the primary determinant of adverse outcomes, increased liver-related morbidity and mortality and nonhepatic malignancy are observed in patients with NAFLD even in the absence of fibrosis on initial biopsy. Nevertheless, patients with NASH and at least stage 2 fibrosis (F2), referred to as “at-risk” NASH, have a demonstrably higher risk of liver-related morbidity and mortality.
Fibrosis progression is influenced by many factors such as the presence and severity of comorbid disease, genomic profile, and environmental factors. A meta-analysis of placebo-treated patients in 35 NASH trials found minimal progression, suggesting that nonpharmacologic factors (frequent visits/monitoring, dietary or lifestyle counseling, or changes) may reduce progression. An earlier meta-analysis of cohorts with longitudinal paired biopsies demonstrated a NAFLD fibrosis progression rate of one stage per 7 years in those with NASH versus 14 years for those with NAFL.
The diagnosis of cirrhosis, determined by biopsy or noninvasively, is important because it changes clinical management. Those with cirrhosis require biannual screening for HCC as well as screening for varices and monitoring for signs or symptoms of decompensation. Among patients with cirrhosis, progression to clinical decompensation ranges from 3% to 20% per year.
Association between disease stage and adverse outcomes
The most common causes of death in patients with NAFLD overall are cardiovascular disease (CVD) and nonhepatic malignancy, followed by liver disease. The amount of liver fibrosis identified histologically in patients with NAFLD has been strongly linked to the development of liver-related outcomes and death. Bridging fibrosis and cirrhosis are associated with an exponentially greater risk of liver-related morbidity and mortality than earlier stages of fibrosis. In a prospective study of 1773 patients, all-cause mortality in those with fibrosis stages 0–2 was 0.32 per 100 person-years, compared with 0.89 per 100 person-years in those with bridging fibrosis and 1.76 per 100 person-years in those with cirrhosis. After correcting for multiple factors, hepatic decompensation was associated with all-cause mortality (HR, 6.8; 95% CI, 2.2–21.3). Cirrhosis regression has been associated with a 6-fold reduction in liver-related events in clinical trials.
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.
MOLECULAR AND CELLULAR PATHOGENESIS
The presence and severity of NAFL and NASH are substantially determined by factors that govern the supply and disposition of fatty acids, diacylglycerols, ceramides, cholesterol, phospholipids, and other intrahepatic lipids. Energy oversupply and limited adipose tissue expansion contribute to insulin resistance and metabolic disease. When energy intake exceeds metabolic needs and disposal capacity, carbohydrates, in the form of dietary sugars (eg, fructose, sucrose, and glucose), drive the formation and accumulation of intrahepatic fat from de novo lipogenesis (DNL). There is substantial interindividual heterogeneity in the role of DNL among patients with NAFLD. In addition, the type of fat consumed plays a role in the development of NASH, with a higher risk associated with saturated versus unsaturated fat consumption (Figure 1).
FIGURE 1
Pathogenic drivers of NAFLD as therapeutic targets. Overview of the major mechanisms that lead to the phenotype of NASH and its consequences, many of which can be leveraged therapeutically. Not shown are the many areas where genetic polymorphisms may play a role and where important modifying factors such as cholesterol, types of dietary fats consumed [saturated vs. polyunsaturated fatty acid (PUFA)], the gut microbiome, uric acid, and periodic hypoxia (sleep apnea) may also influence these pathways. A primary disease driver may be an oversupply of fat to adipocytes such that their ability to store triglyceride without inducing cell stress is exceeded, which activates inflammatory pathways and causes insulin resistance. Understanding the major drivers of NASH facilitates the rational development of therapies for patients with NASH. Specific sites of intervention that might prevent or resolve NASH include interventions that modulate food intake (eg, portion sizes, bariatric surgery, satiety regulators), increase energy disposal (eg, exercise, thermogenesis), improve adipocyte insulin sensitivity [eg, peroxisome proliferator-activated receptor (PPAR)γ ligands], impair de novo lipogenesis (eg, acetyl-coenzyme A carboxylase and fatty acid synthase inhibitors), increase hepatic oxidative metabolism (PPARα ligands and thyroid hormone receptor beta agonists), and attenuate inflammation, cell death, and fibrogenesis. Therapeutic agents affecting multiple metabolic pathways throughout the body with potential beneficial effects on the liver include peptide hormone analogs (eg, analogs of fibroblast growth factor-19, fibroblast growth factor-21, glucagon-like peptide-1, gastric inhibitory peptide, glucagon) and nuclear receptor ligands such as drugs that target PPARα, PPARδ, PPARγ, thyroid hormone receptor β, and farnesoid X receptor. Abbreviations: ER, endoplasmic reticulum; CVD, cardiovascular disease.
Insulin resistance is nearly universal in patients with NAFLD and is present in the liver, adipose tissue, and muscle. Adipose tissue insulin resistance is characterized by increased release of free fatty acids from adipocytes (lipolysis) in the fasting state and worsens with the progression of NAFLD to NASH.
Important factors that govern energy disposal include the frequency and intensity of exercise, the activation of brown adipose tissue to an energy-consuming thermogenic phenotype, and counterregulatory mechanisms that diminish energy disposal in response to reductions in calorie intake. The ability and desire to engage in regular exercise can be strongly influenced by personal, community, corporate, societal, and legislative decisions, all of which thus have roles in the development of NASH.
The heterogeneity of factors contributing to the pathophysiology of NASH among patients has impeded the development of diagnostic tests and therapeutics. Although in some patients, the development and progression of NASH are driven by substrate overload and insulin resistance, in other patients, disease progression is heavily influenced by genetic factors impacting hepatocyte lipid handling. Genetic polymorphisms have been associated with more advanced liver disease and the development of HCC in NASH. The I148M polymorphism of PNPLA3 impairs lipolysis of triglyceride in lipid droplets, and polymorphisms in other proteins that play a role in hepatocyte fat metabolism have also been linked to the prevalence and severity of NAFLD, including transmembrane 6 superfamily member 2 (TM6SF2), which may play a role in cholesterol metabolism, and MBOAT7, which influences phospholipid metabolism. Recently, loss-of-function variants in HSD17B13, a gene that encodes an enzyme that also localizes to lipid droplets in hepatocytes, have been linked to protection against NASH, progressive fibrosis, and HCC. Rare loss-of-function mutations in CIDEB, a protein needed for activation of DNL, have also been shown to be protective.
A host of additional factors, the review of which is beyond the scope of this guidance, contribute to heterogeneity in disease activity and progression. Additional factors such as hepatocyte uric acid production, exposure to products derived from the gut microbiome, and perhaps low hepatic magnesium levels, may also contribute to the NASH phenotype. Transcriptomic profiling of large cohorts of patients is further contributing to our understanding of this disease heterogeneity and its progression. The response of the liver to lipotoxic injury includes activation and recruitment of resident macrophages, which further contributes to hepatocellular injury and stellate cell activation as part of a complex interplay among hepatic cell types. Although markers of oxidative stress have been a consistent finding in NASH, its role in the pathogenesis of NASH in humans remains uncertain.
Key points:
Fundamental elements of NASH pathogenesis include an imbalance between nutrient delivery to the liver and their utilization and disposal coupled with adipose tissue dysfunction. Interindividual differences in genetic, dietary, behavioral, and environmental factors influence disease course.
Systemic inflammation, particularly stemming from dysfunctional adipose tissue, contributes to disease progression.
Insulin resistance contributes to the development of NAFLD and promotes disease progression.
COMORBID CONDITIONS ASSOCIATED WITH NAFLD
NAFLD is closely linked to and often precedes the development of metabolic abnormalities (insulin resistance, dyslipidemia, central obesity, and hypertension). Having several metabolic abnormalities confers an even greater risk of histological progression of NASH and all-cause mortality. The association between NAFLD and metabolic comorbidities may also reflect bidirectional interactions between the liver and other endocrine organs (eg, pancreas, adipose tissue, muscle) through the secretion of hepatokines that regulate fatty acid metabolism, insulin action, and glucose metabolism, adipokines, and myokines.
Obesity
The presence and severity of obesity are associated with NAFLD and disease progression. Body fat distribution is an important determinant of the contributory role of obesity in NAFLD (Table 1). Android body fat distribution, characterized by increased truncal subcutaneous fat and visceral fat confers a higher risk of insulin resistance, CVD, and hepatic fibrosis, irrespective of body mass index (BMI). In contrast, gynoid body fat distribution, characterized by increased subcutaneous body fat predominantly in the hips or buttocks, appears to be protective against NAFLD. Visceral fat, which is more metabolically active and inflammatory than subcutaneous fat, mediates the majority of this risk. As adipose tissue becomes more metabolically stressed, dysfunctional, and inflamed, insulin signaling is progressively impaired, promoting the inappropriate release of fatty acids leading to intrahepatic lipid accumulation and inflammation.
TABLE 1
Initial evaluation of a patient with NAFLD
| History | Weight history; medical comorbidities; recent and current medications; family history of T2DM, NAFLD, or cirrhosis; screening for OSA; alcohol use, including amount, pattern of use, and duration |
| Physical examination | Body fat distribution (eg, android vs. gynoid, lipodystrophic), features of insulin resistance (eg, dorsal-cervical fat pad, acanthosis nigricans), features of advanced liver disease (eg, firm liver, splenomegaly, prominent abdominal veins, ascites, gynecomastia, spider angiomata, palmar erythema) |
| Laboratory tests | Hepatic panel, CBC with platelets, fasting plasma glucose and glycated hemoglobin (A1c), fasting lipid profile, creatinine and urine microalbumin or protein to creatinine ratio, hepatitis C if not previously screened. Consider as appropriate other causes of steatosis/steatohepatitis (Table 2). Additional evaluation if elevated liver chemistries present: autoimmune serologies, transferrin saturation, ceruloplasmin, alpha-1 antitrypsin genotype, or phenotype |
Type 2 diabetes mellitus (T2DM)
T2DM is the most impactful risk factor for the development of NAFLD, fibrosis progression, and HCC. Given the central pathogenic role that insulin resistance plays in the pathogenesis of both T2DM and NAFLD, it is not surprising that patients with T2DM have a higher prevalence of NAFLD (ranging from 30% to 75%) and a higher risk of developing NASH with fibrosis. Furthermore, the probability of advanced fibrosis increases with the duration of T2DM. Although there is potential for lead time and length time biases, these studies underscore the strong relationship between T2DM and NAFLD.
The relationship between NAFLD and T2DM is bidirectional in epidemiological studies. Early in its course, NAFLD is associated with a reduction in insulin sensitivity, even in the absence of overt diabetes. The presence of NAFLD is associated with a 2- to 5-fold risk of incident diabetes, and therefore, patients with NAFLD should be screened for the presence of T2DM (Table 1). Furthermore, as liver disease progresses, so does insulin resistance and beta cell failure, making diabetes more challenging to manage. The role of glycemic control in the progression of NAFLD/NASH remains controversial, with 2 small studies showing an association between poor glycemic control and hepatocellular injury and liver fibrosis, whereas other studies have not corroborated this finding. Although NAFLD has also been described in patients with type 1 diabetes, its prevalence is much lower than in T2DM, and it is closely related to coexistent metabolic risk factors (eg, higher BMI).
Hypertension
Hypertension is commonly associated with NAFLD. There is a higher incidence of hypertension in those with NAFLD across the disease spectrum, with incidence rates of 6.5 per 100 person-years in early disease to 14.5 per 100 person-years in those with cirrhosis. The presence of hypertension is clearly additive to other metabolic comorbidities with respect to the epidemiological risk of NASH and has been associated with fibrosis progression. Whether hypertension mechanistically promotes the development of NAFLD/NASH or the inverse, or both are manifestations of underlying metabolic disease drivers, has not been established.
Dyslipidemia
Patients with NAFLD are twice as likely to exhibit plasma lipid abnormalities as those without NAFLD, and the serum lipid subfractions are more atherogenic in patients with NAFLD. NASH resolution can lead to improved plasma HDL cholesterol and triglyceride levels and favorably impact lipoprotein subfractions, although it is unclear to what extent this is driven by the mechanism of the therapeutic intervention. As patients progress to cirrhosis, they continue to remain at high risk for coronary artery disease despite the normalization of serum lipids and lipoproteins due to hepatic synthetic failure.
Management of dyslipidemia in NAFLD should include the use of moderate-intensity to high-intensity statins as first-line therapy based on lipid risk levels and atherosclerotic CVD risk scores. Combination therapies of statins with other hypolipemic agents, such as ezetimibe, PCSK-9 inhibitors, inclisiran, bempedoic acid, fibrates, omega 3 fatty acids, or icosapent ethyl, should be considered when monotherapy with a statin does not achieve therapeutic goals.
Statins are safe in patients with NAFLD across the disease spectrum, including advanced liver disease, and lead to a demonstrable reduction in cardiovascular morbidity and mortality. However, in clinical practice, they are often underused despite extensive data demonstrating safety, even among patients with cirrhosis. Statins are also considered safe in the context of compensated cirrhosis and may have beneficial effects on future decompensation and HCC risk, although additional confirmatory data are needed. Although statins have been safely used in patients with decompensated cirrhosis, the risk of statin-induced adverse events might be higher in this population, and thus more caution is warranted. In patients with decompensated cirrhosis and high CVD risk undergoing evaluation for liver transplantation, statin use can be considered with careful monitoring.
In patients with NAFLD and severely elevated triglycerides levels (eg, >500 mg/dL), fibrates, or a combination of fibrates with prescription grade omega-3 fatty acids or icosapent ethyl, should be used to reduce the risk of pancreatitis. Fibrates may also improve atherosclerotic CVD outcomes when triglyceride concentrations are ≥200 mg/dL and HDL-C concentrations are <40 mg/dL. In high-risk individuals, icosapent ethyl is indicated as an adjunct to statin therapy to reduce atherosclerotic CVD risk. Pioglitazone can be considered for optimization of glycemic control due to its concomitant benefits on lipid profile. Caution should be taken when statins are used in combination with fibrates due to a higher risk of statin-induced myopathy.
Obstructive sleep apnea (OSA)
OSA is associated with NAFLD, and several studies suggest OSA is also associated with more advanced NAFLD/NASH histology. Intermittent hypoxia, a critical consequence of OSA, has been linked to mitochondrial dysfunction, dysregulation of glucose and lipid metabolism, worse insulin resistance, and increased hepatic DNL. Given the strong association between NAFLD and OSA, patients with NAFLD who are overweight or obese should be screened for OSA, and polysomnography or other sleep studies should be considered for those at high risk.
CVD
CVD is an important cause of death in patients with NAFLD; however, the extent to which NAFLD independently drives CVD is unclear. A strong association exists between NAFLD and atherosclerotic heart disease, heart failure, and arrhythmias, particularly atrial fibrillation. Perturbed lipoprotein metabolism, endothelial function, increased presence and higher-risk nature of atherosclerotic lesions, and impaired ischemic compensatory mechanisms support the link between NAFLD and CVD. Furthermore, in a large prospectively studied observational cohort, the incidence of cardiac events was the same across all fibrosis stages; however, the number of cardiac events was relatively low. Optimizing the management of CVD risk factors with the goal of reducing CVD morbidity and mortality is critical to improving outcomes in patients with NAFLD. Aggressively treating comorbid conditions such as hypertension, dyslipidemia, and hyperglycemia and promoting smoking cessation is recommended to decrease CVD in those at risk.
Chronic kidney disease (CKD)
A meta-analysis of 20 cross-sectional studies (n=28,000 individuals) found that NAFLD was associated with a 2-fold increased prevalence of CKD. NAFLD overall, and NASH specifically, are also associated with microvascular diabetic complications, especially CKD. Recently published data from the NASH CRN demonstrate a higher prevalence of CKD in patients with advanced fibrosis compared with lower fibrosis stages. The extent to which the liver mechanistically contributes to the development of CKD independent of associated metabolic disease remains to be determined.
Guidance statements:
1. Statins are safe and recommended for CVD risk reduction in patients with NAFLD across the disease spectrum, including compensated cirrhosis.
2. Limited data exist on the safety and efficacy of statins in patients with decompensated cirrhosis, although statin use with careful monitoring could be considered in patients with high CVD risk.
3. Hypertriglyceridemia can be managed through lifestyle changes and supplementation with omega-3 fatty acids, icosapent ethyl, or fibrates.
4. Patients with diabetes are at higher risk for NASH and advanced fibrosis and should be screened for advanced fibrosis.
5. Patients with NAFLD should be screened for the presence of T2DM.
Key points:
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.
INITIAL EVALUATION OF A PATIENT WITH NAFLD
Patients with NAFLD are most commonly referred with incidentally noted hepatic steatosis on imaging or elevated liver chemistries. It is important to note that normal values provided by most laboratories are higher than what should be considered normal in NAFLD, in which a true normal alanine aminotransferase (ALT) ranges from 29 to 33 U/L in men and from 19 to 25 U/L in women. Initial evaluation of such patients should include screening for metabolic comorbidities, assessment of alcohol intake, and exclusion of other causes of liver disease as well as physical examination to identify signs of insulin resistance and advanced liver disease (Table 1). When the clinical profile is atypical (eg, not associated with metabolic comorbidities) or accompanied by additional signs or symptoms suggesting additional/alternate etiologies, less common causes of steatosis or steatohepatitis should be excluded (Table 2). Rare causes of steatosis or fibrosing steatohepatitis can present in isolation or explain an exaggerated NASH phenotype and should be considered in specific clinical contexts (Table 2). Several drugs can also lead to hepatic steatosis or steatohepatitis or exacerbate disease in those with underlying NAFLD and should be identified during initial evaluation (Table 3). Although gene-based risk stratification is currently not recommended in clinical practice, familial aggregation of insulin resistance and NAFLD supports gene-environment interactions in the risk for NAFLD, NASH, and advanced fibrosis.
TABLE 2
When to consider testing for less common causes of hepatic steatosis and steatohepatitis
| Condition | Clinical scenario | Diagnostic test | Treatment |
|---|---|---|---|
| Hypobetalipoproteinemia | Low LDL, low triglycerides, fat malabsorption | ApoB level, genetic testing (MTTP, PCSK-9) | Low-fat diet, fat-soluble vitamin supplementation |
| LAL deficiency | Markedly elevated LDL-C and low HDL-C, elevated triglycerides, xanthelasma, hypersplenism, advanced fibrosis in young age, predominately microvesicular steatosis on liver biopsy | Enzyme assay, genetic testing | LAL replacement |
| Nutrient deficiency (eg, carnitine, choline) | Anorexia, short bowel, bypass surgeries | Nutrient levels | Supplementation |
| Wilson disease | Younger age, neuropsychiatric symptoms, low alkaline phosphatase, low ceruloplasmin | 24-h urine copper; quantitative copper on liver biopsy | Chelation |
| Celiac disease | Iron deficiency, abdominal pain, bloating, vitamin D deficiency, bone loss, diarrhea, dermatitis herpetiformis | Tissue transglutaminase IgA, duodenal biopsy | Gluten-free diet |
TABLE 3
Drugs with potential mechanistic links to macrovesicular steatosis or steatohepatitis
| Drug | Mechanism | Histological pattern | References |
|---|---|---|---|
| Amiodarone | Promotion of DNL, impairment of β-oxidation | Hepatic steatosis and steatohepatitis, phospholipidosis, cirrhosis | |
| 5-FU | Accumulation of 5-FU catabolites reduce hepatic capacity to metabolize lipids | Hepatic steatosis | |
| Irinotecan | Induces mitochondrial dysfunction, impaired autophagy | Steatohepatitis | |
| Tamoxifen | Estrogen receptor modulator, promotion of DNL, impairment of β-oxidation. *May or may not be independent of concomitant metabolic risk factors | Steatosis and steatohepatitis | |
| Methotrexate | Mitochondrial injury (inhibits mitochondrial electron transport chain), injury to canals of Hering | Steatosis, steatohepatitis, cirrhosis | |
| Corticosteroids | Exacerbation of metabolic comorbidities, impairment of β-oxidation, impairment of hepatic triglyceride secretion, lipid peroxidation | Steatosis |
Role of alcohol consumption
Alcohol use can be an important contributor to fatty liver disease progression and should be quantified in all patients. Alcohol intake can be broadly classified as mild [up to 20 g (women) and 30 g (men) per day], moderate [21–39 g (women) and 31–59 g (men) per day], or heavy [≥40 g (women) and ≥60 g (men) per day]. Moderate alcohol use increases the probability of advanced fibrosis, particularly in patients with obesity or T2DM, indicating potential synergistic effects of insulin resistance and alcohol on liver disease progression. Obesity and alcohol use synergistically increase the risk of liver injury, cirrhosis, HCC, and death from liver disease. Heavy alcohol consumption accelerates liver injury and fibrosis progression and should be avoided in patients with NAFLD/NASH. Earlier epidemiological studies suggested a protective effect of mild alcohol consumption on the development of NAFLD, but in a subsequent study, moderate alcohol use (defined broadly as >20 g/d) was associated with less improvement in steatosis and aspartate aminotransferase (AST) and lower odds of NASH resolution, compared with patients who did not consume alcohol. In addition, daily alcohol may increase the risk for extrahepatic malignancies and HCC. Importantly, there is substantial variability in individual susceptibility to alcohol-induced liver injury, with an attendant lack of clarity on the dose required to impact disease course at an individual patient level. The impact of alcohol use (type, pattern, frequency, duration, and quantity) on the natural history of NAFLD/NASH requires further investigation.
Guidance statements:
6. In patients with NAFLD, alcohol can be a cofactor for liver disease progression, and intake should be assessed on a regular basis.
7. Patients with clinically significant hepatic fibrosis (≥F2) should abstain from alcohol use completely.
Key points:
Abstinence, particularly for those patients with moderate-to-heavy alcohol intake, may lower the risks of fibrosis progression and hepatic and extrahepatic malignancies in patients with NAFLD.
ASSOCIATED ENDOCRINE DISORDERS
In addition to its strong association with obesity and other metabolic risk factors, higher rates of NAFLD have been reported in patients with hypothyroidism, hypogonadism, growth hormone (GH) deficiency, and polycystic ovarian syndrome (PCOS).
Hypothyroidism
Despite the known role of thyroid hormone in the regulation of hepatic lipid metabolism, the association between NAFLD and systemic hypothyroidism in humans remains controversial. No significant association between NAFLD and hypothyroidism (subclinical or overt) was observed in a large meta-analysis; however, a cohort study of nearly 9500 patients followed for a mean of 10 years found hypothyroidism was associated with a 24% higher chance of NAFLD.
GH deficiency
GH and the primary mediator of its metabolic effects, insulin-like growth factor-1, are important regulators of glucose and lipid metabolism, growth, body composition, and cellular regeneration. GH deficiency is associated with body fat redistribution and increased visceral adipose tissue mass and can result in insulin resistance, hyperglycemia, hyperlipidemia, and NAFLD. In a meta-analysis, insulin-like growth factor-1 levels were lower in patients with NAFLD and strongly associated with obesity and insulin resistance. One cause of GH deficiency, panhypopituitarism, is associated with weight gain, insulin resistance, impaired glucose tolerance, and dyslipidemia, with a small case series demonstrating an increased risk for NASH and fibrosis.
Studies evaluating effects of GH replacement in subjects with GH deficiency and NAFLD have been small and uncontrolled. In a study of adults with hypopituitarism (n=69), GH replacement reduced AST (n=11 with NAFLD) and improved liver histology in NASH (n=5 with paired biopsies). In another study, GH replacement (n=12 subjects) reduced visceral fat and hepatic steatosis by magnetic resonance spectroscopy. In patients with HIV, lipodystrophy, and NAFLD, tesamorelin, a GH-releasing hormone analog, which augments pulsatile GH secretion and increases insulin-like growth factor-1 without adversely affecting insulin sensitivity, reduced liver fat. Overall, the association between a disturbance in the GH axis and NAFLD is strongly linked to changes in visceral fat and insulin resistance, but screening is not recommended for all patients.
Hypogonadism
A number of studies report associations among hypogonadism, impaired glucose and lipid metabolism, and NAFLD. A meta-analysis found that NAFLD was associated with lower serum testosterone levels in men but higher levels in women, a finding confirmed by others. The association between hypogonadism and NAFLD is often confounded by the presence of obesity and insulin resistance, both of which are known to be associated with hypogonadotropic hypogonadism. In contrast, low testosterone levels can also negatively affect body composition, worsen insulin resistance, and thus contribute to the development of hepatic steatosis.
One study in men suggested that a low serum total testosterone level was independently associated with NAFLD, and the association was unchanged even after controlling for visceral adipose tissue volume and insulin resistance. In contrast, in another study including 175 men with T2DM evaluated by 1H-magnetic resonance spectroscopy (MRS) and liver histology, the relationship between lower total testosterone and steatosis disappeared when adjusted for insulin resistance and obesity, with no relationship to the severity of liver necroinflammation or fibrosis. Testosterone replacement in men improves insulin resistance, serum lipids, and visceral adiposity, indicating a more direct role of testosterone on metabolic risk factors for NAFLD in men, but it should be reserved for carefully selected patients, particularly as it may exacerbate OSA.
The role of menopause and sex hormones in NAFLD
In women, hypogonadism is associated with increased liver enzymes as well as a higher prevalence of NAFLD and advanced fibrosis. The prevalence of NAFLD is higher in postmenopausal compared with premenopausal women. Limited data suggest that higher free testosterone levels in premenopausal women are associated with an increased risk of prevalent NAFLD after menopause. Furthermore, there is a 25% likelihood of NAFLD in higher quintiles of testosterone as well as an association between lower serum estradiol levels and NASH. Limited studies demonstrate the benefit of hormone replacement therapy on NAFLD, although adverse hepatic effects were found in one study that were attributed to progesterone. Apart from estrogen deficiency, relative androgen excess and decreased sex hormone-binding protein levels are observed in postmenopausal women. The associated increased abdominal adiposity closely relates to the severity and progression of NAFLD, although direct causality has not been established.
PCOS
In PCOS, hyperinsulinemia promotes hypothalamic luteinizing hormone stimulation of ovarian theca cells resulting in excessive androgen production. Large meta-analyses and population studies have demonstrated a 2- to 4-fold increase in the prevalence of NAFLD and an increased risk of T2DM among women with PCOS, suggesting that insulin resistance is the main driver of disease in PCOS. In a retrospective study of women with biopsy-confirmed NAFLD (n=102), PCOS was associated with the severity of steatohepatitis and advanced fibrosis after adjusting for age and BMI. However, this study did not account for insulin resistance, which may have influenced the association.
Guidance statements:
8. NAFLD is more common in men with androgen deficiency, but current data do not support routine measurement of testosterone levels. If hypogonadism is present, as suggested by clinical signs or symptoms, this should be treated accordingly.
Key points:
Although GH deficiency and panhypopituitarism may be associated with hepatic steatosis, their independent role on the development and progression of steatohepatitis and fibrosis remains to be established.
Androgen excess can worsen insulin resistance in women with PCOS, which together with obesity and T2DM can promote NAFLD and potentially more progressive disease in this population.
NAFLD IN LEAN INDIVIDUALS
Although NAFLD is commonly associated with obesity, it can also occur in nonoverweight (BMI <25 kg/m2 or <23 kg/m2 in Asian individuals) patients. Initial histological findings are typically milder compared with overweight or obese patients, and the prevalence of NAFLD in lean individuals varies from 4.1% in the United States to as high as 19% in Asia. Compared with healthy controls, lean subjects with NAFLD have increased IR, metabolic comorbidities, visceral adiposity, and decreased muscle mass. Alcohol use and alterations in the gut microbiome may also contribute to NAFLD in lean individuals.
Genetic factors likely play a significant role in this population, but the overall genetic contribution to NAFLD requires further study. Lean individuals with NAFLD are more commonly of Hispanic or Asian origin, which is likely in part driven by a higher prevalence of the PNPLA3 I148M polymorphism. In addition, alterations in the TM6SF2 gene, which confers susceptibility to NASH and fibrosis but protection against cardiovascular events, is more prevalent in lean individuals with NAFLD compared with patients who were overweight or had obesity, but genetic testing is currently not recommended, as it does not alter management. Uncommon genetic conditions can also play a role (e.g., lipodystrophy, lysosomal acid lipase deficiency, hypobetalipoproteinemia) and should be considered in selected patients (Table 2).
Management of NAFLD in patients without obesity can be clinically challenging. Recommending weight loss may not be appropriate for lean patients with NAFLD, but dietary modifications and exercise in this group may be beneficial.
WHICH PATIENTS SHOULD BE SCREENED FOR THE PRESENCE OF CLINICALLY SIGNIFICANT FIBROSIS?
Targeted screening of populations at increased risk for advanced liver disease is advised to identify and manage those with clinically significant fibrosis (stage ≥2). Screening in high-risk populations, such as those with T2DM, obesity with metabolic complications, a family history of cirrhosis, or significant alcohol use (see also separate discussion on the contributory role of alcohol), may identify those with asymptomatic but clinically significant fibrosis. Early identification of such at-risk patients allows for interventions that may prevent future hepatic complications. Careful assessment of family history is important because first-degree relatives of probands with NASH cirrhosis have a 12-fold higher risk of advanced fibrosis. Furthermore, the risk of NAFLD and advanced fibrosis may be increased, even among nonrelated household members, likely because of related similar environmental risk factors, lifestyle patterns, and gut microbiota. Screening recommendations are summarized in Table 4.
TABLE 4
Screening for advanced fibrosis in high-risk populations
| Screening recommended | Prevalence of advanced fibrosis, % | References |
|---|---|---|
| T2DM | 6–19 | |
| Medically complicated obesity | 4–33 | |
| NAFLD in context of moderate alcohol use | 17 | |
| First-degree relative of a patient with cirrhosis due to NAFLD/NASH | 18 |
How should NAFLD be managed in primary care and endocrinology practice settings?
In most patients, NAFLD is asymptomatic or associated with vague symptoms, often leaving patients undiagnosed. The prevalence of advanced disease is lower in primary care practices than in hepatology practices, and thus, the approach to evaluation is context dependent (Figure 2). Patients suspected to have NAFLD on the basis of metabolic risk factors or incidentally identified as having fatty liver by imaging in the absence of other etiologies of hepatic steatosis (ie, Wilson disease, celiac disease, HCV, alcohol use, etc.) should undergo primary risk assessment (Figure 2). The objective of this primary risk assessment is to identify patients who are not likely to have advanced fibrosis [low risk, eg, fibrosis-4 index (FIB-4) <1.3]. Due to the excellent negative predictive value of NITs (reviewed in detail below) in excluding advanced fibrosis, patients in low-risk categories can be managed in primary care. However, patients with ≥2 metabolic risk factors, particularly those with pre-diabetes mellitus (pre-DM) or T2DM, should undergo more frequent risk assessment with FIB-4 every 1–2 years (Figure 2). Screening patients with T2DM and suspected NAFLD-related advanced hepatic fibrosis using FIB-4, a score derived from available clinical and laboratory data, may be cost-effective and allow for the prediction of outcomes such as progression to cirrhosis or decompensation, although the performance of NITs may be less robust in patients with diabetes. Once more data are available, it is possible that the recommended cutoffs for FIB-4 in patients with T2DM will change.
FIGURE 2
Algorithm for the evaluation of patients at risk for or with established NAFLD across practice settings. Patients with steatosis noted on imaging or for whom there is a clinical suspicion of NAFLD, such as those with metabolic risk factors or unexplained elevation in liver chemistries, should undergo further evaluation. In settings with a low prevalence of advanced fibrosis, such as in the primary care setting, the emphasis is on excluding advanced fibrosis using a test with a high negative predictive value. When the fibrosis-4 index (FIB-4) is <1.3, patients can be followed in the primary care setting and reassessed periodically. Patients without prediabetes/type 2 diabetes mellitus (T2DM) and 1–2 metabolic risk factors can be reassessed every 2–3 years. Patients with prediabetes/T2DM or 2 or more metabolic risk factors are at higher risk for disease progression, and more frequent FIB-4 monitoring (eg, every 1–2 y) should be considered. In patients older than age 65, a FIB-4 cutoff of >2.0 should be used. FIB-4 has low accuracy in those under age 35; thus, secondary assessment should be considered in those <35 with increased metabolic risk or elevated liver chemistries. FIB-4 should not be used in acutely ill patients. In patients with FIB4 ≥1.3, a secondary assessment should be done [preferentially vibration-controlled elastography (VCTE) or Enhanced Liver Fibrosis (ELF) initially] or the patient referred for further risk stratification (if being seen in a nongastroenterology/hepatology setting). Direct referral to gastroenterology/hepatology should be considered in those with aminotransferases persistently (>6 mo) above normal to exclude other causes of liver disease or when FIB4 > 2.67 due to the increased risk of clinically significant fibrosis. In higher prevalence settings, such as gastroenterology/hepatology clinics, additional risk assessment with magnetic resonance elastography (MRE) may be appropriate when noninvasive tests (NITs) are indeterminate or there is clinical suspicion of more advanced disease. Identification of cirrhosis should prompt screening for HCC and esophageal varices. In addition, MRE or corrected T1 (cT1) may help identify patients with “at-risk” NASH (NASH with NAFLD activity score ≥4 and fibrosis stage ≥2) who may benefit from a therapeutic intervention as they become available. If cirrhosis is suspected based on NITs, clinical data, or imaging findings, then cirrhosis-based management may be initiated without a liver biopsy. Liver biopsy should be considered when NITs suggest significant fibrosis (≥F2), especially if additional evaluation suggests the presence of “at-risk” NASH (eg, using FAST, MEFIB, MAST, or cT1), NIT assessment is indeterminate, aminotransferases are persistently elevated (>6 mo), or additional/alternate diagnoses are suspected. Note that in patients with confirmed or suspected advanced fibrosis, an ELF ≥11.3 is a predictor of future liver-related events and is approved for this purpose; use of other ELF cutoffs in secondary risk assessment is based on expert option. Patients at all stages of disease should be counseled on lifestyle modifications, and those with ≥F2 fibrosis targeted for pharmacological interventions as they become available. Specific threshold values of NITs are approximations supported by current evidence and are meant to guide clinical management through primary care to gastroenterology/hepatology practices rather than be interpreted in isolation. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; PCP, primary care provider.
Those who may have a moderate or high risk of advanced disease based on FIB-4 should undergo secondary risk assessment. In the primary care setting, vibration-controlled elastography (VCTE) or ultrasound-based methods such as acoustic radio force impulse (as available) are favored over magnetic resonance elastography (MRE), as initial secondary assessments due to cost considerations. The Enhanced Liver Fibrosis (ELF) test is approved for prognostication when advanced fibrosis is suspected, although it can be ordered for secondary risk assessment, particularly because the availability of elastography may be limited in some settings. If secondary risk assessment is still consistent with an intermediate or high risk of fibrosis, patients should be referred to specialty care for further evaluation and potential intervention. For those patients with advanced hepatic fibrosis or cirrhosis, primary or secondary prevention of complications of portal hypertension or sarcopenia may decrease the risks of liver-related outcomes (Figure 2).
Serum AST levels are often used clinically to identify patients with liver disease but can be normal in patients with diabetes, NASH, and advanced hepatic fibrosis. Although AST levels are neither sensitive nor specific for the identification of NAFLD/NASH with advanced fibrosis, intermittently (i.e., fluctuating above and below normal thresholds) or chronically (≥6–12 mo) elevated ALT or AST above a threshold of 30 U/L may suggest the presence of chronic liver injury. These thresholds are below the upper reference range values provided by most clinical laboratories, which is likely related to the lack of exclusion of patients with risks for NAFLD from reference populations.
Further risk stratification in the gastroenterology and hepatology practice settings
The primary goal in the specialty care setting is the identification of patients with “at-risk” NASH or advanced fibrosis. Such patients require further assessment and may benefit from targeted interventions (Figure 2). MRI-based tools such as MRE or MRI corrected T1 (cT1) can be used to further risk stratify patients in whom other NITs have been indeterminate or not reflective of clinical suspicion. Liver biopsy should be considered when there is diagnostic uncertainty, as may occur with discordant or indeterminate NITs; discordance between NITs and clinical, radiographic, or laboratory features suggesting a diagnosis of advanced fibrosis; competing or concomitant possible diagnoses (eg, autoimmune hepatitis, DILI, iron overload); or when there is persistent elevation (>6 mo) in liver chemistries.
Guidance statements:
9. General population-based screening for NAFLD is not advised.
10. 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.
11. 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.
12. 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 years.
13. Patients with NASH cirrhosis are at the highest risk for liver-related outcomes and require routine surveillance for HCC, esophageal varices, and monitoring for decompensation.
14. Patients with suspected advanced NASH or discordant NITs should be referred to a specialist for evaluation, management, and/or further diagnostic evaluation.
15. 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.
16. First-degree relatives of patients with NASH cirrhosis should be counseled regarding their increased individual risk and offered screening for advanced hepatic fibrosis.
Key points:
Patients with “at-risk” NASH (NASH with at least stage 2 fibrosis) are at increased risk of developing cirrhosis and liver-related complications.
BIOMARKERS/NITS FOR THE DIAGNOSIS AND ASSESSMENT OF NAFLD
Although liver biopsy assessment remains the reference standard for the grading and staging of NASH, it has important limitations related to risk, cost, and resource utilization. Therefore, liver biopsies for grading and staging of NASH are not consistently performed in clinical practice and should be reserved for specific clinical scenarios (Figure 2). Noninvasive biomarkers are emerging as valuable tools for predicting adverse liver-related outcomes (see more below), hitherto an important function of liver biopsies. Validation of noninvasive biomarkers in accordance with the US Food and Drug Administration (FDA)–National Institutes of Health guidance will facilitate the diagnosis of patients with clinically meaningful disease and evaluate their response to treatment without the need for liver biopsies.
Noninvasive identification and quantification of hepatic steatosis
Although commonly used in clinical practice, conventional B-mode ultrasound lacks sufficient sensitivity for lesser degrees of steatosis, particularly in those with concomitant obesity, and provides only a subjective semiquantitative assessment of steatosis severity. The absence of detectable steatosis on ultrasound does not exclude the presence of NASH or the presence of fibrosis, although ultrasound can be helpful when cirrhotic liver morphology is identified or if it identifies evidence of portal hypertension (eg, ascites, splenomegaly, portosystemic collateral vessels). For the assessment of hepatic steatosis, the controlled attenuation parameter (CAP), typically measured in conjunction with VCTE, provides a point-of-care semiquantitative assessment of hepatic steatosis but does not accurately quantify or monitor changes in liver fat (Table 5).
MRI–proton density fat fraction (PDFF) is an accurate, reproducible, and precise MRI-based biomarker for liver fat quantification that is routinely used in clinical research. Its role in clinical practice is evolving, although it is being increasingly used in tertiary care centers. Although MRI-PDFF is superior to CAP in the diagnosis as well as the quantification of liver fat, this advantage is tempered by cost, patient acceptance, and the disadvantage of not being a point-of-care technique (Table 5).
Estimation of liver fibrosis in patients with suspected or confirmed NAFLD
Clinical and laboratory-based fibrosis biomarkers
NITs derived from clinical variables can estimate of the presence of advanced fibrosis (Table 5). Several have been developed (eg, FIB-4, NAFLD Fibrosis Score, AST Platelet Ratio Index); however, FIB-4 is the most validated. FIB-4 is calculated using a simple algorithm based upon age, ALT, AST, and platelet count and outperforms other calculations in its ability to identify patients with a low probability of advanced fibrosis. High values of FIB-4 and other NITs have also been associated with all-cause and liver-related outcomes in population-based studies. In addition, a change in FIB-4 status category from low risk (<1.3) to intermediate risk (1.3–2.67) to high risk (>2.67) may be used to assess clinical progression. Although FIB-4 is statistically inferior to other serum-based fibrosis markers such as the ELF panel, FIBROSpect II, and imaging-based elastography methods to detect advanced fibrosis, FIB-4 is still recommended as a first-line assessment for general practitioners and endocrinologists based on its simplicity and minimal, if any, added cost. The ELF panel is a proprietary blood test consisting of three elements involved in matrix turnover: hyaluronic acid, tissue inhibitor of metalloproteinase-1, and N-terminal procollagen III peptide. An ELF score of ≥9.8 reliably identifies patients with NAFLD at increased risk of progression to cirrhosis and liver-related clinical events. The ELF test is approved for clinical use as a prognostic biomarker in the US and several other countries. Such serum-based fibrosis tests may be good options as secondary risk assessments when elastography is not available (Figure 2).
TABLE 5
Parameters for the noninvasive assessment of NAFLD according to clinical context of use
| Cut point | |||
|---|---|---|---|
| Modality type | Likely | Unlikely | Strengths/limitations, references/caveats |
| Identification of hepatic steatosis | |||
| Imaging | |||
| Ultrasound | “Detected” | NA | Semiquantitative assessment: mild/moderate/severe; low sensitivity with less severe steatosis; steatosis can have similar echo characteristics as advanced fibrosis |
| FibroScan: CAP | ≥288 dB/min | Limited accuracy for quantification | |
| MRI-PDFF | ≥5% | <5% | Most sensitive across spectrum of steatosis; accurate to assess dynamic change |
| Identification of “at-risk” NASH | |||
| FAST | ≥0.67 | <0.35 | ≤0.35 (sensitivity 90%), ≥0.67 (specificity 90%); in validation cohorts, the PPV of FAST ranged between 0.33 and 0.81 |
| MAST | ≥0.242 | ≤0.165 | 0.242 (specificity 90%), 0.165 (sensitivity 90%) |
| MEFIB | FIB-4 ≥1.6 plus MRE ≥3.3 kPa | FIB-4 <1.6 plus MRE <3.3 kPa | Sequential approach identifies patients with at least stage 2 fibrosis with >90% PPV |
| cT1 | ≥875 ms | <825 ms | Requires further validation |
| Detection of advanced fibrosis | |||
| Serum | |||
| FIB-4 | ≥2.67 | <1.3 | No added cost; not accurate in age <35 y and lower rule-out threshold among high-risk individuals who have high pretest probability |
| NFS | ≥0.672 | <−1.44 | No added cost; not accurate in age <35 y, people with obesity and/or type 2 diabetes |
| ELF | ≥9.8 | <7.7 | Blood test sent to a reference laboratory; cost |
| FIBROSpect II | ≥17 | <17 | Blood test sent to a reference laboratory; cost |
| Imaging | |||
| VCTE | ≥12 kPa | <8 kPa | Point of care |
| ARFI | ≥1.34 | <1.3 | Cut points not well validated |
| SWE | ≥12 kPa | <8 kPa | Cut points not well validated |
| MRE | ≥3.63 kPa | <2.55 kPa | MRE LSM ≥3.63 kPa (associated with advanced fibrosis, AUROC of 0.93) |
| Diagnosis of cirrhosis (rule-in or rule-out) | Rule-in | Rule-out | |
| CPR | |||
| FIB-4 | ≥3.48 | <1.67 | 90% specificity cut point for ruling-in and 90% sensitivity for ruling out cirrhosis, respectively |
| ELF | ≥11.3 | <7.7 | ELF ≥11.3 is associated with increased risk of hepatic decompensation among patients with cirrhosis |
| Imaging | |||
| VCTE | ≥20 kPa | <8 kPa | LSM by VCTE ≥20 kPa is associated with cirrhosis, but for ruling out, cirrhosis optimal cut point is <8 kPa |
| MRE | ≥5 kPa | <3 kPa | LSM by MRE ≥5 kPa has a very good (approaches 95%) specificity for diagnosis of cirrhosis and is also associated with increased risk of incident hepatic decompensation |
Elastography
Liver stiffness is a physical characteristic of the liver that increases with fibrosis severity as well as other processes such as passive congestion, marked inflammation, and infiltrative diseases. VCTE (eg, FibroScan®) is the most commonly used method to assess liver stiffness and can be used to exclude significant hepatic fibrosis. A recent meta-analysis suggested that a VCTE-derived liver stiffness measurement (LSM) <8 kPa can be used to rule out advanced fibrosis, especially if used sequentially after FIB-4. LSMs by VCTE between 8 and 12 kPa may be associated with fibrotic NASH, and LSM >12 kPa is associated with a high likelihood of advanced fibrosis, although the positive predictive value is low (range: 0.34–0.71). Changes in liver stiffness may also be useful in identifying disease progression, such that an increase in liver stiffness of 20% on either VCTE or MRE may be associated with disease progression and long-term clinical outcomes.
In identifying patients with cirrhosis, a sequential approach with a FIB-4 >3.48 and LSM by VCTE ≥20 kPa had a specificity of 90%. However, such an approach will likely miss some patients with cirrhosis due to low sensitivity of these cut points. Sequential combination of low cut points to exclude advanced fibrosis and high cut points to identify advanced fibrosis may be used until more precise methods become available. Similar cut points for shear wave elastography, point shear wave elastography, and other ultrasound-based elastography methods are emerging options but have not been well validated compared with the more extensive data on VCTE (Table 5).
MRE is more sensitive than VCTE in the detection of fibrosis stage ≥2 and is considered to be the most accurate noninvasive, imaging-based biomarker of fibrosis in NAFLD. Although MRE is not a first-line approach to risk stratification in a patient with NAFLD, it can be an important tool if clinical uncertainty exists, if there is a need for concomitant cross-sectional imaging, or when other elastography techniques are unavailable. Among patients with cirrhosis, baseline LSM by MRE predicts future risk of incident hepatic decompensation and death. The range of LSM values that correlate with the stage of fibrosis is technique-dependent (Table 5). An LSM by MRE ≥5 kPa is suggestive of cirrhosis (area under the receiver operating characteristic curve range: 0.89–0.94). Liver stiffness assessed by MRE may also be useful to assess the risk of decompensation. In one study, MRE LSMs of 5 and 8 kPa were associated with 9% versus 20% risk of incident hepatic decompensation or death, respectively. Note that the units for LSM by VCTE and MRE are both kilopascals, but the scales are different. An individual patient meta-analysis provided further validation of these findings with a baseline MRE LSM stratified into three categories of <5 kPa, 5–8 kPa, and >8 kPa that were associated with 1.6%, 17%, and 19% risk of decompensation over 3 years of follow-up, respectively. In addition, a 1 kPa increase in MRE liver stiffness is associated with a higher risk of liver-related as well as CVD outcomes. Although more data are needed, NIT improvements in patients with cirrhosis regression suggest they may be reliable as surrogates for histological improvement in response to therapeutic intervention once properly validated.
Methods under study for the identification of “at-risk” NASH
Several serum and imaging biomarkers are under study for the detection of NASH, but these have not reached the level of clinical evidence needed for use in routine clinical practice. NIS-4 (a panel of 4 biomarkers including microRNA-34a, alpha-2 macroglobulin, YKL-40, and glycated hemoglobin) and other serum and plasma-based lipidomic, metabolomic, and proteomic biomarkers are in development for “at-risk” NASH. Imaging techniques such as cT1 may also be considered for the identification of “at-risk” NASH, In an individual patient meta-analysis of 543 patients, cT1 performed well (area under the receiver operating characteristic curve: 0.78), although this requires further validation in large independent cohorts. Precise cutoffs have not been validated, and superiority over less expensive, point-of-care techniques remains to be demonstrated.
Techniques that combine clinical parameters with liver stiffness assessment that may be predictive of outcomes are emerging. The FibroScan-AST (FAST) score is a composite score calculated from liver stiffness and CAP determined by VCTE and serum AST for the detection of “at-risk” NASH, with one study showing performance differences based on race and BMI across different populations. In a head-to-head comparative study, MRE combined with FIB-4 (FIB-4 ≥1.6 plus MRE ≥3.3 kPa) has been shown to be superior to FAST. A positive MRE combined with FIB-4 has been linked to increased risk of hepatic decompensation, and a negative MRE combined with FIB-4 has a 99% negative predictive value for a 5-year risk of hepatic decompensation. A score derived from MRI-PDFF, MRE, and serum AST is also able to identify “at-risk” NASH. Other emerging combinations, such as a score based on cT1, AST, and fasting glucose (cTAG), may be effective but require further validation. Clear superiority of one approach over the over needs to be determined and the relative importance of point-of-care access weighed in depending on the context of use (Table 5).
Guidance statements:
17. 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.
18. CAP as a point-of-care technique may be used to identify steatosis. MRI-PDFF can additionally quantify steatosis.
19. If FIB-4 is ≥1.3, VCTE, MRE, or ELF may be used to exclude advanced fibrosis.
Key points:
Highly elevated liver stiffness, FIB-4, and ELF scores can predict an increased risk of hepatic decompensation and mortality.
THE ROLE AND INTERPRETATION OF LIVER BIOPSY
Histological evaluation of NAFLD should provide three basic pieces of information: diagnosis, grading of necroinflammatory activity, and staging of fibrosis severity. To adequately assess these features, biopsies obtained with a 16-G needle should be at least 1.5 cm in length but preferably 2–2.5 cm in length. Good-quality sectioning and staining are also important. Within the spectrum of NAFLD there are several distinct patterns: the common zone 3 injury pattern of adult steatohepatitis, the zone 1 steatosis-fibrosis pattern observed most often in young children, and steatosis with or without mild inflammation that does not meet criteria for steatohepatitis. Reporting of severity includes description of the pattern and degree of steatosis, inflammation, ballooning changes, and fibrosis. Although fibrosis stage is the best predictor of long-term outcome in multivariable analyses, ballooning injury and portal inflammation are short-term predictors of fibrosis progression or regression and are commonly combined as measures of disease grade (Figure 3). Composite histological scores such as the NAFLD activity score (NAS) and the steatosis, activity, fibrosis score combine histological features and are used in clinical studies to offer a structured overall assessment of severity. Biopsy remains the best method for providing information on the architectural distortion and the complex anatomic interrelationships of cellular injury, inflammation, and fibrosis.
FIGURE 3
Histology of NAFLD. Liver biopsy shows characteristic features of the spectrum of NAFLD. (A) Hepatic steatosis (typically zone 3) without ballooned hepatocytes or fibrosis [hematoxylin and eosin (H&E), ×200]. (B) Multiple ballooned hepatocytes with Mallory-Denk bodies (arrows) and mild lobular inflammation (circles) (H&E, ×400). (C) Ballooned hepatocytes (arrows) with moderate lobular inflammation (circle) (H&E, ×200). (D) Some cases of steatohepatitis may show significant portal inflammation and interface hepatitis (arrows) (H&E, ×200). (E) Dense perisinusoidal and periportal fibrosis (blue stain), with a thin connecting fibrotic bridge (Masson trichrome, ×200). (F) Cirrhosis (nodule formation) due to steatohepatitis (Masson trichrome, ×100).
Image analysis by artificial intelligence (AI) can provide more granular detail of histological findings as well as quantification of features on a continuous scale rather than the semiquantitative scoring system available to human observers. Evaluation of steatosis and fibrosis are the most developed of the AI algorithms because the physicochemical properties of lipid droplets and collagen allow for easier identification by machines. The inherent variability in the composition and character of lobular and portal inflammation as well as the spectrum of hepatocyte injury that is identified as ballooning presents more challenges in correct classification and quantification by AI algorithms but is under development.
TREATMENT
A healthy diet and regular exercise form the foundation of treatment for the vast majority of those with NAFLD. Even if weight loss is not needed, improved diet composition and increased exercise promote cardiovascular health in addition to improved liver health and metabolic comorbidities. For optimization of associated metabolic comorbid disease, a multidisciplinary team of clinicians provides the best chance for success in reducing liver and cardiovascular morbidity and mortality in patients with NAFLD (Figure 4). Some of the medications approved for commonly associated comorbidities such as T2DM and obesity have been studied in the context of NAFLD and may reduce liver enzymes or steatosis or improve liver histology. Therefore, medications with possible liver-related benefits should be considered when managing comorbidities (Table 5).
FIGURE 4
A multidisciplinary approach to the management of NAFLD. Optimal care of the patient with NAFLD requires a multidisciplinary approach. The majority of patients are in the primary care/endocrine setting, in which management of medical comorbidities should be optimized, with preference given to treatments for type 2 diabetes mellitus, hypertension, or obesity that likely also have beneficial effects on NAFLD. In this setting, at-risk patients should be identified and initial risk stratification performed [ie, fibrosis-4 index (FIB-4) ± vibration controlled elastography or Enhanced Liver Fibrosis]. The role of the gastroenterologist/hepatologist includes more comprehensive liver risk stratification, exclusion of other liver diseases, and a focus on liver-directed therapy. Close communication between gastroenterology/hepatology and primary care or endocrinology facilitates multidisciplinary management of metabolic comorbidities as well as the prioritization of medications or interventions that may also offer liver benefits (see the Treatment section). All patients should undergo dietary/nutritional assessment and a plan established for regular follow-up independent of gastroenterology/hepatology visits. The need for more specialized obesity management, including bariatric surgery referral, health psychology, and additional cardiology or lipid metabolic support, should be assessed on an individual basis (dotted arrows).
Liver protective healthy behaviors (lifestyle intervention)
Weight loss
Even modest amounts of weight loss can be impactful, especially in those with milder disease. Weight loss of 3%–5% improves steatosis, but greater weight loss (>10%) is generally required to improve NASH and fibrosis.
Achieving and sustaining weight loss is challenging. Sustained weight loss reduces adipose tissue stress and improves peripheral insulin sensitivity, which can reduce the drive for liver injury in NASH (Figure 1). Few patients (≤10%) achieve effective weight loss despite structured interventions at 1 year, and fewer than half of these maintain the weight lost 5 years after intervention, highlighting the need for ongoing nutrition support through multidisciplinary care (Figure 4). Unfortunately, reducing caloric intake can also be associated with counterproductive reductions in metabolic energy disposal. Psychological barriers can impede the implementation of a successful dietary and exercise plan; therefore, engagement with a health psychologist can be an invaluable tool for selected patients. A multidisciplinary approach, inclusive of patient support systems and family engagement, with behavioral medicine specialists, dieticians, and/or nutritionists, can optimize success over provider counseling alone in addressing the social, economic, and psychological challenges of lifestyle change (Figure 4).
Role of macronutrient composition
A diet containing excess calories, particularly excess saturated fats, refined carbohydrates, and sugar-sweetened beverages, is associated with obesity and NAFLD. Excessive fructose consumption in particular increases the risk of NAFLD, NASH, and advanced fibrosis independent of calorie intake. Changes in dietary composition (eg, low-carbohydrate vs. low-fat diets, saturated vs. unsaturated fat diets, intermittent fasting, Mediterranean diet, etc.) and different intensities of caloric restriction appear comparable in their ability to improve NAFLD/NASH. Some data suggest that the benefits of dietary intervention may be amplified in patients with certain genetic polymorphisms. The Mediterranean diet is often recommended to patients with NAFLD based on its associated improvement in cardiovascular health and reduction in liver fat. Although the benefits of the Mediterranean diet over other dietary approaches in small randomized trials is debated, it is sustainable and has cardiovascular benefit. Although it may not be directly applicable across cultures and ethnicities, similar dietary modifications tailored to a patient’s cultural and personal preferences may promote long-term adherence and compliance.
Coffee consumption, independent of caffeine content, may also be beneficial. Drinking 3 or more cups per day could be recommended in the absence of contraindications based on the reduced risk for NAFLD and liver fibrosis demonstrated in epidemiological studies and meta-analyses.
Impact of exercise
Exercise, independent of weight loss, has hepatic and cardiometabolic benefit and should be routinely recommended and tailored to the patient’s preferences and physical abilities. Some studies demonstrate that regular moderate exercise at least 5 times per week for a total of 150 minutes per week or an increase in activity level by more than 60 minutes per week can prevent or improve NAFLD. Others suggest that more vigorous exercise is needed to improve NASH histology, with even higher intensity exercise needed to reduce fibrosis. Studies combining diet with exercise consistently demonstrate reductions in liver fat proportional to the intensity of the intervention. Therefore, although the optimal duration and intensity of exercise need to be individualized, patients should be encouraged to exercise as much as possible.
Patients with cirrhosis require a slightly different approach that prioritizes protein intake and recognizes potential physical limitations. In one study of patients with obesity and cirrhosis, weight loss and regular physical activity reduced portal pressure. Exercise can also improve frailty, sarcopenia, and quality of life in patients with chronic liver disease.
Guidance statements:
20. 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 (e.g., Mediterranean diet) should be encouraged due to their additional cardiovascular benefits.
21. 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.
Key points:
Weight loss improves hepatic steatosis, NASH, and hepatic fibrosis in a dose-dependent manner.
The necessary support to manage comorbid disease and foster the adoption of liver protective health behaviors is best achieved using a multidisciplinary approach.
Coffee consumption (caffeinated or not) of at least 3 cups daily is associated with less advanced liver disease.
Bariatric surgery
Although currently accepted criteria for bariatric surgery are BMI ≥40 kg/m2 irrespective of metabolic comorbid disease or BMI ≥35 kg/m2 with comorbidities (T2DM or pre-DM, uncontrolled hypertension, osteoarthritis of hip or knee, urinary incontinence), NAFLD/NASH is increasingly accepted as a comorbid condition benefitting from bariatric surgery. The overwhelming majority of patients undergoing bariatric surgery have NAFLD and many have NASH; however, the prevalence of advanced hepatic fibrosis and cirrhosis is low in published series, in part due to presurgical screening that often excludes those with evidence of chronic liver disease or cirrhosis.
Bariatric surgery can resolve NASH, improve hepatic fibrosis, induce sustained weight loss of up to 30%, cure diabetes, and decrease all-cause morbidity and mortality. In a prospective long-term follow-up study with consecutive liver biopsies, resolution of NASH without worsening of fibrosis occurred in 80% of patients 1 year following bariatric surgery, which was maintained at 5 years. Failure to achieve substantial weight loss following bariatric surgery is associated with persistent NASH. Restrictive surgical procedures result in substantially less weight loss than malabsorptive procedures and are more likely to be associated with persistent NASH. Endoscopic bariatric and metabolic surgery procedures are promising less-invasive options; however, long-term safety and efficacy data are needed.
In the setting of cirrhosis, data regarding hepatic benefits are limited, and the choice of bariatric intervention should be focused on striking a balance between desired weight loss and the risk of complications, including hepatic decompensation. In general, bariatric surgery currently cannot be considered a primary therapy for the treatment of compensated NASH cirrhosis; however, it seems to be safe in carefully selected patients. Bariatric surgery in the setting of decompensated cirrhosis or clinically significant portal hypertension is associated with an increased risk of postoperative mortality and should only be considered at high volume centers under special circumstances such as when combined with liver transplant or as part of a research protocol.
Guidance statements:
22. 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.
Key points:
The type, safety, and efficacy of bariatric surgery in patients with well-compensated NASH cirrhosis is not established and requires a careful benefit–risk assessment by a multidisciplinary team of experts that includes a hepatologist.
Decompensated cirrhosis should be considered an absolute contraindication for bariatric surgery due to increased risk and unproven liver-related benefit, unless performed in conjunction with liver transplantation at experienced centers.
Use of available medications
Although there are currently no FDA-approved drugs for the treatment of NASH at any disease stage, there are medications approved for other indications that have shown benefits for NASH in clinical trials and should be considered under specific circumstances (Table 6).
TABLE 6
Potential impact of available medications on patients with NAFLD
| Medication | FDA indication | Patient population | Clinical benefits | Potential side effects | Cardiac benefit |
|---|---|---|---|---|---|
| Vitamin E (rrr-alpha) 800 IU daily | NA | NASH without T2DM or cirrhosis | Liver related: improves steatosis, NASH resolution? No proven benefit on fibrosis | Hemorrhagic stroke, risk of prostate cancer? | No |
| Pioglitazone 30–45 mg po daily | T2DM | NASH with and without T2DM | Liver related: improves steatosis, activity and NASH resolution, fibrosis improvement? Nonliver related: improves insulin sensitivity, prevention of diabetes, CV risk reduction and stroke prevention | Weight gain, risk of heart failure exacerbation, bone loss | Yes |
| Liraglutide 1.8 mg s.c. daily (T2DM) 0.6–3 mg s.c. daily (obesity) | T2DM, obesity | NASH without cirrhosis | Liver: improves steatosis, no proven impact on fibrosis. Nonliver related: improvement in insulin sensitivity, weight loss, CV risk reduction, may slow progression of renal disease | Gastrointestinal, gallstones (related to weight loss), pancreatitis | Yes |
| Semaglutide 0.4 mg s.c. daily, 0.25–2.4 mg SQ weekly | T2DM, obesity | NASH without cirrhosis | Liver related: improves steatosis, activity, and NASH resolution, no proven benefit on fibrosis, but may slow fibrosis progression. Nonliver related: improvement in insulin sensitivity, weight loss, improves CV and renal outcomes, stroke prevention | Gastrointestinal, gallstones (related to weight loss), pancreatitis | Yes |
| Tirzepatide | T2DM | T2DM or obesity with NAFLD | Liver related: reduces steatosis on imaging. Nonliver related: improvement in insulin sensitivity, significant weight loss | Gastrointestinal, gallstones related to weight loss, pancreatitis | Unknown |
| SGLT-2i | T2DM | T2DM and NAFLD | Liver related: reduction in steatosis by imaging. Nonliver related: may improve insulin sensitivity, improves CV and renal outcomes; benefit in heart failure, modest weight loss | Risk of genitourinary yeast infection, volume depletion, bone loss | Yes |
Vitamin E
In a multicenter, randomized controlled trial (RCT), Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH (PIVENS), treatment with rrr α-tocopherol (the natural form of vitamin E) 800 IU daily for 96 weeks improved histology (≥2-point reduction in NAS) compared with placebo. These findings were supported by a meta-analysis showing that vitamin E improved serum aminotransferases in addition to steatosis, inflammation, and cellular ballooning on biopsy. A reduction in serum ALT to ≤40 U/L and by ≥30% of baseline value after initiation of vitamin E is associated with improvement in histological parameters. Although no study has demonstrated that vitamin E meaningfully reduces fibrosis, a retrospective study of 236 patients with NASH and advanced fibrosis showed that vitamin E use was associated with lower rates of hepatic decompensation (37% vs. 62%, p=0.04) and higher transplant free survival (78% vs. 49%, p<0.01). The reduction in morbidity and mortality was independent of underlying diabetes status. Concern about the risks of vitamin E on bleeding and specifically hemorrhagic stroke has been raised, but prospective data are needed to confirm this observation. In addition, data demonstrating a relationship between vitamin E and prostate cancer are conflicting. Such potential risks should be discussed with patients before initiation of long-term high-dose (eg, 800 IU daily) vitamin E therapy.
Thiazolidinediones
Thiazolidinediones are ligands for peroxisome proliferator-activated receptor γ approved for the treatment of T2DM. In patients with NASH with or without pre-DM or T2DM, treatment with pioglitazone improves histology and insulin resistance. Pioglitazone use also improves serum lipids profiles. In the PIVENS trial, pioglitazone treatment did not meet the a priori primary endpoint of a ≥2-point reduction NAS without worsening of fibrosis, although 47% had NASH resolution compared with 21% of participants receiving placebo (p<0.001). Subsequently, in an 18-month study of patients with either preDM or T2DM and NASH, pioglitazone treatment led to a ≥2-point reduction in NAS and a trend toward fibrosis improvement. A pooled network meta-analysis demonstrated that pioglitazone was better than placebo in achieving NASH resolution as well as fibrosis improvement. Potential side effects associated with pioglitazone include weight gain, osteoporosis in postmenopausal women, a debated risk of bladder cancer, and potential risk for worsening heart failure in those with preexisting cardiac dysfunction. Although pioglitazone may improve CVD, its use in clinical practice has been overtaken by the increasing use of newer antidiabetic agents such as glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium glucose cotransporter-2 (SGLT-2) inhibitors (SGLT-2i) with pleiotropic metabolic benefits, most notably weight loss and reduction in cardiovascular mortality.
GLP-1RAs
The biological effects of GLP-1RAs on lipids, glucose metabolism, weight loss, and cardiovascular outcomes make them attractive agents for treatment of NASH. Some in this class are approved for the treatment of diabetes, and two have been approved for the treatment of obesity. Although several GLP-1RAs are approved for treatment of T2DM, none has been approved for treatment of NASH. In a small study of patients with NASH, liraglutide improved steatosis, resolved NASH, and reduced fibrosis progression compared with placebo. In an adequately powered phase 2b RCT of daily s.c. semaglutide, 320 patients with NASH (F1–3) were randomized to 0.1, 0.2, or 0.4 mg or placebo daily for 72 weeks (primary endpoint, resolution of NASH without worsening fibrosis). NASH resolution was dose dependent and occurred in 59% in the treatment group versus 17% in the placebo group (p<0.001). Despite evidence of fibrosis improvement in the treatment groups, there was no statistically significant reduction in fibrosis compared with placebo; however, a dose-dependent decrease in progression was observed. A larger, phase 3 trial of semaglutide in the treatment of NASH-related fibrosis is currently underway. Tirzepatide, a recently approved glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonist for the treatment of T2DM, demonstrates weight loss as high as 20.9% in nondiabetics compared with 3.1% in the placebo group and an absolute reduction in liver fat content of 8.1%, suggesting a possible benefit in NASH. Similar reductions in liver fat have been observed in other trials.
SGLT-2i
The SGLT-2i target renal glucose resorption from the glomerular filtrate and are approved for the treatment of T2DM. Furthermore, they induce 2%–3% weight loss and have cardiorenal protective benefits. Available studies evaluating the role of SGLT-2i in the treatment of NAFLD/NASH are limited by relatively small sample sizes and lack of histological outcomes. Within these limitations, available data suggest SGLT-2i improve hepatic steatosis; however, the therapeutic impact of SGLT-2i on liver histology needs to be better defined.
Available agents without evidence of histological benefits in NASH
Metformin has been extensively evaluated in patients with NASH but it does not improve histology. Ursodeoxycholic acid has pluripotent hepatic effects related to changes in the bile acid pool, cytoprotection, and immune modulation. Although initial studies suggested benefits in NASH, Ursodeoxycholic acid failed to demonstrate any histological benefit in an RCT of patients with NASH. In short-term phase 2 RCTs, dipeptidyl peptidase-4 inhibitors have not proven efficacious to treat NAFLD. Other available drugs not found to have liver-specific benefits include n-3 polyunsaturated fatty acids and ezetimibe, although some of these approaches are being revisited with different formulations such as alternate ratios of N3:N6 fatty acids or structurally engineered fatty acids.
The effect of silymarin (milk thistle) in patients with NASH remains inconclusive. In phase 2 RCTs, silymarin was safe and well tolerated but did not improve NASH histology. Some studies show improvement in NITs compared with baseline and placebo, suggesting a possible beneficial effect on fibrosis; however, this remains to be confirmed on histology in larger trials.
Guidance statements:
23. 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.
24. Semaglutide can be considered for its approved indications (T2DM/obesity) in patients with NASH, as it confers a cardiovascular benefit and improves NASH.
25. Pioglitazone improves NASH and can be considered for patients with NASH in the context of patients with T2DM .
26. Vitamin E can be considered in select individuals as it improves NASH in some patients without diabetes.
27. Available data on semaglutide, pioglitazone, and vitamin E do not demonstrate an antifibrotic benefit, and none has been carefully studied in patients with cirrhosis.
28. Metformin, ursodeoxycholic acid, dipeptidyl peptidase-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.
SURROGATE MARKERS OF HISTOLOGICAL TREATMENT RESPONSE
Although many studies have linked NITs with liver histology or clinical outcomes, data on biomarkers in a dynamic context to signal treatment response are still evolving. ALT reduction correlates with histological improvement and ALT normalization can predict NASH resolution in response to lifestyle modification as well as various therapeutic interventions. A decrease of ≥17 IU/L in ALT was associated with a higher odds of histological response in the FLINT trial of obeticholic acid. Additional data are needed to identify the benchmark for serum ALT decline associated with fibrosis improvement and whether different thresholds are needed with different mechanisms. An analysis from the REGENERATE trial of obeticholic acid demonstrated that in addition to improvements in ALT, improvement in FIB-4, FAST, ELF, VCTE, and other markers correlated with histological fibrosis reduction, suggesting that histological response may be tracked using NITs. Several studies and a meta-analysis have shown that ≥30% decline in MRI-PDFF is associated with 5-fold improved odds of NASH resolution, but thresholds for changes in liver stiffness measures that correlate with treatment-induced fibrosis improvement are not well established. Additional studies are needed to better understand the long-term association among changes in liver fat, histological response, and clinical outcomes.
Improvements in FIB-4 or serum biomarkers such as ELF, liver stiffness, or combination parameters (Table 5) have been associated with histological response, but the exact thresholds of improvement remain to be validated in large multicenter studies within this context of use.
Additional data are needed to determine if changes in NITs that correlate with treatment response are mechanism-specific or treatment agnostic. Validation of existing biomarkers as measures of treatment response will accelerate the development and approval of therapeutic agents and justify their adoption into clinical practice.
Guidance statements:
29. Improvement in ALT or reduction in liver fat content by imaging in response to an intervention can be used as a surrogate for histological improvement in disease activity.
Key points:
ALT reduction of ≥17 U/L is associated with histological improvement; however, thresholds may differ for type of histological response (eg, NASH resolution or fibrosis improvement) and may be mechanism of action specific.
Future directions
The number of trials in NASH has increased exponentially over the last 10 years. Several therapeutic agents for NASH are in late-stage development, with safety and histological efficacy profiles that may be soon approvable by the FDA. Further validation of biomarkers that predict liver-related outcomes, identify patients who may benefit from treatment, and predict response to therapeutic intervention is underway, and the anticipated acceptance of biomarkers as surrogates of future liver-related events and treatment response will greatly accelerate drug development for single or combination approaches. Adoption of AI-based technologies will allow more accurate quantification of fibrosis and highlight early signs of treatment response. Furthermore, AI may help diminish variability in histological assessment currently plaguing clinical trials. Finally, rapidly evolving knowledge in genetic disease modifiers (eg, PNPLA3 and others) as well as the identification of distinct disease phenotypes using a variety of techniques will enable more individualized approaches to the future management of patients with NAFLD. These advances will likely lead to rapid changes in the current recommendations (Table 7) for diagnosing and management of patients with NAFLD.
TABLE 7
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 • 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 |
AUTHOR CONTRIBUTIONS
All authors contributed to the conceptualization, intellectual content, drafting of the original manuscript, and critical revision for important intellectual content. All authors provided final approval of the manuscript.
ACKNOWLEDGMENTS
The authors are grateful for the valuable contributions of Audrey Davis-Owino and the AASLD NASH Task Force, particularly Raphael Merriman, Naga Chalasani, Donna Cryer, Kenneth Cusi, Stephen Harrison, Arun Sanyal, and Shikha Sundaram for their assistance in reviewing and revising the manuscript. The authors thank Anita Impagliazzo for creating the medical illustrations used in the manuscript.
FUNDING INFORMATION
Funding for the development of this Practice Guidance was provided by the American Association for the Study of Liver Diseases.
CONFLICTS OF INTEREST
Brent A. Neuschwander-Tetri consults/advises Akero, Arrowhead, BMS, Clinical Care Options, GSK, Glympse, Hepion, High Tide, HistoIndex, Labcorp, LG Chem, Madrigal, Merck, Sagimet, Senseion, Target RWE, 89Bio, has stock options with HepGene, HeptaBio and receives research grants paid to his institution from BMS, HighTide, Intercept, Inventiva, Madrigal. Mohammad S. Siddiqui consults/advises Sagimet and AMRA. Manal F. Abdelmalek consults/advises 89 Bio, Bristol-Myers Squibb, Hanmi, Intercept, Inventiva, Madrigal, Merck, NGM Bio, Novo Nordisk, SonicIncytes, Theratechnologies, Fishawack Inc., Terra Firma Inc. and receives research grants paid to her institution from Allergan, Boeringher- Ingelheim, Bristol Myers Squibb, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Hanmi, Intercept, Inventiva, Madrigal, Novo Nordisk, Poxel, Target NASH, Viking. Stephen Caldwell receives research support from Gilead, Galectin, Madrigal, Prometheus, Exact, GenFit, Inventiva, Zydus, Durect, Royalty, Avanos. David E. Kleiner is an unpaid consultant/collaborator with HistoIndex and HighTide. Rohit Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, AstraZeneca, Eli Lilly, Inipharma, Intercept, Ionis, Madrigal, Novo Nordisk, Pfizer, Sagimet, Theratechnologies, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. Co-founder of LipoNexus Inc. The remaining authors have no conflicts to report.
REFERENCES
1
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–57.2
Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022;28:528–62.3
Pons M, Augustin S, Scheiner B, Guillaume M, Rosselli M, Rodrigues SG, et al. Noninvasive diagnosis of portal hypertension in patients with compensated advanced chronic liver disease. Am J Gastroenterol. 2021;116:723–32.4
Mózes FE, Lee JA, Selvaraj EA, Jayaswal ANA, Trauner M, Boursier J, et al. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut. 2022;71:1006–19.5
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123–33.6
Le P, Chaitoff A, Rothberg MB, McCullough A, Gupta NM, Alkhouri N. Population-based trends in prevalence of nonalcoholic fatty liver disease in US adults with type 2 diabetes. Clin Gastroenterol Hepatol. 2019;17:2377–78.7
Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.8
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.9
Le MH, Devaki P, Ha NB, Jun DW, Te HS, Cheung RC, et al. Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States. PLoS One. 2017;12:e0173499.10
Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022;10:284–96.11
Bertot LC, Jeffrey GP, Wallace M, MacQuillan G, Garas G, Ching HL, et al. Nonalcoholic fatty liver disease‐related cirrhosis is commonly unrecognized and associated with hepatocellular carcinoma. Hepatol Commun. 2017;1:53–60.12
Canbay A, Kachru N, Haas JS, Sowa JP, Meise D, Ozbay AB. Patterns and predictors of mortality and disease progression among patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2020;52:1185–94.13
Budd J, Cusi K. Nonalcoholic fatty liver disease: what does the primary care physician need to know? Am J Med. 2020;133:536–43.14
Harrison SA, Gawrieh S, Roberts K, Lisanti CJ, Schwope RB, Cebe KM, et al. Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort. J Hepatol. 2021;75:284–91.15
Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64:1577–86.16
Younossi ZM, Tampi RP, Racila A, Qiu Y, Burns L, Younossi I, et al. Economic and clinical burden of nonalcoholic steatohepatitis in patients with type 2 diabetes in the U.S. Diabetes Care. 2020;43:283–9.17
Schattenberg JM, Lazarus JV, Newsome PN, Serfaty L, Aghemo A, Augustin S, et al. Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: a cost-of-illness analysis. Liver Int. 2021;41:1227–42.18
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124–31.19
Kabbany MN, Conjeevaram Selvakumar PK, Watt K, Lopez R, Akras Z, Zein N, et al. Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the United States: an analysis of National Health and Nutrition Examination Survey data. Am J Gastroenterol. 2017;112:581–7.20
Noureddin M, Vipani A, Bresee C, Todo T, Kim IK, Alkhouri N, et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am J Gastroenterol. 2018;113:1649–59.21
Wong RJ, Singal AK. Trends in liver disease etiology among adults awaiting liver transplantation in the United States, 2014-2019. JAMA Netw Open. 2020;3:e1920294.22
Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, Younossi I, et al. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clin Gastroenterol Hepatol. 2021;19:580–9.23
Taylor RS, Taylor RJ, Bayliss S, Hagström H, Nasr P, Schattenberg JM, et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology. 2020;158:1611–25e.12.24
Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–65.25
Simon TG, Roelstraete B, Khalili H, Hagström H, Ludvigsson JF. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut. 2021;70:1375–82.26
Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67:1265–73.27
Ratziu V. Back to Byzance: Querelles byzantines over NASH and fibrosis. J Hepatol. 2017;67:1134–6.28
Newsome PN, Sasso M, Deeks JJ, Paredes A, Boursier J, Chan WK, et al. FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol Hepatol. 2020;5:362–73.29
Roskilly A, Hicks A, Taylor EJ, Jones R, Parker R, Rowe IA. Fibrosis progression rate in a systematic review of placebo-treated nonalcoholic steatohepatitis. Liver Int. 2021;41:982–95.30
Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13:643–54.31
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2017;65:310–35.32
Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68:723–50.33
Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–9.34
Loomba R, Wong R, Fraysse J, Shreay S, Li S, Harrison S, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020;51:1149–59.35
Sanyal AJ, Van Natta ML, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021;385:1559–69.36
Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–97.37
Sanyal AJ, Harrison SA, Ratziu V, Abdelmalek MF, Diehl AM, Caldwell S, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology. 2019;70:1913–27.38
Sanyal AJ, Anstee QM, Trauner M, Lawitz EJ, Abdelmalek MF, Ding D, et al. Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis. Hepatology. 2022;75:1235–46.39
Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest. 2019;129:3990–4000.40
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.41
Sanders FWB, Acharjee A, Walker C, Marney L, Roberts LD, Imamura F, et al. Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption. Genome Biol. 2018;19:79.42
Beysen C, Ruddy M, Stoch A, Mixson L, Rosko K, Riiff T, et al. Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans. Am J Physiol Endocrinol Metab. 2018;315:E126–32.43
Luukkonen PK, Qadri S, Ahlholm N, Porthan K, Männistö V, Sammalkorpi H, et al. Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2022;76:526–35.44
Luukkonen PK, Sädevirta S, Zhou Y, Kayser B, Ali A, Ahonen L, et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care. 2018;41:1732–9.45
Berná G, Romero-Gomez M. The role of nutrition in non-alcoholic fatty liver disease: pathophysiology and management. Liver Int. 2020;40:102–8.46
Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2021;18:770–86.47
Bril F, Barb D, Portillo-Sanchez P, Biernacki D, Lomonaco R, Suman A, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology. 2017;65:1132–44.48
Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–25.49
Hardy T, Oakley F, Anstee QM, Day CP. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu Rev Pathol. 2016;11:451–96.50
Careau V, Halsey LG, Pontzer H, Ainslie PN, Andersen LF, Anderson LJ, et al. Energy compensation and adiposity in humans. Current Biology. 2021;31:4659–66.51
Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology. 2020;158:1851–64.52
Wang Y, Kory N, BasuRay S, Cohen JC, Hobbs HH. PNPLA3, CGI-58, and inhibition of hepatic triglyceride hydrolysis in mice. Hepatology. 2019;69:2427–41.53
Luo F, Oldoni F, Das A. TM6SF2: a novel genetic player in nonalcoholic fatty liver and cardiovascular disease. Hepatol Commun. 2022;6:448–60.54
Meroni M, Longo M, Fracanzani AL, Dongiovanni P. MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD. EBioMedicine. 2020;57:102866.55
Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378:1096–106.56
Su L, Zhou L, Chen F-J, Wang H, Qian H, Sheng Y, et al. Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites. EMBO J. 2019;38:e100156.57
Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P, et al. Germline mutations in CIDEB and protection against liver disease. N Engl J Med. 2022;387:332–44.58
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774–88.59
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22.60
Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158:1913–28.61
Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184:2537–64.62
Horn CL, Morales. AL, Savard C, Farrell GC, Ioannou GN. Role of cholesterol-associated steatohepatitis in the development of NASH. Hepatol Commun. 2022;6:12–35.63
Radun R, Trauner M. Role of FXR in bile acid and metabolic homeostasis in NASH: pathogenetic concepts and therapeutic opportunities. Semin Liver Dis. 2021;41:461–75.64
Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68:1063–75.65
Sookoian S, Pirola CJ, Valenti L, Davidson NO. Genetic pathways in nonalcoholic fatty liver disease: insights from systems biology. Hepatology. 2020;72:330–46.66
Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279–97.67
Sharpton SR, Schnabl B, Knight R, Loomba R. Current concepts, opportunities, and challenges of gut microbiome-based personalized medicine in nonalcoholic fatty liver disease. Cell Metab. 2021;33:21–32.68
Alexopoulos AS, Crowley MJ, Wang Y, Moylan CA, Guy CD, Henao R, et al. Glycemic control predicts severity of hepatocyte ballooning and hepatic fibrosis in nonalcoholic fatty liver disease. Hepatology. 2021;74:1220–33.69
Simón J, Goikoetxea-Usandizaga N, Serrano-Maciá M, Fernández-Ramos D, Sáenz de Urturi D, Gruskos JJ, et al. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH. J Hepatol. 2021;75:34–45.70
Govaere O, Cockell S, Tiniakos D, Queen R, Younes R, Vacca M, et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Sci Transl Med. 2020;12:eaba4448.71
Hasin-Brumshtein Y, Sakaram S, Khatri P, He YD, Sweeney TE. A robust gene expression signature for NASH in liver expression data. Sci Rep. 2022;12:2571.72
Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66:1300–12.73
Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18:151–66.74
Romeo S, Sanyal A, Valenti L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 2020;31:35–45.75
Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31:936–44.76
Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 2017;13:572–87.77
Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.78
Jinjuvadia R, Antaki F, Lohia P, Liangpunsakul S. The association between nonalcoholic fatty liver disease and metabolic abnormalities in the United States population. J Clin Gastroenterol. 2017;51:160–6.79
Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine. 2018;97:e0214.80
Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59:1410–5.81
Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol. 2021;75:1284–91.82
Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017;13:509–20.83
Mandard S, Zandbergen F, van Straten E, Wahli W, Kuipers F, Müller M, et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem. 2006;281:934–44.84
Xu A, Lam MC, Chan KW, Wang Y, Zhang J, Hoo RLC, et al. Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci USA. 2005;102:6086–91.85
McQueen AE, Kanamaluru D, Yan K, Gray NE, Wu L, Li ML, et al. The C-terminal fibrinogen-like domain of angiopoietin-like 4 stimulates adipose tissue lipolysis and promotes energy expenditure. J Biol Chem. 2017;292:16122–34.86
Awazawa M, Gabel P, Tsaousidou E, Nolte H, Krüger M, Schmitz J, et al. A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle. Nat Med. 2017;23:1466–73.87
Stefan N, Häring HU. Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med. 2013;19:394–5.88
Camporez JP, Asrih M, Zhang D, Kahn M, Samuel VT, Jurczak MJ, et al. Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21. J Endocrinol. 2015;226:207–17.89
Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008;322:1539–43.90
Chakravarthy MV, Siddiqui MS, Forsgren MF, Sanyal AJ. Harnessing muscle–liver crosstalk to treat nonalcoholic steatohepatitis. Front Endocrinol. 2020;11:592373.91
Loomis AK, Kabadi S, Preiss D, Hyde C, Bonato V, St. Louis M, et al. Body mass index and risk of nonalcoholic fatty liver disease: two electronic health record prospective studies. J Clin Endocrinol Metab. 2016;101:945–52.92
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679–89.93
Lonardo A, Bellentani S, Argo CK, Ballestri S, Byrne CD, Caldwell SH, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups. Dig Liver Dis. 2015;47:997–1006.94
Katsuki A, Sumida Y, Urakawa H, Gabazza EC, Murashima S, Maruyama N, et al. Increased visceral fat and serum levels of triglyceride are associated with insulin resistance in Japanese metabolically obese, normal weight subjects with normal glucose tolerance. Diabetes Care. 2003;26:2341–4.95
Conus F, Allison DB, Rabasa-Lhoret R, St-Onge M, St-Pierre DH, Tremblay-Lebeau A, et al. Metabolic and behavioral characteristics of metabolically obese but normal-weight women. J Clin Endocrinol Metab. 2004;89:5013–20.96
van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48:449–57.97
Eguchi Y, Mizuta T, Sumida Y, Ishibashi E, Kitajima Y, Isoda H, et al. The pathological role of visceral fat accumulation in steatosis, inflammation, and progression of nonalcoholic fatty liver disease. J Gastroenterol. 2011;46(suppl 1):70–8.98
Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21:697–738.99
Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93:359–404.100
Yu SJ, Kim W, Kim D, Yoon JH, Lee K, Kim JH, et al. Visceral obesity predicts significant fibrosis in patients with nonalcoholic fatty liver disease. Medicine. 2015;94:e2159.101
Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71–9.102
Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg. 2002;12:49–51.103
Park BJ, Kim YJ, Kim DH, Kim W, Jung YJ, Yoon JH, et al. Visceral adipose tissue area is an independent risk factor for hepatic steatosis. J Gastroenterol Hepatol. 2008;23:900–7.104
Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol. 2007;102:2708–15.105
Kim D, Park BJ, Kim W, Jung Y, Kim Y, Yoon JW, et al. Visceral fat as a strong and independent risk factor of nonalcoholic fatty liver disease (abstract). J Hepatol. 2008;48:S1913.106
Barb D, Bril F, Kalavalapalli S, Cusi K. Plasma fibroblast growth factor 21 is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetes. J Clin Endocrinol Metab. 2019;104:3327–36.107
Lomonaco R, Bril F, Portillo-Sanchez P, Ortiz-Lopez C, Orsak B, Biernacki D, et al. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care. 2016;39:632–8.108
McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62:1148–55.109
Kwok R, Choi KC, Wong GL, Zhang Y, Chan HL, Luk AO, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut. 2016;65:1359–68.110
Bazick J, Donithan M, Neuschwander-Tetri BA, Kleiner D, Brunt EM, Wilson L, et al. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD. Diabetes Care. 2015;38:1347–55.111
El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4:369–80.112
Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71:793–801.113
Ajmera V, Cepin S, Tesfai K, Hofflich H, Cadman K, Lopez S, et al. A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes. J Hepatol. 2023;78:471–78.114
Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56:943–51.115
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–85.116
Ciardullo S, Monti T, Perseghin G. High prevalence of advanced liver fibrosis assessed by transient elastography among U.S. adults with type 2 diabetes. Diabetes Care. 2021;44:519–25.117
Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease. Obesity (Silver Spring). 2021;29:1950–60.118
Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015;100:2231–8.119
Doycheva I, Cui J, Nguyen P, Costa EA, Hooker J, Hofflich H, et al. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther. 2016;43:83–95.120
Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care. 2018;41:372–82.121
Morrison AE, Zaccardi F, Khunti K, Davies MJ. Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: a meta-analysis with bias analysis. Liver Int. 2019;39:557–67.122
Hamaguchi E, Takamura T, Sakurai M, Mizukoshi E, Zen Y, Takeshita Y, et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care. 2010;33:284–6.123
Allen AM, Neuschwander-Tetri BA. The importance of glycemic equipoise in NASH. Hepatology. 2021;74:1145–7.124
Cusi K, Sanyal AJ, Zhang S, Hartman ML, Bue-Valleskey JM, Hoogwerf BJ, et al. Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diabetes Obes Metab. 2017;19:1630–4.125
Kietsiriroje N, Pearson S, Campbell M, Ariëns RAS, Ajjan RA. Double diabetes: a distinct high-risk group? Diabetes Obes Metab. 2019;21:2609–18.126
Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut. 2004;53:1020–3.127
Smits MM, Ioannou GN, Boyko EJ, Utzschneider KM. Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of a US national survey in three ethnic groups. J Gastroenterol Hepatol. 2013;28:664–70.128
Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68:335–2.129
Zhao YC, Zhao GJ, Chen Z, She ZG, Cai J, Li H. Nonalcoholic fatty liver disease: an emerging driver of hypertension. Hypertension. 2020;75:275–84.130
Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, et al. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol. 2015;13:1000–8.131
Patel S, Siddiqui MB, Roman JH, Zhang E, Lee E, Shen S, et al. Association between lipoprotein particles and atherosclerotic events in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2021;19:2202–4.132
Corey KE, Wilson LA, Altinbas A, Yates KP, Kleiner DE, Chung RT, et al. Relationship between resolution of non-alcoholic steatohepatitis and changes in lipoprotein sub-fractions: a post-hoc analysis of the PIVENS trial. Aliment Pharmacol Ther. 2019;49:1205–13.133
Corey KE, Vuppalanchi R, Wilson LA, Cummings OW, Chalasani N. NASH CRN. NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels. Aliment Pharmacol Ther. 2015;41:301–9.134
Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012–24.135
Patel SS, Nabi E, Guzman L, Abbate A, Bhati C, Stravitz RT, et al. Coronary artery disease in decompensated patients undergoing liver transplantation evaluation. Liver Transpl. 2018;24:333–42.136
Patel S, Siddiqui MB, Chandrakumaran A, Rodriguez VA, Faridnia M, Hernandez Roman J, et al. Progression to cirrhosis leads to improvement in atherogenic milieu. Dig Dis Sci. 2021;66:263–72.137
Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Hecht J, Tio F, et al. Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. J Clin Endocrinol Metab. 2017;102:2950–61.138
Kaplan DE, Serper MA, Mehta R, Fox R, John B, Aytaman A, et al. Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis. Gastroenterology. 2019;156:1693–706.139
Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007;47:135–41.140
Abdallah M, Brown L, Provenza J, Tariq R, Gowda S, Singal AK. Safety and efficacy of dyslipidemia treatment in NAFLD patients: a meta-analysis of randomized controlled trials. Ann Hepatol. 2022;27:100738.141
Bays H, Cohen DE, Chalasani N, Harrison SA. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol. 2014;8:S47–57.142
Blais P, Lin M, Kramer JR, El-Serag HB, Kanwal F. Statins are underutilized in patients with nonalcoholic fatty liver disease and dyslipidemia. Dig Dis Sci. 2016;61:1714–20.143
Patel SS, Guzman LA, Lin F-P, Pence T, Reichman T, John B, et al. Utilization of aspirin and statin in management of coronary artery disease in patients with cirrhosis undergoing liver transplant evaluation. Liver Transpl. 2018;24:872–880.144
Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376:1916–22.145
Mesarwi OA, Loomba R, Malhotra A. Obstructive sleep apnea, hypoxia, and nonalcoholic fatty liver disease. Am J Respir Crit Care Med. 2019;199:830–41.146
Corey KE, Misdraji J, Gelrud L, King LY, Zheng H, Malhotra A, et al. Obstructive sleep apnea is associated with nonalcoholic steatohepatitis and advanced liver histology. Dig Dis Sci. 2015;60:2523–8.147
Fu Y, Zhang N, Tang W, Bi Y, Zhu D, Chu X, et al. Chronic intermittent hypoxia contributes to non-alcoholic steatohepatitis progression in patients with obesity. Hepatol Int. 2022;16:824–34.148
Landete P, Fernández-García CE, Aldave-Orzaiz B, Hernández-Olivo M, Acosta-Gutiérrez CM, Zamora-García E, et al. Increased oxygen desaturation time during sleep is a risk factor for NASH in patients with obstructive sleep apnea: a prospective cohort study. Front Med. 2022;9:808417.149
Tanné F, Gagnadoux F, Chazouillères O, Fleury B, Wendum D, Lasnier E, et al. Chronic liver injury during obstructive sleep apnea. Hepatology. 2005;41:1290–6.150
Mishra P, Nugent C, Afendy A, Bai C, Bhatia P, Afendy M, et al. Apnoeic–hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis. Liver Int. 2008;28:1080–6.151
Asfari MM, Niyazi F, Lopez R, Dasarathy S, McCullough AJ. The association of nonalcoholic steatohepatitis and obstructive sleep apnea. Eur J Gastroenterol Hepatol. 2017;29:1380–4.152
Drager LF, Jun JC, Polotsky VY. Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metab. 2010;24:843–51.153
Li J, Savransky V, Nanayakkara A, Smith PL, O'Donnell CP, Polotsky VY. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol. 2007;102:557–63.154
Khalyfa A, Gozal D, Masa JF, Marin JM, Qiao Z, Corral J, et al. Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes. Int J Obes (Lond). 2018;42:1127–39.155
Xu H, Liang C, Zou J, Yi H, Guan J, Gu M, et al. Interaction between obstructive sleep apnea and short sleep duration on insulin resistance: a large-scale study. Respir Res. 2020;21:151.156
Polotsky VY, Patil SP, Savransky V, Laffan A, Fonti S, Frame LA, et al. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med. 2009;179:228–34.157
Hazlehurst JM, Lim TR, Charlton C, Miller JJ, Gathercole LL, Cornfield T, et al. Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents. Metabolism Open. 2022;14:100177.158
Loomba R, Chalasani N. The hierarchical model of NAFLD: prognostic significance of histologic features in NASH. Gastroenterology. 2015;149:278–81.159
Käräjämäki AJ, Pätsi OP, Savolainen M, Kesäniemi YA, Huikuri H, Ukkola O. Non-alcoholic fatty liver disease as a predictor of atrial fibrillation in middle-aged population (OPERA Study). PLoS One. 2015;10:e0142937.160
VanWagner LB, Wilcox JE, Colangelo LA, Lloyd-Jones DM, Carr JJ, Lima JA, et al. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: a population-based study. Hepatology. 2015;62:773–83.161
Mantovani A, Rigamonti A, Bonapace S, Bolzan B, Pernigo M, Morani G, et al. Nonalcoholic fatty liver disease is associated with ventricular arrhythmias in patients with type 2 diabetes referred for clinically indicated 24-hour holter monitoring. Diabetes Care. 2016;39:1416–23.162
Canada JM, Abbate A, Collen R, Billingsley H, Buckley LF, Carbone S, et al. Relation of hepatic fibrosis in nonalcoholic fatty liver disease to left ventricular diastolic function and exercise tolerance. Am J Cardiol. 2019;123:466–73.163
Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care. 2004;27:2498–500.164
Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol. 2008;49:600–7.165
Bonapace S, Perseghin G, Molon G, Canali G, Bertolini L, Zoppini G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care. 2012;35:389–95.166
Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol. 2012;10:646–50.167
Targher G, Valbusa F, Bonapace S, Bertolini L, Zenari L, Rodella S, et al. Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes. PLoS One. 2013;8:e57183.168
Lautamäki R, Borra R, Iozzo P, Komu M, Lehtimäki T, Salmi M, et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2006;291:E282–90.169
Villanova N, Moscatiello S, Ramilli S, Bugianesi E, Magalotti D, Vanni E, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42:473–80.170
Yilmaz Y, Kurt R, Yonal O, Polat N, Celikel CA, Gurdal A, et al. Coronary flow reserve is impaired in patients with nonalcoholic fatty liver disease: association with liver fibrosis. Atherosclerosis. 2010;211:182–6.171
Adams LA, Lymp JF St, Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.172
Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–54.173
Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, et al. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e168–85.174
Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLOS Med. 2014;11:e1001680.175
Marcuccilli M, Chonchol M. NAFLD and chronic kidney disease. Int J Mol Sci. 2016;17:562.176
Byrne CD, Targher G. NAFLD as a driver of chronic kidney disease. J Hepatol. 2020;72:785–801.177
Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18–35.178
Vilarinho S, Ajmera V, Zheng M, Loomba R. Emerging role of genomic analysis in clinical evaluation of lean individuals with NAFLD. Hepatology. 2021;74:2241–50.179
Tamaki N, Munaganuru N, Jung J, Yonan AQ, Loomba RR, Bettencourt R, et al. Clinical utility of 30% relative decline in MRI-PDFF in predicting fibrosis regression in non-alcoholic fatty liver disease. Gut. 2022;71:983–990.180
Lewis JH, Ranard RC, Caruso A, Jackson LK, Mullick F, Ishak KG, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology. 1989;9:679–85.181
Lewis JH, Mullick F, Ishak KG, Ranard RC, Ragsdale B, Perse RM, et al. Histopathologic analysis of suspected amiodarone hepatotoxicity. Hum Pathol. 1990;21:59–67.182
Anthérieu S, Rogue A, Fromenty B, Guillouzo A, Robin MA. Induction of vesicular steatosis by amiodarone and tetracycline is associated with up-regulation of lipogenic genes in HepaRG cells. Hepatology. 2011;53:1895–905.183
Fromenty B, Fisch C, Labbe G, Degott C, Deschamps D, Berson A, et al. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther. 1990;255:1371–6.184
Goldman IS, Winkler ML, Raper SE, Barker ME, Keung E, Goldberg HI, et al. Increased hepatic density and phospholipidosis due to amiodarone. AJR Am J Roentgenol. 1985;144:541–6.185
Raja K, Thung SN, Fiel MI, Chang C. Drug-induced steatohepatitis leading to cirrhosis: long-term toxicity of amiodarone use. Semin Liver Dis. 2009;29:423–8.186
Kouzu K, Tsujimoto H, Nishikawa M, Harada M, Sugihara T, Nagata H, et al. Risk factors for nonalcoholic fatty liver disease after gastrectomy for gastric cancer. Gastric Cancer. 2020;23:356–62.187
Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol. 2009;10:278–86.188
Zeng D, Wang Y, Chen Y, Li D, Li G, Xiao H, et al. Angelica polysaccharide antagonizes 5-FU-induced oxidative stress injury to reduce apoptosis in the liver through Nrf2 pathway. Front Oncol. 2021;11:720620.189
Allard J, Bucher S, Massart J, Ferron PJ, Le Guillou D, Loyant R, et al. Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity. Cell Biol Toxicol. 2021;37:151–75.190
Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005;200:845–53.191
Morris-Stiff G, Tan YM, Vauthey JN. Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases. Eur J Surg Oncol. 2008;34:609–14.192
Pawlik TM, Olino K, Gleisner AL, Torbenson M, Schulick R, Choti MA. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg. 2007;11:860–88.193
Schumacher JD, Guo GL. Mechanistic review of drug-induced steatohepatitis. Toxicol Appl Pharmacol. 2015;289:40–7.194
Meunier L, Larrey D. Chemotherapy-associated steatohepatitis. Ann Hepatol. 2020;19:597–601.195
Haider A, Gooren LJG, Padungtod P, Saad F. Improvement of the metabolic syndrome and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate. Exp Clin Endocrinol Diabetes. 2010;118:167–71.196
Mahli A, Saugspier M, Koch A, Sommer J, Dietrich P, Lee S, et al. ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis. Gut. 2018;67:746–56.197
Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in patients with breast cancer. Lancet. 1998;351:725.198
Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med. 1995;123:236.199
Murata Y, Ogawa Y, Saibara T, Nishioka A, Fujiwara Y, Fukumoto M, et al. Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. Oncol Rep. 2000;7:1299–304.200
Farrell GC. Drugs and steatohepatitis. Semin Liver Dis. 2002;22:185–94.201
Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol. 2003;180:129–34.202
Larosche I, Lettéron P, Fromenty B, Vadrot N, Abbey-Toby A, Feldmann G, et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther. 2007;321:526–35.203
Saphner T, Triest-Robertson S, Li H, Holzman P. The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer. 2009;115:3189–95.204
Birzniece V, Barrett PHR, Ho KKY. Tamoxifen reduces hepatic VLDL production and GH secretion in women: a possible mechanism for steatosis development. Eur J Endocrinol. 2017;177:137–43.205
Langman G, Hall PDLM, Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol. 2001;16:1395–401.206
Hytiroglou P, Tobias H, Saxena R, Abramidou M, Papadimitriou CS, Theise ND. The canals of hering might represent a target of methotrexate hepatic toxicity. Am J Clin Pathol. 2004;121:324–29.207
Yamamoto N, Oliveira MB, Campello ADP, Lopes LC, Klüppel ML. Methotrexate: studies on the cellular metabolism. I. Effect on mitochondrial oxygen uptake and oxidative phosphorylation. Cell Biochem Funct. 1988;6:61–66.208
Letteron P, Brahimi-Bourouina N, Robin MA, Moreau A, Feldmann G, Pessayre D. Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation. Am J Physiol Gastrointest Liver Physiol. 1997;272:G1141–50.209
Abdelmalek MF, Liu C, Shuster J, Nelson DR, Asal NR. Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:1162–9.210
Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68:268–79.211
Blomdahl J, Nasr P, Ekstedt M, Kechagias S. Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus. Metabolism. 2021;115:154439.212
Chang Y, Ryu S, Kim Y, Cho YK, Sung E, Kim HN, et al. Low levels of alcohol consumption, obesity, and development of fatty liver with and without evidence of advanced fibrosis. Hepatology. 2020;71:861–73.213
Loomba R, Yang HI, Su J, Brenner D, Barrett-Connor E, Iloeje U, et al. Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study. Am J Epidemiol. 2013;177:333–42.214
Loomba R, Bettencourt R, Barrett-Connor E. Synergistic association between alcohol intake and body mass index with serum alanine and aspartate aminotransferase levels in older adults: the Rancho Bernardo Study. Aliment Pharmacol Ther. 2009;30:1137–49.215
Hart CL, Morrison DS, Batty GD, Mitchell RJ, Davey Smith G. Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. BMJ. 2010;340:c1240.216
Dunn W, Sanyal AJ, Brunt EM, Unalp-Arida A, Donohue M, McCullough AJ, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol. 2012;57:384–91.217
Ajmera V, Belt P, Wilson LA, Gill RM, Loomba R, Kleiner DE, et al. Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis. Clin Gastroenterol Hepatol. 2018;16:1511–20.218
GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2018;392:1015–35.219
Ochiai Y, Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Okubo S, et al. Effects of alcohol consumption on multiple hepatocarcinogenesis in patients with fatty liver disease. Hepatol Res. 2021;51:62–8.220
Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.221
Araki O, Ying H, Zhu XG, Willingham MC, Cheng SY. Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms. Mol Endocrinol. 2009;23:308–15.222
Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018;14:259–69.223
Mantovani A, Nascimbeni F, Lonardo A, Zoppini G, Bonora E, Mantzoros CS, et al. Association between primary hypothyroidism and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Thyroid. 2018;28:1270–84.224
Guo Z, Li M, Han B, Qi X. Association of non-alcoholic fatty liver disease with thyroid function: a systematic review and meta-analysis. Dig Liver Dis. 2018;50:1153–62.225
Bril F, Kadiyala S, Portillo Sanchez P, Sunny NE, Biernacki D, Maximos M, et al. Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes. J Investig Med. 2016;64:63–8.226
Jaruvongvanich V, Sanguankeo A, Upala S. Nonalcoholic fatty liver disease is not associated with thyroid hormone levels and hypothyroidism: a systematic review and meta-analysis. Eur Thyroid J. 2017;6:208–15.227
Bano A, Chaker L, Plompen EPC, Hofman A, Dehghan A, Franco OH, et al. Thyroid function and the risk of nonalcoholic fatty liver disease: the Rotterdam Study. J Clin Endocrinol Metab. 2016;101:3204–11.228
Bohinc BN, Michelotti G, Xie G, Pang H, Suzuki A, Guy CD, et al. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology. 2014;155:4591–601.229
Vijayakumar A, Novosyadlyy R, Wu Y, Yakar S, LeRoith D. Biological effects of growth hormone on carbohydrate and lipid metabolism. Growth Horm IGF Res. 2010;20:1–7.230
Adamek A, Kasprzak A. Insulin-like growth factor (IGF) system in liver diseases. Int J Mol Sci. 2018;19:1308.231
Mueller KM, Themanns M, Friedbichler K, Kornfeld JW, Esterbauer H, Tuckermann JP, et al. Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development. Mol Cell Endocrinol. 2012;361:1–11.232
Takahashi Y. The role of growth hormone and insulin-like growth factor-I in the liver. Int J Mol Sci. 2017;18:1447.233
Ichikawa T, Nakao K, Hamasaki K, Furukawa R, Tsuruta S, Ueda Y, et al. Role of growth hormone, insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 in development of non-alcoholic fatty liver disease. Hepatol Int. 2007;1:287–94.234
Yao Y, Miao X, Zhu D, Li D, Zhang Y, Song C, et al. Insulin-like growth factor-1 and non-alcoholic fatty liver disease: a systemic review and meta-analysis. Endocrine. 2019;65:227–37.235
Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology. 2004;39:909–14.236
Hong JW, Kim JY, Kim YE, Lee EJ. Metabolic parameters and nonalcoholic fatty liver disease in hypopituitary men. Horm Metab Res. 2011;43:48–54.237
Sumida Y, Yonei Y, Tanaka S, Mori K, Kanemasa K, Imai S, et al. Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease. Hepatol Res. 2015;45:771–81.238
Nishizawa H, Iguchi G, Murawaki A, Fukuoka H, Hayashi Y, Kaji H, et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur J Endocrinol. 2012;167:67–74.239
Gardner CJ, Irwin A, Daousi C, McFarlane IA, Joseph F, Bell JD, et al. Hepatic steatosis, GH deficiency and the effects of GH replacement: a Liverpool magnetic resonance spectroscopy study. Eur J Endocrinol. 2012;166:993–1002.240
Stanley TL, Chen CY, Branch KL, Makimura H, Grinspoon SK. Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. J Clin Endocrinol Metab. 2011;96:150–8.241
Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, Pan CS, et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019;6:e821–30.242
Shen M, Shi H. Sex hormones and their receptors regulate liver energy homeostasis. Int J Endocrinol. 2015;2015:294278.243
Navarro G, Allard C, Xu W, Mauvais-Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity (Silver Spring). 2015;23:713–9.244
Sarkar M, Wellons M, Cedars MI, VanWagner L, Gunderson EP, Ajmera V, et al. Testosterone levels in pre-menopausal women are associated with nonalcoholic fatty liver disease in midlife. Am J Gastroenterol. 2017;112:755–62.245
Salvoza N, Giraudi P, Tiribelli C, Rosso N. Sex differences in non-alcoholic fatty liver disease: hints for future management of the disease. Explor Med. 2020;1:51–74.246
Jaruvongvanich V, Sanguankeo A, Riangwiwat T, Upala S. Testosterone, sex hormone-binding globulin and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Ann Hepatol. 2017;16:382–94.247
Kim S, Kwon H, Park JH, Cho B, Kim D, Oh SW, et al. A low level of serum total testosterone is independently associated with nonalcoholic fatty liver disease. BMC Gastroenterol. 2012;12:69.248
Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC, Skinner JS, et al. Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: the HERITAGE family study. J Clin Endocrinol Metab. 2000;85:1026–31.249
Sarkar M, Yates K, Suzuki A, Lavine J, Gill R, Ziegler T, et al. Low testosterone is associated with nonalcoholic steatohepatitis and fibrosis severity in men. Clin Gastroenterol Hepatol. 2021;19:400–2.250
Dayton KA, Bril F, Barb D, Lai J, Kalavalapalli S, Cusi K. Severity of non-alcoholic steatohepatitis is not linked to testosterone concentration in patients with type 2 diabetes. PLoS One. 2021;16:e0251449.251
Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ. 2005;330:932.252
El-Mansoury M, Berntorp K, Bryman I, Hanson C, Innala E, Karlsson A, et al. Elevated liver enzymes in Turner syndrome during a 5-year follow-up study. Clin Endocrinol (Oxf). 2008;68:485–90.253
Yang YJ, Kim KM, An JH, Lee DB, Shim JH, Lim YS, et al. Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients. Breast. 2016;28:67–72.254
Klair JS, Yang JD, Abdelmalek MF, Guy CD, Gill RM, Yates K, et al. A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology. 2016;64:8–91.255
Suzuki A, Abdelmalek MF, Schwimmer JB, Lavine JE, Scheimann AO, Unalp-Arida A, et al. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012;10:786–94.256
Venetsanaki V, Polyzos SA. Menopause and non-alcoholic fatty liver disease: a review focusing on therapeutic perspectives. Curr Vasc Pharmacol. 2019;17:546–55.257
Wu J, Yao XY, Shi RX, Liu SF, Wang XY. A potential link between polycystic ovary syndrome and non-alcoholic fatty liver disease: an update meta-analysis. Reprod Health. 2018;15:77.258
Jones H, Sprung VS, Pugh CJA, Daousi C, Irwin A, Aziz N, et al. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2012;97:3709–16.259
Ramezani-Binabaj M, Motalebi M, Karimi-Sari H, Rezaee-Zavareh MS, Alavian SM. Are women with polycystic ovarian syndrome at a high risk of non-alcoholic fatty liver disease; a meta-analysis. Hepat Mon. 2014;14:e23235.260
Kumarendran B, O'Reilly MW, Manolopoulos KN, Toulis KA, Gokhale KM, Sitch AJ, et al. Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: a longitudinal study based on a United Kingdom primary care database. PLoS Med. 2018;15:e1002542.261
Sarkar M, Terrault N, Chan W, Cedars MI, Huddleston HG, Duwaerts CC, et al. Polycystic ovary syndrome (PCOS) is associated with NASH severity and advanced fibrosis. Liver Int. 2020;40:355–9.262
Long MT, Noureddin M, Lim JK. AGA Clinical Practice Update: diagnosis and management of nonalcoholic fatty liver disease in lean individuals: expert review. Gastroenterology. 2022;163:764–74.263
Hirose S, Matsumoto K, Tatemichi M, Tsuruya K, Anzai K, Arase Y, et al. Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients. PLoS One. 2020;15:e0241770.264
Sookoian S, Pirola CJ. Systematic review with meta-analysis: the significance of histological disease severity in lean patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2018;47:16–25.265
Lu FB, Zheng KI, Rios RS, Targher G, Byrne CD, Zheng MH. Global epidemiology of lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2020;35:2041–50.266
Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore). 2012;91:319–27.267
Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67:862–73.268
Wei JL, Leung JCF, Loong TCW, Wong GLH, Yeung DKW, Chan RSM, et al. Prevalence and severity of nonalcoholic fatty liver disease in non-obese patients: a population study using proton-magnetic resonance spectroscopy. Am J Gastroenterol. 2015;110:1306–14.269
Cusi K. Nonalcoholic steatohepatitis in nonobese patients: not so different after all. Hepatology. 2017;65:4–7.270
Kim D, Kim WR. Nonobese fatty liver disease. Clin Gastroenterol Hepatol. 2017;15:474–85.271
Ye Q, Zou B, Yeo YH, Li J, Huang DQ, Wu Y, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5:739–52.272
Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A. Adipose tissue-liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease. Gastroenterology. 2020;158:1899–912.273
Buryska S, Ahn JC, Allen AM, Simha V, Simonetto DA. Familial hypobetalipoproteinemia: an underrecognized cause of lean NASH. Hepatology. 2021;74:2897–8.274
Younes R, Bugianesi E. NASH in lean individuals. Semin Liver Dis. 2019;39:86–95.275
Kim NH, Kim JH, Kim YJ, Yoo HJ, Kim HY, Seo JA, et al. Clinical and metabolic factors associated with development and regression of nonalcoholic fatty liver disease in nonobese subjects. Liver Int. 2014;34:604–11.276
Wong VWS, Wong GLH, Chan RSM, Shu SST, Cheung BHK, Li LS, et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol. 2018;69:1349–56.277
Hamurcu Varol P, Kaya E, Alphan E, Yilmaz Y. Role of intensive dietary and lifestyle interventions in the treatment of lean nonalcoholic fatty liver disease patients. Eur J Gastroenterol Hepatol. 2020;32:1352–7.278
Young S, Tariq R, Provenza J, Satapathy SK, Faisal K, Choudhry A, et al. Prevalence and profile of nonalcoholic fatty liver disease in lean adults: systematic review and meta-analysis. Hepatol Commun. 2020;4:953–72.279
Fracanzani AL, Petta S, Lombardi R, Pisano G, Russello M, Consonni D, et al. Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity. Clin Gastroenterol Hepatol. 2017;15:1604–11.280
Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874–82.281
Noureddin M, Jones C, Alkhouri N, Gomez EV, Dieterich DT, Rinella ME, et al. Screening for nonalcoholic fatty liver disease in persons with type 2 diabetes in the United States is cost-effective: a comprehensive cost-utility analysis. Gastroenterology. 2020;159:1985–7.282
Chen K, Sng WK, Quah JH, Liu J, Chong BY, Lee HK, et al. Clinical spectrum of non-alcoholic fatty liver disease in patients with diabetes mellitus. PLoS One. 2020;15:e0236977.283
Lomonaco R, Godinez Leiva E, Bril F, Shrestha S, Mansour L, Budd J, et al. Advanced liver fibrosis is common in patients with type 2 diabetes followed in the outpatient setting: the need for systematic screening. Diabetes Care. 2021;44:399–406.284
Tuong TTK, Tran DK, Phu PQT, Hong TND, Chu Dinh T, Chu DT. Non-alcoholic fatty liver disease in patients with type 2 diabetes: evaluation of hepatic fibrosis and steatosis using Fibroscan. Diagnostics. 2020;10:159.285
Mantovani A, Turino T, Lando MG, Gjini K, Byrne CD, Zusi C, et al. Screening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes. Diabetes Metab. 2020;46:296–303.286
Arab JP, Dirchwolf M, Álvares-da-Silva MR, Barrera F, Benítez C, Castellanos-Fernandez M, et al. Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease. Ann Hepatol. 2020;19:674–90.287
Soresi M, Cabibi D, Giglio RV, Martorana S, Guercio G, Porcasi R, et al. The prevalence of NAFLD and fibrosis in bariatric surgery patients and the reliability of noninvasive diagnostic methods. BioMed Res Int. 2020;2020:5023157.288
Udelsman BV, Corey K, Hutter MM, Chang DC, Witkowski ER. Use of noninvasive scores for advanced liver fibrosis can guide the need for hepatic biopsy during bariatric procedures. Surg Obes Relat Dis. 2021;17:292–8.289
Udelsman BV, Corey KE, Lindvall C, Gee DW, Meireles OR, Hutter MM, et al. Risk factors and prevalence of liver disease in review of 2557 routine liver biopsies performed during bariatric surgery. Surg Obes Relat Dis. 2019;15:843–9.290
Ciardullo S, Pizzi M, Pizzi P, Oltolini A, Muraca E, Perseghin G. Prevalence of elevated liver stiffness among potential candidates for bariatric surgery in the United States. Obes Surg. 2022;32:712–9.291
Luger M, Kruschitz R, Kienbacher C, Traussnigg S, Langer FB, Schindler K, et al. Prevalence of liver fibrosis and its association with non-invasive fibrosis and metabolic markers in morbidly obese patients with vitamin D deficiency. Obes Surg. 2016;26:2425–32.292
Alqahtani SA, Golabi P, Paik JM, Lam B, Moazez AH, Elariny HA, et al. Performance of noninvasive liver fibrosis tests in morbidly obese patients with nonalcoholic fatty liver disease. Obes Surg. 2021;31:2002–10.293
Caussy C, Soni M, Cui J, Bettencourt R, Schork N, Chen CH, et al. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest. 2017;127:2697–704.294
Tamaki N, Ahlholm N, Luukkonen PK, Porthan K, Sharpton SR, Ajmera V, et al. Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease. J Clin Invest. 2022;132:e162513.295
Savolainen VT, Liesto K, Männikkö A, Penttilä A, Karhunen PJ. Alcohol consumption and alcoholic liver disease: evidence of a threshold level of effects of ethanol. Alcohol Clin Exp Res. 1993;17:1112–7.296
Åberg F, Puukka P, Salomaa V, Männistö S, Lundqvist A, Valsta L, et al. Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts. Hepatology. 2020;71:835–48.297
Ekstedt M, Franzén LE, Holmqvist M, Bendtsen P, Mathiesen UL, Bodemar G, et al. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2009;44:366–74.298
Jarvis H, Craig D, Barker R, Spiers G, Stow D, Anstee QM, et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of population-based observational studies. PLOS Med. 2020;17:e1003100.299
Siddiqui MS, Carbone S, Vincent R, Patel S, Driscoll C, Celi FS, et al. Prevalence and severity of nonalcoholic fatty liver disease among caregivers of patients with nonalcoholic fatty liver disease cirrhosis. Clin Gastroenterol Hepatol. 2019;17:2132–3.300
Dourakis SP, Sevastianos VA, Kaliopi P. Acute severe steatohepatitis related to prednisolone therapy. Am J Gastroenterol. 2002;97:1074–5.301
Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. 2006;45:600–66.302
Wong VWS, Chu WCW, Wong GLH, Chan RSM, Chim AML, Ong A, et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut. 2012;61:409–15.303
Harris R, Harman DJ, Card TR, Aithal GP, Guha IN. Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review. Lancet Gastroenterol Hepatol. 2017;2:288–97.304
Lai LL, Wan Yusoff WNI, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography. J Gastroenterol Hepatol. 2019;34:1396–403.305
Kang KA, Jun DW, Kim MS, Kwon HJ, Nguyen MH. Prevalence of significant hepatic fibrosis using magnetic resonance elastography in a health check-up clinic population. Aliment Pharmacol Ther. 2020;51:388–96.306
Sporea I, Mare R, Popescu A, Nistorescu S, Baldea V, Sirli R, et al. Screening for liver fibrosis and steatosis in a large cohort of patients with type 2 diabetes using vibration controlled transient elastography and controlled attenuation parameter in a single-center real-life experience. J Clin Med. 2020;9:1032.307
Yang A, Nguyen M, Ju I, Brancatisano A, Ryan B, van der Poorten D. Utility of Fibroscan XL to assess the severity of non-alcoholic fatty liver disease in patients undergoing bariatric surgery. Sci Rep. 2021;11:14006.308
Siddiqui MS, Yamada G, Vuppalanchi R, Van Natta M, Loomba R, Guy C, et al. Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol Hepatol. 2019;17:1877–85.e5.309
Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. 2017;66:1486–501.310
Roccarina D, Best LMJ, Freeman SC, Roberts D, Cooper NJ, Sutton AJ, et al. Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta‐analysis. Cochrane Database Syst Rev. 2021;6:CD013121.311
Vadera S, Yong CWK, Gluud LL, Morgan MY. Band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices. Cochrane Database Syst Rev. 2019;6:CD012673.312
Plaz Torres M, Best LMJ, Freeman SC, Roberts D, Cooper NJ, Sutton AJ, et al. Secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis: a network meta‐analysis. Cochrane Database Syst Rev. 2021;3:CD013122.313
Lai JC, Tandon P, Bernal W, Tapper EB, Ekong U, Dasarathy S, et al. Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 Practice Guidance by The American Association for the Study Of Liver Diseases. Hepatology. 2021;74:1611–44.314
Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–92.315
McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;59:1265–9.316
Neuschwander-Tetri BA, Unalp A, Creer MH. Nonalcoholic Steatohepatitis Research Network. Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels. Arch Intern Med. 2008;168:663–666.317
Rinella ME, Lominadze Z, Loomba R, Charlton M, Neuschwander-Tetri BA, Caldwell SH, et al. Practice patterns in NAFLD and NASH: real life differs from published guidelines. Therap Adv Gastroenterol. 2016;9:4–12.318
FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource Food and Drug Administration. Silver Spring, MD: National Institutes of Health; 2016.319
Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–50.320
Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14:635–7.321
Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology. 2017;152:598–607.322
Paige JS, Bernstein GS, Heba E, Costa EAC, Fereirra M, Wolfson T, et al. A pilot comparative study of quantitative ultrasound, conventional ultrasound, and MRI for predicting histology-determined steatosis grade in adult nonalcoholic fatty liver disease. AJR Am J Roentgenol. 2017;208:W168–77.323
Caussy C, Alquiraish MH, Nguyen P, Hernandez C, Cepin S, Fortney LE, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018;67:1348–59.324
Caussy C, Reeder SB, Sirlin CB, Loomba R. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018;68:763–72.325
Woreta TA, Van Natta ML, Lazo M, Krishnan A, Neuschwander-Tetri BA, Loomba R, et al. Validation of the accuracy of the FAST™ score for detecting patients with at-risk nonalcoholic steatohepatitis (NASH) in a North American cohort and comparison to other non-invasive algorithms. PLoS One. 2022;17:e0266859.326
Noureddin M, Truong E, Gornbein JA, Saouaf R, Guindi M, Todo T, et al. MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis. J Hepatol. 2022;76:781–77.327
Jung J, Loomba RR, Imajo K, Madamba E, Gandhi S, Bettencourt R, et al. MRE combined with FIB-4 (MEFIB) index in detection of candidates for pharmacological treatment of NASH-related fibrosis. Gut. 2021;70:1946–53.328
Andersson A, Kelly M, Imajo K, Nakajima A, Fallowfield JA, Hirschfield G, et al. Clinical utility of magnetic resonance imaging biomarkers for identifying nonalcoholic steatohepatitis patients at high risk of progression: a multicenter pooled data and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:2451–61.329
McPherson S, Hardy T, Dufour JF, Petta S, Romero-Gomez M, Allison M, et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol. 2017;112:740–51.330
Graupera I, Thiele M, Serra-Burriel M, Caballeria L, Roulot D, Wong GLH, et al. Low accuracy of FIB-4 and NAFLD fibrosis scores for screening for liver fibrosis in the population. Clin Gastroenterol Hepatol. 2022;20:2567–76.331
Day J, Patel P, Parkes J, Rosenberg W. Derivation and performance of standardized enhanced liver fibrosis (ELF) test thresholds for the detection and prognosis of liver fibrosis. J Appl Lab Med. 2019;3:815–26.332
Loomba R, Jain A, Diehl AM, Guy CD, Portenier D, Sudan R, et al. Validation of serum test for advanced liver fibrosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2019;17:1867–76.333
Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156:1264–81.e4.334
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology. 2014;60:1920–8.335
Brandman D, Boyle M, McPherson S, Van Natta ML, Sanyal AJ, Kowdley K, et al. Comparison of clinical prediction rules for ruling out cirrhosis in nonalcoholic fatty liver disease (NAFLD). Aliment Pharmacol Ther. 2022;55:1441–51.336
Hsu C, Caussy C, Imajo K, Chen J, Singh S, Kaulback K, et al. Magnetic resonance vs transient elastography analysis of patients with nonalcoholic fatty liver disease: a systematic review and pooled analysis of individual participants. Clin Gastroenterol Hepatol. 2019;17:630–7.337
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.338
Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. Hepatology. 2017;66:84–95.339
Hagström H, Talbäck M, Andreasson A, Walldius G, Hammar N. Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease. J Hepatol. 2020;73:1023–9.340
Cui J, Ang B, Haufe W, Hernandez C, Verna EC, Sirlin CB, et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther. 2015;41:1271–80.341
Younossi ZM, Corey KE, Alkhouri N, Noureddin M, Jacobson I, Lam B, et al. Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices. Aliment Pharmacol Ther. 2020;52:513–26.342
Miele L, De Michele T, Marrone G, Antonietta Isgrò M, Basile U, Cefalo C, et al. Enhanced liver fibrosis test as a reliable tool for assessing fibrosis in nonalcoholic fatty liver disease in a clinical setting. Int J Biol Markers. 2017;32:e397–402.343
Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–60.344
Siddiqui MS, Vuppalanchi R, Van Natta ML, Hallinan E, Kowdley KV, Abdelmalek M, et al. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019;17:156–63.345
Petta S, Sebastiani G, Viganò M, Ampuero J, Wai-Sun Wong V, Boursier J, et al. Monitoring occurrence of liver-related events and survival by transient elastography in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease. Clin Gastroenterol Hepatol. 2021;19:806–15.346
Gidener T, Dierkhising RA, Mara KC, Therneau TM, Venkatesh SK, Ehman RL, et al. Change in serial liver stiffness measurement by magnetic resonance elastography and outcomes in NAFLD. Hepatology. 2023;77:268–74.347
Tamaki N, Imajo K, Sharpton S, Jung J, Kawamura N, Yoneda M, et al. Magnetic resonance elastography plus Fibrosis-4 versus FibroScan–aspartate aminotransferase in detection of candidates for pharmacological treatment of NASH-related fibrosis. Hepatology. 2022;75:661–72.348
Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150:626–37.e7.349
Yin M, Glaser KJ, Talwalkar JA, Chen J, Manduca A, Ehman RL. Hepatic MR elastography: clinical performance in a series of 1377 consecutive examinations. Radiology. 2016;278:114–24.350
Gidener T, Ahmed OT, Larson JJ, Mara KC, Therneau TM, Venkatesh SK, et al. Liver stiffness by magnetic resonance elastography predicts future cirrhosis, decompensation, and death in NAFLD. Clin Gastroenterol Hepatol. 2021;19:1915–24.351
Ajmera V, Kim BK, Yang K, Majzoub AM, Nayfeh T, Tamaki N, et al. Liver stiffness on magnetic resonance elastography and the MEFIB index and liver-related outcomes in nonalcoholic fatty liver disease: a systematic review and meta-analysis of individual participants. Gastroenterology. 2022;163:1079–89.352
Tamaki N, Higuchi M, Kurosaki M, Loomba R, Izumi N. MRCH Liver Study Group. Risk difference of liver-related and cardiovascular events by liver fibrosis status in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2022;20:1171–3.353
Harrison SA, Ratziu V, Boursier J, Francque S, Bedossa P, Majd Z, et al. A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol Hepatol. 2020;5:970–85.354
Pavlides M, Banerjee R, Tunnicliffe EM, Kelly C, Collier J, Wang LM, et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int. 2017;37:1065–73.355
Staufer K, Halilbasic E, Spindelboeck W, Eilenberg M, Prager G, Stadlbauer V, et al. Evaluation and comparison of six noninvasive tests for prediction of significant or advanced fibrosis in nonalcoholic fatty liver disease. United European. Gastroenterol J. 2019;7:1113–23.356
Dennis A, Mouchti S, Kelly M, Fallowfield JA, Hirschfield G, Pavlides M, et al. A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis. Sci Rep. 2020;10:15308.357
Brunt EM, Kleiner DE, Carpenter DH, Rinella M, Harrison SA, Loomba R, et al. NAFLD: reporting histologic findings in clinical practice. Hepatology. 2021;73:2028–38.358
Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology. 2009;49:1017–44.359
Kleiner DE, Brunt EM, Wilson LA, Behling C, Guy C, Contos M, et al. Association of histologic disease activity with progression of nonalcoholic fatty liver disease. JAMA Netw Open. 2019;2:e1912565.360
Brunt EM, Kleiner DE, Wilson LA, Sanyal AJ, Neuschwander-Tetri BA. Nonalcoholic Steatohepatitis Clinical Research Network. Improvements in histologic features and diagnosis associated with improvement in fibrosis in nonalcoholic steatohepatitis: results from the Nonalcoholic Steatohepatitis Clinical Research Network treatment trials. Hepatology. 2019;70:522–31.361
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.362
Bedossa P. Flip Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60:565–75.363
Taylor-Weiner A, Pokkalla H, Han L, Jia C, Huss R, Chung C, et al. A machine learning approach enables quantitative measurement of liver histology and disease monitoring in NASH. Hepatology. 2021;74:133–47.364
Liu F, Goh GBB, Tiniakos D, Wee A, Leow WQ, Zhao JM, et al. qFIBS: an automated technique for quantitative evaluation of fibrosis, inflammation, ballooning, and steatosis in patients with nonalcoholic steatohepatitis. Hepatology. 2020;71:1953–66.365
Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: beyond the obvious. Liver Int. 2021;41:2249–68.366
American Diabetes Association. Professional Practice Committee. 4. Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45:S46–59.367
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–78.368
Patel NS, Doycheva I, Peterson MR, Hooker J, Kisselva T, Schnabl B, et al. Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2015;13:561–8.369
Patel NS, Hooker J, Gonzalez M, Bhatt A, Nguyen P, Ramirez K, et al. Weight loss decreases magnetic resonance elastography estimated liver stiffness in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2017;15:463–44.370
Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med. 2019;179:1262–71.371
Malespin MH, Barritt AS 4th, Watkins SE, Schoen C, Tincopa MA, Corbin KD, et al. Weight loss and weight regain in usual clinical practice: results from the TARGET-NASH observational cohort. Clin Gastroenterol Hepatol. 2022;20:2393–5.372
Heinitz S, Hollstein T, Ando T, Walter M, Basolo A, Krakoff J, et al. Early adaptive thermogenesis is a determinant of weight loss after six weeks of caloric restriction in overweight subjects. Metabolism. 2020;110:154303.373
Stewart KE, Haller DL, Sargeant C, Levenson JL, Puri P, Sanyal AJ. Readiness for behaviour change in non-alcoholic fatty liver disease: implications for multidisciplinary care models. Liver Int. 2015;35:936–43.374
Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012;56:255–66.375
Postrach E, Aspalter R, Elbelt U, Koller M, Longin R, Schulzke JD, et al. Determinants of successful weight loss after using a commercial web-based weight reduction program for six months: cohort study. J Med Internet Res. 2013;15:e219.376
Lowe MR, Miller-Kovach K, Phelan S. Weight-loss maintenance in overweight individuals one to five years following successful completion of a commercial weight loss program. Int J Obes Relat Metab Disord. 2001;25:325–31.377
Yasutake K, Nakamuta M, Shima Y, Ohyama A, Masuda K, Haruta N, et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand J Gastroenterol. 2009;44:471–7.378
Meng G, Zhang B, Yu F, Li C, Zhang Q, Liu L, et al. Soft drinks consumption is associated with nonalcoholic fatty liver disease independent of metabolic syndrome in Chinese population. Eur J Nutr. 2018;57:2113–221.379
Vilar-Gomez E, Nephew LD, Vuppalanchi R, Gawrieh S, Mladenovic A, Pike F, et al. High-quality diet, physical activity, and college education are associated with low risk of NAFLD among the US population. Hepatology. 2022;75:1491–506.380
Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW, Balasubramanyam A, et al. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology. 2012;56:952–60.381
Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–71.382
Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, et al. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology. 2013;58:1632–43.383
Properzi C, O'Sullivan TA, Sherriff JL, Ching HL, Jeffrey GP, Buckley RF, et al. Ad libitum Mediterranean and low-fat diets both significantly reduce hepatic steatosis: a randomized controlled trial. Hepatology. 2018;68:1741–54.384
Pugliese N, Plaz Torres MC, Petta S, Valenti L, Giannini EG, Aghemo A. Is there an “ideal” diet for patients with NAFLD? Eur J Clin Invest. 2022;52:e13659.385
Ma J, Hennein R, Liu C, Long MT, Hoffmann U, Jacques PF, et al. Improved diet quality associates with reduction in liver fat, particularly in individuals with high genetic risk scores for nonalcoholic fatty liver disease. Gastroenterology. 2018;155:107–17.386
Vilar-Gomez E, Pirola CJ, Sookoian S, Wilson LA, Belt P, Liang T, et al. Impact of the association between PNPLA3 genetic variation and dietary intake on the risk of significant fibrosis in patients with NAFLD. Am J Gastroenterol. 2021;116:994–1006.387
Kouvari M, Boutari C, Chrysohoou C, Fragkopoulou E, Antonopoulou S, Tousoulis D, et al. Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: results from the ATTICA prospective cohort study. Clin Nutr. 2021;40:3314–24.388
Kawaguchi T, Charlton M, Kawaguchi A, Yamamura S, Nakano D, Tsutsumi T, et al. Effects of Mediterranean diet in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression analysis of randomized controlled trials. Semin Liver Dis. 2021;41:225–34.389
Haigh L, Kirk C, El Gendy K, Gallacher J, Errington L, Mathers JC, et al. The effectiveness and acceptability of Mediterranean diet and calorie restriction in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis. Clin Nutr. 2022;41:1913–31.390
George ES, Reddy A, Nicoll AJ, Ryan MC, Itsiopoulos C, Abbott G, et al. Impact of a Mediterranean diet on hepatic and metabolic outcomes in non-alcoholic fatty liver disease: the MEDINA randomised controlled trial. Liver Int. 2022;42:1308–22.391
Yurtdaş G, Akbulut G, Baran M, Yilmaz C. The effects of Mediterranean diet on hepatic steatosis, oxidative stress, and inflammation in adolescents with non-alcoholic fatty liver disease: a randomized controlled trial. Pediatr Obes. 2022;17:e12872.392
Chen YP, Lu FB, Hu YB, Xu LM, Zheng MH, Hu ED. A systematic review and a dose-response meta-analysis of coffee dose and nonalcoholic fatty liver disease. Clin Nutr. 2019;38:2552–7.393
Saab S, Mallam D, Cox GA II, Tong MJ. Impact of coffee on liver diseases: a systematic review. Liver Int. 2014;34:495–504.394
Wijarnpreecha K, Thongprayoon C, Ungprasert P. Coffee consumption and risk of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2017;29:e8–12.395
Hainer V, Toplak H, Stich V. Fat or fit: what is more important? Diabetes Care. 2009;32(Suppl 2):S392–7.396
Sargeant JA, Aithal GP, Takamura T, Misu H, Takayama H, Douglas JA, et al. The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men. Appl Physiol Nutr Metab. 2018;43:482–90.397
Bae JC, Suh S, Park SE, Rhee EJ, Park CY, Oh KW, et al. Regular exercise is associated with a reduction in the risk of NAFLD and decreased liver enzymes in individuals with NAFLD independent of obesity in Korean adults. PLoS One. 2012;7:e46819.398
Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J Hepatol. 2016;65:791–77.399
Ennequin G, Sirvent P, Whitham M. Role of exercise-induced hepatokines in metabolic disorders. Am J Physiol Endocrinol Metab. 2019;317:E11–24.400
Fujiwara Y, Eguchi S, Murayama H, Takahashi Y, Toda M, Imai K, et al. Relationship between diet/exercise and pharmacotherapy to enhance the GLP-1 levels in type 2 diabetes. Endocrinol Diabetes Metab J. 2019;2:e00068.401
St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50:68–76.402
Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A, Thompson MW, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009;50:1105–12.403
Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB, et al. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol. 2011;106:460–8.404
Abdelbasset WK, Tantawy SA, Kamel DM, Alqahtani BA, Soliman GS. A randomized controlled trial on the effectiveness of 8-week high-intensity interval exercise on intrahepatic triglycerides, visceral lipids, and health-related quality of life in diabetic obese patients with nonalcoholic fatty liver disease. Medicine. 2019;98:e14918.405
Franco I, Bianco A, Mirizzi A, Campanella A, Bonfiglio C, Sorino P, et al. Physical activity and low glycemic index Mediterranean diet: main and modification effects on NAFLD score. Results from a randomized clinical trial. Nutrients. 2021;13:66.406
van Kleef LA, Hofman A, Voortman T, de Knegt RJ. Objectively measured physical activity is inversely associated with nonalcoholic fatty liver disease: the Rotterdam study. Am J Gastroenterol. 2022;117:311–8.407
Tsunoda K, Kitano N, Kai Y, Jindo T, Uchida K, Arao T. Dose–response relationships of accelerometer-measured sedentary behaviour and physical activity with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2021;54:1330–9.408
Berzigotti A, Albillos A, Villanueva C, Genescá J, Ardevol A, Augustín S, et al. Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study. Hepatology. 2017;65:1293–305.409
Williams FR, Berzigotti A, Lord JM, Lai JC, Armstrong MJ. Review article: impact of exercise on physical frailty in patients with chronic liver disease. Aliment Pharmacol Ther. 2019;50:988–1000.410
Mechanick JI, Apovian C, Brethauer S, Timothy Garvey W, Joffe AM, Kim J, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures—2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity (Silver Spring). 2020;28:O1–58.411
Mazzini GS, Augustin T, Noria S, Romero-Marrero C, Li N, Hameed B, et al. ASMBS Position Statement on the impact of metabolic and bariatric surgery on nonalcoholic steatohepatitis. Surg Obes Relat Dis. 2022;18:314–25.412
Mahawar KK, Parmar C, Graham Y, Abouleid A, Carr WRJ, Jennings N, et al. Routine liver biopsy during bariatric surgery: an analysis of evidence base. Obes Surg. 2016;26:177–81.413
Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741–52.414
Kwok CS, Pradhan A, Khan MA, Anderson SG, Keavney BD, Myint PK, et al. Bariatric surgery and its impact on cardiovascular disease and mortality: a systematic review and meta-analysis. Int J Cardiol. 2014;173:20–8.415
Zhou X, Yu J, Li L, Gloy VL, Nordmann A, Tiboni M, et al. Effects of bariatric surgery on mortality, cardiovascular events, and cancer outcomes in obese patients: systematic review and meta-analysis. Obes Surg. 2016;26:2590–601.416
Wiggins T, Guidozzi N, Welbourn R, Ahmed AR, Markar SR. Association of bariatric surgery with all-cause mortality and incidence of obesity-related disease at a population level: a systematic review and meta-analysis. PLOS Med. 2020;17:e1003206.417
Kalinowski P, Paluszkiewicz R, Wróblewski T, Remiszewski P, Grodzicki M, Bartoszewicz Z, et al. Ghrelin, leptin, and glycemic control after sleeve gastrectomy versus Roux-en-Y gastric bypass-results of a randomized clinical trial. Surg Obes Relat Dis. 2017;13:181–8.418
Adams TD, Arterburn DE, Nathan DM, Eckel RH. Clinical outcomes of metabolic surgery: microvascular and macrovascular complications. Diabetes Care. 2016;39:912–23.419
Eliasson B, Liakopoulos V, Franzén S, Näslund I, Svensson AM, Ottosson J, et al. Cardiovascular disease and mortality in patients with type 2 diabetes after bariatric surgery in Sweden: a nationwide, matched, observational cohort study. Lancet Diabetes Endocrinol. 2015;3:847–54.420
Fakhry TK, Mhaskar R, Schwitalla T, Muradova E, Gonzalvo JP, Murr MM. Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15:502–11.421
Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, et al. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019;17:1040–60.422
Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–88.423
Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G, Verkindt H, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. 2020;159:1290–301.424
Jirapinyo P, McCarty TR, Dolan RD, Shah R, Thompson CC. Effect of endoscopic bariatric and metabolic therapies on nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:511–24.425
Chandan S, Mohan BP, Khan SR, Facciorusso A, Ramai D, Kassab LL, et al. Efficacy and safety of intragastric balloon (IGB) in non-alcoholic fatty liver disease (NAFLD): a comprehensive review and meta-analysis. Obes Surg. 2021;31:1271–9.426
Lavín-Alconero L, Fernández-Lanas T, Iruzubieta-Coz P, Arias-Loste MT, Rodriguez-Duque JC, Rivas C, et al. Efficacy and safety of endoscopic sleeve gastroplasty versus laparoscopic sleeve gastrectomy in obese subjects with non-alcoholic steatohepatitis (NASH): study protocol for a randomized controlled trial (TESLA-NASH study). Trials. 2021;22:756.427
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.428
Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2019;42:1481–8.429
Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.430
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165:305–15.431
Kawaguchi-Suzuki M, Bril F, Kalavalapalli S, Cusi K, Frye RF. Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2017;46:56–61.432
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–90.433
Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113–24.434
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205–16.435
Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022;10:393–406.436
Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial). Diabetes Care. 2018;41:1801–8.437
Latva-Rasku A, Honka M-J, Kullberg J, Mononen N, Lehtimäki T, Saltevo J, et al. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care. 2019;42:931–7.438
Kahl S, Gancheva S, Straßburger K, Herder C, Machann J, Katsuyama H, et al. Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: a randomized, double-blind, phase 4, placebo-controlled trial. Diabetes Care. 2020;43:298–305.439
Sato K, Gosho M, Yamamoto T, Kobayashi Y, Ishii N, Ohashi T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015;31:923–30.440
Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. Int J Clin Exp Med. 2015;8:3924–34.441
Hoofnagle JH, Van Natta ML, Kleiner DE, Clark JM, Kowdley KV, Loomba R, et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2013;38:134–43.442
Vilar-Gomez E, Vuppalanchi R, Gawrieh S, Ghabril M, Saxena R, Cummings OW, et al. Vitamin E improves transplant-free survival and hepatic decompensation among patients with nonalcoholic steatohepatitis and advanced fibrosis. Hepatology. 2020;71:495–509.443
Gaziano JM, Sesso HD, Christen WG, Bubes V, Smith JP, MacFadyen J, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308:1871–80.444
Neuhouser ML, Barnett MJ, Kristal AR, Ambrosone CB, King IB, Thornquist M, et al. Dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiol Biomarkers Prev. 2009;18:2202–6.445
Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou SA, Katsiki N, et al. Pharmacotherapy of type 2 diabetes: an update. Metabolism. 2018;78:13–42.446
Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.447
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28:1547–54.448
Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S, et al. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharmacol Ther. 2021;54:880–9.449
Tang H, Shi W, Fu S, Wang T, Zhai S, Song Y, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. 2018;7:1070–80.450
Viscoli CM, Inzucchi SE, Young LH, Insogna KL, Conwit R, Furie KL, et al. Pioglitazone and risk for bone fracture: safety data from a randomized clinical trial. J Clin Endocrinol Metab. 2016;102:914–22.451
Yau H, Rivera K, Lomonaco R, Cusi K. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep. 2013;13:329–41.452
Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.453
Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561–73.454
Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321–31.455
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.456
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.457
Sun F, Wu S, Wang J, Guo S, Chai S, Yang Z, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2015;37:225–41.458
Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27:740–56.459
Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19:524–36.460
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002.461
Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1:140–51.462
Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31.463
Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnström M, Moris L, et al. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia. 2018;61:1923–34.464
Cusi K, Bril F, Barb D, Polidori D, Sha S, Ghosh A, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21:812–21.465
Cusi K. Time to include nonalcoholic steatohepatitis in the management of patients with type 2 diabetes. Diabetes Care. 2020;43:275–9.466
Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, et al. Clinical trial: pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;29:172–82.467
Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20:23–8.468
Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Therap Adv Gastroenterol. 2009;2:157–63.469
Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–68.470
Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4:1537–43.471
Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464–7.472
Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54:1011–9.473
Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–8.474
Leuschner UFH, Lindenthal B, Herrmann G, Arnold JC, Rössle M, Cordes HJ, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472–9.475
Smits MM, Tonneijck L, Muskiet MHA, Kramer MHH, Pouwels PJW, Pieters-van den Bos IC, et al. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial. Diabetologia. 2016;59:2588–93.476
Joy TR, McKenzie CA, Tirona RG, Summers K, Seney S, Chakrabarti S, et al. Sitagliptin in patients with non-alcoholic steatohepatitis: a randomized, placebo-controlled trial. World J Gastroenterol. 2017;23:141–50.477
Alam S, Ghosh J, Mustafa G, Kamal M, Ahmad N. Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1-year randomized control trial. Hepat Med. 2018;10:23–31.478
Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE, Weltman AL, et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol. 2015;62:190–7.479
Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M. EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147:377–84.480
Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology. 2015;61:1239–50.481
Fernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis. 2008;40:200–5.482
Wah Kheong C, Nik Mustapha NR, Mahadeva S. A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2017;15:1940–9.483
Navarro VJ, Belle SH, D’Amato M, Adfhal N, Brunt EM, Fried MW, et al. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: a randomized, double-blind, placebo controlled trial. PLoS One. 2019;14:e0221683.484
Mirhashemi SH, Hakakzadeh A, Yeganeh FE, Oshidari B, Rezaee SP. Effect of 8 weeks milk thistle powder (silymarin extract) supplementation on fatty liver disease in patients candidates for bariatric surgery. Metabol Open. 2022;14:100190.485
Cheung A, Neuschwander-Tetri BA, Kleiner DE, Schabel E, Rinella M, Harrison S, et al. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum. Hepatology. 2019;70:1841–55.486
Loomba R, Sanyal AJ, Kowdley KV, Terrault N, Chalasani NP, Abdelmalek MF, et al. Factors associated with histologic response in adult patients with nonalcoholic steatohepatitis. Gastroenterology. 2019;156:88–95.487
Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547–58.488
Rinella ME, Dufour J-F, Anstee QM, Goodman Z, Younossi Z, Harrison SA, et al. Non-invasive evaluation of response to obeticholic acid in patients with NASH: results from the REGENERATE study. J Hepatol. 2022;76:536–48.489
Patel J, Bettencourt R, Cui J, Salotti J, Hooker J, Bhatt A, et al. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2016;9:692–701.490
Loomba R. MRI-proton density fat fraction treatment response criteria in nonalcoholic steatohepatitis. Hepatology. 2021;73:881–3.491
Stine JG, Munaganuru N, Barnard A, Wang JL, Kaulback K, Argo CK, et al. Change in MRI-PDFF and histologic response in patients with nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2021;19:2274–83.
