Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common conditions with a rising burden. Yet there are significant management gaps between clinical guidelines and practice in patients with NAFLD and NASH. Further, there is no single global guiding strategy for the management of NAFLD and NASH. The American Gastroenterological Association, in collaboration with 7 professional associations, convened an international conference comprising 32 experts in gastroenterology, hepatology, endocrinology, and primary care providers from the United States, Europe, Asia, and Australia. Conference content was informed by the results of a national NASH Needs Assessment Survey. The participants reviewed and discussed published literature on global burden, screening, risk stratification, diagnosis, and management of individuals with NAFLD, including those with NASH. Participants identified promising approaches for clinical practice and prepared a comprehensive, unified strategy for primary care providers and relevant specialists encompassing the full spectrum of NAFLD/NASH care. They also identified specific high-yield targets for clinical research and called for a unified, international public health response to NAFLD and NASH.

Nonalcoholic fatty liver disease (NAFLD)—hepatic steatosis on imaging or histology in the absence of known causes—is rapidly becoming the most common cause of chronic liver disease worldwide (1). NAFL is histologically defined as the presence of ≥5% hepatic steatosis without evidence of hepatocellular injury, and nonalcoholic steatohepatitis (NASH) is defined as the presence of ≥5% hepatic steatosis and inflammation with hepatocyte injury (e.g., ballooning), with or without fibrosis (2). At least 20%–30% of patients with NAFLD develop NASH, which can lead to cirrhosis and associated complications, including hepatocellular cancer (HCC) (2). NASH is also associated with an increased risk of cardiovascular disease (3) and increased cardiovascular and liver-related mortality (46).

Although most patients with NAFLD and NASH have traditionally been diagnosed and managed by hepatologists, the recent availability of noninvasive diagnostic procedures is expanding the role of other health care professionals likely to see patients with these conditions, particularly gastroenterologists, endocrinologists, obesity medicine specialists, and primary care providers (PCPs). Previous research has suggested that effectively treating NASH will require more education about both NAFLD and NASH among specialists and PCPs (7). Some published data also showed significant management gaps between published guidance and clinical practice in patients with NAFLD and NASH (8,9). Much of this disparity could come from a lack of recognition of the importance of NAFLD/NASH and an absence of a unified strategy that encompasses all disciplines involved in managing these patients across the full disease spectrum.

To address this need, the American Gastroenterological Association (AGA) conducted a needs assessment survey of health professionals likely to be engaged in managing adult patients with NAFLD/NASH, followed by a virtual conference of international experts representing 7 professional societies to review the current research and outline the future agenda for clinical practice, research, and policy. The overarching goal was to call for a unified, international public health response to NAFLD and NASH. This report summarizes the results from the survey and the virtual conference, “Preparing for a NASH Epidemic: A Call for Action.” Although NAFLD is an important and growing problem in children, the current effort was limited to adults with NAFLD and NASH. Therefore, we do not cover pediatric NAFLD in this report.

The NASH Needs Assessment Survey was conducted in May 2020. The survey sought to assess participants’ knowledge related to screening, diagnosis, and management of NAFLD and NASH; compare current diagnostic and treatment patterns with the most recent practice guidance on NAFLD/NASH; and identify the educational needs that could serve as targets to improve implementation of guideline-based treatment of NAFLD and NASH. The survey included 24 questions regarding screening, diagnosing, and managing NASH (see Supplementary Material for the full survey). In total, 751 gastroenterologists, hepatologists, endocrinologists, and PCPs from 46 states across the United States completed the survey. More than 50% of survey participants were PCPs. Respondents had spent an average of 19.5 years in practice (range, 2–35 years).

The survey revealed significant gaps in knowledge about who to screen and how to diagnose and treat patients at high risk for NASH, including disparities between published practice guidance and clinical practice (Table 1). Most respondents (67%) from all practice types were aware that up to one-quarter of the general population may have NAFLD. However, there were shortfalls in the knowledge about prevalence in several high-risk groups. For example, only 35% of all respondents—including 28% of endocrinologists, 32% of PCPS, and 46% of gastroenterologists/hepatologists—recognized that almost all patients with severe obesity are likely to have NAFLD. Only 49% of endocrinologists and 45% of PCPs recognized that NAFLD is very common in patients with type 2 diabetes (T2D) (Table 1).

Table 1

Key results from the Nonalcoholic Steatohepatitis Needs Assessment Survey

VariableAll participants (n = 751)Gastroenterologists/ hepatologists (n = 175)Endocrinologists (n = 175)Primary care (n = 401)
Proportions of the key patient groups likely to have NAFLD
Patients with severe obesity 35 46 28 32
With T2D 50 62 49 45
With dyslipidemia 40 47 41 36
General population 67 79 65 62
Patient groups that should be screened for NAFLD
Patients with abnormal liver chemistry 96 97 97 85
Patients with T2D 87 88 94 83
Patients older than 50 y who have hypertension and hyperlipidemia 70 81 73 67
Approaches to the initial evaluation of the patient with suspected NAFLD
Exclude competing etiologies for steatosis and coexisting common chronic liver disease 96 95 95 97
Consider the presence of commonly associated comorbidities, such as obesity, dyslipidemia, insulin resistance, or diabetes 95 97 93 95
Cross-sectional abdominal imaging (such as contrast-enhanced CT scan) to screen for HCC 41 50 39 38
Knowledge about strategies for noninvasive diagnosis of steatohepatitis and advanced fibrosis in NAFLD
NAFLD fibrosis score or Fibrosis-4 Index are useful tools for identifying NAFLD patients with high likelihood of advanced fibrosis 82 94 86 75
VCTE (FibroScan) or MRE (imaging) are useful tools for identifying advanced fibrosis in patients with NAFLD 81 93 85 74
Abdominal ultrasound is a useful tool for identifying NAFLD patients with steatohepatitis 16 29 18
Appropriateness of treatments for NASH
GLP-1 agonists 16 21 15 15
Metformin 17 33 17 11
Obeticholic acid 15 33 13
Omega-3 fatty acids 23 37 23 16
Pioglitazonea 53 53 77 42
Ursodeoxycholic acid 22 49 17 12
Vitamin E for nondiabetic adultsa 40 71 51 38
VariableAll participants (n = 751)Gastroenterologists/ hepatologists (n = 175)Endocrinologists (n = 175)Primary care (n = 401)
Proportions of the key patient groups likely to have NAFLD
Patients with severe obesity 35 46 28 32
With T2D 50 62 49 45
With dyslipidemia 40 47 41 36
General population 67 79 65 62
Patient groups that should be screened for NAFLD
Patients with abnormal liver chemistry 96 97 97 85
Patients with T2D 87 88 94 83
Patients older than 50 y who have hypertension and hyperlipidemia 70 81 73 67
Approaches to the initial evaluation of the patient with suspected NAFLD
Exclude competing etiologies for steatosis and coexisting common chronic liver disease 96 95 95 97
Consider the presence of commonly associated comorbidities, such as obesity, dyslipidemia, insulin resistance, or diabetes 95 97 93 95
Cross-sectional abdominal imaging (such as contrast-enhanced CT scan) to screen for HCC 41 50 39 38
Knowledge about strategies for noninvasive diagnosis of steatohepatitis and advanced fibrosis in NAFLD
NAFLD fibrosis score or Fibrosis-4 Index are useful tools for identifying NAFLD patients with high likelihood of advanced fibrosis 82 94 86 75
VCTE (FibroScan) or MRE (imaging) are useful tools for identifying advanced fibrosis in patients with NAFLD 81 93 85 74
Abdominal ultrasound is a useful tool for identifying NAFLD patients with steatohepatitis 16 29 18
Appropriateness of treatments for NASH
GLP-1 agonists 16 21 15 15
Metformin 17 33 17 11
Obeticholic acid 15 33 13
Omega-3 fatty acids 23 37 23 16
Pioglitazonea 53 53 77 42
Ursodeoxycholic acid 22 49 17 12
Vitamin E for nondiabetic adultsa 40 71 51 38

NOTE. Data represent percentages of participants who answered the item correctly. CT, computed tomography; MRE, magnetic resonance elastography; VCTE, vibration-controlled transient elastography.

a

The estimates for pioglitazone and vitamin E indicate percentages of participants who would consider treatment overall (with or without liver biopsy).

Most participants reported that they screen patients with abnormal liver chemistries (96%), those with T2D (87%), and those who are older than 50 years with hypertension and hyperlipidemia (70%) for the presence of NAFLD. Most were also aware of the best practices in the initial evaluation of patients with suspected NAFLD, including the need to exclude competing etiologies (96%) and evaluation for commonly associated com orbidities, such as T2D, obesity, and dyslipidemia (96%). However, only 41% recognized that initial evaluation of patients with suspected NAFLD should not include cross-sectional abdominal imaging (e.g., contrast-enhanced computed tomography) to screen for HCC. There were no significant differences in the responses among gastroenterologists/hepatologists, endocrinologists, and PCPs.

More than 80% of participants were aware that noninvasive tests, including the NAFLD fibrosis score, Fibrosis-4 Index, and imaging-based tests, such as vibration-controlled transient elastography or magnetic resonance elastography, are clinically useful tools for identifying NAFLD/NASH patients with a high likelihood of advanced liver fibrosis. However, 78% also thought that abdominal ultrasound can identify NAFLD patients with NASH.

Most participants were aware that 7%–10% weight loss is recommended for patients with NAFLD, but fewer than half of the participants were aware that pioglitazone or vitamin E can be recommended as treatment in select patients with NASH. Most respondents (>80%) wanted more education about screening, diagnosis, and treatment of NAFLD/NASH.

To address these knowledge gaps, the AGA convened a virtual conference of international experts in gastroenterology, hepatology, endocrinology, obesity management, and primary care on 10 July 2020. Participants represented key opinion leaders from 8 professional societies, and practiced in the United States, Europe, Australia, and Asia. See the Supplementary Material for the names and affiliations of all participants.

In a series of preconference meetings conducted over 2 months (May and June 2020), these key opinion leaders met and discussed the most important and potentially controversial aspects of the current NAFLD/NASH landscape, including epidemiology, risk factors, screening, diagnosis, and management issues. Formal presentations by each participant followed during the 1-day conference, which included the best-available evidence about their topic. Subsequent to the meeting, workgroups (predefined by subject) reviewed, discussed, and collated a summary from all presentations in their respective sections, followed by an internal review of the summary from all workgroup members. The final manuscript (including summaries from each workgroup) was then submitted to the full group for a second round of input and approval. The sections here detail the discussion, conclusions, and recommendations for clinical practice and future research that emerged from this process.

The clinical burden of both NAFLD overall and NASH specifically has increased steadily since the 1980s. NAFLD currently affects 25% of the global population and >60% of patients with T2D (10). Studies evaluating the prevalence of NASH suggest that it may involve an estimated 1.5%–6.5% of the general population and as many as 37% of people with T2D (10). Prevalence of NASH is expected to increase by 63% between 2015 and 2030 (11). Although these numbers seem substantially lower than those for NAFLD overall, they still translate to 4.9 million to 21 million Americans and more than 100 million individuals worldwide. Modeling data estimate that the number of patients with NASH-related advanced fibrosis will likely double by 2030, resulting in 800,000 liver-related deaths (11).

NASH is already the number 1 indication for liver transplantation in women, patients older than 54 years, and Medicare recipients (12). Beyond the significant impairment of quality of life experienced by individuals with NASH and advanced fibrosis (10,13), Younossi et al. (14) estimated in 2017 that the overall lifetime direct costs of NASH in the United States would be $222.6 billion, and approximately$95.4 billion over the next 2 decades, suggesting a substantial economic burden.

Patients with obesity or T2D are at a higher risk of developing NAFLD/NASH (15,16). Conversely, patients with NAFLD are at an increased risk of T2D (17). NAFLD and especially NASH are independently associated with several liver-related complications, including cirrhosis, HCC, and liver-related mortality. Patients with NAFLD also have a twofold increase in risk of cardiovascular disease (18,19). Indeed, individuals with NAFLD/NASH are twice as likely to die of cardiovascular disease as liver disease (17). The risk of cardiovascular disease in NAFLD is not completely explained by the shared risk factors, and might be related in part to abnormalities of cardiac structure and function (17).

In patients with NAFLD, the strongest histologic determinant of hepatic and overall outcomes is the presence and stage of fibrosis, although the presence of NASH is the driving force for fibrosis development. Patients with histologic evidence of fibrosis higher than stage 2 are at higher risk for adverse outcomes (hepatic decompensation, HCC, and liver-related mortality), and this risk increases as fibrosis advances to cirrhosis (5). Specifically, a recent meta-analysis found that, compared with NAFLD patients with no fibrosis (stage 0), patients with fibrosis were at an increased risk for all-cause mortality, and this risk increased with the stage of fibrosis: stage 1: risk ratio (RR) vs. stage 0, 1.58 (95% confidence interval [CI], 1.19–2.11); stage 2: RR, 2.52 (95% CI, 1.85–3.42); stage 3: RR, 3.48 (95% CI, 2.51–4.83); and stage 4: RR, 6.40 (95% CI, 4.11–9.95). The results were more pronounced for risk of liver-related mortality, which increased exponentially with each increase in fibrosis stage, from an RR of 1.41 (95% CI, 0.17–11.95) for stage 1 to an RR of 9.57 (95% CI, 1.67–54.93) for stage 2, and an RR of 42.30 (95% CI, 3.51–510.34) for stage 4 fibrosis (5).

Notably, fibrogenesis does not proceed linearly from simple fatty liver to NASH to cirrhosis, but progresses and regresses in up to 30% of patients during a mean period of 5 years (20). Furthermore, many patients with isolated hepatic steatosis, previously thought to be benign, are likely to progress to NASH (20). On average, patients with NASH and NAFLD progress 1 stage of fibrosis every 7 and 14 years, respectively (21). Older age, visceral obesity, T2D, and hypertension are associated with fibrosis progression (21,22). T2D and number of metabolic comorbidities are also associated with an increased risk of liver-related mortality and HCC (23,24). The severity of steatosis, however, has a modest (if any) correlation with the severity of liver histology (25), and the relationship between severity of steatosis and cardiovascular disease remains unclear.

### Screening and Diagnosis

Effectively screening for and timely diagnosis of NAFLD may prevent progression to NASH and associated complications. Because PCPs are on the front lines of managing individuals with NAFLD, screening patients at risk, stratifying patients based on their risk for advanced fibrosis, and positioning themselves to provide effective management and referrals are important. A recent study showed that screening for NAFLD followed by intensive lifestyle interventions or pioglitazone was cost-effective in patients with T2D diagnosed with clinically significant fibrosis, providing support for these recommendations (26).

To recognize NAFLD, the PCP must be aware of the following facts:

1. NAFLD is the one of the most common causes of abnormal liver enzymes, but serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) can be normal in many cases of NAFLD/NASH at all stages, including in patients with advanced fibrosis (27).

2. Liver fibrosis has been linked to morbidity and reduced overall patient survival (28).

3. NAFLD and fibrosis are reversible with weight loss (29).

4. Alcohol causes fatty liver disease with many histologic features of NAFLD. Although good clinical history is extremely important, one way to differentiate alcoholic from nonalcoholic fatty liver is the AST/ALT ratio, which is generally ≥2 in patients with alcohol as the underlying cause. In certain patients, selective testing for alcohol metabolites may also be appropriate.

Clinical practice guidelines do not recommend screening for NAFLD in the general population, but case finding for NASH and significant fibrosis is advised for key high-risk groups, such as those with moderate to severe obesity (BMI >35 kg/m2), T2D of more than 10 years’ duration or in people older than 50 years, or metabolic syndrome (30). The American Diabetes Association’s 2020 Standards of Medical Care in Diabetes also recommend evaluating patients with prediabetes or T2D with steatosis or elevated ALT for NASH and fibrosis (31).

Diagnosing NAFLD/NASH begins with evaluating patients for alternative or coexisting causes of liver disease, such as viral hepatitis or significant alcohol intake, through history and laboratory testing (Table 2). The accuracy of ultrasound for the detection of moderate and severe steatosis is quite high, >80% in a meta-analysis compared with that of liver biopsy. However, ultrasound has suboptimal sensitivity for mild steatosis (32,33). Among patients with a high pretest probability of NAFLD, moving directly to risk stratification without an ultrasound to confirm steatosis may be appropriate.

Table 2

Initial evaluation in patients with suspected nonalcoholic fatty liver disease

History and medical reviewInvestigations
Obesity Liver biochemistries (ALT, AST)
T2D Exclude/identify other liver diseasesa
Metabolic syndrome HBV and HCV serology (and viral load)
Alcohol intake Auto antibodies (ANA, AMA, ASMA)
<14 drinks/wk for women Serum ferritin, A1AT
<21 drinks/wk for men Liver ultrasound: increased echogenicity
No known pre-existing liver disease —
History and medical reviewInvestigations
Obesity Liver biochemistries (ALT, AST)
T2D Exclude/identify other liver diseasesa
Metabolic syndrome HBV and HCV serology (and viral load)
Alcohol intake Auto antibodies (ANA, AMA, ASMA)
<14 drinks/wk for women Serum ferritin, A1AT
<21 drinks/wk for men Liver ultrasound: increased echogenicity
No known pre-existing liver disease —

A1AT, α1 antitrypsin; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti–smooth muscle antibody; HBV, hepatitis B virus; HCV, hepatitis C virus.

a

NAFLD can coexist with other chronic liver diseases. Of note, 21% of patients with NAFLD may have elevations in autoantibodies in the absence of autoimmune hepatitis (85), and 20% may have high serum ferritin (>300 ng/mL in women and >450 ng/mL in men). Elevated serum ferritin is associated with advanced hepatic fibrosis (86) in patients with NAFLD.

Although an optimal strategy for risk stratification of individuals with NAFLD/NASH in primary care and specialist clinics remains undefined, the guiding principle is to rule out advanced fibrosis by simple, noninvasive fibrosis scores (such as NAFLD fibrosis score or Fibrosis-4 Index). Patients at intermediate or high risk may require further assessment with a second-line test—elastography, or a serum marker test with direct measures of fibrogenesis (such as enhanced liver fibrosis (34) or fragments of propeptide of type III procollagen (35), and may require referral to a hepatology clinic (Fig. 1). Of note, the enhanced liver fibrosis and propeptide of type III procollagen tests are not approved in the United States, limiting their use in clinical practice. In contrast, elastography-based tests are available and can be used for risk stratification. Several recent studies show that this sequential use of noninvasive tests reduces unnecessary referrals to specialists, increases the detection of advanced fibrosis and cirrhosis, and hence may be cost-effective (36,37).

Figure 1

Algorithm for risk stratification in patients with NAFLD/NASH. FIB-4, Fibrosis-4 Index; NFS, NAFLD fibrosis score.

Figure 1

Algorithm for risk stratification in patients with NAFLD/NASH. FIB-4, Fibrosis-4 Index; NFS, NAFLD fibrosis score.

Close modal

Once diagnosis and initial risk stratification have been completed, a more detailed assessment of liver fibrosis is essential. Accurate fibrosis staging provides information regarding prognosis, need for pharmacotherapy, intensive lifestyle modification and/or bariatric surgery, and screening/surveillance for varices and HCC. The most commonly used imaging techniques to evaluate fibrosis are vibration-controlled transient elastography and magnetic resonance elastography. Vibration-controlled transient elastography uses ultrasound waves to investigate the presence or absence of advanced fibrosis with a specificity of 92% (38). Magnetic resonance elastography can identify the intermediate stages of fibrosis more readily, but is not as widely available and is much more costly (30).

Liver biopsy, historically required to diagnosis liver fibrosis and NASH, provides helpful information and should be considered for cases in which there is a diagnostic doubt, such as patients with indeterminate, unreliable, or conflicting noninvasive assessments, or as part of phase 2 or 3 clinical trials. In addition to excluding coexistent liver diseases, liver biopsy allows for assessment of disease activity in the form of lobular and portal inflammation and ballooning degeneration (a marker of liver-cell injury). These 2 processes are thought to be responsible for triggering the development of liver fibrosis.

Assessment of cardiometabolic risk in NAFLD/NASH is also important, especially in patients who are at intermediate to high risk of advanced fibrosis (39). The Atherosclerotic Cardiovascular Disease risk calculator has been validated in NAFLD patients and provides guidance for statin use (40).

### Management

Most patients with NAFLD and many with NASH have a low risk of clinically significant fibrosis and can be managed by PCPs. Because NAFLD is not an isolated disease but a component of cardiometabolic abnormalities typically associated with obesity, the cornerstone of therapy is the same as that for people with obesity and cardiometabolic complications, namely lifestyle-based therapies (altered diet, such as reduced-calorie or Mediterranean diet and regular, moderate physical activity), and replacing obesogenic medications to decrease body weight and improve cardiometabolic health. The magnitude of weight loss correlates with decreases in intrahepatic triglyceride (IHTG) content, hepatocyte ballooning, and hepatic inflammation (29).

IHTG is extraordinarily sensitive to changes in energy balance; even 48 h of a low-calorie diet can decrease IHTG by about 20%, and 7% weight reduction decreases IHTG by approximately 40% (41). The durability of these acute weight-loss–related changes remains to be determined. Furthermore, hepatic fibrosis is more resistant to weight loss and requires larger amounts (≥10%) and possibly longer duration of weight loss to achieve clinically meaningful outcomes. Regular endurance (42,43) or resistance exercise (44) in the absence of weight loss decreases IHTG content only slightly but improves metabolic health. U.S. Food and Drug Administration–approved weight-loss medications can enhance weight loss induced by lifestyle therapy and may contribute to the successful management of patients with NAFLD. Patients at risk for significant fibrosis (based on their clinical profile, blood test panels, and/or imaging) should be referred to a hepatologist to discuss the need for further testing, including biopsy, appropriate follow-up (particularly for those patients with advanced fibrosis/cirrhosis), and possible inclusion in NASH clinical trials (Fig. 1).

Patients with NASH and fibrosis stage 2 or higher are candidates for liver-directed pharmacotherapy (Table 3). Although there are currently no U.S. Food and Drug Administration–approved drugs for treating NASH, vitamin E (800 IU/d) improves steatosis in NASH patients without T2D (45). Although randomized controlled trials have not shown similar efficacy in patients with T2D (46), one retrospective study of patients with NASH and either bridging fibrosis or cirrhosis, with or without T2D, associated vitamin E with greater transplant-free survival and lower rates of hepatic decompensation (47).

Table 3

Management of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

VariableLifestyle interventionaLiver-directed pharmacotherapyDiabetes care (in individuals with diabetes)Cardiovascular risk reduction
NAFL Yes No Standard of care Yes
NASH with fibrosis stage 0 or 1 (F0, F1) Yes No Standard of care Yes
NASH with fibrosis stage 2 or 3 (F2, F3) Yes Yes Pioglitazone, GLP-1 receptor agonistsb Yes
NASH cirrhosis (F4) Yes Yes Individualizec Yes
VariableLifestyle interventionaLiver-directed pharmacotherapyDiabetes care (in individuals with diabetes)Cardiovascular risk reduction
NAFL Yes No Standard of care Yes
NASH with fibrosis stage 0 or 1 (F0, F1) Yes No Standard of care Yes
NASH with fibrosis stage 2 or 3 (F2, F3) Yes Yes Pioglitazone, GLP-1 receptor agonistsb Yes
NASH cirrhosis (F4) Yes Yes Individualizec Yes
a

All patients require regular physical activity and healthy diet and to avoid excess alcohol intake; weight loss recommended.

b

Among GLP-1 receptor agonists, semaglutide has the best evidence of benefit in patients with NASH and fibrosis.

c

Evidence for efficacy of pharmacotherapy in patients with NASH cirrhosis is very limited and should be individualized and used with caution.

If diabetes is present, the PCP may opt to prescribe a medication for diabetes that can also treat NASH. Although metformin is first-line therapy for the pharmacologic management of T2D, it is not effective in treating NASH (2,25). Guidelines suggest that clinicians should instead consider using pioglitazone (a thiazolidinedione acting through activation of proliferator-activated receptor–γ and –α agonism), based on evidence from 5 randomized controlled trials showing that it reverses steatohepatitis in patients with (4850) and without (45,49) diabetes. In the phase 3 Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, pioglitazone led to resolution of steatohepatitis in 47% of patients compared with 21% of patients in the placebo group (P = 0.001; vitamin E in 36%; P = 0.05), although pioglitazone did not meet the prespecified primary end point (45). Studies of patients with prediabetes or T2D with follow-up for up to 3 years have also consistently reported benefit with pioglitazone treatment (4850).

Based on these data, the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity guidelines suggest that pioglitazone can be used for NASH patients with diabetes. The guidelines also state that vitamin E (administered at a daily dose of 800 IU) may be considered in nondiabetic adults with biopsy-proven NASH (2,30). Pioglitazone can also reduce cardiovascular disease in patients with or without T2D, as reviewed elsewhere, although the U.S. Food and Drug Administration has not approved it for this indication (51,52).

Several GLP-1 receptor agonists and SGLT2 inhibitors, which are increasingly used in T2D, as they reduce cardiovascular risk and promote weight loss, also potentially decrease hepatic steatosis in patients with NAFLD. GLP-1 receptor agonists (dulaglutide, exenatide, liraglutide, and semaglutide) have been tested in patients with T2D and NAFLD, with the most robust evidence to date involving semaglutide (5357). A small phase 2 trial (involving 52 patients) that evaluated liraglutide, a synthetic long-acting glucagon-like peptide 1 (GLP-1) receptor agonist available for treating T2D and obesity, resulted in weight loss, resolution of steatohepatitis, and slower progression of fibrosis than placebo, although gastrointestinal adverse effects were common (56). More recently, a report in 320 patients with biopsy-proven NASH offers the strongest evidence for the use of GLP-1 receptor agonists in patients with NASH using subcutaneously administered semaglutide at doses of 0.1, 0.2, or 0.4 mg/d (54). This 72-week study included a population in which 62% of patients had T2D and >70% had moderate to advanced stage F2–3 liver fibrosis. The primary outcome, NASH resolution without worsening of fibrosis, was achieved in 40%, 36%, and 59% of patients treated with semaglutide at doses of 0.1, 0.2, and 0.4 mg/d, respectively, vs. 17% on placebo. Of note, the proportion of patients with liver fibrosis improvement (approximately 30%–44%) did not reach statistical significance in any arm. The reasons remain unclear, although worsening of fibrosis occurred in 10%, 8%, and 5% of the patients in the semaglutide 0.1, 0.2, and 0.4 mg groups, respectively, and in 19% of the patients in the placebo group (54). Of note, the dose used in the study is not currently available for prescription in patients with diabetes, but the weight loss and metabolic effects achieved were similar overall to the effects seen with currently available dose for management of diabetes. Physicians unfamiliar with or unable to prescribe these medications should consider referring patients to an endocrinologist, diabetologist, or obesity medicine specialist (53).

Another small recent study found that dulaglutide also reduced liver fat content and transaminases in people with T2D and NAFLD (55). These findings allow the possibility of treating diabetes, cardiovascular disease, and NASH simultaneously with diabetes medications, such as pioglitazone or a GLP-1 receptor agonist. SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) have also been tested in NAFLD, but these studies have been small and do not examine the effect of these agents on liver histology (58).

Despite the promise of antidiabetes medications, the role of improving glycemic control on the natural history of NASH and development of cirrhosis remains poorly understood, and the role of glycemic control of disease progression in NASH remains to be established. Improving glycemic control with insulin therapy reduces liver steatosis (48), but its impact on liver histology (both NASH or fibrosis) and the natural history of the disease remain unknown. Cross-sectional (59) and longitudinal observational studies (60) do not show a clear correlation between hemoglobin A1c levels over time and liver histology or other clinical outcomes. Lowering hemoglobin A1c levels with pioglitazone treatment for 18 months has been associated with improvement in NASH and slower progression of fibrosis compared with patients with diabetes on placebo but, overall, the histologic response to pioglitazone does not appear to be linked to improved glycemic control, as it is similar in patients with vs. those without diabetes (49).

Bariatric surgery is currently the most effective therapy available for obesity. The 2 most common procedures are sleeve gastrectomy and Roux-en-Y gastric bypass. Marked weight loss (approximately 25%–35%) induced by bariatric surgery has profound effects on steatosis, NAFLD activity score, hepatocyte ballooning, and lobular inflammation, and results in NASH resolution in most patients (61,62). Surgery-induced weight loss also has a considerable therapeutic effect in reducing stages 1 and 2 fibrosis, but is less effective in improving stages 3 and 4. Bariatric endoscopy is emerging as a new treatment for obesity, but the long-term durability of its effects remains to be determined. About 15% weight loss has been reported after therapy with a postprandial gastric aspiration device, which is associated with reduced plasma AST and ALT (63), whereas duodenal mucosal resurfacing has reduced Fibrosis-4 Index scores by mechanisms possibly unrelated to weight reduction (64). Intragastric balloon placement has also been associated with histologic improvement in individuals with NASH (65), although findings remain preliminary. Patients with advanced liver disease, especially with hepatic decompensation, have higher mortality after bariatric surgery. Overall, more efficacy and safety data are needed before these approaches can be recommended as treatment options for patients with NAFLD and NASH.

Special attention to the management of sedentary behavior, as well as to dyslipidemia, diabetes, and hypertension, is recommended for all individuals with NAFLD (66). Alcohol consumption should be limited to 2–3 drinks per week in women and 4–5 drinks per week in men and avoided in patients with advanced fibrosis (67,68), although high-quality data on the exact risk of progressive liver disease in patients with advanced fibrosis are still needed. Many PCPs and nonhepatologists discontinue statins when liver enzymes are elevated (9,69,70). However, numerous studies have also demonstrated that statins are safe and efficacious in patients with NAFLD and NASH, and they can be used to treat dyslipidemia in these patients, including those with compensated cirrhosis. Statins have pleiotropic properties that may be directly beneficial in liver disease. In a meta-analysis of 13 studies, including 3 randomized controlled trials, statin use in cirrhosis was associated with a reduction in hepatic decompensation (hazard ratio, RR, 0.54; 95% CI, 0.46–0.62) and lower mortality (hazard ratio, 0.54; 95% CI. 0.47–0.61) (71).

However, because data remain limited regarding safety and risks of statins in patients with decompensated cirrhosis (72,73), statins should be avoided until we have stronger evidence to support their safety in these patients. The AGA clinical practice update provides some guidance and advises against statin use among patients with Child-Pugh class B or C cirrhosis (74). The underlying rationale is that the generally grave liver-related prognosis of patients with Child-Pugh class B or C cirrhosis makes it unlikely that they will benefit from the cardiovascular benefits associated with lipid-lowering therapy. In a large retrospective cohort study of statins in patients with cirrhosis, the survival benefit did not extend to patients with Child class C cirrhosis (75).

### Emerging Tools

Given the high prevalence of NAFLD and the limited patient awareness about this disease, applying artificial intelligence/machine learning tools to the big data repositories of electronic health records holds considerable potential for efficient disease identification and risk stratification. (76) “Machine learning” is a subset of artificial intelligence in which computer algorithms are improved through experience (77). These tools can produce noninvasive calculated scores by using information about patient demographic and clinical characteristics from both narrative (i.e., free text) and codified (e.g., administrative disease codes and laboratory tests) sources. Artificial intelligence is also being tested to improve the accuracy and reliability of liver histologic interpretation using quantitative scoring systems for NAFLD/NASH radiologic and histopathologic features (78,79). However, although the availability of noninvasive tests to accurately assess response to treatment beyond histopathology would greatly facilitate the efficient enrollment in NASH treatment clinical trials, existing options still require further validation and eventual acceptance by regulatory agencies.

Several liver-targeted and other potential therapies are also currently under investigation, targeting a broad range of pathologic changes associated with NASH, including insulin resistance, alterations in the microbiome and gut permeability, oxidative stress, apoptosis, lipotoxicity, inflammation, and bile acid metabolism. Given the multiple pathways involved in NASH pathogenesis, combination regimens may ultimately be needed to treat NASH most effectively (80,81).

### Develop More Sensitive and Specific Diagnostic Methods

The invasive nature and relatively high expense of liver biopsy limit its use and call for more sensitive and specific noninvasive diagnostic methods for NASH. Several novel noninvasive tools with the potential to provide more sensitive and specific diagnosis are currently under development. These include top–down approaches, such as multiomics and narrowing down to the minimum number of molecules that could provide the maximum positive and negative predictive value (82,83).

### Adopt a Multidisciplinary Approach to Nonalcoholic Steatohepatitis

Optimal care of patients with NASH may require clinicians from a variety of specialties, including primary care, hepatology, obesity management, and endocrinology, to tackle both the hepatic manifestations of the disease and the comorbid metabolic syndrome and cardiovascular risk, as well as screening and treating other comorbid conditions (e.g., obstructive sleep apnea). When NAFLD progresses to NASH, multidisciplinary, team-based care involving these specialties is crucial. Improving the traditional model of primary, secondary, and tertiary care will require not only developing and validating algorithmic approaches (e.g., who can be managed where and how), but also connectivity and multidirectional referrals among these practice settings. Examining other models of care, such as medical homes either dedicated to NAFLD/NASH or incorporated within similar homes that manage metabolic disease more broadly, could also be valuable in developing care models. These integrated models can create and align expertise and incentives among different specialties.

### Develop Clinical Care Pathways

Developing clinical care pathways that use validated and efficient noninvasive tests and calculators is crucial to a multidisciplinary approach to managing NAFLD/NASH. Clinical care pathways, with careful explication of each step-in screening, diagnosis, and treatment, have been shown to improve the quality of health care delivery in other areas of medicine. Members of the NASH: A Call-to-Action Steering Committee and several other conference participants are currently developing such a pathway for NAFLD/NASH. Rapid and timely dissemination of these pathways to all stakeholders, especially the frontline PCPs, will be important in developing a systematic approach to managing NAFLD/NASH.

### Pursue a Unified, International, Public Health Response

The public health response to NAFLD remains rudimentary. There is no single guiding strategy in the United States or Europe. A survey of 29 European countries highlighted the absence of a concrete NAFLD/NASH management strategy or action plans in every one of these countries (84). This deficit has even more proximal roots. For example, not all hepatology/gastroenterology societies have clear screening, testing, or referral guidelines for NAFLD/NASH, and existing guidelines often conflict with one another (Table 4). Intersociety collaboration for harmonizing guidelines to optimize screening, diagnosis, and therapy is urgently required. Furthermore, because virtually all current guidance regarding HCC surveillance in NAFLD is derived from the viral hepatitis and alcoholic cirrhosis literature, new data and updated guidelines are needed that are specific to NAFLD/NASH-related cirrhosis. In addition, large cohorts with longitudinal data on clinical course and outcomes, particularly cohorts that allow the transition from childhood through adolescence to adulthood to be evaluated, are needed to inform the science and clinical practice of managing NAFLD/NASH.

Table 4

Summary of published nonalcoholic fatty liver disease guidelines

OrganizationYearFirst-line diagnosis testWhen to refer to hepatologistNoninvasive tests
American Association for the Study of Liver Diseases (AASLD) 2018 Not clear in the guideline
Routine screening for NAFLD in high-risk groups is not recommended
Not clear in the guideline Diagnosis for NASH: liver biopsy
Assessment for fibrosis: NFS or FIB-4
American Gastroenterological Association (AGA) 2012 Routine screening for NAFLD is not recommended Not clear in the guideline Metabolic syndrome can be used to target patients for liver biopsy
European Association for the Study of the Liver (EASL) 2016 Ultrasound + liver enzymes for patients with risk factors Refer patients with abnormal liver enzymes or medium-/high-risk fibrosis markers to specialist Diagnosis for NASH: liver biopsy Assessment for fibrosis: NFS or FIB-4
World Gastroenterology Organization (WGO) 2012 Ultrasound + liver enzymes for patients with risk factors Not clear in the guideline Diagnosis for NASH: liver biopsy
National Institute for Health Care and Excellence (NICE) 2016 Ultrasound + liver enzymes for patients with risk factors
But routine liver function blood tests are not sensitive, and ultrasound is not cost-effective
Refer children with suspected NAFLD to a pediatric specialist in hepatology
Assessment for advanced fibrosis: enhanced liver fibrosis (every 2–3 y)
OrganizationYearFirst-line diagnosis testWhen to refer to hepatologistNoninvasive tests
American Association for the Study of Liver Diseases (AASLD) 2018 Not clear in the guideline
Routine screening for NAFLD in high-risk groups is not recommended
Not clear in the guideline Diagnosis for NASH: liver biopsy
Assessment for fibrosis: NFS or FIB-4
American Gastroenterological Association (AGA) 2012 Routine screening for NAFLD is not recommended Not clear in the guideline Metabolic syndrome can be used to target patients for liver biopsy
European Association for the Study of the Liver (EASL) 2016 Ultrasound + liver enzymes for patients with risk factors Refer patients with abnormal liver enzymes or medium-/high-risk fibrosis markers to specialist Diagnosis for NASH: liver biopsy Assessment for fibrosis: NFS or FIB-4
World Gastroenterology Organization (WGO) 2012 Ultrasound + liver enzymes for patients with risk factors Not clear in the guideline Diagnosis for NASH: liver biopsy
National Institute for Health Care and Excellence (NICE) 2016 Ultrasound + liver enzymes for patients with risk factors
But routine liver function blood tests are not sensitive, and ultrasound is not cost-effective
Refer children with suspected NAFLD to a pediatric specialist in hepatology
Assessment for advanced fibrosis: enhanced liver fibrosis (every 2–3 y)

FIB-4, Fibrosis-4 Index; NFS, NAFLD fibrosis score.

There is also a large unmet need for programs that can increase disease awareness in the medical community and the general population. Finally, the closely interlinked nature with related metabolic diseases suggests that reducing the clinical and economic burden of NASH and NAFLD will require fundamental societal changes driven by policies to address failing public health systems and the social determinants of health.

The upward trend in NAFLD/NASH incidence and prevalence underscores the importance and urgency of developing and implementing effective screening, diagnosis, and treatment strategies in the United States and globally, particularly among emerging at-risk cohorts, such as patients with diabetes and obesity. This goal cannot be achieved if the different specialties engaged in managing this burgeoning population continue to work in separate silos. The Call-to-Action Meeting described in this report represents one of the first steps needed to align key stakeholders, including PCPs, endocrinologists, diabetologists, obesity medicine specialists, gastroenterologists, and hepatologists, on a collective action plan. Improving the spectrum of care for patients with NAFLD from screening, diagnosis, disease severity stratification, and treatment will require significant changes and innovations in technology, health care delivery, and policy. In addition, optimal care of patients with NAFLD/NASH will require a multidisciplinary team integrating primary care, hepatology, obesity medicine, and endocrinology/diabetology via well-defined care pathways, along with exploration of the high-yield targets for clinical research and practice identified by conference participants. These efforts should help the field move toward a collective strategy with shared goals and objectives that will improve care for the growing population of patients with NAFLD/NASH.

Acknowledgments. This article is based on a conference sponsored by the American Gastroenterological Association (AGA), with the financial support of independent medical education grants from Intercept Pharmaceuticals, Inc, Pfizer Inc, Allergan, and GENFIT, and the support of the following collaborating medical associations: American Association of Clinical Endocrinologists, American Academy of Family Physicians, American Association for the Study of Liver Diseases, American College of Osteopathic Family Physicians, American Diabetes Association, Endocrine Society, and The Obesity Society. The authors are grateful for the contributions of the participants in the July 2020 conference, who are listed, together with affiliations, in the Supplementary Material. F.K. is a member at the Center for Innovations in Quality, Effectiveness and Safety (CIN-13-413), Michael E. DeBakey VA Medical Center, Houston, Texas. In addition, the authors acknowledge Dr. Anya Karavanov for her assistance with the NASH Needs Assessment Survey, Dr. Terra Ziporyn, medical editor, for her assistance with the manuscript, and Alissa Effland for her assistance with the manuscript’s graphics.

1.
Paik
JM
,
Golabi
P
,
Younossi
Y
, et al
.
Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of nonalcoholic fatty liver disease
.
Hepatology
2020
;
72
:
1605
1616
2.
Chalasani
N
,
Younossi
Z
,
Lavine
JE
, 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
357
3.
Wong
CR
,
Lim
JK
.
The association between nonalcoholic fatty liver disease and cardiovascular disease outcomes
.
Clin Liver Dis (Hoboken)
2018
;
12
:
39
44
4.
Younossi
ZM
,
Stepanova
M
,
Rafiq
N
, et al
.
Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease
.
Hepatol Commun
2017
;
1
:
421
428
5.
Dulai
PS
,
Singh
S
,
Patel
J
, et al
.
Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis
.
Hepatology
2017
;
65
:
1557
1565
6.
Stepanova
M
,
Rafiq
N
,
Makhlouf
H
, et al
.
Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD)
.
Dig Dis Sci
2013
;
58
:
3017
3023
7.
Serfaty
L
.
Management of patients with non-alcoholic steatohepatitis (NASH) in real life
.
Liver Int
2018
;
38
(
Suppl. 1
):
52
55
8.
Blais
P
,
Husain
N
,
Kramer
JR
,
Kowalkowski
M
,
El-Serag
H
,
Kanwal
F
.
Nonalcoholic fatty liver disease is underrecognized in the primary care setting
.
Am J Gastroenterol
2015
;
110
:
10
14
9.
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
1720
10.
Younossi
Z
,
Tacke
F
,
Arrese
M
, et al
.
Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
.
Hepatology
2019
;
69
:
2672
2682
11.
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
133
12.
Younossi
ZM
,
Stepanova
M
,
Ong
J
, et al
.
Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States
.
Clin Gastroenterol Hepatol
2021
;
19
:
580
589.e5
13.
Younossi
ZM
,
Wong
VW-S
,
Anstee
QM
, et al
.
Fatigue and pruritus in patients with advanced fibrosis due to nonalcoholic steatohepatitis: the impact on patient-reported outcomes
.
Hepatol Commun
2020
;
4
:
1637
1650
14.
Younossi
ZM
,
Tampi
R
,
M
,
F
,
Younossi
IM
,
Racila
A
.
Burden of illness and economic model for patients with nonalcoholic steatohepatitis in the United States
.
Hepatology
2019
;
69
:
564
572
15.
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
16.
Younossi
Z
,
Anstee
QM
,
Marietti
M
, et al
.
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
.
Nat Rev Gastroenterol Hepatol
2018
;
15
:
11
20
17.
Vanni
E
,
Marengo
A
,
Mezzabotta
L
,
Bugianesi
E
.
Systemic complications of nonalcoholic fatty liver disease: when the liver is not an innocent bystander
.
Semin Liver Dis
2015
;
35
:
236
249
18.
Ekstedt
M
,
Hagström
H
,
Nasr
P
, 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
1554
19.
Spahillari
A
,
Mukamal
KJ
,
DeFilippi
C
, et al
.
The association of lean and fat mass with all-cause mortality in older adults: the Cardiovascular Health Study
.
Nutr Metab Cardiovasc Dis
2016
;
26
:
1039
1047
20.
Kleiner
DE
,
Brunt
EM
,
Wilson
LA
, et al.;
Nonalcoholic Steatohepatitis Clinical Research Network
.
Association of histologic disease activity with progression of nonalcoholic fatty liver disease
.
JAMA Netw Open
2019
;
2
:
e1912565
21.
Singh
S
,
Allen
AM
,
Wang
Z
, et al
.
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
654
;
e641
649
;
quiz e639–e640
22.
Cotter
TG
,
Rinella
M
.
Nonalcoholic fatty liver disease 2020: the state of the disease
.
Gastro enterology
2020
;
158
:
1851
1864
23.
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 (Baltimore)
2018
;
97
:
e0214
24.
Kanwal
F
,
Kramer
JR
,
Li
L
, et al
.
Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease
.
Hepatology
2020
;
71
:
808
819
25.
Maximos
M
,
Bril
F
,
Portillo Sanchez
P
, et al
.
The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease
.
Hepatology
2015
;
61
:
153
160
26.
Noureddin
M
,
Jones
C
,
Alkhouri
N
, et al
.
Nashnet: screening for non-alcoholic fatty liver disease in persons with type 2 diabetes in the U.S. is cost effective: a comprehensive cost-utility analysis
.
Gastroenterology
2020
;
159
:
1985
1987.e4
27.
Gawrieh
S
,
Wilson
LA
,
Cummings
OW
, et al.;
NASH Clinical Research Network
.
Histologic findings of advanced fibrosis and cirrhosis in patients with nonalcoholic fatty liver disease who have normal aminotransferase levels
.
Am J Gastroenterol
2019
;
114
:
1626
1635
28.
Taylor
RS
,
Taylor
RJ
,
Bayliss
S
, 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
1625
;
e1612
29.
Vilar-Gomez
E
,
Martinez-Perez
Y
,
L
, et al
.
Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis
.
Gastroenterology
2015
;
149
:
367
378
;
e365
;
quiz e314–e365
30.
European Association for the Study of the Liver (EASL)
;
European Association for the Study of Diabetes (EASD)
;
European Association for the Study of Obesity (EASO)
.
EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease
.
J Hepatol
2016
;
64
:
1388
1402
31.
American Diabetes Association
.
Standards of medical care in diabetes-2020 abridged for primary care providers
.
Clin Diabetes
2020
;
38
:
10
38
32.
Hernaez
R
,
Lazo
M
,
Bonekamp
S
, et al
.
Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis
.
Hepatology
2011
;
54
:
1082
1090
33.
Bril
F
,
Ortiz-Lopez
C
,
Lomonaco
R
, et al
.
Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients
.
Liver Int
2015
;
35
:
2139
2146
34.
Vali
Y
,
Lee
J
,
Boursier
J
, et al.;
LITMUS systematic review team(†)
.
Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: a systematic review and meta-analysis
.
J Hepatol
2020
;
73
:
252
262
35.
Bril
F
,
McPhaul
MJ
,
Caulfield
MP
, et al
.
Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes
.
Diabetes Care
2020
;
43
:
290
297
36.
Srivastava
A
,
Gailer
R
,
Tanwar
S
, et al
.
Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease
.
J Hepatol
2019
;
71
:
371
378
37.
Crossan
C
,
Majumdar
A
,
Srivastava
A
, et al
.
Referral pathways for patients with NAFLD based on non-invasive fibrosis tests: diagnostic accuracy and cost analysis
.
Liver Int
2019
;
39
:
2052
2060
38.
Wong
VW
,
Vergniol
J
,
Wong
GL
, et al
.
Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease
.
Hepatology
2010
;
51
:
454
462
39.
Baratta
F
,
Pastori
D
,
Angelico
F
, et al
.
Nonalcoholic fatty liver disease and fibrosis associated with increased risk of cardiovascular events in a prospective study
.
Clin Gastroenterol Hepatol
2020
;
18
:
2324
2331
;
e2324
40.
Golabi
P
,
Fukui
N
,
Paik
J
,
Sayiner
M
,
Mishra
A
,
Younossi
ZM
.
Mortality risk detected by atherosclerotic cardiovascular disease score in patients with nonalcoholic fatty liver disease
.
Hepatol Commun
2019
;
3
:
1050
1060
41.
Kirk
E
,
Reeds
DN
,
Finck
BN
,
Mayurranjan
SM
,
Patterson
BW
,
Klein
S
.
Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction
.
Gastroenterology
2009
;
136
:
1552
1560
42.
Hashida
R
,
Kawaguchi
T
,
Bekki
M
, et al
.
Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review
.
J Hepatol
2017
;
66
:
142
152
43.
Sabag
A
,
Way
KL
,
Sultana
RN
, et al
.
The effect of a novel low-volume aerobic exercise intervention on liver fat in type 2 diabetes: a randomized controlled trial
.
Diabetes Care
2020
;
43
:
2371
2378
44.
Hallsworth
K
,
Fattakhova
G
,
Hollingsworth
KG
, et al
.
Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss
.
Gut
2011
;
60
:
1278
1283
45.
Sanyal
AJ
,
Chalasani
N
,
Kowdley
KV
, et al.;
NASH CRN
.
Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis
.
N Engl J Med
2010
;
362
:
1675
1685
46.
Bril
F
,
Biernacki
DM
,
Kalavalapalli
S
, et al
.
Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial
.
Diabetes Care
2019
;
42
:
1481
1488
47.
Vilar-Gomez
E
,
Vuppalanchi
R
,
Gawrieh
S
, et al
.
Vitamin E improves transplant-free survival and hepatic decompensation among patients with nonalcoholic steatohepatitis and advanced fibrosis
.
Hepatology
2020
;
71
:
495
509
48.
Cusi
K
,
Orsak
B
,
Bril
F
, 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
315
49.
Bril
F
,
Kalavalapalli
S
,
Clark
VC
, et al
.
Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes
.
Clin Gastroenterol Hepatol
2018
;
16
:
558
566
;
e552
50.
Belfort
R
,
Harrison
SA
,
Brown
K
, et al
.
A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis
.
N Engl J Med
2006
;
355
:
2297
2307
51.
Gastaldelli
A
,
Cusi
K
.
From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options
.
JHEP Rep
2019
;
1
:
312
328
52.
Di Pino
A
,
DeFronzo
RA
.
Insulin resistance and atherosclerosis: implications for insulin-sensitizing agents
.
Endocr Rev
2019
;
40
:
1447
1467
53.
Cusi
K
.
A diabetologist’s perspective of non-alcoholic steatohepatitis (NASH): knowledge gaps and future directions
.
Liver Int
2020
;
40
(
Suppl. 1
):
82
88
54.
Newsome
PN
,
Buchholtz
K
,
Cusi
K
, et al.;
NN9931-4296 Investigators
.
A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis
.
N Engl J Med
2021
;
384
:
1113
1124
55.
Kuchay
MS
,
Krishan
S
,
Mishra
SK
, et al
.
Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial)
.
Diabetologia
2020
;
63
:
2434
2445
56.
Armstrong
MJ
,
Gaunt
P
,
Aithal
GP
, et al.;
LEAN trial team
.
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
690
57.
Harrison
SA
,
Calanna
S
,
Cusi
K
, et al
.
Semaglutide for the treatment of non-alcoholic steatohepatitis: trial design and comparison of non-invasive biomarkers
.
Contemp Clin Trials
2020
;
97
:
106174
58.
Cusi
K
.
Time to include nonalcoholic steatohepatitis in the management of patients with type 2 diabetes
.
Diabetes Care
2020
;
43
:
275
279
59.
Bril
F
,
Barb
D
,
Portillo-Sanchez
P
, et al
.
Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease
.
Hepatology
2017
;
65
:
1132
1144
60.
Vilar-Gomez
E
,
L
,
Wong
VW
, et al
.
Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, Child-Pugh A cirrhosis
.
Clin Gastroenterol Hepatol
2021
;
19
:
136
145.e6
61.
Lassailly
G
,
Caiazzo
R
,
Buob
D
, et al
.
Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients
.
Gastroenterology
2015
;
149
:
379
388
;
quiz e15–e16
62.
Lee
Y
,
Doumouras
AG
,
Yu
J
, et al
.
Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis
.
Clin Gastroenterol Hepatol
2019
;
17
:
1040
1060
;
e1011
63.
Jirapinyo
P
,
de Moura
DTH
,
Horton
LC
,
Thompson
CC
.
Effect of aspiration therapy on obesity-related comorbidities: systematic review and meta-analysis
.
Clin Endosc
2020
;
53
:
686
697
64.
van Baar
ACG
,
Beuers
U
,
Wong
K
, et al
.
Endoscopic duodenal mucosal resurfacing improves glycaemic and hepatic indices in type 2 diabetes: 6-month multicentre results
.
JHEP Rep
2019
;
1
:
429
437
65.
Bazerbachi
F
,
Vargas
EJ
,
Rizk
M
, et al
.
Intragastric balloon placement induces significant metabolic and histologic improvement in patients with nonalcoholic steatohepatitis
.
Clin Gastroenterol Hepatol
2021
;
19
:
146
154.e4
66.
Budd
J
,
Cusi
K
.
Nonalcoholic fatty liver disease: what does the primary care physician need to know?
Am J Med
2020
;
133
:
536
543
67.
Younossi
ZM
,
Stepanova
M
,
Ong
J
, et al
.
Effects of alcohol consumption and metabolic syndrome on mortality in patients with nonalcoholic and alcohol-related fatty liver disease
.
Clin Gastroenterol Hepatol
2019
;
17
:
1625
1633
;
e1621
68.
Sookoian
S
,
Pirola
CJ
.
How safe is moderate alcohol consumption in overweight and obese individuals?
Gastroenterology
2016
;
150
:
1698
1703
;
e1692
69.
Del Ben
M
,
Baratta
F
,
Polimeni
L
, et al
.
Under-prescription of statins in patients with non-alcoholic fatty liver disease
.
Nutr Metab Cardiovasc Dis
2017
;
27
:
161
167
70.
Khoo
S
,
Wong
VW
,
Goh
GB
, et al
.
Suboptimal treatment of dyslipidemia in patients with nonalcoholic fatty liver disease
.
J Gastroenterol Hepatol
2020
;
35
:
320
325
71.
Kim
RG
,
Loomba
R
,
Prokop
LJ
, et al
.
Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis
.
Clin Gastroenterol Hepatol
2017
;
15
:
1521
1530
;
e1528
72.
Barb
D
,
Portillo-Sanchez
P
,
Cusi
K
.
Pharmacological management of nonalcoholic fatty liver disease
.
Metabolism
2016
;
65
:
1183
1195
73.
Bril
F
,
Portillo Sanchez
P
,
Lomonaco
R
, 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
2961
74.
Speliotes
EK
,
Balakrishnan
M
,
Friedman
LS
,
Corey
KE
.
Treatment of dyslipidemia in common liver diseases
.
Clin Gastroenterol Hepatol
2018
;
16
:
1189
1196
75.
Kaplan
DE
,
Serper
MA
,
Mehta
R
, et al
.
Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis
.
Gastroenterology
2019
;
156
:
1693
1706
;
e1612
76.
Yip
TC
,
Ma
AJ
,
Wong
VW
, et al
.
Laboratory parameter-based machine learning model for excluding non-alcoholic fatty liver disease (NAFLD) in the general population
.
Aliment Pharmacol Ther
2017
;
46
:
447
456
77.
Kanwal
F
,
Taylor
TJ
,
Kramer
JR
, et al
.
Development, validation, and evaluation of a simple machine learning model to predict cirrhosis mortality
.
JAMA Netw Open
2020
;
3
:
e2023780
78.
Byra
M
,
Styczynski
G
,
Szmigielski
C
, et al
.
Transfer learning with deep convolutional neural network for liver steatosis assessment in ultrasound images
.
Int J CARS
2018
;
13
:
1895
1903
79.
Kuppili
V
,
Biswas
M
,
Sreekumar
A
, et al
.
Extreme Learning Machine framework for risk stratification of fatty liver disease using ultrasound tissue characterization
.
J Med Syst
2017
;
41
:
152
80.
Francque
S
,
Szabo
G
,
Abdelmalek
MF
, et al
.
Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors
.
Nat Rev Gastroenterol Hepatol
2021
;
18
:
24
39
81.
Stefan
N
,
Häring
HU
,
Cusi
K
.
Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies
.
Lancet Diabetes Endocrinol
2019
;
7
:
313
324
82.
Perakakis
N
,
Stefanakis
K
,
Mantzoros
CS
.
The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease
.
Metabolism
2020
;
111S
:
154320
83.
Perakakis
N
,
Polyzos
SA
,
Yazdani
A
, et al
.
Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: a proof of concept study
.
Metabolism
2019
;
101
:
154005
84.
Lazarus
JV
,
Ekstedt
M
,
Marchesini
G
, et al.;
EASL International Liver Foundation NAFLD Policy Review Collaborators
.
A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe
.
J Hepatol
2020
;
72
:
14
24
85.
Vuppalanchi
R
,
Gould
RJ
,
Wilson
LA
, et al.;
Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
.
Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network
.
Hepatol Int
2012
;
6
:
379
385
86.
Kowdley
KV
,
Belt
P
,
Wilson
LA
, et al.;
NASH Clinical Research Network
.
Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease
.
Hepatology
2012
;
55
:
77
85