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

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