Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults

INTRODUCTION — Metabolic dysfunction-associated steatotic liver disease (MASLD; previously termed nonalcoholic fatty liver disease [NAFLD]) refers to liver steatosis in patients with at least one metabolic risk factor (eg, obesity, diabetes mellitus, dyslipidemia, hypertension). MASLD may progress to cirrhosis and is likely an important cause of cryptogenic cirrhosis.

This topic will review the epidemiology, clinical features, and diagnosis of MASLD in the absence of other etiologies of liver steatosis. Other aspects of MASLD are discussed separately:

●Pathogenesis – (See "Pathogenesis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)".)

●Management – (See "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)

The prevalence, clinical implications, and therapy for metabolic syndrome are discussed separately. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

The evaluation of pregnant patients with elevated liver biochemistries, including those with suspected acute fatty liver disease of pregnancy, is discussed separately. (See "Approach to evaluating pregnant patients with elevated liver biochemical and function tests" and "Acute fatty liver of pregnancy".)

Serologic tests and imaging examinations for assessing hepatic fibrosis in patients with liver disease from any etiology are discussed separately. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

Although MASLD may coexist with other causes of liver steatosis, such as celiac disease, steatogenic medication, or heavy alcohol consumption, the focus of this topic is MASLD in the absence of other causes of liver steatosis.

TERMINOLOGY — Steatotic (fatty) liver disease is a comprehensive term defined as hepatic steatosis identified on radiologic imaging or by liver biopsy. MASLD represents fatty liver disease that is secondary to metabolic dysfunction.  

Steatotic liver disease is further classified by [1-3] (see 'Histologic findings' below):

●Metabolic dysfunction-associated steatotic liver disease (MASLD) – Patients with MASLD alone have fatty liver (>5 percent hepatic steatosis) with at least one risk factor for cardiometabolic dysfunction such as dyslipidemia or obesity (figure 1), no other causes of steatotic liver disease, and minimal or no alcohol consumption (ie, <20 g daily for females and <30 g daily for males).

This category was formerly known as nonalcoholic fatty liver disease (NAFLD).

●MASLD with metabolic dysfunction-associated steatohepatitis (MASH) – Patients with MASH have histologic evidence of inflammation and hepatocellular injury, such as ballooning of hepatocytes, with or without fibrosis. (See 'Histologic findings' below.)

This category was formerly known as nonalcoholic steatohepatitis (NASH).

●MASH cirrhosis – Patients with MASH cirrhosis have cirrhosis with current or previous histologic evidence of MASH or history of MASLD.

●Metabolic dysfunction- and alcohol-associated liver disease (MetALD) – Patients with liver steatosis, at least one metabolic risk factor, and a history of moderate (but not heavy) alcohol use have metabolic dysfunction- and alcohol-associated liver disease (MetALD). This category recognizes that steatotic liver disease can involve a combination of metabolic dysfunction and alcohol. Moderate amounts of alcohol are defined as 20 to 50 g daily (140 to 350 g per week) for females and 30 to 60 g daily (210 to 420 g per week) for males [4]. This range of alcohol intake defines a spectrum between MASLD-predominant and alcohol-predominant disease.

Patients with steatosis and heavy alcohol use (ie, >50 g daily for females and >60 g daily for males) have alcohol-associated liver disease. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)

A standard alcohol-containing beverage is any drink that contains about 14 g of pure alcohol, according to the National Institute on Alcohol Abuse and Alcoholism (figure 2) [5].

EPIDEMIOLOGY

Prevalence and time trends — MASLD is seen worldwide with an estimated prevalence of 30 percent among the general population and with higher prevalence in males compared with females (40 versus 26 percent) [6-10]. In addition, the prevalence varies by geographic region and diagnostic method. In a meta-analysis of 92 studies involving ultrasound screening, the highest prevalence of MASLD was in South America (44 percent), whereas the lowest prevalence was in Western Europe (25 percent) [8]. In a study including over 4000 adults in the United States, the prevalence of liver steatosis was 57 percent, based on vibration-controlled transient elastography (VCTE) using controlled attenuation parameters [6].

The incidence of MASLD appears to be increasing over time. In a meta-analysis of 63 studies including over one million individuals, the incidence of MASLD increased from approximately 20 cases per 1000 person-years (in the year 2000) to 70 cases per 1000 person-years (by the year 2015) [10].

Risk factors and associated conditions — Patients with MASLD have at least one metabolic risk factor (figure 1) [11-14]:

●Obesity, defined as BMI ≥25 kg/m² (or BMI ≥23 kg/m² for Asian individuals) – (See "Obesity in adults: Prevalence, screening, and evaluation" and "Obesity in adults: Overview of management".)

●Hypertension – (See "Overview of hypertension in adults".)

●Dyslipidemia – (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Statins: Actions, side effects, and administration".)

●Type 2 diabetes mellitus – (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)

In addition, patients with more than one metabolic factor have an increased risk for progression to MASH [15,16].

While metabolic factors have been linked to risk of MASLD and cardiovascular disease, whether MASLD may be independently associated with cardiovascular disease has been uncertain. Nevertheless, some studies suggested that MASLD was associated with atherosclerotic heart disease, arrythmias, and heart failure [17-20].

Other conditions that have been associated with MASLD, independent of their associations with obesity, include polycystic ovary syndrome, obstructive sleep apnea, chronic kidney disease, and history of cholecystectomy [21-25].

PATHOGENESIS — The pathogenesis of MASLD has not been fully elucidated. The most widely supported theory implicates insulin resistance as the key mechanism leading to liver steatosis, and possibly to steatohepatitis [26]. Other driving factors include an imbalance between energy intake and metabolic needs in addition to systemic inflammation [27].

Genome-wide association studies (GWAS) have identified genetic variants associated with risk of progression from fatty liver to fibrosing MASH via effects on hepatic fat accumulation [28,29]. Predisposing genetic variants associated with progressive disease include PNPLA3 and IFNL4, and their phenotypic expression is triggered by factors such as adiposity and dietary factors [28]. The pathogenesis of MASLD is discussed in more detail separately. (See "Pathogenesis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)".)

CLINICAL FEATURES

Patient presentation — Most patients with MASLD are asymptomatic, although some patients with MASH may report fatigue, malaise, and vague right upper abdominal discomfort. Asymptomatic patients are usually identified when laboratory testing shows elevated aminotransferases or when abdominal imaging shows liver steatosis as an incidental finding. At the other end of the spectrum are patients who present with decompensated cirrhosis, but such a presentation is uncommon. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Decompensated cirrhosis'.)

Most patients with MASLD have no liver-related abnormalities on physical examination. However, some patients may present with hepatomegaly due to fatty infiltration of the liver. The prevalence of hepatomegaly in patients with MASLD has ranged from 5 to 18 percent [30,31]. A normal liver span by transabdominal ultrasound is usually <16 cm; however, liver size varies with sex and body size [32]. The evaluation of patients with hepatomegaly is discussed in more detail separately. (See "Overview of the evaluation of hepatomegaly in adults".)

Patients who have developed cirrhosis may have stigmata of chronic liver disease (eg, palmar erythema, spider angiomata, ascites). (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Laboratory findings — Laboratory findings in patients with MASLD include:

●Liver enzymes – Patients may have mildly or moderately elevated liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), although some patients with MASLD have normal aminotransferase levels [33-38]. When elevated, the AST and ALT are typically two to five times the upper limit of normal, with an AST to ALT ratio of less than one [39-42]. However, the degree of aminotransferase elevation does not predict the degree of liver inflammation or fibrosis, and a normal ALT level does not exclude histologic injury [34,35,43,44]. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)

In addition, the true prevalence of abnormal liver enzymes among patients with MASLD is uncertain because the diagnosis is usually suspected based on elevated aminotransferases (or incidental imaging findings) rather than on population-based screening.

●Alkaline phosphatase and other liver tests – Alkaline phosphatase may be elevated by two to three times the upper limit of normal. Serum albumin and bilirubin levels are typically within the normal range but may be abnormal in patients who have developed cirrhosis.

●Other laboratory findings – Patients who have developed cirrhosis may have hematologic abnormalities such as thrombocytopenia and neutropenia. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings'.)

Patients with MASLD may have an elevated serum ferritin concentration or transferrin saturation [30,43]. In addition, a serum ferritin greater than 1.5 times the upper limit of normal in patients with MASLD has been associated with increased risk of steatohepatitis and advanced fibrosis [45].  

DIAGNOSTIC EVALUATION — The goals of the diagnostic evaluation in patients with suspected MASLD are to exclude other causes of liver disease and to establish the diagnosis of MASLD (figure 1).

When to suspect MASLD — MASLD may be suspected in patients who fulfill any of the following criteria [46]:

●Liver steatosis on imaging

●Unexplained elevation in liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST])

●Two or more metabolic risk factors (eg, obesity, dyslipidemia, pre- or established type 2 diabetes mellitus, hypertension)

●First-degree relative of a patient with MASLD cirrhosis

Initial evaluation

History and physical examination — The history includes a description of symptoms, existing medical conditions (eg, type 2 diabetes mellitus, dyslipidemia, obesity), medication use (including herbal supplements and over-the-counter medications), family history (ie, cirrhosis, MASLD, or hepatocellular carcinoma), and alcohol consumption (including amount, pattern, and duration of use) (figure 2). (See 'Terminology' above and "Screening for unhealthy use of alcohol and other drugs in primary care".)

Medications that have been linked to liver steatosis include amiodarone, glucocorticoids, methotrexate, and tamoxifen [47-49].

The physical examination includes measuring body mass index and assessing for hepatomegaly and stigmata of chronic liver disease (eg, jaundice, ascites, splenomegaly). (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Physical examination'.)

Laboratory studies — For patients with suspected MASLD, we measure the following laboratory studies to assess liver function and comorbid conditions [50]:

●Aminotransferases – Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

●Alkaline phosphatase

●Total bilirubin

●Serum albumin

●Prothrombin time/international normalized ratio (INR)

●Complete blood count with platelets

●Fasting blood glucose

●Serum total and HDL-cholesterol and triglycerides

We obtain the following tests to evaluate for other causes of liver disease (see 'Differential diagnosis' below):

●Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and total hepatitis B core antibody (anti-HBc) – (See "Hepatitis B virus: Screening and diagnosis in adults".)

●Anti-hepatitis C virus antibody with reflex to hepatitis C viral RNA – (See "Screening and diagnosis of chronic hepatitis C virus infection".)

●Plasma iron, ferritin, and total iron binding capacity – (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

●Antimitochondrial antibody – (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis".)

●Immunoglobulin G (IgG) level, antinuclear antibody, antismooth muscle antibody (for female patients and/or those with aminotransferases >5 times the upper limit of normal or history of autoimmune disease) – (See "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation'.)

●Ceruloplasmin (for patients <50 years of age or those with neurocognitive symptoms) – (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnostic evaluation'.)

●Alpha-1 antitrypsin (AAT) level – (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

●Anti-tissue transglutaminase antibody (tTG-IgA) – (See "Diagnosis of celiac disease in adults".)

Evaluating patients with liver disease for immunity to hepatitis A virus infection and preventive immunizations are discussed separately. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Immunizations for adults with chronic liver disease".)

Diagnostic imaging — Our approach to initial imaging is informed by the availability of recent imaging studies:

●For patients in whom MASLD was initially suspected based on imaging (eg, transabdominal ultrasound, computed tomography [CT], magnetic resonance imaging [MRI]), additional imaging is not necessary to establish the diagnosis if other criteria are met (ie, excluding other primary etiologies and having at least one metabolic risk factor) [51]. (See 'When to suspect MASLD' above.)

However, we assess the stage of liver disease by evaluating the severity of fibrosis in such patients, as discussed below. (See 'Staging (Evaluating for fibrosis)' below.)

●For patients with no recent liver imaging (ie, within 12 months), we obtain transabdominal ultrasound.  

For patients with MASLD, ultrasound often shows a hyperechoic texture or a bright liver because of diffuse fatty infiltration [52]. In a meta-analysis of 49 studies including 4720 patients, the sensitivity and specificity for ultrasound detecting moderate to severe fatty liver were 85 and 94 percent, respectively, when using liver biopsy as the reference standard [53]. However, the sensitivity appears to be lower in patients with obesity [54,55]. In a study of 187 patients with Class 2 obesity undergoing bariatric surgery, hepatic steatosis was present histologically in 95 percent but was detected by ultrasound in only 49 percent of patients [54].

Liver biopsy

Limited indications — Clinical, laboratory, and imaging findings are often adequate to establish a diagnosis of MASLD. Thus, we typically reserve diagnostic liver biopsy for patients with suspected MASLD if the diagnosis remains uncertain despite laboratory and imaging tests or if an alternative etiology is suspected. (See 'Initial evaluation' above.)

We may also obtain a biopsy if noninvasive testing for advanced fibrosis is inconclusive. (See 'Staging (Evaluating for fibrosis)' below.)

The interpretation of liver biopsy specimens in general and methods to obtain liver biopsy specimens are discussed separately. (See "Interpretation of nontargeted liver biopsy findings in adults" and "Approach to liver biopsy".)

Histologic findings — A histologic diagnosis of MASLD is defined as >5 percent steatotic hepatocytes in a liver tissue section [56,57]. In addition to steatosis, patients may also have hepatic iron deposition [58,59].

Histologic findings in patients with MASLD include any of the following [57]:

●Steatosis alone.

●Steatosis with lobular or portal inflammation, without hepatocyte ballooning.

●Steatosis with hepatocyte ballooning but without inflammation [60].

For patients who required a liver biopsy to establish the diagnosis of MASLD, we also use liver histology to assess for metabolic dysfunction-associated steatohepatitis (MASH). Liver biopsy is the most accurate method for determining the severity of architectural distortion, cellular injury, and inflammation [4]. Although imaging methods such as transabdominal ultrasound may detect steatosis, imaging is less reliable than histology for identifying MASH [61,62]. However, use of liver biopsy for grading inflammation and staging all patients with MASLD is limited by risk of biopsy-related adverse events (eg, bleeding) and cost. (See "Approach to liver biopsy", section on 'Complications'.)

The histologic diagnosis of MASH requires the presence of hepatic steatosis in association with hepatocyte ballooning degeneration and hepatic lobular inflammation (typically in acinar zone 3) (table 1) [57,60]. Fibrosis is not required for the diagnosis of MASH but may be seen.

Additional histologic findings of MASH include (picture 1A-C) [63-65]:

●Apoptotic (acidophil) bodies

●Mild chronic portal inflammation

●Perisinusoidal collagen deposition that may result in zone 3 accentuation in a "chicken wire" pattern (related to the deposition of collagen and other extracellular matrix fibers along the sinusoids of zone 3 and around hepatocytes)

●Portal fibrosis without perisinusoidal or pericellular fibrosis

●Mallory-Denk bodies (previously called Mallory bodies or Mallory hyaline)

●Megamitochondria

●Glycogenated (vacuolated) nuclei in periportal hepatocytes (rarely seen in alcohol-associated steatohepatitis)

●Lobular lipogranulomas

●PAS-diastase-resistant Kupffer cells

●Hepatic siderosis (typically mild) involving periportal hepatocytes or panacinar reticuloendothelial cells

●Cirrhosis, which is an end stage result of MASH and is typically macronodular

The NAFLD activity score (NAS) is a validated histologic score that is used to grade disease activity in patients with MASLD [66]. The NAS is the sum of the biopsy's individual scores for steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2). Fibrosis is not included in the NAS. In the original study that derived the NAS, scores of 0 to 2 occurred in cases largely considered not diagnostic of MASH; scores of 3 to 4 were evenly divided among those considered not diagnostic, borderline, or positive for MASH; and scores of 5 to 8 occurred in cases that were largely considered diagnostic of MASH [66]. (See "Histologic scoring systems for chronic liver disease", section on 'Nonalcohol-associated fatty liver activity score'.)

As fibrosis progresses to cirrhosis, steatosis and inflammation may not be reliably identified. However, patients with cirrhosis and metabolic risk factors or metabolic syndrome may be classified as having MASLD-related cirrhosis rather than cryptogenic cirrhosis [65,67].

For patients with MASLD plus another etiology of liver disease, evaluating for MASH may be difficult. As an example, patients with MASH may also have alcohol-associated liver disease, but it is challenging to differentiate the relative contributions of the two processes from a liver biopsy [65]. In a series of 3581 liver biopsies from patients with various chronic liver diseases, concurrent steatohepatitis was found in 5.5 percent of patients with hepatitis C virus (HCV) infection (some with heavy alcohol use) [68]. Among patients with other chronic liver diseases, the prevalence of steatohepatitis ranged from 1.6 percent (autoimmune hepatitis) to 7.9 percent (alpha-1 antitrypsin deficiency). None of the patients with steatohepatitis with chronic liver disease from a cause other than HCV infection had a history of heavy alcohol consumption.

Establishing the diagnosis — The diagnosis of MASLD is typically established on the basis of imaging demonstrating liver steatosis in the absence of other primary etiologies (eg, drug-induced liver injury) in patients with at least one metabolic risk factor (figure 1) [4]. We typically reserve diagnostic liver biopsy for patients with suspected MASLD when the diagnosis remains uncertain despite laboratory and imaging tests. As an example, we may obtain a liver biopsy in patients with suspected MASLD who have positive serologic marker(s) for autoimmune disease (eg, anti-smooth muscle antibody) and/or elevated immunoglobulin G level to evaluate for autoimmune hepatitis.

However, liver biopsy is not usually required to establish the diagnosis. When a liver biopsy is obtained, the diagnosis of MASLD can be confirmed by histology showing steatosis alone or steatosis with either hepatocyte ballooning or with lobular or portal inflammation. (See 'Liver biopsy' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of MASLD includes other conditions associated with liver steatosis, particularly for adult patients who do not have metabolic risk factors (see 'Diagnostic evaluation' above):

●Alcohol-associated liver disease (ALD) – Patients with liver steatosis and heavy alcohol intake (ie, >50 g daily [350 g per week] for females and >60 g daily [420 g per week] for males) have predominantly alcohol-associated liver disease [2]. Another clinical finding that suggests alcohol-associated fatty liver disease is an aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio >2. In patients with MASLD, the AST to ALT ratio is typically <1, except in patients with advanced fibrosis who have a higher AST level [69]. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)

●Chronic hepatitis C virus (HCV) infection – Liver steatosis related to hepatitis C genotype 3 can be excluded with anti-HCV antibody testing [70]. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

●Wilson disease – Patients with symptomatic Wilson disease may have elevated liver enzymes in addition to signs of copper overload (eg, Kayser-Fleischer rings, neurocognitive involvement) and family history of Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

●Parenteral nutrition – Use of parenteral nutrition has been linked to elevated liver enzymes and liver steatosis. (See "Nutrition support in intubated critically ill adult patients: Parenteral nutrition", section on 'Complications'.)

●Drug-induced liver disease – Medications that have been associated with liver steatosis include amiodarone, methotrexate, tamoxifen, glucocorticoids. (See "Drug-induced liver injury".)

●Other genetic diseases – Other genetic diseases such as lysosomal acid lipase deficiency (cholesterol ester storage disease), hypobetalipoproteinemia, and lipodystrophy are in the differential diagnosis; however, these conditions typically present in pediatric patients. The differential diagnosis of MASLD in children and adolescents is discussed separately. (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents".)

STAGING (EVALUATING FOR FIBROSIS) — The goal of staging patients with MASLD is to determine the severity of fibrosis. We evaluate most patients with a noninvasive imaging study and reserve liver biopsy for those with inconclusive findings.

For patients with MASLD who did not require a liver biopsy to establish the diagnosis, we typically evaluate for advanced fibrosis by obtaining ultrasound-based, vibration-controlled transient elastography (VCTE) to assess liver stiffness measurement (image 1). Alternatives to VCTE include imaging with another ultrasound-based method such as acoustic radiation force impulse (ARFI) or with magnetic resonance elastography (MRE). (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography" and "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'Imaging examinations'.)

Liver stiffness as measured by ultrasound-based elastography informs further management, although cutoff values for diagnosing fibrosis vary among studies and underlying liver disease (algorithm 1) [71]:

●Liver stiffness measurement <8 kPa by VCTE corresponds to a low-risk fibrosis score (≤F1) and excludes clinically significant fibrosis.

●Liver stiffness measurement 8 to 12 kPa by VCTE is indeterminate for advanced fibrosis. For such patients, we obtain magnetic resonance elastography (MRE) because ultrasound-based elastography is less accurate in the middle ranges [72]. If the liver stiffness measurement by MRE is also indeterminate for significant fibrosis (ie, 2.55 kPa to 3.63 kPa), we discuss obtaining liver biopsy with the patient [73]. Liver stiffness measurement <2.55 kPa by MRE corresponds to a low-risk fibrosis score (≤F1), whereas a measurement >3.63 kPa suggests advanced fibrosis or cirrhosis (see below).

●Liver stiffness measurement >12 kPa by VCTE suggests advanced fibrosis or cirrhosis. Further management includes hepatology referral for screening and preventing complications of cirrhosis (eg, variceal bleeding, hepatocellular carcinoma). These issues are discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

We use VCTE with liver stiffness measurement for staging patients with MASLD because it is a noninvasive, point-of-care method that can exclude advanced fibrosis with good diagnostic accuracy [71,74,75]. In a systematic review of 44 studies comparing VCTE with liver histology in patients with MASLD, the sensitivity and specificity of VCTE for detecting advanced fibrosis (defined as ≥F3) were 80 and 77 percent, respectively [75].

Studies suggested that MRE was more accurate than ultrasound-based elastography for staging fibrosis in patients with MASLD, although use of MRE may be limited by availability and cost [72,76]. In a pooled analysis of three studies including 230 patients with biopsy-proven MASLD, MRE had higher diagnostic accuracy for detecting each stage of fibrosis (ie, F0 through F4) compared with ultrasound-based transient elastography [72].

As an alternative to imaging, some clinicians initially use the Fibrosis (FIB)-4 index to stratify the patient's risk for fibrosis and then perform imaging (eg, VCTE) for patients with FIB-4 ≥1.3 [4,46,71]. The FIB-4 index predicts advanced fibrosis by combining biochemical values (platelet count, ALT, and AST) and age (calculator 1 and calculator 2) [77]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'Other indirect markers'.)

A FIB-4 index >3.25 is consistent with cirrhosis, and we suggest hepatology referral for such patients [78]. Management of patients with cirrhosis from any etiology is discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Patients with FIB-4 index >2.67 are at risk for advanced fibrosis, and we also suggest hepatology referral for those patients.

TARGETED SCREENING FOR ADVANCED FIBROSIS — We do not screen the general population for MASLD-related advanced fibrosis [4]. However, one issue that arises is whether to screen individuals who are at increased risk for advanced liver fibrosis because of an associated condition, such as type 2 diabetes mellitus or other metabolic risk factor (table 2). (See 'Risk factors and associated conditions' above.)

Society guidelines support screening for advanced fibrosis in the following high-risk groups [4]:

●First-degree relatives of patients with cirrhosis [79].

●Individuals with obesity and at least one obesity-related comorbidity (eg, dyslipidemia) [80]. (See "Overweight and obesity in adults: Health consequences".)

●Individuals with moderate or greater alcohol consumption (ie, moderate alcohol consumption was defined as 20 to 50 g daily for females and 30 to 60 g daily for males).

●Patients with type 2 diabetes mellitus [81,82].

●Patients with ≥2 metabolic risk factors (table 2).

For initial screening, we typically use serologic testing (eg, Fibrosis [FIB]-4 index) [46,83]. The FIB-4 index predicts advanced fibrosis by combining biochemical values (platelet count, ALT, and AST) and age (calculator 1 and calculator 2) [77,84] (see 'Staging (Evaluating for fibrosis)' above):  

●Patients with FIB-4 >2.67 – Patients are at high risk for advanced fibrosis and should be referred to a hepatologist.

●Patients with FIB-4 ≥1.3 and ≤2.67 – We evaluate patients with an indeterminate score with ultrasound-based transient elastography, and elastography results inform further management.

●Patients with FIB-4 <1.3 – For patients with a low-risk FIB-4 index, we reassess based on underlying risk:

•For patients with type 2 diabetes mellitus or ≥2 metabolic risk factors, we repeat FIB-4 index every one to two years.

•For patients without type 2 diabetes mellitus and <2 metabolic risk factors, we repeat FIB-4 index every two to three years.

Observational data have suggested that rates of liver steatosis in patients with type 2 diabetes mellitus were high [81,83,85,86]. In a study including 561 patients with type 2 diabetes who had noninvasive testing (eg, elastography, FIB-4) followed by liver biopsy if the results suggested fibrosis, the prevalence of steatosis and fibrosis (liver stiffness measurement ≥7 kPa) were 70 and 21 percent, respectively [81].

SPECIAL POPULATIONS

Patients without obesity — Obesity is common in patients with MASLD, although liver steatosis can also occur in patients who are not overweight (ie, BMI <25 kg/m² or BMI <23 kg/m² in Asian individuals) [87]. This condition is often referred to as "lean" or "nonobese" MASLD. The prevalence of MASLD for individuals who are not overweight ranges from approximately 5 to 20 percent [88-90].

The diagnostic evaluation for patients with suspected lean MASLD is similar to the evaluation for patients who are overweight or have obesity. (See 'Diagnostic evaluation' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Metabolic dysfunction-associated steatotic liver disease (The Basics)")

●Beyond the Basics topics (see "Patient education: Metabolic dysfunction-associated steatotic liver disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Background – Steatotic (fatty) liver disease refers to liver steatosis of any etiology that was detected by liver imaging or biopsy. Steatotic liver disease may be further classified as (figure 1) (see 'Terminology' above):

•Metabolic dysfunction-associated steatotic liver disease (MASLD) – Patients with MASLD alone have fatty liver (>5 percent hepatic steatosis) with at least one risk factor for cardiometabolic dysfunction such as dyslipidemia or obesity, no other causes of steatotic liver disease, and minimal or no alcohol consumption (ie, <20 g daily for females and <30 g daily for males).

This category was formerly known as nonalcoholic fatty liver disease (NAFLD).

•MASLD with metabolic dysfunction-associated steatohepatitis (MASH) – Patients with MASH have histologic evidence of inflammation and hepatocellular injury, such as ballooning of hepatocytes, with or without fibrosis. This category was formerly known as nonalcoholic steatohepatitis (NASH).

•MASH cirrhosis – Patients with MASH cirrhosis have cirrhosis with histologic evidence of MASH or a history of MASLD.

•Metabolic dysfunction- and alcohol-associated liver disease (MetALD) – Metabolic dysfunction- and alcohol-associated liver disease (MetALD) is a condition of liver steatosis, at least one metabolic risk factor, and a history of moderate (but not heavy) alcohol use. Moderate amounts of alcohol are defined as 20 to 50 g daily (140 to 350 g per week) for females and 30 to 60 g daily (210 to 420 g per week) for males.

●Clinical features – Most patients with MASLD are asymptomatic, although some patients with MASH may complain of fatigue, malaise, and vague right upper abdominal discomfort. Patients are more likely to come to attention because laboratory testing revealed elevated liver biochemistries or because steatosis was detected incidentally on liver imaging. (See 'Clinical features' above.)

Patients with MASLD may have mild or moderate elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), although normal liver enzyme levels do not exclude MASLD.

Liver ultrasound often shows a hyperechoic texture or a bright liver because of diffuse fatty infiltration.

●When to suspect MASLD – MASLD may be suspected in patients with any of the following (see 'Diagnostic evaluation' above):

•Liver steatosis on imaging

•Unexplained elevation in liver enzymes (ALT and AST)

•Two or more metabolic risk factors (eg, dyslipidemia, obesity, pre- or established type 2 diabetes mellitus) (table 2)

•First-degree relative of a patient with MASLD cirrhosis

●Diagnosis – For patients with at least one metabolic risk factor, the diagnosis of MASLD is typically established by imaging that demonstrates liver steatosis and by excluding other primary etiologies for liver disease (figure 1). We reserve diagnostic liver biopsy for patients in whom MASLD is suspected but the diagnosis is uncertain despite laboratory studies and imaging. (See 'Establishing the diagnosis' above.)

●Staging – For patients with MASLD who did not require a liver biopsy to establish the diagnosis, we evaluate for advanced fibrosis by obtaining ultrasound-based, vibration-controlled transient elastography (VCTE) with liver stiffness measurement. (See 'Staging (Evaluating for fibrosis)' above.)

An alternative to imaging with VCTE is magnetic resonance elastography (MRE) or another ultrasound-based method such as acoustic radiation force impulse (ARFI). If imaging methods are not available, alternatives include serologic tests (eg, Fibrosis [FIB]-4 index). (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

If the liver stiffness measured by ultrasound-based elastography suggests advanced fibrosis or cirrhosis (algorithm 1), further management includes screening for and preventing complications of cirrhosis (eg, variceal bleeding, hepatocellular carcinoma), and this is discussed in detail separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)