Version May 2024
INTRODUCTION — Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD) [1], is the most common cause of liver disease in children [2-4]. MASLD is a steatotic liver disease that occurs in the setting of visceral adiposity, dyslipidemia, and/or insulin resistance.
MASLD ranges in severity from steatosis (increased liver fat without inflammation) to metabolic dysfunction-associated steatohepatitis (MASH; increased liver fat with inflammation and hepatocellular injury, with or without fibrosis) (picture 1). The natural history of MASH in children is not well described, but, in a subset of children, it may lead to fibrosis, cirrhosis, and, ultimately, liver failure in adulthood [5-7].
The clinical presentation, evaluation, and management of MASLD in children and adolescents are discussed below. Evaluation and management of other obesity-related comorbidities and the pathogenesis of MASLD are discussed separately. (See "Overview of the health consequences of obesity in children and adolescents" and "Pathogenesis of nonalcoholic fatty liver disease".)
DEFINITIONS — In July 2023, nomenclature and diagnostic criteria for steatotic liver disease were revised following an international Delphi consensus process [8]. The rationale for changing the nomenclature from NAFLD to MASLD was the desire to reduce potential stigma associated with the terms "nonalcoholic" and "fatty," better reflect the underlying pathophysiology of the disorder, and align the nomenclature with specific diagnostic criteria.
Secondary causes of steatotic liver disease, such as hepatitis C, parenteral nutrition, steatogenic medication (eg, valproate), lipodystrophy, or inborn errors of metabolism must be considered in the differential diagnosis of MASLD, particularly in children who do not have typical cardiometabolic risk factors for MASLD [9].
MASLD is subdivided into categories, defined by histologic findings and level of alcohol intake (table 1) [1,10]:
●Metabolic dysfunction-associated steatotic liver disease (MASLD) – MASLD refers to steatotic (fatty) liver as determined by imaging or biopsy (>5 percent hepatic steatosis) with at least one risk factor for cardiometabolic dysfunction including overweight/obesity/visceral adiposity, dysglycemia, hypertension, or dyslipidemia. Other causes of steatotic liver disease should still be excluded but, in some cases, can coexist with MASLD (eg, hepatitis C). Importantly, the diagnosis of MASLD does not require the presence of chronically elevated liver enzymes (which was previously a diagnostic criterion for NAFLD).
●Metabolic dysfunction-associated steatohepatitis (MASH) – MASH is defined as MASLD plus inflammation and hepatocellular injury, such as ballooning of hepatocytes, with or without fibrosis. These diagnostic criteria are identical to nonalcoholic steatohepatitis (NASH) criteria, with no revisions in the 2023 nomenclature consensus paper. In children, a liver biopsy is required to make a definitive diagnosis of MASH because there are no validated, reliable noninvasive biomarkers.
●MASH with fibrosis or cirrhosis – This refers to cirrhosis or advanced fibrosis with current or previous histologic evidence of MASLD or MASH.
●MASLD and increased alcohol intake – This category refers to MASLD in the setting of increased alcohol intake; it is more common in adults but also applies to adolescents. This new category recognizes that steatotic liver disease can involve a combination of metabolic dysfunction and alcohol-related injury below the threshold of alcohol intake required for diagnosis of alcohol-related liver disease. Increased alcohol intake is defined as 140 to 350 g/week for females and 210 to 420 g/week for males. This range defines a spectrum between MASLD-predominant (at lower end of alcohol intake) and alcohol-predominant disease (at higher end).
Because MASLD was defined in 2023, the available data regarding epidemiology, risk factors, natural history, and treatment in children are based on the prior NAFLD definition, which primarily focused on children whose liver disease was identified because of chronically elevated liver enzymes. Concordance between NAFLD and MASLD diagnosis in children has not yet been evaluated. A European consortium of adults with NAFLD demonstrated a high concordance (98 percent) between MASLD and NAFLD diagnoses [8].
Note: Until pediatric studies are available to determine the concordance between MASLD and NAFLD, we will maintain NAFLD nomenclature for historical studies that used the prior NAFLD definition to distinguish these from future studies that will use the newer MASLD definition and terminology.
EPIDEMIOLOGY
Prevalence and demographics — The estimated population prevalence of NAFLD was most often based on indirect evidence of a steatotic liver, either using evidence of hepatic steatosis from imaging or elevations in serum aminotransferase levels in at-risk subjects. In contrast, MASLD is defined by either radiologic or biopsy evidence of steatosis in children with metabolic risk factors. No pediatric prevalence data using MASLD diagnostic criteria exist yet. As an example, there was a modest male predominance in the studies that used biochemistry to diagnose NAFLD but not in studies using ultrasound. Patients are typically diagnosed after nine years of age, in part because clinical practice guidelines recommend that screening begin around age 9 to 10 years. However, case reports describe steatosis developing earlier, including in utero [11], and cirrhosis developing as early as eight years [10,12].
Estimates of NAFLD or MASLD prevalence may vary by method of ascertainment, as well as the population studied (ie, referral, community, ethnic group), as illustrated by the following reports:
●Histology – In an autopsy study of 742 children and adolescents in San Diego County, the prevalence of steatotic liver disease was 9.6 percent overall and 38 percent in children with obesity [13]. Histologic steatohepatitis was seen in 23 percent of the subjects with steatotic liver, or 3 percent of the population overall. The prevalence of steatotic liver disease was strongly associated with race/ethnicity, independent of obesity: Hispanic youth had a fivefold increase in risk for steatotic liver as compared with Black youth, after adjustment for body mass index. White youth had intermediate levels of risk. Because this study used histologic measures of steatotic liver disease in an unselected population, it is the best representation of the prevalence of steatotic liver disease among children and adolescents in the United States. Another autopsy study conducted in New York City confirmed the relatively low rates of hepatic steatosis and steatohepatitis among Black children and adolescents compared with Hispanic or White children and adolescents [14]. However, this study found comparable rates of hepatic steatosis among Hispanic and non-Hispanic White individuals, which may be due to a higher proportion of Caribbean Hispanic ancestry and lower proportion of Mexican/Central American Hispanic ethnicity compared with the San Diego County region. Caribbean Hispanic ancestry is associated with a higher percentage of African genetic admixture that could be protective against hepatic steatosis [15].
●Aminotransferase elevations – Historically, serum aminotransferase elevations were used as an indirect estimate of the prevalence of NAFLD in a population but had limited sensitivity and specificity for detection of steatosis [16]. Typically, the prevalence of hepatic steatosis is underestimated using aminotransferase elevations, but this depends in part on the alanine aminotransferase (ALT) threshold employed in the study.
In a large population-based study in the United States (National Health and Nutrition Examination Survey 2011 to 2018), 16 percent of adolescents had elevated ALT (>22 units/L for females and >26 units/L for males) presumed to be NAFLD, rising to 39 percent of those with obesity [17]. In another large population-based study, 11 percent of all children had ALT above similar thresholds [18]. A meta-analysis estimated the prevalence of NAFLD by abnormal ALT (using various thresholds) to be 7 percent in the general population (9 studies) and 13.7 percent in children with obesity (14 studies) [4].
●Ultrasound – Ultrasound has poor sensitivity and specificity for the detection of hepatic steatosis [19]. In a meta-analysis, the prevalence of hepatic steatosis was 7.6 percent in the general population (10 studies) and 41.3 percent in children with obesity (34 studies) [4].
Risk factors and comorbidities — Historically, NAFLD was strongly associated with obesity in all age groups [20,21]. By definition, MASLD is also closely associated with elements of metabolic syndrome (abdominal fat distribution, insulin resistance, diabetes, dyslipidemia, and hypertension [22-25]). NAFLD was also associated with polycystic ovary syndrome and obstructive sleep apnea (OSA), independent of the degree of obesity [9,26-28]. Therefore, children with suspected or established MASLD should be evaluated for these comorbidities (table 2) and receive counseling regarding healthy lifestyle to help reduce the risk of cardiovascular disease and type 2 diabetes mellitus. (See 'Natural history' below.)
Hepatic steatosis may occur in individuals without obesity, often accompanied by insulin resistance and dyslipidemia (consistent with a diagnosis of MASLD under the new nomenclature system), or it may occur in association with genetic disorders such as lipodystrophy syndromes [29]. Several single-nucleotide polymorphisms have been associated with increased risk of NAFLD; among lean children, genetic risk factors may be a stronger predictor of liver fat than cardiometabolic markers [30,31].
Other risk factors for NAFLD include maternal obesity during gestation [32], panhypopituitarism [33], sarcopenia or lower muscle mass [34,35], and Hispanic ethnicity (the latter noted in studies from the United States [36,37]). Reasons for the association with Hispanic ethnicity may include higher concentration of a genetic risk factor (predominantly PNPLA3 variants) in some Hispanic populations and/or differences in social drivers of health [38]. (See 'Prevalence and demographics' above.)
Natural history — The natural history of pediatric NAFLD was illustrated by a study of 122 children with biopsy-confirmed NAFLD who were enrolled in the placebo arm of clinical trials and received standard-of-care lifestyle counseling [39]. After a median of 1.6 years of follow-up, repeat liver biopsy revealed:
●Borderline and definite nonalcoholic steatohepatitis (NASH) at baseline – Resolved to no NASH in 29 percent
●NAFL or borderline NASH at baseline – Progressed to definite NASH in 18 percent
●Complete resolution of NAFLD – Occurred in 2.4 percent (3 of 122 children, all of whom had NAFL but not NASH at baseline)
●Fibrosis – Improved in 34 percent and progressed in 23 percent
Clinical characteristics associated with disease progression/fibrosis worsening included baseline adolescent age, ALT, and total and low-density lipoprotein (LDL) cholesterol levels. Longitudinal predictors of disease progression were a rising ALT, gamma-glutamyl transpeptidase (GGTP), and hemoglobin A1c as well as the development of type 2 diabetes. These factors may help guide escalation to more intensive interventions and decisions regarding repeat liver biopsy (see 'Follow-up' below). Overall, 7 percent of the cohort developed incident type 2 diabetes within two years, at a cumulative incidence rate nearly 300-fold the rate of the general pediatric population.
A study from Sweden found that biopsy-confirmed NAFLD in children and young adults was associated with substantially higher mortality risk compared with population-based controls over 15 years of follow-up (adjusted hazard ratio [aHR] 5.9) [40]. The mortality risk was higher for NASH (aHR 11.5) compared with simple steatosis (aHR 5.3). Excess mortality derived from cancer (aHR 15.6), liver disease (aHR 16.5), and cardiovascular disease (aHR 4.3).
Natural history studies of children diagnosed using the revised MASLD criteria have not yet been published.
CLINICAL PRESENTATION — Most patients are asymptomatic [20]. A minority of children may complain of right upper quadrant pain or nonspecific symptoms such as abdominal discomfort and fatigue [41,42]. Other symptoms that have been reported in patients with the historical diagnosis of NAFLD, such as regurgitation, bloating, and musculoskeletal pain, are unlikely to be due to the condition itself. Instead, these symptoms may be related to other obesity-associated comorbidities such as gastroesophageal reflux disease, constipation, functional abdominal pain, or slipped capital femoral epiphysis [43]. In studies of children with NAFLD, signs of end-stage liver disease (such as palmar erythema, spider angiomata, muscle wasting, jaundice, or encephalopathy) have been rare because the disease has rarely progressed to decompensated cirrhosis during childhood.
On examination, acanthosis nigricans is common, reflecting the close association with insulin resistance/type 2 diabetes. Hepatomegaly and/or splenomegaly may be present but may be difficult to ascertain on physical examination if significant abdominal adiposity is present.
In studies of children with NAFLD, laboratory abnormalities typically include elevations in liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and gamma-glutamyl transpeptidase (GGTP) [3,12,20,44,45]. These abnormalities may resolve or improve in children with overweight or obesity who are able to reach a healthier weight and body composition through lifestyle or other measures [44,46]. In some cohorts with historical NAFLD diagnosis, serum aminotransferase concentrations were normal in a significant minority (up to 25 percent in some studies [47]); therefore, the new definition of MASLD does not include elevated liver enzymes as a diagnostic criterion [48]. Aminotransferase concentrations may also decline in the setting of cirrhosis. Although GGTP could be normal or elevated in children with NAFLD, isolated elevations of GGTP may suggest an alternate diagnosis, such as primary sclerosing cholangitis, excess alcohol intake, or a side effect of a medication (eg, antiepileptic medications).
SCREENING
Serum alanine aminotransferase (recommended) — Historically, screening for NAFLD consisted of measuring serum alanine aminotransferase (ALT), as summarized in the algorithm (algorithm 1) [9]. Under the new MASLD criterion, imaging or biopsy evidence of steatosis is the key definition, but updated guidance for screening is not yet available. Until new screening guidelines are developed, we continue to suggest screening with ALT because this strategy will help to identify the subset of children with MASLD who are at increased risk for more severe disease (eg, metabolic dysfunction-associated steatohepatitis/nonalcoholic steatohepatitis [MASH/NASH]), even if it fails to identify the subset of children with hepatic steatosis who have normal liver enzymes.
The 2017 guideline from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommended screening with ALT alone [9]. The 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition guideline recommended screening with both ALT and imaging, recognizing that some children with hepatic steatosis have normal liver enzymes [47,49].
●Indications – Screen all children with obesity (body mass index ≥95th percentile); screen overweight children (body mass index ≥85th percentile) if other risk factors are present (eg, signs of insulin resistance or a family history of NAFLD or MASLD). Begin screening between 9 and 11 years of age. Screening can be considered at a younger age if there are strong risk factors for MASLD. (See 'Risk factors and comorbidities' above.)
●ALT interpretation – For serum ALT interpretation, we suggest using the following upper limit of normal (ULN):
•Adolescents 12 to 17 years:
-Girls – 22 units/L
-Boys – 26 units/L
•Children 1 to <12 years – 30 units/L
Note that these values are substantially lower than the ULNs reported in most pediatric hospital laboratories.
The cutoffs for adolescents represent the 97th percentiles for a healthy lean population, as determined from the National Health and Nutrition Examination Survey for adolescents 12 to 17 years old [50]. Use of these thresholds is supported by a separate study from Germany, which reported comparable ULNs, although somewhat higher thresholds in younger children and a transient rise peripubertally [51]. For younger children, our suggestion for a ULN ALT threshold (30 units/L) is derived from the CALIPER study [52].
●Next steps – Subsequent steps depend on the degree and duration of ALT elevation:
•For those with normal ALT results, repeat screening in one to three years (or sooner in children with increasing obesity or other risk factors), while providing counseling to promote a healthy body weight.
•For those with moderate ALT elevations (ALT >ULN but <80 units/L), repeat the measurement of serum ALT within a few months. If ALT remains elevated, intensify counseling on diet and exercise to achieve weight loss.
•For those with ALT that is persistently >2 × ULN (ie, >44 units/L for adolescent girls and 52 units/L for boys) for three or more months, refer to a gastroenterologist for a full evaluation, as described below.
•Other indications for further evaluation include ALT elevations >80 units/L (on two occasions), signs or symptoms of acute liver disease, or red flags for advanced liver disease, as described below. (See 'Indications' below.)
•For patients with elevated ALT and symptoms of an acute infection (fever, vomiting, diarrhea, pharyngitis, etc), measure ALT again two to four weeks after resolution of the illness to verify if the ALT elevation persists, before initiating further evaluation. Similarly, for asymptomatic patients with more marked acute liver enzyme elevations (>10 × ULN), repeat the test two weeks later rather than initiating a more extensive evaluation. Many viral illnesses, including influenza, Epstein-Barr virus, cytomegalovirus, influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and others, can be associated with mild to marked liver enzyme elevations, and some of these infections can be asymptomatic.
The timing and pace of the evaluation should also be influenced by the presence of other clinical risk factors, such as the degree of obesity, signs of insulin resistance, ethnicity (eg, Hispanic children have higher risk [53]), comorbidities such as type 2 diabetes or obstructive sleep apnea (OSA), or clinical symptoms or signs of more advanced liver disease [54].
●Limitations – Although serum ALT is recommended as the primary screening test for identifying children at higher risk of significant MASLD, it historically has had variable sensitivity and specificity for detecting clinically significant liver disease, depending on the ALT threshold used. In one study of children with overweight and obesity, ALT >2 × ULN had a sensitivity of 88 percent and specificity of 26 percent for detecting NAFLD on liver biopsy [16]. A higher threshold of ALT >80 units/L had a sensitivity of 57 percent and specificity of 71 percent. In a large study of children and adolescents with suspected NAFLD who underwent liver biopsy, fibrosis was seen in 12 percent of those with normal ALT and in 54 percent of those with mildly elevated ALT (defined as ALT 26 to 50 units/L in boys and 23 to 44 units/L in girls) [55]. Advanced fibrosis (bridging fibrosis or cirrhosis) was seen in none of the children with normal ALT, 9 percent of those with mildly elevated ALT, and 15 percent of those with significantly elevated ALT (defined as ALT ≥50 units/L in boys and ≥44 units/L in girls). Thus, the degree of ALT elevation helps to predict the histologic degree of fibrosis.
Ultrasonography — Whether ultrasound should be used as part of screening for MASLD is uncertain. Although ultrasound can detect the presence of hepatic steatosis, indicated by increased echogenicity, the sensitivity and specificity for detecting clinically significant liver disease are poor [9,56,57]. Screening at-risk children with overweight or obesity with ultrasonography was recommended in the 2012 European NAFLD guidelines but not in the 2017 North American guidelines [9,49]. Until further data are available, we do not use ultrasound as a screening tool for MASLD. However, we do include it as part of the further evaluation for individuals with elevated liver enzymes to evaluate for structural abnormalities and to help assess the severity of liver disease [9,19]. (See 'Imaging' below.)
FURTHER EVALUATION
Indications — Indications for further evaluation are (algorithm 1) [9]:
●Alanine aminotransferase (ALT) >2 × upper limit of normal (ULN), ie, >44 units/L for girls or >52 units/L for boys, for more than three months [16].
●ALT >80 units/L on at least two occasions and in the absence of symptoms of acute infection.
●Signs or symptoms suggesting acute liver disease (rather than MASLD), including fever, right upper quadrant tenderness, jaundice, or dark urine (bilirubinuria).
●Signs and symptoms that may indicate advanced liver disease include gastrointestinal bleeding, jaundice, splenomegaly, firm liver edge, enlarged left lobe, encephalopathy manifesting as chronic fatigue and/or declining school performance. In addition, for children with persistently or acutely elevated liver enzymes, the evaluation should include a full liver profile, complete blood cell count, and prothrombin time. Signs of decompensated cirrhosis include low platelets or white blood cell count, elevated direct bilirubin, or elevated international normalized ratio, but this is rare in children with MASLD.
History — Patients with suspected MASLD typically have no symptoms of liver disease. Their symptoms, if any, usually are secondary to complications of obesity (eg, knee/groin pain due to slipped capital femoral epiphysis, intermittent right upper quadrant abdominal pain secondary to gallstones, regurgitation due to gastroesophageal reflux disease, or headaches secondary to increased intracranial pressure). (See "Overview of the health consequences of obesity in children and adolescents".)
In addition, it is particularly important to identify signs and symptoms of the following comorbid conditions, each of which may contribute to the development or worsen the severity of steatotic liver disease:
●Hypothyroidism – Symptoms may include cold intolerance and recent weight gain. In children whose epiphyses have not fused, an important sign is declining height velocity. (See "Acquired hypothyroidism in childhood and adolescence".)
●Obstructive sleep apnea (OSA) – Suggested by persistent snoring, pauses in breathing, nocturnal enuresis, and early morning fatigue or headaches. (See "Evaluation of suspected obstructive sleep apnea in children".)
●Type 2 diabetes – Symptoms may include polyuria, polydipsia, or unexplained weight loss, although many patients are asymptomatic. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents".)
●Depression/anxiety – Mental health issues are prevalent in this population and may affect the patient's ability to implement the recommended lifestyle interventions [58].
●Alcohol and drugs – Evaluate specifically for alcohol use and the possibility of hepatotoxic drugs (especially anticonvulsant medications and certain antimicrobials). (See "Drug-induced liver injury".)
●Family history – Evaluate the family history for liver disease (eg, MASLD/NAFLD, autoimmune conditions, Wilson disease, cryptogenic cirrhosis, or liver transplantation) and cardiometabolic disease (type 2 diabetes, heart disease, or stroke).
Physical examination — The physical examination is focused on identifying the following (table 3):
●Height, weight, and body mass index. (See "Clinical evaluation of the child or adolescent with obesity", section on 'Body mass index'.)
●Risk factors for MASLD (abdominal fat distribution, acanthosis nigricans).
●Signs of comorbid conditions or other causes of hepatic steatosis, including:
•Declining height velocity or delayed or accelerated pubertal development – Suggests hypothyroidism or multiple pituitary hormone deficiencies. (See "Acquired hypothyroidism in childhood and adolescence".)
•Acanthosis nigricans – Suggests insulin resistance, which may be associated with diabetes risk or polycystic ovary syndrome. Hirsutism is another common feature of polycystic ovary syndrome. Unexplained weight loss, sometimes with polyuria and polydipsia, can also be a sign of new-onset diabetes. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)
•Abnormal fat distribution – Loss of subcutaneous adipose tissue, sometimes with apparent accumulation of fat in other regions of the body, raises the possibility of a lipodystrophic syndrome. (See "Lipodystrophic syndromes".)
•Hepatomegaly and/or splenomegaly – Splenomegaly raises the possibility of cirrhosis (with portal hypertension), while hepatosplenomegaly may be secondary to underlying storage disease or lysosomal acid lipase deficiency. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Organomegaly' and 'Tests to exclude other liver diseases' below.)
●Signs suggesting end-stage liver disease (eg, jaundice, palmar erythema, edema, spider angiomata, or asterixis). End-stage liver disease has historically been rare in pediatric patients with MASLD.
●Elevated systolic and diastolic blood pressure, measured with an appropriately sized cuff. (See "Evaluation of hypertension in children and adolescents".)
Laboratory evaluation
Routine laboratory testing
●Complete blood count with differential
●ALT, aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGTP), total and direct bilirubin, albumin
●Evaluation for cardiometabolic risk factors (included in criteria required for diagnosis of MASLD (table 1))
•Hemoglobin A1c and/or fasting glucose
•Fasting lipid panel (triglycerides, total cholesterol, high-density lipoprotein and low-density lipoprotein [LDL] cholesterol)
Testing for additional comorbid conditions — Children and adolescents with MASLD should be screened for other comorbidities associated with overweight and obesity, including dyslipidemia, hypertension, type 2 diabetes, renal impairment, polycystic ovary syndrome, and OSA (table 2). Screening and management are the same as for other children with obesity. However, screening is particularly important in children with MASLD due to the clustering of these comorbidities among children with obesity. (See "Clinical evaluation of the child or adolescent with obesity", section on 'Initial management'.)
An increased prevalence of chronic kidney disease has been associated with NAFLD in children and adults [59,60]. We therefore suggest annual screening with serum blood urea nitrogen and creatinine as well as urine albumin-to-creatinine ratio to detect early injury and allow early intervention [61]. This is particularly relevant for children who have concomitant conditions associated with higher risk of developing chronic kidney disease, including severe obesity, hypertension, and diabetes. (See "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Screening'.)
Although several studies have suggested a risk of decreased bone mineral density in children with NAFLD, particularly those with nonalcoholic steatohepatitis (NASH), the degree of reduction is mild and of unclear long-term clinical significance [62]. Therefore, we do not recommend routine dual-energy x-ray absorptiometry screening for osteopenia.
Tests to exclude other liver diseases — The differential diagnosis of moderate aminotransferase elevations with evidence of steatotic liver on imaging is outlined in the table (table 4). Testing is recommended because some of these disorders require specific treatment, including celiac disease, autoimmune hepatitis, hemochromatosis, viral hepatitis, and Wilson disease. Particularly in younger children (<5 years of age) or in those without overweight or obesity, there should be increased suspicion for causes other than MASLD, such as inborn errors of metabolism.
The yield of screening for these disorders has historically varied in different cohorts of children with NAFLD. In a cohort of 900 children referred for suspected NAFLD, only 2 percent were diagnosed with another disorder that caused or contributed to the liver disease [63]. Substantially higher yield was found in a separate single-center cohort, in which the prevalence of alternate diagnoses was 18 percent, most commonly autoimmune hepatitis (4 percent) [16]. Future studies using the new definitions of MASLD will be needed to determine the prevalence of alternate diagnoses.
For all patients with persistent elevations in ALT >2 × ULN, we suggest the following tests (algorithm 1):
●Viral hepatitis – Anti-hepatitis C antibodies, hepatitis B surface antigen, and tests for other chronic viral infections if indicated by the history.
●Celiac disease – Tissue transglutaminase and total immunoglobulin A (IgA). (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Non-gastrointestinal manifestations'.)
●Hypothyroidism – Thyrotropin and free thyroxine.
●Autoimmune hepatitis – Anti-nuclear antibodies, anti-liver/kidney microsomal antibodies, anti-smooth muscle antibodies, and total protein and IgG level. Of note, positive serum autoimmune antibodies have been reported in approximately 20 percent of children and adults with NAFLD [64-66]. Therefore, low-positive titers (eg, anti-nuclear antibodies 1:40) do not exclude the diagnosis of MASLD, but patients with high-positive titers should be further evaluated for the possibility of autoimmune hepatitis [10]. High globulins or increased total protein-to-albumin ratio also support the possibility of autoimmune hepatitis. (See "Overview of autoimmune hepatitis".)
●Wilson disease – The minimum screen for Wilson disease is to measure serum ceruloplasmin levels. In addition, for patients with signs or symptoms that increase suspicion for this disorder (eg, low ceruloplasmin, marked elevations in AST and ALT, especially with elevated AST:ALT ratio, or neurologic or psychiatric symptoms), include a 24-hour urine collection for copper excretion. If performing a liver biopsy, a hepatic tissue concentration of copper can be quantified. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)
●Alpha-1 antitrypsin deficiency – Screen for this disorder by measuring serum alpha-1 antitrypsin levels or "PI" typing/phenotype. PI phenotypes associated with liver disease are ZZ or SZ. Heterozygotes (MZ or MS) do not have overt alpha-1 antitrypsin-related liver disease, but the genotype may contribute to the severity of their MASLD [67,68]. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)
●Monogenetic liver diseases associated with hepatic steatosis – For selected patients, such as those with early onset of liver disease (eg, preschool age), evidence of steatotic liver in the context of a lean phenotype, significant dyslipidemia, or other atypical features, we also screen for the following conditions:
•Lysosomal acid lipase deficiency (cholesteryl ester storage disease; MIM #278000) – Screen for this disorder in any patient with hepatosplenomegaly, prepubertal evidence of advanced liver fibrosis or cirrhosis, xanthelasma, or family history of unexplained hepatic dysfunction or early-onset cardiovascular disease [69-74]. Due to the steatotic liver, some patients with lysosomal acid lipase deficiency are misdiagnosed as having MASLD or another storage disease (Gaucher or Niemann-Pick). Patients with lysosomal acid lipase deficiency tend to have greater elevations of serum LDL compared with patients with MASLD and develop premature atherosclerosis [69].
Lysosomal acid lipase deficiency can be diagnosed using an enzyme-based biochemical test [75]. A list of laboratories that perform this test can be accessed through the Genetic Testing Registry website. Treatment with sebelipase alfa leads to improved aminotransferases, hepatic steatosis, and lipid profiles, and the drug is now approved for use in the United States and several other countries [76-81].
A fulminant infantile form, known as Wolman disease, is characterized by hepatosplenomegaly, hepatic fibrosis, failure to thrive, and adrenal calcifications or insufficiency. (See "Causes of primary adrenal insufficiency in children", section on 'Defects in cholesterol biochemistry'.)
•Abeta/hypobetalipoproteinemia (MIM #615558, MIM #605019) – These disorders are suggested by the findings of low triglycerides and undetectable or low LDL on a lipid profile; other laboratory findings include low fat-soluble vitamin levels (due to fat malabsorption) [82]. Abetalipoproteinemia (MIM #200100) typically presents in infancy with more severe symptoms including steatorrhea, failure to thrive, and progressive neurologic complications; this would be an unlikely cause of steatotic liver in an older child with obesity. If the results of these tests are concerning for these conditions, lipoprotein electrophoresis or genetic testing can be used to confirm the diagnosis. A list of laboratories that perform these tests can be accessed through the Genetic Testing Registry website. (See "Low LDL-cholesterol: Etiologies and approach to evaluation".)
•Lipodystrophy (MIM #608594, MIM #151660, MIM #269700) – When lipodystrophy is suspected based on physical examination findings of abnormal fat distribution and steatotic liver in the context of a lean body habitus, insulin resistance, and dyslipidemia, refer to genetics for further workup. (See "Lipodystrophic syndromes".)
●Monogenic obesity – For patients with marked hyperphagia and/or early-onset (eg, in infancy) severe (class II to III) obesity, genetic testing for monogenic causes of obesity may be appropriate. Though not a specific cause of MASLD, these patients may be at higher risk of MASLD and the genetic diagnosis may inform treatment options. (See "Clinical evaluation of the child or adolescent with obesity", section on 'Tests for selected patients'.)
A general approach to evaluating a patient with abnormal liver biochemistries is presented separately. (See "Approach to the patient with abnormal liver biochemical and function tests".)
Imaging
●Ultrasound – We suggest performing liver ultrasound as part of the full evaluation in a child with chronically elevated liver enzymes. The main purpose is to evaluate for liver or biliary abnormalities, particularly if the history and physical examination suggest the presence of gallbladder disease or complications such as portal hypertension (eg, splenomegaly).
●Magnetic resonance imaging (MRI) – MRI provides a more accurate quantitative measure of steatosis than does ultrasound, particularly in individuals with severe obesity [83-85]. However, it is not useful for screening for clinically important MASLD, because the severity of hepatic steatosis does not correlate with clinical features of advanced MASLD (eg, presence of steatohepatitis, fibrosis, etc) [42,56,86,87].
●Methods to assess fibrosis severity
•Vibration-controlled transient elastography (eg, FibroScan) – This point-of-care ultrasound technique shows some promise in noninvasively assessing the severity of hepatic steatosis and fibrosis [88-92]. However, the technique has limited ability to distinguish between early stages of the disease and further validation studies are needed to determine its accuracy in pediatric cohorts diagnosed using MASLD criteria.
-Hepatic steatosis is reflected in the Controlled Attenuation Parameter (CAP) score. In a study of children with biopsy-confirmed NAFLD, a CAP score of ≥259 strongly correlated with steatosis grade (area under the curve 0.98 for distinguishing any steatosis from no steatosis) [88].
-Hepatic fibrosis is correlated with measures of liver stiffness (in kPA). In a North American cohort of 116 children with NAFLD, liver stiffness differentiated those with Ishak stage fibrosis 0 to 2 from those with stages 3 to 6 (area under the curve 0.70) [92].
•Ultrasound shear wave elastography – Ultrasound-based (eg, acoustic radiation force impulse) shear wave elastography correlates with significant fibrosis in pediatric patients with NAFLD, but this modality is limited by higher technical failure rates in patients with obesity [89].
•Magnetic resonance elastography – This is a noninvasive approach to evaluate liver stiffness. It can detect advanced fibrosis, with overall accuracy of 89 to 90 percent, negative predictive value of 95 to 96 percent, and positive predictive value of 29 to 30 percent [93-95]. However, the technique is not able to discriminate well between no fibrosis versus mild fibrosis and its ability to detect inflammation has not been established [96]. Further, high cost, lack of widespread availability, and need for further validation of appropriate cutoff values render it inappropriate for routine screening of MASLD [93].
These tools may also be useful noninvasive measures to follow disease progression [94] but require further validation in longitudinal cohort of children with MASLD to determine optimum thresholds for detecting progression in fibrosis, as well as optimal populations, as some of the techniques have higher failure rates as severity of obesity worsens. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Radiographic examinations'.)
Liver biopsy
●Indications – Indications for liver biopsy in patients with suspected MASLD have not been established, and practice varies.
•Arguments in favor of performing a liver biopsy are that it is the most accurate approach to assess severity, particularly the presence and extent of inflammation and fibrosis [3,9]. If the liver biopsy identifies metabolic dysfunction-associated steatohepatitis (MASH), more intensive weight loss interventions (eg, consideration of obesity pharmacotherapy or weight loss surgery) and close monitoring are warranted. Furthermore, the liver biopsy is sometimes required to identify an alternate cause, such as autoimmune hepatitis or drug-induced liver injury.
•Arguments against liver biopsy are that it is invasive and the results most often confirm the presence of MASLD and do not inform management, because there is no approved treatment for MASLD other than weight loss interventions.
Therefore, the decision about whether to perform a liver biopsy should be made on a case-by-case basis, after discussion of the benefits and risks with the patient and their family. In our practice, we generally suggest a liver biopsy for patients with the following features:
•Clinical features that are associated with more severe or progressive liver disease, such as ALT persistently >80 units/L or splenomegaly, thrombocytopenia, or increased liver stiffness by elastography, particularly in patients with prediabetes or diabetes or significant dyslipidemia.
•Patients with severe obesity who are candidates for weight loss surgery but are undecided about whether to proceed. (See "Surgical management of severe obesity in adolescents".)
•Patients with features that suggest an alternate or additional cause of the liver disease for which liver biopsy would be useful or essential to confirm the diagnosis (such as autoimmune hepatitis).
(See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
●Interpretation of results – If biopsy is performed, the histologic features of MASLD include steatosis, which, if concurrently present with lobular or portal inflammation and ballooning degeneration of hepatocytes, is consistent with MASH. Fibrosis indicates more significant disease, particularly if stage 2 or higher (picture 1). Cirrhosis has been rare in pediatric NAFLD studies.
Compared with older adolescents or adults, children in the early phases of puberty often display unique histopathologic features, including portal inflammation and portal fibrosis in the absence of hepatocellular ballooning; this histologic pattern has historically been called "type 2" or borderline zone 1 NASH, while the pattern typically seen in adults (steatosis with lobular inflammation and ballooning degeneration) has been called "type 1" or definite NASH (table 1) [10,97,98].
DIAGNOSIS — Diagnosis and categorization of MASLD involves these steps:
●MASLD should be suspected in a child with typical clinical features (obesity or cardiometabolic risk factors) and evidence of steatosis by imaging or biopsy.
●In children with one or more of the above features, a diagnosis of MASLD can be made by excluding other causes of liver disease through a focused history, physical examination, and laboratory/imaging evaluation.
●A definitive diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) can only be made by liver biopsy, but this is not always necessary for clinical management (see 'Liver biopsy' above). The decision to perform a liver biopsy depends on the degree and persistence of alanine aminotransferase (ALT) elevation and whether there are any atypical features that raise the possibility of another form of liver disease.
MANAGEMENT — Available data on management and outcomes was derived from studies of children diagnosed with NAFLD or nonalcoholic steatohepatitis (NASH).
Weight loss-focused approaches — Weight management has been the only established treatment for NAFLD and the primary treatment recommendation in guidelines from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the American Gastroenterological Association [9,10] Small nonrandomized studies in children with NAFLD have shown improvement in liver histology or aminotransferase activity after weight loss [3,44,99-101]. We anticipate that weight management approaches will also remain the foundation for treatment of MASLD in children, with the addition of adjunctive medications and/or weight loss surgery to help achieve a healthier metabolic status.
●Diet and exercise – The main approach is lifestyle modification, with emphasis on dietary changes, which can result in improvement of the steatotic liver disease as well as reduction in excess weight. No particular diet has been clearly shown to be superior to any other in the treatment of NAFLD, although avoidance of sugar-sweetened beverages is often recommended, based on supportive studies [9]. One open-label, randomized trial in a cohort of 40 adolescent males, predominantly Hispanic (95 percent), reported that a diet with low free sugars for eight weeks resulted in greater reduction in hepatic fat compared with usual diet (adjusted mean difference -6.23 percent, 95% CI -9.45 to -3.02) [102]. It is possible that these effects were mediated, in part, by weight loss since the subjects on the low-sugar diet lost more weight during the study compared with those consuming their usual diet (mean between-group difference -2 kg, 95% CI -3.3 to -0.8 kg). Notably, this differential weight loss in the intervention group occurred despite the fact that the intervention diet only restricted free sugar intake to <3 percent of daily caloric intake but did not restrict total energy intake (in kcal), which did not decrease significantly during the eight-week period in the intervention group. Because the prescribed foods were given to the household during the study, these findings may not be generalizable to other populations treated with dietary counseling alone.
Weight loss and/or weight maintenance in younger children are difficult to achieve but tend to be enhanced by family-based and patient-centered approaches and more intensive interventions [103]. These strategies are discussed separately. (See "Prevention and management of childhood obesity in the primary care setting".)
Physical activity can be beneficial in reducing adiposity and improving body composition (reducing risk of relative sarcopenia, which has been associated with NAFLD severity). Similar to dietary changes, no type of exercise has been demonstrated to be superior in this context, but pediatric studies have been limited. In one study, physical activity improved NAFLD (as measured by alanine aminotransferase [ALT] elevations), independent of weight loss [104]. Activity targets are similar to those for weight management and include promoting unstructured and structured physical activity and limiting screen time. (See "Prevention and management of childhood obesity in the primary care setting", section on 'Counseling'.)
●Surgery – Weight loss surgery may be appropriate in selected adolescents with severe obesity [10]. Surgically induced weight loss improves NAFLD in adults (resolution rates of up to 90 percent), and observational evidence suggests that this is also true for adolescents. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Bariatric surgery' and "Surgical management of severe obesity in adolescents", section on 'Comorbidity improvement'.)
●Medications that target weight loss and metabolic improvement – Medications that target weight loss are increasingly available and may have indirect benefits on MASLD. These include glucagon-like peptide 1 receptor (GLP-1) agonists (also approved for use in adolescents with type 2 diabetes) and phentermine-topirimate, which have not been studied as specific treatments for NAFLD or MASLD in youth but have shown benefit in studies in adults with NAFLD. The evidence and other considerations are discussed separately. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Potential pharmacologic therapies' and "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy'.)
Pharmacotherapy — No medications are recommended for routine treatment of MASLD in children [9]. Several pharmacologic approaches have been investigated in children with NAFLD including vitamin E, metformin, cysteamine bitartrate, and losartan [105]. In clinical trials, none of these have shown a convincing advantage over lifestyle intervention alone [106,107].
●Suggested for selected patients:
•Vitamin E – Vitamin E has a limited role in management of MASLD, based on indirect evidence that it has beneficial effects on some serologic and histologic markers of NAFLD but that prolonged high-dose treatment might be associated with adverse health outcomes in adults. In the absence of specific recommendations from guidelines [9,10], we suggest the following approach:
-For most patients who have not had liver biopsy or for those with steatosis alone (minimal inflammation), we do not advise treatment with vitamin E.
-For patients with biopsy-proven steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH] with or without fibrosis) who are not improving with lifestyle intervention recommendations and other weight loss treatments (eg, GLP-1 receptor agonists or weight loss surgery), we suggest a trial of vitamin E treatment in conjunction with lifestyle changes (see 'Weight loss-focused approaches' above). The decision to treat with vitamin E is made on a case-by-case basis, after a discussion of the potential benefits and risks with the patient and family. Lifestyle modification should continue whether or not vitamin E is initiated as an adjunctive treatment. Some patients may reasonably choose to defer vitamin E treatment, given the uncertainty of clinical benefit in children.
-If treatment with vitamin E is undertaken, we suggest a dose of 800 units daily (typically given as 400 units twice daily for children <18 years). Patients should be monitored for response using serial measurements of ALT (every three months) and treatment continued only if there is evidence of response, with a significant, sustained decline in ALT (eg, at least a 50 percent decline in ALT during the first three to six months). Vitamin E is continued for up to two years. A repeat liver biopsy should be considered at the end of a two-year treatment cycle as this is the only way to assess histologic response to vitamin E and determine if there is any benefit to continuing the treatment long term. Two-year trials of vitamin E in children and adults with NAFLD reported no associated safety risks; however, the long-term safety of high-dose vitamin E in children with NAFLD/MASLD has not been established.
The main evidence supporting vitamin E treatment comes from a multicenter randomized trial that included 173 children and adolescents with biopsy-proven NAFLD [6]. This study found no benefit from vitamin E (800 units daily for two years) on the primary outcome of serum aminotransferase levels. However, in a subset of 121 children with NASH, significantly more children had histologic resolution of steatohepatitis after 96 weeks of treatment with vitamin E compared with placebo (58 versus 21 percent, p<0.01). No significant risks were noted during the two years of the trial. Randomized trials and observational studies in adults also suggest some benefits of vitamin E on markers of NAFLD [108,109]. However, indirect and limited evidence from observational studies in adults suggests an association between high-dose vitamin E and risk of all-cause mortality, cardiovascular events, and prostate cancer. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Patients with NASH but without diabetes' and "Overview of vitamin E", section on 'Potential risks'.)
Another report suggests that vitamin E leads to significant reductions in ALT (>50 percent from baseline or normalization) in 38 percent of children with NASH in a "real-world" setting [110].
•Medications that target weight loss – Medications that target weight loss are discussed above and may lead to subsequent improvement in MASLD and MASH, though MASLD/MASH outcomes in pediatric clinical trials are largely lacking. (See 'Weight loss-focused approaches' above and "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy'.)
●Not effective for MASLD:
•Metformin – Metformin was not effective for treatment of NAFLD and is not recommended for this purpose. In the multicenter trial described above, metformin (1000 mg daily) was no more effective than placebo for outcomes of ALT elevation or histologic features of MASLD [6]. However, metformin is a first-line treatment for adolescents with type 2 diabetes. (See "Management of type 2 diabetes mellitus in children and adolescents".)
•Cysteamine bitartrate – In a multicenter, placebo-controlled, randomized trial in 169 children with biopsy-confirmed steatohepatitis, treatment with cysteamine bitartrate delayed-release for one year resulted in significant reductions in serum aminotransferase levels and lobular inflammation but no overall reduction in histologic markers of NAFLD severity, compared with placebo [7].
•Losartan – Losartan, an angiotensin II receptor blocker used for the treatment of hypertension, was ineffective in reducing the ALT of children and adolescents with histologically confirmed NAFLD (dose studied was 100 mg daily for 24 weeks) [105].
•Other – Ursodeoxycholic acid, probiotic supplements, and omega-3 fatty acid supplements have not been shown to be effective for NAFLD in adults [9,10]. No robust clinical trials have evaluated these interventions in children.
Experience with the use of these and other drugs in adults with MASLD is discussed separately. (See "Management of nonalcoholic fatty liver disease in adults".)
Other counseling
●Alcohol and smoke exposure – Children and adolescents with MASLD should be counseled that alcohol consumption may exacerbate liver disease. Thresholds for "safe" alcohol consumption in patients with MASLD are unclear, but binge drinking or heavy alcohol use is associated with progressive disease in adults. Patients and families should also be counseled against smoking and secondhand smoke exposure [9].
●Immunizations – The clinician should ensure that the patient has been immunized against hepatitis A and B by reviewing immunization records or performing serologic testing and providing immunization as needed. Because both obesity and liver disease are associated with higher risk of severe coronavirus disease 2019 (COVID-19) infection, COVID-19 vaccination should be especially encouraged for people with MASLD. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Risk factors' and "COVID-19: Vaccines".)
●Sleep habits and symptoms – Sleep quality/duration is associated with obesity and response to weight loss efforts. Accordingly, we suggest counseling regarding age-appropriate sleep habits in addition to other guidance to support weight control. (See "Prevention and management of childhood obesity in the primary care setting" and "Behavioral sleep problems in children".)
Obstructive sleep apnea (OSA) is associated with MASLD and liver fibrosis. Accordingly, children with symptoms suggesting OSA (eg, persistent snoring or mouth-breathing) should be further evaluated for OSA. If OSA is present, treatment may improve MASLD severity, although evidence is inconsistent [111,112]. (See "Evaluation of suspected obstructive sleep apnea in children".)
Follow-up — Weight management is most successful with frequent follow-up, support, and reinforcement of healthy habits. Body weight, body mass index, and lifestyle habits should be reviewed at each visit. New comorbid conditions can emerge over time, particularly if the obesity persists or worsens; therefore, screening should be done at minimum annually (table 2).
We suggest serial ALT monitoring every three to six months for patients with MASLD, especially if actively working on lifestyle modification or undergoing other treatments. We suggest annual monitoring of ALT in patients with liver steatosis alone on imaging/biopsy but with no history of liver enzyme elevations or evidence of fibrosis (on biopsy or by imaging).
This is similar to the historical approach to monitoring patients with NAFLD. In clinical trials, improvement in ALT of >50 percent or complete normalization of ALT were often used as surrogate markers of improvement or resolution, respectively, because these outcomes have been associated with histologic improvement in liver disease severity in several studies [39]. However, changes in ALT should be interpreted in conjunction with the information obtained from the patient's history and physical examination.
In patients with MASH or advanced fibrosis on initial liver biopsy, or with onset of new, significant risk factors such as type 2 diabetes, we generally consider a repeat liver biopsy two to three years after diagnosis [9] to evaluate disease progression, given the limitations of noninvasive tests in children. Repeat liver biopsy may also be useful to evaluate response following intensification of treatment, such as weight loss surgery, although practice varies.
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: Nonalcoholic fatty liver disease" and "Society guideline links: Obesity in children" and "Society guideline links: Diabetes mellitus in children".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Categories of steatotic liver disease associated with metabolic dysfunction are (table 1) (see 'Definitions' above):
•Metabolic dysfunction-associated steatotic liver disease (MASLD) – MASLD is the overarching term for steatotic liver disease (>5 percent hepatic steatosis) with at least one risk factor for cardiometabolic dysfunction including overweight/obesity, dysglycemia, or dyslipidemia and no other cause of steatotic liver disease. This category includes individuals who would previously have been given a diagnosis of nonalcoholic fatty liver disease (NAFLD; defined by chronically elevated liver enzymes, hepatic steatosis, and absence of other causes) but also includes individuals with evidence of steatosis but without elevated liver enzymes.
•Metabolic dysfunction-associated steatohepatitis (MASH) – MASH refers to MASLD with inflammation and hepatocellular injury, such as ballooning of hepatocytes, with or without fibrosis. This category was formerly called nonalcoholic steatohepatitis (NASH), and histologic criteria remain the same.
•MASH with fibrosis or cirrhosis – Advanced fibrosis or cirrhosis with current or previous histologic evidence of MASLD or MASH.
•Metabolic and increased alcohol intake – MASLD with a history of increased alcohol use; it may be MASLD predominant or alcohol-related liver disease predominant depending on range of alcohol intake. This is a new category that recognizes that steatotic liver disease can involve a combination of metabolic dysfunction and alcohol. It does not include individuals with alcohol-related liver disease.
●Risk factors and clinical presentation – By definition, MASLD is strongly associated with obesity and associated cardiometabolic risk factors. Predictors of more advanced disease among children with MASLD remain to be established but probably include insulin resistance, prediabetes/diabetes, and Hispanic ethnicity. Similar to NAFLD, many children with MASLD are likely to have signs or symptoms of other obesity-related comorbidities (table 2). (See 'Epidemiology' above and 'Clinical presentation' above.)
●Screening
•Indications – We suggest screening for MASLD for all children with obesity (body mass index ≥95th percentile), as well as for those who are overweight (body mass index ≥85th percentile) and have other risk factors (eg, signs of insulin resistance or a family history of MASLD) (Grade 2C) (algorithm 1). Screening should be initiated between 9 and 11 years. (See 'Screening' above.)
•Method – We screen for MASLD by measuring serum alanine aminotransferase (ALT) to detect children at higher risk of more significant liver disease. Under prior diagnostic criteria for NAFLD, most children had liver enzymes >2 times the upper limit of normal (ULN), but some had more markedly elevated liver enzymes (but rarely >5 times the ULN). There is insufficient evidence to recommend universal screening of at-risk children by imaging modalities, outside of research studies. (See 'Screening' above.)
●Further evaluation – Patients with suspected MASLD and persistent elevations of serum ALT (>2 times the ULN for >3 months) should be further evaluated to exclude other causes of liver disease through a focused history, physical examination, and laboratory evaluation (algorithm 1). The timing and extent of the evaluation depends on the degree of ALT elevation and whether any atypical features are present. (See 'Further evaluation' above.)
●Diagnosis – A provisional diagnosis of MASLD can be made by excluding other causes of liver disease through a focused clinical evaluation (table 4). A definitive diagnosis of MASH can only be made by liver biopsy, but this is not always necessary for initial clinical management. Histologic assessment of severity of disease can help guide therapeutic decisions such as whether to treat with vitamin E or to intensify weight management approaches, including considering weight loss medications or weight loss surgery for selected patients with more advanced disease. (See 'Liver biopsy' above and 'Diagnosis' above.)
●Management
•Weight loss – The mainstays of treatment for MASLD are interventions to reduce overweight and obesity. The first-line approach in youth is counseling directed at improving diet (reduction in added sugars and ultraprocessed foods) and exercise habits (increasing moderate to vigorous activity). These interventions can reduce visceral adiposity and hepatic steatosis, as well as provide other general health benefits and also may be beneficial for individuals with MASLD but without obesity. Weight loss surgery or obesity-directed pharmacotherapy (eg, a glucagon-like peptide 1 [GLP-1] receptor agonist) may be appropriate for selected adolescents with moderate or severe obesity, especially if liver biopsy shows evidence of advanced MASLD. (See 'Weight loss-focused approaches' above.)
•Pharmacotherapy – Vitamin E has a limited role in management of MASLD. For patients with biopsy-proven MASH (with or without fibrosis) who have not improved with lifestyle interventions alone and who are not candidates for other weight loss treatments (eg, GLP-1 receptor agonists or weight loss surgery), we suggest a trial of vitamin E (Grade 2C). If serum ALT improves, we continue vitamin E for a period of up to two years. Limited evidence suggests that high-dose vitamin E improves some markers of MASH but that long-term treatment may be associated with adverse cardiovascular outcomes. Vitamin E does not play a role in management for patients who have not had liver biopsy or for those with steatosis alone (minimal inflammation). (See 'Pharmacotherapy' above.)
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