NAFLD / MASLD Rare and Atypical Presentations: What Clinicians Miss

Why Atypical Presentations of MASLD Get Missed

Standard clinical screening for MASLD targets patients with obesity, type 2 diabetes, or dyslipidemia. That approach captures the majority but systematically excludes presentations that fall outside the metabolic-syndrome template. A 2023 global meta-analysis of 72 studies (N = 1,030,160) estimated worldwide MASLD prevalence at 32.4%, yet the subgroups discussed below are frequently underrepresented in both clinical awareness and published trials. [1]

The Nomenclature Shift and Why It Matters

In 2023, an international multi-society consensus panel replaced "NAFLD" with "MASLD" (metabolic dysfunction-associated steatotic liver disease) and introduced "MetALD" for patients with significant alcohol intake alongside metabolic risk. [2] The new framework requires at least one of five cardiometabolic criteria for the MASLD label. Patients who do not meet any criterion fall into a residual category called "cryptogenic SLD," which itself constitutes a rare and diagnostically challenging group.

Understanding this taxonomy prevents misclassification. A patient labeled cryptogenic SLD deserves a different workup than one labeled MASLD, including evaluation for genetic and autoimmune causes.

Epidemiological Blind Spots

Registry data tend to over-represent patients referred from gastroenterology or endocrinology clinics. Primary care cohorts show higher proportions of lean and asymptomatic MASLD than specialty cohorts do. A 2019 population-based study from the UK Biobank (N = 336,439) found steatosis on imaging in 21% of participants, and approximately 19% of those had a BMI below 25 kg/m². [3]

Lean MASLD: The Most Clinically Underrecognized Phenotype

Lean MASLD is defined as MASLD occurring in individuals with a BMI <25 kg/m² (or <23 kg/m² in Asian populations). Prevalence estimates range from 7% to 20% of all MASLD cases, depending on the population studied. Despite lower adipose mass, these patients often carry visceral adiposity, insulin resistance, and fibrosis rates that rival those in obese cohorts. [4]

Pathophysiology in Lean Patients

Lean MASLD does not simply reflect a milder disease. A 2020 meta-analysis published in the Journal of Hepatology (34 studies, N = 93,666) found that lean NAFLD patients had lower rates of metabolic comorbidities than obese patients but similar or higher liver-related mortality when matched for fibrosis stage. [5] The mechanistic basis appears to involve impaired adipose expandability, ectopic lipid deposition in the liver and muscle, and heightened mitochondrial oxidative stress.

Several genetic variants amplify lean MASLD risk. The PNPLA3 rs738409 (I148M) variant is overrepresented in lean MASLD cohorts and correlates with accelerated fibrosis progression independent of BMI. TM6SF2 rs58542926 carries a similar signal. [6]

Diagnostic Pitfalls in Lean MASLD

Because lean patients do not trigger metabolic-syndrome screening algorithms, their steatosis often surfaces incidentally on abdominal imaging ordered for unrelated reasons. Liver enzymes may be normal: a retrospective cohort study (N = 458) reported that 40% of biopsy-confirmed lean NAFLD patients had persistently normal ALT. [7]

Clinicians should consider non-invasive fibrosis staging with FIB-4 and vibration-controlled transient elastography (VCTE) in any patient with incidental steatosis, regardless of BMI. The AASLD 2023 Practice Guidance recommends FIB-4 as the first-line risk-stratification tool for all patients with suspected steatotic liver disease. [8]

Management Differences

Weight-loss targets differ for lean MASLD. The conventional goal of 7 to 10% body weight reduction to improve histology is difficult to apply when a patient's BMI is already 22 kg/m². Dietary quality (Mediterranean pattern) and aerobic exercise each improve hepatic steatosis independent of weight loss in this subgroup. [9] GLP-1 receptor agonists have not yet been specifically validated in lean MASLD trials, though post-hoc analyses of the LEAN trial and SUSTAIN-6 suggest benefit.

Pediatric and Adolescent MASLD

MASLD in children is not simply a smaller version of adult disease. The global prevalence in children is approximately 7.6%, rising to 34% in obese youth. [10] The histological pattern differs: pediatric MASLD (formerly called "type 2 NASH") tends to show periportal rather than centrilobular inflammation and ballooning, which can confuse pathologists using adult scoring systems.

Age-Specific Risk Factors

Intrauterine metabolic programming matters. Children born to mothers with gestational diabetes have a measurably higher prevalence of hepatic steatosis by age 10, independent of childhood BMI. [11] Fructose intake from sugar-sweetened beverages is a particularly potent driver in adolescents, mediated through de novo lipogenesis.

Boys are disproportionately affected in the pediatric age group. A multicenter NASH CRN study (N = 519 biopsy-confirmed pediatric NAFLD patients) found that males accounted for 67% of cases, and Hispanic ethnicity was associated with more severe histological scores. [12]

Diagnostic Approach in Children

The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommends ALT screening in children with obesity (BMI >95th percentile) starting at age 9. [13] ALT thresholds for children differ from adult ranges: the upper limit of normal is approximately 22 U/L for girls and 26 U/L for boys by Prati criteria.

Liver biopsy remains the gold standard for pediatric staging, because non-invasive scores validated in adults (e.g., NAFLD fibrosis score, FIB-4) perform less reliably in children. MRI proton density fat fraction (MRI-PDFF) offers the most accurate non-invasive steatosis quantification in pediatric cohorts. [14]

Long-Term Trajectory

Pediatric MASLD can progress to cirrhosis before adulthood. A landmark 2006 autopsy study by Schwimmer et al. Found steatosis in 9.6% of children aged 2 to 19 years at postmortem examination, with fibrosis present in a subset, indicating that advanced liver disease in children is not as rare as once assumed. [15]

Cryptogenic Cirrhosis as a MASLD Endpoint

Cryptogenic cirrhosis (CC) is cirrhosis with no identifiable cause after standard workup. MASLD is now the leading candidate for the majority of CC cases. Population-based estimates suggest MASLD accounts for 30 to 75% of cryptogenic cirrhosis, depending on the cohort and how rigorously other causes are excluded. [16]

Why MASLD "Burns Out"

As cirrhosis develops, hepatic fat content often decreases, ALT normalizes, and BMI may fall due to sarcopenia and malnutrition. This phenomenon, sometimes called "burned-out NASH," erases the metabolic fingerprints that would otherwise point toward MASLD as the underlying etiology.

A retrospective cohort from the Mayo Clinic (N = 70) found that 60% of patients with cryptogenic cirrhosis had historical evidence of obesity or type 2 diabetes when medical records were reviewed systematically, compared with only 31% identified at initial cirrhosis evaluation. [17] Careful metabolic history-taking, review of prior imaging, and genetic testing for PNPLA3 and TM6SF2 variants may recover the MASLD diagnosis in cases initially labeled cryptogenic.

Clinical Implications

Patients with burned-out NASH/MASLD cirrhosis carry a high hepatocellular carcinoma (HCC) risk even without cirrhosis. A 2019 analysis from the SEER-Medicare database found that NAFLD-related HCC incidence increased 9% per year between 2004 and 2016, and a meaningful proportion arose in patients without documented cirrhosis. [18] Biannual liver ultrasound surveillance should be applied to any patient with MASLD-related cirrhosis, and individualized risk assessment should guide surveillance in those with advanced fibrosis but not yet cirrhosis.

Extrahepatic and Cardiac-Dominant MASLD Presentations

Cardiovascular disease, not liver failure, is the leading cause of death in MASLD patients. A 2021 meta-analysis (17 studies, N = 7,629,048) found that MASLD independently raised the risk of major adverse cardiovascular events (MACE) by 63% compared with matched controls. [19] In some patients, cardiac manifestations precede overt liver symptoms.

MASLD and Atrial Fibrillation

A bidirectional relationship between MASLD and atrial fibrillation (AF) has been described. A 2020 meta-analysis (11 studies, N = 93,197) reported that MASLD was associated with a 34% higher odds of incident AF, independent of obesity, hypertension, and sleep apnea. [20] Clinicians evaluating new-onset AF in a lean or apparently low-risk patient should consider metabolic liver disease as a contributing factor.

Subclinical Atherosclerosis

MASLD correlates with higher carotid intima-media thickness (CIMT), coronary artery calcium (CAC) scores, and endothelial dysfunction, even after adjustment for traditional Framingham risk factors. The MESA cohort demonstrated that hepatic steatosis on CT was independently associated with incident coronary heart disease events over a 7.6-year follow-up. [21]

Cardiac Autonomic Dysfunction

An underappreciated MASLD complication is cardiac autonomic neuropathy. Heart rate variability indices are reduced in MASLD patients compared with metabolically matched controls, and the degree of reduction tracks with histological severity. [22] This autonomic dysfunction may partly explain the excess sudden cardiac death risk observed in population cohorts.

MASLD in Specific Populations: Sex, Ethnicity, and Genetics

Sex-Based Differences

Premenopausal women appear to have lower MASLD prevalence than age-matched men, likely due to estrogen's favorable effects on lipid metabolism and adipokine signaling. After menopause, female MASLD prevalence rises sharply and approaches male rates. A cross-sectional analysis (N = 3,402) found postmenopausal women had a 1.8-fold higher odds of MASLD than premenopausal women after adjustment for age and BMI. [23]

Women with polycystic ovary syndrome (PCOS) represent a high-risk atypical subgroup. MASLD prevalence in PCOS ranges from 35% to 70% across published series, driven by insulin resistance and androgen excess independent of BMI. [24]

Ethnicity and the Hispanic Paradox

Hispanic individuals, particularly those of Mexican ancestry, have higher MASLD prevalence and severity than non-Hispanic whites at the same BMI, largely attributable to higher PNPLA3 I148M allele frequency. Black Americans have lower MASLD prevalence than Caucasians despite higher rates of obesity, a discrepancy that is not fully explained but may involve APOC3 and adiponectin variation. [25]

Monogenic and Rare Genetic Causes of Steatotic Liver Disease

Several monogenic disorders produce hepatic steatosis that mimics MASLD clinically and histologically. Recognizing these is essential because their management differs fundamentally:

• Familial hypobetalipoproteinemia (FHBL): Mutations in APOB cause low LDL-C and hepatic fat accumulation. Total cholesterol below 130 mg/dL in a patient with steatosis should prompt genetic testing.
• Lysosomal acid lipase deficiency (LAL-D): Presents with dyslipidemia, hepatomegaly, and steatohepatitis. Diagnosis requires LAL enzyme activity assay on dried blood spot. Sebelipase alfa (FDA-approved 2015) is the specific treatment. [26]
• Abetalipoproteinemia: Absence of apoB-containing lipoproteins leads to fat malabsorption and hepatic steatosis; neurological and retinal findings distinguish it from MASLD.
• Wilson disease: Hepatic copper accumulation can produce steatosis and elevated transaminases in young adults; serum ceruloplasmin and 24-hour urinary copper should be checked in any patient under 40 with unexplained steatohepatitis.

The American Association for the Study of Liver Diseases (AASLD) 2023 Practice Guidance states: "In patients with SLD who do not meet any cardiometabolic criteria, evaluation for secondary and genetic causes of hepatic steatosis is warranted." [8]

Drug-Induced and Secondary Steatotic Liver Disease Masquerading as MASLD

A range of medications and systemic conditions produce steatosis that is histologically indistinguishable from MASLD on biopsy. Recognizing drug-induced steatohepatitis (DISH) prevents unnecessary lifelong MASLD labeling.

Common Offending Agents

Amiodarone causes a macrovesicular steatohepatitis that progresses to cirrhosis in approximately 1 to 3% of long-term users. Methotrexate accumulates in hepatocytes and produces fibrosis at cumulative doses above 1.5 g in patients with pre-existing metabolic risk. Tamoxifen raises hepatic steatosis risk 3-fold through estrogen-receptor-mediated lipid effects. Corticosteroids produce steatosis within weeks at doses above 20 mg/day of prednisone equivalent. [27]

Systemic Diseases Producing Secondary Steatosis

Hypothyroidism, hypopituitarism, celiac disease, and inflammatory bowel disease each associate with hepatic steatosis through distinct mechanisms. A 2018 meta-analysis found hypothyroidism independently associated with NAFLD (OR 1.63, 95% CI 1.27 to 2.09). [28] TSH should be measured in all patients presenting with steatosis of unclear cause.

Total parenteral nutrition (TPN) produces steatosis within days and steatohepatitis with prolonged use, a pattern clinically important in post-surgical and critically ill patients.

Diagnostic Framework for Atypical MASLD Presentations

When a patient has steatosis but does not fit the classic obese, metabolically abnormal MASLD profile, a structured differential workup prevents premature diagnostic closure.

Step 1: Confirm Steatosis and Exclude Competing Diagnoses

Controlled attenuation parameter (CAP) on VCTE or MRI-PDFF quantifies steatosis grade with acceptable accuracy. ALT elevation alone is insufficient, given that 40% of biopsy-confirmed MASLD patients have normal transaminases. [7]

Exclude: alcohol use disorder (detailed history, CDT/PEth biomarkers), viral hepatitis (HBsAg, anti-HCV), autoimmune hepatitis (ANA, anti-smooth muscle antibody, IgG), primary biliary cholangitis (AMA), hemochromatosis (transferrin saturation >45%, HFE genotyping), and Wilson disease (ceruloplasmin in patients <40 years).

Step 2: Risk-Stratify for Fibrosis

FIB-4 score below 1.30 carries a negative predictive value of approximately 90% for advanced fibrosis (F3, F4) and supports a watchful waiting approach with annual reassessment. [29] FIB-4 above 2.67 warrants referral for elastography or liver biopsy. The AASLD recommends this two-tier approach as standard care.

Step 3: Screen for Extrahepatic Manifestations

Every confirmed MASLD patient, regardless of typical or atypical presentation, should receive a 10-year cardiovascular risk assessment using a validated tool (Framingham, ASCVD Pooled Cohort Equations) and be screened for type 2 diabetes with fasting glucose and HbA1c. Chronic kidney disease screening (eGFR, urine albumin-to-creatinine ratio) is appropriate given the MASLD-CKD association, which carries a pooled odds ratio of 1.79 in a 2016 meta-analysis. [30]

Approved and Emerging Therapies Relevant to Atypical MASLD

In March 2024, the FDA approved resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist, for adults with noncirrhotic MASH and moderate to advanced fibrosis (F2, F3), based on the MAESTRO-NASH trial (N = 966). At 80 mg/day, resmetirom produced MASH resolution without fibrosis worsening in 25.9% of patients versus 14.2% placebo (P<0.001). [31] This approval explicitly excludes cirrhotic patients and has not been studied in lean MASLD or pediatric populations, so extrapolation requires caution.

GLP-1 receptor agonists, while not FDA-approved specifically for MASLD, showed histological benefit in the LEAN trial (liraglutide 1.8 mg/day, N = 52): NASH resolution occurred in 39% of liraglutide-treated patients versus 9% placebo (P = 0.019). [32] Ongoing trials are evaluating semaglutide 2.4 mg in MASH (ESSENCE trial, NCT04822181).

For LAL-D specifically, the FDA approved sebelipase alfa (Kanuma) in December 2015, marking the first enzyme replacement therapy for a genetic cause of hepatic steatosis. [26] Patients with MASLD-mimic phenotypes caused by LAL-D who receive standard lifestyle advice rather than sebelipase will not improve.