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Abstract

Trans Abstract

I. Introduction

Steatotic liver disease (SLD) is currently classified into two major entities: alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD)1. MASLD affects approximately 25-30% of the adult population worldwide, making it the most prevalent chronic liver disease, whereas ALD shows a lower prevalence but accounts for a disproportionately high burden of liver-related mortality, contributing to nearly half of cirrhosis-related deaths globally2,3. This epidemiological paradox underscores fundamental differences in disease behavior and clinical risk profiles between the two conditions.

From a clinical perspective, ALD and MASLD exhibit contrasting patterns of organ involvement. ALD is primarily driven by direct hepatotoxic effects of alcohol metabolites and is characterized by a high propensity for inflammation and fibrosis, with 20-40% of heavy drinkers progressing to alcoholic steatohepatitis or advanced fibrosis4. In contrast, MASLD is defined by metabolic dysfunction and prominent hepatic steatosis, yet cardiovascular disease rather than liver failure remains the leading cause of death, accounting for over 40% of mortality in affected patients5,6. These differences highlight the intrahepatic-dominant risk in ALD versus the extrahepatic-dominant risk in MASLD.

Despite these conceptual distinctions, differentiation between ALD and MASLD in routine practice remains challenging. Biochemical abnormalities often overlap, and noninvasive assessments may reveal discordant patterns of hepatic steatosis and fibrosis. Clear clinical illustrations that emphasize the divergent diagnostic and therapeutic priorities of these two SLD entities are therefore needed.

In this report, we present two age-matched cases of ALD and MASLD to highlight their contrasting intrahepatic and extrahepatic risk profiles and to underscore key considerations for individualized diagnosis and management.

II. Report of the Cases

2. Laboratory findings

Laboratory evaluation revealed evidence of hepatic inflammation in both patients. Serum alanine aminotransferase (ALT) levels were modestly elevated in the male and female patients (44 IU/L and 52 IU/L, respectively), while aspartate aminotransferase (AST) levels remained within the normal range (37 IU/L and 26 IU/L, respectively). In contrast, γ-glutamyltransferase (GGT) levels showed a marked difference between the two cases, with the male patient exhibiting a substantially higher GGT level (118 IU/L) than the female patient (69 IU/L), consistent with his history of alcohol intake (Fig. 1C).

Fig. 1

Comparative summary of key clinical parameters in two patients.

The upper panel presents FibroScan-based assessments of hepatic steatosis and fibrosis in the two patients. Steatosis is quantified by the controlled attenuation parameter (CAP, dB/m), and fibrosis by liver stiffness measurement (LSM, kPa) (Panels A and B). The lower panel summarizes key metabolic dysfunction-associated parameters, including blood chemistry, insulin resistance, and inflammatory markers (Panel C).

Regarding metabolic dysfunction-related profiles, the male patient demonstrated normal high- and low-density lipoprotein cholesterol levels (HDL-C 50.9 mg/dL; LDL-C 33.1 mg/dL), with a moderately elevated triglyceride (TG) level (230 mg/dL). In contrast, the female patient showed reduced HDL-C (40.5 mg/dL), elevated LDL-C (113.8 mg/dL), and marked hypertriglyceridemia (TG 273 mg/dL), along with a borderline glycated hemoglobin (HbA1c) level (6.0%) (Fig. 1C). In both patients, total bilirubin levels, serum albumin concentrations, and platelet counts were within normal limits, indicating preserved hepatic synthetic function (data not shown).

III. Discussion

In this comparative case report, we describe two age-matched patients who exhibited markedly divergent hepatic and systemic phenotypes despite comparable biochemical evidence of hepatic inflammation. By integrating clinical history, laboratory findings, and transient elastography, these cases highlight fundamental differences between alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), particularly with respect to intrahepatic versus extrahepatic risk dominance.

Under the current classification, a U.S. national survey estimates that MASLD affects over 30% of adults, a prevalence approximately 30-fold higher than the <1% observed for ALD7. Although ALD affects a remarkably smaller proportion of the population than MASLD, it showed 10-fold higher risk of liver-related mortality than MASLD among SLD population8. Among subjects with SLD, the liver-related mortality generally relies on the progression into hepatic fibrosis, while fibrosis level 2 (threshold over 8 kPa of LSM) is considered as a significant fibrotic change9. In the present comparison, the male patient with ALD/ASH demonstrated significant fibrosis (LSM 8.6 kPa) despite minimal steatosis (CAP 218) (Fig. 1A), whereas the female patient with MASLD/MASH exhibited marked steatosis but minimal fibrosis (LSM 5.1 kPa) (Fig. 1B). A CAP score of 218 indicates an absence of steatosis (S0) in male patient, which is suggestive of ’burn-out fatty liver,’ a phenomenon occasionally observed in cases of advanced fibrosis. Continuous hepatic fat loss accompanied by fibrosis progression is associated with high rates of all-cause mortality SLD10. Consistent with previous reports, chronic heavy alcohol consumption leads to progression to alcoholic steatohepatitis and/or advanced fibrosis in approximately 20-40% of individuals, underscoring the intrahepatic-dominant risk profile of ALD4.

By contrast, the female patient with MASLD showed a steatosis-dominant phenotype, evidenced by severe hepatic fat accumulation (S3) (Fig. 1B). Progressive weight gain after menopause and a sedentary lifestyle may have contributed to the development of severe hepatic steatosis. MASLD is known to exhibit sex-dimorphic features, with male predominance before 50 years of age and female predominance thereafter in both incidence and prevalence11. Unlike ALD, extrahepatic risk factors-particularly cardiovascular disease-constitute the leading causes of mortality in MASLD, as highlighted by recent epidemiological and pathophysiological studies12. The female patient exhibited multiple metabolic comorbidities, including mild overweight (BMI 23.6 kg/m²), hypertension, dyslipidemia, and prediabetes (HbA1c 6.0%) (Fig. 1C). Notably, she had been unaware of her prediabetes, despite evidence that progression to diabetes mellitus is a major determinant of increased mortality in MASLD patients13.

Regarding diagnosis and management, ALD and MASLD should be approached differently in light of their distinct clinical risk profiles. Hepatic inflammation-referred to as alcoholic steatohepatitis (ASH) in ALD and metabolic dysfunction-associated steatohepatitis (MASH) in MASLD-is a critical determinant for assessing the likelihood of intrahepatic pathological progression to fibrosis, cirrhosis, or hepatocellular carcinoma14,15. Although both patients exhibited elevated serum ALT levels (44 IU/L and 52 IU/L), significant fibrosis was observed only in the male patient with ASH. In typical ALD, the AST level dominantly rises above ALT; however, the present case showed a paradoxical dominance of ALT (44 IU/L) over AST (37 IU/L) (Fig. 1C). We attribute this to the advanced fibrosis (LSM 8.6 kPa) and the ’burn-out’ of liver fat (CAP 218) (Fig. 1A), suggesting a chronic, stabilized phase of liver injury rather than an acute inflammatory flare. Furthermore, the patient’s metabolic risk factors (BMI 27.4 kg/m² and TG 230 mg/dL) likely contributed to this ALT-dominant pattern, which is suggestive of an overlap between both conditions (MetALD). In ALD, clinically significant fibrosis may develop even in the presence of relatively modest steatosis and liver enzymes within the normal range, highlighting the need for careful assessment of fibrotic burden regardless of fat accumulation or concurrent hepatic damage. Consistent with this, the ALD patient exhibited a markedly higher serum GGT level than the MASLD patient (118 IU/dL vs. 69 IU/dL) (Fig. 1C). Although GGT levels can be elevated in individuals with severe hepatic steatosis in MASLD, GGT remains a well-established biochemical marker associated with alcohol consumption16. Conversely, while most patients with MASLD remain in a steatosis-predominant stage, only a relatively small proportion progress to clinically significant fibrosis over time. Accordingly, risk stratification in MASLD should extend beyond liver-centered parameters to encompass metabolic and cardiovascular risk factors17.

These two cases concisely illustrate the clinical differences in hepatic phenotypes between ALD and MASLD. Beyond the liver itself, they also demonstrate a clear divergence in how intrahepatic and extrahepatic factors contribute to each disease. From a therapeutic perspective, these distinctions underscore the importance of individualized management strategies. In ALD, interventions aimed at preventing fibrosis progression and liver-related complications-most critically sustained alcohol abstinence-are paramount. In MASLD, by contrast, effective management requires a broader strategy focused on weight reduction, metabolic control, and cardiovascular risk modification, as extrahepatic complications frequently determine long-term outcomes.

IV. Conclusion

In conclusion, although ALD and MASLD are classified under the umbrella of steatotic liver disease, they represent distinct clinical entities with fundamentally different risk architectures. Recognition of the intrahepatic risk-dominant nature of ALD versus the extrahepatic risk-dominant nature of MASLD-supported by noninvasive tools and epidemiological evidence-is essential for accurate diagnosis and tailored management.

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