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Page 4 of 11 Zerehpooshnesfchi et al. Metab Target Organ Damage. 2025;5:15 https://dx.doi.org/10.20517/mtod.2025.04

COEXISTENCE OF METABOLIC DYSFUNCTION-ASSOCIATED LIVER DISEASE WITH
OTHER LIVER DISEASE ETIOLOGIES: GROWING BURDEN
The coexistence of MAFLD with other liver conditions, such as ALD and viral hepatitis, represents a
significant and complex clinical challenge [21,22] .

For instance, in the Asia-Pacific regions where chronic hepatitis B infection (CHB) is endemic, studies show
a 32.8% prevalence of hepatic steatosis in CHB patients . It has also been shown that in CHB patients
[23]
[24]
undergoing antiviral therapy, persistent steatosis is associated with reduced fibrosis regression . This
overlap is not merely incidental; metabolic dysfunction amplifies liver disease progression, with patients
exhibiting three or more metabolic risk factors facing a 2.32-fold higher risk of hepatocellular carcinoma
[25]
(HCC) and a 2.72-fold increased risk of liver-related mortality . Additionally, the coexistence of MAFLD
and CHB has been linked to a doubling of chronic kidney disease (CKD) risk, highlighting its systemic
impact beyond just accelerating liver disease progression .
[26]

In the case of chronic hepatitis C (CHC), hepatic steatosis is observed in 30%-45% of patients [27,28] and up to
[31]
50%-70% based on histology [29,30] , with the prevalence of MAFLD in CHC patients ranging from 9%-38% .
CHC and MAFLD share common pathogenic mechanisms, including insulin resistance (IR), oxidative
stress, and mitochondrial dysfunction, all of which exacerbate liver fibrosis and increase the risk of
HCC [31-33] . Moreover, HCV-related steatosis is linked to hepatitis C-associated dysmetabolic syndrome
[34]
(HCADS), which involves metabolic abnormalities such as hyperuricemia and arterial hypertension .

Studies have shown that the presence of MAFLD negatively impacts the progression and outcomes of CHC.
Metabolic factors such as IR, obesity, and dyslipidemia, particularly in the context of HCV genotype 3,
amplify the risk of fibrosis and HCC development, especially in patients with concomitant T2DM [35,36] .
While earlier studies indicated that MAFLD reduced the efficacy of interferon-based antiviral therapies, the
advent of direct-acting antivirals (DAAs) has resolved this issue, with MAFLD showing no detrimental
effect on treatment success . However, the persistent metabolic derangements associated with MAFLD,
[37]
such as steatosis and dyslipidemia, remain significant contributors to long-term cardiovascular and liver-
[38]
related complications in CHC patients .

Beyond viral etiologies, the coexistence of MAFLD and ALD is increasingly recognized, reflecting the global
prevalence of metabolic dysfunction and widespread alcohol consumption, with 283 million individuals
having alcohol use disorder . Studies indicate that 39% of non-viral advanced liver disease cases involve
[39]
both metabolic risk factors and moderate alcohol intake (10 to 20 g/day for women, 10 to 30 g/day for
men) . While modest alcohol consumption (< 30 g/day for males, < 20 g/day for females) was historically
[40]
considered safe, recent evidence shows that even low amounts of alcohol can exacerbate fibrosis progression
in MAFLD . The interaction between ALD and MAFLD accelerates liver damage through shared
[41]
mechanisms, including lipotoxicity, inflammation, and gut microbiome dysregulation, with genetic variants
like PNPLA3 further contributing to disease progression [21,42] . Additionally, alcohol consumption can
dissociate IR from certain cardiometabolic risk factors, complicating patient classification .
[43]

In summary, the coexistence of metabolic dysfunction-associated liver disease with other liver conditions is
a significant and frequently encountered issue. This overlapping occurrence substantially escalates the
overall burden of liver-related and systemic complications and necessitates a comprehensive approach to
management.