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Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20 Page 7 of 17

gluconeogenesis and lipogenesis, and also the release of free fatty acids from adipose tissue to the liver -
trademarks similar to metabolic syndrome associated with MASLD [95-97] . However, in a study from 2003,
Rockall et al. investigated 50 patients with Cushing’s syndrome for the presence of SLD using computed
[98]
tomography . Only 20% were found to have SLD, and although it was not associated with BMI, it did
correlate with both visceral and total fat volume. Furthermore, the prevalence of SLD among patients with
Cushing’s syndrome does not exceed the estimated global prevalence of MASLD (i.e., 30%) [6,99] .
Additionally, of interest, cortisol levels did not differ between patients with and without SLD, results which
[101]
[100]
are corroborated by Hubel et al. . Hence, the main cause of SLD in patients with short- and long-term
corticosteroid treatment is the disruption of the metabolic equilibrium leading to hyperglycemia, insulin
[102]
resistance and central obesity, and ultimately SLD .
[97]
Viral hepatitis-associated steatosis
Chronic infection with hepatitis C virus (HCV), genotype 3, is commonly associated with SLD. The
prevalence of SLD in patients with chronic hepatitis C varies between 40%-80%, depending on the
prevalence of alcohol consumption, overweight, T2DM, and other risk factors of hepatic lipid
accumulation . Several observations also indicate a correlation between the grade of hepatic steatosis and
[103]
elevated aminotransferases [104,105] . Furthermore, the steatogenic effect seems to be cytopathic, with an
increased grade of hepatic steatosis being associated with HCV RNA levels in both serum and liver [106,107] ,
and attenuation occurring after sustained therapeutic response . Furthermore, chronic HCV infection
[108]
seems to be associated with acquired hypobetalipoproteinemia and hypocholesterolemia, the latter often
normalizing after therapeutic response [109-111] .

Hepatitis C virus has an intertwined connection with hepatic and systemic metabolism. Genotype 3 HCV
proteins have been proven to interact with glucose and lipid metabolism by stimulating de novo lipogenesis,
and synthesis of phospholipids, via activation of several transcription factors to favor HCV assembly .
[112]
Furthermore, HCV assembly interferes with VLDL assembly and export by interfering with the VLDL
secretion pathway .
[113]
Overweight and T2DM are frequently present [107,114,115] and often exaggerate HCV-associated SLD,
irrespective of genotype. Further, the presence of SLD in chronic HCV infection is independently associated
[116]
with an increased risk of HCC .
In recent years, effective direct-acting antiviral treatment has changed the HCV landscape, where sustained
virologic response (SVR) is often achieved after an 8-12(-24) weeks course of treatment. In contrast to
cholesterol, SVR does not seem to attenuate steatosis in responders to a significant degree , but instead
[117]
appears to increase steatosis [118,119] . This could be partly attributed to the weight gain often observed after
sustained virological response . Hence, chronic HCV infection with genotype 3 is independently
[120]
associated with SLD, a trait associated with disrupted hepatic metabolism, and is exaggerated by
comorbidities associated with the metabolic syndrome.

HIV-associated hepatic steatosis
The presence of SLD in patients living with human immunodeficiency virus (HIV) is common, affecting
approximately 35% [121,122] . Although SLD secondary to traditional risk factors is common among patients
living with HIV, the presence of SLD is also seen in normal or underweight patients living with HIV .
[123]
Therefore, it is suggested that the exact etiology may differ from patients with MASLD, but the
pathophysiological mechanism is still unclear . Yet, in lipodystrophic patients with HIV, insulin resistance
[123]
[124]
is highly prevalent, showing signs of impaired glucose tolerance and T2DM in 35% and 7%, respectively .
The proposed mechanism is theorized to be related to defect lipid metabolism and active inflammation,