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Page 2 of 7 Lonardo. Metab Target Organ Damage 2024;4:7 https://dx.doi.org/10.20517/mtod.2023.56

[4]
between NAFLD and metabolic syndrome , the development of extrahepatic cancer has come as somewhat
more unexpected. At any rate, these findings strongly suggest that liver fibrosis is a major determinant of
the natural course of NAFLD.

[5]
In this context, the discovery of sexual dimorphism in the NAFLD arena has come as one of the most
intriguing lessons for molecular biologists and clinical investigators. Indeed, to the detriment of precision
medicine approaches, the assessment of sex as a biological variable in Physiology and Medicine has
historically been neglected, and only in the more recent past has it begun to be remedied .
[6]

Putting all the above notions together, Mantovani et al. were the first to report that NAFLD was associated
with a 1.2- to 1.5-fold increased risk of developing gynecological cancers irrespective of potential
[7]
confounders (i.e., age, smoking, obesity, and diabetes) . However, the umbrella meta-analysis conducted by
Yi et al., based on the analysis of 39 previously published meta-analyses, reported that individuals with
NAFLD exhibited an increased risk of a variety of extrahepatic cancers including breast cancer .
[8]
Nevertheless, the association of NAFLD with the female genital tract was non-significant . Of interest, a
[8]
large meta-analysis of 64 studies totaling 41,027 individuals found that the uterine and breast cancers were
among the most common extrahepatic cancers, occurring over eight-fold more commonly than
hepatocellular carcinoma in NAFLD; however, these cancer types were not associated with the stage of
hepatic fibrosis in this study . Regarding the potential role of variables, such as patient populations and
[9]
others, in modulating the odds of extrahepatic cancers among those with NAFLD, the study by Mantovani
et al. found only four studies addressing the association of breast cancer with NAFLD and as many studies
evaluated the association of NAFLD with cancer of the female genital tract, which prevents any significant
subgroup analysis . Similarly, in the study by Yi et al., the number of included studies in North Americans
[7]
vs. Asians was too small to draw any definite conclusions . Finally, the study by Thomas et al. found that
[8]
the pooled incidence rate for extrahepatic cancer did not vary according to the method of NAFLD
diagnosis: liver histology, ICD code, and hepatic imaging; in clinic/hospitals vs. population-based studies; in
studies from Asia and Europe; in prospective and retrospective studies; and between studies published
[9]
before or after 2018 .
MAFLD AND GYNECOLOGICAL CANCERS
While NAFLD remains a diagnosis of exclusion, the nomenclature “metabolic dysfunction-associated fatty
liver disease” (MAFLD) emphasizes positive criteria . Dysmetabolism may trigger cancer initiation and
[10]
progression through a variety of pathomechanisms, which are acknowledged potential risk factors for
cancer in humans. These comprise hormonal derangement, insulin resistance, chronic hyperglycemia,
dysregulation of insulin-like growth factors, cell proliferation and angiogenesis and inhibited apoptosis,
chronic systemic low-grade inflammation, increased formation of reactive oxygen species, increasing cell
cycle rates, and decreased tumor suppressor function . On these grounds, MAFLD is expected to be even
[11]
more strongly associated with extrahepatic cancers than NAFLD, although it remains uncertain whether the
female genital tract is specifically affected.

Studies have addressed this research question. Liu et al. studied 352,911 individuals from the UK Biobank,
23,345 of whom developed cancers . Of interest, these authors found that, compared to non-MAFLD
[12]
controls, those with MAFLD had significantly increased odds of corpus uteri [hazard ratio (HR) = 2.36,
95%CI: 1.99-2.80] and breast (1.19, 1.11-1.27) cancers . Wei et al. investigated the incidence rates of cancer
[12]
associated with MAFLD in their historical cohort of 47,801 participants managed at a tertiary Chinese
hospital, 33.7% of whom had MAFLD . During a median 3.3 -year follow-up, MAFLD individuals
[13]
exhibited a higher incidence of cancer than the MAFLD-free controls and, after adjustment for confounding