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Moriguchi et al. Hepatoma Res 2019;5:43 I http://dx.doi.org/10.20517/2394-5079.2019.20 Page 5 of 14
[35]
1.90, respectively . There have been other reports linking HCC and obesity. In a prospective cohort study
in Europe, general obesity (RR: 2.19) and abdominal obesity (RR: 2.03) were reported to be related to the
[44]
risk of HCC . Compared to the normal body weight, the RR of HCC was 1.17 (95%CI: 1.02-1.34) in those
[45]
who are overweight and 1.89 (95%CI: 1.51-2.36) in those who are obese .
In terms of the relationship between BMI and HCC, a study cohort in Italy showed that the RR of HCC
[46]
2
onset for BMI > 30 kg/m was 1.97 times higher . Studies in South Korea showed that it was 1.56 times
higher for BMI > 30 kg/m . Other studies showed, as mentioned above, that it was 1.13 for BMI of 25-
2[47]
2
29.9 kg/m and increased to 4.52 for BMI between 35 and 39.9 kg/m 2[35] . Furthermore, a meta-analysis
[45]
of 11 cohort studies showed that an increase in BMI by 5 kg/m increases the risk of HCC by 24% .
2
Furthermore, the European Prospective Investigation into Cancer reported that the waist-hip ratio and a
rough estimate of abdominal fat are good prognostic factors of HCC and suggests that the assessment
[44]
of fat deposition is just as important as assessing BMI. It was also reported that obesity during early
adulthood is a risk factor of HCC and that the increase in BMI during early adulthood speeds up the onset
[48]
of HCC .
T2DM
HCC has been increasing among T2DM patients [49,50] . An epidemiological study in the US on the RR of
HCC in T2DM patients showed that the risk of HCC increased by 2.87 times (95%CI: 2.49-3.30) due to
[51]
T2DM . A multicenter case-control study in Italy reported that the risk of HCC due to T2DM had an
[36]
odds ratio of 4.33 (95%CI: 1.89-9.86) . Furthermore, examination of non-HCV HCC cases showed that
[52]
the risk of HCC in T2DM patients is twice as high , and the risk of developing HCC due to T2DM when
[53]
there is no liver cirrhosis is 1.353 times higher (95%CI: 1.249-1.465) , whereas a history of T2DM is also a
[54]
risk factor (HR: 2.14, 95%CI: 1.69-2.71) . Furthermore, a meta-analysis showed that HCC prevalence and
[55]
incidence rates increase by 2.5 times due to T2DM .
T2DM is mediated by insulin resistance, and the subsequent inflammatory cascade is thought to be
involved in the progression of the condition to NAFLD and HCC [55-58] . With respect to the relationship
between NAFLD-related HCC and T2DM, it was reported that, while the prevalence of T2DM in HCV-
related HCC patients was 24.9%, the prevalence was 73.1% in NAFLD-related HCC patients, which suggests
[59]
a strong relationship between the two .

Age and sex
[60]
Incident rate of HCC is high in men regardless of etiology including NAFLD . A study in the US suggests
that the incidence rate of HCC is higher in men than in women (0.22 vs. 0.04 per 1000 PYs), whereas the
incidence rate of HCC in NAFLD patients was found to be higher in patients aged ≥ 65 years than in
[21]
younger patients [0.41 vs. 0.01 (< 45 years) and 0.02 (45-64 years) per 1000 PYs] . As mentioned above,
BMI is related to the onset of HCC, and, although UK studies have shown a positive correlation between
BMI and HCC (HR: 1.19, 99%CI: 1.12-1.27), this relationship was reportedly more profound in men, in
2[61]
whom the risk of HCC increases linearly from a BMI of > 22 kg/m . The severity of NAFLD and the level
of progression of fibrosis are risk factors of HCC development. In the young, NASH is more prominent
in males, while, in older patients (> 50 years), it is more common in women and the severity of NASH is
higher in women as well [60,62] . Furthermore, a cross-sectional study on NAFLD reported that increasing age
is correlated with the severity of fibrosis in NASH patients [63-65] .

Race and genetic elements
Although it has been reported that there is no difference in the extent of liver damage between Hispanic
and Caucasian patients with NAFLD [66,67] , the incidence of HCC was highest in Hispanic patients (0.29 per
1000 PYs), followed by Caucasian patients (0.21 per 1000 PYs) and African American patients (0.12 per 1000