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Teschke. Hepatoma Res 2019;5:40 I http://dx.doi.org/10.20517/2394-5079.2019.0017 Page 11 of 16

Figure 7. Macroscopic picture of alcoholic cirrhosis

Acquired comorbidities
Risk factors for AHCC include not only AC but also cirrhosis of various other causes and chronic co-
infection by hepatitis B or C [5,59] . Indeed, a broad range of confounding variables exists that can contribute
to the development of AHCC [5,43,59] . Among these are diabetes mellitus with the metabolic syndrome,
NASH or nonalcoholic fatty liver disease due to overweight or morbid obesity [5,59] . In this context, not only
ROS generated in the fat tissues and the liver [5,59,63-65] but also lipotoxicity in general and more specifically as
[65]
[5]
lipotoxic liver injury may represent additional risk factors for causing AC and AHCC .
Genetic diseases
Genetic liver diseases like α -antitrypsin (AT) deficiency leading to storage of AT in the liver, Wilson
1
disease with Cu storage in the liver, or the primary hereditary hemochromatosis (HH) with Fe storage in
the liver, all these inherited diseases may lead per se to liver cirrhosis, and HCC are specific risk factors.
They are risky due to their existence starting at birth and preexisting mostly for many years before alcohol
abuse is initiated. HH is of special interest due to its high Fe content in the liver. From a metabolic aspect,
Fe was early recognized in unpublished studies as promoter of MEOS activity, which led to the addition of
EDTA to each MEOS assay to capture any Fe in the assay system [22-24] . Subsequent studies have confirmed
[36]
that Fe stimulates not only MEOS activity but also ROS including hydroxyl radical generation . This
mechanism could explain why the risk of AHCC is increased in patients with HH who abuse alcohol for a
[66]
long time , substantiated by a subsequent analysis of available data, which suggest that iron accumulation
[67]
in the liver is an independent risk factor for HCC in patients with AC . In particular, iron accumulation
in the liver is considered to be a co-factor for progression of liver disease, and iron overload can enhance
the effects of oxidative stress and influence the natural history of patients with cirrhosis, exposing them to
a higher risk of HCC.

Gene polymorphisms
Enzymes metabolizing ethanol and acetaldehyde in the liver are individually characterized and modified
by gene polymorphisms [7,8,15] , with abundant studies that addressed the relevance of respective gene
[7]
polymorphisms for their risk of AHCC . However, results were contradictory. With ADH and ALDH
studied in a Japanese cohort as an example, gene polymorphisms of ADH2 and ALDH2 were found to
[7]
correlate with AHCC development , findings not confirmed subsequently [7,68] .
Gender
[7]
Overall prevalence of AHCC is small in women compared with that in men . Considering this limitation
and a subgroup of consumers who used more than 80 g alcohol per day, the risk of AHCC development
was fivefold higher in women than in men [7,69] . In general, female alcoholic patients are at a higher risk