**2.4 Alcohol**

The relationship between alcohol use and HCC is both by direct effect and being a cofactor in viral infections [31, 32]. Reactive oxygen radicals, that occur while alcohol is metabolized to acetaldehyde, initiate hepatocarcinogenesis by causing damage and transformation in DNA. HCC development in alcoholic cirrhosis is in the form of DNA instability caused by DNA hypomethylation [33–36].

*Histopathological Features of the Steatohepatitic Variant of Hepatocellular Carcinoma… DOI: http://dx.doi.org/10.5772/intechopen.99842*

#### **2.5 Metabolic diseases**

HCC can develop in some of the livers with metabolic diseases. However, the development of HCC is more common with hereditary hemochromatosis, tyrosinemia and α1-antiripsin deficiency [37–41]. In these diseases, the direct toxic effect of accumulations (such as iron), mutation (p53 mutation), immunological abnormalities and DNA damage by lipid peroxidation initiate the development of HCC [8, 42, 43].

#### **2.6 Metabolic syndrome and fatty liver disease**

Metabolic syndrome is a mortal endocrinopathy that is accompanied by systemic disorders such as abdominal obesity that begins with insulin resistance, diabetes, dyslipidemia, hypertension and coronary artery disease. This situation has led to an increase in HCC formation, which has the characteristics of metabolic syndrome [44–47]. The risk of HCC increases 2–3 times in patients with diabetes [37, 48, 49]. The increase in metabolic syndrome in developed countries also brought an increase in nonalcholic fatty liver disease (NAFLD) [50–55].

In obese patients, the decrease in the release of fatty acids from adipose tissue, tumor necrosis factor-α and adiponectin causes insulin resistance and thus chronic hyperinsulinemia. Insulin and insulin growth factor-1 (IGF-1) contribute to hepatocarcinogenesis by preventing apoptosis and increasing cellular proliferation with the signals they send to insulin receptors and IGF-1 receptors [8].

Since steatohepatitic HCC (SH-HCC) will be mentioned here, NAFLD, steatohepatitis and their associated HCC formation mechanism are explained in a little more detail.

There are many studies on the incidence and prevalence of HCC in NAFLD cases, with rates varying between 3 and 35% [51, 56, 57]. Steatohepatitis varies between 3 and 5%. In some cohort studies, the rate of development of HCC (1-year cumulative incidence) was reported as 2–5% in patients with NAFLD compared to hepatitis C cases. The 5-year incidence was reported as 11% [51, 58]. In another study, the annual cumulative rate was 2–6%. In a retrospective study, NAFLD was detected in 21.2% of HCC cases. In fact, 23% of NAFLD patients without histopathologically and radiologically significant cirrhosis developed HCC [59]. In a different study, HCC develops in 5% of patients with cirrhosis secondary to NAFLD [53]. In cohort studies with large case series, both steatosis and steatohepatitis in nontumoral liver were found to be statistically significant with HCC. Moreover, a close relationship between the steatohepatitic variant of HCC (SH-HCC), which has been recently defined, and NAFLD has been described and demonstrated [22, 53, 58, 60]. Although its relationship with fatty liver diseases has been clarified, there are studies showing that SH-HCC can also develop in viral hepatitis [16, 61].

### **3. Clinical features**

The clinical manifestations of HCC are quite ambiguous and are related to the tumor and underlying chronic liver disease [1]. Usually, patients show signs in advanced stages and even miss the chance of treatment. Patients may present with upper abdominal pain, hepatomegaly, splenomegaly, weight loss, jaundice or decompensated liver finding such as ascites [1, 8]. HCC most commonly spreads intrahepaticly via the portal vein [1]. While HCC spreads with intrahepatic portal vein branches, the main portal vein and hepatic vein involvement can also be seen.

#### *Hepatocellular Carcinoma - Challenges and Opportunities of a Multidisciplinary Approach*

Invasion of the bile duct causes liver decompensation, resulting in rapid ascites accumulation, obstructive jaundice, variceal hemorrhages, and hepatic encephalopathy [8]. Although extrahepatic dissemination is rare, it can metastasize to the lung, lymph nodes, bone, and adrenal gland in advanced disease [1]. Paraneoplastic syndrome findings such as hypoglycemia, hypercholesterolemia, hyperkalemia, gynecomastia, carcinoid syndrome, hypertrophic pulmonary osteoarthropathy, osteopetrosis, hypertension, hyperthyroidism, porphyria cutanea tarda can be seen [8]. Median suvival in patients with clinical findings who have the chance for curative treatment is around 1–3 months, and survival over 1 year is also unusual. Today, thanks to definitive treatments and advanced surgeries, patients at risk of developing HCC are followed more closely and the tumor is diagnosed at an early stage [8, 28]. Radiologic imaging methods (ultrasound, computed tomography, magnetic resonance imaging, angiography) are used for the diagnosis of liver masses and HCC [8, 17, 62, 63].
