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Page 2 of 6                                             Carvalho et al. Hepatoma Res 2018;4:15  I  http://dx.doi.org/10.20517/2394-5079.2018.13

                                                                                                    [1]
               also the second cause of deaths related to cancer, accounting for 700,000 deaths every year worldwide .

               In Brazil, HCC is the 8th most frequent malignant neoplasm and represents approximately 10,000 cases per
                   [2]
               year .
               A Brazilian national survey conducted in 2009 showed that hepatic cirrhosis was present in 98% of HCC
               patients, and this tumor was more frequent in cirrhosis patients with hepatitis C virus (HCV), hepatitis B
                                                              [3]
               virus (HBV) chronic hepatitis and alcoholic liver disease .

               However, HCC can also be associated with other liver diseases, such as non-alcoholic fatty liver disease
                                                                                        [4]
               (NAFLD), nonalcoholic steatohepatitis (NASH), and hemochromatosis as well as toxins .

               In patients without cirrhosis, the prevalence of HCC varies between 7% to 54% of the cases and can have a
                                                 [5]
               major influence on the geographical area . In Western countries, the prevalence of hepatocellular carcinoma
                                                                               [6-8]
               in non-cirrhosis (HCC-NC) patients was estimated in 15% to 20% of cases , and the most common risk
               factors were HBV and HCV. However, a majority of the information was obtained from Asia and Africa,
               where the prevalence of hepatitis B and C viral infections is also elevated [9-11] .

                                                                           [12]
               NASH is considered a relevant risk factor of liver disease worldwide . Associated metabolic syndrome
                                                                                            [13]
               manifestations may also contribute to the development of HCC in patients without cirrhosis .
               The present study evaluated the frequency, associated factors and clinical characteristics of HCC in Brazilian
               patients without cirrhosis.


               METHODS
               Design and population study
               The present cross-sectional study included patients with HCC diagnosis from two reference centers for liver
               disease in Northeast Brazil from 2010 to 2016.

               Inclusion criteria were as follows: patients diagnosed with hepatocellular carcinoma of different etiologies
               (NAFLD, HBV, HCV, alcohol, hemochromatosis, and etiology related to toxic agents)


               Exclusion criteria were as follows: patients diagnosed with hepatocellular carcinoma and cirrhosis.

               Diagnostic criteria
               The diagnostic criteria for HCC were according to European Association for the Study of the Liver (EASL)
                              [14]
               recommendations .

               The criteria for the diagnosis of cirrhosis was histological and/or by the evaluation of non-invasive markers,
                                                                                               9
               such as FIB-4 {FIB-4 = age (years) × aspartate aminotransferase (AST) (U/L)/[Platelets (PLT) (10 /L) × alanine
                                1/2
               transaminase (ALT)  (U/L)]}.
               Clinical assessment
               All the data were obtained from a questionnaire containing the following variables: gender, age, and risk
               factors for liver diseases (HBV, HCV, NASH, alcohol, and metabolic- and toxic-related factors). The data
               from physical examinations and completed additional tests [liver, lipid, and glycemic profiles, serum
               insulin, hepatitis B surface antigen (HBsAg), anti-HCV, ferritin, and transferrin saturation index] were
               considered. All the patients were also evaluated by at least two imaging methods, such as total abdominal
               ultrasonography (US), computed tomography (CT) or magnetic resonance imaging (MRI).
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