Non-B, non-C hepatocellular carcinoma (Review)

  • Authors:
    • Hiroki Nishikawa
    • Yukio Osaki
  • View Affiliations

  • Published online on: August 20, 2013     https://doi.org/10.3892/ijo.2013.2061
  • Pages: 1333-1342
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Abstract

Although most hepatocellular carcinoma (HCC) is related to viral infection, there is a substantial population of HCC patients (5-20%) who are negative for both markers of hepatitis B virus and hepatitis C virus infection [non-B, non-C (NBNC) hepatitis] in Japan and the incidence of NBNC-HCC has recently tended to increase. The most common cause of liver disease in developed countries is non‑alcoholic fatty liver disease (NAFLD), which includes non‑alcoholic steatohepatitis (NASH) and its related complications. Increased body mass index and diabetes mellitus are associated with developing NAFLD and NASH, which is a severe form of NAFLD. Furthermore, increasing clinical evidence supports the fact that NAFLD and NASH can progress to liver cirrhosis and even HCC. A detailed understanding of the epidemiology, etiology, molecular mechanism, clinical features and prognosis of NBNC-HCC could improve our screening and therapy of this disease. In this review, we primarily focus on clinical aspects of NBNC-HCC and refer to our current knowledge of this cancer.

Contents

Introduction

Epidemiological trends, etiology and risk factors of NBNC-HCC

Alcohol-related HCC

NAFLD and NASH

DM

Obesity

Iron

Other causes

Mechanism of carcinogenesis in NBNC-HCC

Clinicopathological features and prognosis in patients with NBNC-HCC

Conclusion

Introduction

Hepatocellular carcinoma (HCC) is a common malignancy in Asia and South Africa. HCC usually develops in patients with hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and alcoholic liver disease (13). HCC is diagnosed in more than half a million people worldwide each year, and therefore it is a major global health problem. HCC is the fifth most common cancer in the world and the third most common cause of cancer-related death, behind only lung cancer and gastric cancer (15). Japan has one of the highest rates of incidence of HCC among developed countries (46).

Although most HCC is related to viral infection, there is a substantial population of HCC patients (5–20%) who are negative for both markers of HBV and HCV infection [non-B, non-C (NBNC) hepatitis] in Japan and the incidence of NBNC-HCC has recently tended to increase (712). Furthermore, investigations in the US assessing risk factors for chronic liver disease and HCC have failed to identify HBV, HCV or excessive alcohol intake in a large population (13,14).

The most common cause of liver disease in developed countries is non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH) and its related complications (7,15). The incidence of NASH is reported to be 1–3% among the adult Japanese population, and ∼6% in Western countries (7,15). Increased body mass index (BMI) and diabetes mellitus (DM) are associated with developing NAFLD and NASH, which is a severe form of NAFLD (17). Increasing clinical evidence supports the fact that NAFLD and NASH can progress to liver cirrhosis and HCC (7,1316). The exponentially growing incidence of HCC may be partially attributable to increased numbers of patients with NASH-related cirrhosis, although recent evidence demonstrates that NAFLD or NASH may directly promote liver carcinogenesis independent of the presence of liver cirrhosis (15).

Obesity and the metabolic syndrome are growing epidemics related to an increased risk for several types of cancer including HCC (16). In the liver, inflammatory and angiogenic changes caused by insulin resistance and fatty liver disease are associated with an increased incidence of HCC (17,18). In contrast, regardless of underlying liver disease, liver cirrhosis remains the most important risk factor for the development of HCC, although as mentioned earlier, HCC arising without liver cirrhosis raises the possibility of direct carcinogenesis.

A detailed understanding of the epidemiology, etiology, molecular mechanism, clinical features and prognosis associated with NBNC-HCC could improve our screening and therapy of this disease. In this review, we primarily focus on clinical aspects of NBNC-HCC and refer to our current knowledge of this cancer.

Epidemiological trends, etiology, and risk factors of NBNC-HCC

The major causes of cirrhosis in HCC are HBV, HCV and alcohol. The risk of HCC increases sharply in response to chronic liver damage at the fibrosis stage (2). HCV infection is the most prevalent risk factor for HCC in Japan (2,4,5,19). In the US, the leading cause of underlying liver disease among HCC patients is HCV (51%), and the second most common is cryptogenic cirrhosis (CC) (29%) (14).

Although most HCC still occurs in patients with chronic hepatitis C in Japan, the incidence of HCV-related HCC has been decreasing in recent years because of the improvement of therapy for chronic hepatitis C and a decrease in the number of patients newly diagnosed with chronic hepatitis C (6,2022). In addition, there has been a recent increasing trend in NBNC-HCC in Japan (7). Nagaoki et al reported in 1,374 consecutive HCC patients in their institution that 17 and 67% of HCC was related to HBV and HCV, respectively, and 15% was related to NBNC-HCC (10). Tokushige et al conducted a nationwide survey of 14,530 Japanese HCC patients. They reported that alcohol-related HCC accounted for 7.2% of all HCC, followed by unknown causes (5.1%) and NAFLD-related HCC (2.0%). The characteristics of these three groups were clearly different (median age, 72 years for NAFLD-related HCC, 68 years for alcohol-related HCC, and 73 years for unknown HCC; female sex, 38, 4 and 37%, respectively) and obesity and lifestyle-related diseases were significantly more frequent in NAFLD- than alcohol-related HCC and unknown HCC (7). Ertle et al reported in 162 HCC patients that HCV-related HCC accounted for 23.3%, HBV-related HCC for 19.9%, alcohol-related HCC for 12.7%, and NAFLD-related HCC for 24.0% (23).

The background liver diseases of NBNC-HCC vary considerably and they include NAFLD, NASH, alcoholic liver disease, autoimmune liver disease such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), congestive liver disease such as Budd-Chiari syndrome (BCS), congenital metabolic liver disease such as hereditary hemochromatosis and Wilson disease, occult HBV infection (OBI) and aflatoxins, as well as liver disease of unknown etiology. Different etiologies of HCC may cause different clinical characteristics and clinical outcomes. Fig. 1 shows a schematic representation of the different etiologies of NBNC-HCC.

Alcohol-related HCC

The alcohol consumption criterion for defining alcoholic liver disease as proposed by the Japanese Study Group on Alcoholic Liver Disease is an ethanol intake of >70 g/day for >5 years. As compared with Western countries, the prevalence of alcohol-related HCC is lower in Japan (19). This is partly because of the high incidence of hepatitis virus-related HCC (19).

The mechanism by which alcohol consumption increases the risk of HCC is primarily due to the development of liver cirrhosis. It has been shown that excessive alcohol consumption of >80 g/day ethanol for >5 years increases the risk of HCC by nearly 5-fold (24). According to a meta-analysis from Italy, hazard ratios (HRs) for HCC development of 1.19 [95% confidence interval (CI)=1.12–1.27], 1.40 (95% CI=1.25–1.56), and 1.81 (95% CI=1.50–2.19) were associated with alcohol consumption of 25, 50 and 100 g/day, respectively. This indicates that the risk of HCC development is proportional to the amount of alcohol consumed, although the risk in those who consume low or moderate levels remains unclear (25).

NAFLD and NASH

NAFLD is characterized by liver steatosis without a history of significant alcohol use or liver disease of unknown etiology (26). NAFLD is the most common cause of chronic liver disease worldwide and it is a hepatic manifestation of the metabolic syndrome, which is a constellation of problems that includes hypertension, obesity, insulin resistance and dyslipidemia (26). The prevalence of NAFLD increases with age, however, it has been described in persons of all ages (27). The prevalence of NAFLD and its related complications is expected to increase in the future (28).

The prevalence of NAFLD is reported to range from 10 to 30% in adults and its prevalence is increasing in Japan as well as in Western countries, because of the epidemic rise in DM and obesity (29). NASH is part of the spectrum of NAFLD and it is a severe form of NAFLD. Approximately 10% of patients with NAFLD progress to NASH and 20% of NASH cases can slowly progress to liver cirrhosis and even HCC (13,30). Powell et al reported the first case of NASH-related HCC (31). Since then, several case series of NASH-related HCC have been reported and it has attracted the attention of oncologists (32,33). The majority of CC cases are thought to be end-stage NASH because several clinical features such as obesity and DM in patients with CC are associated with NASH. However, histological findings often are not informative when liver cirrhosis is already established because it is hypothesized that CC often represents ‘burned out’ NASH (34,35). Thus, the impact of NASH on the incidence of liver cirrhosis and HCC may be underestimated. Marrero et al reported that 20% of patients in the cryptogenic liver disease group had evidence of NASH on liver biopsies prior to HCC occurrence (14). In addition, half of the patients with CC had prior NASH or suspected NAFLD and they concluded that NAFLD was the underlying liver disease in 13% of patients with HCC.

The natural history and prognosis of NASH remains elusive, because there are few data from prospective cohort studies (36). Ashca et al reported that yearly cumulative incidence of HCC was 2.6% in patients with NASH-related cirrhosis (n=195), compared with 4.0% in patients with HCV-related cirrhosis (n=315) (37). Likewise, Yatsuji et al conducted a comparative study between 68 patients with NASH-related cirrhosis and 69 with HCV-related cirrhosis, to clarify the incidence of HCC and clinical outcomes (38). They reported that the 5-year rate of HCC development was 11.3% for NASH-related cirrhosis and 30.5% for HCV-related cirrhosis, and the 5-year survival rates were 75.2% for NASH-related cirrhosis and 73.8% for HCV-related cirrhosis. The hepatocarcinogenesis rate in patients with NASH-related cirrhosis is considered to be lower than that in patients with HCV-related cirrhosis.

Metabolic syndrome is reported to be associated with development of HCC and intrahepatic cholangiocarcinoma (ICC). A population-based study from the US comprising 3,649 HCC cases, 743 ICC cases and 195,953 comparative persons demonstrated that metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than in the comparison group (17.1%). After adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (HR=2.13; 95% CI=1.96–2.31) and ICC (HR=1.56; 95% CI=1.32–1.83) (39).

DM

El-Serag et al conducted a large longitudinal study comprising 173,643 patients with DM and 650,620 without DM (98% male) to elucidate an association between DM and chronic liver disease and/or HCC (41). They demonstrated that DM was associated with an HR of 1.98 (95% CI=1.88–2.09) for chronic non-alcoholic liver disease and an HR of 2.16 (95% CI=1.86–2.52) for HCC development (40). Furthermore, Wang et al recently conducted a meta-analysis including a total of 25 cohort studies to examine the relationship between DM and HCC (41). They reported that DM was associated with an increased incidence of HCC (HR=2.01, 95% CI=1.61–2.51), compared with individuals without DM and it was also positively associated with HCC mortality (HR=1.56, 95% CI=1.30–1.87). Thus, DM was demonstrated to be an independent risk factor for progression of chronic liver disease and HCC development.

Up to 70% of patients with type II DM have some degree of fatty liver disease (42). About 10% of patients with liver cirrhosis have overt DM and a larger percentage of patients have impaired glucose tolerance (43). DM may be the result of liver cirrhosis, because in patients with liver cirrhosis, insulin is not cleared properly (44).

El-Serag et al conducted a matched case-control study comprising 1,303 cases with DM and 5,212 controls to investigate the effect of statins on HCC development. The adjusted HR for statin reduction of HCC development was 0.74 (95% CI=0.64–0.87) and they concluded that statin use is associated with a significant reduction in the risk of HCC in patients with DM (45).

Obesity

Up to 90% of obese individuals have some degree of chronic fatty liver disease and hepatic steatosis correlated significantly with increasing BMI (42,46). Obesity and related metabolic abnormalities, including chronic inflammatory conditions, increase the risk of HCC development. Dysregulation of tumor necrosis factor-α and interleukin-6 expressed in adipose tissue, which are essential cancer promoters in inflammation-related carcinogenesis, is associated with the development of steatosis and liver inflammation. These cytokines are also pivotal in the development of obesity-related HCC (47).

Obesity is reported to be linked to HCC development and HCC patients with obesity may have worsened clinical outcomes (16,48). Based on the prevalence of HCC, it was estimated that 28% of male HCC cases and 27% of female cases were due to overweight or obesity (49). Calle et al indicated that obesity is associated with significantly increased HCC death rates with an HR of 4.52 in patients with BMI >35 kg/m2 (16). Another large population-based study from Denmark demonstrated in >40,000 obese patients that the HR of developing liver cancer was increased to 1.9 compared with the general population (50). Likewise, the Korea National Health Insurance Corporation Study reported that there was an HR of 1.53 for development of HCC in men with BMI >30 kg/m2 as compared with normal controls, even after controlling for HBV infection, which is the most common cause of HCC in Korea (51).

Iron

Liver iron overload is suspected when the levels of serum iron and ferritin are high. In patients with hepatitis virus infection, iron overload, which is distinct from hereditary hemochromatosis, is associated with poor prognosis (52). Furthermore, Sorrentino et al measured hepatic iron retrospectively in liver biopsies of 153 patients with NASH-related cirrhosis (51 with HCC and 102 controls without HCC) (53). They reported that iron deposits were more frequent in HCC patients than in controls and the median corrected total iron score was significantly higher in HCC patients. Excessive alcohol consumption and iron overload may act in synergy to promote liver fibrosis and carcinogenesis (54). Ioannou et al demonstrated that elevated serum transferrin-iron saturation is associated with an increased incidence of liver cirrhosis or HCC; particularly in patients with heavy alcohol consumption (54). Liver iron overload may be associated with the progression of liver disease and the development of HCC in patients with underlying liver disease of various etiologies. Iron overload is not a benign condition regardless of etiology, and when recognized, surveillance for HCC and adequate therapy for reducing iron overload should be undertaken.

Other causes

PBC

There are several reports of NBNC-HCC with other causes than alcohol or NAFLD/NASH. According to the Japanese national data of patients with PBC, the HCC incidence was 2.4% (71/2946) and the HCC incidence according to sex was 5.1% (19/370) in men and 2.0% (52/2576) in women (55). Multivariate analysis of risk factors associated with PBC-related HCC development according to sex revealed histological fibrosis stage at the time of PBC diagnosis as an independent risk factor in women, but not in men (55). The authors concluded that male PBC patients should be particularly carefully screened for HCC from the early stages of PBC.

AIH

Although the clinical outcome in patients with AIH is generally good, there have been several patients with AIH who developed HCC (56). The National Hospital Organization Liver Network Study Group in Japan reported in 193 AIH patients that seven (3.6%) developed HCC during follow-up, and the presence of liver cirrhosis at presentation was an independent risk factor for HCC in patients with AIH.

PSC

PSC is a chronic inflammatory disease involving the biliary tract. PSC can lead to liver cirrhosis due to persistent inflammation in the liver, therefore, it is not surprising that PSC-related cirrhosis can develop into HCC. The risk of HCC development in PSC patients with liver cirrhosis is estimated to be up to 2% per year (57). However, the incidence of HCC for patients with PSC has not been fully studied (58).

Hereditary hemochromatosis and Wilson disease

Hereditary hemochromatosis is one of the most common autosomal recessive genetic disorders. It is caused by mutations in the HFE gene and/or other mutations in the iron metabolism system and is characterized by excess iron absorption and storage in the liver (59,60). Several population-based and case-control studies have demonstrated that hereditary hemochromatosis markedly elevates the risk of HCC (6164). A large population-based study from Sweden demonstrated that patients with hereditary hemochromatosis had a 20-fold increased risk of HCC (HR=21, 95% CI=16–22) but an almost unaltered risk of all other cancers (HR=1.2, 95% CI=1.0–1.4) (64).

Wilson disease is an autosomal recessive disorder of copper metabolism (65). A nationwide survey to examine the etiology of liver cirrhosis in Japan found Wilson disease in two (0.01%) of 16,117 patients with liver cirrhosis and HCC (66). Liver cirrhosis is a well-recognized complication of Wilson disease, but HCC is extremely rare (66).

Budd-Chiari syndrome

BCS is a rare hepatic disease caused by occlusion of the hepatic venous outflow. Several reports indicate that hepatic congestion caused by obstruction of hepatic venous outflow can lead to liver cirrhosis and even HCC (67,68). A meta-analysis from China including 16 studies in patients with BCS revealed that the prevalence of HCC in BCS was 2.0–46.2% in 12 Asian studies, 40.0–51.6% in two African studies, 11.3% in one European study and 11.1% in one American study (69). These results suggest that the prevalence of HCC in patients with BCS varies depending on geographical location. However, because a relatively high incidence of HCC in patients with BCS was observed in each study, routine radiological surveillance for HCC is warranted in patients with BCS.

OBI

In a small proportion of individuals, detectable HBV DNA in the serum and/or liver is observed in the absence of circulating hepatitis B surface antigen (HBsAg) (7072). OBI is defined by the presence of HBV DNA in the liver tissue of individuals who test negative for HBsAg, regardless of the detection of HBV DNA in the serum. The clinical implications of OBI involve causing cryptogenic liver disease and contributing to the progression of liver disease or even HCC (71,73). OBI may maintain direct mechanisms of HBV-related carcinogenesis via the ability to integrate into the host genome, and production of transforming proteins including mainly X and preS-S proteins (7375). In addition, OBI may exert pro-oncogenic properties through indirect mechanisms (72,74,75). These are associated with its propensity to induce persistent necroinflammation in the liver and to promote the progression of chronic hepatitis to liver cirrhosis. This indicates the step preceding HCC occurrence in the majority of cases.

Aflatoxins

Aflatoxins are naturally occurring mycotoxins produced by Aspergillus species. They commonly contaminate foods such as grain, peanuts and corn, and aflatoxin exposure is reported to elevate the risk of HCC (76). Chen et al conducted a community-based cohort study combined with molecular dosimetry of aflatoxin exposure to elucidate the relationship between the risk of HCC development and aflatoxins (77). Elevated aflatoxin exposure measured by detectable aflatoxin B1-albumin adducts was an independent risk factor for HCC development after adjusting for important confounders (HR=5.5, 95% CI=1.2–24.5). However, in Japan, aflatoxin-associated HCC is extremely rare (7).

Mechanism of carcinogenesis in NBNC-HCC

Although the detailed mechanism of liver carcinogenesis in patients with NBNC chronic liver disease remains elusive, insulin resistance and oxidative stress may be involved, especially in patients with NASH. NASH is characterized by insulin resistance with hyperinsulinemia, and the insulin resistance is reported to be associated with liver carcinogenesis (26,78). Insulin-like growth factor (IGF)-1 significantly activates mitogen-activated protein kinase, and increases over-expression of the c-Fos and c-Jun proto-oncogenes in cultured hepatoma cells, and IGF-1 is potentially involved in the development of HCC (7882). c-Jun N-terminal kinase (JNK)1 has also recently attracted attention because it is linked with obesity, insulin resistance, NASH and HCC. Obesity is linked to abnormal elevation of JNK activity (83). In addition, Puri et al reported that JNK activation increases hepatic inflammation and apoptosis (84). JNK1 may thus be the most essential kinase that is upregulated in HCC.

Adipose tissue is thought to be an endocrine organ because of its ability to secrete adipokines such as adiponection and leptin (85). Adiponectin and leptin are related to insulin resistance and obesity (85,86). Adiponectin has emerged as the most abundant circulating adipocytokine and is an anti-inflammatory polypeptide in adipose tissue (85). It is decreased in the presence of insulin resistance and inhibits angiogenesis through modulation of apoptosis in animal models (87). Severe liver steatosis and fibrosis are found in adiponectin knockout mice as compared with wild-type mice (86). In addition, liver adenoma and hyperplastic nodules develop within the liver in adiponectin knockout mice, whereas no tumor formation is found in wild-type mice (86). These observations suggest that adiponectin is inversely associated with liver disease progression. Leptin is the product of the obese gene and is mainly produced by adipose tissue, and promotes angiogenesis and mediates the progression of NASH to HCC in animal models (88,89). Leptin-mediated neovascularization, which coordinates with vascular endothelial growth factor, may accelerate liver fibrosis and cause liver carcinogenesis in patients with NASH, although its role in NAFLD or NASH is still unclear (88,89).

In NAFLD patients, mitochondrial dysfunction also leads to free radical production and oxidative stress, which may provide the ‘second hit’ that allows progression from steatosis to steatohepatitis, liver cirrhosis and even HCC (90). NASH-related insulin resistance causes inhibition of liver mitochondrial fatty acid oxidation, and increased intra-cellular fatty acids can lead to oxidative DNA damage via stimulating microsomal peroxidases (91). Oxidative stress may also promote carcinogenesis (92). Insulin resistance, hepatic steatosis, oxidative stress and imbalances in adipokines/cytokines interplay, which are the most essential factors involved in NAFLD pathogenesis and progression, could also have a pivotal role in liver carcinogenesis, through DNA damage and promoting cellular growth (90,93,94). In HCC patients with obesity, these correlations indicate a possible association between the metabolic syndrome and poor clinical outcomes.

Reactive oxygen species (ROS) can also activate fibrosis (90). Ishii et al demonstrated in animal models that eicosapentaenoic acid (EPA) improved steatohepatitis with decreasing serum ROS, which is associated with inhibited development of HCC (95). Treatment with EPA may minimize the risk of HCC development in patients with NASH. However, there are few promising drugs with the potential to reduce the risk of HCC development in patients with NASH.

Overall, obesity and insulin resistance are known to be related significantly to hepatic steatosis (96). Increased levels of hepatic steatosis are linked to more severe necroinflammatory activity and liver fibrosis, and several studies reported that the increase in steatosis may be a predictor for liver fibrosis progression (46,97,98). Subsequently, liver disease occurs more frequently in patients with more severe metabolic disorders, possibly leading to a higher rate of development of HCC.

Clinicopathological features and prognosis in patients with NBNC-HCC

Several studies have investigated the clinicopathological features of NBNC-HCC. Takuma et al reviewed 11 patients with NASH-associated HCC (6 male, 5 female; mean age, 73.8 years) who received curative treatment (99). They reported that most (91%) patients were diagnosed with obesity, DM, hypertension or dyslipidemia, and 7 patients (64%) also had a non-cirrhotic liver. Duan et al reported 169 patients with NAFLD-associated HCC (68 with non-cirrhotic liver and 101 with cirrhosis); 72.8% were male with a median age at abnormal liver function tests and diagnosis of NAFLD and HCC of 60, 64 and 67 years, respectively (100). Most patients had obesity (75%) and DM (59.8%), 32.3% had dyslipidemia, and 53% had hypertension. Nearly all patients were complicated with at least one metabolic disorder. In terms of tumor characteristics, the majority (76%) of the HCC patients had a solitary tumor nodule 0.8-20 cm in diameter (mean 3.4 cm) and most (61.1%) patients had moderately differentiated HCC. Reddy et al compared 52 patients with NASH-related HCC and 162 with HCV and/or alcohol-related HCC (101). NASH-related HCC patients were older, more often female, had higher BMI at HCC diagnosis, and more frequently had DM, dyslipidemia and the metabolic syndrome. Liver function at presentation was worse in patients with HCV/alcohol-related HCC.

Whether patients with NBNC-HCC have comparable prognosis to patients with HCC with other causes remains controversial. In a single-center retrospective study of patients with a maximum tumor size <5 cm, who received curative surgery, Kaibori et al reported that patients with NBNC-HCC tended to have a higher overall survival rate than those with HCV-related HCC (8). Patients with NBNC-HCC had a significantly higher disease-free survival rate than those with HCV-related HCC, although the difference in overall and disease-free survival between the two groups was not significant.

In a large retrospective comparative study, Li et al investigated 675 patients with NBNC-HCC and 3529 with hepatitis B surface antigen-positive/HCV-antibody-negative HCC who underwent curative resection (102). There were no significant differences between the two groups regarding overall survival, cumulative incidence of HCC-specific death and recurrence. Furthermore, in their multivariate analysis they found that female sex, serum γ-glutamyl transpeptidase level, tumor size, tumor capsule and tumor differentiation were independent risk factors associated with HCC-specific survival in patients with NBNC-HCC. They also claimed that women with NBNC-HCC should be closely monitored even after curative surgery.

Malik et al reported in a single-center prospective study that survival after liver transplantation in patients with HCC and NASH-related liver cirrhosis was 88%, with a mean follow-up of 2.5 years (103). There was no significant difference in 5-year survival between patients transplanted for NASH-related liver cirrhosis with and without HCC. There was no significant difference in 5-year survival after liver transplantation between HCC patients with and without NASH-related cirrhosis. They therefore concluded that patients with NASH and HCC have a favorable clinical outcome after liver transplantation.

Giannini et al demonstrated that HCC patients with CC had a significantly greater prevalence of advanced HCC stage, lower amenability to any treatment, and shorter survival compared with HCV-related HCC patients (104). This was because HCC in patients with CC is often diagnosed at an advanced stage owing to the lack of imaging surveillance systems.

Tokushige et al conducted prospective studies to clarify the outcomes and recurrence of HCC in NASH, compared with patients with HCV-related HCC (105). The 5-year survival rate was 55.2% and cumulative recurrence of HCC at 5 years was 69.8% in treated NASH-HCC, and both groups showed similar survival and recurrence rates.

Overall, owing to the lack of adequate surveillance of HCC in patients with NBNC liver disease, NBNC-HCC tends to be diagnosed at an advanced stage. However, in NBNC-HCC patients who undergo curative therapy, clinical outcomes after HCC therapy in NBNC-HCC patients are comparable or even better than those in patients with hepatitis-related HCC. Previous reports of clinical characteristics and clinical outcomes in patients with NBNC-HCC are summarized in Table I.

Table I.

Reported studies of clinical characteristics and outcomes in non-B and non-C hepatocellular carcinoma.

Table I.

Reported studies of clinical characteristics and outcomes in non-B and non-C hepatocellular carcinoma.

Authors/(Refs.)No. of patients (m/f)AgeTreatmentLC (yes/no)Tumor size (cm)Tumor no. (s/m)Prevalence of comorbid disease (%)Survival after therapy

DMBMI ≥ 25 kg/m2DL
Kusakabe et al (106)45 (28/17)65.8 (mean)NANA4.4 cm (mean)30/1517/45 (38%)15/45 (33%)NANA
Hatanaka et al (107)240 (186/54)67.4 (mean)NANA5.1 cm (mean)NA43/80 (53.8%)NANANA
Abe et al (9)64 (51/13)69 (median)NA53/64 (82.8%)NA32/6429/64 (45.3%)12/64 (18.8%)NANA
Tokushige et al (105)34 (21/13)70 (median)NAF3 or F4 (88%)NANA25/34 (74%)21/34 (62%)10/34 (29%)5-year OS, 69.8% 5-year RFS, 30.2%
Reddy et al (101)52 (27/25)65 (median)TACE, surgery, RFA38/143.0 cm (median)NA28/52 (53.8%)Median, 31.3 kg/m2 Range, 27.6–33.9 kg/m217/52 (32.7%)3-year OS, 60.9%
Duan et al (100)169 (123/46)67 (median)TACE, surgery, LT, RFA, PEI101/683.4 cm (mean)128/41101/169 (59.8%)127/169 (75%)32.3%NA
Kaibori et al (8)60 (52/8)66.6 (mean)Surgery15/455.57 cm (mean)50/1025/60 (41.7%)NANA3-year OS, 75% 3-year RFS, 45%
Li et al (102)675 (521/154)181 (≤ 50 years) 494 (>50 years)Surgery367/308<5 cm, 263 (39%) >5 cm, 412 (61%)599/76NANANA3-year OS, 57% 5-year OS, 48.8%
Nishikawa et al (108)260 (199/61)70 (median)TACE, surgery, RFA, PEINA3.0 cm (median)169/91128/260 (49.2%)116/260 (44.6%)NA3-year OS, 77% 3-year RFS, 36%
Cauchy et al (109)62 (58/4)70 (median)SurgeryF0-2, 24/62 F3,4, 38/62Range, 2.5–3.5 cmNA52/62 (84%)Median, 30.4 kg/m2 Range, 20.2–42.0 kg/m240/62 (65%)3-year OS, 75% 3-year RFS, 70%

[i] LC, liver cirrhosis; DM, diabetes mellitus; BMI, body mass index; DL, dyslipidemia; TACE, transcatheter arterial chemoembolization; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; LT, liver transplantation; OS, overall survival; RFS, recurrence-free survival; NA, not available; m/f, male/female; s/m, single/multiple.

Conclusion

Various factors unrelated to hepatitis virus are implicated in the development of HCC. Cumulative evidence suggests that NAFLD and NASH, which are hepatic manifestations of the metabolic syndrome that includes hypertension, obesity, insulin resistance and hyperlipidemia, can progress to cirrhosis and HCC. Obesity or DM itself can be an independent risk factor for the development of HCC. Insulin resistance, oxidative stress and adipokines are closely associated with liver carcinogenesis. Most patients with NBNC-HCC may have at least one metabolic disorder. Owing to the lack of adequate surveillance of NBNC-HCC, HCC tends to be diagnosed at an advanced stage. However, in NBNC-HCC patients who undergo curative therapy, clinical outcomes after HCC therapy in NBNC-HCC patients may be comparable or even better than in patients with hepatitis-related HCC. Furthermore, the ability to decide which patients with liver disease with non-viral causes will develop HCC will have screening implications in the future.

Acknowledgements

The authors would like to thank all the staff in their hospital for their valuable support.

References

1. 

Livraghi T, Mäkisalo H and Line PD: Treatment options in hepatocellular carcinoma today. Scand J Surg. 100:22–29. 2011.PubMed/NCBI

2. 

El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 142:1264–1273. 2012. View Article : Google Scholar : PubMed/NCBI

3. 

De Lope CR, Tremosini S, Forner A, Reig M and Bruix J: Management of HCC. J Hepatol. 56(Suppl 1): S75–S87. 2012.

4. 

Nishikawa H, Osaki Y, Iguchi E, Takeda H, Matsuda F, Nakajima J, Sakamoto A, Hatamaru K, Saito S, Nasu A, Kita R and Kimura T: Radiofrequency ablation for hepatocellular carcinoma: the relationship between a new grading system for the ablative margin and clinical outcomes. J Gastroenterol. Oct 12–2012.(Epub ahead of print).

5. 

Nishikawa H, Arimoto A, Wakasa T, Kita R, Kimura T and Osaki Y: Surgical resection for hepatocellular carcinoma: clinical outcomes and safety in elderly patients. Eur J Gastroenterol Hepatol. 25:912–919. 2013. View Article : Google Scholar : PubMed/NCBI

6. 

Umemura T, Ichijo T, Yoshizawa K, Tanaka E and Kiyosawa K: Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol. 44(Suppl 19): 102–107. 2009. View Article : Google Scholar

7. 

Tokushige K, Hashimoto E, Horie Y, Taniai M and Higuchi S: Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey. J Gastroenterol. 46:1230–1237. 2011. View Article : Google Scholar

8. 

Kaibori M, Ishizaki M, Matsui K and Kwon AH: Clinicopathologic characteristics of patients with non-B non-C hepatitis virus hepatocellular carcinoma after hepatectomy. Am J Surg. 204:300–307. 2012. View Article : Google Scholar

9. 

Abe H, Yoshizawa K, Kitahara T, Aizawa R, Matsuoka M and Aizawa Y: Etiology of non-B non-C hepatocellular carcinoma in the eastern district of Tokyo. J Gastroenterol. 43:967–974. 2008. View Article : Google Scholar : PubMed/NCBI

10. 

Nagaoki Y, Hyogo H, Aikata H, Tanaka M, Naeshiro N, Nakahara T, Honda Y, Miyaki D, Kawaoka T, Takaki S, Hiramatsu A, Waki K, Imamura M, Kawakami Y, Takahashi S and Chayama K: Recent trend of clinical features in patients with hepatocellular carcinoma. Hepatol Res. 42:368–375. 2012. View Article : Google Scholar : PubMed/NCBI

11. 

Suzuki Y, Ohtake T, Nishiguchi S, Hashimoto E, Aoyagi Y, Onji M and Kohgo Y: The Japan Non-B, Non-C Liver Cirrhosis Study Group: Survey of non-B, non-C liver cirrhosis in Japan. Hepatol Res. Dec 26–2012.(Epub ahead of print).

12. 

Kim SK, Marusawa H, Eso Y, Nishikawa H, Ueda Y, Kita R, Kimura T, Chiba T, Osaki Y and Kudo M: Clinical characteristics of non-B non-C hepatocellular carcinoma: a single-center retrospective study. Digestion. 84(Suppl 1): 43–49. 2011. View Article : Google Scholar : PubMed/NCBI

13. 

Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L and Salizzoni M: Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 123:134–140. 2002. View Article : Google Scholar : PubMed/NCBI

14. 

Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM and Lok AS: NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 36:1349–1354. 2002. View Article : Google Scholar : PubMed/NCBI

15. 

Torres DM and Harrison SA: Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma: fertile soil. Semin Liver Dis. 32:30–38. 2012. View Article : Google Scholar : PubMed/NCBI

16. 

Calle EE, Rodriguez C, Walker-Thurmond K and Thun MJ: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med. 348:1625–1638. 2003. View Article : Google Scholar : PubMed/NCBI

17. 

Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Shirai Y, Douhara A and Fukui H: Possible involvement of angiogenesis in chronic liver diseases: interaction among renin-angiotensin-aldosterone system, insulin resistance and oxidative stress. Curr Med Chem. 19:1889–1898. 2012. View Article : Google Scholar

18. 

Yasui K, Hashimoto E, Tokushige K, Koike K, Shima T, Kanbara Y, Saibara T, Uto H, Takami S, Kawanaka M and Komorizono Y: Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. Hepatol Res. 42:767–773. 2012. View Article : Google Scholar : PubMed/NCBI

19. 

Chung H, Ueda T and Kudo M: Changing trends in hepatitis C infection over the past 50 years in Japan. Intervirology. 53:39–43. 2010.PubMed/NCBI

20. 

Schaefer EA and Chung RT: Anti-hepatitis C virus drugs in development. Gastroenterology. 142:1340–1350. 2012. View Article : Google Scholar : PubMed/NCBI

21. 

Jacobson IM, Pawlotsky JM, Afdhal NH, Dusheiko GM, Forns X, Jensen DM, Poordad F and Schulz J: A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat. 19(Suppl 2): 1–26. 2012. View Article : Google Scholar : PubMed/NCBI

22. 

Rosen HR: Clinical practice. Chronic hepatitis C infection N Engl J Med. 364:2429–2438. 2011.PubMed/NCBI

23. 

Ertle J, Dechêne A, Sowa JP, Penndorf V, Herzer K, Kaiser G, Schlaak JF, Gerken G, Syn WK and Canbay A: Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. 128:2436–2443. 2011. View Article : Google Scholar : PubMed/NCBI

24. 

Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, Decarli A, Trevisi P, Ribero ML, Martelli C, Porru S and Nardi G: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol. 155:323–331. 2002. View Article : Google Scholar : PubMed/NCBI

25. 

Corrao G, Bagnardi V, Zambon A and La Vecchia C: A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med. 38:613–619. 2004. View Article : Google Scholar : PubMed/NCBI

26. 

Sookoian S and Pirola CJ: The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis. 16:467–485. 2012. View Article : Google Scholar : PubMed/NCBI

27. 

Shen L, Fan JG, Shao Y, Zeng MD, Wang JR, Luo GH, Li JQ and Chen SY: Prevalence of nonalcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey. World J Gastroenterol. 9:1106–1110. 2003.PubMed/NCBI

28. 

Ong JP and Younossi ZM: Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis. 11:1–16. 2007. View Article : Google Scholar : PubMed/NCBI

29. 

Kojima S, Watanabe N, Numata M, Ogawa T and Matsuzaki S: Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol. 38:954–961. 2003.PubMed/NCBI

30. 

Harrison SA, Torgerson S and Hayashi PH: The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 98:2042–2047. 2003. View Article : Google Scholar : PubMed/NCBI

31. 

Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW and Powell LW: The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 11:74–80. 1990.PubMed/NCBI

32. 

Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K and Shiratori K: Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol. 44(Suppl 19): 89–95. 2009. View Article : Google Scholar

33. 

Hashizume H, Sato K, Takagi H, Hirokawa T, Kojima A, Sohara N, Kakizaki S, Mochida Y, Shimura T and Sunose Y: Primary liver cancers with nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol. 19:827–834. 2007. View Article : Google Scholar : PubMed/NCBI

34. 

Yoshioka Y, Hashimoto E, Yatsuji S, Kaneda H, Taniai M, Tokushige K and Shiratori K: Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol. 39:1215–1218. 2004. View Article : Google Scholar : PubMed/NCBI

35. 

Ayata G, Gordon FD, Lewis WD, Pomfret E, Pomposelli JJ, Jenkins RL and Khettry U: Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation. Hum Pathol. 33:1098–1104. 2002. View Article : Google Scholar : PubMed/NCBI

36. 

Starley BQ, Calcagno CJ and Harrison SA: Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 51:1820–1832. 2010. View Article : Google Scholar : PubMed/NCBI

37. 

Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF and Zein NN: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 51:1972–1978. 2010. View Article : Google Scholar : PubMed/NCBI

38. 

Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K and Shiratori K: Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol. 24:248–254. 2009. View Article : Google Scholar : PubMed/NCBI

39. 

Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA and McGlynn KA: Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 54:463–471. 2011. View Article : Google Scholar : PubMed/NCBI

40. 

El-Serag HB, Tran T and Everhart JE: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 126:460–468. 2004. View Article : Google Scholar : PubMed/NCBI

41. 

Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, Li G and Wang L: Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 130:1639–1648. 2012. View Article : Google Scholar : PubMed/NCBI

42. 

Neuschwander-Tetri BA and Caldwell SH: Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 37:1202–1219. 2003. View Article : Google Scholar : PubMed/NCBI

43. 

Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA and Maldonado-Garza H: Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol. 15:280–288. 2009. View Article : Google Scholar : PubMed/NCBI

44. 

Allison ME, Wreghitt T, Palmer CR and Alexander GJ: Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 21:1135–1139. 1994. View Article : Google Scholar : PubMed/NCBI

45. 

El-Serag HB, Johnson ML, Hachem C and Morgana RO: Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 136:1601–1608. 2009. View Article : Google Scholar : PubMed/NCBI

46. 

Ohata K, Hamasaki K, Toriyama K, Matsumoto K, Saeki A, Yanagi K, Abiru S, Nakagawa Y, Shigeno M, Miyazoe S, Ichikawa T, Ishikawa H, Nakao K and Eguchi K: Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. 97:3036–3043. 2003. View Article : Google Scholar : PubMed/NCBI

47. 

Shimizu M, Tanaka T and Moriwaki H: Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis. Semin Immunopathol. 35:191–202. 2013. View Article : Google Scholar : PubMed/NCBI

48. 

Bianchini F, Kaaks R and Vainio H: Overweight, obesity, and cancer risk. Lancet Oncol. 3:565–574. 2002. View Article : Google Scholar : PubMed/NCBI

49. 

Larsson SC and Wolk A: Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 97:1005–1008. 2007.PubMed/NCBI

50. 

Moller H, Mellemgaard A, Lindvig K and Olsen JH: Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer. 30A:344–350. 1994. View Article : Google Scholar : PubMed/NCBI

51. 

Oh SW, Yoon YS and Shin SA: Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol. 23:4742–4754. 2005. View Article : Google Scholar

52. 

Drakesmith H and Prentice A: Viral infection and iron metabolism. Nat Rev Microbiol. 6:541–552. 2008. View Article : Google Scholar

53. 

Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A and Vecchione R: Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steatohepatitis. J Hepatol. 50:351–357. 2009. View Article : Google Scholar : PubMed/NCBI

54. 

Ioannou GN, Weiss NS and Kowdley KV: Relationship between transferrin-iron saturation, alcohol consumption, and the incidence of cirrhosis and liver cancer. Clin Gastroenterol Hepatol. 5:624–629. 2007. View Article : Google Scholar : PubMed/NCBI

55. 

Harada K, Hirohara J, Ueno Y, Nakano T, Kakuda Y, Tsubouchi H, Ichida T and Nakanuma Y: Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology. 57:1942–1949. 2013. View Article : Google Scholar : PubMed/NCBI

56. 

Migita K, Watanabe Y, Jiuchi Y, Nakamura Y, Saito A, Yagura M, Ohta H, Shimada M, Mita E, Hijioka T, Yamashita H, Takezaki E, Muro T, Sakai H, Nakamuta M, Abiru S, Komori A, Ito M, Yatsuhashi H, Nakamura M and Ishibashi H: Japanese NHO-Liver-network study group: Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study). Liver Int. 32:837–844. 2012. View Article : Google Scholar

57. 

Harnois DM, Gores JG, Ludwig J, Steers JL, LaRusso NE and Wiesner RH: Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol. 27:512–516. 1997. View Article : Google Scholar : PubMed/NCBI

58. 

Razumilava N, Gores GJ and Lindor KD: Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology. 54:1842–1852. 2011. View Article : Google Scholar : PubMed/NCBI

59. 

Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH and Kushner JP: Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med. 318:1355–1362. 1988. View Article : Google Scholar : PubMed/NCBI

60. 

Powell LW, Subramaniam VN and Yapp TR: Haemochromatosis in the new millennium. J Hepatol. 32:48–62. 2000. View Article : Google Scholar

61. 

Hsing AW, McLaughlin JK, Olsen JH, Mellemkjar L, Wacholder S and Fraumeni JF Jr: Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int J Cancer. 60:160–162. 1995. View Article : Google Scholar : PubMed/NCBI

62. 

Fracanzani AL, Conte D, Fraquelli M, Taioli E, Mattioli M, Losco A and Fargion S: Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology. 33:647–651. 2001. View Article : Google Scholar : PubMed/NCBI

63. 

Yang Q, McDonnell SM, Khoury MJ, Cono J and Parrish RG: Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of multiple-cause mortality data. Ann Intern Med. 129:946–953. 1998. View Article : Google Scholar : PubMed/NCBI

64. 

Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Olsson S, Olsson R, Lindgren S, Lööf L, Stål P, Wallerstedt S, Almer S, Sandberg-Gertzén H and Askling J: Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology. 125:1733–1741. 2003. View Article : Google Scholar : PubMed/NCBI

65. 

Wang Y, Xie CL, Fu DL, Lu L, Lin Y, Dong QQ, Wang XT and Zheng GQ: Clinical efficacy and safety of Chinese herbal medicine for Wilson's disease: a systematic review of 9 randomized controlled trials. Complement Ther Med. 20:143–154. 2012.

66. 

Michitaka K, Nishiguchi S, Aoyagi Y, Hiasa Y, Tokumoto Y and Onji M: Japan Etiology of Liver Cirrhosis Study Group: Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 45:86–94. 2010. View Article : Google Scholar : PubMed/NCBI

67. 

Tanaka M and Wanless IR: Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules. Hepatology. 27:488–496. 1998. View Article : Google Scholar : PubMed/NCBI

68. 

Okuda K: Inferior vena cava thrombosis at its hepatic portion (obliterative hepatocavopathy). Semin Liver Dis. 22:15–26. 2002. View Article : Google Scholar : PubMed/NCBI

69. 

Ren W, Qi X, Yang Z, Han G and Fan D: Prevalence and risk factors of hepatocellular carcinoma in Budd-Chiari syndrome: a systematic review. Eur J Gastroenterol Hepatol. 25:830–841. 2013. View Article : Google Scholar : PubMed/NCBI

70. 

Raimondo G, Pollicino T, Cacciola I and Squadrito G: Occult hepatitis B virus infection. J Hepatol. 46:160–170. 2007. View Article : Google Scholar : PubMed/NCBI

71. 

Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxì A, Donato F, Ferrari C, Gaeta GB, Gerlich WH, Levrero M, Locarnini S, Michalak T, Mondelli MU, Pawlotsky JM, Pollicino T, Prati D, Puoti M, Samuel D, Shouval D, Smedile A, Squadrito G, Trépo C, Villa E, Will H, Zanetti AR and Zoulim F: Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 49:652–657. 2008. View Article : Google Scholar : PubMed/NCBI

72. 

Nishikawa H, Arimoto A, Wakasa T, Kita R, Kimura T and Osaki Y: Lack of correlation between the antibody to hepatitis B core antigen and survival after surgical resection for hepatitis C virus-related hepatocellular carcinoma. Oncol Rep. 30:91–98. 2013.

73. 

Raimondo G, Caccamo G, Filomia R and Pollicino T: Occult HBV infection. Semin Immunopathol. 35:39–52. 2013. View Article : Google Scholar

74. 

Squadrito G, Pollicino T, Cacciola I, Caccamo G, Villari D, La Masa T, Restuccia T, Cucinotta E, Scisca C, Magazzu D and Raimondo G: Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients. Cancer. 106:1326–1330. 2006. View Article : Google Scholar : PubMed/NCBI

75. 

Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Craxi A, Farinati F, Missale G, Smedile A, Tiribelli C, Villa E and Raimondo G: Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology. 126:102–110. 2004. View Article : Google Scholar : PubMed/NCBI

76. 

Wu HC and Santella R: The role of aflatoxins in hepatocellular carcinoma. Hepat Mon. 12:e72382012.PubMed/NCBI

77. 

Chen CJ, Wang LY, Lu SN, Wu MH, You SL, Zhang YJ, Wang LW and Santella RM: Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma. Hepatology. 24:38–42. 1996. View Article : Google Scholar : PubMed/NCBI

78. 

Kawaguchi T, Izumi N, Charlton MR and Sata M: Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 54:1063–1070. 2011. View Article : Google Scholar : PubMed/NCBI

79. 

Price JA, Kovach SJ, Johnson T, Koniaris LG, Cahill PA, Sitzmann JV and McKillop IH: Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology. 36:1089–1097. 2002. View Article : Google Scholar : PubMed/NCBI

80. 

Buzzelli G, Dattolo P, Pinzani M, Brocchi A, Romano S and Gentilini P: Circulating growth hormone and insulin-like growth factor-I in nonalcoholic liver cirrhosis with or without superimposed hepatocarcinoma: evidence of an altered circadian rhythm. Am J Gastroenterol. 88:1744–1748. 1993.

81. 

Kasprzak A and Adamek A: The insulin-like growth factor (IGF) signaling axis and hepatitis C virus-associated carcinogenesis (Review). Int J Oncol. 41:1919–1931. 2012.PubMed/NCBI

82. 

Shimizu M, Kubota M, Tanaka T and Moriwaki H: Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis. Int J Mol Sci. 13:579–595. 2012. View Article : Google Scholar : PubMed/NCBI

83. 

Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M and Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature. 420:333–336. 2002. View Article : Google Scholar : PubMed/NCBI

84. 

Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM and Sanyal AJ: Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 134:568–576. 2008. View Article : Google Scholar : PubMed/NCBI

85. 

Duan XF, Tang P, Li Q and Yu ZT: Obesity, adipokines and hepatocellular carcinoma. Int J Cancer. Feb 12–2013.(Epub ahead of print).

86. 

Asano T, Watanabe K, Kubota N, Gunji T, Omata M, Kadowaki T and Ohnishi S: Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J Gastroenterol Hepatol. 24:1669–1676. 2009. View Article : Google Scholar : PubMed/NCBI

87. 

Brakenhielm E, Veitonmäki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T and Cao Y: Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA. 101:2476–2481. 2004. View Article : Google Scholar : PubMed/NCBI

88. 

Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K, Yoshii J, Yanase K, Namisaki T and Asada K: Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology. 44:983–991. 2006. View Article : Google Scholar : PubMed/NCBI

89. 

Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T and Sato N: Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology. 122:1399–1410. 2002. View Article : Google Scholar : PubMed/NCBI

90. 

Angulo P: Nonalcoholic fatty liver disease. N Engl J Med. 346:1221–1231. 2002. View Article : Google Scholar : PubMed/NCBI

91. 

Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA and Diehl AM: Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 378:259–268. 2000. View Article : Google Scholar : PubMed/NCBI

92. 

Nowsheen S, Aziz K, Kryston TB, Ferguson NF and Georgakilas A: The interplay between inflammation and oxidative stress in carcinogenesis. Curr Mol Med. 12:672–680. 2012. View Article : Google Scholar : PubMed/NCBI

93. 

Marnett LJ: Oxyradicals and DNA damage. Carcinogenesis. 21:361–370. 2000. View Article : Google Scholar : PubMed/NCBI

94. 

Petta S and Craxì A: Hepatocellular carcinoma and non-alcoholic fatty liver disease: from a clinical to a molecular association. Curr Pharm Des. 16:741–752. 2010. View Article : Google Scholar : PubMed/NCBI

95. 

Ishii H, Horie Y, Ohshima S, Anezaki Y, Kinoshita N, Dohmen T, Kataoka E, Sato W, Goto T and Sasaki J: Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice. J Hepatol. 50:562–571. 2009. View Article : Google Scholar : PubMed/NCBI

96. 

Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P and Poynard T: Liver fibrosis in overweight patients. Gastroenterology. 118:1117–1123. 2000. View Article : Google Scholar : PubMed/NCBI

97. 

Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R and Ruggiero G: Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 33:1358–1364. 2001. View Article : Google Scholar : PubMed/NCBI

98. 

Westin J, Nordlinder H, Lagging M, Norkrans G and Wejstal R: Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol. 37:837–842. 2002. View Article : Google Scholar : PubMed/NCBI

99. 

Takuma Y and Nouso K: Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. World J Gastroenterol. 16:1436–1441. 2010. View Article : Google Scholar : PubMed/NCBI

100. 

Duan XY, Qiao L and Fan JG: Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 11:18–27. 2012. View Article : Google Scholar : PubMed/NCBI

101. 

Reddy SK, Steel JL, Chen HW, DeMateo DJ, Cardinal J, Behari J, Humar A, Marsh JW, Geller DA and Tsung A: Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology. 55:1809–1819. 2012. View Article : Google Scholar : PubMed/NCBI

102. 

Li T, Qin LX, Gong X, Zhou J, Sun HC, Qiu SJ, Ye QH, Wang L and Fan J: Hepatitis B virus surface antigen-negative and hepatitis C virus antibody-negative hepatocellular carcinoma: clinical characteristics, outcome, and risk factors for early and late intrahepatic recurrence after resection. Cancer. 119:126–135. 2013. View Article : Google Scholar

103. 

Malik SM, Gupte PA, de Vera ME and Ahmad J: Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma. Clin Gastroenterol Hepatol. 7:800–806. 2009. View Article : Google Scholar : PubMed/NCBI

104. 

Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P, Benvegnù L, Farinati F, Zoli M and Borzio F: Hepatocellular carcinoma in patients with cryptogenic cirrhosis. Clin Gastroenterol Hepatol. 7:580–585. 2009. View Article : Google Scholar : PubMed/NCBI

105. 

Tokushige K, Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N and Shiratori K: Prospective study of hepatocellular carcinoma in nonalcoholic steatohepatitis in comparison with hepatocellular carcinoma caused by chronic hepatitis C. J Gastroenterol. 45:960–967. 2010. View Article : Google Scholar : PubMed/NCBI

106. 

Kusakabe A, Tanaka Y, Orito E, Sugauchi F, Kurbanov F, Sakamoto T, Shinkai N, Hirashima N, Hasegawa I, Ohno T, Ueda R and Mizokami M: A weak association between occult HBV infection and non-B non-C hepatocellular carcinoma in Japan. J Gastroenterol. 42:298–305. 2007. View Article : Google Scholar : PubMed/NCBI

107. 

Hatanaka K, Kudo M, Fukunaga T, Ueshima K, Chung H, Minami Y, Sakaguchi Y, Hagiwara S, Orino A and Osaki Y: Clinical characteristics of nonBnonC-HCC: comparison with HBV and HCV related HCC. Intervirology. 50:24–31. 2007. View Article : Google Scholar : PubMed/NCBI

108. 

Nishikawa H, Osaki Y, Takeda H, Sakamoto A, Saito S, Nishijima N, Nasu A, Arimoto A, Kita R and Kimura T: Effect of body mass index on survival after curative therapy for non-B non-C hepatocellular carcinoma. J Gastrointestin Liver Dis. 22:173–181. 2013.PubMed/NCBI

109. 

Cauchy F, Zalinski S, Dokmak S, Fuks D, Farges O, Castera L, Paradis V and Belghiti J: Surgical treatment of hepatocellular carcinoma associated with the metabolic syndrome. Br J Surg. 100:113–121. 2013. View Article : Google Scholar : PubMed/NCBI

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APA
Nishikawa, H., & Nishikawa, H. (2013). Non-B, non-C hepatocellular carcinoma (Review). International Journal of Oncology, 43, 1333-1342. https://doi.org/10.3892/ijo.2013.2061
MLA
Nishikawa, H., Osaki, Y."Non-B, non-C hepatocellular carcinoma (Review)". International Journal of Oncology 43.5 (2013): 1333-1342.
Chicago
Nishikawa, H., Osaki, Y."Non-B, non-C hepatocellular carcinoma (Review)". International Journal of Oncology 43, no. 5 (2013): 1333-1342. https://doi.org/10.3892/ijo.2013.2061