Hepatocellular carcinoma (HCC) is the fifth-most-common cancer worldwide and the third-most-common cause of cancer mortality (Bosch et al., 2004). According to the most recent nationwide Japanese registration data, primary liver cancer ranks fourth in men and sixth in women as a cause of death from malignant neoplasm (Health and Welfare Statistics Association Japan, 2009). With regard to underlying liver disease, the latest nationwide report by the Liver Cancer Study Group of Japan, which registers such a report every 2 years, showed that hepatitis C virus (HCV) is the most common underlying liver disease in HCC (Ikai et al., 2007). HCV-related HCC accounts for 67% of all cases of HCC, followed by hepatitis B virus (HBV) at 16%. However, the incidence of HCV-related HCC has gradually decreased in recent years and that of HCC in cases of liver disease with a nonviral cause has gradually increased. According to our national survey of HCC, 15.8% of HCC cases were caused by nonviral liver diseases (Tokushige et al., 2011). Among the nonviral liver diseases, 45.6% were alcoholic liver diseases (ALDs), 32.3% were of unknown etiology, and 12.7% were nonalcoholic fatty liver diseases (NAFLDs). The increase in HCC related to NAFLD or ALD is becoming an especially urgent problem in Japan. It is important to accurately determine the development rate of HCC and the risk factors for HCC in both diseases.
Both ALD and NAFLD have similar liver histology, with changes such as steatosis or steatohepatitis, and NAFLD and ALD are distinguished only by alcohol consumption. However, the clinical features are clearly different between these 2 types of steatohepatitis (Scaglioni et al., 2011). Concerning extrahepatic malignancies, their development, such as prostate cancer, is becoming a problem in patients with NAFLD (Arase et al., 2012). It is well known that ALD occurs more frequently in western countries, but its prevalence is now increasing in Japan (Taniai et al., 2012). Alcohol is carcinogenic to humans, and alcohol intake is related to cancer at several sites, including the oral cavity, pharynx, esophagus, colorectum, and female breast (Boffetta and Hashibe, 2006). However, there have been few studies of extrahepatic malignancies in cirrhotic ALD (ALD-LC) patients, and it is unclear whether HCC or extrahepatic malignancies have a critical influence on the prognosis of ALD-LC.
Differences in the carcinogenic factors among steatohepatitis, nonalcoholic steatohepatitis (NASH), and ALD are also unknown. Some clinical entities of fatty liver disorder, including alcohol, insulin resistance, and others, have been proposed (Neuschwander-Tetri and Caldwell, 2003). When managing patients with NASH or ALD, it is important to know the carcinogenic features of both diseases.
To clarify the factors related to carcinogenesis in patients with steatohepatitis, we investigated carcinogenesis in the liver and other organs, as well as the risk factors for HCC associated with NASH and ALD.
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- Materials and Methods
- Supporting Information
Table 1 lists the clinical data for the NASH-LC and ALD-LC groups. The gender difference was significant (percentage of women, NASH-LC: 68%; ALD-LC: 12%).The median age of the NASH-LC group was significantly higher than that of the ALD-LC group (NASH-LC: 63.5 ± 12.9 years; ALD-LC: 55.0 ± 10.7 years). The smoking rate of the ALD-LC group was significantly higher than that of the NASH-LC group, while the NASH-LC group had significantly higher prevalence rates of obesity, DM, dyslipidemia, and HT than the ALD-LC group. Regarding biochemical data, serum albumin, prothrombin time, and ALT levels were significantly higher in NASH-LC, while serum total bilirubin and γ-GTP levels were significantly higher in ALD-LC. Child–Pugh grade and platelet count were not significantly different between the 2 groups. The histological features are shown in Table S1. The grade of steatosis was higher in NASH-LC, but the grade of ballooning hepatocytes and the frequencies of pericellular and perivenular fibrosis were higher in ALD-LC.
Table 1. Clinical Profiles of the 2 LC Groups
| ||NASH-LC||ALD-LC|| p-Value|
|Gender (F/M)||49/23 (68%/32%)||10/75 (12%/88%)||0.002|
|Age||63.5 ± 12.9||55.0 ± 10.7||0.000|
|Follow-up (months)||50 ± 43.1||36 ± 40.5||NS|
|Smoking||16 (22.2%)||57 (67.1%)||0.000|
|Obesity||53 (74%)||15 (17.6%)||0.000|
|BMI (kg/m2)||27.7 ± 5.3||22.2 ± 3.2||0.000|
|Diabetes mellitus||42 (58%)||30 (35%)||0.004|
|Dyslipidemia||30 (42%)||14 (16%)||0.0005|
|Hypertension||39 (54%)||20 (23.5%)||0.00001|
|Albumin (g/dl)|| 3.8 ± 0.69|| 3.3 ± 0.65||0.002|
|Total bilirubin (mg/dl)|| 0.8 ± 0.81|| 1.1 ± 2.36||0.005|
|AST (IU/l)||50.5 ± 42.3||55 ± 208.3||NS|
|ALT (IU/l)||46.0 ± 43.2||31 ± 91.6||0.006|
|γ-GTP (IU/l)||80.5 ± 68.7||159 ± 313.4||0.000|
|Platelet count (×104/μl)||11.8 ± 6.1||11.8 ± 7.1||NS|
|Prothrombin time (%)||81.0 ± 15.8||68.0 ± 20.9||0.005|
|Child (A/B or C)||56/16 (78%/22%)||57/28 (67%/33%)||NS|
During follow-up, 10 NASH-LC patients and 6 ALD-LC patients developed HCC, but there were no cases of cholangio-cellular carcinoma. The clinical data of the 10 HCCs from NASH-LC and 6 HCCs from ALD-LC are shown in Table S2. There was no difference between the 2 groups. As all LC patients were checked every 3 months, most HCCs were found at a relatively early stage. Representative images of NASH-HCC and ALD-HCC are shown in Fig. S1.
Figure 1 A shows the development rate of HCC in the NASH-LC and ALD-LC groups. The curves of the 2 groups were similar, with the 5-year HCC development rate being 10.5% in the NASH-LC group and 12.3% in the ALD-LC group. After adjusting for age and gender (ALD-LC, n = 32; mean age, 55.8 ± 8.2 years; male, 69%; NASH-LC, n = 32; median age, 55.6 ± 13.7 years; male, 69%), the HCC rates were also quite similar (Fig. 1 B).
Figure 1. Development of HCC in NASH-LC and ALD-LC groups. (A) HCC rate in all patients. HCC incidence was similar. The 5-year HCC development rate was 10.5% in the NASH-LC group and 12.3% in the ALD-LC group. (B) HCC rate in adjusted patients. After adjusting for age and gender, HCC rates were still similar. ALD, alcoholic liver disease; HCC, hepatocellular carcinoma; NASH, nonalcoholic steatohepatitis.
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By Cox hazards model, 3 significant risk factors for HCC development, namely older age (p = 0.024), higher serum γ-GTP level (p = 0.023), and higher Child–Pugh score (p = 0.006), were identified in NASH-LC (Table 2A). On the other hand, no significant risk factor for HCC was found in the ALD-LC group.
Table 2. Risk Factors for HCC in NASH-LC and ALD-LC Groups According to Cox Hazards Model
| || p-Value||HR||95% CI|
|Factors: age, gender, BMI, ascites, Varies, encephalopathy, DM, HT, dyslipidemia, total bilirubin, albumin, AST, ALT, ALP, γ-GTP, platelets, prothrombin time, Child–Pugh score|
|Age||0.024||1.12||1.014 to 1.226|
|γ-GTP||0.023||1.01||1.002 to 1.022|
|Child–Pugh score||0.006||3.09||1.374 to 6.934|
|Factors: age, gender, alcohol intake, BMI, DM, HT, ascites, Varies, encephalopathy, dyslipidemia, total bilirubin, albumin, AST, ALT, ALP, γ-GTP, platelets, prothrombin time, Child–Pugh score|
|Age||0.434||2.26||0.29 to 17.6|
|DM||0.705||4.239||0.00 to >10,000|
These risk factors for HCC in the NASH-LC group were confirmed by Kaplan–Meier analysis using the log-rank test (Fig. 2 A–C). NASH-LC patients aged ≥58 years had a significantly higher HCC rate compared with NASH-LC patients aged ≤57 years (p = 0.017). In addition, NASH-LC patients with a serum γ-GTP level ≥115 U/l also had a higher HCC rate compared with those with γ-GTP ≤114 U/l (p = 0.077). Furthermore, NASH-LC patients with Child–Pugh B or C showed a significantly higher HCC rate compared with patients with Child–Pugh A (p = 0.037).
Figure 2. Comparison of HCC rates by risk factors. (A) Association between age and HCC rate in NASH-LC. NASH-LC patients aged ≥58 years had a significantly higher HCC rate compared with NASH-LC patients aged ≤57 years (p = 0.017). (B) Association between γ-GTP and HCC rate in NASH-LC. NASH-LC patients with serum γ-GTP ≥115 U/l had a higher HCC rate compared with NASH-LC patients with γ-GTP ≤114 U/l (p = 0.077). (C) Association between Child–Pugh grade and HCC rate in NASH-LC. NASH-LC patients with Child–Pugh B or C had a significantly higher HCC rate compared with NASH-LC patients with Child–Pugh A (p = 0.037). (D) Association between diabetes mellitus (DM) and HCC rate in ALD-LC. ALD-LC patients with DM had a significantly higher HCC rate compared to those without DM as determined by Kaplan–Meier analysis (p = 0.013). ALD-LC, cirrhotic alcoholic liver disease; HCC, hepatocellular carcinoma; NASH-LC, cirrhotic nonalcoholic steatohepatitis.
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Regarding risk factors for HCC in the ALD-LC group, patients with DM showed a significantly higher HCC development rate compared with patients without DM as determined by Kaplan–Meier analysis using the log-rank test (p = 0.013). These Kaplan–Meier analyses in adjusted patients (n = 32) showed the same tendency, but without significant difference.
Regarding extrahepatic malignancies, only 1 NASH-LC patient developed endometrial cancer. In the ALD-LC group, 2 patients had esophageal cancer, 2 had gastric cancer, 1 had pancreatic cancer, 1 had pharyngeal cancer, and 1 had both esophageal and pharyngeal cancer. Thus, a total of 7 ALD-LC patients had extrahepatic cancers (Table 3), and the ALD-LC group showed a higher malignancy rate compared with the NASH-LC group (NASH-LC, 1.4%; ALD-LC, 8.2%, p = 0.052). The incidences of HCC and extrahepatic malignancies appeared to be similar in ALD-LC. After being adjusted for age and gender, there was no extrahepatic tumor in NASH-LC. In contrast, the adjusted ALD-LC group had 2 extrahepatic tumors, 1 gastric cancer, and 1 esophageal cancer. Regarding extrahepatic tumors between the 2 adjusted groups, there was no significant difference, but the same tendency was observed.
Table 3. Extrahepatic Cancers
|(A) NASH-LC (n = 72)|
|(B) ALD-LC (n = 85)|
|Esophageal cancer||3a |
|Pharyngeal cancer||2a |
|Total||7 (8.2%)b |
- Top of page
- Materials and Methods
- Supporting Information
ALD-LC patients without biopsy were excluded to avoid 2-group bias, because NASH is diagnosed by liver biopsy. Baseline data of the NASH-LC and ALD-LC groups differed with respect to gender and age at diagnosis. Concerning gender difference, the low number of women in the ALD-LC group can be attributed to the very low alcohol consumption of older Japanese women. These differences were also observed for patients with HCC related to NAFLD and ALD in our national survey (Tokushige et al., 2011). Age at ALD-LC diagnosis was younger than that at NASH-LC diagnosis, although the reason for this difference was not clear. It is possible that the severity of liver damage and the progression rate differ between the 2 diseases. Another factor may be that obesity and metabolic syndrome were uncommon in Japan before 2000. In the future, the age at NASH-LC diagnosis might become younger by 10 or 20 years because of the dramatic increase in obesity and metabolic syndrome in Japan. The difference in smoking rates might be associated with gender difference, as smoking rate is not common among elderly Japanese women. The meanings of age and gender differences in LC in Japan will be clarified in the future.
This is the first report about the assessment of hepatic and extrahepatic malignancies in NASH-LC and ALD-LC in Japan. The present study showed that the development rates of HCC of these 2 conditions were quite similar. In contrast, the risk factors for HCC and the rates of extrahepatic malignancies were strikingly different. Although our NASH-LC patients were older and included many females, analysis in which adjustments were made to compensate for these differences yielded the same HCC development rate. To compare the real HCC rates, larger patient populations of the same gender and similar age will be needed. Ascha and colleagues (2010) and Sanyal and colleagues (2006) reported that the 5-year HCC rate in NASH-LC patients was 10 to 13.6% in the United States. Therefore, the HCC rate of NASH-LC patients is almost the same in the United States and Japan. We had previously compared NASH-LC to LC induced by HCV infection (Yatsuji et al., 2009). It was found that the HCC development rate was lower in NASH-LC than in LC associated with HCV, while HCC and Child–Pugh B or C were important prognostic factors for NASH-LC (Yatsuji et al., 2009). The fact that steatohepatitis caused by insulin resistance and that caused by alcohol showed similar HCC development rates is very important in assessing the carcinogenesis of ALD and NASH. Hashimoto and colleagues (2012) reported that inflammatory cytokines, oxidative stress, and insulin resistance might induce hepatic carcinogenesis in NASH. Inflammatory cytokines and oxidative stress were shared in ALD-LC. Therefore, it was considered that a common mechanism might be responsible for inducing almost the same hepatic carcinogenesis between NASH-LC and ALD-LC.
In this study, older age, higher γ-GTP level, and higher Child–Pugh grade were detected as risk factors in NASH-LC patients. Old age is well known as an important risk factor for many kinds of malignancies. Several authors have reported that the serum γ-GTP level is influenced by oxidative stress (Abdul-Rasheed et al., 2010), and oxidative stress with the release of reactive oxygen species is likely to contribute to the development of both NASH and HCC (Hashimoto and Tokushige, 2012). Oxidative stress may favor tumorigenesis by promoting inflammation and cell proliferation, or it may directly induce cancer-promoting gene mutations (Hu et al., 2002). Fibrosis is the single most important risk factor for HCC. Ratziu and colleagues (2002) reported that patients with suspected burnt-out NASH had a high rate of HCC (27%). It was thought that our NASH-LC patients with Child–Pugh B or C were close to the burnt-out state. Thus, it is reasonable that NASH-LC patients with Child–Pugh B or C had a significantly higher HCC rate.
DM was a risk factor for HCC in ALD-LC patients according to the log-rank test. We could not detect risk factors using Cox hazards analysis, perhaps because it included too many factors for analyzing 85 samples. In addition, in ALD-LC, 88% were males. This obvious male gender prevalence made it difficult to find other significant factors. Several authors have reported that DM is a risk factor for HCC and other malignancies (El-Serag et al., 2004; Jiang et al., 2011). In the case of NASH, patients without HCC often have DM, which may explain why it was not detected as a risk factor for HCC.
Regarding extrahepatic cancer, ALD-LC patients developed esophageal, pharyngeal, gastric, and pancreatic cancers. In particular, Asians often show slower conversion of acetaldehyde to acetic acid, making it even more important to check for extrahepatic cancers in Asian ALD-LC patients. As all 7 ALD-LC patients with extrahepatic cancer were smokers, a synergistic effect of alcohol and smoking might be associated with extrahepatic carcinogenesis. Six ALD-LC patients developed HCC during follow-up, meaning that the incidences of HCC and extrahepatic cancer were similar in ALD-LC. In contrast, only 1 NASH-LC patient had extrahepatic (endometrial) cancer, suggesting that the risk of cancer outside the liver is relatively low in NASH-LC.
It is well known that alcohol intake is a significant risk factor for esophageal and pharyngeal cancer (Boffetta and Hashibe, 2006). Synergy among alcohol intake, genetic background, and tobacco smoking has been reported for squamous cell carcinoma of the esophagus (Yokoyama et al., 2008). As for gastric cancer, a positive association with alcohol intake was found in 2 of 12 cohort studies and 8 of 40 case–control studies (Franceschi and La Vecchia, 1994). However, the prevalence of Helicobacter pylori infection was not clarified in these studies. Most investigations of an association between alcohol and pancreatic cancer have come to a negative conclusion (Bagnardi et al., 2001). However, in our study, the 1 case in which pancreatic cancer developed was complicated with alcoholic chronic pancreatitis.
A limitation of this paper was the drop-out rate of ALD-LC patients during follow-up. It is very difficult to follow-up ALD-LC patients perfectly owing to their unpredictable behavior. In conclusion, a comparison of NASH-LC and ALD-LC in terms of HCC incidence revealed similar carcinogenesis curves. However, the risk factors and rate of extrahepatic cancer differed between these 2 diseases. The incidences of HCC and malignancies were similar, especially in ALD-LC. When managing LC patients with NASH or ALD, these risk factors and the extrahepatic malignancies associated with ALD-LC should be considered.