Hepatol Int (2013) 7:645–654 DOI 10.1007/s12072-012-9375-2

ORIGINAL ARTICLE

Alcoholism worsens the survival of patients with hepatitis B virus and C virus-related hepatocellular carcinoma Yun-Hsuan Lee • Chia-Yang Hsu • Cheng-Yuan Hsia Yi-Hsiang Huang • Chien-Wei Su • Yi-You Chiou • Han-Chieh Lin • Teh-Ia Huo • Shou-Dong Lee



Received: 16 January 2012 / Accepted: 20 April 2012 / Published online: 17 May 2012 Ó Asian Pacific Association for the Study of the Liver 2012

Abstract Background/Aims Chronic hepatitis B and hepatitis C virus (HBV, HCV) infection and alcoholism are common etiologies for hepatocellular carcinoma (HCC). The characteristics and impact of alcoholism and/or HCV/HBV infection on HBV- and HCV-related HCC, respectively, are investigated in this study.

Y.-H. Lee and C.-Y. Hsu have contributed equally to this work. Y.-H. Lee  C.-Y. Hsu  Y.-H. Huang  C.-W. Su  H.-C. Lin  T.-I. Huo (&) Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei 112, Taiwan e-mail: [email protected] Y.-H. Lee  C.-Y. Hsu  C.-Y. Hsia  C.-W. Su  Y.-Y. Chiou  H.-C. Lin  S.-D. Lee Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan C.-Y. Hsia Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan Y.-H. Huang Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan Y.-Y. Chiou Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan T.-I. Huo Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan S.-D. Lee Cheng Hsin General Hospital, Taipei, Taiwan

Methods A total of 1,888 patients were retrospectively investigated and categorized into six groups, HBV only (n = 977), HBV with alcoholism (n = 197), HCV only (n = 544), HCV with alcoholism (n = 67), dual HBV and HCV (n = 82), and dual virus with alcoholism (n = 21), to examine their interactions on the outcome. Results Compared to their counterparts, alcoholic patients coinfected with HBV and/or HCV tended to be younger, had higher male-to-female ratios, worse performance status, more severe liver cirrhosis, advanced cancer staging, and tumor burden than patients without alcoholism. In survival analysis, patients with HBV with alcoholism had a significantly decreased survival than the HBV-only group (p = 0.001). A shortened survival was also observed in HCV with alcoholism group compared to the HCV-only group (p = 0.011). Dual virus infection with alcoholism did not significantly worsen the survival compared to the dual virus infection group. In the Cox proportional hazards model, HBV with alcoholism group [risk ratio (RR) 1.299, p = 0.032] and HCV with alcoholism (RR 1.523, p = 0.025) group were independent predictors associated with decreased survival compared to their counterpart of HBV- and HCV-only groups. Conclusions Alcoholism in patients with HBV or HCV infection is characterized by early development of HCC with advanced cirrhosis and cancer staging at diagnosis. Alcoholism independently predicts an increased risk of mortality in patients with HBV- and HCV-related HCC. Keywords Alcoholism  Dual virus infection  HBV  HCV  Hepatocellular carcinoma Abbreviations AFP a-Fetoprotein Anti-HCV Antibody against HCV

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BCLC CLIP CT CTP ECOG HBsAg HBV HCC HCV INR MELD MRI TACE TTV

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Barcelona Clinic Liver Cancer Cancer of the Liver Italian Program Computed tomography Child–Turcotte–Pugh Eastern Cooperative Oncology Group Hepatitis B surface antigen Hepatitis B virus Hepatocellular carcinoma Hepatitis C virus International normalized ratio Model for end-stage liver disease Magnetic resonance imaging Transarterial chemoembolization Total tumor volume

carcinogenic factors has not yet been established. This study aimed to specifically evaluate the role and impact of alcoholism on the clinico-pathological features and outcomes in a large cohort of HBV- and/or HCV-associated HCC patients and to investigate whether alcohol abuse in patients with previous virus infection constitutes a distinct disease group that is diverse from patients without alcoholism. In addition, the additional impact of HCV/HBV infection, with or without alcoholism, on HBV- or HCVrelated HCC patients was also investigated.

Patients and methods Patients

Introduction Hepatocellular carcinoma (HCC) is a common malignancy worldwide with an increasing incidence [1, 2]. Chronic hepatitis B and hepatitis C virus (HBV, HCV) infections are established etiologies for patients with HCC [3, 4]. In addition, alcohol consumption may also predispose to the development of HCC, especially in the Western countries [5]. Alcohol consumption may have synergy with HBV or HCV infection to exacerbate liver disease. Reports have shown that alcohol consumption may result in enhanced viral replication, increased oxidative stress, cytotoxicity, and impairment of immune response [6]. Consequently, alcohol use in patients with viral hepatitis is associated with an accelerated progression of liver damage, earlier development of cirrhosis, and higher incidence of HCC formation [7–10]. Moreover, excessive alcohol consumption in these virus-infected patients is associated with an increased rate of liver-related deaths [11–14]. The clinical presentation of patients with different virusassociated HCC is often heterogeneous owing to the diverse biological behavior of HBV and HCV infection. The additive effect of alcohol consumption may further alter the clinical course of liver inflammation and fibrosis and even carcinogenesis and result in a different outcome in these patients. Several studies have addressed the importance of synergic carcinogenesis effect of alcohol on previously HBV- and/or HCV-infected HCC patients [5, 8, 15, 16]. However, the clinical characteristics of HBV- or HCV-associated HCC patients, with or without alcoholism and viral superinfection, are not clear. In addition, the prognostic impact of alcoholism on the long-term survival of these HCC patients has seldom been investigated. The surveillance strategy for patients exposed to multiple

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Taipei Veterans General Hospital provides primary to tertiary medical care to the residents of northern Taiwan, an area of about 12 million inhabitants. Between February 2002 and March 2011, patients with newly diagnosed HCC were retrospectively analyzed. The baseline information, including patient demographics, etiology of underlying liver disease, number and size of tumor nodules, serum biochemistries, severity and complications of liver cirrhosis, performance status, cancer stage, and treatment modality, was collected at the time when the diagnosis was established. This study complies with the standards of Declaration of Helsinki and current ethical guidelines. Diagnosis and definitions The diagnosis of HCC was histologically confirmed or based on the findings of typical radiological features in at least two imaging examinations, including ultrasound, contrast-enhanced dynamic computed tomography (CT), magnetic resonance imaging (MRI), and hepatic arterial angiography, or by a single positive imaging technique associated with serum a-fetoprotein (AFP) level[400 ng/mL [17, 18]. HCC characteristics, including number of nodules, maximal diameter of the largest nodule, extrahepatic spreading, and vascular invasion, were detected by dynamic contrast-enhanced CT or MRI. Total tumor volume (TTV) was calculated as the sum of all the tumor nodule volume and each tumor nodule volume is calculated as 4/3 9 3.14 9 maximum radius of the tumor nodule in cm3, as previously described [19]. Vascular invasion was defined by the presence of adjacent thrombus to the tumor in portal vein with blurring boundary confirmed by at least two imaging modalities or by the direct malignant tissue obtained from the thrombus [20]. Ascites was recognized as free peritoneal fluid identified by ultrasound or CT. The Child–Turcotte–Pugh (CTP) classification, based on serum levels of albumin and bilirubin, prothrombin time

Hepatol Int (2013) 7:645–654

prolongation, and the severity of ascites and encephalopathy, was assessed. The model for end-stage liver disease (MELD) score was calculated using the equation: 9.57 9 loge [creatinine (mg/dL)] ? 3.78 9 loge [bilirubin (mg/dL)] ? 11.2 9 loge INR ? 6.43 [21], where the minimal values were set to 1.0 for calculation purposes. The maximal serum creatinine level considered within the MELD score equation was 4.0 mg/dL. Performance status was evaluated using the Eastern Cooperative Oncology Group (ECOG) performance scale: 0 (asymptomatic) to 4 (confined to bed). Supplementary studies such as bone scan and brain CT were arranged, if clinically indicated. The Cancer of the Liver Italian Program (CLIP) and Barcelona Clinic Liver Cancer (BCLC) were used to define clinical staging [22, 23]. All patients were treatment naı¨ve and none had received specific anticancer treatment at the time of diagnosis. Etiology of HCC The underlying etiology of HCC was attributed to HBV infection if serological detection of hepatitis B surface antigen (HBsAg) was positive (RIA kits, Abbott Laboratories, North Chicago, IL, USA). HCV infection was diagnosed if patients were seropositive for antibody against HCV (anti-HCV) by a second-generation enzyme immunoassay (Abbott Laboratories). Alcoholism was diagnosed in subjects with a documented history of alcohol excess of at least 40 g alcohol daily for 5 years or more [24]. Patients were classified, according to the etiologies of chronic liver disease (HBV, HCV, and alcoholism), to explore their characteristics and prognostic impact. Treatment Criteria of surgical resection for patients with HCC were (1) patients with tumor involving no more than three Healey’s segments, (2) CTP class A with \25 % retention of indocyanine green 15 min after injection, and (3) no main portal vein trunk involvement or distant metastasis. Liver transplantation was considered in patients fulfilling the Milan criteria with coexisting CTP class B or C cirrhosis [25, 26]. For patients who had unresectable lesions, local ablation therapy and transarterial chemoembolization (TACE) were performed depending on the size and number of tumor nodules, as previously reported [27, 28]. Local ablation therapy included percutaneous acetic acid or ethanol injection or radiofrequency ablation. Systemic chemotherapy or targeted therapy was given to selected patients with preserved liver functions and distant tumor metastasis. For patients with CTP class C, main portal vein thrombosis or evidence of distant metastasis, or when treatment efficacy was considered limited or associated

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with a substantially high treatment-associated risk, only best supportive care was given. Statistical methods The Kruskal–Wallis test was used to compare the statistical difference in patients if there were three groups or more. Patients were introduced to two models to individually investigate the impact of HCV/HBV infection and/or alcoholism on the survival difference in HBV- and HCVrelated HCC, respectively. Model 1 included four groups of patients with HBV infection with or without HCV coinfection and/or alcoholism. Model 2 involved four groups of patients with HCV infection with or without HBV coinfection and/or alcoholism. The patient survival was inspected and calculated every 3–4 months until death or dropout from the follow-up program. The Kaplan–Meier method with log-rank test was applied to compare the survival distributions. The prognostic factors that were significant (p \ 0.05) in the univariate survival analysis were introduced into the Cox proportional hazards model to determine the adjusted risk ratio (RR). All statistical analyses were conducted with the SPSS version 14 (SPSS, Inc., Chicago, IL, USA). A p value \0.05 was considered statistically significant.

Results Distribution of the etiology of liver disease During the study period, 2,308 HCC patients were identified and classified into eight groups, according to the etiology of underlying liver disease (Fig. 1). Patients with neither HBV/HCV infection nor alcoholism history (n = 323) and patients with a history of alcoholism only (n = 97) were excluded from the analysis. The remaining 1,888 patients from the other six groups formed the basis of this study. Of them, 977 (42 %) patients had HBV infection only, 544 (24 %) patients had HCV infection only, 82 (4 %) patients had dual virus infection, 197 (9 %) patients had HBV infection with alcoholism, 67 (3 %) patients had HCV infection with alcoholism, and 21 (1 %) patients had dual virus infection with alcoholism. Patient characteristics The baseline demographics of the 1,888 patients are shown in Table 1. Patients with alcoholism coinfected with HBV, HCV, or dual HBV and HCV (mean age, 57, 66, and 60 years, respectively) tended to develop HCC 3–4 years earlier than their counterpart patients without alcoholism (mean age, 61, 69, and 64 years, respectively); the mean age of HCC

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infection (p = 0.001) and patients with alcoholism and HCV infection (p = 0.019). Patients with HCV infection only also had a significantly longer survival than patients with alcoholism and HCV infection (p = 0.011) and patients with alcoholism and HBV infection (p \ 0.001). There were no significant survival differences between patients with dual virus infection and dual virus infection with alcoholism (p = 0.168), patients with HBV and dual virus infection (p = 0.205), and patients with HCV and dual virus infection (p = 0.263). Model 1: analysis of prognostic predictors in patients with HBV-related HCC with and without HCV infection and/or alcoholism

Fig. 1 Distribution of the 2,308 patients according to the presence and absence of hepatitis B, hepatitis C, and alcoholism as the underlying etiology of HCC. The composition of model 1 and model 2 used in this study was demonstrated

development in patients with dual virus infection was younger than in patients with HCV infection, but older than in patients with HBV infection in both alcoholic and nonalcoholic groups. The male-to-female ratios tended to be higher in alcoholic patients with HBV and/or HCV infection (range 10- to 24-fold), when compared to their counterparts (range 1.2- to 4.6-fold). Alcoholic patients with HBV and/or HCV infection tended to have a larger TTV, more frequent vascular invasion, and ascites formation, when compared to their counterparts. In addition, there was a trend of having lower serum albumin level, higher serum bilirubin level, worse performance status, higher MELD score, more advanced CTP and BCLC staging, and higher CLIP score in alcoholic patients with virus infection when compared to their counterparts. More patients in the HBV group (32 %) underwent surgical intervention than did other groups (range 19–24 %), and a higher proportion of patients with alcohol consumption (range 16–29 %) received supportive care than did the non-alcoholic groups (range 12–14 %). Pairwise comparison of survival distributions between six groups of patients with different etiologies of HCC The median survival of patients with different etiologies of HCC and the p values of the pairwise comparison of survival between every two groups of patients out of the six groups are shown in Table 2. There was a significantly better long-term survival in patients with HBV infection when compared to patients with alcoholism and HBV

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The comparison of the survival distribution according to different baseline parameters of 1,277 HBV-related HCC patients is shown in Table 3 (model 1). The continuous data were dichotomized by the median value into two groups. There was a significant difference in long-term survival among the four groups of HBV-related HCC patients (Fig. 2; p = 0.003). Patients with a decreased survival were characterized by older age (p = 0.019), lower serum albumin level (p \ 0.001), higher serum bilirubin level (p \ 0.001) and international normalized ratio (INR) of prothrombin time (p \ 0.001), lower serum sodium level (p \ 0.001), multiple tumor numbers (p \ 0.001), larger tumor size (p \ 0.001), larger TTV (p \ 0.001), poorer performance status (p \ 0.001), presence of ascites and vascular invasion (both p \ 0.001), and higher serum AFP level (p \ 0.001). Factors that were significant in the univariate survival analysis were introduced into the Cox proportional hazards model to determine the adjusted RR. Independent prognostic predictors in HBV-related HCC patients included serum bilirubin level C0.9 mg/dL (RR 1.312, p = 0.005), INR of prothrombin time C1.04 (RR 1.564, p \ 0.001), serum sodium level\139 mmol/L (RR 1.402, p = 0.001), tumor size C3 cm (RR 1.322, p = 0.04), TTV C62 cm3 (RR 1.724, p \ 0.001), performance status C2 (RR 2.389, p \ 0.001), ascites (RR 1.346, p = 0.033) and AFP level C58 ng/mL (RR 1.709, p \ 0.001). In addition, HBV infection and alcohol consumption (RR 1.299, p = 0.032) was identified as an independent predictor of poor prognosis compared with the reference group (HBV infection only). Model 2: analysis of prognostic predictors in patients with HCV-related HCC with and without HBV infection and/or alcoholism A total of 714 patients with HCV-related HCC with and without HBV infection and/or alcoholism entered the analysis. Using a similar strategy as in model 1, the comparison of

61 ± 14 82/18

Age (years, mean ± SD)

Male/female (%)

81 ± 68 138 ± 4

1.1 ± 0.9 1.1 ± 0.2 70 ± 77 139 ± 4

INR of PT

ALT (U/L)

67/15/9/5/4

Performance status 0/1/2/3/4 (%)

6.1 ± 1.7

Mean CTP score (mean ± SD)

9.5 ± 4.2

Score (mean ± SD)

21

42 21

Vascular invasion (%)

10 14

Chemotherapy or targeted therapy

Supportive care

30/31/20/8/7/4/1

11/31/15/32/11

12

4

35

28

0

20

182 ± 488

23/28/15/13/9/11/1

7/26/13/40/13

12

15

29

20

0

24

17

46

281 ± 517

39/61

49/51

10.0 ± 4.5

40/43/7/2/7

5.9 ± 1.5

76/20/5

67/16/4/10/4

14,959 ± 69,636

139 ± 4

89 ± 86

1.1 ± 0.1

1.5 ± 2.2

21 ± 15

1.7 ± 3.6

3.7 ± 0.6

73/27

64 ± 11

82

HBV ? HCV

15/17/17/15/18/13/5

4/19/17/49/12

21

14

25

16

0

23

41

55

523 ± 756

27/73

55/45

10.6 ± 5.0

38/39/11/6/7

6.8 ± 2.0

57/29/14

49/23/14/12/2

37,068 ± 132,813

137 ± 4

75 ± 90

1.1 ± 0.2

1.1 ± 0.5

18 ± 12

2.3 ± 4.0

3.6 ± 0.7

96/4

57 ± 12

197

HBV ? alcoholism

24/22/12/18/13/6/5

8/25/12/40/15

16

6

30

28

0

19

40

42

285 ± 485

39/61

52/48

10.0 ± 4.4

33/49/13/0/5

6.6 ± 1.8

61/31/8

46/25/9/12/8

24,067 ± 100,991

139 ± 4

121 ± 257

1.1 ± 0.1

1.1 ± 0.3

20 ± 10

2.0 ± 4.7

3.5 ± 0.6

91/9

66 ± 11

67

HCV ? alcoholism

19/19/14/10/29/10/0

5/24/24/33/14

29

14

14

14

5

24

38

62

407 ± 550

33/67

57/43

11.2 ± 5.7

43/24/19/5/10

7.0 ± 2.0

52/33/14

43/10/19/4/14

14,294 ± 48,825

137 ± 5

72 ± 34

1.1 ± 0.2

1.1 ± 0.7

22 ± 16

2.1 ± 3.2

3.4 ± 0.7

100/0

60 ± 13

21

HBV ? HCV ? alcoholism

\0.001

0.009

\0.001

\0.001

\0.001

\0.001

\0.001

0.084

0.0096

0.007

\0.001

\0.001

\0.001

0.0855

0.0032

\0.001

0.0413

\0.001

\0.001

\0.001

\0.001

\0.001

\0.001

p

AFP a-fetoprotein, ALT alanine transaminase, BCLC Barcelona Clinic Liver Cancer, BUN blood urea nitrogen, CLIP Cancer of the Liver Italian Program, CTP Child–Turcotte–Pugh, HBV hepatitis B virus, HCV hepatitis C virus, INR international normalized ratio, MELD model for end-stage liver disease, No. number, PT prothrombin time, SD standard deviation, TACE transarterial chemoembolization

25/25/14/13/13/7/2

26

TACE

8/23/17/42/11

18

Local ablation

CLIP score 0/1/2/3/4/5/6 (%)

1

Transplantation

BCLC stage 0/A/B/C/D (%)

32

Resection

Treatment modality (%)

Ascites (%)

24

424 ± 799

Total tumor volume (cm3, mean ± SD)

46/54

62/38 30/70

Single/multiple

59/41

9.5 ± 3.7

45/37/11/5/3

6.0 ± 1.4

76/20/4

66/16/8/6/4

8,469 ± 50,461

1.1 ± 0.1

\3 cm/C3 cm

No. and size of tumor (%)

49/33/11/4/3

\8/8–12/12–16/16–20/[20 (%)

MELD score

74/19/6

A/B/C (%)

CTP class

38,748 ± 370,396

AFP (ng/mL, mean ± SD)

Sodium (mmol/L)

19 ± 13

18 ± 10

BUN (mg/dL)

Creatinine (mg/dL)

1.2 ± 1.1

1.3 ± 1.6

3.7 ± 0.6 1.6 ± 2.9

Albumin (g/dL)

3.6 ± 0.6

55/45

69 ± 9

544

HCV

Bilirubin (mg/dL)

Serum biochemistry (mean ± SD)

977

Number of patients

HBV

Table 1 Baseline demographics of the 1,888 HBV and/or HCV-infected HCC patients with or without alcoholism

Hepatol Int (2013) 7:645–654 649

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Table 2 The p values of pairwise comparison for long-term survival between patients with HBV and HCV-related HCC with or without alcoholism HBV

HCV

HBV ? HCV

HBV ? alcoholism

HCV ? alcoholism

HBV ? HCV ? alcoholism

36

33

32

28

25

56

(95 % CI, months)

(33–39)

(30–36)

(29–35)

(19–37)

(21–29)

(9–103)

HBV



– 0.053



Median survival

HCV

0.933



HBV ? HCV

0.205

0.263



HBV ? alcoholism

0.001

\0.001

0.319



HCV ? alcoholism HBV ? HCV ? alcoholism

0.019 0.341

0.011 0.275

0.35 0.168

0.907 0.09

CI confidence interval, HBV hepatitis B virus, HCV hepatitis C virus

Table 3 Univariate and multivariate analyses of prognostic variables in HBV-related HCC patients with and without HCV infection and/or alcoholism N

Univariate analysis 3-year survival (%)

Multivariate analysis 5-year survival (%)

p

Risk ratio

95 % CI

p

Sex (male/female)

1,068/209

47/48

18/11

0.823

Age (\60/C60 years)

633/644

44/51

15/18

0.019

977

50

18

1 1.299

1.023–1.65

0.032

1.312

1.084–1.587

0.005

Etiology of liver disease HBV

0.003

HBV ? alcoholism

197

37

8

HBV ? HCV

82

41

13

21

61

41

Albumin (\3.8/C3.8 g/dL)

HBV ? HCV ? alcoholism

614/663

40/53

15/18

\0.001

Bilirubin (\0.9/C0/9 mg/dL)

613/664

54/41

19/14

\0.001

Creatinine (\1/C1 mg/dL)

628/649

48/47

16/17

0.236

INR of PT (\1.04/C1.04)

593/684

56/39

20/13

\0.001

1.564

1.282–1.909

\0.001

Sodium (\139/C139 mmol/L)

551/726

30/57

10/20

\0.001

1.402

1.14–1.724

0.001

No. of tumor (single/multiple)

768/509

52/40

18/13

\0.001

Tumor size (\3/C3 cm)

388/889

64/37

28/10

\0.001

1.322

1.013–1.725

0.04

TTV (\62/[ 62 cm3) Performance status (0–1/2–4)

635/642 1,020/257

61/27 53/16

22/9 19/3

\0.001 \0.001

1.724 2.389

1.337–2.224 1.807–3.159

\0.001 \0.001

Ascites (No/Yes)

967/310

52/26

19/5

\0.001

1.346

1.024–1.771

0.033

Vascular invasion (No/Yes)

709/568

56/31

20/11

\0.001

AFP (\58/C58 ng/mL)

636/641

57/34

23/8

\0.001

1.709

1.41–2.073

\0.001

AFP a-fetoprotein, CI confidence interval, HBV hepatitis B virus, HCV hepatitis C virus, INR international normalized ratio, No. number, PT prothrombin time, TTV total tumor volume

the survival distribution according to different baseline characteristics is shown in Table 4 (model 2). There was a significant survival difference among the four groups of HCV-related HCC patients with and without HBV coinfection and/or alcoholism (Fig. 3; p = 0.032). A significantly worse outcome was identified in patients with lower serum albumin level (p \ 0.001), higher serum bilirubin level (p = 0.001) and INR of prothrombin time (p \ 0.001), lower serum sodium level (p \ 0.001), multiple

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tumor numbers (p = 0.002), larger tumor size (p \ 0.001), higher TTV (p \ 0.001), poorer performance status (p \ 0.001), presence of ascites and vascular invasion (both p \ 0.001), and higher serum AFP level (p \ 0.001) in the univariate survival analysis. In the Cox multivariate model, independent prognostic predictors that were associated with a decreased survival included INR C1.04 (RR 1.554, p = 0.001), multiple tumor nodules (RR 1.458, p = 0.003), TTV C22 cm3 (RR 1.455,

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Fig. 2 The survival distribution of patients with HBV-related HCC with or without HCV co-infection and/or alcohol consumption. There is a significant difference in long-term survival among the four groups of patients (p = 0.003)

p = 0.007), performance status C2 (RR 3.338, p \ 0.001), ascites (RR 2.108, p \ 0.001), and vascular invasion (RR 1.877, p \ 0.001). In addition, patients with HCV infection with alcoholism (RR 1.523, p = 0.025) were independently associated with a poor outcome in comparison to patients with HCV infection only (reference group).

Discussion Alcohol abuse is commonly seen in clinical practice, with a prevalence rate of up to 25 % among hospitalized patients in Taiwan [29]. In this study, 15 % (285/1,888) of patients with HBV- or HCV-related HCC had a documented history of alcoholism. Therefore, a combination of viral infection and alcohol abuse in HCC is not a rare clinical entity. Notably, in this large cohort study that specifically investigated the interaction between alcoholism and viruses, it was found that alcoholism is independently associated with 30 and 52 % increased risk of mortality in HCC patients with HBV and HCV infection, respectively, when the survival was compared to their counterparts without alcoholism in the adjusted Cox model. In addition to the established prognostic factors, such as tumor burden, performance status and severity of cirrhosis, the results indicate that different etiologies of HCC may also significantly affect the survival of these patients and should be taken into consideration in treatment planning. Patients with HCC and alcohol abuse were characterized by larger tumor burden, poorer liver functional reserve, and more advanced cancer staging than their counterpart

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patients at the time of diagnosis. These results are consistent with the previous literatures showing that alcohol use may alter the pathogenesis in the inflammation and fibrosis of liver in HBV- and/or HCV-infected patients and result in accelerated liver cirrhosis [6, 7]. Importantly, the mean age at the diagnosis of HCC is 3–4 years earlier in patients with HBV and/or HCV with alcoholism than that of their counterpart patients without alcoholism. This finding suggests that alcohol consumption may not only worsen liver functions but could also accelerate the speed of carcinogenesis pathway and HCC formation in HBV- and/or HCV-infected patients. Therefore, these patients should be considered as super-high risk group of HCC development and are suggested to undergo more intensive surveillance program for earlier detection and management of HCC. Comparison of gender differences across all six groups of patients disclosed that male patients are the predominant population in patients with alcohol abuse. The exact mechanism for this finding is not clear. A possible explanation is that drinking habit is more prevalent in the male population in Taiwan [30, 31]. Another possibility is that the interaction between alcohol and estrogen may play a significant role. Estrogen was proposed to have a protective effect against HCC formation [32], and this effect is probably more apparent in patients with alcohol consumption and chronic HBV or HCV infection. Further studies are needed to clarify the pathogenesis of the potentially protective effect of estrogen and its interaction with alcohol and viral hepatitis. In the Cox multivariate analysis (models 1 and 2), consistent with previous studies [18, 19, 33–35], it was found that the performance status, severity of cirrhosis, and tumor burden were all independently associated with a decreased survival in both HBV- and HCV-related patients. Interestingly, patients with dual virus infection with alcoholism did not have a significantly worse survival in comparison with those with dual virus infection only. This is possibly because a relatively small sample size (only 21 patients) was available for the analysis. Alternatively, the impact of alcoholism on patients with dual virus infection might be masked by other important factors, such as the extent of tumor involvement and hepatic functional reserve. Given so, HCC occurred early in patients with alcoholism and dual virus infection compared to their counterparts, suggesting that alcoholism still greatly increases the speed of tumor formation in this subgroup. In this study, the mean age of HCC patients with dual virus infection, either with or without alcohol consumption, is between that of the patients with HBV and HCV infections. This result is consistent with previous observation in Taiwan [33, 36] that most of the patients acquire HBV infection during childhood, and the superinfection of HCV later in life may suppress the virulence of HBV and act as a

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Table 4 Univariate and multivariate analyses of prognostic variables in HCV-related HCC patients with and without HBV infection and/or alcoholism N

Univariate analysis 3-year survival (%)

Multivariate analysis 5-year survival (%)

p

Risk ratio

95 % CI

p

Sex (male/female)

442/272

40/48

15/13

0.450

Age (\67/C67 years)

305/409

47/43

16/13

0.623

Etiology of liver disease HCV

544

46

13

1

HCV ? alcoholism

67

34

8

1.523

1.053–2.202

0.025

HCV ? HBV

82

41

13

HCV ? HBV ? alcoholism

21

61

41

Albumin (\3.6/C3.6 g/dL)

309/405

32/52

11/16

\0.001

Bilirubin (\0.9/C0/9 mg/dL)

323/391

53/38

18/11

0.001

Creatinine (\1/C1 mg/dL)

359/355

45/44

16/13

0.239

INR of PT (\1.04/C1.04)

329/385

58/34

20/10

\0.001

1.554

1.197–2.018

0.001

Sodium (\139/C139 mmol/L)

303/411

30/51

8/16

\0.001

No. of tumor (single/multiple)

408/306

48/40

19/9

1.458

1.136–1.872

0.003

Tumor size (\3/C3 cm)

313/400

54/36

17/11

\0.001

TTV(\22/[22 cm3)

354/360

55/32

20/6

\0.001

1.455

1.108–1.909

0.007

Performance status (0–1/2–4)

573/141

51/8

16/0

\0.001

3.338

2.34–4.762

\0.001

0.032

0.002

Ascites (No/Yes)

553/161

50/9

16/0

\0.001

2.108

1.467–3.028

\0.001

Vascular invasion (No/Yes) AFP (\46/C46 ng/mL)

504/210 354/360

48/36 51/38

16/8 17/10

\0.001 \0.001

1.877

1.364–2.583

\0.001

AFP a-fetoprotein, CI confidence interval, HBV hepatitis B virus, HCV hepatitis C virus, INR international normalized ratio, No. number, PT prothrombin time, TTV total tumor volume

Fig. 3 The survival distribution of patients with HCV-related HCC with or without HBV coinfection and/or alcohol consumption. There is a significant difference in long-term survival among the four groups of patients (p = 0.032)

predominant oncogenic role in carcinogenesis [37–39]. As a result, dual virus infection does not seem to accelerate the formation of HCC in HBV carriers.

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This study has a few limitations. First, most HBV carriers in Taiwan acquire infection at birth via vertical transmission, whereas HCV infection and/or alcohol consumption occur later in life. This feature may be different from the Western countries, so the results need to be cautiously interpreted. Second, the magnitude (exact amount and duration of alcohol consumption) of alcoholism has not been quantified in this study. Therefore, its association with the long-term survival is not clear. Finally, the chronological sequence of HCV infection and alcohol consumption is not documented. Different orders of hepatitis virus infection and alcohol consumption might generate diverse mechanisms in the inflammation, fibrosis, and carcinogenesis of liver and subsequently result in a different outcome. In conclusion, alcoholism may induce earlier development of HCC by an average of 3–4 years in patients with HBV and/or HCV infections. At the time of diagnosis, patients with alcoholism and viral hepatitis more often have larger tumor burden, advanced cancer staging, worse liver functional reserve and performance status than their counterparts without alcohol abuse. The results indicate that the different etiologies of HCC may affect the survival, and alcohol abuse is independently associated with an increased risk of mortality in patients with HBV- and

Hepatol Int (2013) 7:645–654

HCV-related HCC. Based on these findings, more aggressive HCC surveillance program is needed for this superhigh risk patient group for early detection and anticancer intervention. Acknowledgements This study was supported by grants from the Center of Excellence for Cancer Research at Taipei Veterans General Hospital (DOH100-TD-C-111-007), Taiwan, from Taipei Veterans General Hospital (V101C-170), Taipei, Taiwan, and from the Ministry of Education, Aim for the Top University Plan (101AC-D101), Taiwan. Conflict of interest There are no conflicts of interest that are relevant to the manuscript in all authors.

References 1. Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127:S5–S16 2. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750 3. Gelatti U, Donato F, Tagger A, et al. Etiology of hepatocellular carcinoma influences clinical and pathologic features but not patient survival. Am J Gastroenterol 2003;98:907–914 4. Tan A, Yeh SH, Liu CJ, et al. Viral hepatocarcinogenesis: from infection to cancer. Liver Int 2008;28:175–188 5. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004;127:S87–S96 6. Gitto S, Micco L, Conti F, et al. Alcohol and viral hepatitis: a mini-review. Dig Liver Dis 2009;41:67–70 7. Gramenzi A, Caputo F, Biselli M, et al. Review article: alcoholic liver disease—pathophysiological aspects and risk factors. Aliment Pharmacol Ther 2006;24:1151–1161 8. Hassan MM, Hwang LY, Hatten CJ, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002;36:1206–1213 9. Yuan JM, Govindarajan S, Arakawa K, et al. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the US. Cancer 2004;101: 1009–1017 10. Ohnishi K, Iida S, Iwama S, et al. The effect of chronic habitual alcohol intake on the development of liver cirrhosis and hepatocellular carcinoma: relation to hepatitis B surface antigen carriage. Cancer 1982;49:672–677 11. Kim WR, Gross JB Jr, Poterucha JJ, et al. Outcome of hospital care of liver disease associated with hepatitis C in the United States. Hepatology 2001;33:201–206 12. Tsui JI, Pletcher MJ, Vittinghoff E, et al. Hepatitis C and hospital outcomes in patients admitted with alcohol-related problems. J Hepatol 2006;44:262–266 13. Harris HE, Ramsay ME, Andrews N, et al. Clinical course of hepatitis C virus during the first decade of infection: cohort study. BMJ 2002;324:450–453 14. Marcellin P, Pequignot F, Delarocque-Astagneau E, et al. Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption. J Hepatol 2008;48:200–207 15. Corrao G, Torchio P, Zambon A, et al. Exploring the combined action of lifetime alcohol intake and chronic hepatotropic virus infections on the risk of symptomatic liver cirrhosis. Collaborative Groups for the Study of Liver Diseases in Italy. Eur J Epidemiol 1998;14:447–456

653 16. Yu MC, Yuan JM, Lu SC. Alcohol, cofactors and the genetics of hepatocellular carcinoma. J Gastroenterol Hepatol 2008;23(Suppl 1):S92–S97 17. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–430 18. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236 19. Hsu CY, Huang YH, Hsia CY, et al. A new prognostic model for hepatocellular carcinoma based on total tumor volume: the Taipei Integrated Scoring System. J Hepatol 2010;53:108–117 20. Kikuchi LO, Paranagua-Vezozzo DC, Chagas AL, et al. Nodules less than 20 mm and vascular invasion are predictors of survival in small hepatocellular carcinoma. J Clin Gastroenterol 2009;43:191–195 21. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–96 22. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004;10:S115–S120 23. Cillo U, Vitale A, Grigoletto F, et al. Prospective validation of the Barcelona clinic liver cancer staging system. J Hepatol 2006;44: 723–731 24. Grant BF, Dufour MC, Harford TC. Epidemiology of alcoholic liver disease. Semin Liver Dis 1988;8:12–25 25. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–699 26. Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439–474 27. Huo TI, Lin HC, Huang YH, et al. The model for end-stage liver disease-based Japan Integrated Scoring system may have a better predictive ability for patients with hepatocellular carcinoma undergoing locoregional therapy. Cancer 2006;107:141–148 28. Huo TI, Lin HC, Wu JC, et al. Proposal of a modified Child– Turcotte–Pugh scoring system and comparison with the model for end-stage liver disease for outcome prediction in patients with cirrhosis. Liver Transpl 2006;12:65–71 29. Wu SI, Liu SI, Fang CK, et al. Prevalence and detection of alcohol use disorders among general hospital inpatients in eastern Taiwan. Gen Hosp Psychiatry 2006;28:48–54 30. Chen KT, Chen CJ, Fagot-Campagna A, et al. Tobacco, betel quid, alcohol, and illicit drug use among 13- to 35-year-olds in I-Lan, rural Taiwan: prevalence and risk factors. Am J Public Health 2001;91:1130–1134 31. Liu JD, Leung KW, Wang CK, et al. Alcohol-related problems in Taiwan with particular emphasis on alcoholic liver diseases. Alcohol Clin Exp Res 1998;22:164S–169S 32. Yu MW, Chang HC, Chang SC, et al. Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk. Hepatology 2003;38:1393–1400 33. Huo TI, Huang YH, Hsia CY, et al. Characteristics and outcome of patients with dual hepatitis B and C-associated hepatocellular carcinoma: are they different from patients with single virus infection? Liver Int 2009;29:767–773 34. Tandon P, Garcia-Tsao G. Prognostic indicators in hepatocellular carcinoma: a systematic review of 72 studies. Liver Int 2009;29: 502–510 35. Carr BI, Pancoska P, Branch RA. Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study. Hepatol Int 2009;4:396–405 36. Chen MF, Jeng LB, Lee WC. Surgical results in patients with hepatitis virus-related hepatocellular carcinoma in Taiwan. World J Surg 2002;26:742–747

123

654 37. Liaw YF, Tsai SL, Chang JJ, et al. Displacement of hepatitis B virus by hepatitis C virus as the cause of continuing chronic hepatitis. Gastroenterology 1994;106:1048–1053 38. Sheen IS, Liaw YF, Lin DY, et al. Role of hepatitis C and delta viruses in the termination of chronic hepatitis B surface antigen

123

Hepatol Int (2013) 7:645–654 carrier state: a multivariate analysis in a longitudinal follow-up study. J Infect Dis 1994;170:358–361 39. Liaw YF, Tsai SL, Sheen IS, et al. Clinical and virological course of chronic hepatitis B virus infection with hepatitis C and D virus markers. Am J Gastroenterol 1998;93:354–359

Alcoholism worsens the survival of patients with hepatitis B virus and C virus-related hepatocellular carcinoma.

Chronic hepatitis B and hepatitis C virus (HBV, HCV) infection and alcoholism are common etiologies for hepatocellular carcinoma (HCC). The characteri...
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