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Vol. 7. Núm. 2.
Páginas 148-151 (abril - junio 2008)
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Visitas
2957
Vol. 7. Núm. 2.
Páginas 148-151 (abril - junio 2008)
Open Access
Impact of diabetes mellitus on outcome of HCC
Visitas
2957
Deepak N. Amarapurkar1,
Autor para correspondencia
, Nikhil D. Patel2, Praful M. Kamani2
1 Head
2 Clinical assistants, Gastroenterology Department, Bombay Hospital and Medical Research Centre, Mumbai
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Tablas (3)
Table I. Age-wise distribution.
Table II. Different etiologies of HCC.
Table III. Presenting features and outcome of both groups.
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Abstract

Background: Diabetes mellitus (DM) is recently identified risk factor for development and progression of chronic liver disease as well as hepatocellular carcinoma (HCC). We planned a prospective analysis to identify impact of DM in Indian patients with HCC. Methods: During last 10 years, 160 consecutive patients of HCC were evaluated. Demographic profile like age of presentation, clinical features, etiology of HCC, tumor size at presentation, management and ultimate outcome was compared diabetic with non-diabetic HCC patients. Results: During last 10 years, 160 consecutive patients of HCC were evaluated (Mean age = 59.6 ± 12.9 years, sex ratio (M: F) = 5.4: 1). Etiology for HCC were hepatitis B in 45 (28.2%), hepatitis C in 18 (11.3%), alcohol in 27 (16.8%), alcohol with hepatitis B in 12 (7.5%), alcohol with hepatitis C in 1 (0.6%), non-alcoholic steatohepatitis in 4 (2.5%) and cryptogenic in 53 (33.2%) patients. Patients of HCC with DM (group-A, n =46, age = 62.6 ± 9.5 years, sex (M: F) = 6.6:1) were compared with patient of HCC without DM (group-B, n =114, age = 66.7 ± 13.7 years, sex (M: F) = 5.4:1). Duration of diabetes in group-A was 7.6 ± 3.2 years. Patients in group-A had more advanced HCC (size of lesion > 5 cm and >3 lesions of 3 cm or more diameter, portal vein thrombosis or intra-hepatic bile duct involvement) than group-B [34 (73.9%) vs 72 (54.3%)]. Mortality with in one year was significantly more in group-A compared to group-B [36 (78.2%) vs 56 (49.1%)]. Conclusion: DM is associated with more advanced lesion and poor outcome in patient with HCC.

Key words:
Hepatocellular carcinoma
Diabetes Mellitus
Non-alcoholic fatty liver disease
Chronic liver disease
Texto completo
Introduction

Type-2 diabetes mellitus (DM) increases risk of development of chronic liver disease (CLD).1 Commonest CLD in DM is non-alcoholic fatty liver disease (NAFLD).2 Hepatocellular carcinoma (HCC) occurs in patients with CLD and mostly in presence of cirrhosis. Known predisposing causes of HCC are hepatitis B virus, hepatitis C virus (HCV), chronic alcohol abuse, hemochromatosis and, recently, nonalcoholic fatty liver disease (NAFLD).3 Cryptogenic cirrhosis remains responsible for HCC in 15-50% cases.4,5

Although earlier studies denied the association between type-2 diabetes mellitus (DM) and HCC;6-8 in most of the recent studies, DM is shown to increase risk of HCC by 2-to 4-fold, even after adjusting for other predisposing factors.5,9-29 In presence of viral hepatitis and alcohol intake, DM increases risk for HCC by 10-fold.25 DM is a major risk factor for NAFLD,30-33 which is shown to predispose for cryptogenic cirrhosis34 and HCC.35-37 There is increased incidence of DM in HCV infection, a known risk factor for HCC. Cirrhosis itself is diabetogenic state and also a predisposition for HCC. Diabetes is a risk factor, if not actually etiologic for HCC, but temporal relationship is not yet clearly defined.9,27 Only few studies have shown DM to precede HCC.1,38 World-wide, incidence of DM as well as HCC is increasing.1 India is experiencing an epidemic of DM.39 Establishing epidemiological relation and cause-effect relationship between these two is important.

There are only few studies on impact of DM on management and outcome of HCC. None of the studies from India have shown relation of DM with HCC. This study was planned to evaluate impact of DM on management and outcome of HCC.

Materials and methods

This case-control observational study was carried out over study period of 10 years (1997-2006) on all the consecutive patients of HCC. Diagnosis of HCC was based on hyper-vascular tumor in the liver on two imaging studies or hyper-vascular tumor on single imaging modality with serum alpha-fetoprotein level greater than 400 ng/dL.

Patients were divided into 2 groups: a) Diabetic patients with HCC and b) Non-diabetic patients with HCC. Diabetes was diagnosed according to American Diabetes Association criteria on the basis of use of oral hypoglycemic drugs; fasting plasma glucose level • •126 mg/dL; 2-hour plasma glucose • •200 mg/dL during oral glucose tolerance test; and/or random or 2-hour post-prandial plasma glucose level • •200 mg/dL.

In both groups following features were noted: age of presentation, clinical features, laboratory features, Child class (CPT score), etiology (hepatitis B, hepatitis C, alcohol, NASH or other etiologies), tumor characteristics at presentation (advanced HCC), management (resection and ablative therapy or palliative management) and survival. Advanced HCC (morphological) was diagnosed on basis of tumor size > 5 cm or > 3 tumors each measuring > 3 cm diameter or portal vein thrombosis or bile duct invasion.

Statistical analysis was performed using Chi square test and student t test.

Results

As seen in Table I, majority of the patients in both groups were in age group 51-70 years. There was no statistically significant difference in both the study groups regarding age distribution.

Table I.

Age-wise distribution.

Age in years, n (%)  Group A, n = 46  Group B, n = 114 
< 50  8 (17.4)  17 (14.9)  NS 
51-60  13 (28.3)  28 (24.6)  NS 
61-70  19 (41.3)  46 (40.3)  NS 
> 70  6 (13)  23 (20.2)  NS 

Different etiologies of HCC are tabulated in Table II. As an etiology for HCC, alcohol and NASH were significantly higher in group-A.

Table II.

Different etiologies of HCC.

Etiology, n (%)  Group A, n = 46  Group B, n = 114  Total n = 160 
Hepatitis B alone  11 (23.9)  34 (29.8)  NS  45 (28.1) 
Hepatitis B with alcohol  6 (13)  6 (5.3)  NS  12 (7.5) 
Alcohol alone  14 (30.4)  13 (11.4)  27 (16.8) 
Hepatitis C alone  2 (4.3)  16 (14)  NS  18 (11.3) 
Hepatitis C with alcohol  0 (0)  1 (0.9)  NS  1 (0.6) 
NASH  4 (8.7)  0 (0)  4 (2.5) 
Cryptogenic  9 (19.6)  44 (38.6)  53 (33.1) 

As seen in Table III, in group-A there was higher child class C patients and more advanced HCC. Also there was lower rate of curative treatment for HCC. Mortality rates at 1-year were higher in group-A.

Table III.

Presenting features and outcome of both groups.

Parameters  Group A, n = 46  Group B, n=114 
Mean age, year  62.6 ± 9.5  66.7 ± 13.7  NS 
Sex ratio (M:F)  6.6:1  5.4:1  NS 
Mean duration of       
Diabetes, years  7.6 ± 3.2  --- 
Mean CPT score  11.8 ± 2.6  10.2 ± 2.1  NS 
Child class C, n (%)  37 (80.4)  70 (61.4) 
• •fetoprotein       
(> 400 ng/dL), n (%)  16 (34.8)  46 (40.3)  NS 
Mean • •fetoprotein,       
ng/dL  1864.5 ± 441.5  2309 ± 726.6  NS 
Advanced lesions, n (%)  34 (73.9)  62 (54.3) 
Resection or ablative       
therapy, n (%)  4 (8.6)  20 (17.5) 
Mean survival, months  10.1 ± 3.1  18.7 ± 6.1 
Mortality at 1-year, n (%)  36 (78.2)  56 (49.1) 
Discussion

Previously, DM is shown to be a bad prognostic factor for long-term survival of cirrhotic patients and mortality mainly being related to liver failure.40

Among 7 studies done to find out impact of DM on HCC management, with few exceptions, most have shown increased post-resection complications and decreased post-resection survival, most probably due to increased risk of hepatic decompensation in DM.41-47 In our study, DM is associated with morphologically advanced lesions and with advanced liver disease regardless of etiology. This can be a deciding factor for delineating management strategies, namely surgical resection, percutaneous therapies and trans-arterial chemoembolization. Our study also shows that DM has adverse prognosis in HCC with high 1-year mortality rate.

It is still unclear whether HCC occurs because of insulin resistance, which leads to NASH, which leads to cirrhosis, or whether the stimulatory effects of insulin on hepatocyte growth lead more directly to neoplasia. Recent studies have thrown light on how DM leads to HCC. DM is a state of hyperinsulinemia. Hyperinsulinemia may directly induce HCC: 1. by the up-regulation of receptors of specific growth factors (insulin and insulinlike-growth factor-1);48,49 2. by activating mitogen activated kinase that leads to phosphorylation of insulin receptor substance-1(IRS-1) a key protein involve in cellular proliferation.50,51 Insulin resistance may play a role by increasing oxidative stress and generation of reactive oxygen species that leads to a. p53 tumor suppressor gene mutation via by-product of lipid peroxidation (4-hydroxynoneal),52,53 or b. up-regulation of proinflammatory cytokines. Thus, inflammation, cellular proliferation, apoptosis inhibition and tumor suppressor gene mutations in setting of advanced liver disease (as a result of insulin resistance and hyperinsulinemia) may lead to HCC formation. Hyperinsulinemia is associated with increased risk of HCC as well as it is shown to increase growth rate of HCC.54,55

In conclusion, Diabetic patients with HCC had more advanced liver failure, morphologically more advanced lesions and poorer long-term prognosis compared to non-diabetic patients with HCC.

References
[1.]
El-Serag H.B., Tran T., Everhart J.E..
Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
Gastroenterology, 126 (2004), pp. 460-468
[2.]
Amarapurkar D., Das H.S..
Chronic liver disease in diabetes mellitus.
Tropical Gastroenterol, 23 (2002), pp. 3-5
[3.]
Ruhl C.E., Everhart J.E..
Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States.
Gastroenterology, 124 (2003), pp. 71-79
[4.]
Di Bisceglie A.M., Carithers Jr R.L., Gores G.L..
Hepatocellular carcinoma.
Hepatology, 28 (1998), pp. 1161-1165
[5.]
El-Serag H.B., Richardson P.A., Everhart J.E..
The role of diabetes in hepatocellular carcinoma: a case-control study among United States veterans.
Am J Gastroenterol, 96 (2001), pp. 2462-2467
[6.]
Kessler I.I..
Cancer mortality among diabetics.
J Natl Cancer Inst, 44 (1970), pp. 2051-2055
[7.]
Ragozzino M., Melton III L.J., Chu C.P., Palumbo P.J..
Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus.
J Chronic Dis, 35 (1982), pp. 13-19
[8.]
Lu S.N., Lin T.M., Chen C.J., Chen J.S., Liaw Y.F., Chang W.Y., et al.
A case-control study of primary hepatocellular carcinoma in Taiwan.
[9.]
Beasley R.P..
Diabetes and hepatocellular carcinoma.
Hepatology, 44 (2006), pp. 1408-1410
[10.]
El–Serag H.B., Hampel H., Javadi F..
The Association Between Diabetes and Hepatocellular Carcinoma: A Systematic Review of Epidemiologic Evidence.
Clin Gastroenterol Hepatol, 4 (2006), pp. 369-380
[11.]
La Vecchia C., Negri E., D’Avanzo B., Boyle P., Franceschi S.D..
Medical history and primary liver cancer.
Cancer Res, 50 (1990), pp. 6274-6277
[12.]
La Vecchia C., Negri E., Franceschi S.D., D’Avanzo B., Boyle P..
A case-control study of diabetes mellitus and cancer risk.
Br J Cancer, 70 (1994), pp. 950-953
[13.]
La Vecchia C., Negri E., DeCarli A., Franceschi S.D..
Diabetes mellitus and the risk of primary liver cancer.
Int J Cancer, 73 (1997), pp. 204-207
[14.]
Adami H.O., McLaughlin J., Ekbom A., Berne C., Silverman D., Hacker D., et al.
Cancer risk in patients with diabetes mellitus.
Cancer Causes Control, 2 (1991), pp. 307-314
[15.]
Adami H.O., Chow W.H., Nyren O., Berne C., Linet M.S., Ekbom A., et al.
Excess risk of primary liver cancer in patients with diabetes mellitus.
J Natl Cancer Inst, 88 (1996), pp. 1472-1477
[16.]
Kingston M.E., Ali M.A., Atiyeh M., Donnelly R.J..
Diabetes mellitus in chronic active hepatitis and cirrhosis.
Gastroenterology, 87 (1984), pp. 688-694
[17.]
Lawson D.H., Gray J.M., McKillop C., Clarke J., Lee F.D., Patrick R.S..
Diabetes mellitus and primary hepatocellular carcinoma.
Q J Med, 61 (1986), pp. 945-955
[18.]
Davila J.A., Morgan R.O., Shaib Y., et al.
Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.
[19.]
Yu M.C., Tong M.J., Govindarajan S., Henderson B.E..
Non-viral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California.
J Natl Cancer Inst, 83 (1991), pp. 1820-1826
[20.]
Braga C., La Vecchia C., Negri E., Franceschi S..
Attributable risks for hepatocellular carcinoma in Northern Italy.
Eur J Cancer, 33 (1997), pp. 629-634
[21.]
Wideroff L., Gridley G., Mellemkjaer L., Chow W.H., Linet M., Keehn S., et al.
Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark.
J Natl Cancer Inst, 89 (1997), pp. 1360-1365
[22.]
Lagiou P., Kuper H., Stuver S., Tzonou A., Trichopoulos D., Adami H.O..
Role of diabetes mellitus in the etiology of hepatocellular carcinoma.
J Natl Cancer Inst, 92 (2000), pp. 1096-1099
[23.]
Fujino Y., Mizoue T., Tokui N., Yoshimura T..
Prospective study of diabetes mellitus and liver cancer in Japan.
Diabetes Metab Res Rev, 17 (2001), pp. 374-379
[24.]
Tazawa J., Maeda M., Nakagawa M., Ohbayashi H., Kusano F., Yamane M., et al.
Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C.
Dig Dis Sci, 47 (2002), pp. 710-715
[25.]
Hassan M., Hwang L., Hatten C., Swaim M., Li D., Abbruzzese J., et al.
Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.
Hepatology, 36 (2002), pp. 1206-1213
[26.]
Lai M.S., Hsieh M.S., Chiu Y.H., Chen T.H..
Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.
Hepatology, 43 (2006), pp. 1295-1302
[27.]
Harrison S.A..
Liver disease in patients with diabetes mellitus.
J Clin Gastroenterol, 40 (2006), pp. 68-76
[28.]
Kaczynski J., Hansson G., Wallerstedt S..
Diabetes: one of few remarkable differences in clinicopathologic features between cirrhotic and noncirrhotic Swedes with hepatocellular carcinoma.
Dig Dis Sci, 51 (2006), pp. 796-802
[29.]
Di Bisceglie A.M..
What every hepatologist should know about endocrinology: Obesity, diabetes, and liver disease.
Gastroenterology, 126 (2004), pp. 604-606
[30.]
Matteoni C., Younossi Z., Gramlich T., Bopari N., Liu Y., McCullough A..
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
Gastroenterology, 116 (1999), pp. 1413-1419
[31.]
Marchesini G., Brizi M., Morselli-Labate A., Bianchi G., Bugianesi E., McCullough A., et al.
Association of nonalcoholic fatty liver disease with insulin resistance.
Am J Med, 107 (1999), pp. 450-455
[32.]
Belfiore F., Iannello S..
Insulin resistance in obesity: metabolic mechanisms and measurement methods.
Mol Genet Metab, 65 (1998), pp. 121-128
[33.]
Falck-Ytter, Younossi Z., Marchesini G., McCullough A..
Clinical features and natural history of nonalcoholic steatosis syndromes.
Semin Liver Dis, 21 (2001), pp. 17-26
[34.]
Powell E., Cooksley W., Hanson R., Searle J., Halliday J., Powell L..
The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.
Hepatology, 11 (1990), pp. 74-80
[35.]
Cotrim H., Parana R., Braga E., Lyra L..
Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history?.
Am J Gastroenterol, 95 (2000), pp. 3018-3019
[36.]
Zen Y., Katayanagi K., Tsuneyama K., Harada K., Araki I., Nakanuma Y..
Hepatocellular carcinoma arising in non-alcoholic steatohepatitis.
Pathol Int, 51 (2001), pp. 127-131
[37.]
Shimada M., Hashimoto E., Taniai M., Hasegawa K., Okuda H., Yayashi N., et al.
Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
J Hepatol, 37 (2002), pp. 154-160
[38.]
Harris M.I., Klein R., Welborn T.A., Knuiman M.W..
Onset of NIDDM occurs at least 4–7 years before clinical diagnosis.
Diabetes Care, 15 (1992), pp. 815-819
[39.]
Iyer S.R..
Type 2 diabetes mellitus express highway, where is the ‘U’ turn?.
JAPI, 51 (2003), pp. 495-500
[40.]
Bianchi G., Marchesini G., Zoli M., Bugianesi E., Fabbri A., Pisi E..
Prognostic significance of diabetes in patients with cirrhosis.
Hepatology, 20 (1994), pp. 119-125
[41.]
Huo T-I, Lui W-Y, Huang Y-H, et al.
Diabetes mellitus is a risk factor for hepatic decompensation in patients with hepatocellular carcinoma undergoing resection: a longitudinal study.
Am J Gastroenterol, 98 (2003), pp. 2293-2298
[42.]
Huo T-I, Wu J-C, Lui W-Y, et al.
Differential mechanism and prognostic impact of diabetes mellitus on patients with hepatocellular carcinoma undergoing surgical and nonsurgical treatment.
Am J Gastroenterol, 99 (2004), pp. 1479-1487
[43.]
Toyoda H., Kumada T., Nakano S., et al.
Impact of diabetes mellitus on the prognosis of patients with hepatocellular carcinoma.
Cancer, 91 (2001), pp. 957-963
[44.]
Ikeda Y., Shimada M., Hasegawa H., et al.
Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection.
Hepatology, 27 (1998), pp. 1567-1571
[45.]
Poon R.T., Fan S.T., Wong J..
Does diabetes mellitus influence the perioperative outcome or long-term prognosis after resection of hepatocellular carcinoma?.
Am J Gastroenterol, 97 (2002), pp. 1480-1488
[46.]
Shimada M., Matsumata T., Akazawa K., et al.
Estimation of risk of major complications after hepatic resections.
Am J Surg, 167 (1994), pp. 339-403
[47.]
Yanaga K., Matsumata T., Hayashi H., et al.
Effect of diabetes mellitus on hepatic resection.
Arch Surg, 128 (1993), pp. 445-448
[48.]
Moore M.A., Park C.B., Tsuda H..
Implication of the hyperinsulinemia-diabetes-cancer link for preventive effect.
Eur J Cancer Prev, 7 (1998), pp. 89-107
[49.]
Kim S.O., Park G.J., Lee Y.I..
Increased expression of the insulin like growth factor receptor –I (IGF-1) receptor gene in hepatocellular carcinoma cell lines: implication of IGF-I receptor gene activation by hepatitis B virus X gene products.
Cancer Res, 56 (1996), pp. 3831-3836
[50.]
Kaburagi Y., Yamachui T., Yamamoto-Honda R., et al.
The mechanism of insulin-induced signal transduction mediated by the insulin receptor substrate family.
Endocr J, 56 (1999), pp. 25-34
[51.]
Tanaka S., Mohr L., Schmidt E.V., et al.
Biologic effect of human insulin receptor substrat-1 overexpression in hepatocytes.
Hepatology, 26 (1997), pp. 598-604
[52.]
Hu W., Feng Z., Eveleigh J., et al.
The major lipid peroxidation product, trans-4-hydroxy-2-noneal, preferentially from DNA adduct at codon 249 of human p53gene, a unique mutational hotspot in hepatocellular carcinoma.
Carcinogenesis, 23 (2002), pp. 1781-1789
[53.]
Hsu H.C., Peng S.Y., Lai P.L., et al.
Allotype loss of heterogeneity of p53 in primary and recurrent hepatocellular carcinoma: a stuffy of 150 patient.
[54.]
Balkau B., Kahn H.S., Courbon D., et al.
Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites.
Diabetes Care, 24 (2001), pp. 843-849
[55.]
Saito K., Inoue S., Saito T., et al.
Augmentation effect of postprandial hyperinsulinemia on growth of human hepatocellular carcinoma.
Gut, 51 (2002), pp. 100-104
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