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 Table of Contents  
ORIGINAL ARTICLES
Year : 2019  |  Volume : 10  |  Issue : 3  |  Page : 123-126

Diabetes mellitus as a risk factor for hepatocellular carcinoma: A single-centre experience from South India


1 Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
2 Department of Diabetology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
3 Department of Liver Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, India

Date of Web Publication27-Aug-2019

Correspondence Address:
Dr. Mayank Jain
Department of Gastroenterology, Gleneagles Global Health City, Chennai - 600 100, Tamil Nadu.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_40_18

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  Abstract 

Aim: Retrospective analysis of medical records to determine whether diabetes mellitus (DM) was a risk factor for hepatocellular carcinoma (HCC) and whether it enhances the neoplastic potential of hepatotropic virus-related chronic liver disease (CLD). Materials and Methods: Patients registered between April 2017 and March 2018 with a clinical diagnosis of HCC in a pre-existing CLD were included. Controls were patients with CLD registered during the same period but with no HCC. Prevalence of DM, hypertension and coronary artery disease (CAD) alone or in combinations was noted in the two groups. The odds ratio (OR) of developing HCC was calculated independently for DM, hepatitis B and hepatitis C infection alone and in combinations. Chi-square test, Mann–Whitney test and OR calculation were done. A P < 0.05 was considered statistically significant. Results: The study population consisted of 150 cases of CLD with HCC and 812 controls (CLD with no HCC). CLD patients with HCC were significantly older (P < 0.0001) with a male preponderance, but no gender predisposition (P = NS). The overall prevalence of DM in patients with CLD was 31.9%, more significant amongst cases than in controls (50.7% vs. 28.7%) (P < 0.0001) and also for a significant duration (10.6 vs. 3.8 years; P < 0.03). Amongst the cases, comorbid conditions such as hypertension and CAD and diabetes in combination with hypertension and CAD was also more frequent among cases (P = 0.0001).The odds of developing HCC in CLD was higher for DM. The OR for HCC was highest for DM with hypertension and/or CAD at 4.69 (3.19–6.88, P < 0.0001). Conclusion: DM and other constituents of metabolic syndrome such as hypertension and CAD are significantly more common in CLD patients with HCC. DM is of prolonged duration and is a risk factor increasing the neoplastic potential of CLD.

Keywords: Cancer, cirrhosis, diabetes, liver


How to cite this article:
Jain M, Baraneedharan K, Sameer Kumar G S, Joshi V, Reddy MS, Rela M, Venkataraman J. Diabetes mellitus as a risk factor for hepatocellular carcinoma: A single-centre experience from South India. J Diabetol 2019;10:123-6

How to cite this URL:
Jain M, Baraneedharan K, Sameer Kumar G S, Joshi V, Reddy MS, Rela M, Venkataraman J. Diabetes mellitus as a risk factor for hepatocellular carcinoma: A single-centre experience from South India. J Diabetol [serial online] 2019 [cited 2019 Nov 18];10:123-6. Available from: http://www.journalofdiabetology.org/text.asp?2019/10/3/123/265415




  Introduction Top


Diabetes mellitus (DM) is a complex metabolic state defined by the level of hyperglycaemia, giving rise to risk of microvascular or macrovascular complications.[1] The prevalence of diabetes in India is around 10%.[2],[3] Indians develop diabetes at a younger age, with lower degree of obesity and an increased risk of chronic diabetic complications. Asians have strong genetic susceptibility for Type II diabetes.[2],[4]

In India, hepatitis B virus (HBV), with or without an aflatoxin exposure, hepatitis C virus (HCV) and alcoholism are leading causes of cirrhosis of the liver and are the predominant risk factors for hepatocellular carcinoma (HCC).[5],[6],[7]

The present retrospective study was done to determine if Type 2 DM is a risk factor for HCC in patients with chronic liver disease (CLD) and whether it enhances the neoplastic potential of known aetiological factors such as HBV- and HCV-related CLD.


  Materials and Methods Top


Patients registered between April 2017 and March 2018 with a clinical diagnosis of HCC in a pre-existing CLD were included for the study. Controls were patients with CLD registered during the same period but with no HCC. The study was retrospective, and data retrieval was from the medical records of patients registered during this period (International Statistical Classification of Diseases and Related Health Problems) codes. The records were screened for codes K70-K77, and a total of 1860 patients were initially screened. Of these, 1263 had CLD, cirrhosis or HCC. Three hundred and one were excluded due to insufficient data or unclear diagnosis. A total of 962 patient records were then analysed for the study.

Definitions used in the study

  1. Chronic hepatitis: Transaminitis for more than 6 months


  2. Cirrhosis of liver: Diagnosis based on clinical, biochemical and radiological that included triple-phase computed tomography in the presence or absence of varices


  3. Decompensated cirrhosis: Cirrhosis with ascites, gastrointestinal bleed, hepatic encephalopathy and jaundice (combination of any 2)


  4. HCC: Classical imaging findings on contrast-enhanced computed tomography (CECT)/magnetic resonance imaging abdomen (early arterial enhancement with early washout) with or without a rise in alpha-fetoprotein levels.


The study cohort included patients with chronic hepatitis (transaminitis beyond 6 months) and cirrhosis of the liver (confirmed by CECT abdomen) with or without decompensation. Patient information comprised of age, gender, aetiology (alcohol, cryptogenic/non-alcoholic steatohepatitis [NASH]/HBV/HCV/others) of liver disease and comorbid states (DM, hypertension, coronary heart disease, hypothyroid state, others). The duration of diabetes was noted. The data on anthropometry, lipid profile and treatment were not available in most cases and hence not included in the analysis. Patients below the age of 18 years and those with incomplete information and inconclusive diagnosis were excluded.

The study was approved by the institutional ethics committee via letter no. HR/2017/MS/014. However, individual patient’s consent was not taken as the study was retrospective and no patient identifiers were used.

Statistical analysis

For analysis, initial comparison was done between cases and controls for demography and aetiology. Prevalence of DM, hypertension and coronary artery disease (CAD) alone or in combinations was noted in the two groups. The odds ratio (OR) of developing HCC was calculated for independently for DM, hepatitis B and hepatitis C infection alone and in combinations. Descriptive analysis was done by median and range for quantitative variables and frequency and proportion for categorical variables. Chi-square test, Mann–Whitney test and relative risk (RR) calculation were done. Age-adjusted incidence was calculated for DM, HCC and DM with HCC to determine the effect of age on occurrence of HCC. A P < 0.05 was considered statistically significant.


  Results Top


The study population consisted of 150 cases of CLD with HCC and 812 controls (CLD with no HCC).

Comparing cases with controls, we observed that CLD patients with HCC were significantly older (P < 0.0001) with a male preponderance, but no gender predisposition (P = NS) [Table 1]. Alcohol per se or in combination with other factors such as HBV and HCV were significantly associated with CLD (P < 0.0001) but not for HCC. However, HBV (P < 0.0001), HCV (P < 0.0001) and NASH (P = 0.03) were independently associated with HCC.
Table 1: Comparative data on demography, aetiology and comorbidity in chronic liver disease patients with and without hepatocellular carcinoma

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Comorbidity and hepatocellular carcinoma

The overall prevalence of DM in patients with CLD was 31.9%, more significant amongst cases than in controls (50.7% vs. 28.7%) (P < 0.0001) and for a significant duration (10.6 vs. 3.8 years; P < 0.03).

Amongst the cases, comorbid conditions such as hypertension and CAD and diabetes in combination with hypertension and CAD were also more frequent among cases (P = 0.0001) [Table 2].
Table 2: Co-morbidity and hepatocellular carcinoma

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The OR of developing HCC in CLD was higher for DM compared to HBV and HCV infections [Table 3]. The OR for developing HCC with DM was 2.19 (95% confidence interval [CI] 1.63–2.92, P < 0.0001) compared to 1.85 (95% CI 1.35–2.54, P < 0.0001) for HBV and 1.90 (95% CI 1.31–2.74) for HCV. Type 2 DM in the presence of HBV (3.14, CI 2.21–4.48, P < 0.0001) and HCV (3.51; 95% CI 2.35–5.23, P < 0.0001) increased the risk for HCC [Table 3]. The OR for HCC was highest for DM with hypertension and/or CAD at 4.69 (3.19–6.88, P < 0.0001), highlighting the impact of metabolic syndrome in development of HCC.
Table 3: Odds ratio for developing hepatocellular carcinoma for diabetes mellitus, hepatitis B virus and hepatitis C virus and its combinations

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Age-adjusted incidence rates are summarised in [Table 4] and presented in [Figure 1].
Table 4: Incidence rates (per 100 population) for diabetes mellitus, hepatocellular carcinoma and diabetes mellitus + hepatocellular carcinoma in various age groups

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,
Figure 1: Age-adjusted incidence. DM: Diabetes mellitus, HCC: Hepatocellular carcinoma

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[Table 4] shows that incidence of DM increased with increasing age in the cases. The incidence of HCC was highest in the age group of 51–60 years, followed by 61–70 years. Higher incidence of both DM and HCC was noted in the age groups of 81–90 years, 51–60 years and 41–50 years. Although we did find linear correlation between increasing HCC and DM with age, the numbers were too small, particularly at extreme age group, to draw firm conclusions.


  Discussion Top


The present study from South India highlights that DM and other constituents of metabolic syndrome such as hypertension and CAD are significantly more common in CLD patients with HCC. DM is of prolonged duration and is a risk factor increasing the neoplastic potential of CLD.

DM has been identified as an independent risk factor for the HCC in western studies.[8],[9],[10],[11] Analysis of 2061 patients with HCC showed a significant increase risk in the development of HCC (OR 2.87, 95% CI: 2.49–3.3) in the presence of DM regardless of the existence of other risk factors. Moreover, the authors also reported a significant positive interaction between obesity and HCV (P < 0.0001) for HCC.

DM with cirrhosis demonstrated the highest risk for HCC (RR = 82.25, 95% CI: 76.84–94.58).[12] A recent surveillance, epidemiology and end results (SEER)-Medicare data analysis showed that the OR of DM for HCC was 2.9.[13] The Me-Can survey from Norway, Sweden and Austria examining more than 5,00,000 subjects reported a relative risk of 2.13 (95% CI: 1.55–2.94) for DM in the development of HCC.[14]

Hypertension is an important component of the metabolic syndrome. Very few studies examined the relationship of HCC with hypertension. SEER-Medicare data analysis reported that OR of hypertension for HCC was 2.22.[13] A single-centre study also showed that among 209 non-B non-C-HCC patients, 38% had hypertension, and 11% had dyslipidaemia.[15]

The present study is a large retrospective analysis highlighting the role of DM in pathogenesis of HCC in the Indian setting for the first time. However, it has a few limitations such as retrospective analysis; selection bias as our centre is a liver transplant centre; no data regarding lipid profile, anthropometry and treatment details; few cases in extremes of age groups and so effect of age on HCC not clearly noted; cases and controls unmatched in age.


  Conclusion Top


It is extremely important for the scientific community, especially the diabetologists and practicing family and general physicians to be aware of not only the neurovascular complications in their patients but also the associated risk of HCC in long-standing diabetics. Is HCC a natural onslaught of long-standing diabetes, or is the combination of comorbid states or co-existence of HBV and HCV that enhances the risk for HCC needs exploration by prospective studies. Do anti-diabetic drugs enhance the risk for HCC also needs to be addressed. Finally, all DM patients must be screened for hepatotropic viruses such as HBV and HCV and non-alcoholic steatohepatitis for stratifying the risk factors mentioned in a large cohort.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet 2006;368:1681-8.  Back to cited text no. 1
    
2.
Amarapurkar DN, Patel ND. Increased prevalence of type II diabetes mellitus in hepatitis C virus infection in Western India. Trop Gastroenterol 2008;29:148-52.  Back to cited text no. 2
    
3.
World Health Organization, Global Report on Diabetes. Geneva, 2016. [Last accessed on 2018 Aug 28].  Back to cited text no. 3
    
4.
Amarapurkar D, Das HS. Chronic liver disease in diabetes mellitus. Trop Gastroenterol 2002;23:3–5.  Back to cited text no. 4
    
5.
Kar P. Risk factors for hepatocellular carcinoma in India. J Clin Exp Hepatol 2014;4:S34-42.  Back to cited text no. 5
    
6.
Murugavel KG, Mathews S, Jayanthi V, Shankar EM, Hari R, Surendran R, et al. Alpha-fetoprotein as a tumor marker in hepatocellular carcinoma: Investigations in South Indian subjects with hepatotropic virus and aflatoxin etiologies. Int J Infect Dis 2008;12:e71-6.  Back to cited text no. 6
    
7.
Murugavel KG, Naranatt PP, Shankar EM, Mathews S, Raghuram K, Rajasambandam P, et al. Prevalence of aflatoxin B1 in liver biopsies of proven hepatocellular carcinoma in India determined by an in-house immunoperoxidase test. J Med Microbiol 2007;56:1455-9.  Back to cited text no. 7
    
8.
Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 2000;92:1096-9.  Back to cited text no. 8
    
9.
Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: A population based case control study. Gut 2005;54:533-9.  Back to cited text no. 9
    
10.
Schattenberg JM, Schuppan D. Nonalcoholic steatohepatitis: The therapeutic challenge of a global epidemic. Curr Opin Lipidol 2011;22:479-88.  Back to cited text no. 10
    
11.
Wideroff L, Gridley G, Mellemkjaer L, Chow WH, 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 1997;89:1360-5.  Back to cited text no. 11
    
12.
Chen HF, Chen P, Li CY. Risk of malignant neoplasms of liver and biliary tract in diabetic patients with different age and sex stratifications. Hepatology 2010;52:155-63.  Back to cited text no. 12
    
13.
Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: A study in the SEER-Medicare database. Hepatology 2011;54:463-71.  Back to cited text no. 13
    
14.
Borena W, Strohmaier S, Lukanova A, Bjørge T, Lindkvist B, Hallmans G, et al. Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer 2012;131:193-200.  Back to cited text no. 14
    
15.
Nagaoki Y, Hyogo H, Aikata H, Tanaka M, Naeshiro N, Nakahara T, et al. Recent trend of clinical features in patients with hepatocellular carcinoma. Hepatol Res 2012;42:368-75.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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