Liver cancer and diabetes

The incidence of hepatocellular carcinoma (HCC) varies widely by sex and geographical area, for example from approximately 5 per 100,000 women and 8 per 100,000 men in northern Europe in 2010 to 12 per 100,000 women and 30 cases per 100,000 men in eastern Asia in 2008; 82% of liver cancers are estimated to occur in less developed countries. Liver cancer incidence in developed countries has increased over time since the 1970s. The variability by sex, place and time partly reflects difference in prevalence of hepatitis B and C infection but also relates to changing patterns of other risk factors including ageing populations, alcohol consumption, obesity and diabetes.

Liver cancer and diabetes

Relative risks for cancers among people with diabetes are highest for cancers of the liver and the pancreas. Most of the evidence is based on people with type 2 diabetes and there are limited data on risk of HCC among people with type 1 diabetes. A systematic review and meta-analysis of 25 cohort studies published in 2012 reported that diabetes was associated with an increased HCC incidence and mortality compared to people without diabetes in 18 studies giving summary relative risks of 2.01 (95% CI: 1.61-2.51) for incidence and 1.56 (1.30-1.87) for mortality[1].

There was statistically significant heterogeneity among studies for incidence (but not mortality) estimates and the excess risk associated with diabetes appeared to be independent of the potential confounding or common risk factors of geographic location, alcohol consumption, history of cirrhosis, or hepatitis B or hepatitis C virus infection status. The authors found no evidence of publication bias.

Evidence for reverse causality or detection bias in the association between diabetes and liver cancer has been identified from studies that have shown that relative risks of HCC among people with diabetes are particularly high soon after diagnosis of diabetes[2][3]. One small study from the United States has suggested that metastatic disease is more common at presentation of liver cancer among people with diabetes than those without diabetes[4].

Possible Mechanisms

The higher risk of HCC among people with diabetes could potentially be related to exposure of the liver to high insulin concentrations in the portal circulation that are particularly elevated among people with insulin resistance and type 2 diabetes, particularly if the tumour cells remain sensitive to insulin.

Hyperinsulinaemia could increase risk of HCC by increasing synthesis of insulin-like growth factor-1 (IGF-1) which promotes cell growth and proliferation and inhibits apoptosis with evidence for this mechanism provided by in vitro studies, animal models, and epidemiologic studies (reviewed in reference[5]). A further possible biological mechanism for the association between diabetes and liver cancer is that up to 80% of people with type 2 diabetes are thought to have non-alcoholic fatty liver disease which increases risk of non-alcoholic steato-hepatitis, cirrhosis and subsequent HCC.

Common risk factors and confounding factors in the association between diabetes and HCC

Risk and potential confounding factors are considered separately below although it should be noted that several studies suggest that there may be important interactions between individual risk factors to increase risk of cirrhosis and HCC[6][7]. An analysis of linked data from Medicare and Surveillance, Epidemiology and End Results (SEER) databases in the United States for 5607 people that developed liver cancer between 1994 and 2005 found that diabetes was present in 34%, alcohol-related disorders in 24% hepatitis C virus infection in 21%, hepatitis B virus infection in 6%, rare metabolic disorders in 3% and obesity in 3%[8].

Non-modifiable

Age and sex: increasing age and male sex increase risk of both diabetes and HCC and may confound the association between the two conditions

Ethnicity: incidence of diabetes and HCC varies by ethnicity but the associations may be explained in part by differences in prevalence of modifiable risk factors between different ethnic groups

Modifiable

Obesity: is the most strongly associated risk factor for the development of type 2 diabetes. Obesity is associated with approximately double the risk of cancer of the liver compared to people who are of normal weight according to a meta-analysis[9]. Obesity is associated with increased prevalence of non-alcoholic fatty liver disease which in turn increases the risk of liver inflammation, cirrhosis and HCC.

Alcohol and smoking: are both associated with type 2 diabetes and liver cancer although the relationships are complex, for example the relationship between alcohol and diabetes appears to be J shaped and smoking is likely to be associated with alcohol intake in many populations[10][11].

Development of cancer
Development of cancer
Hepatitis infection: increases the risk of cirrhosis and HCC[12]. Hepatitis C infection may also increase risk of diabetes through its effects on pancreatic beta cells and insulin signalling[13][14].

Haemochromatosis: increases risk of both diabetes and liver disease as a consequence of excessive intestinal absorption of dietary iron resulting in a pathological increase in total body iron stores[15].

Treatments for diabetes and their effect on risk of liver cancer

Investigating the association between diabetes treatments, intensive glycaemic control and cancer is difficult as a consequence of limited follow-up periods and un-representativeness of randomised clinical trial participants and the potential for bias and confounding in observational studies.

None of the currently published trials or the meta-analysis of their results has sufficient power to investigate associations between different treatments or intensive glycaemic control and HCC. The finding that metformin appeared to be associated with a hazard ratio (95% CI) of 0.06 (0.02–0.16) in an observational study using Taiwanese health insurance data[16] can at least partly be explained by the introduction of immortal time bias in the study design[17].

Similar biases as well as confounding by indication may influence a meta-analysis of four observational studies of HCC among people with diabetes which reported an odds ratio (95% CI) of 0.30 (0.17, 0.52)[18]. Confounding by indication is likely to occur because metformin and thiazolidinediones are contra-indicated in people with liver disease, meaning that people who are treated with these drugs are likely to be at lower risk of liver cancer than people who are not treated with them. However metformin protects against chemically induced liver tumours in mice apparently through its effects on lipogenesis[19]and further research is required to establish the role of different treatments for diabetes on risk of liver cancer.

References

  1. ^ Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y et al.: Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer 2012, 130: 1639-1648.

  2. ^ Johnson JA, Bowker SL, Richardson K, Marra CA: Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia 2011, 54: 2263-2271.

  3. ^ Carstensen B, Witte DR, Friis S: Cancer occurrence in Danish diabetic patients: duration and insulin effects. Diabetologia 2012, 55: 948-958.

  4. ^ Connolly GC, Safadjou S, Chen R, Nduaguba A, Dunne R, Khorana AA et al.: Diabetes mellitus is associated with the presence of metastatic spread at disease presentation in hepatocellular carcinoma. Cancer Invest 2012, 30: 698-702.

  5. ^ Weng CJ, Hsieh YH, Tsai CM, Chu YH, Ueng KC, Liu YF et al.: Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma. Ann Surg Oncol 2010, 17: 1808-1815.

  6. ^ Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL et al.: Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008, 135: 111-121.

  7. ^ Hart CL, Morrison DS, Batty GD, Mitchell RJ, Davey SG: Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. BMJ 2010, 340: c1240.

  8. ^ McGlynn KA, Quraishi S, Welzel TM, Davila JA, El-Serag HB, Grabaud BI. Attributable risks for hepatocellular carcinoma in the United States. Cancer Research2010, 70:[8 (Supplement)]: Abstract 1816.

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

  10. ^ Baliunas DO, Taylor BJ, Irving H, Roerecke M, Patra J, Mohapatra S et al.: Alcohol as a risk factor for type 2 diabetes: A systematic review and meta-analysis. Diabetes Care 2009, 32: 2123-2132.

  11. ^ Hsing AW, McLaughlin JK, Hrubec Z, Blot WJ, Fraumeni JF, Jr.: Cigarette smoking and liver cancer among US veterans. Cancer Causes Control 1990, 1: 217-221.

  12. ^ Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP: The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006, 45: 529-538.

  13. ^ Masini M, Campani D, Boggi U, Menicagli M, Funel N, Pollera M et al.: Hepatitis C virus infection and human pancreatic beta-cell dysfunction. Diabetes Care 2005, 28: 940-941.

  14. ^ Miyamoto H, Moriishi K, Moriya K, Murata S, Tanaka K, Suzuki T et al.: Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 2007, 81: 1727-1735.

  15. ^ Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G: Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996, 110: 1107-1119.

  16. ^ Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC: Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011, 11: 20.

  17. ^ Suissa S, Azoulay L: Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 2012, 35: 2665-2673.

  18. ^ Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE: Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012, 97: 2347-2353.

  19. ^ Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK et al.: Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila) 2012, 5: 544-552.

Comments

  1. no profile image
    Vadim Shapoval added a suggestion on 19 June 2015 at 02:40PM
    Type 2 Diabetes, Cancer and Father of Oncology. Anyone can get diabetes or cancer. Unlike people with type 1 diabetes, the bodies of people with type 2 diabetes make insulin. Hemochromatosis is a common inherited disorder in which the body absorbs and stores abnormally high amounts of iron. Healthy people usually absorb about 10% of the iron contained in the food they eat. People with hemochromatosis absorb up to 30% of iron. Over time, they absorb and retain between 5 to 20 times more iron than the body needs. Hemochromatosis tends to coexist with diabetes, for reasons that aren’t completely clear, scientists say. The association between hemochromatosis and diabetes was first recognized in the late 1800’s, when doctors coined the term Bronze Diabetes in reference to the changes in skin pigmentation caused by hemochromatosis. The damage to the pancreas from excessive iron deposits can cause diabetes, experts say. Even though people have defective hemochromatosis genes from birth, the symptoms usually don’t occur until adulthood. The symptoms associated with hemochromatosis are diverse; however, it sometimes causes no symptoms. To rid the body of excess iron, people with hemochromatosis are given regular treatments of phlebotomy, or blood removal, that are simple, inexpensive, and safe. The normal iron content of the body is 3 to 4 grams. Hemochromatosis can be diagnosed based on certain blood tests. It is best to catch hemochromatosis early. Patients with hemochromatosis may be asymptomatic or may present with general and organ-related signs and symptoms. Excess iron is stored (asymptomatically) in body tissues and patient can get type 2 diabetes, type 1 diabetes or/and cancer (liver cancer, pancreatic cancer, brain cancer, etc); there is an epidemic of diabetes today; there is an epidemic of cancer today; the Father of Oncology says. The majority of cancers are the result of bad luck rather than unhealthy lifestyles or inherited genetic faults, researchers say. The human body is composed of trillions of cells. Cancer is a disease of iron-overloaded cells. Primary tumors always develop at body sites of excessive iron deposits. Such deposits can be inherited or acquired. Aging is the single biggest risk factor for developing cancer because older adults have disorders of iron metabolism. Iron homeostasis must be tightly regulated. Genes that maintain iron homeostasis may facilitate iron uptake, storage or egress, or the regulation of any of these processes. Usually, cancer patients are born with strong cancer genes (iron-overloaded genes) and weak anticancer genes (iron-deficiency genes). Direct intratumoral injections of iron-deficiency agents (ceramic needles) are needed when tumors and metastases cannot be removed with surgery (ceramic blades); all cancers can be treated with iron-deficiency therapy (special diets, blood donations) in hospitals http://www.medicalnewstoday.com/opinions/185755
  2. no profile image
    Vadim Shapoval added a suggestion on 3 February 2015 at 11:18AM
    Diabetes and Liver Cancer. Diabetes is typically divided into two major subtypes, type 1 and type 2 diabetes, while cancer is typically classified by its anatomic origin. Studies have shown that diabetes carries an increased risk for a number of different forms of cancer. Secondary diseases related to diabetes affect iron metabolism in different organs. Patients with diabetes may have high blood sugar levels (hyperglycemia) or low blood sugar levels (hypoglycemia) from time to time. Medical nutrition therapy for diabetics can be divided into dietary interventions and physical activity. Like all medications, patients need to take insulin in the right amounts. Overdosing on insulin can cause serious side effects and even death. Cancer Loves Sugar - Truth or Rumor? At the cellular level, liver cancer occurs when cellular iron overload chaotically affects organic molecules, DNA and chromosomes. Liver cancer is a disease of iron-overloaded cells. Diabetes-related primary tumors always develop at body sites of excessive iron deposits. Iron deposits can be inherited or acquired. Liver cancer is a form of iron lottery, explains the Father of Oncology. Local/regional iron overload can affect any part of the body (pancreatic tumors, liver tumors, lung tumors, etc). Surgery (ceramic blades), direct intratumoral injections of iron-deficiency agents (ceramic needles) and clinical iron-deficiency methods (special diets; accurate blood donations) can successfully eliminate liver tumors, metastases and micrometastases. Oncologists must work together with endocrinologists if patient has both liver cancer and diabetes. Diabetics become less adherent to their diabetes medications following a diagnosis of cancer. Today the psycho-oncology has become an accepted part of cancer treatment. Cancer can have a huge effect on emotions, as well as on the practical aspects of life. Sigmund Freud was one of the trailblazers of modern-day psychology. Freud consulted many specialists, during the course of his ordeal with oral cancer. He underwent 34 surgical procedures before his eventual death in 1939 through euthanasia. Cancer-related depression can affect a patient's capacity to deal with their diabetes, including managing blood glucose levels appropriately. Moreover, modern chemotherapy and radiotherapy (inadequate therapies) can be very harmful for diabetics. If inadequately treated or untreated, cancer can be fatal. Currently, 14 million people are diagnosed with cancer each year, with 8 million dying because of it. Cancer costs the world economy nearly US$3 trillion ($3,000,000,000,000) every year. Are we losing the war on cancer? Cancer will be tied with iron chains, Vanga predicted. http://www.medicalnewstoday.com/opinions/182753
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