Liver cancer risk factors

Prevention

Preventable cases of liver cancer, UK

Smoking

Liver cancer cases linked to exposure to tobacco smoke, UK

Infection

Liver cancer cases linked to infections, UK

Alcohol

Liver cancer cases linked to alcohol consumption, UK

42% (49% in males and 28% in females) of liver cancer cases each year in the UK are linked to major lifestyle and other risk factors.[1]

Liver cancer risk is associated with a number of risk factors.[2,3]

Liver Cancer Risk Factors

  Increases risk Decreases risk
'Sufficient' or 'convinicing' evidence
  • Aflatoxins
  • Alcoholic drinks
  • Liver flukes (Clonorchis sinensis and Opisthorchis viverrini)
  • 1,2-Dichloropropane
  • Oestrogen-progestogen contraceptives
  • Hepatitis B and C viruses
  • Plutonium
  • Thorium-232 and its decay products
  • Tobacco smoking (in smokers and in smokers’ children)
  • Vinyl chloride
  • Body fatness
 
'Limited' or 'probable' evidence
  • Androgenic (anabolic) steroids
  • Arsenic and inorganic arsenic compounds
  • Betel quid without tobacco
  • DDT
  • Dichloromethane (Methylene chloride)
  • Human immunodeficiency virus (HIV) type 1
  • Schistosoma japonicum
  • Trichloroethylene
  • X-radiation, gamma-radiation
  • Coffee

International Agency for Research on Cancer (IARC) and The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) classifications.

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Infection with the hepatitis B (HBV) or hepatitis C virus (HCV) is classified by the International Agency for Research on Cancer (IARC) as a cause of hepatocellular carcinoma (HCC); and is classified as a probable cause of cholangiocarcinoma (CCA), based on limited evidence.[1] An estimated 16% of liver cancers in the UK are linked to HBV or HCV infection.[2] An estimated 90% of liver cancer cases in developing countries, and 40% of cases in developed countries, are caused by HBV or HCV infection.[3]

Worldwide around 2 billion people are infected with HBV, and around 80 million with HCV.[4] Chronic infection occurs in around 10% (HBV) and 80% (HCV) of newly-infected people.[4]

HCC risk is around 20 times higher in people with HBV and/or HCV infection, in areas such as the UK where prevalence of infection is low.[5] HCC risk in people with HCV infection is higher among those who are older, male, or have a previous alcohol-related hospital admission, a cohort study showed.[6] 80-90% of patients with HBV- or HCV-related HCC also have cirrhosis, but HBV infection may also be associated with HCC risk in the absence of cirrhosis.[7,8]

CCA risk is increased to a lesser extent with HBV and/or HCV infection.[9]

References

  1. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI 2011;103:1827-39.
  2. Parkin DM. Cancers attributable to infection in the UK in 2010. BJC 2011;105 Suppl 2:S49-56.
  3. Parkin DM. The global health burden of infection-associated cancers in the year 2002. IJC 2006;118:3030-44.
  4. International Agency for Research on Cancer (IARC). World cancer report 2008. Lyon: IARC; 2008.
  5. Cho LY, Yang JJ, Ko KP, et al. Coinfection of hepatitis B and C viruses and risk of hepatocellular carcinoma: systematic review and meta-analysis. IJC 2011;128:176-84.
  6. McDonald SA, Hutchinson SJ, Bird SM, et al. A record-linkage study of the development of hepatocellular carcinoma in persons with hepatitis C infection in Scotland. BJC 2008;99:805-10.
  7. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. IJC 1998;75:347-54.
  8. Adami HO, Hunter D, Trichopoulos D, eds. Textbook of Cancer Epidemiology. New York: Oxford University Press; 2002.
  9. Zhou Y, Zhao Y, Li B, et al. Hepatitis viruses infection and risk of intrahepatic cholangiocarcinoma: evidence from a meta-analysis. BMC Cancer 2012;12:289.
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Tobacco smoking is classified by the International Agency for Research on Cancer (IARC) as a cause of liver cancer; and smoking by either parent (pre-conception or during pregnancy) is classified as a cause of childhood heptoblastoma.[1] An estimated 23% (27% in men and 15% in women) of liver cancers in the UK are linked to smoking.[2]

Hepatocellular carcinoma (HCC) risk is 51-56% higher in current smokers compared with never-smokers, meta-analyses have shown.[3,4] HCC risk is almost 10 times higher in smokers who also heavily drink alcohol.[5] Smoking and HCV infection have a multiplicative effect on HCC risk.[6]

Heptoblastoma risk is almost five times higher in children whose parents both smoked in the preconception period, a cohort study showed.[7]

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Betel quid without tobacco is classified by the International Agency for Research on Cancer (IARC) as a probable cause of liver cancer, based on limited evidence.[1,2]

Liver cancer risk is higher in betel quid users, case-control and cohort studies have shown.[3-6]

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Oestrogen-progestogen contraceptives are classified by the International Agency for Research on Cancer (IARC) as a cause of liver cancer.[1] However, hepatocellular carcinoma (HCC) risk is not associated with the use of oral contraceptives, a meta-analysis showed.[2]

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Hepatocellular carcinoma (HCC) risk is 8-55 times higher in people with liver cirrhosis Open a glossary item, case-control and cohort studies show.[1-5] HCC risk is higher in HBV/HCV-related cirrhosis (accounting for 57% of cirrhosis cases worldwide[6,7]) than alcoholic cirrhosis.[8,9]

Cholangiocarcinoma (CCA) risk is ten times higher in people with cirrhosis, a case-control study showed.[10]

References

  1. Franceschi S, Montella M, Polesel J, et al. Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy. Cancer Epidemiol Biomarkers Prev 2006;15:683-9.
  2. Randi G, Altieri A, Gallus S, et al. History of cirrhosis and risk of digestive tract neoplasms. Ann Oncol 2005;16:1551-5.
  3. La Vecchia C, Negri E, Cavalieri d'Oro L, et al. Liver cirrhosis and the risk of primary liver cancer. Eur J Cancer Prev 1998;7:315-20.
  4. Persson EC, Quraishi SM, Welzel TM, et al. Risk of liver cancer among US male veterans with cirrhosis, 1969-1996. BJC 2012;107:195-200.
  5. Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35-50.
  6. Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45:529-38.
  7. Ribes J, Cleries R, Rubio A, et al. Cofactors associated with liver disease mortality in an HBsAg-positive Mediterranean cohort: 20 years of follow-up. IJC 2006;119:687-94.
  8. Persson EC, Quraishi SM, Welzel TM, et al. Risk of liver cancer among US male veterans with cirrhosis, 1969-1996. BJC 2012;107:195-200.
  9. Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35-50.
  10. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 2007;5:1221-8.
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Hepatocellular carcinoma (HCC) risk is 66% higher in diabetics, a meta-analysis showed.[1] HCC risk among diabetics may be lower in metformin users, and higher in sulfonylurea or insulin users, each compared with non-users; but HCC risk is not associated with thiazolidinedione use, a meta-analysis showed.[2]

HCC risk may increase with duration of diabetes, a cohort study (mainly including men) showed.[3] HCC risk in diabetics appears to be independent of other liver cancer risk factors,[4-6] and diabetes is associated with further increased HCC risk in people with chronic liver disease, hepatitis C virus (HCV) infection, or cirrhosis.[7]

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Liver cancer risk is more than 4 times higher in people hospitalised with non-alcoholic fatty liver disease (NAFLD, related to obesity and diabetes[1]), compared with the general population, a cohort study showed.[2]

Liver cancer risk is 49% higher in people with metabolic syndrome, a meta-analysis showed.[3]

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Cholangiocarcinoma (CCA) develops in 7-13% of people with primary sclerosing cholangitis.[1,2]

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Liver cancer risk is 47% higher in people who have had their gallbladder removed (cholecystectomy), a meta-analysis of cohort studies showed.[1]

Liver cancer risk is 90% higher in people who have had gallstones (cholelithiasis), a meta-analysis of cohort studies showed.[1]

 

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Liver cancer risk is higher in blood transfusion recipients compared with the general population, a cohort study showed; this probably reflects other liver cancer risk factors in transfusion recipients, but may be linked to hepatitis B (HBV) or hepatitis C virus (HCV) transmission (though blood products are now screened for these infections).[1]

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The liver flukes Clonorchis sinensis and Opisthorchis viverrini are classified by the International Agency for Research on Cancer (IARC) as causes of liver cancer, and the blood fluke Schistosoma japonicum is classified as a probable cause of liver cancer, based on limited evidence.[1]

An estimated 2,500 liver cancer cases worldwide each year are caused by liver flukes infection;[2] infection occurs mainly in endemic regions in China and other parts of Asia.[3-5]

References

  1. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI 2011;103:1827-39.
  2. Parkin DM. The global health burden of infection-associated cancers in the year 2002. IJC 2006;118:3030-44.
  3. Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma. PLoS Med 2007;4:e201.
  4. Shin HR, Oh JK, Masuyer E, et al. Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci 2010;101:579-85.
  5. Gray DJ, Thrift AP, Williams GM, et al. Five-year longitudinal assessment of the downstream impact on schistosomiasis transmission following closure of the Three Gorges Dam. PLoS Negl Trop Dis 2012;6:e1588.
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Consuming alcoholic drinks is classified by the International Agency for Research on Cancer (IARC) and the World Cancer Research Fund, American Institute for Cancer Research (WCRF/AICR) as a cause of liver cancer.[1,2] An estimated 9% of liver cancers in the UK are linked to alcoholic consumption.[3] Almost one-third of liver cancer deaths in high-income countries are caused by alcohol.[4]

Liver cancer risk is 16% higher in people who heavily drink alcohol (3+ drinks per day), compared with non-drinkers a meta-analysis showed.[5] Liver cancer risk is not associated with moderate drinking (less than 3 drinks per day) or light drinking (up to 1 drink per day), meta-analyses have shown.[5,6]

Hepatocellular carcinoma (HCC) risk among people with hepatitis B (HBV) or hepatitis C virus (HCV) infection is doubled in heavy drinkers compared with moderate or non-drinkers, a case-control study showed.[7]

Alcohol misuse is associated with cirrhosis, but may also cause liver cancer in the absence of cirrhosis.[5]

References

  1. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI 2011;103:1827-39.
  2. World Cancer Research Fund, American Institute for Cancer Research. Food, nutrition, physical activity and the prevention of cancer: A global perspective. Washington: American Institute for Cancer Research; 2007.
  3. Parkin DM. 3. Cancers attributable to consumption of alcohol in the UK in 2010. BJC 2011;105 Suppl 2:S14-8.
  4. Danaei G, Vander Hoorn S, Lopez AD, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors . Lancet 2005;366:1784-93.
  5. Turati F, Galeone C, Rota M, et al. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. Ann Oncol 2014.
  6. Bagnardi V, Rota M, Botteri E, et al. Light alcohol drinking and cancer: a meta-analysis. Ann Oncol 2013;24(2):301-8.
  7. Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155:323-31.
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Body fatness is classified by the World Cancer Research Fund / American Institute for Cancer Research (WCRF/AICR) as a probable cause of liver cancer.[1]

Liver cancer risk among men is 42% higher in those who are overweight or obese (body mass index [BMI] 25+), and 91% higher in those who are obese (BMI 30+), a meta-analyses showed.[2] Liver cancer risk among women is 18% higher in those who are overweight or obese and 55% higher in those who are obese, a meta-analyses showed.[2]

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Aflatoxins are classified by the International Agency for Research on Cancer (IARC) and the World Cancer Research Fund, American Institute for Cancer Research (WCRF/AICR) as a cause of liver cancer.[1,2] Most alfatoxin-associated cases are in developing countries, where hepatitis B (HBV) infection and aflatoxin contamination are most prevalent.[3,4]

Hepatocellular carcinoma (HCC) risk is around 30 times higher in people with aflatoxin exposure and chronic HBV infection, versus uninfected people with aflatoxin exposure.[4]

References

  1. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI 2011;103:1827-39.
  2. World Cancer Research Fund, American Institute for Cancer Research. Food, nutrition, physical activity and the prevention of cancer: A global perspective. Washington: American Institute for Cancer Research; 2007.
  3. Chuang SC, La Vecchia C, Boffetta P. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett 2009;286:9-14.
  4. Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 2010;118:818-24.
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Hepatocellular carcinoma (HCC) risk is up to 11 times higher in people with haemochromatosis Open a glossary item, compared with healthy controls, a meta-analysis showed.[1] The risk increase may be limited to specific haemochromatosis types,[1] and people with coexisting cirrhosis.[2]

Liver cancer risk is also higher in people with porphyrias,[3] alpha1-antitrypsin deficiency or tyrosinemia.[4,5]

References

  1. Ellervik C, Birgens H, Tybjaerg-Hansen A, et al. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology 2007;46(4):1071-80.
  2. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127:S79-86.
  3. Sardh E, Wahlin S, Björnstedt M, et al. High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria. J Inherit Metab Dis 2013;36(6):1063-71.
  4. Schottenfeld D, Fraumeni J, eds. Cancer epidemiology and prevention. 3rd ed: Oxford University Press; 2006.
  5. Dragani TA. Risk of HCC: genetic heterogeneity and complex genetics. J Hepatol 2010;52(2):252-7.
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Immune suppression may inhibit hepatitis infection clearance and/or accelerate hepatitis-related liver damage.[1,2]

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HIV type 1 infection is classified by the International Agency for Research on Cancer (IARC) as a cause of liver cancer, based on limited evidence.[1] Liver cancer risk is 5-6 times higher in people with HIV/AIDS, compared with the general population, meta-analyses have shown.[2,3] Co-infection with HIV is not associated with liver risk in hepatitis C-positive people, a meta-analysis showed.[4]

References

  1. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI 2011;103:1827-39.
  2. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370:59-67.
  3. Shiels MS, Cole SR, Kirk GD, et al. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 2009;52(5):611-22.
  4. Deng LP, Gui XE, Zhang YX, et al. Impact of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. World J Gastroenterol 2009;15(8):996-1003.
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Liver cancer risk is around doubled in organ transplant recipients, compared with the general population, a meta-analysis and cohort study have shown.[1,2] Liver transplant recipients appear to have even greater risk, but this probably reflects previously-undiagnosed cancer in the donor liver.[3]

References

  1. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370:59-67.
  2. Koshiol J, Pawlish K, Goodman MT, et al. Risk of Hepatobiliary Cancer After Solid Organ Transplant in the United States. Clin Gastroenterol Hepatol 2014;12(9):1541-9.e3.
  3. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306(17):1891-901.
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Liver cancer risk is more than doubled in people with systemic lupus erythematosus Open a glossary item, compared with the general population, a meta-analysis showed.[1]

HCC risk is 19 times higher in people with a history of primary biliary cirrhosis, versus those without the condition, a meta-analysis showed.[2] Liver cancer risk is 79% higher in people with sarcoidosis Open a glossary item, versus those without the condition, a meta-analysis showed.[3]

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Plutonium and Thorium-232 are classified by the International Agency for Research on Cancer (IARC) as causes of liver cancer, and X-radiation and gamma-radiation are classified as probable causes, based on limited evidence.[1] An estimated 1% of liver cancers in the UK are linked to radiation exposure, all of these due to diagnostic radiology.[2]

Hepatocellular carcinoma (HCC) risk is higher in people exposed to radiation, this is independent of hepatitis B (HBV) or hepatitis C virus (HCV) infection.[3]

References

  1. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human cancers. JNCI 2011;103:1827-39.
  2. Parkin DM, Darby SC. 12. Cancers in 2010 attributable to ionising radiation exposure in the UK. BJC 2011;105 Suppl 2:S57-65.
  3. Ohishi W, Fujiwara S, Cologne JB, et al. Impact of radiation and hepatitis virus infection on risk of hepatocellular carcinoma. Hepatology 2011;53:1237-45.
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Vinyl chloride is classified by the International Agency for Research on Cancer (IARC) as a cause of hepatocellular carcinoma (HCC) and liver angiosarcoma.[1] Arsenic, polychlorinated biphenyls and trichloroethylene are classified by IARC as possible causes of liver cancer, based on limited evidence.[1]

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Coffee consumption is classified by the World Cancer Research Fund, American Institute for Cancer Research (WCRF/AICR) as probably protective against liver cancer.[1] Fish consumption is classified by WCRF/AICR as possibly protective against liver cancer, based on limited-suggestive evidence.[1]

Liver cancer risk is lower in people with the highest intake of the following foods, meta- and pooled analyses, or systematic reviews have shown:

  • Coffee (50-35% lower).[2,4]
  • Vegetables (22-28% lower).[5,6]
  • Fish (18% lower).[7]
  • Green tea (22% lower in women, no association in men, Asian populations only).[8]

References

  1. World Cancer Research Fund / American Institute for Cancer Research. Continuous Update Project Findings & Reports. Accessed October 2016.
  2. Sang LX, Chang B, Li XH, et al. Consumption of coffee associated with reduced risk of liver cancer: a meta-analysis. BMC Gastroenterol 2013;13:34.
  3. Bravi F, Bosetti C, Tavani A, et al. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin Gastroenterol Hepatol 2013;11(11):1413-1421.e1.
  4. Bai K, Cai Q, Jiang Y, et al. Coffee consumption and risk of hepatocellular carcinoma: a meta-analysis of eleven epidemiological studies. Onco Targets Ther. 2016 Jul 19;9:4369-75.
  5. Yang Y, Zhang D, Feng N, et al. Increased intake of vegetables, but not fruit, reduces risk for hepatocellular carcinoma: a meta-analysis. Gastroenterology 2014;147(5):1031-42.
  6. Luo AJ, Wang FZ, Luo D, et al. Consumption of vegetables may reduce the risk of liver cancer: Results from a meta-analysis of case-control and cohort studies. Clin Res Hepatol Gastroenterol 2014. pii: S2210-7401(14)00183-1.
  7. Huang RX, Duan YY, Hu JA. Fish intake and risk of liver cancer: a meta-analysis. PLoS One 2015;10(1):e0096102.
  8. Huang YQ, Lu X, Min H, et al. Green tea and liver cancer risk: A meta-analysis of prospective cohort studies in Asian populations. Nutrition. 2016;32(1):3-8.
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The World Cancer Research Fund, American Institute for Cancer Research (WCRF/AICR) make no judgment on the association between liver cancer risk and intake of cereals (grains) and their products; non-starchy vegetables; fruits; peanuts (groundnuts); meat and poultry; salted fish; tea; green tea; calcium and vitamin D supplements; vitamin C; water source; and a low fat diet, due to limited evidence.[1]

Liver cancer risk is not associated with the following factors, meta- and pooled analyses or systematic reviews have shown:

  • Vitamin D supplements.[2]
  • Fruits.[3]

References

  1. World Cancer Research Fund / American Institute for Cancer Research. Continuous Update Project Findings & Reports. Accessed October 2016.
  2. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev 2014;6:CD007469.
  3. Yang Y, Zhang D, Feng N, et al. Increased intake of vegetables, but not fruit, reduces risk for hepatocellular carcinoma: a meta-analysis. Gastroenterology 2014;147(5):1031-42.
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Cancer Statistics Explained

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