Liver cancer: descriptive epidemiology and risk factors other than hbv and hcv infection

Liver cancer: Descriptive epidemiology and risk factorsother than HBV and HCV infection Shu-Chun Chuang a, Carlo La Vecchia b,c, Paolo Boffetta a,* a Lifestyle, Environment and Cancer Group, International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, Franceb Department of General Epidemiology, Mario Negri Institute of Pharmacological Research, Milan, Italyc Institute of Biostatistics and Biometry, University of Milan, Milan, Italy The incidence of liver cancer is high in all low-resource regions of the world, with the exception of Northern Africa and Western Asia. The estimated worldwide number of new cases of liver cancer in 2002 is 600,000, of which 82% are from developing countries.
Given the poor survival from this disease, the estimated number of deaths is similar to thatof new cases.
Hepatocellular carcinoma (HCC) is the main form of liver cancer. A part from chronic infections with Hepatitis B and Hepatitis C viruses, which are the main causes of HCC, con- tamination of foodstuff with aflatoxins, a group of mycotoxins produced by the fungi Asper- gillus flavus and Aspergillus parasiticus, is an important contributor to HCC burden in many low-income country. Alcoholic cirrhosis is an important risk factor for HCC in populations with low prevalence of HBV and HCV infection, and the association between tobacco smok- ing and HCC is now established. Diabetes is also related to an excess risk of HCC and theincreased prevalence of overweight and obesity likely contributes to it.
The second most important type of liver cancer is cholangiocarcinoma, whose main known cause is infestation with the liver flukes, Opistorchis viverrini and Clonorchis sinensis,which is frequent in some areas in South-East Asia. Angiosarcoma is a rare form of livercancer whose occurence is linked to occupational exposure to vinyl chloride.
Ó 2008 Published by Elsevier Ireland Ltd.
common cause of cancer mortality . The estimatedworldwide number of new cases of liver cancer in 2002 The epidemiology of liver cancer is made complex by is 600,000, of which 82% are from developing countries.
the large number of secondary tumours, which are difficult China alone accounts for 55% liver cancer death worldwide to separate from primary liver cancers without histological The incidence of liver cancer is high in all low-resource verification. The most common histological type of liver regions of the world, with the exception of Western Asian malignant neoplasm is hepatocellular carcinoma (HCC).
and Northern African countries other than Egypt. The high- Other forms include: (i) childhood hepatoblastoma, and est rates (above 40/100,000 in men and above 10/100,000 (ii) adult cholangiocarcinoma (originating from the intra- in women) are recorded in Thailand, Japan, Korea, and cer- hepatic biliary ducts) and (iii) angiosarcoma (from the tain parts of China. In most high-resource countries, age- intrahepatic blood vessels). Primary liver cancer is the standardized rates are below 5/100,000 in men and 2.5/ sixth most common cancer in the world and the third most 100,000 in women. Intermediate rates (5–10/100,000 inmen) are observed in areas of Southern and Central EuropeThe 5-year survival rate was 8% in the United Statesduring 1988–2001 9% in Europe during 1995–1999 * Corresponding author. Tel.: +33 472738554; fax: +33 472738320.
and 5% in developing countries in 2002 .
0304-3835/$ - see front matter Ó 2008 Published by Elsevier Ireland Ltd.
doi:10.1016/j.canlet.2008.10.040 S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14 Table 1Overall age-adjusted (world standard population) mortality rates from hepatocellular carcinoma (HCC) per 100,000 men and women in selected Europeancountries in 1990–1994 and 2000–2004 (unless mentioned in parentheses), and the corresponding change in rates.
Countries whose data did no allow distinction between HCC and other liver cancersEstonia Number of deaths in the more recent year available.
Within Europe, male overall mortality from HCC in- tion, alcohol drinking, tobacco smoking, and aflatoxin. The creased in Austria, Germany, Switzerland, while decreased suspected risk factors for liver cancer include diet, obesity, in recent years in France and Italy, which showed upward diabetes and insulin resistance, use of oral contraceptives, trends up the mid 1990s In the early 2000s the iron overload In the following, we will review risk fac- highest HCC rates in men were in France (6.8), Italy (6.7) tors other than infections with HBV and HCV, which are and Switzerland (5.9), while the lowest ones were in Nor- way (1.0), Ireland (0.8) and Sweden (0.7). In women, amoderate increase in HCC mortality was observed in Spain and Switzerland, while mortality decreased in severalEuropean countries, particularly since the mid 1990s. In Ecological studies have shown that the incidence of HCC the early 2000s, female HCC mortality rates were highest correlates not only with HBV and HCV infection, but also in Italy (1.9/100,000), Switzerland (1.8) and Spain (1.5), with contamination of foodstuff with aflatoxins, a group and lowest in Greece, Ireland and Sweden (0.3) Inci- of mycotoxins produced by the fungi Aspergillus flavus dence and mortality from liver cancer have been rising and Aspergillus parasiticus, which cause liver cancer in many species of experimental animals Contamination The male to female ratio in liver cancer incidence is originates mainly from improper storage of cereals, pea- about 2.4 and the difference is stronger in high- incidence nuts and other vegetables and is prevalent in particular in Africa, South-East Asia and China. The investigation of The epidemiology of liver cancer is linked to the inci- the carcinogenic role of aflatoxins in humans has been dence and mortality rates from liver cirrhosis, since a large complicated by the inadequacy of traditional methods of proportion of HCCs develop from cirrhotic liver . The im- exposure assessment (e.g., questionnaires). During the last proved survival and reduced mortality from cirrhosis, due decades, however, prospective studies have shown a to improvements in the prevention and treatment of this strong association between biological markers of aflatoxin condition, have in fact increased the possibility of develop- exposure in serum or urine and risk of subsequent liver ing HCC in cirrhotic patients. Of some importance are also cancer. A carcinogenic role of aflatoxins, in particular of the improvements in diagnosis, mainly due to widespread aflatoxin B1 (AFB1), has therefore been confirmed and use of ultrasound and measurement of a-fetoprotein since shown to be independent from – and to interact with – the early 1980s, which led to more frequent detection of that exerted by HBV infection AFB1 frequently induces neoplastic liver in cirrhotic patients.
G:C to T:A transversions at the third base in codon 249 of The established risk factors for hepatocellular carci- P53. HBV alone does not affect the mutation rate while noma include Hepatitis B or C viruses (HBV and HCV) infec- the coexistence of AFB1 exposure was associated with in- S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14 creased mutation prevalence . In area where HBV infec- among HBV positive subjects , while another Japanese tion is prevalent, AFB1 exposure is usually also a problem study found a higher RR among HBV positive subjects . HBV infected persons might be benefited by eliminat- and an Italian study reported an interaction between to- bacco smoking and infection with HBV and HCV .
Alcohol drinking is associated with an increased risk of Several data have been reported on a potentially favor- liver cancer A meta-analysis has shown a dose re- able effect of coffee on liver function and liver diseases, sponse relationship between alcohol intake and liver can- including liver cancer . Data on coffee and liver cancer cer with relative risks (RRs) of 1.19 (95% CI = 1.12–1.27), are based on at least 10 studies, 6 case–control (from 1.40 (95% CI = 1.25–1.56), and 1.81 (95% CI = 1.50–2.19) Greece, Italy and Japan) and 4 cohort investigations (all for 25, 50, and 100 g of alcohol intake per day, respectively of these from Japan). Overall, the pooled relative risk (RR) . It is believed that there is no ‘‘safety threshold” for the was 0.54 (95% confidence interval, CI, 0.39–0.76) for case–control studies, and 0.64 (95% CI 0.56–0.74) for co- The most probable mechanism of alcohol-related liver hort studies Such an inverse relation may however cancer is through the development of liver cirrhosis be spurious, and due to the fact that subjects with a broad . In a Swedish cohort study , the risk of liver can- spectrum of digestive tract disorders, liver diseases or cir- cer among alcoholisms was 2.3 (95% CI = 2.0–2.7). Among rhosis may reduce their coffee consumption. Indeed, caf- patients who were diagnosed with alcoholism and cirrho- feine metabolism is impaired in patients with cirrhosis, sis, the risk increased to 16.5 (95% CI = 12.7–21.2). In addi- who could therefore reduce coffee intake in order to avoid tion, HCV infection appeared to accelerate the course of side effects of caffeine. Thus, bias due to reduction of coffee alcoholic liver disease and to cause the development drinking in unhealthy subjects cannot be excluded of HCC at a younger age among drinkers than among The inverse association between long-term coffee con- non-drinkers . Donato et al. examined the associ- sumption and type 2 diabetes was also suggested It ation between alcohol intake and HCC among 464 cases is interesting to investigate the main or joint effect of cof- and 824 hospital controls. They found that for each level fee drinking on the risk of liver cancer with or without the of alcohol intake, the highest risks were observed among subjects with HCV infection, followed by those with HBV Green-yellow vegetables were associated with a reduc- infection, and finally by those without hepatitis virus infec- tion in liver cancer mortality among Japanese atomic- tion, with parallelism between the curves. Furthermore, bomb survivors (RR = 0.81, 95% CI = 0.67–0.97 for ‘‘2–4 synergistic interactions between alcohol intake and smok- times per week” and RR = 0.75, 95% CI = 0.60–0.95 for ‘‘dai- ing, obesity and diabetes had been observed The pop- ly or almost daily” comparing to ‘‘once per week or less”, p ulation attributable risks in Mediterranean area to liver for trend = 0.0092) . However, no evidence has been cancer were 28.8% for alcohol, 21.6% for HCV, and 16.2% found in Greece that vegetable intake may reduce the risk for HCV and alcohol combined . Alcoholic cirrhosis is of HCC Nonetheless, a marginally inverse association probably the most important risk factors for HCC in popu- was implied between milk and dairy products and HCC risk lations with low prevalence of HBV and HCV infection and (OR = 0.70, 95% CI = 0.49–1.01). In another case–control low exposure to aflatoxins, such as North America and study in Italy, investigators observed protective effect from milk and yoghurt (OR = 0.28, 95% CI = 0.13–0.61), white The reduction in per capita alcohol consumption ob- meats (OR = 0.44, 95% CI = 0.20–0.95), eggs (OR = 0.31, served since the 1970s in various countries of southern 95% CI = 0.14–0.69), and fruits (OR = 0.48, 95% CI = 0.22– Europe has likely contributed to the decrease in cirrhosis 1.05) In conclusion, there is limited suggestive pro- incidence and mortality in those countries during the last tective effect from fresh fruits; while the evidence for other decade, with a consequent impact on HCC mortality, too.
dietary factors is not conclusive Most of the evidenceon diet and liver cancer is based on case–control studies,and the retrospective assessment of diet is particularly problematic in studies involving chronically ill individualssuch as liver cancer patients.
Tobacco smoking is causally associated with liver can- cer A meta-analysis on smoking and liver cancerconcluded an overall OR of 1.56 (95% CI = 1.29–1.87) comparing current-smokers to never-smokers and of 1.49(95% CI = 1.06–2.10) comparing former smokers to never- Obesity is now widely recognized as a significant risk smokers. The associations among current smokers ap- for the development of many types of cancers. A meta- peared to be consistent with the overall RR regardless of analysis found that the relative risks (RR) for liver can- region, study design, study sample size, and publication cer were 1.17 (95% CI = 1.02–1.34) for those who were overweight (BMI = 25–30) and 1.89 (95% CI = 1.51–2.36) The synergistic interaction between tobacco smoking for those who were obese (BMI P 30).
and HBV/HCV are inconsistent. A Taiwanese study found Diabetes, a condition closely associated with obesity, a higher RR of tobacco smoking among HBV negative than has been proposed as a risk factor for both chronic liver S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14 disease and HCC. A case–control study conducted in CI = 1.07–2.38; excess: OR = 2.10, 95% CI = 1.25–3.52) Italy found an odds ratio (OR) for liver cancer of 2.1 (95% The effect of iron overload seems to be independent CI = 1.4–3.2) after adjustment for age, sex, area of resi- from development of cirrhosis and may interact with alco- dence, alcohol and tobacco consumption, history of hepati- hol and HBV/HCV infections. Most of the HH is associated tis and liver cirrhosis, BMI, and family history of liver with HFE gene mutation. HFE mutation seems to be associ- ated with iron overload in patients with end-stage liver It is well known that patients with various forms of liver diseases and might accelerate hepatic fibrosis in patients disease can be predisposed to impaired glucose tolerance with chronic hepatitis C infection . However, results and suggested that the relationship between diabetes from small studies considering HFE mutations in HCC pa- and HCC is a result of HCV infection . However, a co- tients are conflicting, showing either no increased HCC risk hort study in high hepatitis virus infection area (Tai- or a positive association of iron overload only in the wan) found that the effect of type 2 diabetes was higher presence of viral or alcohol induced liver damage or cirrho- in those with HCV negative than in those with HCV posi- (HR) = 2.08 (95% CI = 1.03–4.18) and 0.62 (95% CI = 0.22– 1.76) for HCV negative and positive, respectively). A popu-lation-based case–control study conducted in Los Angeles, CA, USA on non-Asian population found an in-creased risk of HCC among diabetic patients free of HBV/ Hepatoblastoma is the most common childhood hepatic HCV (OR = 3.2, 95% CI = 1.5–6.7) and an interaction with tumor . It represented 1% of malignancies for children HBV/HCV (ORint = 4.8, 95% CI = 2.7–6.9 on an additive younger than 20 years old with a peak incidence of 11.2/ scale). Interaction with drinking (>4 drinks per day) was 1,000,000 during infancy . The etiology of hepatoblas- also observed in the study (ORint = 4.2, 95% CI = 2.6–5.8 toma is still unknown. Current knowledge on the cause include Beckwith–Wiedemann syndrome, hemohypertro- The potential mechanism from obesity and diabetes to phy, familial adenomatous polyposis, and Gardner’s syn- HCC may be through fatty liver or non-alcoholic fatty liver drome. Evidences for parental occupational exposures are disease (non-alcoholic steatohepatitis, NASH) How- ever, NASH is usually asymptomatic and difficult to iden-tify until liver cancer or cirrhosis is established. The most important issue now is the temporal ambiguity betweendiabetes and chronic liver diseases. Whether diabetes is a Intrahepatic cholangiocarcinoma is the second most result of cirrhosis, which in turn predisposes the subject frequent type of liver cancer and accounts for about 3% of to HCC, or an independent risk factor for HCC, is still under gastrointestinal cancers worldwide In most regions debate. In addition, the effect of duration and treatment of of the world the incidence in the range 0.2–2/100,000; diabetes on the risk of HCC might be worthwhile to the incidence is much higher in areas where liver fluke infestation is common, such as North-East Thailand .
During the last decades the incidence has increased in many high-income countries; the reasons of this trendare not known Infestation with the liver flukes, Opis- Use of combined estrogen–progestogen oral contracep- torchis viverrini and Clonorchis sinensis, is the main known tives (OC) greatly increases the risk of liver adenomas, and cause of this form of malignancy. Infection occurs via con- is associated with the risk of HCC, although the absolute sumption of improperly cooked fish. Liver cirrhosis, risk is likely to be small and has been shown in populations chronic HCV infection, heavy alcohol consumption , at low HBV risk . Case reports have associated use of obesity, and gallstones were reported to be associated anabolic steroids with development of liver cancer, but with the malignancy. Other risk factors include inflamma- the evidence is not conclusive at present. A recent meta- tory bowl disease, primary sclerosing cholangitis, and a 1- analysis was failed to link the use of oral contraception antitrypsin deficiency . Exposure to thorotrast, a con- and the risk of HCC due to the huge variation among stud- trast medium containing radioactive thorium used for ies Future investigations on the duration, intermit- angiography in Europe and Japan during 1930–1955, re- tency, recency of OC use, effect modification by HBV/ sulted in an increase of cholangiocarcinoma and of liver HCV, and other reproductive factors might help to improve Hepatic angiosarcoma is a rare mesenchymal tumor of An increase in iron storage in the body is a likely cause the liver which usually presents in elderly men The of HCC: the evidence comes from studies of patients with estimated incidence was about 0.14–0.25/1,000,000 in hemochromatosis (HH) or other disorders of iron metabo- the USA . Workers exposed to vinyl chloride, a mono- lism. Iron was observed to be associated with HCC in a mer used in the chemical industry for production of the group of patients in their end stage of liver diseases other plastic polymer, polyvinyl chloride, experience an in- than HH as well (none: reference; mild: OR = 1.59, 95% creased risk of angiosarcoma. The identification of clusters S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14 of cases of liver angiosarcoma in these workers has led to a [16] F. Donato, A. Tagger, U. Gelatti, G. Parrinello, P. Boffetta, A. Albertini, drastic reduction in occupational exposure to vinyl et al, Alcohol and hepatocellular carcinoma: the effect of lifetimeintake and hepatitis virus infections in men and women, Am. J.
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