Purpose: Hepatocellular carcinoma (HCC) is a leading health problem worldwide. Any agent causing chronic liver damage and cirrhosis is a risk factor for HCC. Genetic and environmental factors may be responsible for regional variations in the occurrence of HCC worldwide. The aim of this review was to describe the risk factors that may be contributing to low prevalence of HCC in the Mexican population. Methods: An electronic systematic search was conducted in four databases to retrieve studies on hepatocellular carcinoma inMexico. Results: Eighteen publications gave a total of 1042 HCC cases with a percentage that ranged from 0.25% to 1.87%. Cirrhosis was registered in 7 studies while the main etiologies were: HCV (66%), HBV (11%) and alcoholism (6.6%). Conclusions: In the last 50 years, the studies performed inMexicohave shown a very low incidence and/or mortality rate of HCC. These findings contrast from those reported in high endemic regions, such asAsia, where viral hepatitis and HCC are prevalent. One significant difference is the predominance of HBV genotype H in Mexico and HBV/B and C in Asia. InMexico, high endemic areas of HBV infection have been detected, mainly among the native population; however, infection seems to resolve very quickly, due to a prominent immunological response among the population. Other factors are that patients with liver cirrhosis die prematurely before that HCC can be detected. Furthermore, an environmental factor that may exert a protective effect against HCC, in spite of the high consumption of potentially aflatoxin-contaminated food products, is the neutralization of these substances by alkaline treatment. This study shows that genetic and environmental factors associated to HCC among the Mexican population are different from others reported worldwide.
Hepatitis B virus (HBV) infection is a serious worldwide healthcare problem. It may be spread by horizontal transmission of the virus through parenteral exposure to infectious blood or body fluids such as semen and vaginal fluids. Vertical transmission is caused by perinatal exposure from infected mother-to-infant [
The prevalences of HBV infection in populations vary according to the incidence and age of the primary infection. In the endemic regions of the world, vertical transmission of HBV infection is most prevalent among infants and children, while in the low-risk regions, adolescents and adults are mainly infected by horizontal transmission [
The severity and outcomes of chronic liver disease such as liver cirrhosis and hepatocellular carcinoma (HCC) may depend on a complicated viral-host-environment interaction. Thus, viral factors such as HBV genotypes as well as the host/ethnic immune response may play an important role, whereas, environmental factors such as the use of alcohol and exposure to aflatoxins are also involved [2-4].
Hepatocellular carcinoma (HCC) is a common cancer worldwide, responsible for approximately 6% of all new cases of human cancer (fifth cause in men, and eight cause in women), and for one million deaths/year worldwide [1-4]. The burden of HCC disease is reported as incidence, prevalence or mortality rates, all of which can be subject to significant uncertainties [
HCC is a serious health problem associated to cirrhosis in 80% of the cases. Thus, any agent leading to severe liver damage, and ultimately cirrhosis, should be seen as a risk factor for HCC [6-9]. The main causes of HCC are the same as for cirrhosis: HBV, HCV and alcohol [
The prevalence rate of HBV infection among the general Mexican population has been estimated to be 0.3% (HBsAg serological marker), which has remained stable since 1974 [
Despite the presence of several environmental etiologic factors, the incidence rate of HCC has been reported as low, at least in the western region of Mexico [
A systematic query was conducted to search for publications regarding the existence of hepatocellular carcinoma in Mexico. PubMed (http://www.ncbi.nlm.nih.gov/pubmed), by means of the MeSH terms, “hepatocellular carcinoma” and “Mexico” or together with “epidemiology”; Artemisa (http://www.artemisaenlinea.org.mx), Medigrafic (http://www.medigraphic.com) and Imbiomed (http://www.imbiomed.com.mx) were consulted with the terms in Spanish, “carcinoma hepatocelular” or “cancer primario de higado”. The electronic search was filtered for publications dated from 1989 (after HCV testing was available) until July 2012. Additional studies were manually identified by back tracking the reference list of the selected papers, which were verified either by PubMed or Google Scholar.
The authors selected either prospective or retrospective epidemiological studies regarding cohort or serial cases of HCC in pediatric or adult Mexican patients. Publications were admitted if cases of HCC were defined as primary liver cancer, whereas other types of liver cancers, such as cholangiocarcinoma or hepatoblastoma were not considered. Case reports were included for descriptive purposes only.
Inclusion criteria were related to sample size, number of HCC cases, frequency rate, patient’s demographics, description of histopathological or clinical findings, and recognized environmental factors associated to HCC.
Publications regarding studies on coliangiocarcinoma, hepatoblastoma, metastatic tumors of the liver, treatment modalities, imaging studies, clinical trials or management, experimental animal models, liver transplantation or drug therapy were not included in this review. Also, if study information was insufficient to draw conclusions, the paper was also excluded.
Each author conducted his/her own search by means of the keywords aforementioned. All eligible or excluded publications were cross-checked among all authors, and then read by authors SR and AP. SR conducted the data extraction of accepted studies by enlisting them according to the time interval and registering the following data: sample size, number of HCC cases, reported frequency rate, patient’s demographics, description of histopathological or clinical findings, and use of alcohol or aflatoxin exposure. Frequencies were estimated as proportions and expressed as percentages. The extracted data were summarized in tables arranged by the inclusion criteria aforementioned.
A descriptive analysis of quantitative and qualitative results was conducted and then integrated into a comprehensive discussion of the main features of HCC cases in Mexico within each subheading.
A total of 132 publications were retrieved by means of the designated keywords, of which 18 of them met the eligibility criterion. Among these, if information was missing, it was marked as “not reported” in the respective table.
Among the 18 publications, 20 studies of HCC cases were conducted. The demographic and clinical data of 1042 HCC cases reported from 1953 to 2007 are summarized in
No. = Consecutive number. Ref. = Reference. NR = Not reported. NA = Not applicable, Inst. = Institution: 0All public hospitals that attends pediatric cancer patients; 1Hospital General, SSA. Mexico City; 2Centro Médico Nacional, 20 de Noviembre, ISSSTE, Mexico City; 3Hospital Dr. Jose E. Gonzales, Universidad Autónoma de Nuevo León, Monterrey, Nuevo Leon; 4Instituto Nacional de Cancerologia, Mexico City; 5Centro Médico Nacional de Occidente, Guadalajara, Jalisco; 6IMSS, Mexico City; 7Instituto Nacional de Ciencias Medicas y Nutrición, Salvador Zubirán, Mexico City; 8Médica Sur, Mexico Cty; 9Hospital de Pediatria, Centro Medico Nacional Siglo XXI and Hospital General del Centro Medico Nacional La Raza, Mexico City. CP = Child-Pugh staging, O = Okuda staging.
centers in Central (Mexico City, n = 16), West Mexico (Guadalajara, Jalisco, n = 2) and North Mexico (Monterrey, Nuevo Leon, n = 2). The age range of the adult patients was 16 to 87 years. In 7 studies, cirrhosis was present among liver biopsy or autopsy of HCC cases [20- 25,31,33]. In these cases, cirrhosis was attributed either to alcohol or viral hepatitis. In 6 studies, fibrolamellar HCC was diagnosed, especially among young patients [24,28-30,34,36].
However, certain limitations were identified in this revision, such as, a lack of updated prospective studies, very few studies reported seroprevalence of viral markers and none of the studies performed nucleic acid testing (NAT) for viral hepatitis.
The demographic data presented in this study is representative of individuals that reside mainly in Mexico City and in a lesser extent from other regions of the country that attend tertiary hospitals to receive specialized health care. It may not reflect the total number of cases, since not all individuals can travel to their respective regional hospital for treatment nor does it cover most private institutions. Additionally, the lack of estimations based on AAIR (by 100,000 inhabitants) in adults besides the incidence rate previously reported earlier (0.22/100,000) [
The low percentage of HCC cases is consistent with earlier observations reported from our locality [
In this present study, the primary risk factor was HCV infection as described previously [
*= Institutions are provided in
Bold = preponderant cause, NR = not reported, *Other factors: Reference [
valence of viral hepatitis infections detected by immunoassays against highly sensitive molecular techniques [12,13,39] and the validity of the immunological diagnostic techniques. For example, in patients with HBV infection, there is evidence that the major commercial immunoassays developed to detect HBsAg have a low specificity and sensitive for the predominant HBV genotype H [13,14]. Furthermore, this may also explain the steady state of HBsAg seroprevalence among the general Mexican population, and in blood donors [
On the other hand, hepatitis C seroprevalence and correspondence between viral load and viral genotype among primary care clients in Mexico is present, but the number of HCC cases does not correlate to the number of HCV infected patients as in other countries [
HBV genotypes are associated to the course and outcome of the further complications. For instance, HBV genotype F and its four subtypes [F1-F4] are endemic to America and are regionally distributed throughout the continent [
Regarding HBV infection in Mexico, HBV genotype H is predominant among both the native [
One reasonable explanation is the presence of a very low viral load [
Altogether, these features differ from those reported in the high endemic areas of Asia, where HBV genotype B and genotype C carriers are prone to develop HCC [42, 50]. Further prospective studies are required to understand the HBV genotype H-Mexican host connection that could justify the low prevalence of HCC in Mexico compared to high-risk HCC populations.
Alcohol-induced cirrhosis is the second cause of death among the Mexican population between the ages of 15 to 64 years [
Another aspect that occurs in Mexican patients is that, in the public institutions not all patients with chronic liver diseases or cirrhosis have an adequate screening for HCC, causing that many patients are not diagnosed opportunely. Interestingly, in this present study, 6.6% of the HCC cases were reported to relate to alcohol abuse and only a slightly higher proportion were related to viral hepatitis (
Several studies have shown a strong association between dietary habits and human cancer incidence, including liver cancer [38,53,54]. Aflatoxin B1 is one of the most common mycotoxin that contaminates human foodstuffs such as corn, peanuts and cotton seeds [
Regarding the Mexican population, we are the number one consumers of corn products in the world. The average consumption of “tortillas” is 300 - 325 g/person/day, which could account, for a daily exposure of serum aflatoxins of 14 - 85 ng/kg body weight [
However, an intriguing paradox can be expressed due to the following evidence. Many traditional Mexican meals include maize (corn) tortillas and other similar products are prepared with a maize dough designated as “nixtamal”, a word derived from the “nixtamalli”, (nextli, ashes and tamalli, tamal) from the Aztec language, Nahuatl. The process of nixtamalization was developed by the Mesoamericans (in Mexico and Central America) in the pre-Columbian era and has been practiced without modifications ever since. To make the “nixtamal”, dry corn grains are soaked and cooked in water added with alkaline lime either by CaO or Ca(OH)2, washed thoroughly and rinsed to remove the pericarp and then grinded by a stone or a mill [
It has been shown that nixtamalization can reduce significant amounts of aflatoxins in maize that would otherwise be present due to poor crop storage. [
In this present analysis, only one study reported serum alfatoxins with no clear association to HCC [
Another way to estimate the burden of HCC on the Mexican population was to evaluate the mortality rates reported as the number of fatalities/100,000 inhabitants. These are available as a nationwide repository at the Secretariat of Health website (http://sinais.salud.gob.mx/mortalidad/). However, neither the incidence nor prevalence rate of liver cancer cases, (specifically as HCC cases) is recollected on a population-based registry. Moreover, there are some limitations concerning the liver cancer mortality rates in Mexico, which gave rise to this research. First, information regarding liver cancer mortality before 1999 is considered unreliable [
Our arguments are based on the discrepancy between the low percentage of HCC cases found in each study reviewed herein, contrary to what other authors could have overestimated [60,61] This may be because all International Classification of Diseases codes for liver cancer (C22.0 - C22.9) were included in the mortality rate study. Additionally, the higher mortality rate may differ from the occurrence rate reviewed in this study, because HCC is not detected earlier. Consequently, it is diagnosed until relatively advanced stages of disease. In this situation, HCC may not be diagnosed with a histopathological confirmation that could allow distinguishing primary liver cancers from secondary metastasis of malignancy, thus leading to an equivocal registration of HCC on the death certificate. Yet another situation could be that diagnosis and certification of primary liver cancer may be influenced by increased surveillance of cirrhotic patients through different imaging techniques, which may lead to an apparent increase in the incidence of HCC [33,62].
Furthermore, the predication that the mortality rate due to liver cancer could increase in the next 50 years represents a theoretical point of view, which seems hard to accept, due to the low percentage of HCC cases and low prevalence of associated risk factors identified in the present study. However, it is important to state that obesity and obesity-related conditions such as type 2 diabetes mellitus, steatosis and nonalcoholic steatohepatitis are currently rising in Mexico (Secretariat of Health, 2010 Edition.). Altogether, given the evidence that we have shown regarding the early death of cirrhotic patients, it is more likely that these morbidities could have a more significant impact on the incidence and mortality for liver cirrhosis per se than in the development of HCC in Mexican patients.
Overall, despite these drawbacks, Mexico may still be consider of low incidence and low mortality rate for HCC cases compared to other countries worldwide [1,4], that may differ from one region to another. Further verification of the diagnosis criterion and estimates of HCC disease burden are required in order to avoid misleading statistics [
In the last 50 years, the studies performed in Mexico have shown a very low incidence and/or mortality rate of HCC. These findings contrast from those reported in high endemic regions, such as Asia, where both, viral hepatitis and HCC are prevalent. One significant difference is the predominance of HBV genotype H in Mexico and HBV/B and C in Asia. In Mexico, high endemic areas of HBV infection have also been detected, mainly among the native population; however, the disease seems to resolve very quickly, as a consequence of a prominent immunological response among the Mexican population.
Other factors that are in involved are that patients with liver cirrhosis die prematurely before that HCC can be detected. Furthermore, an environmental factor that may exert a protective effect against HCC, in spite of the high consumption of potentially aflatoxin-contaminated food products, is the neutralization of these substances by alkaline treatment. This study shows that genetic and environmental factors associated to HCC among the Mexican population are different from others worldwide.
We thank the Jalisco State Council of Science and Technology (COECYTJAL 2009-PS431) to AP and the National Council of Science and Technology (CONACYTFondo Sectorial S0008-2010-1-139085) to SR for financial support.