Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.

Liver cirrhosis (LC) is a chronic illness caused by multiple, long-term injuries to the liver[1]. Globally, LC represents the 14^th leading cause of mortality[2] but is the 12^th leading cause of mortality in the United States[1] and the 4^th leading cause in Central Europe[3] and Mexico[4]. In general, the main etiologies of LC are chronic alcohol abuse, followed by viral infections (hepatitis C and B viruses) and nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH)[5]. Other causes that occur in a lesser extent are autoimmune hepatitis, obstructive cholestasis, hereditary hemochromatosis, alpha-1-antitrypsin deficiency, Wilson’s disease and drug toxicity[6].

Liver cirrhosis is characterized by the degeneration and necrosis of hepatocytes, the replacement of liver parenchyma with fibrotic tissues and regenerative nodules and loss of liver function[7]. The impaired liver architecture induces intrahepatic vascular distortion and portal hypertension, which manifests in major complications, such as ascites, upper gastrointestinal bleeding, jaundice and hepatic encephalopathy[8]. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with particular ethnic backgrounds[9]. Consequently, genes involved in various metabolic pathways are influenced by distinct environmental lifestyle factors, such as diet, physical inactivity, and emotional stress[10].

Thus, this Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. The inheritance of a heterogenic distribution of European, Amerindian and African ancestry in this population[11,12] may play a central role in the clinical outcome of liver disease in conjunction with specific environmental factors.

Hepatic fibrogenesis is a key factor for the progression of liver damage as a result of an excessive healing response triggered by acute and chronic liver injury associated with the continuous deposition of extracellular matrix (ECM), mainly fibrillary collagen[13]. The accumulation of ECM is due to both increased synthesis and decreased degradation that contributes to the loss of hepatocyte microvilli and endothelial fenestrations, resulting in LC and liver failure[14,15]. Hepatic fibrosis is driven by a population of activated fibrogenic cells known as myofibroblasts (MFs)[16]. The hepatic stellate cells (HSCs) are the primary source of MFs, orchestrating the deposition of ECM in normal and fibrotic liver, and activation of the immune response[17]. However, recent research has revealed that several cell types contribute to MF formation, including portal fibroblasts and bone marrow-derived mesenchymal cells[18].

The clinical assessment of cirrhosis and the staging of fibrosis have given rise to a number of non-invasive techniques that have been validated as surrogate tests for liver biopsy, such as the most recently developed transient elastography (FibroScan; Echosens, Paris, France). By this method, shear wave velocity correlates with liver stiffness, which is staged from F0 to F4, regardless of the etiological agent of liver fibrosis (Figure 1)[1].

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Figure 1 Stages of liver fibrosis. Liver fibrosis may be evaluated by liver biopsy and non-invasive methods. Regardless of etiological factors, liver fibrosis encompasses 3 stages until the development of cirrhosis. NAFLD: Nonalcoholic fatty liver disease.

Regarding the cellular and molecular mechanisms of LC, activation of HSCs involves two main stages (Figure 2). The first stage of initiation renders the cells responsive to diverse agents of liver injury, which results from the paracrine stimulation of neighboring cells, such as hepatocytes, circulating leukocytes, platelets and endothelial and Kupffer cells (KCs). Such stimuli include reactive oxygen species (ROS) and inflammatory cytokines. Others effectors are transcriptional factors, such as the three types of peroxisome proliferator-activated receptors (PPAR-α, -β and -γ), c-Myb, nuclear factor kappa B (NF-κB), Kruppel-like factor 6 (KLF6) and the CCAAT/enhancer binding protein-β (C/EBPβ). In addition, growth factors, mainly transforming growth factor beta 1 (TGF-β1), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1), play an important role in the activation of HSCs[19,20].

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Figure 2 Hepatic fibrogenesis. Different etiological factors induce production of several stimuli to HSCs activation. Activated HSCs promote fibrosis and necrosis of hepatocytes. These pathogenic processes can be modulated by genetic polymorphisms involved in each stage of the pathophysiological process. HSC: Hepatic stellate cells; DRD2: Dopamine receptor D2; TAS2R38: Bitter taste receptor; CYP2E1: Cytochrome P450, family 2, subfamily E, polypeptide 1; ALDH2: Aldehyde dehydrogenase 2 family; ADH1B: Alcohol dehydrogenase class I, beta polypeptide; PNPLA3: Patatin-like phospholipase 3; MTTP: Microsome triglyceride transfer protein; PPAR-γ2: Peroxisome proliferator-activated receptors; IL-28B: Interleukin-28B; APOE: Apolipoprotein E; LDLr: Low-density lipoprotein receptor; TGF-β1: transforming growth factor beta 1; COL: Collagenases; MMP: Matrix metalloproteinase; TNF-α: Tumor necrosis factor alpha; NF-κB: Nuclear factor kappa B; ROS: Reactive oxygen species.

Once the HSCs are activated, the perpetuation stage encompasses phenotypic changes in cell biology, such as proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis, retinoid loss, cytokine release and white blood cell chemoattraction. These events are regulated in an autocrine and paracrine manner by proinflammatory, pro-fibrogenic and pro-mitogenic signals to exacerbate the accumulation of ECM[20]. Finally, if the causal agent is eliminated, liver injury may be resolved. In this case, activated HSCs limit the fibrogenic response through the up-regulation of genes involved in apoptosis, enhanced immune surveillance and the increased secretion of ECM-degrading enzymes[21].

Obesity is considered the main factor associated with multiple metabolic disorders, such as NAFLD, which comprises simple steatosis, NASH, cirrhosis and HCC[78,79]. Hepatic steatosis is defined by the presence of cytoplasmic triglyceride (TG) droplets in more than 5% of hepatocytes as a result of an imbalance between lipid input and output[80,81]. The abnormal accumulation of TGs in the liver induces lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and inflammation, which all result in fibrosis (Figure 3)[82,83]. Conventionally, international guidelines and intervention strategies have been proposed for the treatment of NAFLD/NASH. However, because disparities in genetic and environmental factors among populations were not considered, the application of these strategies may not be feasible for all populations worldwide. Therefore, intervention strategies for the prevention and management of such obesity-related diseases should be based on a regionalized genome-based diet by focusing on the specific ancestry of each population and the convenience of consuming traditional ethnic food[11].

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Figure 3 Nonalcoholic fatty liver disease pathogenesis. The spectrum of NAFLD includes simple steatosis, NASH, LC and even HCC. Risk factors such as obesity, hepatopathogenic diet, insulin resistance and adipose tissue lipolysis lead to accumulation of triglycerides. This abnormality can stimulate lipotoxicity, ER stress, mitochondria dysfunction and inflammation, promoting fibrosis. Chronic fibrogenesis causes histological changes in the liver that lead to LC, which in turn may evolve to HCC. NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; LC: Liver cirrhosis; HCC: Hepatocellular carcinoma; FA: Fatty acids; VLDL: Very low-density lipoprotein; ER: Endoplasmic reticulum.

Currently, Mexico is one of the countries with the highest number of obese individuals, which is closely related to dietary factors and physical inactivity[84]. The diet in West Mexico is hepatopathogenic because of its high content of fat derived mainly from the habitual consumption of meat, fried foods and sausages[11,38]. Interestingly, we have observed that a genetic variant in the fat taste CD36 receptor may play an important role in this condition[85]. High-fat diets are associated with an increase in body weight, the upregulation of blood glucose levels, the progression of steatosis, and marked inflammation of the liver[86]. Moreover, more than 70% of the Mexican population frequently consumes soda, which increases fructose input[38]. Fructose promotes steatosis, insulin resistance, necroinflammation, and fibrosis[87-89]. In contrast, our diet is deficient in n-3 polyunsaturated fatty acids (PUFA) and antioxidants, which favors oxidative stress and lipid alterations[90]. Finally, inadequate dietary behaviors, such as missing breakfast and a lack of feeding schedules, are common among the Mexican population[38] and have been linked to obesity[91].

Other interactions between genes and environmental lifestyle factors that favor changes in the body mass index have been studied in West Mexico. Dietary modifications consisting of a lower intake of saturated fat (< 7%) significantly decreased body mass index, waist circumference, waist-to-hip ratio, and reactive C protein in FABP2 Thr⁵⁴ allele carriers compared to Ala54 allele carriers[92]. Additionally, recent studies in an obese cohort demonstrated that the expression of adiponectin levels may be modulated by changes in lifestyle regardless of the presence of an adiponectin (ADIPOQ) 11391G/A polymorphism[93].

However, despite the strong correlation between obesity and NAFLD, approximately 5% of morbidly obese patients do not develop NAFLD[94]. This finding supports the role of genetic factors in the development of NAFLD and NASH (Table 4). These factors may include polymorphisms in genes that affect lipid metabolism, such as apolipoprotein C3 (APOC3), PNPLA3, MTTP, and phosphatidylethanolamine N-methyltransferase (PEMT). Polymorphisms in genes that affect insulin sensitivity, such as ADIPOQ, adiponectin receptors 1 and 2 (ADIPOR 1 and ADIPOR 2), PPAR-γ, PPAR-γ coactivator 1α gene (PPARGC1A) and PPAR-α, may play a role in the development of NAFLD and NASH. Additionally, regulatory genes of oxidative stress, including glutamate cysteine ligase (GCLC), inducible nitric oxide synthase (NOS2), and manganese superoxide dismutase (SOD2), have been implicated. Genes related to immune regulation, including signal transducer and activator of transcription 3 (STAT3), TNF-α, IL-8 and interleukin-6 (IL-6); as well as MTHFR and HFE have been described. Finally, other less common genes that have been associated with the development of NAFLD and NASH include ATP-binding cassette subfamily C member 2 (ABCC2, also known as multidrug resistance protein 2, MRP2) and angiotensin II type I receptor (AGTR1)[95].

Globally, HCC is the most common form of liver cancer, the sixth most prevalent cancer and the third most frequent cause of cancer-related death[96]. Nearly 75% of HCC cases are attributed to chronic HBV and HCV infections in high endemic regions[97]. Therefore, the particular characteristics of these viruses and the genetic structure and environmental factors that prevail in each population may explain the epidemiological differences in HCC worldwide. Regions with higher incidence rates of this malignant disease include sub-Saharan Africa, Eastern Asia, followed by Southern European countries[32]. However, HCC is rare in other geographical areas, such as North and South America, Northern Europe, Oceania, and Mexico[98]. The low incidence of HBV-related HCC among the Mexican population is associated with a low steady HBsAg seroprevalence[64]. Furthermore, because Mexican patients with alcoholic cirrhosis are young, death occurs earlier due to long-term complications. This fact hinders the study of the association between alcohol consumption and HCC in Mexico because the average age of death from HCC is at least one or two decades after the clinical diagnosis of LC[98]. Similarly, epidemiological studies have indicated a positive correlation between liver cancer and the consumption of several foodstuffs contaminated with aflatoxins and fumonisins, including maize, cereals, ground nuts and tree nuts[99]. These mycotoxins are potent liver carcinogens through the formation of pro-mutagenic DNA adducts. Nonetheless, the process of “nixtamalization” in the elaboration of Mexican tortillas since pre-Hispanic times[100] inactivates up to 95% of aflatoxins in corn (maize), which may exert a protective effect against the development of HCC[101].

Epigenetic changes affect gene expression without altering the underlying DNA sequence[102]. These changes include DNA methylation, histone modifications, chromatin remodeling, and microRNAs (miRs), which are essential for the proper maintenance of cellular homeostasis[103]. However, such processes are regulated by environmental factors, including diet, alcohol, drugs, exercise and stress[104]. Growing evidence suggests that epigenetic alterations are correlated with a wide range of chronic disorders, including liver diseases. Diverse miRs have been implicated in the development and progression of NAFLD by disrupting lipid and glucose metabolism, insulin resistance, the unfolded protein response, mitochondrial damage, ER stress, oxidative stress, cellular differentiation, inflammation and apoptosis[105,106]. Moreover, the reduction of histone expression promotes the differentiation of HSCs to myofibroblasts, thereby enhancing the fibrogenesis process[107]. Interestingly, alcohol directly stimulates changes in chromatin structure, which induces the trans-differentiation of HSCs and the increased expression of ECM proteins[108]. Global DNA hypomethylation and the dysregulated expression of non-coding RNAs and epigenetic regulatory genes have been found to trigger carcinogenesis of hepatocytes[109]. Taken together, these findings support the need to evaluate epigenetic factors in distinct populations and their relationship to the severity of liver damage.

LC is a complex disease. The onset, progression, and clinical outcome of LC are influenced by genetic polymorphisms that are associated with particular ethnic backgrounds and their interaction with environmental factors, such as lifestyle. Currently, chronic alcohol abuse is the main etiological factor of LC in Mexico, which is associated mainly with cultural and genetic aspects. To date, HCV genotypes 1a and 1b favor chronicity, liver damage and therapeutic failure among Mexicans. In contrast, the more favorable natural course of HBV infection in the native Mexican population may be linked to an evolutionary immune adaptation to HBV genotype H. Finally, the hepatopathogenic diet and the high prevalence of obesity in our population contribute to the onset and progression of NAFLD. These findings highlight the influence of genetic and environmental factors in the development of LC, which may be different than those reported in other regions of the world. Therefore, these factors represent a challenge for hepatologists and gastroenterologists in Mexico and worldwide because they require the incorporation of personalized genomic medicine into current medical practices. However, the development of intervention strategies according to individual or population-based features will have a substantial impact on the prevention, management and treatment of LC.