Comparative Analysis of Risk Factors for Liver Cirrhosis in the World

Liver cirrhosis is the final pathological result of various chronic liver diseases. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver cirrhosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of hepatic stellate cells (HSCs). Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis [1]. Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that early cirrhosis may be reversible. When clinical signs, symptoms, or abnormal liver function tests are discovered, further evaluation should be pursued promptly. Only one in three people with cirrhosis knows they have it. Most patients with cirrhosis remain asymptomatic until the onset of decompensation. The most common causes of cirrhosis are viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis [2].

Alcohol is a major risk factor for liver cirrhosis with risk increasing exponentially. Women may be at higher risk compared to men even with little alcohol consumption. More high-quality research is necessary to elucidate the role of other risk factors, such as genetic vulnerability, body weight, metabolic risk factors, and drinking patterns over the life course [3]. Alcohol use disorders cause significant morbidity and early mortality but remain largely unexplored. Medicines are used much less. Excessive drinking is a significant cause of mortality, morbidity, and social problems in many countries. Mean baseline alcohol consumption was 244 g/ week (30.5 standard UK units) among the studies that reported these data. Authors found moderate-quality evidence that brief interventions can reduce alcohol consumption in hazardous and harmful drinkers compared to minimal or no intervention [4,5].

Among men, conventional epidemiology showed that selfreported alcohol intake had U-shaped associations with the incidence of ischaemic stroke. men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers [6]. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease [7]. Alcohol consumption had a significantly larger impact on mortality of liver cirrhosis compared with morbidity. Also, the same amount of average consumption was related to a higher risk of liver cirrhosis in women than in men [8]. In Western countries, non-alcoholic fatty liver disease is becoming the most common indication for liver transplantation [9].

Cirrhosis with portal hypertension and related complications are associated with a high mortality. Excess of circulating vasodilators and cardio depressive substances lead to a hyperdynamic circulation with changed myocardial structure and function. The entity cirrhotic cardiomyopathy seems to be involved in different aspects of hepatic decompensation, which focuses on new targets of treatment. Areas covered [10]. Patients suffering from liver cirrhosis (LC) frequently require non-hepatic abdominal surgery, even before liver transplantation. LC is an important risk factor itself for surgery, due to the higher than average associated morbidity and mortality [11]. Alcohol abuse has been estimated to be the third largest risk factor for disease and disability in the world [12]. Despite extensive research into understanding the pathophysiology of liver disease, there are still no targeted treatments available [13].

Patients who have undergone liver transplants for alcoholic liver disease have a higher risk of cardiovascular and cerebrovascular events, and malignant tumors [14]. Authors call for attention to defining safe limits for ethanol consumption in different demographic regions of the world [15]. The authors analyze the strengths of alcohol models and summarize the results of alcohol-induced liver and other organ damage [16]. The infraslow acetylator genotypes NAT2 will have the greatest impact on the increased risk of anti-TB drugs ATDILI [17]. A higher mortality rate from liver cirrhosis was found in countries with a high proportion of rapid NAT2 phenotypes [18,19]. Despite extensive experience and knowledge, the risk factors for liver cirrhosis remain not fully understood. Safe doses and timing of their use are a big problem.

Study design: statistical analysis of observations. For the purposes of the study, a database was created on the burden of NCDs, cardiovascular diseases, diabetes, alcoholism, cancer, and cirrhosis of the liver (ICD-10 codes). Two groups of countries were created:
Group 1 - countries with the highest burden of liver cirrhosis - 21 countries.
Group 2 - countries with the lowest burden of liver cirrhosis - 21 countries.

Table 1:Country Groups 1 & 2 – Lists.

Disease burden (DALY) data for men in 21 countries, Age-standardized were selected from the GBD 2004 database [20]. To characterize the “quality of life” (QOL) in the countries a number of indicators were used: income per capita or gross domestic product (GDP) in 2000 - 2016 (US dollars per person per year) [21]; the geographical position of the countries by latitude and the level of ultraviolet radiation in the capital (UV) (J/m2 2004) [22]; life expectancy for men and women (LE) [23]; access to good health care, clean water, and clean air [24]; Happiness Index (IH) in 2016 [25]. Body mass index (BMI) ≥ 25 kg/m2 and ≥ 30 kg/m2 have been studied as predictors of metabolic syndrome (MSP) - the percentage of men and women in the country who are overweight and obese; the % of population with blood cholesterol (Chol ≥ 5.0 mmol/L and ≥ 6.2 mmol/L); blood glucose level (Glu ≥ 7.0 mmol/L); blood pressure (BP ≥ 140/90 mm Hg); low physical activity (LPA) ≤ 60 min/day walking [26]. The daily level of food consumption (TDC) (g/person/day) (50 types of products) for each country was selected from the FAO database for 1992 - 2005 [27]. The nutritional structure (NS) of the countries is presented in the form of 4 blocks in absolute and percentage terms (TDC): 1 - products of animal origin (AP); 2 - cereals and vegetables (CV); 3 - fruits and sweeteners (FS); 4 - alcoholic beverages (AB) [27]. Statistical analysis of the study results was performed using Mann- Whitney-Wilcoxon U-criterion. U is the numerical value of the Mann- Whitney test. The central tendency in the sample data distribution was represented by the median with a quartile range and a mean with a standard deviation. The variance of the data in the samples was estimated using a quartile range (QR) between the first and third quartiles, that is, between the 25th and 75th percentiles. The level of statistical significance, reflecting the degree of confidence in the conclusion about the differences in the indicators of groups 1 and 2 countries: two levels of accuracy were estimated: (1) p ≤ 0.01, 1% error probability; (2) p ≤ 0.05, 5% error probability. The Bonferoni correction was also used to assess the significance of the study results, taking into account the two hypotheses p ≤ 0.025 for multiple comparisons. Analysis of the Burden of Cardiovascular Diseases, Prostate and Breast Cancer and Alcoholism in Countries with High and Low Daily Alcohol Consumption 14 Citation: Ludmila Alexandrovna Radkevich and Daraya Andreyevna Radkevich. “Analysis of the Burden of Cardiovascular Diseases, Prostate and Breast Cancer and Alcoholism in Countries with High and Low Daily Alcohol Consumption”. EC Pharmacology and Toxicology 9.10 (2021): 12-25. NCD burden and MSP dependence on TDC products, including CAB, were analyzed using Multiple Linear Regression Analysis for independent variables (LMA). Standardized NCD burden of disease indicators: cardiovascular, prostate cancer, breast cancer, and alcoholism from 2004 for 158 countries [20] and MSP predictors [26] were used as the dependent variable, LMA. Daily blocks of TDC: AP (animal products), CV (cereals and vegetables), FS (fruits and sweeteners) and AB (alcoholic beverages) for 158 countries (2003 - 2005) were used as predictors (independent variables) [27]. A stepwise procedure of inclusion of independent variables was applied to obtain the best regression equations containing the minimum number of predictors statistically significantly associated with the dependent variable. The quality of the regression model was assessed using multiple correlation coefficient (R1), coefficient of determination (R2), Fdistribution, t-criteria for regression coefficients, and residuals analysis. The residuals in all models had a normal distribution. Analysis of the values and signs of the coefficients of β* and β regression equations allowed us to estimate the contribution of UP of different products to the values of the specified types of NCD and MS predictors. All calculations were performed using the program STATISTICA (version 13).

We performed an analysis of risk factors for liver cirrhosis based on a comparison of quality of life, incidence of liver cirrhosis and comorbid pathologies, metabolic syndrome, and levels of food consumption, including alcoholic beverages, in two groups of countries in the world with the highest and lowest burden of liver cirrhosis. Group 1 includes 21 countries with the highest burden of liver cirrhosis in the world in 2004 [GBD] (Table 1).
Group 2 shows the minimum burden of liver cirrhosis in 21 countries of the world in 2004 [GBD, Geneva, 2009] (Table 1). The burden (DALY) of liver cirrhosis in group 1 was 12 times higher than that of liver cirrhosis in group 2 (p≤0.001) (Table 2).
In Group 1, the burden of cirrhosis was 819 ± 222 (Mean 1 ± Std. Dev. 1) and 757 ± 254 (Median 1 ± Quartile 1) (Table 2).
In group 2 countries, the burden of liver cirrhosis was 71 ± 27 (Mean 2 ± Std.Dev.2) and 80 ± 34 (Median 2 ± Quartile 2) (Table 2).
In Group 1 countries, the highest burden of cirrhosis was in 3 countries: Kyrgyzstan (1321 DALYs),
R Moldova (1275 DALY) and Guatemala (1103 DALY). In group 2, the minimum burden (DALY)) of liver cirrhosis was in 3 countries Kuwait (42 DALYs), Iceland (14 DALYs), Albania (0 DALYs) (Table 1).

Quality of life in 1 and 2 groups of countries

The countries of the 1st group were 4 times poorer than the countries of the 2nd group. The per capita income in the 1st group of countries was 4 times lower than the 2nd group of countries (p≤0.001) (Table 2). The geographic latitude and the level of ultraviolet radiation in the capitals of the countries of groups 1 and 2 did not differ statistically (p = 0.3). Wherein, The 1st group of countries was located 20 ° east of the Greenwich meridian compared to the 2nd group of countries (p≤0.010) (Table 2). In the 1st group of countries, social conditions were 1.5 - 2 times worse: prosperity, education, social capital, corruption, health care, clean water and air, environmental safety, Human Development Index and Happiness Index (p≤0.01) (Table 2). Life expectancy in group 1 of countries for women was 7 years, for men it was 10 years shorter than group 2 of countries (p≤0.001) (Table 2). In group 1, countries statistically significantly belonged to the NAT2 phenotype of rapid acetylation, in contrast to group 2 countries (p≤0.001) (Table 2).

Table 2:Comparative analysis of the quality of life, the burden of NCDs and the metabolic syndrome (Mann-Whitney U-test).

Disease burden in countries 1 and 2

In the 1st group of countries, the overall mortality was 3 times higher, and the overall morbidity was in 2 higher in comparison with the 2nd group of countries (p≤0.001) (Table 2).

Infectious morbidity in the 1st and 2nd groups of countries

In the first group of countries, in comparison with the second group of countries, the burden of Infectious and parasitic diseases was 4 times higher (p≤0.001); including 3 times higher burden of Hepatitis B (g) (p≤0.044); there was no statistical difference in the burden of Hepatitis C (g) (p = 0.8) and was 4 times the burden of Tuberculosis (p≤0.001) (Table 2).

Non-communicable morbidity in groups 1 and 2

Group 1 compared to Group 2 has 1.5 times the NCD burden (p≤0.001); 1.7 times the burden of liver cancer (p≤0.008); no statistically significant difference in the burden of diabetes mellitus (p = 0.15); 2.1 times higher burden of Alcohol use disorders (p≤0.002); double the burden of Cardiovascular diseases, Hypertensive heart disease and Cerebrovascular disease (p≤0.003); 12 times the burden of Cirrhosis of the liver (p≤0.001); 2.5 times higher burden of Nephritis and nephrosis (p≤0.001) and 2.5 times higher burden of Self-inflicted injuries (p≤0.005) (Table 2), (Figures 1-4) Predictors of Metabolic Syndrome in Groups 1 and 2 In the 1st group of countries, in comparison with the 2nd group of countries, the number (%) of men with disorders of the predictors of Metabolic Syndrome (p≤0,001) was on average 1.5 - 2 times lower (Table 2). In the 1st group of countries, in comparison with the 2nd group of countries, there were 1.5 times less men with overweight, 2 times less men with obesity and hyperlipidemia, as well as 1, 5 times fewer men with low physical activity (p≤0.001). In the 1st group of countries there was no statistical difference from the 2nd group of countries in the number of men with hyperglycemia and hypertension in the countries (p = 0.1) (Table 2).

Figure 1:Burden of cirrhosis of the liver in Maxi and Mini countries: 2- Burden of cirrhosis of the liver in Maxi and Mini countries; 3. Burden of cirrhosis of the liver in countries with UV mini maxi.

Figure 2:Burden of cardiovascular disease in countries with maxi and mini cirrhosis: 2- Burden of cardiovascular disease in countries with maxi and mini income; 3. Burden of Cardiovascular Disease in UV Mini Maxi Countries.

Figure 3:Burden of diabetes in countries with maxi and mini cirrhosis: 2 - diabetes burden in countries with maxi and mini income; 3. The burden of diabetes in countries with UV mini maxi.

Figure 4:Burden of alcoholism in countries with maxi and mini cirrhosis: 2- alcoholism burden in countries with maxi and mini income; 3. The burden of alcoholism in countries with UV mini maxi.

Food consumption levels

In group 1 of countries, in comparison with the second group of countries, the total daily food consumption was 1.3 times lower (p≤0.022); 1.3 times lower consumption of animal products (p≤0.042) *; there was no statistical difference between the groups of countries in the level of consumption of cereals and vegetables (p = 0.3) and alcoholic beverages (alcohol, spirits, wine and beer (p = 0.5) and was 1.5 times lower in consumption of fruits, coffee and sweeteners (p≤0.001) (Table 3).

Table 3:Comparative analysis of the levels of consumption of food, alcohol, and nutrients in the countries of the 1st and 2nd groups (Mann-Whitney U-test) (Figure 1). Per capita income and the general level of food consumption in the 1st and 2nd group of countries.

Macronutrient Intake Levels in Group 1 and Group 2 1990-02 years

In the 1st group of countries in comparison with the 2nd group, the consumption of total energy, total proteins and total fats was 1.5-2 times lower (p≤0.001). At the same time, the percentage of carbohydrates was higher in the 1st group of countries (p≤0.001). But the percentage of protein and fat was slightly higher in group 2 countries (p≤0.001). The share (%) of consumption of animal products (energy and protein) was 1, 5 times higher in the 2nd group of countries (p≤0.019). The proportion of animal fat consumption was not statistically different between group 1 and group 2 (p = 0.7).

2003-2005 years

The analysis of nutrient consumption showed that in the 1st group of countries the consumption of total nutrients increased by 24% (p≤0.001). In group 2 of countries, the increase in consumption of total nutrients was 5% compared to 1990-02 (p≤0.001) (Table 3).

The WHO considers the use of tobacco, alcohol, unhealthy diet and physical inactivity to be the main risk factors for NCDs [28]. The research results were unexpected. The 12-fold gradient in the burden of liver cirrhosis between country groups 1 and 2 was not accompanied by statistically significant differences in the main risk factors for NCDs (Tables 2 & 3). We have not found statistically significant differences in the burden of incidence of viral hepatitis B and C between group 1 and group 2 of countries. This hepatitis is considered the main risk factors for non-alcoholic cirrhosis of the liver [2, 29]. Higher consumption of animal products, including animal fat, was higher in group 2 countries with a low burden of cirrhosis. Overweight, obesity and hyperlipidemia were 2 times higher in group 2 countries. Thus, the risk factors for non-alcoholic cirrhosis in the 1st group of countries were lower than in the 2nd group of countries [2, 29]. Consequently, the 12-fold gradient of liver cirrhosis in group 1 of countries cannot be justified by lower risk factors for non-alcoholic cirrhosis of the liver than in group 2 of countries [2, 29].

It should be noted that in the GBD database of 2004 [20] there is no division of cirrhosis into alcoholic and non-alcoholic forms. The GBD 2004 database [20] provides a summary indicator of the burden of liver cirrhosis. It is known that alcoholic cirrhosis of the liver is caused by the abuse of alcoholic beverages by patients [3, 8]. However, in our studies, the consumption of alcoholic beverages (spirits, wine and beer) did not statistically significantly differ in group 1 of countries from group 2 of countries.

Thus, the absence of statistically significant differences between groups 1 and 2 countries in alcohol consumption (the third risk factor for liver cirrhosis) could not explain the striking difference in the burden of liver cirrhosis between groups 1 and 2 countries [3, 8]. We have undertaken several validations of our original data: the 2004 GBD disease burden database [20], the FAO food and alcohol consumption rate database [27], and the statistics program. To check our results, we used the list of countries by consumption of pure alcohol for 2016-18 [30].

There were no statistically significant differences between the countries of the 1st and 2nd groups in the consumption of pure alcohol in 2016-18. As a result, we have come to believe that our results are not an error. Thus, we have no reason to assert that the high burden of liver cirrhosis in group 1 of countries is due to a higher incidence of viral hepatitis, alcohol abuse and malnutrition. It should be noted that I was unable to obtain a model of liver cirrhosis using only alcohol in studies on Wistor rats and outbred rats. Against the background of alcohol consumption, rats always had to inject carbon tetrachloride or D-galactosamine in a certain regimen [31]. However, in the modern literature, this model is called alcoholic cirrhosis of the liver [32].

We noted that in group 1 there were statistically significantly more countries with the phenotype of rapid NAT2 - acetylation (Table 2). Back in the second half of the 20th century, textbooks on hepatology wrote that the NAT2 enzyme system suffers in liver cirrhosis [33]. It has been argued that patients who are fast in the NAT2 phenotype can become slow NAT2 - acetylators and vice versa in the development of liver cirrhosis [33]. We conducted a study of the stability of the NAT2-acetylation system in 82 patients with liver cirrhosis at the Center of Surgery of the Academy of Sciences. The control consisted of 150 men and women of the Moscow population [34]. As a result of research, we found that with the phenotype fast NAT2 in the control group was 45% of Muscovites. In total, the control group and the group of patients with liver cirrhosis did not statistically differ in NAT2 phenotype. But among patients with active liver cirrhosis, that is, with a severe form of liver cirrhosis, there were statistically significantly more rapid NAT2 phenotypes [34].

Among patients with inactive cirrhosis, there were 22% of rapid NAT2 phenotypes; with active cirrhosis of the liver - 61% of rapid NAT2 phenotypes; with decompensated liver cirrhosis - 100% of slow NAT2 phenotypes [34]. None of the 82 patients showed a change in the rate of NAT2 acetylation during 12 months of follow-up. Among patients with cirrhosis of the liver of fast NAT2 acetylators, the mortality rate was 2 times higher than among slow NAT2 acetylators [34]. Patients with cirrhosis of the liver with the rapid NAT2 phenotype were on average 3-4 years younger and had a more severe course of LC than patients with the slow NAT2 phenotype [34]. The reason for the more severe course of LC and higher mortality from liver cirrhosis in patients with a rapid NAT2 phenotype may be associated with the mechanism of accelerated NAT2-dependent collagen synthesis. During the development of liver cirrhosis, this mechanism can contribute to the development of fibrosis of the liver parenchyma and impairment of portal microcirculation [19,34].

In several studies, we have shown that mortality from liver cirrhosis is significantly higher in countries with a high percentage of the population of rapid NAT2 phenotypes [18, 19]. Recently, new surgical methods for the treatment of liver cirrhosis have appeared with the use of bariatric surgery. Bariatric surgery contributes to the reduction of the Body Mass Index and the prevention of liver cirrhosis [35-37].

Earlier, we also proposed a surgical method for the treatment of chronic hepatitis and cirrhosis of the liver. The method was developed on models of chronic hepatitis and liver cirrhosis in rats [38-40]. We noticed that ischemia, or stenosis of the left or right branch of the portal vein in rats, is accompanied by a reduction in the lobe of the liver, devoid of portal inflow. In this case, all the adductor and discharge vessels in portal ischemia of the liver lobes should be preserved. Reduction of the liver lobe occurs by apoptosis.

But the complete reduction of the liver lobe never occurs and does not depend on the duration of ischemia of the portal vein branch. Even the maximum degree of reduction of the lobe to 10% of the initial mass does not cause disturbances in the reduced lobe of the liver of its bar structure of the parenchyma. In addition, there are many stem cells in the parenchyma of the reduced lobe [40-43]. Cessation of portal ischemia (reperfusion) restores the lobe of the liver by stimulating hepatocyte division. Histological preparations and morphometry of the parenchyma structure indicated complete organotypic liver renewal [39, 40]. So, returning to the goal set in our work and the results obtained, we cannot answer the question about the reason for the 12-fold difference in the burden of liver cirrhosis in 1 and 3 groups of countries of the world.

In conclusion, we would like to note that the burden of liver cirrhosis, cardiovascular diseases, diabetes mellitus and alcoholism exhibits a specific dependence on per capita income, latitude, and “pure” UV. This is shown in Figures 1-4. The figures combine the results of this study of liver cirrhosis and data from our other work [44].

In accordance with the set goal, in our studies it was found that in group 1 of countries in comparison with group 2 of countries, the burden of Cirrhosis of the liver is 12 times higher (p≤0,001). The burden of comorbid liver cirrhosis is alcoholism and cardiovascular disease was also 2 times higher in 1 group of countries in comparison with 2 group of countries (p≤0.001). The burden of diabetes was not statistically significant between groups 1 and 2 countries. Major risk factors for liver cirrhosis - The burden of viral hepatitis B and C did not differ statistically between groups 1 and 2. Consumption levels of food, including animal fats, red meat, animal energy and total energy were, on average, 1.5 to 2 times higher in Group 2, with a low burden of liver cirrhosis and comorbid diseases (p≤0.003). Consumption of all types of alcoholic beverages: pure alcohol, strong alcohol, wine and beer were not statistically different between the two study groups of countries (p = 0.7). The results obtained do not allow us to draw a conclusion about the risk factors for liver cirrhosis in this study. Further research on risk factors for liver cirrhosis is needed.

Authors are grateful For ongoing consultations, Alexander Nemtsov, M.D. National Center for Addiction Medicine.

No conflict of interest.