David Kershenobich

Variant in PNPLA3 is associated with alcoholic liver disease

Two genome-wide association studies (GWAS) have described associations of variants in PNPLA3 with nonalcoholic fatty liver and plasma liver enzyme levels. We investigated the contributions of these variants to liver disease in Mestizo subjects with a history of alcohol dependence. We found that rs738409 in PNPLA3 is strongly associated with alcoholic liver disease and clinically evident alcoholic cirrhosis (unadjusted OR= 2.25, P=1.7 × 10−10; ancestry-adjusted OR=1.79, P=1.9 × 10−5).

The Quest for Universal Health Coverage: Achieving Social Protection for All in Mexico

Mexico is reaching universal health coverage in 2012. A national health insurance programme called Seguro Popular, introduced in 2003, is providing access to a package of comprehensive health services with financial protection for more than 50 million Mexicans previously excluded from insurance. Universal coverage in Mexico is synonymous with social protection of health. This report analyses the road to universal coverage along three dimensions of protection: against health risks, for patients through quality assurance of health care, and against the financial consequences of disease and injury. We present a conceptual discussion of the transition from labour-based social security to social protection of health, which implies access to effective health care as a universal right based on citizenship, the ethical basis of the Mexican reform. We discuss the conditions that prompted the reform, as well as its design and inception, and we describe the 9-year, evidence-driven implementation process, including updates and improvements to the original programme. The core of the report concentrates on the effects and impacts of the reform, based on analysis of all published and publically available scientific literature and new data. Evidence indicates that Seguro Popular is improving access to health services and reducing the prevalence of catastrophic and impoverishing health expenditures, especially for the poor. Recent studies also show improvement in effective coverage. This research then addresses persistent challenges, including the need to translate financial resources into more effective, equitable and responsive health services. A next generation of reforms will be required and these include systemic measures to complete the reorganisation of the health system by functions. The paper concludes with a discussion of the implications of the Mexican quest to achieve universal health coverage and its relevance for other low-income and middle-income countries.Mexico is reaching universal health coverage in 2012. A national health insurance programme called Seguro Popular, introduced in 2003, is providing access to a package of comprehensive health services with financial protection for more than 50 million Mexicans previously excluded from insurance. Universal coverage in Mexico is synonymous with social protection of health. This report analyses the road to universal coverage along three dimensions of protection: against health risks, for patients through quality assurance of health care, and against the financial consequences of disease and injury. We present a conceptual discussion of the transition from labour-based social security to social protection of health, which implies access to effective health care as a universal right based on citizenship, the ethical basis of the Mexican reform. We discuss the conditions that prompted the reform, as well as its design and inception, and we describe the 9-year, evidence-driven implementation process, including updates and improvements to the original programme. The core of the report concentrates on the effects and impacts of the reform, based on analysis of all published and publically available scientific literature and new data. Evidence indicates that Seguro Popular is improving access to health services and reducing the prevalence of catastrophic and impoverishing health expenditures, especially for the poor. Recent studies also show improvement in effective coverage. This research then addresses persistent challenges, including the need to translate financial resources into more effective, equitable and responsive health services. A next generation of reforms will be required and these include systemic measures to complete the reorganisation of the health system by functions. The paper concludes with a discussion of the implications of the Mexican quest to achieve universal health coverage and its relevance for other low-income and middle-income countries.

Colchicine in the Treatment of Cirrhosis of the Liver

There is preliminary evidence that colchicine, an inhibitor of collagen synthesis, may be beneficial in the treatment of cirrhosis of the liver. To evaluate the use of colchicine (1 mg per day, five days per week) in the treatment of hepatic cirrhosis, we performed a randomized, double-blind, placebo-controlled trial in which 100 patients were followed for up to 14 years. Forty-five patients had alcoholic cirrhosis, 41 had posthepatitic cirrhosis, and the remaining 14 had cirrhosis with various other causes. Histologic studies were available for 92 percent of patients. Seventy-three patients were in Child-Turcotte class A, 26 were in class B, and one was in class C. Fifty-four patients received colchicine, and 46 received placebo. The overall survival in the colchicine group was markedly better than in the placebo group (median survival, 11 and 3.5 years, respectively; P less than 0.001). The cumulative 5-year survival rates were 75 percent in the colchicine group and 34 percent in the placebo group; the corresponding 10-year survival rates were 56 percent and 20 percent. Among the 30 patients treated with colchicine who underwent repeated liver biopsies, histologic improvement was seen in 9; the liver appeared normal in 2, and 7 had minimal portal fibrosis. No histologic improvement was observed in the 14 members of the placebo group who had two or more biopsies. Few side effects were observed in either group.

Trends and projections of hepatitis C virus epidemiology in Latin America

Background and aim: The purpose of the present investigation is to provide an analysis of previous works on the epidemiology of the hepatitis C virus (HCV) infection from six countries throughout Latin America, to forecast the future HCV prevalence trends in Argentina, Brazil, Mexico and Puerto Rico, and to outline deficiencies in available data, highlighting the need for further research.

Matching Strategies for Genetic Association Studies in Structured Populations

Association studies in populations that are genetically heterogeneous can yield large numbers of spurious associations if population subgroups are unequally represented among cases and controls. This problem is particularly acute for studies involving pooled genotyping of very large numbers of single-nucleotide-polymorphism (SNP) markers, because most methods for analysis of association in structured populations require individual genotyping data. In this study, we present several strategies for matching case and control pools to have similar genetic compositions, based on ancestry information inferred from genotype data for approximately 300 SNPs tiled on an oligonucleotide-based genotyping array. We also discuss methods for measuring the impact of population stratification on an association study. Results for an admixed population and a phenotype strongly confounded with ancestry show that these simple matching strategies can effectively mitigate the impact of population stratification.

The relationship between the free pool of proline and collagen content in human liver cirrhosis.

The free proline, free glutamic acid, and total collagen contents of the livers of cirrhotic and noncirrhotic patients were determined. The amounts of free proline in the sera of the patients were also determined. The results indicated that certain metabolic changes occurred in cirrhotic livers of humans that were similar to the metabolic changes observed previously in CCl(4)-induced cirrhosis in the rat. The amount of free proline was coordinate with the increase in total collagen, and both were inversely related to the amount of free glutamic acid. The average proline concentration in sera of cirrhotic patients was not higher than that of non cirrhotic patients, suggesting that the metabolic alteration noted above is a local event in the liver related to fibrogenesis. These and other results suggest that the pool size of free proline may play a prime role in regulation of collagen biosynthesis in liver cirrhosis.

Effect of colchicine on collagen, albumin and transferrin synthesis by cirrhotic rat liver slices

Collagen synthesis was found to be increased in liver slices of rats made cirrhotic by chronic administration of CCl4. The liver function was impaired, as determined by an increased retention of conjugated bilirubin and low serum albumin values. However, when animals received colchicine simultaneously with CCl4, collagen synthesis and deposition were inhibited, and the liver function appeared normal. When a group of rats was made cirrhotic by chronic administration of CCl4, and then kept for 30 days without further treatment, fibrosis persisted and collagen synthesis was very low. However, the liver function was severely impaired. When similar rats received L-azetidine-2-carboxylic acid during the 30-days period following CCl4 administration, there was a slight but not significant improvement in liver function. The collagen synthesis and the extent of fibrosis were similar to the controls. However, if similar rats received colchicine during the 30 days period, collagen synthesis was almost negligible, there was a slight decrease in fibrosis and there was a great improvement in liver function. In all the cirrhotic animals studied, transferrin biosynthesis remained constant.

Health-related quality of life and depression in patients with chronic hepatitis C

BACKGROUND Hepatitis C is a major cause of liver disease worldwide. It has been associated with decreased health-related quality of life (HRQL) and psychiatric symptoms. Our aim was to assess HRQL, depression, and illness understanding in patients with chronic hepatitis C without previous interferon therapy. METHODS Consecutive patients attending a referral center were enrolled. HRQL was measured using SF-36 questionnaire, depression with Zung self-rating depression scale, and illness understanding with self-applied knowledge test. RESULTS Of 157 patients enrolled, 112 were female (71%) and 45 male (29%). Ninety-seven patients (61.8%) had cirrhosis. HRQL was significantly decreased in chronic hepatitis C patients compared to historical normal controls in all eight domains of the SF-36 (p < 0.001). In hepatitis C cirrhotic patients, HRQL was significantly lower among Child-Pugh class B and C subjects in domains reflecting physical health (p <0.05). Ninety-two patients (58.6%) had depression that resulted in lower HRQL when compared to nondepressed patients (p <0.05). One hundred fourteen patients (72.6%) had poor illness understanding of hepatitis C. These subjects had significantly lower HRQL scores in six of eight SF-36 domains when compared to patients with better understanding of the disease (p <0.05). CONCLUSIONS Chronic hepatitis C patients attending a tertiary-referral center had significant decrease in HRQL associated with depression (58.6%) and poor illness understanding (72.6%). Educational programs and their impact on HRQL need to be addressed in detail, particularly for the pre-treatment scenario.

Seroprevalencia de la hepatitis C en adultos de México: ¿un problema de salud pública emergente?

Objective. Hepatitis C Virus (HCV) infection is becoming a chronic disease in 60-85% of individuals and is a cause of hepatic cirrhosis and hepatocellular carcinoma. The objective of this study was to report the seroprevalence of HCV infection in a probabilistic sample of the Mexican population. Material and Methods. This study is based on information obtained from the National Health Survey conducted in 2000. A total of 21 271 sera randomly selected for anti-HCV and RNA of HCV was studied. It was performed at the National Institute of Public Health in 2005. Results. Seroprevalence of HCV antibodies was 1.4% (IC95% 1.1%-1.6%), of which 35.7% had active infection. Risk factors for infection were using heroine (RM= 9.8, IC: 2.1-41.4), being separated from his/her spouse (RM= 2.6, IC: 1.1-5.9), being a widower (RM= 2.2, IC: 1.1-4.3) and living in the northern states in the country (RM= 1.9, IC: 1.1-3.2). Conclusion. Results from this study indicate that HCV is an emerging public health problem in Mexico. Risk factors indicate that the main route of transmission is through transfusion of blood products (previous to 1996) and the second route is through usage of intravenous drugs and sexual practices.

Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage

Acetaldehyde (Ac), the main metabolite of ethanol oxidation, is a very reactive compound involved in alcohol-induced liver damage. In the present work, we studied the effect of Ac in mitochondria functionality. Mitochondria from Wistar rats were isolated and treated with Ac. Ac decreased respiratory control by 50% which was associated with a decrease in adenosine triphosphate content (28.5%). These results suggested that Ac could be inducing changes in cell redox status. We determined protein oxidation, superoxide dismutase (SOD) activity, and glutathione ratio, indicating that Ac induced an enhanced oxidation of proteins and a decrease in SOD activity (90%) and glutathione/oxidized GSH ratio (36%). The data suggested that Ac-induced oxidative stress mediated by mitochondria dysfunction can lead to cell sensitization and to a second oxidative challenge. We pretreated hepatocytes with Ac followed by treatment with antimycin A, and this experiment revealed a noticeable decrease in cell viability, determined by neutral red assay, in comparison with cells treated with Ac alone. Our data demonstrate that Ac impairs mitochondria functionality generating oxidative stress that sensitizes cells to a second damaging signal contributing to the development of alcoholic liver disease.