Milestones in the discovery of hepatitis C.

The discovery of hepatitis C has been a landmark in public health as it brought the opportunity to save millions of lives through the diagnosis, prevention and cure of the disease. The combined work of three researchers, Alter H, Houghton M and Rice C, which set the basis for the diagnosis, treatment and prevention of hepatitis C apart from laying the ground work for a new approach to study infections in general and developing new antiviral agents. This is a story of a transfusion-associated infection. A series of clinical studies demonstrated the existence of an infectious agent associated with hepatitis. That was followed by the identification of what was later known to be the hepatitis C virus (HCV) and the development of diagnostic tests. It all preceded the full molecular identification and demonstration of a causal effect. Finally it ended up with the development and discovery of a new class of therapeutic drugs, the direct acting antivirals, which are now used not only to cure the disease but most probably, to eliminate the problem. This work started with Dr Alter H who demonstrated that a new virus was responsible for the majority of post-transfusion hepatitis followed by Houghton M who cloned the virus and developed the blood test to identify those cases that carried the virus. Finally, the work of Rice C demonstrated that a cloned HCV produced after applying molecular biology techniques could cause long-standing infection and cause the same disease as the one observed in humans.

Andrew K. Burroughs: a research hepatologist extraordinaire.

Andrew K (Andy) Burroughs passed away in March 2014 at the early age of 60 years. Andy was one of the last of the great all round giants of hepatology. He was a consummate physician, clinical investigator and educator. Over a period of 35 years at the Royal Free Hospital Liver Unit he produced a prodigious quantity of original research and made major contributions in many areas of hepatology including portal hypertension, liver transplantation and chronic liver disease. His work on the methodology of clinical trials is carried on by the Baveno consensus meetings. From bedside clinical mastery to early molecular biology applications to diagnosis and pathology, his contributions left a mark in liver science and advanced medical science in general. He also was praised by his work in medical education particularly in post-graduate mentorship and, an admirable human touch with patients. We will not see his like again.

50 years of Hepatology: The Royal Free Hospital School of Hepatology.

Writing about the history of Hepatology would necessarily imply writing about the history of the Liver Unit and the School of Hepatology created by Dr. Sheila Scherlock at the Royal Free Hospital (London). On the 70th anniversary of the creation of the first liver unit (Hammersmith Hospital) this article presents a brief account of the history, organization, structure, educational program and contributions of perhaps the first and the most influential medical research models created for the study of liver diseases: the Royal Free Hospital Liver Unit.

Alcohol and the Liver: The Return of the Prodigal Son.

With the discovery of direct-acting antivirals and the prospective of viral hepatitis becoming curable, alcohol liver disease (ALD) is back to primetime. In the last 20 years, there have been many advances in the understanding of the biology, the psychology and the social and environmental factors associated with this long-known medical problem. Recent information about regional, ethnic, cultural and genetic factors seem to be relevant for the Latin American (LA) population. New approaches based on the new concepts and current information will render better results in the overall management of patients with this problem. Considering alcohol use disorder and ALD as part of the same entity managing it in a multidisciplinary approach seems to be best way to deal with this disease.

Factors associated with tobacco, alcohol, and other drug use among youth living in West Central Mexico.

AIM: To determine the prevalence of drug and substance abuse among high school students in Jalisco and its association with the severity of health, behavior and psychosocial problems in order to provide evidence for possible prevention and treatment needs. METHODS: A multi-stage random sample of Jalisco high school students was given a paper-and-pencil survey based upon an adapted version of the drug use screening inventory (DUSI) (n = 24699; n = 2832). The DUSI showed adequate psychometric characteristics in this population. The statistical analyses accommodated the complex survey design with attention to unequal probability of selection and clustering of participants within schools and regions. RESULTS: An estimated 44% of the students had smoked tobacco, one in five students was a current smoker, and one in four students used to smoke but had not smoked for one year or more. By contrast, 6.8% of the students reported having used marijuana, cocaine, or both. Behavioral problems, deviant peer affiliation, and troubled families were independently associated with drug use. One in two students who used tobacco or alcohol had used these drugs in the past year (46% and 54%, respectively), and one in four students who used marijuana or cocaine in their lifetime had used those drugs in the past year (28% in both cases). CONCLUSION: The rates of cocaine use as well as the proportion of current users were higher than expected among high school students and indicate changing patterns of drug use in Mexico. These results corroborate that the general trend of drug use by youth in Mexico is increasing. Results from this study help us better understand the needs of at-risk youth and the need for new treatment and prevention strategies.

Protein tolerance to standard and high protein meals in patients with liver cirrhosis.

AIM: To investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis. METHODS: The plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects. In addition the response to a high protein meal (1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy (HE) following a porto-caval shunt procedure. To test for covert HE, the "number connection test" (NCT) was done on all patients, and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage. RESULTS: The changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase (P < 0.05) in isoleucine, leucine and tyrosine concentrations in the cirrhotics. The baseline branched chain amino acids/aromatic amino acids (BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group. After the high protein meal there was a marked increase in the levels of most amino acids, but only small changes occurred in the levels of taurine, citrulline, cysteine and histidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal. Slightly elevated basal plasma ammonia levels showed no particular pattern. Overt HE was not observed in any patients. CONCLUSION: Patients with stable liver disease tolerate natural mixed meals with a standard protein content. The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE. These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis.

High frequency of the DRD2/ANKK1 A1 allele in Mexican Native Amerindians and Mestizos and its association with alcohol consumption.

BACKGROUND: Mexico has an ancient tradition of alcohol drinking influenced by genetic and sociocultural factors. This study aimed to determine the distribution of the DRD2/ANKK1 TaqIA polymorphism in Mexican populations and to analyze its association with heavy drinking. METHODS: In a cross-sectional and analytical study, 680 unrelated subjects including two Native Amerindians groups (87 Nahuas and 139 Huicholes), and two Mestizos groups (158 subjects from Tepic, Nayarit and 296 subjects from Guadalajara, Jalisco) were enrolled. DRD2/ANKK1 genotyping was performed by PCR-RFLP and allelic discrimination assays. Genetic analyses were conducted by Arlequin and Structure software. Heavy drinking was defined as ≥300g alcohol/week. The association of the DRD2/ANKK1 TaqIA polymorphism with heavy drinking was estimated. RESULTS: Heavy drinking was prevalent in 64.7% of the study population. The DRD2/ANKK1 A1 allele prevailed in 67% and 65% of Nahuas and Huicholes, respectively and 51% and 47.3% in Mestizos from Tepic and Guadalajara, respectively. Heavy drinking was associated with the A1A1 genotype in the Mestizos of Guadalajara (A1A1 vs. A1A2 OR=4.79, 95%CI 1.81-12.68, p=0.0006; A1A1 vs. A1A2+A2A2, OR=4.09, 95%CI 1.56-10.68, p=0.0021) and in the Mestizos from Tepic (A1A1 vs. A1A2, OR=5.92, 95%CI 2.12-16.49, p=0.0002); A2A2, OR=14.56, 95%CI 3.57-59.24, p=0.00004); A1A2+A2A2, OR=6.68, 95%CI 2.42-18.42, p=0.00005). In Native Amerindians, a lack of association was found. CONCLUSIONS: High frequencies of the DRD2/ANKK1 A1 allele were present in Mexican populations. Native Amerindians exhibited the highest frequencies of the A1 allele documented worldwide to date. The A1A1 genotype was associated with heavy drinking in Mestizos.

Mexico's precursor chemical controls: emergence of less potent types of methamphetamine in the United States.

BACKGROUND: This study examines whether Mexico's controls on ephedrine and pseudoephedrine, the two precursor chemicals that yield the most potent form of methamphetamine, d-methamphetamine, impacted the prevalence/availability of less potent types of methamphetamine in the United States-types associated with the alternative precursor chemical P2P. METHOD: Using ARIMA-intervention time series analysis of monthly drug exhibits (a prevalence/availability indicator) from the System to Retrieve Information from Drug Evidence (STRIDE), we tested whether Mexico's controls, which began in 2005, were associated with growth/decline in d-methamphetamine and growth/decline in P2P-associated, less potent l-methamphetamine, racemic methamphetamine (a 50:50 ratio of d- and l-isomers), and mixed isomer methamphetamine (an unequal ratio of d- and l-isomers). Heroin, cocaine and marijuana exhibits were used for quasi-control (01/2000-04/2011). RESULTS: Mixed-isomer exhibits constituted about 4% of the methamphetamine exhibits before Mexico's controls, then rose sharply in association with them and remained elevated, constituting about 37% of methamphetamine exhibits in 2010. d-Methamphetamine exhibits dropped sharply; l-methamphetamine and racemic methamphetamine exhibits had small rises. d-Methamphetamine exhibits partially recovered in the US West, but little recovery occurred in the US Central/South. Quasi-control series were generally unaffected. CONCLUSION: The US methamphetamine market changed. Widespread emergence of less potent methamphetamine occurred in conjunction with Mexico's controls. And prevalence/availability of the most potent type of the drug, d-methamphetamine, declined, a partial recovery in the West notwithstanding. Granting that lower potency drugs typically engender less dependence and attendant problems, these findings suggest that, following Mexico's controls, the potential harm of a sizeable amount of the US methamphetamine supply decreased.

Non-injection drug use and hepatitis C among drug treatment clients in west central Mexico.

BACKGROUND: Research on hepatitis C virus (HCV) prevalence among non-injecting drug treatment clients in the United States, Europe and Asia indicate substantial differences by place. To date, little or no research on HCV and non-injection drug use (NIDU) has been conducted in Mexico. METHODS: We examined the prevalence of HCV, hepatitis B virus (HBV), and HIV among non-injecting drug users (NIDUs) in community-based drug treatment (N=122) and NIDUs in a prison-based drug treatment program (N=30), both located in west central Mexico. RESULTS: Among the community clients, prevalence was 4.1% (95% confidence interval [CI]: 1.8-9.2) for HCV, 5.7% for HBV (95% CI: 2.8-11.4), and 1.6% for HIV (95% CI: 0.4-5.8). Among the in-prison clients, prevalence was 40.0% (95% CI: 24.6-57.7) for HCV, 20.0% for HBV (95% CI: 9.5-37.3), and 6.7% for HIV (95% CI: 1.9-21.3). None of the clients were aware of being infected. CONCLUSION: The HCV prevalence found for the NIDU community treatment clients ranks among the lower HCV estimates published for NIDUs in treatment to date. The prevalence found for the in-prison clients ranks among the higher, raising a concern of possible elevated HCV infection among NIDUs in the west central Mexico prison--one compounded by the finding that none of this study's clients knew they were HCV positive.

Proximity to the US-Mexico border: a key to explaining geographic variation in US methamphetamine, cocaine and heroin purity.

AIMS: Although illicit drug purity is a widely discussed health risk, research explaining its geographic variation within a country is rare. This study examines whether proximity to the US-Mexico border, the United States' primary drug import portal, is associated with geographic variation in US methamphetamine, heroin and cocaine purity. DESIGN: Distances (proximity) between the US-Mexico border and locations of methamphetamine, cocaine and heroin seizures/acquisitions (n = 239,070) recorded in STRIDE (System to Retrieve Information from Drug Evidence) were calculated for the period of 1990-2004. The association of drug purity with these distances and other variables, including time and seizure/acquisition size, was examined using hierarchical multivariate linear modeling (HMLM). SETTING: Coterminous United States. FINDINGS: Methamphetamine, cocaine and heroin purity generally decreased with distance from the US-Mexico border. Heroin purity, however, after initially declining with distance, turned upwards-a U-shaped association. During 2000-04, methamphetamine purity also had a U-shaped association with distance. For each of the three drugs, temporal changes in the purity of small acquisitions (<10 g) were typically more dynamic in areas closer to the US-Mexico border. CONCLUSIONS: Geographic variance in methamphetamine, cocaine and heroin purity throughout the coterminous United States was associated with US-Mexico border proximity. The U-shaped associations between border-distance and purity for heroin and methamphetamine may be due to imports of those drugs via the eastern United States and southeast Canada, respectively. That said, areas closer to the US-Mexico border generally had relatively high illicit drug purity, as well as more dynamic change in the purity of small ('retail level') drug amounts.

Mexico's methamphetamine precursor chemical interventions: impacts on drug treatment admissions.

AIMS: To help counter problems related to methamphetamine, Mexico has implemented interventions targeting pseudoephedrine and ephedrine, the precursor chemicals commonly used in the drug's synthesis. This study examines whether the interventions impacted methamphetamine treatment admissions-an indicator of methamphetamine consequences. DESIGN: Quasi-experiment: autoregressive integrated moving average (ARIMA)-based intervention time-series analysis. INTERVENTIONS: precursor chemical restrictions implemented beginning November 2005; major rogue precursor chemical company closed (including possibly the largest single drug-cash seizure in history) March 2007; precursor chemicals banned from Mexico (North America's first precursor ban) August 2008. SETTINGS: Mexico and Texas (1996-2008). MEASUREMENTS: Monthly treatment admissions for methamphetamine (intervention series) and cocaine, heroin and alcohol (quasi-control series). FINDINGS: The precursor restriction was associated with temporary methamphetamine admissions decreases of 12% in Mexico and 11% in Texas. The company closure was associated with decreases of 56% in Mexico and 48% in Texas; these decreases generally remained to the end of the study period. Neither intervention was associated with significant changes in the Mexico or Texas quasi-control series. The analysis of Mexico's ban was indeterminate due largely to a short post-ban series. CONCLUSIONS: This study, one of the first quasi-experimental analyses of an illicit-drug policy in Mexico, indicates that the country's precursor interventions were associated with positive impacts domestically and in one of the Unites States' most populous states--Texas. These interventions, coupled with previous US and Canadian interventions, amount to a new, relatively cohesive level of methamphetamine precursor control across North America's largest nations, raising the possibility that the impacts found here could continue for an extended period.

Molecular epidemiology of hepatitis C virus genotypes in west Mexico.

The identification of hepatitis C virus (HCV) genotypes and subtypes may be helpful to identify the source of an HCV outbreak among a specific group of individuals within a given country or the pattern of spread throughout nations worldwide. Mexico is a transit country for people who migrate north towards the United States from Central and South America, however, to date, no Mexican HCV sequences have been reported. The present study was conducted to identify the HCV genotypes and subtypes prevalent in Mexico by DNA sequencing and phylogenetic analysis in the NS5B region of the HCV genome. Serum samples from a total of 75 anti-HCV positive patients were included in this study. Out of the 75 samples, 48 cases (64%) were amplifiable in the 5' UTR and 46 (61%) in NS5B region. HCV genotype 1a determined in 54.3% (25/46) was predominant in this cohort, followed by 1b 21.8% (10/46), 2b 13% (6/46), 3a 6.5% (3/46), and 2a 4.4% (2/46). Phylogenetic analysis showed that HCV sequences of genotype 1 (1a and 1b) were clustering more closely to the United States isolates published previously. These results may suggest that both Mexico and the United States share an epidemiological network of HCV genotype 1 while other genotypes represent sporadic infections that are specific to Mexico.

[Hepatitis C virus infection and alcohol]. / Infección por virus de la hepatitis C y alcohol.

It was thought that HCV infection was very frequent among alcoholics; some even though that this disease affected nearly 35% of this group. Now there seems to be a consensus among the main investigator groups that the correlation of hepatitis C and alcohol increases the risk of complications, cirrhosis and liver cancer included. Moreover, it's now certain that among patients with HCV infection, alcohol consumption increases the risk of death from live diseases during the first 10 years of the disease. Alcoholism is also considered a predisposing factor for HCV infection, but not for hepatitis B virus infection. Prospective studies about post-transfusional hepatitis C showed the risk of cirrhosis increases from 7.8 to 31.1 times if the patient consumed significant amounts of alcohol (> 80 g a day). One of the recommendations for every patient with HCV infection is to abstain from drinking alcohol.

Características epidemiológicas de la cirrosis hepática en el Hospital Civil de Guadalajara / Epidemiology of liver cirrhosis at the Hospital Civil de Guadalajara

Objetivo. Estudiar prospectivamente las características demográficas y epidemiológicas de los pacientes con cirrosis hepática en el Hospital Civil de Guadalajara en un periodo de un año. Material y métodos. Se estudiaron 157 pacientes (48 mujeres y 109 hombres), de los servicios de Medicina Interna, Gastroenterología y Clínica de Hígado con diagnóstico de cirrosis hepática el cual se hizo con base en la información clínica, bioquímica o histopatológica; asimismo, se les aplicó un cuestionario especializado en enfermedades hepáticas. Resultados. La principal causa de la cirrosis fue el alcoholismo (38 por ciento en mujeres y 95 por ciento en hombres), seguida de la etiología viral. Las bebidas más frecuentes fueron el tequila y el alcohol de 96º G.L. El grado de insuficiencia hepática más frecuentemente observado fue el de Child-Pugh "B" en mujeres y "C" en los hombres. Las complicaciones más frecuentes fueron hemorragia de tubo digestivo, ascitis y encefalopatía hepática. Se observaron diferencias en varias características relacionadas con el sexo de los pacientes. Conclusiones. El alcoholismo fue la primera causa de cirrosis hepática. En mujeres la segunda causa fue la viral (16.7 por ciento). Se propone un comité nacional de vigilancia de enfermedades del hígado, para generar una información más completa y detallada acerca de la epidemiología de la cirrosis hepática

Asociación entre los niveles de amonio y GABA plasmáticos y el grado de encefalopatía hepática / Association of plasma ammonia and GABA levels and the degree of hepatic encephalopathy

Varias substancias presumiblemente tóxicas tales como el amonio se han implicado en la patogenia de la encefalopatía hepática porto-sistémica (EPS). Recientemente se ha propuesto la hipótesis del ácido gama-aminobutríco (GABA) donde el aumento del tono gabaérgico y la presencia de uno o más ligandos para el receptor GABA/benzodiacepínicos juegan un papel central. Con el objeto de investigar la asociación entre las elevaciones plasmáticas de amonio y GABA y el grado de encefalopatía hepática, estudiamos tres grupos de pacientes con enfermedad hepática que cursaban con episodio de EPS aguda espontánea o precipitada por hemorragia gastrointestinal o sepsis, en quienes se determinaron los niveles de amonio y GABA en plasma antes y después de tratamiento convencional con lactulosa. La EPS se valoró mediante el índice de EPs incluyendo pruebas del estado mental y electroencefalograma (EEG) entre otras. Los niveles de GABA en plasmas se encontraron significativamente elevados en pacientes con EPS pura (458+-108 pmol/mL) comparados con sujetos sanos (110+-23 pmol/mL)(p<0.01) aunque no se encontró correlación entre las concentraciones de GABA y el grado de encefalopátía. Sin embargo, los cambios en los niveles de amonio correlacionaron con los cambios en el índice de EPS (r=0.56;p<0.02) y con las alteraciones en el EEG (r=0.65;

The BCAA/AAA ratio of plasma amino acids in three different groups of cirrhotics

Con el objeto de investigar las diferencias en el perfil de aminoácidos en plasma y reevaluar el uso de la razón AACR/AAA (aminoácidos de cadena ramificada/aminoácidos aromáticos) (valina+isoleucina+leucina/fenilalanina+tirosina) para la valoración del grado de deterioro hepático, se estudió la concentración de aminoácidos plasmáticos en tres grupos de pacientes cirróticos: cirróticos compensados (estables), cirróticos descompensados y cirróticos con encefalopatía portosistémica (EPS) agudo, comparados con un grupo de sujetos normales (control). Los cirróticos estables mostraron concentraciones de aminoácidos similares al grupo control; la razón AACR/AAA en los cirróticos estables (2.9 +- 0.2) fue significativamente menor que en el grupo control (3.9+-0.3) (p<0.05). Los cirróticos descompensados mostraron diferencias en los aminoácidos plasmáticos y la razón AACR/AAA (1.7+-0.3) fue significativamente menor comparados con los cirróticos estables y con el grupo control, respectivamente (p<0.005 y p<0.01). Los pacientes con EPS aguda mostraron una elevación externa en la mayoría de los aminoácidos comparados con los otros grupos y la razón AARC/AAA (0.8+-0.07)fue la menor de los cuatro grupos (p<0.001 comparado con el grupo control). Se concluye que es posible detectar diferencias en las concentraciones de aminoácidos plasmáticos en diferentes grupos de cirróticios con diferentes grados de daño hepático y que la razón AACR/AAA es un índice útil en la valoración del grado de deterioro en la función hepática. Se propone el uso de este índice en el seguimiento de pacientes cirróticos seleccionados, tales como aquellos pacientes candidatos a cirugía mayor y trasplante hepático en quienes se podría utilizar este índice para precisar el momento más apropiado para el trasplante.