First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile.

First-degree relatives (FDR) of early-onset gastric cancer (EOGC) is presumed to be a population with a distinct molecular and phenotypic profile, regarding the prevalence of gastric premalignant conditions and the association with Helicobacter pylori infection and host proinflammatory gene polymorphisms. A case-control study was conducted with FDR of EOGC patients (n = 103) and age and gender matched controls (n = 101; ranging from spouses to neighbors and dyspeptics). Upper endoscopy was performed, Operative Link on Gastritis Assessment (OLGA) system used for staging and H. pylori (cagA and vacA) and host IL1B-511, IL1RN intron2 VNTR and IFNGR1-56 genotyping. Seventy percent of cases showed atrophy, while 19 % presented with high-stage gastritis (OLGA stage III or IV) (p < 0.001); gastric dysplasia was present in seven cases (vs none in controls) (p = 0.007). In cases, H. pylori was present in 82 % (vs 62 % in controls; p = 0.004) with vacA s1 and vacA m1 + strains significantly associated with the presence of atrophy; individuals homozygous for IL1B-511*T present a significantly higher risk for dysplasia. An increased global prevalence of IFNGR1-56*T/*T polymorphism (37 % in cases vs 24 % in controls; p = 0.03) was observed with no association with atrophic changes or dysplasia. All trends observed were kept when comparing FDR of EOGC with spouses, neighbors, or dyspeptic controls. We demonstrated that FDR of EOGC patients have an increased prevalence of high-risk OLGA stages and dysplasia that seem to be associated with high virulence H. pylori strains and pro-inflammatory host genotypes, including a possible population-specific risk marker. FDR of EOGC patients may merit specific management through endoscopic and histopathological adequate assessment of gastric mucosa and surveillance.

First degree relatives and familial aggregation of gastric cancer: who to choose for control in case-control studies?

Gastric carcinogenesis is a multifactorial process involving host gene and environmental interactions. Diverse case-control studies using different types of controls addressed the familial aggregation role for gastric cancer development. Our aim is to discuss the advantages and expected bias according to the different type of eligible controls. A PubMed search of papers on a query on first degree relatives of gastric cancer patients was conducted. The retrieved studies were evaluated regarding quality based on STROBE checklist. Data concerning risk of premalignant lesions and Helicobacter pylori infection was retrieved as the type of controls used on each study. Nine case-control studies were selected. A variety of controls were used ranging from general population to dyspeptic patients and spouses of the cases. We have observed that, independently of the type of control, the risk for the prevalence of premalignant lesions and H. pylori infection was higher for the cases. However, all of the evaluated case-control studies were average quality studies (mean 28 out of 45), with a small number of cases and controls (range from 39 to 300). Furthermore, concerning gene-environment interaction, each of the discussed type of control (general population, dyspeptic, spouse and neighbor) has potential advantages and disadvantages. The current data suggests that selection of any type of the aforementioned controls is feasible and seems to be mainly related to the feasibility of recruitment more than the genetic or environmental backgrounds. General population and dyspeptic patients would be equally appropriate for studies on familial aggregation of gastric cancer. Nevertheless, high-quality cohort studies are needed to validate this assumption.

Chronic liver disease and cirrhosis among patients with hepatitis B virus infection in northern Portugal with reference to the viral genotypes.

The prevalence of infection with hepatitis B virus in Portugal is around 1% of the population; 20-30% of those infected typically develop cirrhosis. The study focuses on the epidemiological profile of patients with hepatitis B infection and liver damage, in particular, cirrhosis. Of the 358 individuals that comprised the study, a liver biopsy was performed in 249 to identify the presence of cirrhosis. Cirrhosis was observed in 59 patients (23.7%) The Child-Pugh classification was used to assess the prognosis of cirrhosis: 3 out of the 59 patients were classified as Child-Pugh grade C, the most severe, 17 (28.8%) as grade B, and 39 (66.2%) as grade A. Patients classified as grade B were older, drank more, and showed higher levels of AST and alkaline phosphatase when compared with individuals classified as grade A. Genotypes A and D were predominant, and no significant differences with respect to genotype distribution were observed. Analysis of the hematological parameters showed that patients classified as Child's grade B had lower levels of platelets and higher levels of prothrombin time than those classified as Child's grade A. The profile of the patients with cirrhosis, including an extended number of individual characteristics, provides useful information, however, only a prospective study could evaluate definitively if liver disease is influenced by these factors. Future studies would benefit from the analysis of the impact of genotypes on liver disease, particularly genotypes A and D, the most predominant genotypes in northern Portugal.

[Hepatitis B genotype distribution in Portugal and worldwide]. / A expressão genotípica do vírus da hepatite B em portugal e no mundo.

INTRODUCTION: Infection with Hepatitis B is a public health problem worldwide. In Portugal, around 1% of the population is chronically infected. Some genotypes are only predominant in some geographical regions; however migration around the world can lead to the dissemination of the different genotypes. The heterogeneity of hepatitis B genotypes seems to be related to differences in clinical evolution of the infection and response to antiviral treatment. AIM: The present study was designed to review the worldwide geographical distribution of Hepatitis B genotypes, and to analyze the possible relationships with the distribution of genotypes in Portugal. METHODS: Studies of interest were identified by search on indexed journals. Search of Portuguese information was extended to conference proceedings in the areas of Virology and Hepatology. RESULTS: In Asia genotypes B and C were prevalent; in the North of Africa the genotype D was prevalent, and in the East Coast genotype E was predominant. In the American continent the most predominant genotypes were A, D, F, G and H. In South America, Venezuela and Argentina showed a high prevalence of genotype F, in Brazil genotype A was prevalent. In Europe, including Portugal, genotypes A and D were predominant. In Portugal genotypes C, E and F were observed in Portuguese patients and in immigrant patients. DISCUSSION: The pattern of global migration affects the pattern of genotype distribution, introducing genotypes in regions where the clinical outcome can differ from the population of origin. The genotypic distribution found in Portugal seems to be associated not just with being a European country, but also with immigration from Africa, Brazil, Eastern Europe, and Asian countries like China. The study of the hepatitis B genotypic distribution should be extended to all regions in Portugal, namely Lisbon where the immigration levels are higher, as well as to the autonomous regions of Portugal, the Azores and Madeira islands. The relationship between hepatitis B genotypes and pathogenicity remains largely unknown, however evidence suggests the clinical and public health relevance of these genotypes. Further research is needed, not only to know how genotypes affect the severity of liver disease, but also to understand if and how the response to treatments is influenced by hepatitis B virus genotype.

Perfil epidemiológico e genotípico da infecção pelo vírus da hepatite B no Norte de Portugal / Perfil epidemiológico y genotípico de la infección por el virus de la hepatitis B en el Norte de Portugal / Epidemiological and genotypic profile of hepatitis B virus infection in Northern Portugal

OBJECTIVO: Descrever o perfil epidemiológico e genotípico da infecção crônica pelo vírus da hepatite B na Região Norte de Portugal. MÉTODOS: Foram incluídos 358 indivíduos oriundos das consultas de especialidade que apresentavam resultados positivos para o antígeno da hepatite B durante pelo menos seis meses em dois hospitais do Norte de Portugal em 2008 e 2009. Os dados foram obtidos a partir dos processos clínicos, determinações laboratoriais feitas quando da genotipagem do vírus, ecografia e/ou ultra-sonografia e biópsia hepática. As características demográficas, marcadores víricos, carga viral e genótipos, e severidade da doença hepática foram avaliadas e comparadas entre sexos. RESULTADOS: Os genótipos A e D predominaram. A transmissão intrafamiliar ocorreu predominantemente nas mulheres. Um terço das mulheres apresentava ingestão alcoólica superior a 20 g/dia, aumentando para 58,9 por cento nos homens. A ausência do AgHBe foi semelhante nos dois sexos (p = 0,662). Os parâmetros bioquímicos em geral apresentaram-se com valores mais altos nos homens, assim como nos estágios necro-inflamatório e de esteatose hepática (p = 0,003). CONCLUSÕES: As diferenças relativas às vias de transmissão da infecção pelo vírus da hepatite B entre homens e mulheres podem ser conseqüência de comportamentos de risco associadas ao género. A ingestão excessiva de álcool é predominante nos indivíduos do sexo masculino, assim como maior severidade da doença hepática em relação às mulheres.

OBJETIVO: Describir el perfil epidemiológico y genotípico de la infección crónica por el virus de la hepatitis B en la Región Norte de Portugal. MÉTODOS: Se incluyeron 358 individuos oriundos de las consultas de especialidad que presentaban resultados positivos para el antígeno de la hepatitis B durante por lo menos seis meses en dos hospitales del Norte de Portugal en 2008 y 2009. Los datos fueron obtenidos a partir de los procesos clínicos, determinaciones laboratoriales hechas a partir del genotipaje del virus, ecografía y/o ultrasonografía y biopsia hepática. Las características demográficas, marcadores virales, carga viral y genotipos, y severidad de la enfermedad hepática fueron evaluados y comparados entre sexos. RESULTADOS: Los genotipos A y D predominaron. La transmisión intrafamiliar ocurrió predominantemente en las mujeres. Un tercio de las mujeres presentaba ingestión alcohólica superior a 20g/día, aumentando para 58,9% en los hombres. La ausencia del AgHBe fue semejante en los dos sexos (p=0,662). Los parámetros bioquímicos en general se presentaron con valores más altos en los hombres, así como en las fases necro-inflamatoria y de esteatosis hepática (p=0,003). CONCLUSIONES: Las diferencias relativas a las vías de transmisión de la infección por el virus de la hepatitis B entre hombres y mujeres poden ser consecuencias de comportamientos de riego asociada al género. La ingestión de alcohol excesiva es predominante en los individuos del sexo masculino, así como mayor severidad de la enfermedad hepática con relación a las mujeres.

Epidemiological and genotypic profile of hepatitis B virus infection in Northern Portugal.

OBJECTIVE: To describe the epidemiological and genotypic profile of chronic hepatitis B infection in Northern Portugal. METHODS: This survey comprised 358 subjects with positive serology for hepatitis B antigen for at least six months, recruited from specialist appointments in two hospitals in Northern Portugal between 2008 and 2009. Data were obtained from patient files, laboratory tests performed at the time of viral genotyping, echograms and/or ultrasonogram results, and liver biopsies. Demographic characteristics, viral markers, viral load and genotype, and severity of liver disease were evaluated and compared between sexes. RESULTS: Genotypes A and D were predominant in both sexes. Intrafamilial transmission occurred mostly among female patients. One-third of females and 58,9% of males showed alcohol intake above 20 g/day. Absence of AgHBe was similar in both sexes (p = 0.662). Elevated biochemical parameters and presence of necroinflammatory activity and steatosis in liver biopsies were more frequent among male patients (p=0.003). CONCLUSIONS: Differences in terms of route of HBV infection between men and women may be a consequence of gender-associated risk behaviors. Excessive alcohol intake is more frequent among males than females, as is more severe liver disease.

Alcohol consumption among patients with hepatitis B infection in northern Portugal considering gender and hepatitis B virus genotype differences.

Alcohol abuse is an important public health problem. In Portugal with a population of 10 millions of inhabitants, there are around 10% of alcoholics or excessive alcohol drinkers and 1% of chronically infected patients with hepatitis B virus (HBV). To examine the characteristics of patients with higher levels of alcohol consumption and to investigate the association between alcohol consumption and liver damage a total of 298 chronically infected individuals, with HBV genotyped and submitted to liver biopsy, were classified with Child's grading and separated by habits of alcohol intake, less and greater than 20g/day. No significant differences were observed about genotype but genotypes A and D were predominant in both of them. A higher percentage of males (P<.001) were observed in the group with alcohol intake above 20g/day, as well a lower proportion of patients with HBeAg negativity (P< or =.035). In this group, biochemistry parameters, such as alanine aminotransferase (P=.006), aspartate aminotransferase (P=.001), gamma-glutamyl transferase (P<.001) were elevated in a significantly higher proportion than in the other group. The analysis of hematological parameters showed significantly lower values of platelets (P=.042) and mean corpuscular volume (P<.001) and significantly higher values of prothrombin time (P<.001) in the group with higher levels of alcohol consumption. The characteristics of biopsy (P<.001) and Child-Phug's classification (P=.002) revealed more severe results in this group. Logistic regression showed a positive association between liver damage and alcohol intake, increasing with age. In female patients, a strong positive association between alcohol intake and liver damage was also found (odds ratio: 9.379; 95% confidence interval: 0.859-468.422; P = .037); however, the most severe cases were only observed in women older than 45 years. In patients with HBV infection, alcohol is associated with a more severe liver disease. No evidence was found concerning association with HBV genotype.

Epidemiological study of genotypes of hepatitis B virus in northern Portugal.

While the overall prevalence of hepatitis B virus (HBV) infection in Portugal is around 1%, there are no published studies examining HBV genotypes in this country. This study aimed to survey HBV genotypes in the northern Portugal and to examine the possible associations between genotypes and gender, viral transmission routes, viral markers, viral load, and biochemical tests of liver function. The study sample consists of 340 patients with HBV infection of whom 42.9% were women. Tests were carried out for HBV genotypes and biochemical liver function while demographic information, including alcohol intake, was obtained from the patient files. The results indicate the predominance of genotype D (60.3%) and genotype A (31.5%). Intrafamilial transmission was predominant in female patients, while males were infected in equal proportions by perinatal, sexual, and intrafamilial transmission. Absence of HBeAg was found in a significantly smaller proportion of female patients with genotype D as compared to A (56.6% vs. 82.1%, P = 0.028). High viral load was associated significantly and independently with genotype D and HBeAg. Both alanine and aspartate aminotransferases (ALT and AST) were associated with gender and HBeAg. Thus, genotypes A and D were found to be the most prevalent in the north of Portugal. Patients infected with genotype D had higher levels of HBV DNA. HBeAg was associated with genotype D, viral load, and ALT and AST.

Massive lower gastrointestinal bleeding from idiopathic ileocolonic varix: report of a case.

Idiopathic varices of the entire colon are very rare. We report on a 64-year-old patient with massive lower gastrointestinal hemorrhage from an extensive ileocolonic varix. Diagnosis was established by colonoscopy. The patient underwent an emergency ileocolectomy with satisfactory results. This rare case shows the importance of colonoscopy in the evaluation of patients with lower gastrointestinal hemorrhage and reminds us that sometimes the diagnosis is not what we expect. Recognition of this abnormality is important because varices may be the cause of massive lower gastrointestinal hemorrhage.

Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B.

One year of lamivudine treatment results in increased hepatitis B e antigen (HBeAg) seroconversion and serum hepatitis B virus (HBV) DNA negativity in children with chronic hepatitis B and high serum alanine aminotransferase concentrations. Two hundred seventy-six children who participated in a 1-year randomized, placebo-controlled study of lamivudine were enrolled in a 24-month, open-label extension. Patients were stratified into two groups based on HBeAg status at week 48 of the previous study: 213 HBeAg-positive children were entered into a treatment arm, and 63 HBeAg-negative children were entered into an observation arm to evaluate durability of HBeAg loss. In the treatment arm, 28 of 133 (21%) children previously treated with lamivudine and 23 of 77 (30%) children who previously received placebo achieved the primary end point: virological response (VR) (HBeAg loss and HBV DNA negativity) at month 24. The incidence of YMDD (tyrosine, methionine, aspartate, aspartate) mutations at month 24 was 64% (66/103) in the children previously treated with lamivudine and 49% (34/70) in those previously treated with placebo. The incidence of VR at month 24 was 5% (5/100) for patients with YMDD mutant HBV and 54% (39/72) for patients without. The durability of response in the observation arm was 89% (48/54) at month 24. In conclusion, further clinical response was seen over the 24-month open-label study period in children who had not initially achieved a VR after 12 months of lamivudine treatment. However, the incidence of YMMD mutations increased over time and resulted in lower response rates. VR was maintained in most patients who had initially responded to lamivudine in the first 12 months.

Clinical trial of lamivudine in children with chronic hepatitis B.

BACKGROUND: Lamivudine therapy is effective for chronic hepatitis B infection in adults. We evaluated the efficacy and tolerability of lamivudine as a treatment for chronic infection with hepatitis B virus (HBV) in children. METHODS: Children with chronic hepatitis B were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg per kilogram of body weight; maximum, 100 mg) or placebo once daily for 52 weeks. The primary end point was virologic response (defined by the absence of serum hepatitis B e antigen and serum HBV DNA) at week 52 of treatment. RESULTS: Of the 403 children screened, 191 were randomly assigned to receive lamivudine and 97 to receive placebo. The rate of virologic response at week 52 was higher among children who received lamivudine than among those who received placebo (23 percent vs. 13 percent, P=0.04). Lamivudine therapy was well tolerated and was also associated with higher rates of seroconversion from hepatitis B e antigen to hepatitis B e antibody, normalization of alanine aminotransferase levels, and suppression of HBV DNA. CONCLUSIONS: In children with chronic hepatitis B, 52 weeks of treatment with lamivudine was associated with a significantly higher rate of virologic response than was placebo.