Bioimpedance analysis of body composition in an international twin cohort.

OBJECTIVE: Multiple twin studies have demonstrated the heritability of anthropometric and metabolic traits. However, assessment of body composition parameters by bioimpedance analysis (BIA) has not been routinely performed in this setting. DESIGN: A cross-sectional study. SETTING: Study subjects were recruited and assessed at twin festivals or at major university hospitals in Italy, Hungary, and the United States to estimate the influence of genetic and environmental components on body composition parameters in a large, wide age range, international twin cohort by using bioelectrical impedance analysis. SUBJECTS: 380 adult twin pairs (230 monozygotic and 150 dizygotic pairs; male:female ratio, 68:32; age years 49.1 ± 15.4; mean ± standard deviation; age range 18-82) were included in the analysis. RESULTS: Heritability was calculated for weight (82%; 95% confidence interval [CI]: 78-85), waist and hip circumferences (74%; 95%CI: 68-79), body fat percentage (74%; 95%CI: 69-79), fat-free mass (74%; 95%CI: 69-79) and body mass index (79%; 95%CI: 74-83). The completely environmental model showed no impact of shared environmental effects on the variance, while unshared environmental effects were estimated as between 18% and 26%. CONCLUSIONS: BIA findings provide additional evidence to the heritability of anthropometric attributes related to obesity and indicate the practical value of this simple method in supporting efforts to prevent obesity-related adverse health events.

Genetic impact dominates over environmental effects in development of carotid artery stiffness: a twin study.

Arterial stiffness is an independent predictor of cardiovascular, cerebrovascular and all-cause mortality. Quantifying the genetic influence on the stiff arterial phenotype allows us to better predict the development of arterial stiffness. In this study, we aimed to determine the heritability of carotid artery stiffness in healthy twins. We studied 98 twin pairs of both sexes. We determined carotid artery stiffness locally using echo tracking and applanation tonometry. We estimated the heritability of stiffness parameters using structural equation modeling. The carotid distensibility coefficient showed the highest heritability (64%, 95% confidence interval 45-77%). The incremental elastic modulus, compliance and stiffness index ß also showed substantial heritability (62%, 61% and 58%, respectively). The remaining 36-42% phenotypic variance was attributed to unshared environmental effects. Genetic influence appears to dominate over environmental factors in the development of carotid artery stiffness. Environmental factors may have an important role in favorably influencing the genetic predisposition for accelerated arterial stiffening.

Association of body mass index with arterial stiffness and blood pressure components: a twin study.

RATIONALE: Obesity, blood pressure and arterial stiffness are heritable traits interconnected to each other but their possible common genetic and environmental etiologies are unknown. METHODS: We studied 228 monozygotic and 150 dizygotic twin pairs aged 18-82 years from Italy, Hungary and the United States, of which 45 monozygotic and 38 dizygotic pairs were discordant for body mass index (BMI; intrapair difference (Δ) in BMI ≥ 3 kg/m(2)). Blood pressure components and arterial stiffness were measured by TensioMed Arteriograph. RESULTS: Hypertension was more prevalent among obese than non-obese individuals (55% vs. 29%, p < 0.001). Age-, sex- and country-adjusted heritability estimates were high for hemodynamic measures (45%-58%) and BMI (78%). According to bivariate Cholesky decomposition, phenotypic correlations between BMI and blood pressure components (r = -0.15 to 0.24, p < 0.05) were largely explained by additive genetic factors (65%-77%) with the remaining explained by the unique environment. When controlling for genetic factors within all monozygotic pairs, ΔBMI was significantly correlated with Δbrachial systolic blood pressure (SBP) and diastolic blood pressure (DBP), Δmean arterial pressure, and Δaortic SBP (r = 0.15-0.17, p < 0.05). For the same measures, heavier co-twins of BMI-discordant monozygotic pairs had significantly higher values than their leaner counterparts (p < 0.05). CONCLUSION: Blood pressure components are moderately correlated with BMI, largely because of shared genetic factors. However, for the association of BMI with brachial SBP and DBP, aortic SBP and mean arterial pressure, acquired, modifiable factors were also found to be important.

Genetic influence on the relation between exhaled nitric oxide and pulse wave reflection.

Nitric oxide has an important role in the development of the structure and function of the airways and vessel walls. Fractional exhaled nitric oxide (FE(NO)) is inversely related to the markers and risk factors of atherosclerosis. We aimed to estimate the relative contribution of genes and shared and non-shared environmental influences to variations and covariation of FE(NO) levels and the marker of elasticity function of arteries. Adult Caucasian twin pairs (n = 117) were recruited in Hungary, Italy and in the United States (83 monozygotic and 34 dizygotic pairs; age: 48 ± 16 SD years). FE(NO) was measured by an electrochemical sensor-based device. Pulse wave reflection (aortic augmentation index, Aix(ao)) was determined by an oscillometric method (Arteriograph). A bivariate Cholesky decomposition model was applied to investigate whether the heritabilities of FE(NO) and Aix(ao) were linked. Genetic effects accounted for 58% (95% confidence interval (CI): 42%, 71%) of the variation in FE(NO) with the remaining 42% (95%CI: 29%, 58%) due to non-shared environmental influences. A modest negative correlation was observed between FE(NO) and Aix(ao) (r = -0.17; 95%CI:-0.32,-0.02). FE(NO) showed a significant negative genetic correlation with Aix(ao) (r(g) = -0.25; 95%CI:-0.46,-0.02). Thus in humans, variations in FE(NO) are explained both by genetic and non-shared environmental effects. Covariance between FE(NO) and Aix(ao) is explained entirely by shared genetic factors. This is consistent with an overlap among the sets of genes involved in the expression of these phenotypes and provides a basis for further genetic studies on cardiovascular and respiratory diseases.

Evidence for a strong genetic influence on carotid plaque characteristics: an international twin study.

BACKGROUND AND PURPOSE: Few family studies reported moderate genetic impact on the presence and scores of carotid plaques. However, the heritability of carotid plaque characteristics remains still unclear. Twin studies more reliably estimate the relative contribution of genes to these traits in contrast to family study design. METHODS: One hundred ninety-two monozygotic and 83 dizygotic adult twin pairs (age 49±15 years) from Italy, Hungary, and the United States underwent B-mode and color Doppler ultrasound of bilateral common, internal, and external carotid arteries. RESULTS: Age-, sex-, and country-adjusted heritability was 78% for the presence of carotid plaque (95% CI, 55%-90%), 74% for plaque echogenicity (hypoechoic, hyperechoic, or mixed; 95% CI, 38%-87%), 69% for plaque size (area in mm2 in longitudinal plane; 50 percentile; 95% CI, 16%-86%), 74% for plaque sidedness (unilateral or bilateral; 95% CI, 25%-90%), 74% for plaque numerosity (95% CI, 26%-86%), 68% (95% CI, 40%-84%), and 66% (95% CI, 32%-90%) for the presence of plaque in carotid bulbs and proximal internal carotid arteries. No role of shared environmental factors was found. Unique environmental factors were responsible for the remaining variance (22%-34%). Controlling for relevant covariates did not change the results significantly. CONCLUSIONS: The heritability of ultrasound characteristics of carotid plaque is high. Unshared environmental effects account for a modest portion of the variance. Our findings should stimulate the search for genes responsible for these traits.

Heritability of central blood pressure and arterial stiffness: a twin study.

OBJECTIVE: Central blood pressure and aortic stiffness have been consistently reported as strong cardiovascular risk factors. Twin studies by comparing identical with nonidentical twins produce information on the relative contribution of genes and environment. METHODS: One hundred and fifty-four monozygotic (MZ) and 42 dizygotic (DZ) twin pairs (age 43 ± 17 years) from Hungary and the United States underwent brachial and central augmentation index (AIx), brachial and central pressure, and aortic pulse wave velocity (PWV) measurements with the invasively validated Arteriograph device. Bivariate Cholesky decomposition models were applied. RESULTS: Age-adjusted, sex-adjusted and country-adjusted heritability was 60.0% for central SBP [95% confidence interval (CI), 44.8-69.6%], 50.1% for aortic PWV (95%CI, 26.0-66.8%), 48.7% for aortic AIx (95%CI, 1.7-74.0%), 46.8% for brachial AIx (95%CI, 1.1-73.8%), 46.7% for central pulse pressure (PP) (95%CI, 12.4-61.4%), and 30.0% for brachial PP (95%CI, 0.0-53.4%). Central SBP and PP had strong bivariate correlations with brachial (r = 0.461 and 0.425) and central AIx (r = 0.457 and 0.419), as well as with aortic PWV (r = 0.341 and 0.292, all P < 0.001). Brachial PP had a weak correlation with brachial AIx (r = -0.118, P < 0.05), central AIx (r = -0.122, P < 0.05), and none with aortic PWV (r = 0.08, P = n.s.). Genetic factors explained a moderate phenotypic correlation between central PP, SBP, brachial SBP and aortic PWV. CONCLUSIONS: Central systolic and PPs, brachial PP, AIx, aortic PWV are moderately heritable. A moderate genetic covariance among aortic PWV and central PP, central SBP and brachial SBP was found.

Heritability of non-alcoholic fatty liver disease and association with abnormal vascular parameters: a twin study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been linked to increased cardiovascular morbidity. However, genetic factors have an unclear role in this condition. AIMS: To analyse heritability of NAFLD and its association with abnormal vascular parameters in a large twin cohort. METHODS: Anthropometric and lipid metabolic parameters were obtained from 208 adult Hungarian twins (63 monozygotic and 41 dizygotic pairs; 58 men and 150 women; age 43.7 ± 16.7 years). B-mode ultrasonography was performed to detect steatosis and categorize severity. Brachial and aortic augmentation indices and aortic pulse wave velocity were assessed using oscillometry (TensioMed Arteriograph). Carotid intima media thickness (IMT) was measured using ultrasonography on the proximal common, distal common and internal carotid arteries. RESULTS: NAFLD was identified in 47 subjects (22.6%), of which 44 (93.6%) had mild and 3 (6.4%) had moderate steatosis. These subjects were older (age: 50.9 ± 14.3 vs. 41.5 ± 16.7 years, P < 0.001) and had a higher body mass index (BMI; 30.1 ± 5.2 vs. 24.6 ± 4.1 km/m(2) , P < 0.001) than non-NAFLD twins. Based on 91 same-sex twin pairs, heritability analysis indicated no discernible role for genetic components in the presence of NAFLD (95% confidence interval, 0.0-36.0%), while shared and unshared environmental effects accounted for 74.2% and 25.8% of variations adjusted for age and BMI. Augmentation indices and carotid IMT in twins with NAFLD were increased at most examined locations (P < 0.05-P < 0.001). CONCLUSION: These findings do not support heritability of NAFLD, although it coexists with vascular parameters linked to increased cardiovascular risk, underscoring the importance and value of prevention in this very common disorder.

Effect of genetic and environmental influences on cardiometabolic risk factors: a twin study.

BACKGROUND: Both genetic and environmental factors play a role in the pathogenesis of type 2 diabetes and cardiovascular diseases. The magnitude of genetic and environmental influences may vary in different populations and can be investigated by twin studies. METHODS: In this cross-sectional study, 101 (63 monozygotic and 38 dizygotic) adult twin pairs (n = 202; mean age: 44.3 ± 15.8 years) were investigated. Past medical history was recorded and physical examination was performed. Fasting venous blood samples were taken for measuring laboratory parameters. For assessing heritability of 14 cardiovascular risk factors, the structural equation (A-C-E) model was used. RESULTS: The following risk factors were highly (> 70.0%) or moderately (50.0 - 69.0%) heritable: weight (88.1%), waist circumference (71.0%), systolic blood pressure (57.1%), diastolic blood pressure (57.7%), serum creatinine (64.1%), fibrinogen (59.9%), and serum C-reactive protein (51.9%). On the other hand, shared and unique environmental influences had the highest proportion of total phenotypic variance in serum total cholesterol (46.8% and 53.2%), serum HDL-cholesterol (58.1% and 14.9%), triglycerides (0.0% and 55.9%), fasting blood glucose (57.1% and 42.9%), fasting insulin (45.4% and 54.5%), serum uric acid (46.0% and 31.3%), and serum homocysteine (71.8% and 28.2%, respectively). CONCLUSION: Some cardiometabolic risk factors have strong heritability while others are substantially influenced by environmental factors. Understanding the special heritability characteristics of a particular risk factor can substantiate further investigations, especially in molecular genetics. Moreover, identifying genetic and environmental contribution to certain cardiometabolic risk factors can help in designing prevention and treatment strategies in the population investigated.

Reversible autonomic dysfunction during antiviral treatment in patients with chronic hepatitis C virus infection: Anti-HCV therapy and autonomic function.

BACKGROUND: The first clinical sign of chronic hepatitis C virus (HCV) infection can be one of the various extrahepatic manifestations. During antiviral treatment, symptoms of HCV-associated neuropathies usually improve, but can also worsen and lead to discontinuation of anti-HCV therapy. Recently, we have reported autonomic dysfunction in patients with HCV infection. OBJECTIVES: In the present prospective study, we analyzed the changes of autonomic function during anti-HCV treatment. PATIENTS AND METHODS: Cardiovagal autonomic function was assessed in 22 HCV RNA-positive, treatment-naive patients by determining heart rate variability (HRV) and baroreflex sensitivity (BRS), at the beginning of treatment and 12, 24 and 48 weeks of antiviral therapy. interferon alfa-2 and ribavirin were given according to the guidelines. RESULTS: Both HRV and BRS time and frequency domain indices decreased after 12 weeks of therapy compared to the pre-treatment values; then the mean±SD values increased significantly by week 24 and continued to improve by week 48 of therapy-253.0±156.1 ms before therapy vs 111.6±81.9 at week 12, and 183.4±169.6 at week 24 vs 211.6±149.1 ms at week 48 for low-frequency HRV index; p<0.05 for all comparisons). These changes were independent from the presence of cryoglobulins and from virologic response. CONCLUSIONS: The first rise followed by reversible autonomic dysfunction during antiviral therapy may be caused by the immunomodulatory actions of interferon alfa-2.

[Heritability of the risk factors characteristic for the metabolic syndrome: a twin study]. / A metabolikus szindróma összetevoinek genetikai meghatározottsága: ikervizsgálatok eredményei.

UNLABELLED: Both genetic and environmental factors play role in the pathogenesis of the metabolic syndrome. The magnitude of genetic and environmental influences on the components of metabolic syndrome may vary in different populations. AIMS: The present study was aimed to determine the effects of genetic and environmental factors on risk factors characteristic for the metabolic syndrome. METHODS: A total of 101 (63 monozygotic and 38 dizygotic) adult twin pairs (n=202; mean age: 43.3±15.8 years) were investigated. Medical history was recorded and physical examination was carried out for each subject. Fasting venous blood samples were used for measuring laboratory parameters. The presented estimates include the heritability structural equation (A-C-E) model results. In Model-1, all presented parameters are age- and gender- corrected. In Model-2, parameters were corrected for age, gender, body mass index and waist circumference. RESULTS: Heritability in waist circumference (as well as in other anthropometric parameters such as weight and height) was high (Model-1: 71.0-88.1%). Similarly, genetic factors had the highest proportion of total phenotypic variance in systolic and diastolic blood pressure (Model-2: 57.1% and 57.7%, respectively). Based on the results of Model-2, unique environmental factors dominate alterations in serum triglycerides values (55.9%) while shared environmental factors proved to be substantial in alterations of HDL-cholesterol and fasting blood glucose values (58.1% and 57.1%, respectively). Comparing the results of Model-1 and Model-2, the difference in A-C-E model varied from 0.0% to 17.1%, indicating that only a minor proportion of genetic and environmental influences can be explained by the effects of anthropometric parameters. CONCLUSIONS: Among adult Hungarian healthy people, genetic factors have substantial influence on waist circumference and blood pressure values while environmental factors dominate alterations in serum triglycerides, HDL-cholesterol and fasting blood glucose values. The different heritability of individual risk factors challenges the original unifying concept of the metabolic syndrome. The results may be useful for establishing and implementing primary cardiovascular prevention both at individual and population levels.

Presence of anti-microbial antibodies in liver cirrhosis--a tell-tale sign of compromised immunity?

BACKGROUND: Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn's disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections. METHODOLOGY/PRINCIPAL FINDINGS: Sera of 676 patients with various chronic liver diseases (autoimmune diseases: 266, viral hepatitis C: 124, and liver cirrhosis of different etiology: 286) and 100 controls were assayed for antibodies to Saccharomyces cerevisiae (ASCA) and to antigens derived from two intestinal bacterial isolates (one gram positive, one gram negative, neither is Escherichia coli). In patients with liver cirrhosis, we also prospectively recorded the development of severe episodes of bacterial infection. ASCA and anti-OMP Plus™ antibodies were present in 38.5% and 62.6% of patients with cirrhosis and in 16% and 20% of controls, respectively (p<0.001). Occurrence of these antibodies was more frequent in cases of advanced cirrhosis (according to Child-Pugh and MELD score; p<0.001) or in the presence of ascites (p<0.001). During the median follow-up of 425 days, 81 patients (28.3%) presented with severe bacterial infections. Anti-microbial antibody titers (p = 0.003), as well as multiple seroreactivity (p = 0.036), was associated with infectious events. In logistic regression analysis, the presence of ascites (OR: 1.62, 95%CI: 1.16-2.25), co-morbidities (OR: 2.22, 95%CI: 1.27-3.86), and ASCA positivity (OR: 1.59, 95%CI: 1.07-2.36) were independent risk factors for severe infections. A shorter time period until the first infection was associated with the presence of ASCA (p = 0.03) and multiple seropositivity (p = 0.037) by Kaplan-Meier analysis, and with Child-Pugh stage (p = 0.018, OR: 1.85) and co-morbidities (p<0.001, OR: 2.02) by Cox-regression analysis. CONCLUSIONS/SIGNIFICANCE: The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies.

Mannose-binding lectin deficiency confers risk for bacterial infections in a large Hungarian cohort of patients with liver cirrhosis.

BACKGROUND & AIMS: Mannose-binding lectin (MBL) is a serum lectin synthesized by the liver and involved in innate host defense. MBL deficiency increases the risk of various infectious diseases mostly in immune-deficient conditions. Bacterial infections are a significant cause of morbidity and mortality in liver cirrhosis due to the relative immuncompromised state. METHODS: Sera of 929 patients with various chronic liver diseases [autoimmune liver diseases (ALD), 406; viral hepatitis C (HCV), 185; and liver cirrhosis (LC) with various etiologies, 338] and 296 healthy controls (HC) were assayed for MBL concentration. Furthermore, a follow-up, observational study was conducted to assess MBL level as a risk factor for clinically significant bacterial infections in cirrhotic patients. RESULTS: MBL level and the prevalence of absolute MBL deficiency (<100 ng/ml) was not significantly different between patients and controls (ALD: 14.5%, HCV: 11.9%, LC: 10.7%, HC: 15.6%). In cirrhotic patients, the risk for infection was significantly higher among MBL deficient subjects as compared to non-deficient ones (50.0% vs. 31.8%, p=0.039). In a logistic regression analysis, MBL deficiency was an independent risk factor for infections (OR: 2.14 95% CI: 1.03-4.45, p=0.04) after adjusting for Child-Pugh score, co-morbidities, gender, and age. In a Kaplan-Meier analysis, MBL deficiency was associated with a shorter time to develop the first infectious complication (median days: 579 vs. 944, pBreslow=0.016, pLogRank=0.027) and was identified as an independent predictor in a multivariate Cox-regression analysis (p=0.003, OR: 2.33, 95% CI: 1.34-4.03). CONCLUSIONS: MBL deficiency is associated with a higher probability and shorter time of developing infections in liver cirrhosis, further supporting the impact of the MBL molecule on the host defense.

Sex-dependent alterations in erythrocyte trace element levels and antioxidant status after a month of moderate daily red wine consumption.

OBJECTIVE: We tested the hypothesis whether trace elements and antioxidant status change in a sex-dependent manner may contribute to sex-dependent hepatic effects of moderate daily wine consumption. PATIENT AND METHODS: Twenty-one healthy young men and women were enrolled to this study who consumed red wine 0.3 and 0.2 l per day, respectively, for a month. Blood was taken at baseline (BV) and at end of the study (EV). Red cell trace element levels, red cell and plasma antioxidant status and serum routine blood chemistry were assessed at baseline and at the end of the study. RESULTS: No sign of hepatotoxicity was detected. BV level of some trace elements (i.e. Zn, Pb) and Zn/Cu ratios were higher in women than in men. Ca, Mg, Pb, Sr and Zn levels and the Zn/Cu ratio had lower EV than BV in women. In men, Al, Ca, Li, Pb and Sr levels had lower EV than BV. The tested antioxidant parameters improved in both the sexes. CONCLUSION: Although no hepatotoxicity was observed, changes in trace element content were detected after 1 month of moderate red wine consumption. The most remarkable sex-specific alteration was the decrease of Zn levels and of the Zn/Cu ratio in women. Given the protective effect of Zn against liver damage, this finding suggests a possible contribution of decreased Zn levels to sex-dependent effects of red wine.

[H1N1 influenza - pandemic, 2009]. / H1N1-influenza - pandémia, 2009.

In March, 2009, a novel strain of swine-origin influenza-A H1N1 caused human infection in Mexico, and spread to all regions in the world in the following three months. On June 11, 2009, the World Health Organization declared that a global pandemic of influenza A H1N1 was underway. This action was a reflection of the spread of the new H1N1 virus, not the severity of illness caused by the virus. As of October, 2009, there are about 400,000 confirmed cases and 5000 mortalities due to pandemic H1N1 all over the world. The symptoms are usually mild: fever, cough, sore throat, muscle aches, and they usually disappear spontaneously within 3-7 days. Recommendations suggest staying at home with mild symptoms, and avoiding the contact with other people. In case of warning signs of complications or emergency symptoms, medical care is required, and antiviral treatment, hospitalization might be needed. The most important duty against pandemic H1N1 is prevention, which means first of all the adherence of hygienic rules and the use of vaccination. Based on epidemiologic data and worldwide experiences on influenza vaccination, both seasonal and H1N1 vaccinations are recommended for anyone 6 months of age or older who is at risk of becoming ill or of transmitting the viruses to others. Pregnant women during the first trimester are not recommended for vaccination, due to the lack of experiences. Overall, the rates and seriousness of a possible complication of influenza vaccination are much smaller than the risk of serious complications and mortality of influenza infection.

Chronic hepatitis C virus infection associated with autonomic dysfunction.

BACKGROUND: Impaired autonomic function has been described in patients with chronic liver diseases from different aetiologies, and has proven to be a poor prognostic indicator. To date, it is not known how chronic hepatitis C virus (HCV) infection affects the autonomic nervous system. AIMS: In the present study, we compared cardiovagal autonomic function in patients with chronic HCV infection and healthy controls and examined the relation between autonomic function and serum levels of aminotransferases, HCV RNA, cryoglobulins, albumin and glucose. METHODS: Autonomic function was assessed in 45 treatment-naïve patients with chronic HCV infection and in 40 healthy controls by determining spontaneous baroreflex sensitivity (BRS) and heart rate variability (HRV) indices. The R-R interval was determined by electrocardiogram recording; continuous radial artery pressure was monitored simultaneously by applanation tonometry. Laboratory analyses and quantitative polymerase chain reaction for serum HCV RNA level were performed by standard procedures. RESULTS: BRS and HRV time and frequency domain indices were lower in patients with HCV infection compared with healthy controls [7.1+/-3.4 vs. 11.5+/-6.5 ms/mmHg for BRS, 168.5+/-160.9 vs. 370.7+/-349.4 ms(2) for low-frequency HRV (mean+/-SD); P<0.01]. Multivariate analysis showed that autonomic dysfunction in HCV-infected patients correlated with elevated alanine aminotransferase levels, but was not associated with serum HCV RNA levels and cryoglobulins. CONCLUSION: Our results suggest that impaired autonomic function is caused by chronic HCV infection. Further studies are needed, however, to identify the underlying mechanisms.

ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgeryin Hungarian patients with inflammatory bowel diseases.

OBJECTIVE: MDR1 (ABCB1), a member of the ATP-binding cassette (ABC) transporters, is an attractive candidate gene for the pathogenesis of inflammatory bowel diseases (IBD) and perhaps for response to therapy. Since limited data are available on MDR1 and ABCG2 polymorphisms in East European IBD patients, the aim of this study was to investigate ABCG2 and MDR1 variants and responses to medical therapy and/or disease phenotype in Hungarian patients. MATERIAL AND METHODS: A total of 414 unrelated IBD patients (Crohn's disease (CD): 265, age: 35.2+/-12.1 years, duration: 8.7+/-7.6 years and ulcerative colitis (UC): 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. ABCG2 G34A, C421A and MDR1 C3435T, G2677T/A single nucleotide polymorphisms (SNPs) were detected using real-time polymerase chain reaction (PCR). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The frequency of the ABCG2 and MDR1 SNPs was not significantly different among IBD, CD, UC patients and controls. There was no difference in risk for steroid resistance in CD patients carrying variant ABCG2 (19.6% versus non-carriers 18.4%, p=NS) or MDR1 3435T (CC: 22.2% versus CT/TT: 17.6%) alleles. In addition, carriage of the variant allele was not associated with disease phenotype, presence of extra-intestinal manifestations, smoking, response to infliximab therapy or the need for surgery. In UC, the carriage of variant ABCG2 alleles seemed to be preventive for arthritis (15.5% versus 31.7%, OR: 0.39, 95% CI: 0.16-0.98). CONCLUSIONS: MDR1 and ABCG2 SNPs were not associated with disease susceptibility or disease phenotype in Hungarian patients, and variant alleles did not predict the response to medical therapy or the need for surgery. Further studies are needed to clarify the association between the presence of ABCG2 variants and arthritis in UC.

Common NOD2/CARD15 variants are not associated with susceptibility or the clinicopathologic characteristics of sporadic colorectal cancer in Hungarian patients.

BACKGROUND: Epidemiological observations suggest that cancer arises from chronically inflamed tissues. Inflammatory bowel disease (IBD) is a typical example as patients with longstanding IBD are at an increased risk for developing colorectal cancer (CRC) and mutations of the NOD2/CARD15 gene increase the risk for Crohn's disease (CD). Recently, NOD2/CARD15 has been associated with a risk for CRC in some studies, which stemmed from ethnically diverse populations. Our aim was to identify common NOD2/CARD15 mutations in Hungarian patients with sporadic CRC. METHODS: A total of 194 sporadic CRC patients (m/f: 108/86, age at diagnosis of CRC: 63.2 +/- 9.1 years old) and 200 healthy subjects were included. DNA was screened for SNP8, SNP12 and SNP13 NOD2/CARD15 mutations by denaturing-HPLC and confirmed by direct sequencing. RESULTS: NOD2/CARD15 mutations were found in 28 patients (14.4%) and in 23 controls (11.5%, p = NS). Allele frequencies for SNP8/R702W (1.8% vs. 1.5%) SNP12/G908R (1.8% vs. 1.8%) and SNP13/3020insC (3.6% vs. 2.5%) were also not statistically different between patients and controls. The clinicopathologic characteristics of CRC patients with or without NOD2/CARD15 mutations were not significantly different. CONCLUSION: Our results suggest that common NOD2/CARD15 mutations alone do not contribute to CRC risk in the Hungarian population.

Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease.

BACKGROUND/AIMS: Diagnosis of Wilson's disease may be difficult in patients presenting with liver disease and in asymptomatic siblings. The aim of the present study was to assess the impact of genetic testing for diagnosis of the disease in a large cohort (n=109) from Hungary. PATIENTS/METHODS: One hundred and nine patients with Wilson's disease were studied (65 men and 44 women; mean age at onset of symptoms: 20+/-9 years). Diagnosis of the disease was based on typical clinical and laboratory features (all had a Wilson's disease score of >or=4). H1069Q was assessed by the semi-nested polymerase chain reaction-based restriction fragment length polymorphism assay. H1069Q heterozygotes and H1069Q negative samples were then screened for mutations (on exons 6 to 20) by denaturating high-performance liquid chromatography and than sequenced on a genetic analyser. RESULTS: Twenty-three different mutations were found. H1069Q was the most frequent mutation in Hungary, detected in 77 patients (71%). Fourteen further known mutations were found by sequencing. We identified eight new mis-sense mutations not described before: N676I, S693Y, Y715H, M769L, W939C, P1273S, G1281D and G1341V. In 36/109 patients (33%) the diagnosis of Wilson's disease was established by adding mutational analysis. The Kayser-Fleischer ring was more frequent in H1069Q homozygous patients and their mean age at the time of diagnosis was higher than in patients heterozygous or negative for H1069Q. CONCLUSION: Eight novel mutations in addition to the 15 that are already known were found in Hungarian patients with Wilson's disease. Our results underline the importance and usefulness of genetic testing for patients presenting with liver disease and for family screening.

[Xanthomatosis and extreme hypercholesterolemia after laparoscopic cholecystectomy. Total reversibility following surgical treatment of iatrogenous stenosis of the common bile duct]. / Extrém hypercholesterinaemia es xanthomatosis laparoszkópos cholecystectomia után. Teljes reverzibilitás az iatrogén szukület mutéti megoldását követoen.

INTRODUCTION: Hypercholesterolemia and xanthomatosis are known complications of chronic cholestasis. This is the first report on xanthomatosis and severe hypercholesterolemia caused by common bile duct stenosis following laparoscopic cholecystectomy. CASE REPORT: Laparoscopic cholecystectomy was performed in a 32-year old woman because of numerous tiny gallstones. Bile leakage was observed in the early postoperative period which stopped spontaneously. Six months later itching, progressively increasing serum bilirubin level, cholestasis syndrome, xanthelasma and widespread eruptive xanthomatosis developed in a few months. The cholesterol level was extremely high (92.3 mmol/l), while the triglyceride level was normal. Though the ultrasound and the cholangio-MR did not showed any dilatation of bile ducts, the ERCP verified a 2 mm long, hair's-breadth thin stenosis of choledochus in the level of cystic duct. Primary biliary cirrhosis and primary sclerosing cholangitis were excluded, no evidence for familial hypercholesterolemia was found. Choledochojejunostomy was performed and the patient became complaint- and symptom-free within two months. All xanthomas disappeared, the extremely high cholesterol level gradually decreased to the normal level, and all the laboratory data became normal. The anticholesterol antibody level was undetectable at presentation, but later reached the level of the healthy controls. CONCLUSION: The presented case is an example for laparoscopic cholecystectomy caused bile duct stenosis and for extra-hepatic cholestasis induced xanthomatosis and severe hypercholesterolemia. The bile leakage as early complication of bile duct damage may predict the later developed stenosis. Even severe xanthomatosis and extreme hypercholesterolemia can be totally reversible following elimination of biliary obstacle.