Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year. RESULTS: We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. CONCLUSIONS: Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.

Fatty Acid desaturase gene variants, cardiovascular risk factors, and myocardial infarction in the costa rica study.

Genetic variation in fatty acid desaturases (FADS) has previously been linked to long-chain polyunsaturated fatty acids (PUFAs) in adipose tissue and cardiovascular risk. The goal of our study was to test associations between six common FADS polymorphisms (rs174556, rs3834458, rs174570, rs2524299, rs174589, rs174627), intermediate cardiovascular risk factors, and non-fatal myocardial infarction (MI) in a matched population based case-control study of Costa Rican adults (n = 1756). Generalized linear models and multiple conditional logistic regression models were used to assess the associations of interest. Analyses involving intermediate cardiovascular risk factors and MI were also conducted in two replication cohorts, The Nurses' Health Study (n = 1200) and The Health Professionals Follow-Up Study (n = 1295). In the Costa Rica Study, genetic variation in the FADS cluster was associated with a robust linear decrease in adipose gamma-linolenic, arachidonic, and eicosapentaenoic fatty acids, and significant or borderline significant increases in the eicosadienoic, eicosatrienoic, and dihomo-gamma-linolenic fatty acids. However, the associations with adipose tissue fatty acids did not translate into changes in inflammatory biomarkers, blood lipids, or the risk of MI in the discovery or the replication cohorts. In conclusion, fatty acid desaturase polymorphisms impact long-chain PUFA biosynthesis, but their overall effect on cardiovascular health likely involves multiple pathways and merits further investigation.

Genetic variation in fatty acid elongases is not associated with intermediate cardiovascular phenotypes or myocardial infarction.

BACKGROUND/OBJECTIVES: Elongases 2, 4 and 5, encoded by genes ELOVL2, ELOVL4 and ELOVL5, have a key role in the biosynthesis of very long chain polyunsaturated fatty acids (PUFAs). To date, few studies have investigated the associations between elongase polymorphisms and cardiovascular health. We investigated whether ELOVL polymorphisms are associated with adipose tissue fatty acids, serum lipids, inflammation and ultimately with nonfatal myocardial infarction (MI) in a Costa Rican population. SUBJECTS/METHODS: MI cases (n=1650) were matched to population-based controls (n=1650) on age, sex and area of residence. Generalized linear and multiple conditional logistic regression models were used to assess the associations between seven common ELOVL polymorphisms and cardiometabolic outcomes. Analyses were replicated in The Nurses' Health Study (n=1200) and The Health Professionals Follow-Up Study (n=1295). RESULTS: Variation in ELOVL2, ELOVL4 and ELOVL5 was not associated with adipose tissue fatty acids, intermediate cardiovascular risk factors or MI. In the Costa Rica study, the number of the minor allele copies at rs2294867, located in the ELOVL5 gene, was associated with an increase in total and LDL cholesterol (adjusted P-values=0.001 and <0.0001 respectively). Additionally, the number of the minor allele copies at rs761179, also located in the ELOVL5 gene, was significantly associated with an increase in total cholesterol (adjusted P-value=0.04). However, the observed associations were not replicated in independent populations. CONCLUSION: Common genetic variants in elongases are not associated with adipose tissue fatty acids, serum lipids, biomarkers of systemic inflammation, or the risk of MI.

Association between hepatic lipase -514 C/T promoter polymorphism and myocardial infarction is modified by history of hypercholesterolemia and waist circumference.

BACKGROUND AND AIMS: To examine whether the association between the -514 C/T polymorphism of the hepatic lipase gene and myocardial infarction (MI) is modified by history of hypercholesterolemia and increased waist circumference. METHODS AND RESULTS: A total of 1940 pairs of nonfatal MI cases and population-based controls were genotyped. Multiple conditional logistic regression was used for data analyses. The -514T variant was not associated with MI in the whole population. However, among people with history of hypercholesterolemia the T allele increased MI risk for heterozygous and homozygous carriers, respectively [OR=1.25 (95%CI=0.92-1.70) and OR=1.59 (95%CI=1.09-2.32). In contrast, the T allele decreased MI risk among people with no history of hypercholesterolemia [OR=0.85 (95%CI=0.70-1.03) and OR=0.76 (95%CI=0.60-0.97)], p for interaction=0.004. Among subjects with normal waist circumference there was no association between the -514T allele and MI for heterozygous and homozygous carriers, respectively [OR=1.04 (95%CI=0.86-1.25) and OR=0.96 (95%CI=0.77-1.21)], while among subjects with waist circumference above the limits of the metabolic syndrome definition there was a protective association [OR=0.63 (95%CI=0.45-0.90) and OR=0.81 (95%CI=0.53-1.25) p for interaction=0.04]. CONCLUSION: The -514T allele is associated with MI in opposite directions depending on the background of the studied population. This could explain what seem like inconsistent results across studies.