LDL/apo B ratio predict coronary heart disease in Type 2 diabetes independent of ASCVD risk score: A case-cohort study

Background and aimsCoronary heart disease (CHD) is a major mortality risk factor in patients with diabetes. LDL cholesterol (LDL-C) is a major risk factor for the development of atherosclerosis. There is one apolipoprotein B (ApoB) molecule in each LDL particle. We aimed to evaluate the predictive value of the LDL-C/ApoB ratio for CHD in patients with type 2 diabetes (T2D).Methods and resultsIn this case-cohort study (apo)lipoproteins and glycemic indices were measured in 1058 individuals with T2D from February 2002 to March 2019, with a median duration of follow up of 10 years. Of 1058 patients with T2D, coronary heart disease occurred in 242 patients. Increased waist circumference, waist-to-hip ratio, and hemoglobin A1c, low-density lipoprotein cholesterol (LDL-C)/Apolipoprotein B (ApoB) ratio, presence of hypertension and metabolic syndrome, and insulin and statin use were more prevalent among patients with CHD (P < 0.001). Logistic regression analysis showed that an LDL-C/ApoB ratio equal or lower than 1.2 could predict CHD independent of ASCVD risk score [adjusted OR:1.841, CI:1.257–2.698, P < 0.001] when adjusted for multiple confounders. The atherogenic index of plasma (AIP) did not predict CHD.ConclusionThis study showed that LDL-C/ApoB ratio, but not the atherogenic index of plasma, may be considered as an indicator of CHD independent of the ASCVD risk score in patients with T2D. This finding merits further clarification to optimize preventive strategies for CHD.     

Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia

The efficacy of the inhibitors of HMG CoA reductase shows considerable interindividual variation and intense research has focused in the recent years to identify the genetic loci and environmental factors responsible for this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG CoA reductase inhibitor, was conducted in 63 adolescents (47 treated versus 17 controls) with heterozygous FH. The patients were grouped according to known low-density lipoprotein (LDL) receptor gene mutation class. After 6 weeks of treatment with 20 mg/d of simvastatin, the mean reduction in plasma LDL-cholesterol in patients with a receptor-negative mutation (n=33) was 39% whereas, in the receptor-defective mutation group (n=14), it was 31% (P=0.01). Multiple regression analyses showed that there was a significant association between the apo E polymorphism and LDL-cholesterol response to simvastatin only among heterozygotes for a receptor-negative mutation. In subjects carrying a receptor-defective mutation, however, we observed that 51% of the variability in LDL-cholesterol response was explained by variations in the dosage of simvastatin expressed in mg/kg/day (P=0.0028). There was no significant association between LDL-cholesterol response and the dosage of simvastatin among heterozygotes for a receptor-negative mutation. The results of the present study have shown that the contribution of apo E polymorphism and the dosage of simvastatin to the LDL-cholesterol responsiveness is influenced by the nature of the LDL receptor gene mutation.     

冠心病患者对氧磷酯酶1活性与氧化型低密度脂蛋白的关系

目的　探讨冠心病患者血清对氧磷酯酶 1(PON1)活性变化与氧化型低密度脂蛋白 (oxLDL)水平的关系。方法用分光光度法测定 99例冠心病患者 [稳定性心绞痛 (SAP) 35例 ,不稳定性心绞痛 (UAP) 30例 ,急性心肌梗死 (AMI)34例 ]和 4 2例健康体检者 (对照组 )血清PON1活性 ,用酶联免疫吸附法测定血浆oxLDL水平。同时用直线相关分析法分析PON1活性和oxLDL水平的相关性。结果　冠心病组血清PON1活性与对照组比较显著下降 ,而血浆oxLDL水平与对照组比较显著增加。冠心病组中的SAP、UAP和AMI患者 ,血清PON1活性依次下降 ,而oxLDL浓度依次升高。PON1活性与oxLDL呈显著负相关。结论　冠心病患者存在的PON1活性降低 ,导致抗氧化能力的减弱 ,使血浆oxLDL水平增加 ,这种改变可能与冠心病的发生和发展有关。     

冠心病患者经调脂治疗后血清小而密低密度脂蛋白胆固醇水平的变化

目的探讨冠心病(CHD)患者经调脂治疗后血清小而密低密度脂蛋白胆固醇(sdLDLC)水平变化。方法收集2016年3月至7月同期选取1065例CHD患者及469名健康对照者血液标本。直接测定法检测血清低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDLC)及sdLDLC水平,酶法检测血清甘油三酯(TG)、总胆固醇(TC)水平。建立健康对照组参考区间。根据CHD患者经调脂治疗后血清LDLC水平,确定调脂后LDLC达标组和强化调脂后LDLC达标组。比较各组血脂指标,分析比较sdLDLC水平和sdLDLC/LDLC比值的变化。结果 (1)调脂治疗后CHD组与健康对照组比较,TG、HDLC、sdLDLC/LDLC比值两组差异有统计学意义(P0.05),TC、LDLC及sdLDLC水平两组差异无统计学意义(P0.05)。(2)调脂LDLC达标组与健康对照组比较,sdLDLC/LDLC比值增高(P0.05),sdLDLC水平两组差异无统计学意义(P0.05);调脂达标者中有2.3%CHD患者sdLDLC水平和7.7%CHD患者sdLDLC/LDLC比值高于本研究建立的参考区间。(3)强化调脂LDLC达标组sdLDLC水平较健康对照组降低(P0.05),sdLDLC/LDLC比值较健康对照组增高(P0.05);强化调脂达标者中有0.8%CHD患者sdLDLC水平和15.3%CHD患者sdLDLC/LDLC比值高于本研究建立的参考区间。结论 CHD患者调脂治疗及强化调脂治疗中血清sdLDLC水平及sdLDLC/LDLC比值的变化,对残存的心血管事件风险分析具有重要意义;降低sdLDLC水平可能是最终降低CHD发生风险的重要指标之一。     

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.     

Age-related changes in plasma lipid levels and tissue lipoprotein lipase activities of Fischer-344 rats

Fischer-344 rats of 6, 12, 18, 21 and 24 mth of age were investigated. The data were collected from groups of rats ranging from 5-10 rats per age group. Modest age-related increases were noted in body weight, plasma triglycerides, total cholesterol and free (unesterified) cholesterol. Much more significant changes were noted in tissue lipoprotein lipase activities where the adipose tissue lipases declined sharply (r = -0.90, P less than 0.0001; r = -0.86, P less than 0.0001) and the muscle tissue lipases decreased moderately (r = -0.86, P less than 0.0001; r = -0.58, P less than 0.0001) with age. These observed trends suggest that enzymatic parameters, specifically tissue lipoprotein lipase activities, may be considerably more accurate indicators of age-related physiological changes than levels of plasma lipids such as cholesterol and triglyceride.     

Cell adhesion molecules in relation to simvastatin and hormone replacement therapy in coronary artery disease.

AIMS: To assess the effect of simvastatin, hormone replacement therapy and their combination on soluble cell adhesion molecules and plasma lipids, in hypercholesterolaemic post-menopausal women with coronary artery disease. METHODS: We studied 16 post-menopausal women with coronary artery disease and hypercholesterolaemia (total cholesterol >200mg x dl(-1) and LDL cholesterol >130 mg x dl(-1)). We compared simvastatin (20 mg daily) with hormone replacement therapy (0.625 mg conjugated oestrogen and 2.5 mg medroxyprogesterone acetate daily) and their combination, in a randomized, crossover, placebo controlled study. Each treatment period was 8 weeks long with a 4 week washout interval between treatments. Circulating cell adhesion molecules and plasma lipids were evaluated at the end of each treatment period. RESULTS: All three active treatments--simvastatin, hormone replacement therapy and the combination therapy--significantly reduced total and LDL cholesterol, compared to placebo (P<0.001). Only hormone replacement therapy, alone and in combination with simvastatin, significantly decreased lipoprotein(a) when compared to placebo (P<0.05), whereas simvastatin had no significant effect. Likewise, hormone replacement therapy and the combination therapy significantly reduced the intercellular adhesion molecule (ICAM-1) plasma levels (P=0.03 and P=0.02, respectively), while simvastatin, which was superior to hormone replacement therapy in lowering total and LDL cholesterol, did not modify ICAM-1 levels; the combination therapy was not more effective than hormone replacement therapy alone in ICAM-1 reduction. Neither the effect, on any treatment when compared to placebo, of VCAM-1 nor E-selectin levels differed significantly. CONCLUSIONS: Hormone replacement therapy may limit the inflammatory response to injury by modulating the expression of cell adhesion molecules from the endothelial cells, possibly in association with lipoprotein (a) reduction.     

Antibodies to malondialdehyde oxidized low-density lipoproteins predict long term cardiovascular mortality in high risk patients

Aims

Antibodies to oxidized low-density lipoproteins (oxLDLAbs) are detectable in the serum of patients with and without atherosclerosis, but it is unclear if they play a pathogenic or a protective role in atherogenesis or if they are simply a marker of atherosclerosis. Therefore, in a prospective cohort study we investigated if oxLDLAbs titer predicts cardiovascular (CV) events in high-risk coronary artery disease patients.

Methods and results

The titer of IgG antibodies to malondialdehyde modified oxidized low-density lipoproteins was measured in 748 randomly selected patients of the GENICA study who underwent coronary angiography and assessment of incident CV events at follow-up. Patients were classified by oxLDLAbs into a low and a high titer group, corresponding to the first three and the last quartile, respectively. Cardiovascular event-free survival was compared between oxLDLAbs groups by Kaplan–Meier and multivariate technique including propensity score matching analysis. During long-term follow-up (median 7.2 years) CV deaths were observed in 65 patients (11.6%), more commonly in the high than in the low oxLDLAbs group (patients free from CV death 83.1% vs. 89% respectively, p = 0.025). The incidence of CV events was also higher in the former than in latter (event-free survival 69.2% vs. 77.7% respectively, p = 0.030).

Conclusions

An oxLDLAbs titer above the 75th percentile is a marker of LDL oxidation which predicts a worse CV prognosis at long term follow-up in high-risk Caucasian patients referred for coronary angiography.     

HDL-C and triglyceride levels: relationship to coronary heart disease and treatment with statins

The association between low-density lipoprotein cholesterol (LDL-C) levels and risk of coronary heart disease (CHD) is well established and LDL-C-lowering is currently the primary target for the treatment of dyslipidemia. However, low levels of high-density lipoprotein cholesterol (HDL-C), and high levels of triglycerides (TG) are also risk factors for CHD and modifying levels of these lipid subfractions, in addition to LDL-C lowering, may have clinical benefits in many patients.Statins are the first-line drug therapy for the treatment of dyslipidemia because of their efficacy in lowering LDL-C and good tolerability. Statins also have beneficial effects on TG and HDL-C levels although they differ in the degree to which they modify the levels of these lipoproteins. Improvements across the atherogenic components of the lipid profile may be optimized by the co-administration of a statin with a fibrate, niacin or omega-3 fatty acids; however, particular combination therapies have been associated with side effects and may be poorly tolerated. Newer combinations with better tolerability, or new statins with improved efficacy on non-LDL-C lipid subfractions, would be welcome additions to the currently available therapies for the treatment of dyslipidemia.     

Vitamin D levels: its relationship to bone mineral density response and disease activity in premenopausal Malaysian systemic lupus erythematosus patients on corticosteroids

Aim: To determine if baseline vitamin D levels would influence the gain in bone mineral density (BMD) in female systemic lupus erythematosus (SLE) patients on corticosteroids (CS) taking bone‐active medication. Method: Premenopausal SLE patients participating in a trial assessing the efficacy of calcium alone, calcitriol and calcium, and alendronate and calcium, on BMD in patients on CS, were studied. Patients were randomly allocated to the treatment groups at the start of the study and followed up for 2 years. Serum 25‐hydroxy vitamin D [25(OH)D] was measured at baseline. Results: Thirty‐eight patients were studied. One (2%) patient had osteoporosis, nine (24%) had osteopenia and all others had normal BMD. The mean baseline 25(OH)D levels were 21.6 ± 4.6 ng/mL (± 1 SD). Twelve (32%) patients had vitamin D deficiency [25(OH)D < 20 ng/mL]. There was a significant negative correlation between SLEDAI scores and 25(OH)D levels, that is, patients with high SLEDAI scores had significantly lower 25(OH)D levels (P = 0.033). Left femoral neck BMD was significantly lower in the deficient compared to insufficient group (P = 0.042). There was a trend toward better BMD gain at 2 years in the vitamin D insufficient compared to the deficient group, which did not reach statistical significance. Conclusion: This study showed that in female SLE patients, low vitamin D levels are associated with higher disease activity and suggests that patients who have higher vitamin D levels have a better BMD response during treatment with bone‐active agents.     

Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER

Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLR C44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCR i18 T > G, MAF 0.019) gene loci with baseline lipid values, statin-induced LDL-cholesterol (C) lowering response, and incident coronary heart disease (CHD) and cardiovascular disease (CVD) on trial. Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors, who were randomly allocated to pravastatin or placebo. Other risk factors and apolipoprotein (apo) E phenotype were controlled for in the analysis. Despite a prior report, no relationships with the HMGCR SNP were noted. For the LDLR SNPs C44857T and A44964G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels, a modest association of the C44857T with LDL-C lowering to pravastatin in men, and significant associations with incident CHD and CVD of both SNPs, especially in men on pravastatin. Our data indicate that genetic variation at the LDLR locus can affect baseline lipids, response to pravastatin, and CVD risk in subjects placed on statin treatment.     

Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection

Summary. Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s‐B12) on end‐of‐treatment response (ETR) in patients with chronic HCV. Ninety‐nine treatment naïve HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s‐B12) was analysed in samples collected before treatment start. Pretreatment s‐B12 levels were correlated to ETR using univariate analysis. S‐B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s‐B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s‐B12 levels ≤ 360 pm , 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s‐B12 > 360 pm , one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s‐B12 > 360 vs≤360 pm : OR 28.6 CI 2.31–354, P = 0.008. Fibrosis stage 3–4 vs 0–2: OR 0.29 CI 0.074–1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87–83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048–0.91 P = 0.034. Standard interferon vs pegylated‐interferon: OR 0.079, CI 0.0091–0.68 P = 0.019. Age and gender were not correlated to ETR. S‐B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti‐HCV treatment.     

Predictive value of aminotransferase and hepatitis B virus DNA levels on response to interferon therapy for chronic hepatitis B

In a previously reported randomized controlled trial of interferon-α (IFN-α) for chronic hepatitis B, we found a significant difference in response between Chinese adults with elevated vs normal pretreatment aminotransferase (ALT) levels. The aim of this study was to determine the correlation between serum hepatitis B virus (HBV) DNA levels and response to IFN therapy. HBV DNA levels in residual stored sera from patients who participated in the above trial were quantified by a branched DNA (bDNA) assay. Nominal logistic regression was used to estimate the probability of response to IFN treatment as a function of pretreatment ALT and/or HBV DNA levels. We found a significant ( P <0.01) correlation between the HBV DNA levels at midtreatment and response to IFN therapy. Response was achieved in 53% of patients who had undetectable HBV DNA levels at midtreatment but in only 17% of those who remained HBV DNA positive ( P <0.01). In contrast, the probabilities of response for patients with baseline HBV DNA levels over the range 10 to 10000 million equivalents (MEq)ml^–1 were almost identical. We also found a significant correlation between the pretreatment ALT levels and response to IFN therapy. The probabilities of response for patients with pretreatment ALT levels of 500 and 100IUl^–1 were higher than for patients with normal ALT levels by two and onefold, respectively. Our findings may help to improve the cost-effectiveness of IFN therapy for chronic hepatitis B by guiding the selection of patients for therapy and in optimizing the duration of treatment for the individual patient.     

Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy

SUMMARY: Phylogenetic analysis has led to the classification of hepatitis B virus into eight genotypes, designated A to H. The genotypes have differences in biological properties and show heterogeneity in their global distribution. These attributes of the genotypes may account not only for differences in the prevalence of hepatitis B virus mutants in various geographic regions, but also be responsible for differences in the clinical outcome and response to antiviral treatment in different population groups.     

单核细胞/高密度脂蛋白胆固醇比值与绝经后女性冠心病患者急性心力衰竭的关系

目的 探讨入院时基线水平单核细胞/高密度脂蛋白胆固醇比值(MHR)与绝经后女性冠心病患者住院期间发生急性心力衰竭(AHF)的关系。方法 入组2014年12月—2016年7月在汕头市中心医院接受冠状动脉造影术确诊为冠心病的绝经后女性180例,根据住院期间是否出现AHF分为两组:AHF组(n＝55)和对照组(n＝125)。采用Logistic回归分析MHR与AHF的关系。结果 AHF组MHR水平[0.48(0.1,0.61)]比对照组[0.35(0.3,0.44)]升高(P＝0.005)。Spearman相关分析显示MHR与左心室射血分数(LVEF)呈负相关(r＝－0.304,P＝0.001)。校正年龄后,MHR与LVEF仍呈负相关(r＝－0.215,P＝0.005)。MHR预测绝经后女性冠心病患者住院期间发生AHF的最佳截点是0.367 7(特异度70.6%,灵敏度59.8%,曲线下面积0.646,标准误0.048,P＝0.003,95%CI 0.551~0.740)。多因素Logistic回归分析显示绝经后女性冠心病患者住院期间发生AHF的独立危险因素包括MHR(OR 2.0,5%CI 1.141~5.743,P＝0.023)、糖尿病(OR 2.245,95%CI 1.012~4.977,P＝0.047)、脑钠肽(OR 5.518,95%CI 2.140~14.226,P＜0.001)和血清肌酐(OR 1.014,95%CI 1.001~1.026,P＝0.032)。结论 MHR是绝经后女性冠心病患者住院期间发生AHF的独立预测因子。     

Adiponectin levels among patients with chronic hepatitis B and C infections and in response to IFN-alpha therapy.

AIMS: The study was designed to survey the change of adiponectin levels before and after interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis B and C infections. METHODS: Twenty-one biopsy-proved patients with chronic hepatitis B (10 cases) and hepatitis C (11 cases) were given IFN-alpha for a total of 24 weeks. Fasting plasma glucose, insulin and adiponectin levels were obtained before and 12 weeks after completion of IFN-alpha therapy. Insulin suppression test was conducted before and within 1 week after IFN-alpha therapy. RESULTS: The change of adiponectin levels differed significantly between responders (eight cases) and non-responders (13 cases) to IFN-alpha treatment (-4.8+/-2.2 vs. 0.5+/-1.0 microg/ml, P=0.03). After adjusting for age, gender and change in body mass index, the study found the change of adiponectin levels still significantly related to the response to IFN-alpha (P=0.04). When hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected patients were separately analyzed, the adiponectin levels reported a trend to decrease in HCV responders (11.9+/-3.2 vs. 10.8+/-3.0 microg/ml, P=0.02, n=4) and HBV responders (17.7+/-4.1 vs. 9.2+/-1.0 microg/ml, P=0.10, n=4). In addition, a significant decrease of steady-state plasma glucose in insulin suppression test was noted in responders (13.6+/-1.8-11.7+/-1.2 mmol/l, P=0.03), but not in non-responders (12.3+/-1.1-11.0+/-1.0 mmol/l, P=0.20), after IFN-alpha therapy. CONCLUSIONS: IFN-alpha resulted in a decrease of serum adiponectin levels but an improvement of insulin resistance in responders to the treatment. The result contradicts previous concept of the relationship between insulin resistance and adiponectin levels. Whether and how the augmented immune response, which was supposed to result from the disappearance or the profound down-regulation of the virus or viral antigens in responders to IFN-alpha treatment, contributes to the lowering of adiponectin levels needs to be further investigated.     

急性冠状动脉综合征患者基线C反应蛋白和低密度脂蛋白水平对其急性期预后的意义

目的分析基线高敏C反应蛋白（hs—CRP）和低密度脂蛋白胆固醇（LDL—C）水平与不同急性冠状动脉综合征（ACS）急性期预后的相关性及意义。方法连续入选172例ACS患者,入院24h内测定患者基线状态的hs—CRP和LDL—C水平,对所有患者随访30d,记录任何原因死亡、心血管事件（事件）发生次数和时间。按出现死亡、事件和无事件对患者进行分组,分析和比较三组患者基线hs—CRP、LDL～C和hs—CRP／LDL—C。应用Logistic回归分析包括年龄,治疗前、后血肌酐（Cr）水平等共19项危险因素对死亡率和事件发生率的影响。结果单因素分析显示,三组ACS患者基线LDL—C水平差异无统计学意义,死亡患者的LDL—C有更低的倾向。死亡患者的hs—CRP是无“事件”患者的13．0倍,是单纯有“事件”患者的5．5倍,差异有统计学意义。结论基线hs—CRP是ACS患者急性期死亡和心血管事件的非独立危险因素,基线LDL—C与急性预后不相关。hs—CRP可作为急性期治疗的靶目标。     

Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia

Objectives

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH.

Methods

For 14 ± 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class.

Results

The frequencies of the types of LDLR mutations were: null-mutation (n = 40, 25.6%), defective-mutation (n = 59, 37.8%), and without an identified mutation (n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 ± 1.9 mmol/L, 7.9 ± 1.7 mmol/L), compared to those with a defective (8.9 ± 2.2 mmol/L, 7.0 ± 2.0 mmol/L), or no mutation (7.9 ± 1.9 mmol/L, 5.8 ± 1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) (p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41–58.16, p = 0.02).

Conclusions

Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation.     

The optimal threshold: Baseline serum hepatitis B virus DNA and alanine transaminase levels can predict the 2-Year on-treatment virological response to lamivudine

Background

HBV is still a worldwide health problem. Annually about 0.5-1.2 million patients die of HBV-related diseases such as liver cirrhosis and hepatocellular carcinoma. Lamivudine (LAM) is the first nucleoside analog used in the treatment of chronic hepatitis B. As LAM has been clinically used for a long time, increasing clinical experience has been achieved showing that the resistance mutation rate is relatively high. Numerous studies have also focused on the predictive factors of long-term efficacy of LAM treatment.

Objectives

To determine the optimal cutoff values of baseline hepatitis B virus (HBV) DNA and alanine transaminase (ALT) levels as predictors for the long-term efficacy of LAM treatment in patients with chronic hepatitis B.

Patients and Methods

A total of 163 HBeAg-positive chronic hepatitis B patients receiving LAM treatment were recruited into the present study. Logistic regression analysis was performed to find out the independent predictors of 2-year on-treatment virological response among the baseline parameters. The receiver operating characteristic (ROC) curve was used to evaluate the optimal cutoff values of these independent predictors. The accuracy of the prediction was assessed using the area under curve (AUC) and optimal cutoff values were determined through maximizing the Youden''s index.

Results

After 2 years of LAM treatment, undetectable HBV DNA was maintained in 114 (69.9%) patients. LAM-related resistance mutation (YMDD mutation) was detected in 45 (27.6%) patients. Logistic regression analysis indicated that the baseline ALT and HBV DNA levels were the independent predictors of the efficacy. ROC curve analysis suggested the integration parameter derived from the baseline ALT and HBV DNA levels had the maximal predictive value for a 2-year on-treatment virological response. The optimal cutoff values of ALT and HBV DNA were 220 IU/L and 8.2 log10 copies/mL, respectively.

Conclusions

The incidence of LAM-resistant mutations in HBeAg-positive chronic hepatitis B patients may be significantly reduced and long-term efficacy improved when the baseline ALT was greater than 220 IU/L and HBV DNA was less than 8.2 log10 copies/mL.