Dysbetalipoproteinemia: Two cases report and a diagnostic algorithm.

Dysbetalipoproteinemia is a rare familial dyslipidemia characterized by approximately equally elevated serum cholesterol and triglyceride levels due to accumulated remnant lipoproteins in apolipoprotein E2/E2 homozygotes. It is associated with an increased risk for premature cardiovascular disease. Thus, making a diagnosis of dysbetalipoproteinemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up can be challenging. Diagnosis of dysbetalipoproteinemia should be considered in patients mixed dyslipidemia when the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated low density lipoprotein (LDL) and directly measured LDL cholesterol concentrations. Other indices are also informative in the diagnostic process. We present herein two phenotypically different cases (a 44-year-old man with severe hypertriglyceridemia and a 49-year-old woman with mixed dyslipidemia) of genotypically proven familial dysbetalipoproteinemia and a diagnostic algorithm of the disease.

Endothelial dysfunction, but not structural atherosclerosis, is evident early in children with heterozygous familial hypercholesterolemia.

Children with heterozygous familial hypercholesterolemia (heFH) are prone to premature atherosclerosis. Vascular endothelial dysfunction may predict increased cardiovascular risk in children with heFH. The aim of this study was to assess for early functional and structural vascular changes in children with heFH. This cross-sectional study included 30 children with heFH (mean age 12 years) and 30 age- and sex-matched controls. Brachial artery flow-mediated dilation (FMD), carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity, and large- and small vessel compliance were measured noninvasively. HeFH children exhibited significantly greater total and LDL cholesterol, apolipoprotein B, and lipoprotein (a) levels (p < 0.05 for all) and lower FMD (6.23 ± 3.88 vs. 9.46 ± 4.54 %, p < 0.004) compared with controls. When children were divided in age subgroups, FMD was found to be significantly decreased in heFH compared with control subjects only in ages >10 years (p < 0.05). However, FMD was found to be similarly impaired in heFH children in all age subgroups (two-way analysis of variance, p = 0.39). No differences in other vascular function indices were found. In heFH patients, but not in controls, FMD was inversely correlated with cIMT (r = -0.378, p = 0.036). In conclusion, endothelial dysfunction occurs early in heFH children indicating an increased risk for premature cardiovascular disease and reflecting probably the need for early initiation of anticholesterolemic treatment. Decreased FMD is detected before structural atherosclerotic changes occur.

Spectrum of LDLR gene mutations, including a novel mutation causing familial hypercholesterolaemia, in North-western Greece.

BACKGROUND: Familial Hypercholesterolaemia (FH) is a clinical syndrome characterised by elevated serum low-density lipoprotein (LDL) cholesterol, by tendon xanthomata and clinical manifestations of ischaemic heart disease in early life. Typically, it results from mutations in the low-density lipoprotein receptor (LDLR) gene. Furthermore, there are 3 additional genetic disorders that cause clinical syndromes that mimic FH. These are: 1) familial ligand-defective apolipoprotein (apo)-B (FLDH), 2) familial hypercholesterolaemia type 3 (FH3) and 3) autosomal recessive hypercholesterolaemia (ARH). The aim of this study was to elaborate the impact of the above genetic disorders in Greek patients with a clinical diagnosis of FH. METHODS: In this study, we assessed the contribution of the LDLR, Apo B, ARH and PCSK9 genes in the expression of FH in North-western Greece. Two hundred and fifty-four (254) probands with a clinical diagnosis of FH were included in the study. RESULTS: One hundred and sixty-nine (169) patients had one of the following LDLR gene mutations: 81T>G, 1775G>A, 517T>C, 858C>A, 1352T>C, 1285G>A, 761A>C, 1195G>A, 1646G>A and a deletion mutation g.387-410del24 in exon 4. We sequenced the Apo B, ARH and PCSK9 genes in 40, randomly selected patients, from the 85 patients with no identified LDLR gene defects. In these 40, randomly selected patients, with the exception of benign single nucleotide polymorphisms, no functional mutations were identified for all the above mentioned sequenced genes. CONCLUSION: Our results reveal substantial genetic heterogeneity for FH in North-western Greece with at least ten LDLR gene mutations present in the study population. One of these mutations although quite rare is reported here for the first time in the scientific literature. The detection of these mutations is important as they may be used to design multiplex detection assays for large scale population screening programmes to facilitate primary and secondary prevention of cardiovascular disease in the region. Finally, ARH, Apo B and PCSK9 gene defects were excluded from causing FH in a subgroup of the study population indicating that other yet unrecognized genes may be involved in causing the clinical feature of FH, and/or that large scale deletions/duplications evaded the applied mutation detection techniques of this study.

Native valve endocarditis due to Micrococcus luteus: a case report and review of the literature.

INTRODUCTION: Micrococcus luteus endocarditis is a rare case of infective endocarditis. A total of 17 cases of infective endocarditis due to M luteus have been reported in the literature to date, all involving prosthetic valves. To the best of our knowledge, we describe the first case of native aortic valve M luteus endocarditis in an immunosuppressed patient in this report. CASE REPORT: A 74-year-old Greek-Cypriot woman was admitted to our Internal Medicine Clinic due to fever and malaise and the diagnosis of aortic valve M luteus endocarditis was made. She was immunosuppressed due to methotrexate and steroid treatment. Our patient was unsuccessfully treated with vancomycin, gentamicin and rifampicin for four weeks. The aortic valve was replaced and she was discharged in good condition. CONCLUSIONS: Prosthetic infective endocarditis due to M luteus is rare. To the best of our knowledge, we report the first case in the literature involving a native valve.

Characterization of low density lipoprotein receptor (LDLR) gene mutations in Albania.

INTRODUCTION: Familial hypercholesterolaemia (FH) is a clinical syndrome characterised by elevated serum total cholesterol (TCHOL) levels due to an increase in low-density lipoprotein (LDL) cholesterol, by tendon xanthomata and clinical manifestations of ischaemic heart disease in early life. Typically, it results from mutations in the low-density lipoprotein receptor (LDLR) gene. So far, more than 800 mutations have been reported for the LDLR gene and account for FH. The nature of LDLR gene mutations varies among different ethnicities. Until now no mutations of LDLR have been reported in the Albanian population. MATERIAL AND METHODS: We assessed the contribution of the LDLR gene mutations as causes of FH in an Albanian population. Fifty probands with a clinical diagnosis of FH were included. We analysed all the exons and the promoter of the LDLR gene by using restriction isotyping or direct sequencing. RESULTS: Twenty-one patients were heterozygous for the 1646G>A mutation (FH Genoa) in exon 11 and 9 patients were heterozygous for the 81T>C mutation in exon 2 of the LDLR gene. CONCLUSIONS: This report describes two LDLR gene mutations accounting for FH in Albania (1646G>A, 81T>C).

Low HDL cholesterol, smoking and IL-13 R130Q polymorphism are associated with myocardial infarction in Greek Cypriot males. A pilot study.

This study was carried out in Greek Cypriot males to identify risk factors that predispose to myocardial infarction (MI). Genetic and lipid risk factors were investigated for the first time in a Greek Cypriot male case-control study.Contrary to other studies, mean low density lipoprotein cholesterol did not differ between cases and controls. High density lipoprotein cholesterol on the other hand, although within normal range in cases and controls, was significantly higher in the control population. In agreement with many other studies, smoking was significantly more prevalent in cases compared with controls. In pooled cases and controls, smokers had a significantly lower HDL-C level compared with non-smokers. The frequency of the IL-13 R130Q homozygotes for the mutation (QQ), as well as the mutant allele were significantly higher in cases compared with controls. The IL-13 R130Q variant, or another locus, linked to it, may increase the risk of MI.

Causes and mechanisms of acid-base and electrolyte abnormalities in cancer patients.

Patients with cancer frequently exhibit acid-base and electrolyte disturbances that complicate their management and prolong their hospitalization. The mechanisms encountered for these abnormalities are multifactorial in origin. Both the underlying disease and the therapeutic interventions can contribute to the development of these disturbances. An understanding of the mechanisms involved in their pathogenesis is of paramount importance for their prevention and treatment in cancer patients. This article briefly reviews the causes and the pathophysiology of acid-base and electrolyte abnormalities observed in cancer patients.

Effect of paraoxonase 1 polymorphisms on the response of lipids and lipoprotein-associated enzymes to treatment with fluvastatin.

BACKGROUND: Decreased paraoxonase 1 (PON1) and increased total serum lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activities are suggested to be risk factors for vascular disease. Common PON1 genetic polymorphisms (Q192R and L55M) significantly affect PON1 activity and may also influence high-density lipoprotein (HDL)-associated Lp-PLA(2) activity. However, little is known about the possible effect of PON1 common genetic polymorphisms on the response of lipids as well as PON1 and Lp-PLA(2) activities to treatment with statins. METHODS: Two hundred two hypercholesterolemic patients were treated with fluvastatin 40 mg/day. Fasting serum lipids, Q192R and L55M PON1 polymorphisms as well as PON1 and Lp-PLA(2) (total serum and HDL-associated) activities were determined before and after 6 months of treatment. RESULTS: Fluvastatin treatment did not affect HDL-cholesterol or apolipoprotein (apo) AI but resulted in significant decreases in total cholesterol, triglycerides, low-density lipoprotein-cholesterol, apo B and apo E, as well as total serum Lp-PLA(2) activity. In contrast, PON1 activity significantly increased. None of these changes was influenced by Q192R or L55M PON1 polymorphisms. Overall, HDL-Lp-PLA(2) did not change but L55M polymorphism significantly influenced its response to fluvastatin. Specifically, LL homozygotes experienced a significant increase, while M carriers (LM or MM) experienced a non-significant decrease in HDL-Lp-PLA(2) activity (p = 0.030 between groups). CONCLUSIONS: Q192R and L55M PON1 polymorphisms did not affect the response of lipids, PON1 and total serum Lp-PLA(2) to treatment with a statin. However, L55M PON1 polymorphism significantly modulated the response of HDL-Lp-PLA(2). It should be noted that this is an association study and therefore provides no proof but only indication that PON1 may also exert Lp-PLA(2) activity in HDL.

The effect of apolipoprotein E polymorphism on the response to lipid-lowering treatment with atorvastatin or fenofibrate.

Although the effect of apolipoprotein E gene polymorphism on the response to treatment with statins has been studied, the results are conflicting. Moreover, little is known about the possible effect of apolipoprotein E alleles on the response to treatment with fibrates. The purpose of this study was to evaluate the effect of apolipoprotein E polymorphism on lipid-lowering response to treatment with atorvastatin and fenofibrate in patients with different types of dyslipidemia. The study population included 136 patients with heterozygous familial hypercholesterolemia (type IIA dyslipidemia) treated with atorvastatin (20 mg/day) and 136 patients with either primary hypertriglyceridemia (type IV dyslipidemia) or mixed hyperlipidemia (type IIB dyslipidemia) treated with micronized fenofibrate (200 mg/day). Overall, no significant associations were detected between apolipoprotein E genotype and response to treatment with atorvastatin. In patients treated with fenofibrate, significant associations were noted between apolipoprotein E genotype and changes in apolipoprotein B, apolipoprotein E and triglyceride levels. Specifically, in apolipoprotein E2, apolipoprotein E3, and apolipoprotein E4 individuals, apolipoprotein B reductions were 22%, 17%, and 8%, respectively (P = .003); apolipoprotein E reductions were 45%, 20%, and 15%, respectively (P = .006); whereas triglyceride reductions reached 53%, 36%, and 33%, respectively (P = .033). In conclusion, apolipoprotein E genotype had no significant effect on the response to treatment with atorvastatin in patients with heterozygous familial hypercholesterolemia, but in patients with primary hypertriglyceridemia or mixed hyperlipidemia, there was a clear association between apolipoprotein E genotype and response to treatment with fenofibrate.

Plasma lipoprotein(a) levels and LDL-cholesterol lowering response to statin therapy in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is characterised by elevated plasma LDL-cholesterol levels and premature ischemic heart disease. Statin therapy is mandatory in order to prevent atherosclerosis in patients with heterozygous FH. Both genetic and environmental factors affect the statin-induced LDL-cholesterol lowering effect in patients with heterozygous FH. Recently published data suggest that plasma lipoprotein(a) levels may affect the efficacy of statin therapy in patients with nephrotic syndrome. However, no data are available concerning the effect of lipoprotein(a) levels on the efficacy of statin therapy in patients with heterozygous FH. This report demonstrates negative correlation between plasma lipoprotein(a) levels and the LDL-cholesterol lowering effect of statin therapy in 49 patients with heterozygous FH.

Gene polymorphisms affecting HDL-cholesterol levels in the normolipidemic population.

BACKGROUND AND AIM: HDL-cholesterol (HDL-C) is inversely related to the risk of ischemic heart disease. Many genes are reported to affect HDL-C serum levels in both hyperlipidemic and normolipidemic populations, though the data are controversial. We examined the effect of common gene polymorphisms known to interfere with HDL-C metabolism (apolipoprotein E, cholesterol ester transfer protein and apolipoprotein A-IV gene polymorphisms) on HDL-C plasma levels in normolipidemic subjects. METHODS AND RESULTS: The study population consisted of 200 normolipidemic individuals visiting our clinic for a routine check-up. None of the above gene polymorphisms affected HDL-C levels in our population. However, participants carrying the allele E4 of the apolipoprotein (apo) E gene, the allele B1 of the TaqIB polymorphisms in the cholesterol ester transfer protein (CETP) gene and the allele T of the apoA-IV gene (A to T polymorphism at site 347) (n = 28) had statistically significantly lower HDL-C levels compared to those not carrying the above allele combination (0.99+/-0.33 vs 1.28+/-0.35 mmol/L, p = 0.04). CONCLUSION: In this study, we describe a subgroup of normolipidemic individuals with low HDL-C levels due to genetic variability, and we discuss the underlying possible mechanisms involved.

Effect of apolipoprotein E polymorphism on serum uric acid levels in healthy subjects.

BACKGROUND: We have previously shown that apolipoprotein E (apo E-) polymorphism may affect serum creatinine concentration and predicted glomerular filtration rate in healthy individuals. On the other hand, there are limited data regarding the possible influence of apo E- polymorphism on serum uric acid (SUA) levels. METHODS: Two hundred ninety (148 male, 142 female) apparently healthy white individuals were studied. apo E- genotypes, serum lipid parameters including apolipoproteins, insulin resistance using the homeostasis model assessment (HOMA) as a marker, serum and urine creatinine levels, and serum and urine uric acid concentration were determined in all participants. RESULTS: The apo E-2 allele was associated with lower serum levels of total cholesterol, higher levels of triglycerides and apo E-, and increased serum creatinine concentration compared with the apo E-3 and apo E-4 alleles in our population. Furthermore, the apo E-2 allele was associated with higher SUA levels (321.3+/-101.1 micrmol/L [5.4+/-1.7 mg/dL]) compared with the apo E-3 allele (261.8+/-89.2 micromol/L [4.4+/-1.5 mg/dL]; p= .012) and the apo E-4 allele (243.9+/-65.4 micromol/L [4.1+/-1.1 mg/dL]; p= .010), whereas the apo E-2 allele was associated with a nonsignificantdecrease in the fractional renal excretion of uric acid (FEUA) compared with the apo E-3 and apo E-4 alleles (7.9+/-2.2% vs 8.7+/-4.2% vs 8.9+/-5.1%, respectively; p = .53). These observations remained statistically significant when the effect of apo E- polymorphism on SUA levels was adjusted for gender, age, systolic and diastolic blood pressure, body mass index, serum creatinine, and triglyceride and apo E- levels, as well as for HOMA index and FEUA. CONCLUSIONS: Our data provide evidence, for the first time, that the apo E-2 allele is independently associated with increased SUA levels in healthy individuals.

Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease characterized by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and ischaemic heart disease early in life. Early diagnosis and treatment are essential to prevent premature atherosclerosis in FH patients. The aim of our study was the evaluation of the effects of genetic [class of the LDL receptor (LDLR) gene mutation, apolipoprotein (apo)E, apoA-IV and cholesterol ester transfer protein gene polymorphisms] and environmental factors (age, sex, smoking habit and body mass index) on the lipid-lowering response to statin therapy in patients with molecularly defined FH. Atorvastatin 20 mg/day was prescribed in 49 patients with heterozygous FH. The lipid profile was examined before and after 12 weeks of therapy. Statin therapy resulted in a decrease of 37% and 36% in LDL-C and apoB levels, respectively. The study population was then divided into 2 groups according to the class of the LDLR mutation [patients sharing a class V mutation (the G1775A mutation, n=21) and patients sharing class II mutations (the G1646A and the C858A mutations, n=28)]. In both groups, the percentage decrement in LDL-C and apoB levels were correlated with the initial LDL-C and apoB levels, respectively. The class of the LDLR mutation affected the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. In detail, heterozygotes sharing a class V mutation of the LDLR showed a higher percentage decrement in LDL-C and apoB levels after atorvastatin administration compared to patients sharing class II mutations (49+/-9% versus 34+/-9%, P=0.001 for LDL-C and 42+/-16% versus 35+/-20%, P=0.001 for apoB). The influence of the classes of the LDLR gene mutations on the change of LDL-C and apoB levels to atorvastatin was still significant in a multivariate analysis. None of the other genetic and environmental factors studied affected the lipid-lowering response to atorvastatin therapy in patients with heterozygous FH in a multivariate analysis. Our data indicate that the class of the LDLR gene mutation affects the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. Specifically, patients with a class V mutation exhibit higher percentage decrease in LDL-C and apoB levels after statin therapy compared to patients sharing class II mutations.

Fenofibrate: metabolic and pleiotropic effects.

Disturbances of lipoprotein metabolism represent one of the most important risk factors for vascular events. However, dyslipidaemic patients often have a number of additional abnormalities (such as endothelial dysfunction, hypertension, low-grade inflammation, haemostatic abnormalities and hyperuricaemia) that may accelerate the atherosclerotic process. Thus, the ideal lipid-modifying drug, along with exerting beneficial effects on lipoprotein metabolism, should also improve these coexisting disturbances. Fibric acid derivatives (fibrates) are a class of lipid-modifying drugs mainly used in patients with elevated triglyceride levels. These drugs mainly exert their actions via the activation of specific nuclear receptors called peroxisome proliferator-activated receptors alpha (PPARalpha). In this review, we summarize the current evidence suggesting that fenofibrate, one of the most widely used fibric acid derivatives, along with its well established actions on lipids also exerts several other antiatherogenic actions. Based on recently published studies, fenofibrate is a useful option for patients with primary combined dyslipidaemias or secondary dyslipidaemias, such as those associated with diabetes mellitus, metabolic syndrome or HIV infection. Additionally, in cases of refractory dyslipidaemia, the combination of fenofibrate with statins is a therapeutic option.

Alterations of paraoxonase and platelet-activating factor acetylhydrolase activities in patients on peritoneal dialysis.

OBJECTIVE: The more atherogenic lipid profile seen in peritoneal dialysis (PD) patients cannot fully explain the increased incidence of atherosclerosis in this population. Oxidative modification of low-density lipoproteins (LDL) is considered to play a central role in the atherogenic process, whereas high-density lipoprotein (HDL) protects LDL from oxidation. On the other hand, it has been suggested that the LDL and HDL of PD patients are more resistant to oxidation than those of control subjects, while PD-HDL equally protects LDL from oxidation compared to control-HDL. Two HDL-associated enzymes have been shown to protect both LDL and HDL from oxidation: paraoxonase (PON1) and HDL-associated platelet-activating factor acetylhydrolase (HDL-PAF-AH). Furthermore, low PON1 activity and high total plasma PAF-AH concentration, which represents mainly the LDL-associated enzyme, have been shown to be independent risk factors for coronary artery events in the general population. However, there are limited data regarding possible alterations of these enzymes in PD patients. The aim of our study was to examine the possible alterations of PON1 and PAF-AH activities in patients undergoing PD. DESIGN: A cross-sectional study. SETTING: A university medical center. PARTICIPANTS: 56 PD patients of Caucasian origin and 86 matched controls were studied. MEASUREMENTS: In all subjects, serum PON1 activity toward paraoxon (paraoxonase) and phenylacetate (arylesterase), as well as total serum and HDL-PAF-AH activities were measured; PON1 genetic polymorphisms known to influence PON1 activity (Q192R and M55L) were determined. RESULTS: The PD patients exhibited significantly increased serum PON1 (paraoxonase) and PON1 (arylesterase) activities compared to controls, regardless of the PON1 polymorphisms or the levels of HDL cholesterol. Additionally, PD patients had significantly elevated activities of total serum PAF-AH and HDL-PAF-AH, independently of the levels of LDL or HDL cholesterol. The ratio of HDL-PAF-AH/ total PAF-AH, which has recently been suggested to be a potential marker of atherogenicity, was decreased in these patients compared to controls. Moreover, no difference in the prevalence of PON1 polymorphisms between PD patients and controls was found. CONCLUSION: The elevated activities of PON1 and HDL-PAF-AH could explain the increased resistance of PD-HDL to oxidation; the higher activity of total PAF-AH and the decreased HDL-PAF-AH/ total PAF-AH ratio could contribute to the increased incidence of atherosclerosis in these patients.

Apolipoprotein E polymorphism in northwestern Greece: frequency and effect on lipid parameters.

Apolipoprotein (apo) E gene polymorphism and its effect on serum lipid parameters were examined in a Greek population originating from northwestern Greece (n = 555). The allele frequencies were epsilon2: 6.3%, epsilon3: 80.7%, and epsilon4: 13.0%. The epsilon4 allele frequency was higher in our population than was previously reported in individuals from other parts of Greece. ApoE polymorphism was associated with significant differences in serum lipid, and lipoprotein levels. Particularly, individuals with the epsilon2 allele had higher serum triglyceride and apoE levels and lower levels of total cholesterol, low-density lipoprotein cholesterol, and apoB, compared to those with the alleles epsilon3 and epsilon4. However, the impact of the epsilon4 allele on lipid parameters seen in other populations was not observed in our population. Furthermore, the combination of apoE polymorphism and serum apoE concentration explained a larger percentage of serum lipid variability than the polymorphism alone. In conclusion, the results of our study suggest that ethnic differences, as well as alterations of serum apoE levels, significantly modify the relationship between apoE gene polymorphism and serum lipid variability.

The influence of serum apolipoprotein E concentration and polymorphism on serum lipid parameters in hemodialysis patients.

BACKGROUND: Apolipoprotein E (ApoE) polymorphism has been shown to influence serum lipid parameters and ApoE levels in both healthy subjects and hemodialysis (HD) patients. Conversely, ApoE concentration significantly affects serum lipid levels in the general population, independently of ApoE polymorphism, by modulating lipoprotein production, lipolytic conversion, and receptor-mediated clearance. Therefore, studying the effect of ApoE polymorphism on serum lipid levels without taking into account ApoE levels could lead to confounding results. However, such a combined study has not been performed in HD patients to date. METHODS: Three hundred one patients without diabetes on long-term maintenance HD therapy and 200 matched healthy subjects were studied. Determination of levels of fasting serum ApoE and other lipid parameters, as well as common ApoE genotypes, was performed in all subjects. RESULTS: HD patients had a significantly lower prevalence of the epsilon4 allele and greater levels of ApoE compared with the control population. ApoE2 allele carriers had significantly lower levels of ApoB and serum total, low-density lipoprotein, and non-high-density lipoprotein cholesterol, as well as increased ApoE levels. When ApoE levels were included in analysis, ApoE levels themselves were proven to be important determinants of serum lipid levels, whereas the effect of ApoE polymorphism became more pronounced. The combination of these 2 factors explains a much greater percentage of the variation in the studied parameters than each factor alone. CONCLUSION: For the first time, our study provides data to support that ApoE concentration in combination with the ApoE polymorphism significantly influences serum lipid parameters in HD patients.