Familial hypercholesterolemia: recognition and prevention of cardiac complications at a young age

A man aged 35 and a woman aged 30 visited a lipid clinic because of a raised total cholesterol level, which was also present in a number of first-degree relatives. Apart from the lipid abnormalities they had no risk factors for coronary disease. Both proved to have familial hypercholesterolaemia. The man had vague angina pectoris symptoms and a high dose of cholesterol synthesis inhibitors was prescribed. Coronary angiography showed severe stenoses; a coronary balloon angioplasty was successfully performed. The woman, however, died at age 33 suddenly from myocardial infarction. Familial hypercholesterolaemia may cause unexpected cardiovascular complications and sudden death of young persons. Timely diagnosis of the condition on the basis of adequate anamnesis and thorough physical examination, more rapid administration of cholesterol-lowering agents and alertness for anginous complaints may prevent myocardial infarctions and save lives in these patients.     

Familial high-density-lipoprotein deficiency causing corneal opacities (fish eye disease) in a family of Dutch descent.

Fish eye disease (FED) is an extremely rare familial disorder characterized by severe HDL deficiency and extensive corneal opacities. This disorder appears to be a variant of familial lecithin: cholesterol acyltransferase (LCAT) deficiency in which the enzyme remains partly active yet the ability of the enzyme to esterify cholesterol in high-density lipoprotein (HDL) has been lost. The rarity of this disorder has limited advances in our understanding of the pathophysiology of the HDL deficiency. However, we here describe the clinical and biochemical presentation of a family with FED who are of Dutch descent. The proposition presented with HDL deficiency and corneal opacity. Subsequently, they were diagnosed as having FED by the absence of LCAT activity against a small proteoliposome substrate despite the presence of half-normal LCAT mass and a near-normal ratio of unesterified to total cholesterol in plasma. Heterozygotes presented with half-normal LCAT activity, but not with decreased HDL. With the identification of this three-generation family, renewed investigation of this intriguing disorder of HDL is now possible.     

Urinary creatine: biochemical indicator for evaluation of sickle cell crises

In a patient with known sickle cell beta 0-thalassemia we measured serum lactate dehydrogenase (LD) activity and 24-h urinary creatine excretion rate as markers to evaluate sickle cell crises. We believe that a distinction based on biochemical findings can be made between hemolytic and painful vaso-occlusive sickle cell crises with muscular involvement. To assess hemolytic crises by objective biochemical measures, we have used assay of LD activity, and to assess painful crises with muscular involvement objectively, the 24-h urinary creatine excretion rate. We conclude that hemolytic crises are characterized by high serum LD activities. Furthermore, we conclude that--at least in this patient--painful crises are accompanied by high 24-h urinary creatine excretion rates. Our findings suggest that muscle involvement may play an important role in painful vaso-occlusive sickle cell crises.     

The acute effect of atorvastatin on proteinuria in patients with chronic glomerulonephritis

BACKGROUND: Hyperlipidemia may develop early in the course of renal disease, and statin treatment to lower lipid levels in these patients is effective. In addition, it has been suggested that proteinuria may decrease after prolonged periods of statin treatment. In the present study, we set out to evaluate the short-term effect of atorvastatin after only six weeks of therapy. MATERIAL AND METHODS: Plasma albumin, creatinine, creatinine clearance, proteinuria and lipid profiles were assessed in 31 consecutive patients with glomerulonephritis and proteinuria > 0.3 g/24 h. All patients were treated with ACE inhibition for more than three months. Twenty patients consented to receive additional treatment with atorvastatin 10 mg daily in conjunction with a cholesterol-reducing diet, while 11 patients received standard care. Analyses were performed at baseline and after six weeks. RESULTS: After six weeks of treatment with atorvastatin urinary protein excretion was reduced from 1.80 g/24 h to 1.42 g/24 h (22%, p = 0.005), while no change was observed in this parameter in the untreated patients over the same period. Plasma albumin did not change in treated or in untreated patients. Lipid and lipoprotein parameters improved in all treated patients (all p < 0.001). No correlation was observed between the percentual changes in lipids and proteinuria. Plasma creatinine and creatinine clearance did not change (p > 0.05). CONCLUSIONS: Six weeks of therapy with low-dose atorvastatin, added to ACE inhibition, resulted in a 22% decrease of proteinuria compared to untreated patients.     

Gene therapy for genetic lipoprotein lipase deficiency: from promise to practice

Lipoprotein lipase (LPL) deficiency is a rare, hereditary disorder of lipoprotein metabolism characterised by severely increased triglyceride levels, and associated with an increased risk for pancreatitis. Since no adequate treatment modality is available for this disorder, we set out to develop an LPL gene therapy protocol. This paper focuses on the clinical presentation of LPL deficiency, summarises the preclinical investigations in animal models and describes the rationale to evaluate gene therapy for this monogenetic disorder of lipid metabolism in humans.     

Expression of interleukin-27 by human trophoblast cells

Cytokines produced at the fetal-maternal interface play a key role in regulating maternal tolerance to the fetus and successful pregnancy. Previously, we showed that EBV-induced gene 3 (EBI3), an interleukin (IL)-12 p40 homologue, was expressed at very high levels by syncytiotrophoblasts and extravillous trophoblasts throughout human pregnancy. EBI3 was recently shown to associate with a novel ligand, p28, to form a new heterodimeric cytokine with important immunoregulatory functions, IL-27. In this study, we investigated whether EBI3 expression by trophoblast cells is associated with that of p28 to form IL-27. We found that genes encoding IL-27 (EBI3 and p28) and its receptor (IL-27R and gp130) were expressed in the placenta at various stages of pregnancy. Co-immunoprecipitation experiments performed from placental lysates, and ELISA of culture supernatants from placental explants, showed that IL-27 heterodimer was produced and released from placental cells. In situ studies of placentae of first, second and third trimester of pregnancy, and of choriocarcinomas, demonstrated that syncytiotrophoblast cells co-expressed EBI3 and p28. Similarly, extravillous trophoblast cells invading the decidua were found to co-express both subunits of IL-27. These data suggest that IL-27 may be part of the cytokine network regulating local immune responses and angiogenesis during human pregnancy.     

Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes

OBJECTIVE: The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study. METHODS: The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders. RESULTS: The frequency of the PPARA intron 7 G/G genotype was higher in high TG-responders than in low TG-responders (85% vs. 69%, P < 0.05). There was no significant difference between the percentage of high TG-responders and low TG-responders for any of the other genetic polymorphisms examined. In stepwise logistic regression, baseline TG and only the PPARA intron 7 polymorphism among the others were selected in the model as significant predictors of TG-response (odds ratio: 3.10, 95% CI: 1.28-7.52, P = 0.012 for PPARA polymorphism). With age, gender, body mass index, smoking status and HbA1c as additional factors, baseline TG (P< 0.0001), intron 7 (P = 0.013), body mass index (P = 0.040) and LPL-S447X (P = 0.084) were significant predictors of TG-response. CONCLUSION: These results indicate that elevated baseline TG levels and PPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes.