Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.

Hypobetalipoproteinemias (HBL) represent a heterogeneous group of disorders characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in the population. HBL are defined as primary or secondary according to the underlying causes. Primary monogenic HBL are caused by mutations in several known genes (APOB, PCSK9, MTP, SARA2) or mutations in genes not yet identified. Familial hypobetalipoproteinemia (FHBL) is the most frequent monogenic form of HBL with a dominant mode of inheritance. It may be due to loss-of-function mutations in APOB or, less frequently, in PCSK9 genes. The rare recessive forms of primary monogenic HBL are represented by abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) due to mutations in MTP and SARA2 genes, respectively. The clinical phenotype of heterozygous FHBL is usually mild, being frequently characterized by fatty liver. The clinical phenotype of homozygous FHBL, ABL, and CMRD is usually severe being characterized by intestinal lipid malabsorption and fat-soluble vitamin deficiency. Secondary HBL are due to several nongenetic factors such as diet, drugs, and disease-related conditions. The aim of this review is to discuss the biochemistry, genetics, and clinical spectrum of HBL and to provide a clinical and laboratory diagnostic algorithm

Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia

The microsomal triglyceride transfer protein (MTP) inhibitor lomitapide is a licenced adjunct to a low-fat diet and other lipid-lowering medication, with or without low-density lipoprotein apheresis, for the treatment of adults with homozygous familial hypercholesterolaemia (HoFH). In a recently published phase 3 study, patients with HoFH received lomitapide in addition to maximally tolerated lipid-lowering therapy. Treatment with lomitapide resulted in a mean approximate 50% reduction in LDL-C levels after 26 weeks compared with baseline levels (p < 0.0001). This decrease in LDL-C was maintained at Weeks 56 and 78 (44% [p < 0.0001] and 38% [p = 0.0001], respectively). This paper offers clinical perspectives based on selected case histories of patients participating in the phase 3 lomitapide study. These cases provide illustrative examples of the efficacy of lomitapide, with or without apheresis, and show that the effective management of adverse effects can enable patients to remain on effective treatment

Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by markedly elevated plasma levels of low-density lipoprotein-cholesterol (LDL-C). Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor approved as an adjunct to other lipid-lowering therapies (LLTs), with or without lipoprotein apheresis (LA), for the treatment of adult HoFH. Diet with <20% calories from fat is required. Due to a varying genetic and phenotypic profile of patients with HoFH, individual patients may respond to therapy differently; therefore examining individual cases in a 'real-world' setting provides valuable information on the effective day-to-day management of HoFH cases. Four HoFH cases were selected for analysis and discussion: a 20-year-old female compound heterozygote; a 62-year old female homozygote; a 42-year-old female compound heterozygote; and a 36-year-old male homozygote. Each patient was commenced on lomitapide according to the prescribed protocol and subjected to routine follow-up. All four patients experienced clinically meaningful reductions in LDL-C levels of 35-73%. Three of the patients had evidence of steatosis or mildly elevated liver function tests) before lomitapide was started, but effects of lomitapide on hepatic function were not universal. Three of the patients experienced gastrointestinal adverse events, but were managed with appropriate dietary control. Lomitapide is an effective adjunct LLT in the management of patients with HoFH, with or without LA. Real-world use of lomitapide has a side-effect profile consistent with clinical trials and one that can be managed by adherence to recommendations on dose escalation, dietary modification and dietary supplements

Nuove linee guida americane 2013 ACC/AHA sul trattamento del colesterolo plasmatico per ridurre il rischio cardiovascolare aterosclerotico: confronto con le raccomandazioni ESC/EAS per la gestione delle dislipidemie

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The pathophysiology of intestinal lipoprotein production

Intestinal lipoprotein production is a multistep process, essential for the absorption of dietary fats and fat-soluble vitamins. Chylomicron assembly begins in the endoplasmic reticulum with the formation of primordial, phospholipids-rich particles that are then transported to the Golgi for secretion. Several classes of transporters play a role in the selective uptake and/or export of lipids through the villus enterocytes. Once secreted in the lymph stream, triglyceride-rich lipoproteins (TRLs) are metabolized by Lipoprotein lipase (LPL), which catalyzes the hydrolysis of triacylglycerols of very low density lipoproteins (VLDLs) and chylomicrons, thereby delivering free fatty acids to various tissues. Genetic mutations in the genes codifying for these proteins are responsible of different inherited disorders affecting chylomicron metabolism. This review focuses on the molecular pathways that modulate the uptake and the transport of lipoproteins of intestinal origin and it will highlight recent findings on TRLs assembly

Behavior of the total antioxidant status in a group of subjects with metabolic syndrome.

AIM: Our purpose was to examine the total antioxidant status (TAS) in subjects with metabolic syndrome (MS) subdivided according to the presence or not of diabetes mellitus. METHODS: We enrolled 106 subjects (45 women, 61 men) with MS subsequently subdivided in diabetics (14 women, 29 men) and nondiabetics (31 women, 29 men). TAS was obtained using an Assay kit which relies on the ability of plasma antioxidant substances to inhibit the oxidation of 2,2'-azino-bis(3-ethylbenzthiazoline sulfonic acid) to the radical ABTS+. RESULTS: In the group of MS subjects a significant decrease in TAS (p<0.05) in comparison with normal controls was evident. This difference was present between normal subjects and nondiabetic subjects with MS (p<0.001) but not between normal and diabetic subjects with MS. Examining the linear regression among TAS, age, anthropometric profile, blood pressure values and glycometabolic pattern, conflicting data were found. CONCLUSIONS: Although we know that TAS includes several enzymatic and non enzymatic antioxidants, we retain that the difference observed in the two subgroups of subjects with MS must be looked in particular into two pathophysiological aspects regarding bilirubin and uric acid

Fatty liver in familial hypobetalipoproteinemia: Triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis

Familial hypobetalipoproteinemia (FHBL) subjects may develop fatty liver. Liver fat was assessed in 21 FHBL with six different apolipoprotein B (apoB) truncations (apoB-4 to apoB-89) and 14 controls by magnetic resonance spectroscopy (MRS). Liver fat percentages were 16.7 ± 11.5 and 3.3 ± 2.9 (mean ± SD) (P = 0.001). Liver fat percentage was positively correlated with body mass index, waist circumference, and areas under the insulin curves of 2 h glucose tolerance tests, suggesting that obesity may affect the severity of liver fat accumulation in both groups. Despite 5-fold differences in liver fat percentage, mean values for obesity and insulin indexes were similar. Thus, for similar degrees of obesity, FHBL subjects have more hepatic fat. VLDL-triglyceride (TG)-fatty acids arise from plasma and nonplasma sources (liver and splanchnic tissues). To assess the relative contributions of each, [2H2] palmitate was infused over 12 h in 13 FHBL subjects and 11 controls. Isotopic enrichment of plasma free palmitate and VLDL-TG-palmitate was determined by mass spectrometry. Nonplasma sources contributed 51 ± 15% in FHBL and 37 ± 13% in controls (P = 0.02). Correlations of liver fat percentage and percent VLDL-TG-palmitate from liver were r = 0.89 (P = 0.0001) for FHBL subjects and r = 0.69 (P = 0.01) for controls. Thus, apoB truncation-producing mutations result in fatty liver and in altered assembly of VLDL-TG

LINEE GUIDA CLINICHE PER LA PREVENZIONE DELLA CARDIOPATIA ISCHEMICA NELLA IPERCOLESTEROLEMIA FAMILIARE Una patologia sotto-diagnosticata e sotto-trattata

AIMS. Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD) due to lifelong elevated plasma low-density lipoprotein (LDL) cholesterol levels. This paper aims to describe the problem of FH underdiagnosis and undertreatment and to promote CHD prevention providing recommendations for the screening and treatment of patients with FH. Methods and results. In many countries, less then 1% of FH patients are diagnosed, although the estimated prevalence of this condition is about 1/500 for heterozygous FH and the results of FH screening in a general population of Northern Europe suggest a prevalence of 1/200. Studies on FH patients agree on a widespread failure to achieve recommended target of LDL-cholesterol and on a 12-fold increased CHD risk. With a theoretical prevalence between 1/500 and 1/200, it is estimated that 14 to 34 million subjects worldwide have FH. With evidence of plasma cholesterol ≥8 mmol/L (≥310 mg/dL) in an adult or ≥6 mmol/L (≥230 mg/dL) in a child, premature CHD, tendon xanthomas, or sudden premature cardiac death, we recommend the screening for FH of this subject and of all first-degree relatives. The treatment of a patient with diagnosis of FH should have LDL targets of <3.5 mmol/L (<135 mg/ dL) for children, <2.5 mmol/L (<100 mg/dL) for adults, and <1.8 mmol/L (<70 mg/dL) for adults with known CHD or diabetes. Beside life-style and dietary modifications, first line therapies are statins, ezetimibe, and bile acid binding resins in children, and maximal potent statin dose, ezetimibe, bile acid binding resins, and fibrates in adults. Homozygotes FH and in treatment-resistant heterozygotes FH with CHD should be referred for LDL-apheresis. Conclusion. Familial hypercholesterolemia is a common condition that carries a high risk of CHD. The underdiagnosis and undertreatment of FH require a focused intervention that implements the screening and promote the early and aggressive treatment of these patients