Dysbetalipoproteinemia and other lipid abnormalities related to apo E. / Disbetalipoproteinemia y otras alteraciones relacionadas con la apolipoproteína E.

Dysbetalipoproteinaemia (or type III hyperlipoproteinaemia) is a severe mixed hyperlipidaemia resulting from the accumulation of remnant chylomicron and VLDL particles in plasma, also called ß-VLDL. It is caused by a defect in the recognition by hepatic LDL and lipoprotein receptor-related protein (LRP) of ß-VLDL. Mutations in the APOE gene, especially in subjects homozygous for the ɛ2/ɛ2 allele, are responsible for this lack of receptor recognition. Dysbetalipoproteinaemia represents 2-5% of the mixed dyslipidaemias seen in Lipid Units, is highly atherogenic and predisposes to diffuse atheromatosis, either coronary, peripheral vascular, or carotid, so early diagnosis and treatment is necessary. The presence of hypertriglyceridaemia, with non-HDL cholesterol/apolipoprotein B ratios>1.43 (in mg/dL) followed by APOE genotyping is the method of choice in the diagnosis of dysbetalipoproteinaemia. It is a dyslipidaemia that responds well to hygienic-dietary treatment, although the combination of statin and fenofibrate is often necessary to achieve optimal control.

Case of familial hyperlipoproteinemia type III hypertriglyceridemia induced acute pancreatitis: Role for outpatient apheresis maintenance therapy.

Hypertriglyceridemic pancreatitis (HTGP) accounts for up to 10% of acute pancreatitis presentations in non-pregnant individuals and is the third most common cause of acute pancreatitis after alcohol and gallstones. There are a number of retrospective studies and case reports that have suggested a role for apheresis and insulin infusion in the acute inpatient setting. We report a case of HTGP in a male with hyperlipoproteinemia type III who was treated successfully with insulin and apheresis on the initial inpatient presentation followed by bi-monthly outpatient maintenance apheresis sessions for the prevention of recurrent HTGP. We also reviewed the literature for the different inpatient and outpatient management modalities of HTGP. Given that there are no guidelines or randomized clinical trials that evaluate the outpatient management of HTGP, this case report may provide insight into a possible role for outpatient apheresis maintenance therapy.

Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy.

Familial dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism associated with an increased risk for premature cardiovascular disease. In about 10% of the cases, FD is caused by autosomal dominant mutations in the apolipoprotein E gene (APOE). This review article provides a pathophysiological framework for autosomal dominant FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE. ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to increased remnants. Remnants are hepatically cleared by the low-density lipoprotein receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD is associated with secondary factors like insulin resistance that lead to HSPG-R degradation through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible misdiagnosis as familial hypercholesterolemia. FD patients respond well to lifestyle changes and to combination therapy with statins and fibrates. To conclude, diagnosing ADFD is important to adequately treat patients and their family members. In patients presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered as part of the diagnostic work up.

Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder.

PURPOSE OF REVIEW: To review pathophysiological, epidemiological and clinical aspects of familial dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk. RECENT FINDINGS: Familial dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most familial dysbetalipoproteinemia patients are homozygous for apolipoprotein ε2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although familial dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an ε2ε2 genotype 15% develops familial dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of familial dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of familial dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in familial dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination. SUMMARY: Familial dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.

Type III Hyperlipoproteinemia: Still Worth Considering?

Familial type III hyperlipoproteinemia (HLP) was first recognized as a distinct entity over 60 years ago. Since then, it has proven to be instructive in identifying the key role of apolipoprotein E (apoE) in removal of the remnants of very low density lipoproteins and chylomicrons produced by the action of lipoprotein lipase on these triglyceride-transporting lipoproteins. It has additionally shed light on the potent atherogenicity of the remnant lipoproteins. This review describes the history of development of our understanding of type III HLP, discusses the several genetic variants of apoE that play roles in the genesis of type III HLP, and describes the remarkable responsiveness of this fascinating disorder to lifestyle modification, especially carbohydrate restriction and calorie restriction, and, when required, the addition of pharmacotherapy.

[Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment]. / Hyperlipoproteinemie a dyslipidemie jako vzácná onemocnení: diagnostika a lécba.

Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by a very early manifestation of a cardiovascular disease. Myocardial infarction is not an exception even in childhood. The therapy is based on high-dose statins, statins in combination with ezetimib and now also newly on PCSK9 inhibitors. Lomitapid and partly also mipomersen hold great promise for patients. LDL apheresis then represents an aggressive form of treatment. Lipoprotein lipase deficiency (type I HLP) is mainly characterized by severe hypertriglyceridemia, serum milky in colour, and xanthomatosis. A fatal complication is acute recurrent pancreatitis. A critical part of the treatment is diet, however it alone is not enough to control a genetic disorder. The only approved treatment is gene therapy. Experimentally, as an "off label" therapy, it is used in case studies with a lomitapid effect. We have our own experience with this experimental therapy. Dysbetalipoproteinemia is a congenital disorder of lipoprotein metabolism, characterized by high cholesterol (CH) and triglyceride (TG) levels. The underlying cause of this disease is the defect of the gene providing for apolipoprotein E. It is clinically manifested by xanthomatosis, however primarily by an early manifestation of atherosclerosis (rather peripheral than coronary).Key words: Lipoprotein lipase deficiency - dysbetalipoproteinemia - familial hypercholesterolemia - gene therapy - homozygous FH - LDL apheresis - lomitapid - mipomersen - PCSK9 inhibitors - rare diseases.

Hyperlipoproteinemia type 3: the forgotten phenotype.

Hyperlipoproteinemia type 3 (HLP3) is caused by impaired removal of triglyceride-rich lipoproteins (TGRL) leading to accumulation of TGRL remnants with abnormal composition. High levels of these remnants, called ß-VLDL, promote lipid deposition in tuberous xanthomas, atherosclerosis, premature coronary artery disease, and early myocardial infarction. Recent genetic and molecular studies suggest more genes than previously appreciated may contribute to the expression of HLP3, both through impaired hepatic TGRL processing or removal and increased TGRL production. HLP3 is often highly amenable to appropriate treatment. Nevertheless, most HLP3 probably goes undiagnosed, in part because of lack of awareness of the relatively high prevalence (about 0.2% in women and 0.4-0.5% in men older than 20 years) and largely because of infrequent use of definitive diagnostic methods.

[LDL-apheresis in patients with familial autosomal recessive hypercholesterolemia]. / LDL aferesi nella Ipercolesterolemia Autosomica Recessiva (ARH).

LDL-apheresis reduces the cardiovascular risk in patients with familial hypercholesterolemia. The addition of statin therapy in patients with autosomal recessive hypercholesterolemia may change the lipid profile to a less atherogenic pattern.

[Hypertricglyceridemia: prognostic impact and treatment options]. / Hypertriglyceridämie: prognostische Bedeutung und Therapiemöglichkeiten.

Elevated Triglyceride levels are associated with increased risk for atherosclerotic disease and additional vascular risk factors such as obesity, hypertension and impaired glucose tolerance. To estimate the individual cardiovascular risk of a patient with elevated triglycerides LDL- and HDL-cholesterol levels, concomitant diseases, composition of triglyceride rich lipoproteins and a family history for premature coronary heart disease are important. Primary goals for the management of hypertriglyceridemia are a reduction of cardiovascular risk and prevention of triglyceride associated complications such as the chylomicronemia syndrome. The basis of treatment are lifestyle changes: dietary intervention, alcohol avoidance, regular physical activity, weight loss and smoking cessation to modify risk factors. If triglyceride levels can not be sufficiently reduced by lifestyle intervention pharmacotherapy (nicotinic acid, fibrates and omega-3-acid ethyl esters) is indicated. Beyond reduction of triglyceride levels optimization of non-HDL-cholesterol by statin treatment is warranted to reduce vascular risk.

Case series of type III hyperlipoproteinemia in children.

Type III hyperlipoproteinemia (type III HLP) rarely manifests in childhood. Long-term follow-up (37 years) of the first patient revealed hypothyroidism at diagnosis requiring thyroxine replacement, palmar xanthomas requiring surgical removal, splenomegaly requiring splenectomy, 18 episodes of pancreatitis and premature coronary artery disease. Investigation revealed an apolipoprotein E phenotype of E2/E2 and partial lipoprotein lipase deficiency. Investigation of the second patient revealed a combination of apoE2/E2 phenotype and heterozygous familial hypercholesterolaemia. The third patient had a complete deficiency of lipoprotein lipase activity, an abnormal thyroid stimulating hormone on diagnosis (with subsequent normalisation without treatment), and apoE2/E2 phenotype. Type III HLP is a serious disorder with lifelong consequences of premature vascular disease and recurrent pancreatitis. Early presentation of disease in our patients was associated with additional precipitating factors. Drug treatment of paediatric type III HLP is indicated if dietary modifications alone are insufficient in managing the dyslipidaemia.

[Apolipoprotein E deficiency associated with type III hyperlipoproteinemia--analysis of apolipoprotein E].

CASE REPORT: The patient was a 50-year old male who was found to have a high cholesterol level during a routine health check up at work 5 years before and was examined at Keio University Hospital. Lipoprotein electrophoresis on agarose gel revealed type III hyperlipidemia, and a screening test yielded the following values (mg/dl): total cholesterol, 420; TG, 138; and HDL-cholesterol, 105. Turbidimetric immunoassay showed that the apolipoprotein E (apoE) level was below the limit of detection. Since he was 25 years old, the patient had sometimes noticed xanthomas on his knees and eyelids, and for that reason we made a diagnosis of apoE deficiency associated with type III hyperlipidemia. We tried using SDS-polyacrylamide gel electrophoresis, Western blot, and the protein chip method to detect apoE in this case, but the level was below the limit of detection by the first two methods, and it was so low that it was detected near the sensitivity limit of the protein chip method. Diet therapy, statin therapy, and fibrate therapy have been continued, and the latest data are: total cholesterol, 373; TG, 95; and HDL-cholesterol, 83. No manifestations associated with arteriosclerotic disease other than mild xanthomas have been observed.

Type III hyperlipoproteinemia exaggerated by Sheehan's syndrome with advanced systemic atherosclerosis: a 28-year clinical course.

A 38-year-old Japanese woman was admitted to hospital for further examination of systemic xanthomas. She had a past history of genital bleeding during her third delivery at the age of 21 years. She was diagnosed with Sheehan's syndrome. Her serum total cholesterol and triglyceride concentrations were 500 and 898 mg/dl, respectively. She was also diagnosed as having type III hyperlipoproteinemia on the basis of the presence of a broad-beta-band on agarose gel electrophoresis and extremely high concentrations of very-low-density lipoprotein cholesterol (310 mg/dl). The diagnosis was later confirmed by her apolipoprotein E isoforms (E2/E2) and genotypes (epsilon2/epsilon2). Thyroid and corticosteroid hormone replacement therapy cured the xanthomas, but also elevated her blood pressure. The serum concentration of intermediate-density lipoprotein cholesterol was consistently high, whereas that of low-density lipoprotein cholesterol was relatively low during the follow-up. Coronary atherosclerosis had already developed by the age of 38 years, and progressed significantly over the following 28 years. Severe stenotic lesions were observed in the bilateral renal arteries and carotid arteries, and in the abdominal aorta when she was 66 years old. These findings suggest that the continuous elevation of intermediate-density lipoprotein cholesterol for a long period contributed to the development of the atherosclerotic lesions.

Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects.

In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.

Coexisting type III hyperlipoproteinemia and familial hypercholesterolemia: a case report.

A 39-year-old man presented with type III hyperlipoproteinemia in association with heterozygous familial hypercholesterolemia (FH). He had extensive tuberous xanthomas over the knees and elbows and xanthomas in the Achilles tendons. He also had palmar xanthomas. He exhibited severe hypercholesterolemia and hypertriglyceridemia. This patient was heterozygous for FH, as evidenced by low low-density lipoprotein (LDL) receptor function on lymphocytes, and had type III hyperlipoproteinemia, as determined by apolipoprotein (apo) E phenotype 2/2 in isoelectric focusing of the E isoproteins and the presence of a broad beta band on electrophoresis. Because therapy consisting of diet restrictions and lipid-lowering agents such as clinofibrate and niceritrol did not decrease serum total cholesterol ([TC] 15.26 mmol/L) and triglyceride ([TG] 10.79 mmol/L) levels effectively, the patient underwent plasmapheresis once every 2 weeks using a dextran sulfate-cellulose column. Repeated plasmapheresis markedly reduced serum TC and TG and induced complete regression of the palmar xanthoma after 6 months. The severity of tuberous xanthomas on the knees and elbows was reduced after 2.5 years. After plasmapheresis, TC decreased to 1.94 mmol/L from 10.40 mmol/L and TG decreased to 0.33 mmol/L from 7.90 mmol/L. Plasmapheresis performed with a dextran sulfate-cellulose column was highly effective in removing the lipoprotein-remnant particles in this patient, leading to generalized improvement in the lipoprotein profile.

Electroforesis de lipoproteínas en gel de agarosa / Lipoproteins in agar gel electrophoresis

Los perfiles de los tipos clásicos mencionados pueden encontrarse en forma aislada o en diversas combinaciones. Muchas veces el perfil resulta limítrofe entre dos clasificaciones, siendo difícil incluirlo en uno de los dos tipos. Este problema se presenta en el 10%de las muestras

Electroforesis de lipoproteínas en gel de agarosa / Lipoproteins in agar gel electrophoresis

Los perfiles de los tipos clásicos mencionados pueden encontrarse en forma aislada o en diversas combinaciones. Muchas veces el perfil resulta limítrofe entre dos clasificaciones, siendo difícil incluirlo en uno de los dos tipos. Este problema se presenta en el 10%de las muestras