Lipoprotein apheresis in the management of severe hypercholesterolemia and hyperlipoproteinemia(a)-The Portuguese experience.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are established causal risk factors for cardiovascular disease (CVD). Lipoprotein apheresis is often required for treatment of patients with a high risk for CVD due to hypercholesterolemia and/or hyperlipoproteinemia(a). AIM: To describe our experience with lipoprotein apheresis in patients with severe hypercholesterolemia or with hyperlipoproteinemia(a). METHODS: We retrospectively investigated patients treated with Lipoprotein apheresis using direct adsorption of lipoproteins (DALI) technique, between December 2008 and March 2018, in our center. Adverse events, acute and long term reductions in lipid parameters were analyzed. RESULTS: Between December 2008 and March 2018, a total of 950 treatments were performed in five patients, four with heterozygous familial hypercholesterolemia (HeFH), all on maximally tolerated cholesterol-lowering drug therapy and in one patient with hyperlipoproteinemia(a) and progressive CVD. In the four patients with HeFH we obtained mean acute reductions in LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) of 62.0 ± 7.8% and 60.4 ± 6.8%, respectively. Regarding long-term efficacy we achieved a mean reduction of 43.1% in LDL-C and of 41.2% in non-HDL-C. In the patient with hyperlipoproteinemia(a) we attained mean acute reductions of 60.4 ± 6.4% in Lp(a) and of 75.4 ± 7.3% in LDL-C per session and long term reductions in Lp(a) and LDL-C of 67.4% and 40.5%, respectively. Adverse events were recorded in only 1.2% of treatments. CONCLUSION: Lipoprotein apheresis is an efficient and safe treatment in severely hypercholesterolemic patients who are refractory to conservative lipid-lowering therapy or with hyperlipoproteinemia(a) and progressive CVD.

Plasma lipoproteins: genetic influences and clinical implications.

Susceptibility to the growing global public health problem of cardiovascular disease is associated with levels of plasma lipids and lipoproteins. Several experimental strategies have helped us to clarify the genetic architecture of these complex traits, including classical studies of monogenic dyslipidaemias, resequencing, phenomic analysis and, more recently, genome-wide association studies and analysis of metabolic networks. The genetic basis of plasma lipoprotein levels can now be modelled as a mosaic of contributions from multiple DNA sequence variants, both rare and common, with varying effect sizes. In addition to filling gaps in our understanding of plasma lipoprotein metabolism, the recent genetic advances will improve our ability to classify, diagnose and treat dyslipidaemias.

Cognitive impairment and polidistrectual atherosclerotic disease in chylomicronemia syndrome: a case report.

A case of chylomicronemia syndrome is reported in a 72-year-old male with distinctive features of chronic pancreatic damage, severe hypertriglyceridemia, polidistrectual atherosclerosis and premature cognitive impairment. Although the patient had a positive history for recurrent episodes of pancreatitis the characteristic lesions of the hyperchylomicronemia syndrome, such as eruptive xanthomas and lipemia retinalis, were not present and splenomegaly could not be documented due to a previous post-traumatic splenectomy. Based on clinical phenotype, an apolipoprotein C-II deficiency was excluded by a fresh plasma infusion test, in which clarification of the patient plasma was not obtained. The absence of changes in the lipoprotein electrophoretic plasma after heparin infusion can be secondary to a lipoprotein lipase deficiency, a rare genetic disorder with an incidence of one per million. In relation to the resistance to diet and drugs, plasma exchange therapy was performed. After 3 years of this treatment there was no significant progression of atherosclerosis.

A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia.

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie--to an apparently even greater degree--susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples.

Novel polymorphisms associated with hyperalphalipoproteinemia and apparent cardioprotection.

BACKGROUND: Hyperalphalipoproteinemia (HALP) is inversely correlated with coronary heart disease (CHD) although genetic variants associated with high serum levels of high-density lipoprotein cholesterol (HDL-C) have not been shown to be cardioprotective. OBJECTIVE: The objective of the study was to uncover novel genetic variants associated with HALP and possibly with reduced risk of CHD. METHODS: Exome sequencing data, HDL-C, and triglyceride levels were analyzed in 1645 subjects. They included the University of Maryland outpatients with high HDL-C (n = 12), Cardiovascular Health Study (n = 210), Jackson Heart Study (n = 402), Multi-Ethnic Study of Atherosclerosis (n = 404), Framingham Heart Study (n = 463), and Old Order Amish (n = 154). RESULTS: Novel nonsynonymous single-nucleotide polymorphisms (nsSNPs) were identified in men and women with primary HALP (mean HDL-C, 145 ± 30 mg/dL). Using PolyPhen-2 and Combined Annotation Dependent Depletion to estimate the predictive effect of each nsSNP on the gene product, rare, deleterious polymorphisms in UGT1A3, PLLP, PLEKHH1, ANK2, DIS3L, ACACB, and LRP4 were identified in 16 subjects with HALP but not in any tested subject with low HDL-C (<40 mg/dL). In addition, a single novel polymorphism, rs376849274, was found in OSBPL1A. The majority of these candidate genes have been implicated in fat and lipid metabolism, and none of these subjects has a history of CHD despite 75% of subjects having risk factors for CHD. Overall, the probability of finding these nsSNPs in a non-high HDL-C population ranges from 1 × 10-17 to 1 × 10-25. CONCLUSION: Novel functional polymorphisms in 8 candidate genes are associated with HALP in the absence of CHD. Future study is required to examine the extent to which these genes may affect HDL function and serve as potential therapeutic targets for CHD risk reduction.

The two novel CETP mutations Gln87X and Gln165X in a compound heterozygous state are associated with marked hyperalphalipoproteinemia and absence of significant coronary artery disease.

High levels of high-density lipoprotein cholesterol (HDL-C) occur with cholesteryl ester transfer protein (CETP) deficiency. However, the extent to which CETP deficiency states may be associated with protection against coronary artery disease (CAD) has been controversial. We evaluated a Greek pedigree with high levels of HDL-C and no history of premature CAD. The proband, a 45-year-old male with an HDL-C of 194 mg/dl with absent CETP activity, was heterozygous for two novel CETP mutations (Q87X and Q165X). A 64-slice multidetector CT scan revealed minimal (<10%) narrowing of the proximal left anterior descending artery without any other evidence of coronary atherosclerosis. In contrast to previous studies, these data suggest that complete CETP deficiency does not promote premature atherosclerosis. However, it remains unclear as to whether the relative lack of coronary atherosclerosis was the direct consequence of CETP deficiency and/or the lack of traditional CAD risk factors.

Experimental models of hyperlipoproteinemia and atherosclerosis.

The first experimental model of atherosclerosis (in rabbits) is more than hundred years old. Several animal species have been used to produce hyperlipoproteinemia and possible atherosclerosis. The gene manipulation produced the most used models recently. This review acknowledges the extensive study of atherosclerotic changes in experimental models of hyperlipoproteinemia and atherosclerosis to come to light thus far and the purpose here is not only to summarize the published data but also to try to add some details of our experience in using these models. In addition to rabbit (the old but also improved model by reno-vascular hypertension) dog, birds, pig, hamster, mice, rat and non-human primate's animal models are described. The gene manipulation produced the most used models two decades ago. Germline genetically engineered (without apoE or LDL receptor genes) animals have become the most used models producing atherosclerotic changes in the aorta. Recent new models also producing atherosclerotic changes but without germline genetic manipulation are also described.

Serum amyloid A regulates monopoiesis in hyperlipidemic Ldlr(-/-) mice.

We previously showed that feeding a Western-type diet (WTD) to Ldlr(-/-) mice lacking serum amyloid A (SAA) (Saa(-/-) Ldlr(-/-) mice), the level of total blood monocytes was higher than in Ldlr(-/-) mice. In this investigation we demonstrate that higher levels of bone marrow monocytes and macrophage-dendritic cell progenitor (MDP) cells were found in WTD-fed Saa(-/-) Ldlr(-/-) mice compared to Ldlr(-/-) mice and lower levels of GMP cells and CMP cells in Ldlr(-/-) mice. These data indicate that SAA regulates the level of bone marrow monocytes and their myeloid progenitors in hyperlipidemic Ldlr(-/-) mice.

Effect of pravastatin, a HMG CoA reductase inhibitor, on blood lipids and aortic lipidosis in cholesterol-fed White Carneau pigeons.

The effect of pravastatin, an inhibitor of HMG CoA reductase, on blood lipids and aortic lipidosis was studied in young cholesterol-fed White Carneau pigeons. The birds were fed with normal ('N group', n = 20) or atherogenic diet (grains + 0.4% cholesterol + 4% lard) alone ('C group', n = 20) and in association with pravastatin ('P group', n = 20). Plasma lipids and aortic intima lipidosis were studied after 3-5 and 8-12 months of the diet. Compared to the N group, pigeons from C group exhibited hypercholesterolemia (TC = 1000 mg/dl) and hyperlipoproteinemia of which level was independent of the duration of the diet. Total VLDL (VLDL+LDL)-cholesterol and apolipoprotein-B levels rose significantly 15, 8 and 4 times, respectively, whereas HDL were increased two times (P < 0.01) in females only. Macroscopically visible intima lipidosis areas covered 40% and 80% of aortic surface after 3-5 and 8-12 months of the diet. In P group, the increase in plasma lipid values was significantly lower than in WC from C group: -40% for total cholesterol (600 mg/dl) (P < 0.01), -71% for VLDL (P < 0.001), -53% for (VLDL+LDL)-cholesterol (P < 0.01) and -54% for apo-B (P < 0.05). HDL remained as high as in C group. Consequently TC/HDL-C ratio was improved and atherogenic risk of cholesterol was reduced by 41% (P < 0.05). Intima lipidosis areas were lowered by 35% (P < 0.01). We conclude that pravastatin treatment involves (1) a decrease in hypercholesterolemia and hyperlipoproteinemia and (2) a lowering in extensiveness and severity of macroscopically visible aortic lipidosis in cholesterol-fed White Carneau pigeon.

Lipoprotein disorder, cirrhosis, and olivopontocerebellar degeneration in two siblings.

Two siblings had olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. This condition was distinct from other cerebellar atrophies and ataxias and was not due to malabsorption or malnutrition. Cerebellar degeneration progressed rapidly during the first year of life, and both children died from intercurrent infections and surgical complications at 11 and 17 months. Stereotyped clinical and pathologic findings in the two patients suggest a previously unreported genetic metabolic disorder affecting the liver and the CNS.

Prevalence and association of atherosclerosis at three different arterial sites in patients with type III hyperlipoproteinemia.

We have examined the prevalence of clinically significant atherosclerosis in 78 patients with type III hyperlipoproteinemia (HLP) and homozygosity for apolipoprotein (apo) E2. Forty-six of these individuals (59%) had no atherosclerosis, 32 patients (41%) had atherosclerosis, i.e., atherosclerosis of the extracranial carotid arteries (CAA), coronary arteries (CAD) or/and peripheral arteries of the legs (PVD), either singly or in combination. No association could be shown with respect to the co-prevalence of atherosclerotic lesions at these different arterial sites, except for the high predictive value (pv = 0.88, P = 0.006) of CAA for the presence of PVD. Hence, documentation of atherosclerosis under clinical aspects at one of these exposed arterial territories does not allow a reliable prediction of generalised atherosclerosis or local atherosclerosis at other sites of the arterial tree in individuals with this familial lipoprotein disorder. Therefore, assessment of the extent of clinically significant atherosclerosis in type III HLP patients should include careful and thorough examination of the extracranial carotid arteries, the coronary arteries, and the peripheral arteries of the legs.

Hyperlipoproteinemia in one-year-old analbuminemic rats.

Plasma lipoprotein distribution and apolipoprotein concentrations, as well as kidney function and histopathology of heart, aorta, liver and kidney were investigated in 1-year-old Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR). The NAR, particularly the females, were found to be severely hyperlipidemic. Plasma total cholesterol in non-fasted animals was 6.1 +/- 0.3 mM in the female NAR vs. 2.5 +/- 0.2 mM in the female SDR (P less than 0.01). Most of the cholesterol was located in the LDL (1.019-1.063 g/ml) and HDL2 (1.063-1.125 g/ml) density range. Plasma triglycerides were 6.1 +/- 0.6 mM in the female NAR vs. 1.3 +/- 0.3 mM (P less than 0.01) in the female SDR. Plasma phospholipids were raised up to 5.4 +/- 0.3 mM vs. 2.4 +/- 0.1 mM (P less than 0.01). NAR have increased concentrations of plasma apolipoproteins A-I (about 3-4-fold) and B (about 2-fold), but the levels of apolipoproteins A-IV and E are not increased. There was less proteinuria in the male NAR than in the male SDR (P less than 0.01). Relevant histopathological findings in the NAR included hepatocytic lipofuscinosis and hemosiderosis in Kupffer cells. Tubular lesions were more common in kidneys from NAR than from SDR, and included protein casts, cortical lipofuscinosis, proximal tubular hyperplasia and proliferative interstitial nephritis. Glomerular changes were similar in both strains. Calcinosis of the aortic media and the corticomedullary region of the kidney was characteristically present in the female SDR but absent in the female NAR. Atherosclerotic lesions were not observed. In summary, 1-year-old NAR maintained on standard rat chow, are hyperlipoproteinemic. The increased levels of plasma LDL and HDL cholesterol are not associated with an increase in the incidence or severity of atherosclerotic or glomerular lesions.

Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment.

The effects of long-term gemfibrozil (Lopid) therapy on human liver structure are not known. Studies of this nature are becoming essential in determining the risk/benefit ratio since gemfibrozil is an effective agent for the control of hyperlipoproteinemia types IIa, IIb, and IV. Particularly, gemfibrozil is effective when dietary management or available therapeutic control fail to reduce serum cholesterol and triglycerides as well as normalizing the lipoprotein pattern. Percutaneous liver biopsies of 9 patients on long-term gemfibrozil therapy were evaluated by light microscopy, interference contrast optics and transmission electron microscopy. The distribution of patients according to lipoprotein phenotype was 3 Type IIa, 3 Type IIb, and 3 Type IV. Their lipoprotein patterns approached normal and the serum lipids were controlled during gemfibrozil therapy. By light microscopy, the lobular architecture and other parameters were within normal limits. Varying degrees of fatty change were found as would be expected. No preferential lobular disposition of the fat globules was evident. Coalescence of fat droplets, nuclear displacement and fatty cysts were noted. Differential interference contrast microscopy revealed several degrees of contrast amplitude in these droplets suggesting a heterogeneous lipid deposition in hepatocytes. The subcellular analysis revealed a moderate degree of glycogen deposition, absence of nuclear abnormalities and unremarkable mitochondria; the rough endoplasmic reticulum was not significantly altered and smooth surfaced membranes appeared proliferated. Detailed analysis of the peroxisome population showed matrix rarefaction, marginal plate formation and spurious densities though no significant proliferation occurred. Distribution of peroxisomes in hepatocytes varied widely from cell to cell and in different lobular areas. This study confirmed the association of hepatic fatty change with hyperlipoproteinemia irrespective of the pattern observed in circulating lipoproteins. Peroxisome proliferation, as seen in rodents when receiving gemfibrozil, did not occur and the structure of these subcellular organelles was not compromised. It was concluded that the long-term administration of this compound did not show adverse effects on the hepatocyte in hyperlipoproteinemia.

Familial lipoprotein lipase deficiency: abnormal lipoproteins and defective metabolism of low density lipoproteins in cultured human skin fibroblasts.

Lipoproteins (chylomicrons + VLDL, VLDL, IDL, LDL and HDL) were separated from the plasma of 2 patients with primary, familial lipoprotein lipase deficiency. Chylomicrons were excessively enriched with cholesteryl esters. VLDL and IDL were of almost normal composition. LDL separated into 2 fractions LDL1 and LDL2, both triglyceride- and protein-rich and cholesteryl ester-poor. LDL2, the main LDL fraction, was denser and smaller than normal LDL. HDL3 was the only HDL population identified and was also triglyceride- and protein-rich and cholesteryl ester-poor. These observations indicate excessive triglyceride and cholesteryl ester transfer between chylomicrons and LDL and HDL. VLDL and its immediate catabolic product, IDL, seem to be spared the effects of the lipid transfer reaction. The biological reactivity of LDL1 and LDL2 was investigated in upregulated cultured human skin fibroblasts. Both exhibited defective specific binding to the LDL receptor and ineffective capacity to down-regulate sterol synthesis. These abnormalities were more pronounced with LDL3. The ineffective downregulation of sterol synthesis is most probably due to both the cholesterol content of the LDLs and their reduced binding to the LDL receptor. The defective binding of the LDLs to the receptor can be attributed to the abnormal composition of the lipoproteins and, to a lesser degree, reduced diameters (only LDL2). It is concluded that abnormal composition of LDL, in particular of lipid moieties, may change the affinity of the moiety of the lipoprotein towards the LDL receptor.

Mitochondrial abnormalities of muscle tissue in mice with juvenile visceral steatosis associated with systemic carnitine deficiency.

A mouse with juvenile visceral steatosis (the JVS mouse) has been recognized as a novel animal model for systemic carnitine deficiency. We examined cardiac, skeletal and smooth muscle cells in JVS and control mice by light and electron microscopy. Cardiac and skeletal muscle cells of these mice at 4 weeks of age exhibited a ragged-red appearance after trichrome staining. Electron microscopy, demonstrated increased numbers of mitochondria and lipid droplets in the cells. Compression or distortion of the myofibril bundles, primarily due to the increased number of mitochondria, suggests the possible existence of a functional disturbance of the cardiac and skeletal muscle. In the urinary bladder, only one or two large lipid droplets and slightly increased number of mitochondria were recognized in the perinuclear region of the smooth muscle cells. At 8 weeks of age, the mouse enzyme histochemistry specific for mitochondria, such as cytochrome c oxidase and succinic dehydrogenase, and oil red O staining, confirmed further increases in the number of mitochondria and lipid droplets in the heart. However, the accumulation of these organelles in the skeletal and smooth muscle cells was no greater than that noted in JVS mice at 4 weeks of age. In the cardiac muscle cells, autolysosomes or autophagic vacuoles containing electron-dense membranous, lamellar or whorled structures closely associated with mitochondria and pseudoinclusion bodies in the nucleus were recognized, and bundles of myofibrils were buried under numerous mitochondria, suggesting the existence of disturbed contractile function in the heart of JVS mice. These results indicate that this murine strain associated with systemic carnitine deficiency exhibits a generalized mitochondrial abnormality in the muscle system especially in the heart.

LPS induced procoagulant activity and plasminogen activator activity in mononuclear cells from persons with high or low levels of HDL lipoprotein.

UNLABELLED: We have examined spontaneous and lipopolysaccharide (LPS) induced procoagulant activity (PCA) and plasminogen activator activity (PA) in peripheral blood mononuclear cells (PBMC) from ten persons with high, and ten persons with low levels of serum high-density lipoprotein (HDL). PBMC were incubated +/- 100 ng LPS/ml up to 160 h. Additionally, we have measured the release of urokinase (uPA), tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) into the cell culture media. Spontaneous PA was significantly higher in PBMC from persons with low HDL, combined with lower release of uPA to the media and higher uPA-receptor (uPA-R) bound uPA on PBMC. Upon stimulation with LPS, PCA and released PAI-2 increased sharply, while PA and released uPA declined. These changes were not significantly different between the two groups. tPA and PAI-1 were not detected in cell lysates or in cell culture media. CONCLUSIONS: 1) LPS sharply stimulated PBMC PCA (similar in both groups). 2) PBMC from persons with low HDL showed higher spontaneous PA, due to higher uPA-R bound uPA, probably of importance in cell migration during the early events of atherosclerosis.

Effects of experimental hyperlipoproteinaemia on the retina and optic nerve in rhesus monkeys.

Hyperlipoproteinaemia resulting from thyroid suppression and long-term ingestion of a high cholesterol diet caused prolonged lipaemia retinalis in 6 rhesus monkeys. No atherosclerotic deposits or other ophthalmoscopically visible changes of the retinal vasculature were detectable. In 2 animals histopathological examination revealed segmental atrophy and gliosis of the optic nerves bearing a resemblance to chronic ischaemic optic neuropathy. One monkey developed ophthalmoscopically visible temporal pallor of the optic discs. Emboli of fat laden cells in blood vessels of the brain in one of these 2 monkeys, and in a penicillated splenic artery in the other animal, were associated with signs of systemic embolic occlusion, suggesting a similar course in the development of optic nerve damage.

Hyperlipoproteinemia impairs endothelium-dependent vasodilation.

Atherogenic lipoproteins can cause endothelial dysfunction in the initial stage of atherogenesis. In our study we examined 134 patients with defined hyperlipoproteinemia (non-HDL cholesterol>4.1 mmol/l or triglycerides>2.5 mmol/l or taking any of lipid lowering drugs)--94 men and 40 women. The subgroup of controls of comparable age contained 54 normolipidemic individuals--30 men and 24 women. Patients with hyperlipoproteinemia revealed significantly lower ability of endothelium-dependent flow-mediated vasodilation (EDV) measured on brachial artery (4.13+/-3.07 vs. 5.41+/-3.82 %; p=0.032) and higher carotid intima media thickness than normolipidemic controls (0.68+/-0.22 vs. 0.58+/-0.15 mm; p=0.005). In regression analysis, EDV correlated significantly with plasma concentrations of oxLDL (p<0.05) HDL-cholesterol (p<0.05), Apo A1 (p<0.05), ATI (p<0.01) and non-HDL cholesterol (p<0.05). Patients with hyperlipoproteinemia showed higher plasma levels of oxLDL (65.77+/-9.54 vs. 56.49+/-7.80 U/l; p=0.015), malondialdehyde (0.89+/-0.09 vs. 0.73+/-0.08 micromol/l; p=0.010) and nitrites/nitrates (20.42+/-4.88 vs. 16.37+/-4.44 micromol/l; p=0.018) indicating possible higher long-term oxidative stress in these patients.

The pathology of an inherited hyperlipoproteinaemia of cats.

The gross and histological features of congenital lipoprotein lipase deficiency are described in eight cats. The main histological features could be directly related to the presence of the chylomicronaemia. They consisted of lipid accumulation within clear vacuoles or ceroid accumulation within residual bodies in parenchymatous organs such as the liver, spleen, lymph nodes, kidney and adrenal gland. Xanthomata were seen in various sites, probably arising either from frank haemorrhage or the leakage of lipid-rich plasma perivascularly. As in human lipoprotein lipase deficiency there was no evidence of the formation of atherosclerotic plaques. Focal degenerative changes were, however, present within arteries and this may indicate blood vessel weakness and explain the tendency to haemorrhage and xanthomata/granulomata formation. The degeneration and fibrous replacement of glomeruli and nephrons possibly arises from pressure necrosis of adjacent xanthomata and alterations in renal blood flow.

Flexural planar xanthomas: report of four cases.

Four patients with primary hyperlipoproteinemia, Frederickson's type IIb, were observed to have symmetrical planar xanthomas affecting flexures: finger webs, antecubital and popliteal fossae, axillae, and intergluteal cleft. Other types of xanthomas were also present and serum lipid electrophoresis showed type IIb pattern. We draw attention to the peculiar pattern of symmetrical planar xanthomatosis hitherto described only with type III disease and some forms of normolipemic xanthomatoses.