Cutaneous Xanthomas Research Articles

Colocalization of scavenger receptor in CD68 positive foam cells in verruciform xanthoma

Verruciform xanthoma is a rare variant of xanthoma that appears predominantly on oral mucosa and the anogenital area. The histologic features are characterized by marked accumulation of foam cells in the papillary dermis with verrucous epidermal acanthosis and hyperkeratosis. However, little is known of the nature or origin of foam cells. Recent studies have emphasized the crucial role of macrophage scavenger receptors in the formation of foam cells in atherogenesis. We examined the immunohistologic localization of scavenger receptors in genital verruciform xanthoma. We found that the massively infiltrated foam cells in the papillary dermis were CD68 + monocyte-macrophage lineage cells, and that the majority of CD68 + cells coexpressed scavenger receptors. The in situ staining pattern of scavenger receptor in foam cells was mainly of an intracytoplasmic vacuolar pattern similar to that of dermal resident macrophages found in normal skin. Furthermore, CDla + Langerhans cells, completely negative for scavenger receptor, were markedly decreased in number in verruciform xanthoma. These results indicate that scavenger receptor-bearing CD68 + cells are also actively involved in the development of cutaneous verruciform xanthoma, as has been shown to be the case in atherogenesis.

Cutaneous Xanthomas in Homozygous Familial Hypercholesterolemia

Figure 1. A baby boy was found to have familial hypercholesterolemia at the age of six months. His parents also had hypercholesterolemia. Seven and a half years later, studies of the activity of low-density lipoprotein (LDL) receptors in proliferating lymphocytes indicated that the parents were heterozygous and the child was homozygous for LDL-receptor deficiency. The child's serum cholesterol concentration ranged from 850 to 1000 mg per deciliter (22 to 26 mmol per liter), and he had cutaneous xanthomas on his knees (as shown), elbows, and interdigital folds. Because the hypercholesterolemia was refractory to treatment with lovastatin and cholestyramine, the patient . . .

Apolipoprotein E Deficiency Leads to Cutaneous Foam Cell Formation in Mice

Apolipoprotein E deficiency leads to familial dysbetalipoproteinemia characterized by increases in serum lipid levels, atherosclerosis, and cutaneous xanthoma. Apolipoprotein E is synthesized in many tissues in the body, including the epidermis. In the present study, we determined whether transgenic mice deficient in apolipoprotein E develop cutaneous xanthoma and the effect of dietary fat intake on these lesions. We also determined whether apolipoprotein E-deficient mice have abnormalities in cutaneous barrier function or stratum corneum structure. Homozygous apolipoprotein E-deficient mice (-/-) fed a high-fat diet displayed a diffuse inflammatory infiltrate in the dermis surrounding fat droplets in macrophages. In homozygous mice (-/-) fed a low-fat diet, similar lesions were seen but they tended to be focal and less prominent. In heterozygous mice (+/-) fed the high-fat diet, a few inflammatory cells were present in the dermis but foam cells were not seen. Control mice (+/+) fed a high-fat diet displayed scattered inflammatory cells in the dermis. Heterozygous mice (+/-) fed a low-fat diet were similar to control mice (+/+) fed a low-fat diet. The extent of foam cell formation correlated directly with the degree of atherosclerosis. There were no abnormalities in permeability-barrier function or stratum corneum structure in apolipoprotein E-deficient mice. Thus, the lack of apolipoprotein E production in the epidermis does not appear to lead to any detectable abnormality in structure or function of the stratum corneum. However, lack of apolipoprotein E leads to cutaneous foam cell formation, presumably secondary to disturbances in lipoprotein metabolism.

Phytosterolaemia in three unrelated South African families

Phytosterolaemia (beta-sitosterolaemia), a rare, autosomal recessive disorder, has not hitherto been reported in Southern Africa. We report four new homozygous patients, from three unrelated families with significant beta-sitosterolaemia (6.6-11.3%), campesterolaemia (2.2-4.6%) and clearly detectable, though unquantified, levels of cholestanol. Three of the four patients had characteristic cutaneous and tendinous xanthomas within the first decade of life. The fourth patient, a 5 year old, was free of xanthomas despite persistently elevated concentrations of plant sterols in her plasma. All our patients were female bringing the male:female ratio in reported cases to 8:23. All were at or below the 50th percentile for height and weight, and presented at some stage with borderline, hypochromic anaemia associated with red cell abnormalities and thrombocytopaenia. The oldest patient showed suggestive clinical evidence of atherosclerosis affecting her aorta, ileofemoral bifurcation and possibly coronary arteries. All homozygotes responded to a diet restricted in phytosterols and the administration of cholestyramine with falls in plasma sterols of up to 68%. The recent discovery of a possible inherited defect in the synthesis of HMG CoA reductase in patients with phytosterolaemia makes this disorder a model system for studying the biological role of this enzyme in regulating the absorption and clearance of sterols other than cholesterol, and the factors governing the sterol composition of cell membranes.

Hypocholesterolemic effects of mixture Da Huai on experimental rats and treatment of a homozygous FH child

This study observes the hypocholesterolemic effects of Mixture Da Huai — a drug of enhancing monocyte macrophage system — on experimental rats, and the treatment of a homozygous familial hypercholesterolemia (FH) child. The results show that TC, VLDL-C and LDL-C in Mixture Da Huai group were significantly reduced and HDL-C was significantly increased. Fractional clearance rates for 125I-GLC-LDL, and the 125I-GLD-LDL uptake of rat peritoneal macrophages were significantly increased. Excretions of total sterol and acidic sterol in feces were also increased. After treatment for 3 months, serum TC and LDL-C of a homozygous FH child were significantly decreased. Tendon and cutaneous xanthomas were limited. This study indicates that by promoting the monocyte macrophage system to degrade LDL, a promising prevention and treatment of hypercholesterolemia and atherosclerosis might be provided, especially in the treatment of homozygous FH.

Management of lipoprotein-x accumulation in severe cholestasis by semi-selective ldl-apheresis

Liver disorders characterized by prolonged bile stasis are often associated with the accumulation of an abnormal lipoprotein, lipoprotein-X (LP-X), in plasma. LP-X is separated in the low-density lipoprotein (LDL) density range, but lacks apolipoprotein B and does not interact with the LDL receptor; LP-X can cause hyperlipidemia, cutaneous xanthomas, and worsening of arterial disease. We report the case of a patient with severe cholestasis, markedly elevated plasma cholesterol levels (26.8 to 31.5 mmol/L), mainly due to a massive accumulation of LP-X in plasma, and diffuse xanthomas. To reduce the elevated cholesterol levels, the patient was given extracorporeal treatment aimed at removing atherogenic lipoprotein (LDL-apheresis). LDL-apheresis was performed at weekly or bi-weekly intervals, either by a semi-selective technique using filters with a defined pore diameter (double filtration, DF) or by a more selective technique using dextran-sulfate-cellulose (DSC) columns able to bind LDL. The semi-selective DF technique proved more effective than DSC, removing 48% of total cholesterol (compared to 30% with DSC), and lowering cholesterol levels to 11.1 mmol/L in 6 weeks. DF removed both LDL and LP-X from plasma, whereas DSC selectively decreased the LDL content. The reduction of plasma cholesterol levels was associated with a complete regression of the xanthomas, supporting DF apheresis as a first-choice treatment for patients with massive LP-X accumulation due to cholestasis.

Management of lipoprotein-X accumulation in severe cholestasis by semi-selective LDL-apheresis

Liver disorders characterized by prolonged bile stasis are often associated with the accumulation of an abnormal lipoprotein, lipoprotein-X (LP-X), in plasma. LP-X is separated in the lowdensity lipoprotein (LDL) density range, but lacks apolipoprotein B and does not interact with the LDL receptor, LP-X can cause hyperlipidemia, cutaneous xanthomas, and worsening of arterial disease. We report the case of a patient with severe cholestasis, markedly elevated plasma cholesterol levels (26.8 to 31.5 mmol/L), mainly due to a massive accumulation of LP-X in plasma, and diffuse xanthomas. To reduce the elevated cholesterol levels, the patient was given extracorporeal treatment aimed at removing atherogenic lipoprotein (LDL-apheresis). LDLapheresis was performed at weekly or bi-weekly intervals, either by a semi-selective technique using filters with a defined pore diameter (double filtration, DF) or by a more selective technique using dextran-sulfate-cellulose (DSC) columns able to bind LDL. The semi-selective DF technique proved more effective than DSC, removing 48% of total cholesterol (compared to 30% with DSC), and lowering cholesterol levels to 11.1 mmol/L in 6 weeks. DF removed both LDL and LP-X from plasma, whereas DSC selectively decreased the LDL content. The reduction of plasma cholesterol levels was associated with a complete regression of the xanthomas, supporting DF apheresis as a first-choice treatment for patients with massive LP-X accumulation due to cholestasis.

Long-term plasmapheresis in the treatment of homozygous familial hypercholesterolemia in two Chinese patients

Two Chinese brothers with receptor-defective homozygous familial hyper-cholesterolemia were treated by plasmapheresis for 4 yr. Concurrent medication included cholestyramine, nicotinic acid, probucol and lovastatin. There was gradual regression of tendon xanthomas. Serial coronary angiograph studies showed no progression of coronary atherosclerosis and most lesion in the adult patients with homozygous FHC resulting in regression of cutaneous xanthomas and coronary artery lesions.

Probucol. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia.

Probucol is a lipid-regulating agent structurally dissimilar to other known agents, with a unique pharmacodynamic and clinical profile. It is effective in the treatment of primary Type IIa and IIb hyperlipoproteinaemias, including polygenic (non-familial) hypercholesterolaemia and both heterozygous and homozygous forms of familial hypercholesterolaemia, with reductions in plasma total cholesterol and low density lipoprotein (LDL)-cholesterol levels of about 10 to 20% being attained. Marked effects on cutaneous and tendinous xanthomas have been observed, with significant regression often apparent after 2 or 3 months' therapy. Preliminary trials also indicate efficacy in hyperlipoproteinaemia secondary to nephrotic syndrome and diabetes mellitus. The mechanism of the reduction in LDL-cholesterol levels is yet to be fully elucidated, but it is thought that the decrease results from enhanced catabolism, and there is preliminary evidence of an independent antioxidant effect. In contrast with all other known lipid-lowering agents, probucol also effects a consistent reduction in serum high density lipoprotein (HDL)-cholesterol levels, of around 20 to 30%; the clinical significance of this observation is unclear, although some preliminary investigations suggest a beneficial effect in enhancing reverse cholesterol transport. The influence of probucol treatment on cardiovascular morbidity and mortality remains to be fully investigated; a large trial quantifying the potential effect of probucol against the development of atherosclerotic lesions is currently in progress. Adverse effects of probucol are generally mild, seldom requiring treatment withdrawal, with gastrointestinal effects such as diarrhoea predominating. However, indications of an increased frequency of ventricular arrhythmias and sudden death in association with QT interval prolongation in some animals have prompted some concern. Although there is evidence of a degree of QT prolongation in a number of trials in humans, the nature and clinical significance of this effect requires clarification, as no increased incidence of cardiac arrhythmias is apparent. Thus, probucol appears to be of benefit in primary and secondary hyperlipoproteinaemia of Types IIa and IIb, and particularly in homozygous familial hypercholesterolaemia, with marked effects on xanthomas, and a generally favourable adverse effect profile. There is no evidence to date causally relating occasional QT interval prolongation in patients to any incidence of arrhythmias or sudden death. Pharmacodynamic investigations are likely to clarify further the place of probucol in therapy, particularly with respect to its distinctive lowering of plasma HDL-cholesterol levels.

Prevention of atherosclerotic progression in Watanabe rabbits by probucol

The foam cell has been recognized as a characteristic feature of xanthomas in skin and tendons, and also of atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore macrophages may be the progenitor of certain foam cells that are involved in atherogenesis. Several investigators demonstrated in vitro that macrophages can ingest large amounts of certain chemically modified lipoproteins, such as acetylated low-density lipoprotein (LDL) and malondialdehyde-treated LDL, through the process of receptor-mediated endocytosis. By this process, macrophages become foam cells. But this process has not been demonstrated in vivo. Recently, oxidized LDL has been suggested to play an important role in atherogenesis by facilitating the accumulation of lipids in macrophages in vitro. Probucol, originally developed as an antioxidant, prevents this oxidative modification of LDL in vitro. Moreover, there are some clinical reports that probucol induces regression of cutaneous and tendon xanthomas in patients with homozygous familial hypercholesterolemia. A question was posed whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At age 2 months, 8 WHHL rabbits were classified into 2 groups: group A rabbits were controls and group B rabbits were treated with 1% probucol. After 6 months of treatment, average plasma concentrations of cholesterol were 704 +/- 121 mg/dl in group A and 584 +/- 61 mg/dl in group B. The percentage of surface area of total thoracic aorta with visible plaques in group A vs group B was 54.2 +/- 18.8% vs 7.0 +/- 6.3%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

マクロファージにおけるリポタンパク代謝 ＷＨＨＬウサギの成績を中心に

The foam cell has been recognized as a characteristic feature of xanthomas and atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore, the macrophage may be the progenitor of certain foam cells that are involved in atherogenesis. Several investigators demonstrated in vitro that macrophages can ingest large amounts of native lipoprotein, such as β-VLDL and WHHL-VLDL and also certain chemically modified lipoproteins, such as acetylated LDL and malondialdehyde-treated LDL through the process of receptor-mediated endocytosis and thereby they become foam cells. Yet modified LDL has not been demonstrated to exist in the body. Recently oxidized LDL is suggested to play an important role in atherogenesis by facilitating the accumulation of lipids in macrophages in vitro. Probucol, originally developed as an antioxidant, prevents this oxidative modification of LDL in vitro. Moreover, there are some clinical reports that probucol causes a regression of cutaneous and tendon xanthomas in homoyzgous FH patients.Therefore we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous WHHL-rabbits, an animal model for familial hypercholesterolemia. Six months after treatment with probucol, the percentage of surface area of total thoracic aorta with visible plaques was 7.0±6.3%, whereas 54.2±18.8% in untreated WHHL-rabbits in spite of no reduction of plasma cholesterol level. LDL isolated from WHHL rabbits under treatment with probucol were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages. Our study suggests the possibility that oxidized LDL is the true form of modified LDL that produces foam cells and atherosclerosis in vivo.

LDL-apheresis; potential procedure for prevention and regression of atheromatous vascular lesion.

Nine patients with familial hypercholesterolemia (FH), 6 with homozygotes and 3 with heterozygotes, were treated with long term repetitive LDL-apheresis. The techniques are simple plasma exchange with human albumin solution, double membrane filtration, and selective LDL-adsorption by dextran sulfate-cellulose gel. The average term was 3.5 years except for the two homozygotes for whom the treatment was only initiated in our facility. Plasma total cholesterol levels were controlled between pretreating level, 320 to 500 mg/dl, and posttreating level, 100 to 160 mg/dl, by biweekly treatments. All patients showed remarkable improvement of cutaneous and tendinous xanthomas. One homozygous patient died at 31 years old of myocardial infarction after 2 years of treatment. A homozygous patient who has been treated since 5 years old for 6 years was reexamined by angiography and was shown to have atheromatous lesions regressed in the aortic valve region and in the left renal artery.

ホモ接合型家族性高αリポ蛋白血症の1家系

Lipoprotein patterns and cholesteryl-ester transfer activity (CETA) were examined in the patient with familial hyperalphalipoproteinemia (FHALP). The proband was a 41-year-old Japanese male who was working as a plumber. He was found to have hypercholesterolemia, with serum total cholesterol level of 9.93mmol/l (382mg/dl) and HDL-cholesterol level of 4.60mmol/l (177mg/dl). HDL showed a high cholesterol/apo A-I ratio and appeared to have a larger-sized particle than normal HDL on agarose gel column chromatography. His father, two of the proband's siblings and one of the children showed higher HDL-cholesterol levels (91, 100, 75, 98mg/dl, respectively). Neither had cutaneous and tendinous xanthomas nor any clinical signs of atherosclerosis. Apo A-I isoforms of the proband was not different from that of controls.Cholesteryl-ester transfer activity was studied by Dr. Albers et al. The proband appears to have only one-tenth the normal level of cholesteryl-ester transfer. However, the levels of lipid-transfer protein-I (LTP-I) activity were near normal. Thus this patient most likely has an exaggerated level of LTP-I inhibitor (s). The above mentioned data in the patient with FHALP presumably accounted for the increase in particle size and cholesterol enrichment of HDL.

Xanthogranulomatosis in an adult: Lipid analysis of xanthomas and plasma

Xanthomatosis in the absence of hyperlipidemia is unusual but has been associated with compositional abnormalities of lipoprotein particles. An adult who developed juvenile xanthogranulomatosis in association with oral contraceptive ingestion is reported. Plasma lipids and lipoprotein electrophoresis were normal, as in a few other patients reported with this disorder. However, analysis of cutaneous xanthoma and plasma by thin-layer and gas-liquid chromatography revealed that cholesterol was the principal lipid in xanthoma and that there were no unusual sterols in plasma or tissue. Possible mechanisms of xanthoma formation are discussed. Thus juvenile xanthogranulomatosis should be considered in adults with normolipemic xanthomatosis.

Cytotoxic effect of serum on fibroblasts in one case of normolipidemic plane xanthoma and myeloma IgG λ

Serum was examined for a cytotoxic effect on cultured human fibroblasts, using 8 normal controls and 4 patients. Three of the patients had secondary lipidoses associated with monoclonal gammapathies of IgA κ, IgG κ and IgG λ types. The fourth had systemic lupus erythematosus (SLE) with hyperlipidemia. Only serum containing the monoclonal IgG λ was found to be cytotoxic. This circulating IgG λ was strongly bound to HDL and behaved like an antilipoprotein antibody. The circulating immune complexes may be the serum factor responsible for the cytotoxicity and the cutaneous plane xanthomas, thus giving another example of ‘antibody-dependent’ cellular cytotoxicity previously described for endothelial cells in other diseases.

Treatment of homozygous patients with familial hypercholesterolemia by double-filtration plasmapheresis

Two homozygous patients with familial hypercholesterolemia were treated by double-filtration plasmapheresis. The plasma separated by the first filter was subsequently led to the second filter of ethylene vinylalcohol co-polymer hollow fibers, which trap very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) preferentially to other plasma constituents. Serum, VLDL, IDL, LDL cholesterol levels decreased by 55, 68, 59 and 55%, respectively. HDL cholesterol levels decreased by 39%. Immunoglobulins and fibrinogen levels decreased significantly. Cutaneous and tendinous xanthomas became smaller.

Stimulation of cholesteryl ester synthesis in mouse peritoneal macrophages by cholesterol-rich very low density lipoproteins from the Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia.

Cholesterol-rich very low density lipoproteins (VLDL) from the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbit induced marked cholesteryl ester accumulation in mouse peritoneal macrophages. This WHHL rabbit, an animal model of human familial hypercholesterolemia, has severe hypercholesterolemia, cutaneous xanthomas, and fulminant atherosclerosis due to the deficiency of the low density lipoprotein (LDL) receptor. When incubated with mouse peritoneal macrophages, the VLDL from WHHL rabbit (WHHL-VLDL) stimulated cholesteryl [14C]oleate synthesis 124-fold more than did VLDL from the normal Japanese White rabbit (control-VLDL). The enhancement in cholesteryl ester synthesis and accumulation of WHHL-VLDL was due to the presence of a high affinity binding receptor site on the macrophage cell surface that mediated the uptake and lysosomal degradation of WHHL-VLDL. Competition studies showed that the uptake and degradation of 125I-WHHL-VLDL was inhibited by unlabeled excess WHHL-VLDL and beta-migrating VLDL (beta-VLDL), but not LDL. Furthermore, the degradation of WHHL-VLDL was not blocked by either fucoidin, polyinosinic acid, or polyguanylic acid, potent inhibitors of the acetylated (acetyl)-LDL binding site, or by acetyl-LDL. These results suggest that macrophages possess a high affinity receptor that recognizes the cholesterol-rich VLDL present in the plasma of the WHHL rabbit and that the receptor which mediates ingestion of WHHL-VLDL seems to be the same as that for beta-VLDL and leads to cholesteryl ester deposition within macrophages. Thus the uptake of the cholesterol-rich VLDL from the WHHL rabbit by macrophages in vivo may play a significant role in the pathogenesis of atherosclerosis in the WHHL rabbit.

家族性高コレステロール血症に対するプロブコールの作用機序の検討

We have shown that marked reduction of serum cholesterol and marked regression of cutaneous and tendon xanthomas were obtained by probucol treatment even in homozygous as well as heterozygous cases of familial hypercholesterolemia under low fat and low calory diet, although the treatment caused a remarkable decrease in HDL-cholesterol (Atherosclerosis 48, 157, 1983). In order to elucidate the mechanism of the effects of probucol, we investigated the relation between the extent of the regression of lipid storage evaluated by xeroradiography of Achilles tendon thickness and the changes in lipoproteins. The reduction of Achilles tendon thickness was not correlate with that of serum cholesterol, while it correlated closely with the extent of the reduction of HDL-cholesterol. High performance liquid chromatography of lipoproteins revealed that HDL2 particles from probucol-treated cases with familial hypercholesterolemia were small in size. In addition, net transfer rate of cholesteryl ester from HDL to larger particles was found to be enhanced by probucol treatment. These findings provide us the hypotheses that probucol may enhance cholesterol catabolism through the other pathway but LDL-receptors by stimulating the cholesterol transfer from HDL to larger lipoprotein particles and consequently may enhance the reverse transfer of Ch to take lipids out from the tissues.

Cutaneous Xanthomas Associated With Chronic Myelomonocytic Leukemia

Monocytic leukemia may be associated with specific cutaneous changes in about a third of all cases, most characteristically the plum-colored nodule. Nonspecific cutaneous xanthomas have occasionally been reported with a variety of leukemias, mostly in the pediatric literature, but the first report (to our knowledge) of acute myelomonocytic leukemia presenting with specific cutaneous xanthomatous lesions appeared in 1982. Herein is reported a case of chronic myelomonocytic leukemia presenting with a papular histiocytic eruption, and later showing striking cutaneous xanthomas, together with autopsy findings. Physicians should be aware of this rare but important association.

Cutaneous xanthomas associated with chronic myelomonocytic leukemia

Cutaneous xanthomas associated with chronic myelomonocytic leukemia