3 | DISCUSSION
Eruptive xanthomas develop along with marked hypertriglyceridemia and are an important indicator of metabolic disorders, including dyslipidemia and diabetes mellitus. Grouped papular eruptions 1–4 mm in diameter are specifically observed in the skin over the buttocks, posterior portion of the thigh, elbows, and lumbar region.10, 11 Accumulation of foaming cells derived from macrophage phagocytosis of remnant lipoprotein is observed on histopathological examination.11, 12Hypertriglyceridemia is the highest risk factor for the development of eruptive xanthomas, with 8.5% of the patients with hypertriglyceridemia above 20 mmol/L (1772 mg/dL) developing this condition and subsequently improving after a reduction in serum triglyceride level.8, 13 In this context, hypertriglyceridemia and diabetes mellitus have been considered major causative factors for eruptive xanthoma and need to be treated to prevent the progressions of systemic atherosclerosis.14 Clinicians should be aware that this type of skin lesions can indicate the presence of metabolic disorders, which need to be addressed in order to improve the eruptions11 and prevent cardiovascular events.14
Insulin insufficiency is a major factor for increased remnant lipoprotein, including chylomicron or very low-density lipoprotein (VLDL), and the manifestation of xanthoma and systemic atherosclerosis. A putative relationship between eruptive xanthoma and atherosclerosis is summarized in Figure 5. Obesity and diabetes mellitus can promote insulin insufficiency in extra adipose tissues due to insulin insensitivity caused by the following factors: (1) lipotoxicity, increased skeletal muscle triglyceride content followed by elevation of free fatty acids15; (2) changes in adipokines, including low adiponectin16 and high leptin17 levels; (3) elevations in proinflammatory cytokines, including tumor necrosis factor-α, IL-1β, and IL-6 levels, in the adipose tissues18; (4) activation of the endoplasmic reticulum and related signaling networks19; and (5) elevated hexosamine flux in adipose tissues.20 Insulin insufficiency decreases lipoprotein lipase activity by activating angiopoietin-like protein 3 (ANGPTL3)21–23 expressed in the liver, which increases the levels of VLDL and triglyceride via suppression of lipoprotein lipase activity24 and overproduction through lipolysis-derived free fatty acids and glycerol.23. Thus, high ANGPLT3 activity in patients with hyperglycemia or obesity can induce elevations of serum remnant lipoproteins, chylomicron, or LDL, and VLDL levels.24Remnants infiltrating into the vessel walls or skin25are recognized and engulfed by macrophages. After phagocytosis, macrophages change to foam cells and are deposited into the vessel walls and skin,11 which lead to arthrosclerosis26 and eruptive xanthoma,12 respectively.
Hypertriglyceridemia should be treated early to prevent progression to acute pancreatitis and cardiovascular events. Severe hypertriglyceridemia over 1000 mg/dL has been found to markedly increase the risk of developing acute pancreatitis.27Postprandial hypertriglyceridemia is positively associated with the development of ischemic heart disease, myocardial infarction, and cardiovascular events independent of serum cholesterol levels.28 In this context, casual hypertriglyceridemia, including postprandial levels as high as fasting levels, have also been indicated to significantly increase the risks of developing cardiovascular events.29 Additionally, triglyceride-rich lipoprotein and remnant apo-B48-positive chylomicron derived from short intestine are increased during hypertriglyceridemia.30 Patients with high fasting levels of apo-lipoprotein B48 have been found to be at significant risk for developing coronary artery stenosis.31, 32 Thus, hypertriglyceridemia requires interventions to prevent the progression of cardiovascular diseases and improve prognosis.
In conclusion, this report details our experience with a patient who presented with hypertriglyceridemia and type 2 diabetes mellitus concurrent with eruptive xanthoma, which was ameliorated by the treatment of dyslipidemia and hyperglycemia. Eruptive xanthoma can help clinicians determine the presence of hypertriglyceridemia and insulin insensitivity induced by obesity and diabetes mellitus, as well as genetic disorders related with lipoprotein metabolism. Clinicians should therefore be aware of skin manifestations of metabolic disorders, which can lead to atherosclerosis.