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.