About 52% of patients who develop xanthelasma have a lipid disorder.⁹ Primary lipid disorders include familial hypercholesterolemia (hyperlipidemia type IIa), familial combined hyperlipidemia (hyperlipidemia type IIb), and familial hypertriglyceridemia (hyperlipidemia type IV). Secondary hyperlipidemia may be seen with pregnancy, obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, and cholestasis.¹⁰,¹¹,¹²,¹³ Some medications, such as estrogens, prednisolone, cyclosporine, tamoxifen, oral retinoids, and protease inhibitors can also cause secondary hyperlipidemia.¹⁴,¹⁵,¹⁶ XP has also been reported in patients who previously had erythroderma,¹⁷ generalized cutaneous inflammatory dermatoses,¹⁸ or contact dermatitis.¹⁹

The exact etiology of XP is not clear. Trauma and inflammation can alter vascular permeability, and it has been demonstrated experimentally that the rate of capillary leakage of low-density lipoprotein (LDL) is increased in areas exposed to friction and constant movement.²⁰,²¹ This suggests that trauma, inflammatory cells, and mediators may be a factor in the pathogenesis of XP.³,⁵

The dermis of the eyelid is thin and vascular-rich, and pulsatile blood pressure, as well as local heat, may increase dermal capillary pressure during repeated blinking. This may play a role in the rate of lipid leakage and subsequent deposition in the eyelid by allowing lipoproteins to enter the dermis where they become oxidized by free radicals or ultraviolet
light, phagocytosed by dermal cells, and transformed into xanthoma cells.⁵,²²,²³ These cells have a perivascular arrangement, suggesting that their stored lipid might originate from plasma lipids. Cholesterol entering cells along the capillary walls is mostly LDL, suggesting that the accumulated cholesterol is derived from blood.²¹ These cells form foamy histiocytes causing inflammation and fibrosis in surrounding tissues. The yellowish cholesterol-rich foam cells accumulate in the skin, resulting in the clinical findings of xanthelasma.²⁴

The inciting events leading to the formation of xanthelasma remain obscure. However, the inflammatory environment surrounding their formation is similar to that seen in the early stages of the formation of cardiac atherosclerotic plaques,²⁵ and it has even been suggested that XP may be a predictor of ischemic heart disease, myocardial infarction, or systemic atherosclerosis.⁴,²⁶ Atheromagenesis is believed primarily to be an inflammatory process, driven by oxidized LDL and elevated iNOS, COX, metallopeptidase, and MPO levels. These result in the recruitment of blood monocytes to the vessel wall, monocyte activation, and transformation into lipidized macrophages, or “foam cells” that accumulate cholesterol.²⁷,²⁸,²⁹

Xanthelasmas do not develop in most patients with hypercholesterolemia, suggesting that other factors may contribute to the pathogenesis.⁵ In vitro lipogenesis studies have shown in situ synthesis of all major lipid groups in xanthoma tissue in both hyperlipidemic as well as normolipidemic patients.⁵,²⁰ Impaired cholesterol removal from the tissues resulting in decreased levels of high-density lipoprotein (HDL) may also play a role in the formation of xanthelasma.⁵,²⁰

A xanthelasma-like reaction has been reported as a complication of filler injections.³⁰,³¹ The mechanism of macrophage lipid accumulation and foam cell formation in patients with no lipid abnormalities before filler injection is not understood. However, it has been proposed that hyaluronic acid injections may bind extravasated LDL lipoprotein and that the LDL-glycosaminoglycan complex becomes internalized by macrophages and histiocytes more avidly than does native LDL, resulting in xanthelasma formation.³²

XP typically presents as bilateral, symmetrical, flat or slightly elevated, soft, yellowish papules or plaques in the periorbital region, and they usually grow over time (Figure 123.1). Occasionally they can appear darker red or even brown¹ and can be semisolid or rarely even calcareous (Figure 123.2A). In patients with hypercholesterolemia, lesions tend to be more nodular and tendinous (Figure 123.2B).⁵ Less commonly, lesions can be seen on the neck, trunk, shoulders, and axillae.⁵

XP lesions most commonly occur near the medial canthal portion of the eyelids, more frequently on the upper lid.³³ They typically present in middle-aged and older individuals and are seen more frequently in females.¹,⁶ Lesions progress slowly and do not regress without treatment. When very large on the upper eyelid, they may cause mechanical ptosis (Figure 123.3).³⁴