Are You Confident of the Diagnosis?
What you should be alert for in the history
Xanthomas are macules, papules, nodules, or plaques distinguished by a yellow color due to the lipid found within foam cells that are the histologic hallmark of these lesions. Xanthomatous lesions are of two types: xanthomas, per se, which are discussed here and in succeeding sub-sections; and xanthogranulomas that are discussed in detail in another section.
Most xanthomas are associated with disorders of lipoprotein metabolism, content, or structure. They can be categorized into morphologic groups, each with distinctive clinical associations: eruptive, tendon, tuberous, plane, and xanthelasma.
As the name implies eruptive xanthomas develop rapidly in crops or showers. These red-yellow dermal papules can be quite inflammatory In their acute stage, causing pruritus and tenderness Figure 1, Figure 2, Figure 3).
Slow-growing and sometimes subtle in appearance early in their course, tendon xanthomas present as firm-to-hard subcutaneous nodules with normal overlying skin, predilecting the Achilles tendons and extensor tendons of the digits (Figure 4).
Tuberous xanthomas are papules or nodules that typically appear on the elbows, knees, and buttocks, and less commonly, other areas (Figure 5, Figure 6).
Plane or planar xanthomas are lesions with a relatively flat morphology and thus may appear early as macules. It includes several well-defined subsets, some pathognomonic for specific diseases: intertriginous xanthomas, palmar crease xanthomas, planar xanthomas of cholestasis, diffuse plane xanthoma, and xanthelasma (considered separately below)
Xanthelasma, also called xanthelasma palpebrarum, appear as yellow-to-gray macules or plaques on the eyelids and periorbital skin. They are the most common and least specific of xanthomas (Figure 7).
Mentioned only to provide contrast, xanthogranulomas are associated with disorders of histiocytic proliferation (not lipoprotein abnormalities). More information about them is found in other dedicated sections.
Characteristic findings on physical examination
Each type of xanthoma has distinctive morphology that can aid diagnosis by clinical examination. All are unified by a yellow component imparted by lipid in foam cells. Eruptive xanthomas appear as red-yellow dermal papules, 1 to 4 mm in size with a predilection for the extensor surfaces of the hands, arms, knees, and buttocks. Tendon xanthomas manifest as firm-to-hard subcutaneous nodules with normal overlying skin. They are typically found overlying the Achilles tendon and the extensor tendons of the hand.
Tuberous xanthomas are subcutaneous nodules on the extensor surfaces of the elbows, knees, knuckles, and buttocks. Plane xanthomas appear as well circumscribed (except in the case of diffuse plane xanthoma), non-inflammatory, dermal macules or plaque. Xanthelasma are yellow-to-gray macules or plaques present on the eyelids and the periorbital skin.
Expected results of diagnostic studies
The hallmark histopathologic feature of all xanthomas is the presence of foam cells within the dermis. These cells represent macrophages that have phagocytized lipid. These cells stain positive for lipid with special stains (Oil-red-O).
Some subtypes can have histologic features that can help confirm the clinical diagnosis. For example, eruptive xanthoma, especially in their acute and inflammatory phases can have an inflammatory cell infiltrate comprised of lymphocytes, histiocytes (with the accompanying presence of giant cells), and neutrophils.
Tendon xanthomas (and some tuberous xanthomas) may possess cholesterol clefts that stain positive with special stains (Schultz stain) and are doubly refractile.
Patients with a xanthoma should have a fasting lipid (or lipoprotein) profile performed especially since many are diagnostic of specific lipoprotein abnormalities:
Eruptive xanthomas occur in the setting of chylomicronemia (eg, lipoprotein lipase deficiency) in which patients have markedly elevated chylomicrons (and thus triglycerides).
Tendon xanthomas occur in the setting of elevated low-density lipoproteins or cholesterol (e.g., familial heterozygous hypercholesterolemia and less commonly with cholestanolemia or sitosterolemia). Intertriginous xanthomas are pathognomonic for familial homozygous hypercholesterolemia.
Palmar crease xanthomas (especially concurrent with tuberous xanthomas of the elbow) are pathognomonic of remnant removal disease or dysbetalipoproteinemia. For patients with diffuse, normolipemic planar xanthoma an evaluation to evaluate for underlying plasma cell dyscrasia, multiple myeloma, or lymphoma should include a complete blood count with differential, serum protein electrophoresis, and urine protein electrophoresis.
Each subtype of xanthoma, with its unique morphology has its own set of clinical mimics. Some of the commonly encountered items in the differential diagnosis of xanthomatous lesions are included below:
Eruptive xanthomas especially during the acute inflammatory phase can mimic acne, molluscum, and drug reactions.
Tendon and tuberous xanthomas can be mistaken for cysts, lipomas, and other benign neoplasms.
Plane xanthomas may be confused with amylodiosis, sarcoidosis, and pseudoxanthoma elasticum.
Xanthelasma should be differentiated from adnexal tumors and necrobiotic xanthogranuloma.
Who is at Risk for Developing this Disease?
Those with underlying disorders of lipoprotein metabolism whether primary or secondary.
Eruptive xanthomas are pathognomonic of chylomicronemia, which can be primary or secondary. Primary disorders include lipoprotein lipase deficiency and type V familial hyperlipoproteinemia. Secondary factors include diabetes mellitus, nephrotic syndrome, hypothyroidism, and Type I Glycogen storage disease. Drugs and ingestions can induce chylomicronemia such as alcohol, retinoids, estrogens, antipsychotics, and protease inhibitors.
Tendon xanthomas are associated with: familial heterozygous and homozygous hypercholesterolemia (FH). The heterozygous form is by far more common with approximately 1 in 500 individuals affected. The incidence of the homozygous form of FH is 1 individual in 1 million.
Tuberous xanthoma is commonly associated with remnant removal disease or dysbetalipoproteinemia. Often times, the clinical syndrome of dysbetalipoproteinemia is unmasked in the presence of an additional abnormality characterized by overproduction of VLDL like diabetes mellitus, obesity, or hypothyroidism.
Plane or planar xanthomas encompass several distinct subcategories of lesion, each associated with unique disorders. Intertriginous xanthomas are pathognomonic of homozygous familial hypercholesterolemia. Palmar crease xanthomas are associated with dysbetalipoproteinemia. The planar xanthomas of cholestasis are associated with either primary or secondary obstructions of the biliary system. Diffuse planar xanthomas are associated with paraproteinemias including myeloma, and leukemia and lymphoma.
Xanthelasma can be associated with normal lipid metabolism as well as disordered lipoprotein metabolism (including homozygous and heterozygous FH and dysbetalipoproteinemia).
What is the Cause of the Disease?
Xanthomas are a cutaneous expression of abnormal lipoprotein metabolism, content, or structure, leading to accumulation of lipoproteins in plasma and / or deposition of lipoproteins or their components in tissues. In the dermis, subcutaneous tissue, and tendons, the end result is transformation of macrophages into lipid-laden foam cells and formation of xanthomatous lesions.
Key to understanding the differences among the various xanthomatous lesions is understanding lipoprotein metabolism. The major function of lipoprotein particles is to transport lipids within plasma. Triglycerides and cholesterols are carried within the hydrophobic core of the particle, whereas the hydrophilic surface is composed of phospholipids and apolipoproteins.
The exogenous pathway of lipoprotein metabolism begins with dietary triglycerides transported into enterocytes as free fatty acids and monoglycerides. In the enterocyte these constituents are reformed into triglycerides, which are subsequently combined with unesterified cholesterol, phospholipids, and apolipoproteins to form chylomicrons.
Apolipoproteins act as cofactors and receptors for metabolic functions and trafficking of chylomicrons. The main apolipoprotein present in the chylomicron is B48. However, apolipoproteins C and E act as cofactors and trafficking molecules, respectively. The endogenous pathway begins in the liver and involves export of either newly synthesized or recycled triglycerides and cholesterol particles. In the liver very low density lipoprotein (VLDL) molecules are produced. They are triglyceride-rich particles that contain relatively more cholesterol than the chylomicron. The VLDL molecule contains the Apoliprotein-100 molecule as its predominant apolipoprotein. Like chylomicrons, once VLDL leaves the liver it travels through the peripheral circulation where lipoprotein lipase acts upon its triglyceride elements. As triglycerides are removed from VLDL, residual particles called VLDL remnants are formed that continue to travel through the circulation.
VLDL remnants are removed from circulation by interaction of apolipoprotein-E, and apolipoprotein-100 with receptors on hepatocytes. Upon recognition of the apolipoproteins by receptors on hepatocytes, VLDL remnants are internalized. Many VLDL molecules are degraded within hepatocytes to constituent lipids; however, a portion of these particles interact with hepatic lipase, which removes residual triglycerides and converts VLDL to LDL.
LDL particles transport most of the cholesterol present in the fasting serum. They are associated with apolipoprotein-100 that in turn is recognized by LDL-receptors. Three-fourths of LDL is removed from the circulation by LDL receptors on hepatocytes. The remaining fraction is removed by peripheral tissues through non-receptor mediated pathways.
Identification of these patients and systemic treatment directed at normalizing plasma lipid levels is important, as deposition of these lipids in tissues, promotes atherosclerotic disease.
Systemic Medications to lower plasma lipids
– Fibric acids
– HMG CoA reductase inhibitors (Statins)
– Bile acid sequestrants
Surgical Treatments for Xanthomatous lesions
– Surgical excision
Optimal Therapeutic Approach for this Disease
The treatment of xanthomas is directed at correcting the underlying lipid abnormality. The unique nuances of treatment are discussed in the respective sections in further detail. A variety of modalities may need to be employed including dietary modification, systemic medications, and surgical treatment of larger xanthomatous lesions.
The management of a patient with a xanthomatous lesion is unique for each subtype and can be accessed in each subsection. However, some important, broad themes are worth emphasizing.
The identification of the lipid abnormality is perhaps the singular most important contribution to the care of these patients. Once identified, the correct systemic medications and / or physical modalities or surgical techniques can be utilized. After correcting the lipid abnormality many of the cutaneous lesions can be expected to resolve. Importantly, since many of these conditions confer an elevated risk of atherosclerotic disease, this risk can also be reduced with treatment.
Unusual Clinical Scenarios to Consider in Patient Management
Each type of xanthomatous lesion can be encountered in a unique clinical scenario:
Eruptive xanthomas have been reported in patients with type IV hypertriglyceridemia, hypothyroidism, nephrotic syndrome, and type I glycogen storage disease (von Gierke’s disease).
Tendon xanthomas have been reported in conditions that induce elevation of cholestanol (plant sterols) overproduction of apo-B, familial dysbetalipoproteinemia, dysglobulinemias, and hepatic cholestasis. Tendon xanthomas have also been reported in persons with normal lipids.
Xanthelasma has been reported in patients without any overt elevation of lipids levels, but are heterozygous for the abnormal, apolipoprotein-E2 allele. These patients do not have biochemical or the clinical features of the clinical syndrome of familial dysbetalipoproteinemia, which is manifest in some persons homozygous for apolipoprotien-E2. It is unclear if these patients are at an elevated risk of atherosclerosis.
What is the Evidence?
Cruz, PD, East, C, Bergstresser, PR. “Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders”. J Am Acad Dermatol. vol. 19. 1988. pp. 95-111. (A review of the dermatologic manifestations of the various types of xanthomas is presented.)
Elder, DE. “Lever’s Histopathology of the Skin”. 2005. (The salient histologic features of xanthoma are reviewed.)
Kasper, DL, Harrison, TR. “Disorders of lipoprotein metabolism, in Harrison’s Principles of internal medicine”. 2005. (A review of lipoprotein metabolism and the treatment of hyperlipidemia.)
Gómez, JA, Gónzalez, MJ, de Moragas, JM, Serrat, J, Gónzalez-Sastre, F, Pérez, M. “Apolipoprotein E phenotypes, lipoprotein composition, and xanthelasmas”. Arch Dermatol. vol. 125. 1989. pp. 1281-2. Though nearly one-half patients with xanthelasma are normolipemic, some patients are heterozygous carriers of the abnormal, apolipoprotien-E2 allele. It is unclear if these patients are at an increased risk of atherosclerosis.
Bergman, R. “The pathogenesis and clinical significance of xanthelasma palpebrarum”. J Am Acad Dermatol. vol. 30. 1994. pp. 236-42. In this study of patients with xanthelasma nearly one-half of patients were found to be hyperlipidemic. Illustrating the need to screen patients with xanthelasma, especially patients that are young.
Goodman, LS. “Goodman and Gilman’s pharmacological basis of therapeutics”. 2011. A review of the various treatment options for hyperlipidemia.
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