Introduction
Background
Xanthomas are lesions characterized by accumulations of lipid-laden macrophages. Xanthomas can develop in the setting of altered systemic lipid metabolism or as a result of local cell dysfunction.
Pathophysiology
Lipids are insoluble in water; therefore, they are transported as complexes of lipoproteins and specific apoproteins. These proteins also serve as ligands to specific receptors, they facilitate transmembrane transport, and they regulate enzymatic activity. Lipoproteins may be classified according to their density, as follows: chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Lipoproteins may also be separated by electrophoresis into beta (LDL), prebeta (VLDL), and alpha (HDL) lipoproteins. Beta-VLDL (IDL) can be determined by ultracentrifugation and electrophoresis.
The metabolic pathways of lipoproteins can be divided into exogenous and endogenous pathways. The exogenous lipoprotein pathway refers to the metabolism of intestinal lipoproteins, the triglyceride-rich chylomicrons, primarily formed in response to dietary fat. The endogenous lipoprotein pathway refers to lipoproteins and apoproteins that are synthesized in tissues other than the intestines, predominantly in the liver. The liver secretes the triglyceride-rich VLDL that contains apoproteins B-100, C-II, and E into the circulation.
In the peripheral tissues, particularly adipose and muscle tissue, VLDL is cleaved by lipoprotein lipase (LPL), extracting most of the triglycerides and forming an IDL that contains apoproteins B-100 and E. IDL can be taken up by the liver through the LDL receptor, or it can be converted to the cholesterol-rich LDL that contains apoprotein B-100. LDL is removed from the circulation primarily by the liver through the LDL receptor. HDL particles that contain apoproteins A-I and A-II interact with other lipoproteins, particularly VLDL and LDL, through lipolysis and the action of lecithin cholesterol acyltransferase (LCAT) enzyme. The main role of HDL is to accept cholesterol and to transport it back to the liver (reverse cholesterol transport).
Lipoprotein (a) (Lp[a]) consists of an LDL-like particle with apoprotein B and a side chain of a highly glycosylated protein. Lp(a) has a role not only in atherogenesis but also in thrombogenesis because of its homology with plasminogen.
Alterations in lipoproteins result either from genetic mutations that yield defective apolipoproteins (primary hyperlipoproteinemia) or from some other underlying systemic disorder, such as diabetes mellitus, hypothyroidism, or nephrotic syndrome (secondary hyperlipoproteinemia). The biochemical and genetic basis for the inherited disorders of lipid and lipoprotein metabolism differ considerably.
Traditionally, hyperlipidemias have been classified according to 6 phenotypes described by Fredrickson. These phenotypes are based on the electrophoretic patterns of lipoprotein level elevations that occur in patients with hyperlipoproteinemia. In recent years, the understanding of the genetic and biochemical basis of these disorders has revealed a large and diverse group of diseases, many of which have similar clinical expressions, exposing the limitations of the Fredrickson classification system. Despite the system's shortcomings, Fredrickson phenotypes are a useful tool for the discussion of these disorders. The understanding of the pathophysiology of these defects provides a basis for diagnosis and treatment.
Familial lipoprotein lipase deficiency is an example of a primary disorder in which a deficiency of lipoprotein lipase in tissue leads to a type I pattern of hyperlipidemia, with a massive accumulation of chylomicrons in the plasma. This effect results in a severe elevation of plasma triglyceride levels. Plasma cholesterol levels are not usually elevated. Patients with type I may present in early childhood, often with acute pancreatitis. Eruptive xanthomas are the most characteristic skin manifestation of this disorder.
Cholesterol is bound to apolipoprotein B-100 as LDL in interstitial fluid. Cells may acquire cholesterol via an LDL receptor on the cell membrane. Familial LDL receptor deficiency and familial defective apoprotein B-100 are examples of primary defects that can lead to the accumulation of LDL, which corresponds to a type IIa pattern of hyperlipidemia. Plasma cholesterol levels are severely elevated, but plasma triglyceride levels are typically normal. Patients with type IIa have severe atherosclerosis and may present with tendinous or tuberous xanthomas as well as xanthelasmas.
The type IIb pattern is characterized by the accumulation of both LDL and VLDL, with variable elevations of both triglyceride levels and cholesterol levels in the plasma. Patients with familial combined hyperlipoproteinemia have such a pattern of hyperlipidemia, but a specific genetic defect has not been established. Patients with type IIb may present as adults with tendinous or tuberous xanthomas as well as xanthelasmas.
Type III hyperlipidemia is characterized by the accumulation of IDL (beta-VLDL), which is manifested by increases in both triglyceride levels and cholesterol levels in the plasma. A genetic basis for the primary disorder, familial dysbetalipoproteinemia, has been well established. Various mutations of apoprotein E impair its ability to bind to the IDL receptor. Patients with type III present as adults with premature atherosclerosis and xanthomas, particularly plane (palmar) xanthomas.1
Familial hypertriglyceridemia is an example of a primary defect resulting in type IV hyperlipidemia. Accumulation of VLDL causes severe elevations of plasma triglyceride levels. Plasma cholesterol levels are typically normal. A definitive molecular defect has not been established. Patients with type IV may present with eruptive xanthomas.
Genetic defects of the apolipoprotein C-II gene result in the accumulation of chylomicrons and VLDL, which is the type V pattern of hyperlipidemia. Patients with this type have severe elevations of triglyceride levels in the plasma. These patients, like those with lipoprotein lipase deficiency, may present in early childhood with acute pancreatitis and eruptive xanthomas.
Decreased synthesis of HDL due to decreased formation of apoprotein A-I and apoprotein C-III leads to decreased reversed cholesterol transport, resulting in increased LDL levels, premature coronary artery disease, and plane xanthomas.
Hyperlipidemia is also related to a variety of secondary causes. Secondary hypercholesterolemia can be found in pregnancy, hypothyroidism, cholestasis, and acute intermittent porphyria. Secondary hypertriglyceridemia can be associated with oral contraceptive use, diabetes mellitus, alcoholism, pancreatitis, gout, sepsis due to gram-negative bacterial organisms, and type I glycogen storage disease. Combined hypercholesterolemia and hypertriglyceridemia can be found in nephrotic syndrome, chronic renal failure, and steroid immunosuppressive therapy.
Frequency
United States
Xanthomas are a common manifestation of lipid metabolism disorders.
Mortality/Morbidity
- Cutaneous xanthomas are mostly cosmetic disorders; their presence might suggest an underlying disorder of lipid metabolism.
- Morbidity and mortality are related to atherosclerosis (eg, coronary artery disease) and pancreatitis.
Sex
Equal prevalence is reported in males and females.
Age
Xanthomas can occur in persons of any age. Xanthelasmas usually occur in people older than 50 years.
Clinical
History
- A family history of xanthomas may be encountered in hereditary hyperlipoproteinemias.
- Prior history of myocardial infarction and other forms of atherosclerosis as well as pancreatitis may be encountered in some of the syndromes.
- Cutaneous manifestations may precede a diagnosis of hyperlipidemia.
Physical
Cutaneous xanthomas associated with hyperlipidemia can be clinically subdivided into xanthelasma palpebrarum, tuberous xanthoma, tendinous xanthoma, eruptive xanthoma, plane xanthoma, and generalized plane xanthoma. Xanthoma disseminatum and verruciform xanthoma are usually not associated with hyperlipidemia.
- Xanthelasma palpebrarum is the most common of the xanthomas. The lesions are asymptomatic and usually bilateral and symmetric. The lesions are soft, velvety, yellow, flat, polygonal papules around the eyelids. Xanthelasmas are most common in the upper eyelid near the inner canthus. Usually, the lesions have evolved for several months and enlarged slowly from a small papule. Xanthelasma may be associated with hyperlipidemia. When associated with hyperlipidemia, any type of primary hyperlipoproteinemia can be present. Some secondary hyperlipoproteinemias, such as cholestasis, may also be associated with xanthelasmas.
Xanthelasma. Courtesy of Duke University Medical Center.
- Tuberous xanthomas are firm, painless, red-yellow nodules (see Media File 3). The lesions can coalesce to form multilobated tumors. Tuberous xanthomas usually develop in pressure areas, such as the extensor surfaces of the knees, the elbows, and the buttocks. Tuberous xanthomas are particularly associated with hypercholesterolemia and increased levels of LDL. They can be associated with familial dysbetalipoproteinemia and familial hypercholesterolemia, and they may be present in some of the secondary hyperlipidemias (eg, nephrotic syndrome, hypothyroidism).
Tuberous xanthomas. Courtesy of Duke University Medical Center.
- Tendinous xanthomas appear as slowly enlarging subcutaneous nodules related to the tendons or the ligaments. The most common locations are the extensor tendons of the hands, the feet, and the Achilles tendons. The lesions are often related to trauma. Tendinous xanthomas are associated with severe hypercholesterolemia and elevated LDL levels, particularly in the type IIa form. They can also be associated with some of the secondary hyperlipidemias, such as cholestasis.
- Eruptive xanthomas most commonly arise over the buttocks, the shoulders, and the extensor surfaces of the extremities. Rarely, the oral mucosa or the face may be affected. The lesions typically erupt as crops of small, red-yellow papules on an erythematous base (see Media File 2), and they may spontaneously resolve over weeks. Pruritus is common, and the lesions may be tender. Eruptive xanthomas are associated with hypertriglyceridemia, particularly that associated with types I, IV, and V (high concentrations of VLDL and chylomicrons). They may also appear in secondary hyperlipidemias, particularly in diabetes.2
Eruptive xanthomas. Courtesy of Duke University Medical Center.
- Plane xanthomas are mostly macular and rarely form elevated lesions. They can occur in any site. Involvement of the palmar creases is characteristic of type III dysbetalipoproteinemia. They can also be associated with secondary hyperlipidemias, especially in cholestasis. Generalized plane xanthomas can cover large areas of the face, the neck, and the thorax, and the flexures can also be involved. They may be associated with monoclonal gammopathy and hyperlipidemia, particularly hypertriglyceridemia.
- Xanthoma disseminatum and verruciform xanthoma are particular forms of xanthomas that occur in normolipemic patients.3 Xanthoma disseminatum develops in adults as red-yellow papules and nodules with a predilection for the flexures. Characteristically, the mucosa of the upper part of the aerodigestive tract is involved. It has a benign clinical course and usually resolves spontaneously. Verruciform xanthoma predominantly occurs in the oral cavity of adults as a single papillomatous yellow lesion. Verruciform xanthoma is considered to be a reactive condition with benign behavior, and it is treated with local excision.
Causes
See Pathophysiology.
More on Xanthomas |
 Overview: Xanthomas |
| Differential Diagnoses & Workup: Xanthomas |
| Treatment & Medication: Xanthomas |
| Follow-up: Xanthomas |
| Multimedia: Xanthomas |
| References |
| Next Page » |
References
Sharma D, Thirkannad S. Palmar Xanthoma-An Indicator of a More Sinister Problem. Hand (N Y). Sep 22 2009;[Medline].
Streit E, Helmbold P. [65-year-old man with yellow-orange papules on both forearms. Eruptive xanthomas]. Hautarzt. Oct 2009;60(10):834-7. [Medline].
Caputo R, Monti M, Berti E, Gasparini G. Normolipemic eruptive cutaneous xanthomatosis. Arch Dermatol. Nov 1986;122(11):1294-7. [Medline].
Inazu A, Koizumi J, Kajinami K, Kiyohar T, Chichibu K, Mabuchi H. Opposite effects on serum cholesteryl ester transfer protein levels between long-term treatments with pravastatin and probucol in patients with primary hypercholesterolemia and xanthoma. Atherosclerosis. Aug 1999;145(2):405-13. [Medline].
Fujita M, Shirai K. A comparative study of the therapeutic effect of probucol and pravastatin on xanthelasma. J Dermatol. Sep 1996;23(9):598-602. [Medline].
Yamamoto A, Matsuzawa Y, Yokoyama S, Funahashi T, Yamamura T, Kishino B. Effects of probucol on xanthomata regression in familial hypercholesterolemia. Am J Cardiol. Jun 27 1986;57(16):29H-35H. [Medline].
Kuo PT, Hayase K, Kostis JB, Moreyra AE. Use of combined diet and colestipol in long-term (7--7 1/2 years) treatment of patients with type II hyperlipoproteinemia. Circulation. Feb 1979;59(2):199-211. [Medline].
Mendelson BC, Masson JK. Xanthelasma: follow-up on results after surgical excision. Plast Reconstr Surg. Nov 1976;58(5):535-8. [Medline].
Raulin C, Schoenermark MP, Werner S, Greve B. Xanthelasma palpebrarum: treatment with the ultrapulsed CO2 laser. Lasers Surg Med. 1999;24(2):122-7. [Medline].
Borelli C, Kaudewitz P. Xanthelasma palpebrarum: treatment with the erbium:YAG laser. Lasers Surg Med. 2001;29(3):260-4. [Medline].
Basar E, Oguz H, Ozdemir H, Ozkan S, Uslu H. Treatment of xanthelasma palpebrarum with argon laser photocoagulation. Argon laser and xanthelasma palpebrarum. Int Ophthalmol. Jan 2004;25(1):9-11. [Medline].
Haygood LJ, Bennett JD, Brodell RT. Treatment of xanthelasma palpebrarum with bichloracetic acid. Dermatol Surg. Sep 1998;24(9):1027-31. [Medline].
Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol. Nov 5 1998;82(9A):3Q-12Q. [Medline].
Cruz PD Jr, East C, Bergstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. Jul 1988;19(1 Pt 1):95-111. [Medline].
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. Jan 5 1967;276(1):34-42 contd. [Medline].
Goldstein JL, Brown MS. Familial hypercholesterolemia. A genetic regulatory defect in cholesterol metabolism. Am J Med. Feb 1975;58(2):147-50. [Medline].
Haber C, Kwiterovich PO Jr. Dyslipoproteinemia and xanthomatosis. Pediatr Dermatol. Apr 1984;1(4):261-80. [Medline].
Havel RJ. Approach to the patient with hyperlipidemia. Med Clin North Am. Mar 1982;66(2):319-33. [Medline].
Hu CH, Ellefson RD, Winkelmann RK. Lipid synthesis in cutaneous xanthoma. J Invest Dermatol. Aug 1982;79(2):80-5. [Medline].
Parker F. Xanthomas and hyperlipidemias. J Am Acad Dermatol. Jul 1985;13(1):1-30. [Medline].
Rader DJ. Pathophysiology and management of low high-density lipoprotein cholesterol. Am J Cardiol. May 13 1999;83(9B):22F-24F. [Medline].
Vermeer BJ, Gevers Leuven J. New aspects of xanthomatosis and hyperlipoproteinemia. Curr Probl Dermatol. 1991;20:63-72. [Medline].
Further Reading
Keywords
xanthoma, xanthomas, xanthelasma, xanthelasma palpebrarum, tuberous xanthoma, tendinous xanthoma, eruptive xanthoma, palmar xanthoma, plane xanthoma, generalized plane xanthoma, xanthoma disseminatum, verruciform xanthoma, hyperlipidemia, lipoprotein lipase deficiency
