News & Perspective
Drugs & Diseases
CME & Education
Video
Decision Point
Edition: English

Medscape

English
Deutsch
Español
Français
Português
UKNew

Univadis

Sign Up It's Free!
English Edition

Medscape

Univadis

    X
    Univadis from Medscape

    No Results

      News & Perspective Drugs & Diseases CME & Education Video Decision Point
      Drugs & Diseases > Dermatology

      Xanthomas

      Updated: Jun 09, 2021
      • Author: Kara Melissa Torres Culala, MD; Chief Editor: Dirk M Elston, MD  more...
      • Print
      Overview

      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.

      Next:

      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).

      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. A case reported in 2020 described this type of xanthoma as the presenting and only sign of undiagnosed diabetes mellitus. [1] The cutaneous lesions resolved within 3 months of diet modification and correction of lipid and glycemic parameters.

      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.

      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 IIa and IIb may present as adults with tendinous and tuberous xanthomas and 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, particularly, plane (palmar) xanthomas. [2]

      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. [3]

      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.

      Normolipemic xanthoma may occur as xanthoma disseminatum, diffuse-plane normolipemic xanthomatosis, and verruciform xanthoma. In these patients with normal lipid profiles, inflammation and trauma/local tissue injury are thought to be the implicating factors in the development of the cutaneous lesions. These patients are at risk for underlying myeloproliferative disorders and should be evaluated for paraproteinemia.

      Xanthoma disseminatum is a non–Langerhans cell of class II histiocytic disorder. [4] The etiology is unknown but it is usually associated with diabetes insipidus. [5] Familial inheritance is uncertain. [6]

      Diffuse-plane xanthomatosis is a rare, noninherited disorder related to diseases of the reticuloendothelial system. [7] The pathogenesis remains unclear but is often associated with multiple myeloma and monoclonal gammopathy. In 2020, diffuse normolipidemic–plane xanthoma was reportedly seen in association with necrobiotic xanthogranuloma. [8]

      Verruciform xanthoma is considered a reaction pattern to chronic inflammation or trauma or a result of impaired lymphatic function. [9, 10, 11] A case of verruciform xanthoma that appeared 3 years post resection of genital Paget disease was reported in 2021. [12]

      Cerebrotendinous xanthomatosis is a rare serious autosomal recessive disorder of bile acid synthesis. It is categorized as an adult lipid storage disorder with known mutation in the CYP27A1 gene; there is resultant deficiency in sterol 27-hydroxylase. Cholesterol and cholestanol deposits then accumulate in the nervous system and tendons; hence, neurologic clinical and diagnostic imaging findings and tendon xanthomas are the characteristic findings. [13]

      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 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. [14, 15]

      Iatrogenic causes of hypertriglyceridemia should also be screened. Drug-induced hypertriglyceridemia should be considered in patients taking long-term isotretinoin, sodium valproate, protease inhibitors, sertraline, thiazide diuretics, oral contraceptive pills, cyclosporine, or tacrolimus. [16]

      Previous
      Next:

      Epidemiology

      Frequency

      Xanthomas are a common manifestation of lipid metabolism disorders. Xanthelasmas comprise 6% of eyelid tumors. [17] Diffuse normolipemic forms occur less frequently.

      Sex

      Equal prevalence of xanthoma is reported in males and females. Xanthoma disseminatum occurs in a male-to-female ratio of 2.4:1. [18]

      Age

      Xanthomas may occur in persons of any age. Xanthelasmas usually occur in people older than 50 years. Xanthoma disseminatum occurs before age 25 years in two thirds of cases. [18]

      Previous
      Next:

      Prognosis

      Cutaneous xanthomas are mostly cosmetic disorders; their presence might suggest an underlying disorder of lipid metabolism.

      Recurrences postsurgical treatment of xanthomas are common.

      Significant mortality and morbidity arise in patients with involvement of functional anatomic sites in xanthoma disseminatum. [19] Otherwise, the course of the disease is benign. However, the common types persist and the rest either resolve spontaneously or progress. [20, 5]

      Morbidity and mortality are related to atherosclerosis (eg, coronary artery disease) and pancreatitis.

      Previous
      Clinical Presentation
       
       
      Media Gallery
      of 4
      Find Us On
      About
      About Medscape Privacy Policy Editorial Policy Cookies Manage Preferences Terms of Use Advertising Policy Help Center
      Membership
      Become a Member About You Professional Information Newsletters & Alerts Market Research
      App
      Medscape
      WebMD Network
      Medscape Live Events WebMD MedicineNet eMedicineHealth RxList WebMD Corporate Medscape UK
      Editions
      English Deutsch Español Français Português UK
      All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC. This website also contains material copyrighted by 3rd parties.