Xanthomas

Introduction

Cutaneous xanthomas develop as a result of deposition of lipid in the dermis, primarily within macrophages (foam cells) but also extracellularly. One of their major distinguishing clinical features is a characteristic yellow to orange hue. Xanthomas may present with a variety of morphologies, from macules and papules to plaques and nodules. As discussed below, the morphology and anatomic location of the lesions often suggest the type of underlying lipid disorder or the presence of a paraproteinemia.

Xanthomas can develop in the setting of primary or secondary disorders of lipid metabolism. Thus, early recognition of these lesions can make a significant impact on the diagnosis, management, and prognosis of patients who suffer from an underlying disease. It is therefore important for dermatologists to become familiar with the basic concepts of lipid metabolism and the associated disease states, as well as to be able to recognize the often pathognomonic cutaneous findings.

Epidemiology

Hyperlipidemia is quite common in the general population. In North America alone, it is estimated that over 100 million people currently have an elevated serum cholesterol level >200 mg/dl. Despite the large number of people who suffer from hyperlipidemia, only a minority will develop cutaneous xanthomas. Also, because the exact mechanism by which xanthomas form is not yet fully understood, it is not always possible to predict who will develop them. Xanthomas are thought to result from the permeation of circulating plasma lipoproteins through dermal capillary blood vessels followed by phagocytosis of the lipoproteins by macrophages, forming lipid-laden cells known as foam cells . However, the precise steps and their regulation are still an area of investigation.

Pathogenesis

There is strong evidence to support the theory that the lipids found in the various xanthomas are the same as those in the circulation . The majority of plasma lipids are transported in complex structures known as lipoproteins. The basic structure of the lipoprotein allows the delivery of triglycerides and cholesterol to peripheral cells for their metabolic needs. This structure consists of a hydrophilic outer shell and a hydrophobic core. The outer shell consists of phospholipids, free cholesterol, and non-covalently linked specialized proteins known as apolipoproteins or apoproteins (apo). The inner core contains triglycerides and cholesterol esters.

Lipoproteins differ in their core lipid content. Triglycerides are the major core lipids in chylomicrons and very-low-density lipoproteins (VLDLs), while cholesterol esters dominate the core of low-density lipoproteins (LDLs), high-density lipoproteins (HDLs), and remnants of chylomicrons and VLDLs. The apoproteins found in the outer shell can also differ amongst the various lipoproteins ( Table 92.1 ). These apoproteins serve several important functions, such as mediating the binding of lipoproteins to their respective receptors in target organs and activating enzymes involved in their metabolism.

There are two major pathways of lipoprotein synthesis ( Fig. 92.1A ). The exogenous pathway begins with dietary fat intake. Through the action of pancreatic lipase and bile acids, dietary triglycerides are degraded to fatty acids and monoglycerides. After absorption by the intestinal epithelium, the triglycerides are reformed and packaged with a small amount of cholesterol esters into the central core of a chylomicron. The outer shell of the chylomicron consists of phospholipids, free cholesterol, and several apoproteins, including B-48, E, A-I, A-II, and C-II.

Chylomicrons then enter the lymphatics and eventually the systemic circulation via the thoracic duct. Once in the circulation, hydrolysis of the core triglycerides occurs, releasing free fatty acids to the peripheral tissues. This is mediated through the action of the enzyme lipoprotein lipase that is bound to capillary endothelium. The activation of the lipoprotein lipase system is complex and involves not only hormones such as insulin, but also apoproteins such as C-II, located on the lipoprotein outer surface, and GPIHBP1, a protein expressed on endothelial cells that binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen.

After hydrolysis of approximately 70% of the original triglyceride content, a chylomicron “remnant” exists. The central core now contains predominantly cholesterol ester that has been acquired from circulating HDL molecules. The chylomicron remnant is taken up by the liver via specialized high-affinity apo B-100/E receptors that recognize the apoproteins E ₃ or E ₄ on the remnant's outer shell. Once in the liver, the remaining lipids enter hepatic storage and apoproteins such as B-48 are degraded.

The endogenous pathway begins with the hepatic formation of VLDL particles. The central core of the VLDL consists primarily of triglycerides, which are derived from circulating free fatty acids and hepatic triglyceride stores. Important apoproteins found on the outer shell include B-100, E, and C-II. In a fashion similar to the chylomicron, lipoprotein lipase mediates hydrolysis of the VLDL molecule, removing the majority of its triglyceride content, and its cholesterol esters are acquired from HDL molecules. Lipoprotein lipase activation requires the presence of apo C-II on the VLDL outer shell. After removal of the majority of the triglyceride content, the VLDL “remnant”, also known as an intermediate-density lipoprotein (IDL), can then be taken up by the liver via apo B-100/E receptors and degraded. IDLs that escape uptake by the hepatocyte are stripped of their remaining core triglycerides by extracellular hepatic lipases and enter the circulation as LDLs.

The LDL contains predominantly cholesterol ester in its central core and expresses B-100 on its surface. LDL delivers cholesterol ester to peripheral tissues, where it can be converted to free cholesterol. Cholesterol has several important functions within the body, including being an essential component of cell membrane bilayers. It is also important in the production of the myelin sheath of nerves, adrenal and gonadal steroidogenesis, and the production of bile acids. Hepatocytes play the major role in the catabolism of LDLs. Their uptake is mediated through the high-affinity apo B-100/E receptor found on the cell surface of the hepatocytes. Free cholesterol in excess of metabolic needs is re-esterified for storage.

HDLs serve several important functions in cholesterol metabolism. One of the primary functions of HDLs is the removal of cholesterol from the peripheral tissues. During this process, free cholesterol and phospholipids are transferred from the cell membranes of peripheral cells to the HDL molecules. The free cholesterol is then esterified by the enzyme l ecithin: c holesterol a cyl t ransferase, or LCAT. This enzyme requires the presence of the HDL apoprotein A-I. HDL molecules then transfer the cholesterol esters to other lipoproteins such as LDLs and remnants of chylomicrons or VLDLs for transportation back to the liver.

The liver plays the central role in the overall cholesterol economy. Hepatic intracellular cholesterol levels have a direct impact on the activity of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis, and on the expression of the high-affinity apo B-100/E receptor. When intracellular cholesterol levels are low, HMG-CoA reductase becomes activated and high-affinity apo B-100/E receptor expression increases. The increase in high-affinity receptors leads to increased uptake of cholesterol-containing lipoproteins such as chylomicron remnants, IDLs and LDLs. This is followed by the lowering of plasma cholesterol levels. As discussed later, this mechanism will be the basis for many of the pharmacologic interventions aimed at lowering cholesterol levels.

Clinical Features

Due to the complexity of cholesterol homeostasis, there are several possible ways in which hyperlipidemia may occur, from inherited disorders to metabolic diseases such as diabetes mellitus. Genetic mutations can affect important enzymes, receptors or receptor ligands, with such defects leading to the overproduction of lipoproteins or the inhibition of their clearance ( Fig. 92.1B ). Each possible defect would lead to a different abnormal lipid profile.

In 1965, Lees and Frederickson published a system for classifying various disorders of lipid metabolism based upon the electrophoretic migration of the serum lipoproteins present. This system for phenotyping hyperlipoproteinemias is used today in a modified form ( Table 92.2 ). In the next section, descriptions of underlying lipid disorders will reference not only the Frederickson classification system, but also the specific molecular defects when possible.

With the exception of the homozygous form of familial hypercholesterolemia (type II), most cutaneous xanthomas do not appear until adulthood. Once the diagnosis is established, treatment of associated disorders (e.g. metabolic syndrome [see Table 53.5 ]) should reduce the incidence of potential systemic sequelae such as myocardial infarctions, cerebrovascular accidents, and hepatic steatosis.