Dermatology

Xanthoma, eruptive (hyperchylomicronemia, Fredrickson type I hyperlipoproteinemia, Fredrickson type V hyperlipoproteinemia)

Eruptive xanthoma (hyperchylomicronemia, Fredrickson type I hyperlipoproteinemia, Fredrickson type V hyperlipoproteinemia) ICD-9 272.3

Are You Confident of the Diagnosis?

What you should be alert for in the history

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 and can cause pruritus and tenderness.

These lesions typically resolve over the course of weeks. They first become less inflammatory and less erythematous, next transforming to waxy-yellow papules, which can heal as hyperpigmented scars. Rarely, a patient will have lesions in different phases of evolution.

As discussed below, eruptive xanthomas occur almost exclusively in the setting of elevated plasma levels of chylomicrons, which are the lipoprotein responsible for the transport of triglycerides.

Eruptive xanthomas have been described as a characteristic feature of two primary hyperlipoproteinemias: lipoprotein lipase deficiency and familial hyperlipoproteinemia, type V.

Lipoprotein lipase deficiency typically manifests in childhood (and rarely in young adults). These patients develop eruptive xanthomas, lipemia retinalis, and pancreatitis. Their serum triglycerides are greatly elevated.

Familial hyperlipoproteinemia, type V, which manifests in adulthood, is very often accompanied by concomitant obesity, insulin resistance, and non-insulin dependent diabetes mellitus.

Drugs that affect chylomicron and triglyceride metabolism can also cause the formation of eruptive xanthomas. The ingestion of alcohol, estrogen therapy, systemic retinoids (isotretinoin and bexarotene), certain atypical antipsychotics (olanzapine), and protease inhibitors have all been associated with eruptive xanthomas.

Other rare diseases associated with eruptive xanthomas include Type I glycogen storage disease (von Gierke’s disease), hypothyroidism, and nephrotic syndrome.

Characteristic findings on physical examination

Eruptive xanthomas appear as red-yellow dermal papules, 1 to 4mm in size with a predilection for the extensor surfaces of the hands, arms, knees, and buttocks (Figure 1). They may also arise over the antecubital and popliteal fossa, axilla, lips, eyelids, and ears. They can exhibit the Koebner phenomenon (Figure 2).

Figure 1.

Eruptive xanthoma appear as red-yellow dermal papules seen here on the extensor surfaces of the knees. (Courtesy of the Betty E. Janes Clinical Image Library, Department of Dermatology, University of Texas Southwestern Medical Center)

Figure 2.

Eruptive xanthoma can demonstrate the Koebner phenomenon arising in areas of trauma to the skin. (Courtesy of the Betty E. Janes Clinical Image Library, Department of Dermatology, University of Texas Southwestern Medical Center)

Expected results of diagnostic studies

Histopathology

The hallmark histopathologic feature of all xanthomas is the presence of foam cells within the dermis. These cells represent macrophages that contain lipid. They will stain positive for lipid with special stains (Oil-red-O). Eruptive xanthoma, especially in the acute and inflammatory phases, can have an inflammatory cell infiltrate. This infiltrate can be comprised of lymphocytes, histiocytes (with the accompanying presence of giant cells), and neutrophils.

Serologic tests

A fasting lipid profile should be obtained in all patients with eruptive xanthomas. Since these lesions develop in the setting of chylomicronemia, patients will usually have starkly elevated triglycerides. The degree of elevation can provide a clue to the underlying etiology. In lipoprotein lipase deficiency, plasma triglycerides are typically elevated to greater than 1,000mg/dl. By contrast, in familial hyperlipoproteinemia, type V serum triglycerides are only elevated to 500mg/dl. Patients with non-hereditary etiologies for their increased triglycerides will have variable degrees of elevation.

Diagnosis confirmation

Since the lesions of eruptive xanthomas pass through stages, they can mimic various disease processes (Figure 3). The differential diagnosis includes:

  • Molluscum contagiosum

  • Acne

  • Acneiform drug reactions

Figure 3.

In patients with lighter skin types the erythema of acute, eruptive xanthoma is more pronounced. Lesions in this stage can be confused for acne, acneiform drug reactions, or inflamed molluscum contagiosum. (Courtesy of the Betty E. Janes Clinical Image Library, Department of Dermatology, University of Texas Southwestern Medical Center)

Who is at Risk for Developing this Disease?

Eruptive xanthomas are commonly associated with a number of conditions related to elevated chylomicrons and triglycerides. A useful clinical framework involves separating these entities into primary derangements in lipid metabolism and secondary processes.

The primary processes include lipoprotein lipase deficiency and type V familial hyperlipoproteinemia. Both of these entities are relatively rare with only one in one million persons being homozygous for a mutation in lipoprotein lipase.

Factors causing an elevation of plasma triglycerides can induce the formation of eruptive xanthomas. Systemic illnesses that can induce eruptive xanthomas include diabetes mellitus, nephrotic syndrome, hypothyroidism, and Type I glycogen storage disease. A variety of drugs and ingestions can induce the formation of eruptive xanthomas including alcohol ingestion, systemic retinoids, estrogen, atypical antipsychotics, and protease inhibitors.

What is the Cause of the Disease?

Etiology

Pathophysiology

Eruptive xanthomas occur almost exclusively in the setting of elevated plasma levels of chylomicrons, which are the predominant lipoproteins produced by enterocytes. Dietary triglycerides are transported into the enterocyte 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 the chylomicrons.

The apolipoproteins act as cofactors and receptors for metabolic functions and trafficking of chylomicrons. The main apolipoprotein present in the chylomicron is B48. However, it is the apolipoproteins C and E that act as a cofactor and trafficking molecule, respectively.

Chylomicrons leave the intestinal lymphatics and enter systemic circulation, traveling through the capillary system where lipoprotein lipase recognizes class C apolipoproteins (apo-C) present on chylomicrons and exert their hydrolytic action. Progressive hydrolysis of constituent triglycerides causes reduction in the size of the chylomicron and loss of other surface components including apo-C. The resultant, smaller particles are known as chylomicron remnants. The presence of apolipoprotein E on these particles enables trafficking to the liver for further metabolism.

There is good evidence that the lipid found within xanthomas is the same lipid circulating in high concentrations in the plasma of patients. However, the exact mechanisms that induce xanthoma formation are less clear. It has been demonstrated that using scavenger receptors for low density lipoprotein macrophages can take up lipid and become transformed into foam cells. It has also been shown that extravasated lipid can attract foam cells through modulation of vascular endothelial receptors. Furthermore, oxidized low density lipoprotein has been shown to induce the formation and infiltration of foam cells within the dermis.

Systemic Implications and Complications

Since the underlying pathomechanism of eruptive xanthomas is excess chylomicrons and triglycerides, they are useful cutaneous markers of an underlying lipid abnormality. Patients should have a fasting lipid profile examined, with an emphasis on triglycerides. Any lipid derangement should be corrected accordingly and follow up is warranted.

It is currently felt that isolated elevations of triglycerides do not confer a high risk of atherosclerosis and coronary artery disease. However, when present with other lipid derangements treatment of triglycerides is felt to be beneficial in the prevention of myocardial infarction.

Elevated triglycerides are potent stimuli for pancreatitis and patients can present with symptoms of eruptive xanthoma and pancreatitis concurrently, especially in the setting of lipoprotein lipase deficiency.

Treatment Options

Lifestyle modifications and prevention

  • Dietary restriction of total triglycerides

  • Strict glycemic control in diabetes

  • Weight loss

Systemic medications

  • Fibric acid derivatives (fenofibrate and gemfibrozil)

Optimal Therapeutic Approach for this Disease

Lifestyle modifications

Dietary modifications to reduce the total amount of triglycerides can be useful in patients with all types of hypertriglyceridemia. Counseling patients to avoid high fat foods and to consume less than ten percent of total calories in the form of triglycerides is advisable in patients with lipoprotein lipase deficiency.

For patients with lipoprotein lipase deficiency there are no good medical treatments that will effectively decrease the amount of circulating triglycerides in their blood. The main goal is reduction through dietary means to a goal of less than 1,500mg/dl, which significantly reduces the risk of pancreatitis.

Patients with underlying diabetes benefit from strict glycemic control. They should be started on either oral hypoglycemic agents or insulin based upon their disease severity. Additionally, dietary modifications and weight loss will improve their lipid profiles.

Prevention

Patients starting a medication known to increase triglycerides (isotretinoin, bexarotene, or protease inhibitor) can be counseled to decrease their dietary consumption of triglycerides as a preventative measure. Alternatively, patients with underlying hypertriglyceridemia that will be started on a medication known to increase triglyceride levels, or patients being started at doses known to cause significant increases in triglycerides should have their lipids evaluated before treatment is initiated.

Systemic medications

In addition to the above, treatment with fibric acid derivatives (gemfibrozil and fenofibrate) can be undertaken to reduce plasma triglyceride levels. These drugs are ligands for the nuclear transcription factor peroxisome proliferation-activated receptor-alpha (PPAR-alpha). By binding PPAR- alpha they up-regulate lipoprotein lipase, apolipoproteins A-I, and A-II; and they down-regulate apolipoprotein C-III, which is an inhibitor of lipolysis.

Acting on these effector molecules plasma triglyceride levels are decreased. The fibric acid derivatives exert only a modest effect on LDL and HDL. In some patients LDL levels can actually increase with fibric acid therapy and they should be monitored accordingly.

The usual dose for gemfibrozil is 600mg orally once or twice daily. The dose for fenofibrate is between one to three 48mg tablets daily.

Patient Management

Once the underlying lipid abnormality is corrected eruptive xanthomas begin to resolve. The timing of this process is variable between patients but can be as short as a few weeks. The timing and duration of monitoring depends upon the clinical scenario that induced the elevated triglyceride levels. Patients with hereditary components to their lipid abnormalities (lipoprotein lipase deficiency and type V hyperlipoproteinemia) will need to be followed for the duration of their lives.

Patients with a drug-induced hypertriglyceridemia should initially be followed closely with serial laboratory monitoring. Once triglyceride levels reach steady state, the frequency of monitoring can be decreased. However, at each visit these patients should be queried about new medicines, alcohol intake, and glycemic control (if applicable) as these can cause changes in triglyceride levels.

Unusual Clinical Scenarios to Consider in Patient Management

Rarely eruptive xanthomas have been reported in patients with type IV hypertriglyceridemia, hypothyroidism, nephrotic syndrome, and type I glycogen storage disease (von Gierke’s disease).

What is the Evidence?

Chang, HY, Ridky, TW, Kimball, AB, Hughes, E, Oro, AE. "Eruptive xanthomas associated with olanzapine use". Arch Dermatol. vol. 139. 2003. pp. 1045-1048.

(Three cases of eruptive xanthomas associated with the use of an atypical antipsychotic drug. This report also highlights the effect of these medications on lipoprotein metabolism.)

Teltscher, J, Silverman, RA, Stork, J. "Eruptive xanthomas in a child with the nephrotic syndrome". J Am Acad Dermatol. vol. 21. 1989. pp. 1147-9.

(The effects of the nephrotic syndrome on lipoprotein metabolism and triglyceride levels are exemplified in this case report and brief review.)

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.)

Miller, DM, Brodell, RT. "Eruptive xanthomatosis with linear koebnerization". J Am Acad Dermatol. vol. 33. 1995 Nov. pp. 834-5.

(The Koebner phenomena can be observed in eruptive xanthomas.)

Elder, DE. "Lever’s Histopathology of the Skin". Wilkins. 2005.

(The salient histologic features of eruptive xanthomas are reviewed.)

Kasper, DL. "Harrison’s Principles of Internal Medicine". McGraw-Hill. 2005.

(This reference provides a complete review of lipoprotein metabolism.)

Goodman, LS. "Goodman and Gilman’s pharmacological basis of therapeutics". McGraw-Hill. 2011.

(The therapeutic principles of the treatment of hyperlipidemia are reviewed, as well as dosing regimens.)
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