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Home , Hypertriglyceridemia, Xanthoma

Eruptive : A Case Report

Shannon Pickens, MD; George Farber, MD; Mehdi Mosadegh, MD

Eruptive xanthomatosis is a papular skin disorder and free thyroxine, less than 0.04 ng/dL (reference resulting from , specifically hyper- range, 0.70–1.48 ng/dL). Two punch biopsies were triglyceridemia. It is characterized by yellowish performed. Histologic examination revealed histio- red concentrated on extensor surfaces cytic xanthomatous nodules and foamy histiocytes of the arms and legs. The hyperlipidemia respon- consistent with eruptive xanthoma (Figure 2). sible for this disorder can be caused by a primary genetic defect, a secondary disorder, or both. Comment Eruptive often rapidly resolve after A xanthoma is a deposition of macrophages laden treatment of the hyperlipidemia has begun. with yellowish, lipid-rich material.1 They usually Cutis. 2012;89:141-144. are found in the dermis or around tendons.2 It is believed that xanthomas result from the permeation of circulating plasma through dermal Case Report capillary vessels followed by phagocytosis of A 40-year-old woman was referred to our dermatol- the lipoproteins by macrophages forming foam cells.3 ogy clinic for evaluation of “bumps” that had been Five general types of xanthomas are seen clinically: occurring on her arms, abdomenCUTIS (Figure 1), legs, tendinous xanthoma, xanthoma planum, xanthoma and buttocks for 3 months. The patient reported the tuberosum, eruptive xanthoma, and xanthoma dis- lesions being pruritic. Diphenhydramine was not seminatum. To better understand the abnormality of helpful in resolving the pruritus. Various antibiotics lipid metabolism that produces eruptive xanthomas were previously attempted without any improvement that are associated with markedly elevated triglycer- of symptoms. Her medical history was remarkable for ides, it is helpful to review normal lipid metabolism, , mellitus, and hypo- specifically focusing on very low-density lipopro- thyroidism.Do also was Not noted. The patient’s teins (VLDLs)Copy and chylomicron metabolism as well as family history was remarkable for a father and a sister their association with . with hypercholesterolemia. Lipids found in xanthomas are the same as those On physical examination, the patient had numer- in circulation; the majority of plasma lipids are ous yellowish red papules concentrated on the exten- transported as lipoproteins. Plasma lipoproteins are sor surfaces of her arms and legs. Papules also were a polydisperse collection of particles composed of present on her buttocks and abdomen. Some of the lipids and specific proteins called apoproteins, the papules were arranged in a mulberry-type pattern. structure of which allows the delivery of All of the papules were similar in size ranging from and to peripheral cells for their meta- 3 to 5 mm. Abnormal laboratory values included bolic needs. The plasma lipoproteins may be divided the following: glucose, 247 mg/dL (reference range, into 5 major classes: chylomicrons, VLDL (pre– 65–99 mg/dL); hemoglobin A1C (glycated hemoglo- b-lipoproteins), intermediate-density lipoproteins, bin), 8.8% (reference range, 4.5%–6.3%); total cho- low-density lipoproteins (b1-lipoproteins), and high- lesterol, 821 mg/dL (reference range, 100–200 mg/dL); density lipoproteins (a1-lipoproteins). When pre–b- triglycerides, 4591 mg/dL (reference range, lipoproteins or remnant lipoproteins accumulate in 0–149 mg/dL); high-density cholesterol, 26 mg/dL the plasma, increases in both plasma triglycerides and (reference range, 35–85 mg/dL); thyrotropin, cholesterol occur as these aggregates transport sub- 9.405 mIU/L (reference range, 0.350–4.940 mIU/L); stantial quantities of both kinds of lipids. There are 2 lipid sources from which circulating From Gulf South Surgical and Medical Institute, Kenner, Louisiana. The authors report no conflict of interest. plasma lipoproteins are formed: (1) exogenous dietary Correspondence: Shannon Pickens, MD, 3705 Florida Ave, Kenner, and (2) endogenous synthesized of hepatic ori- LA 70065 ([email protected]). gin. The exogenous cascade involves -rich

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fatty acids, which are moved into the cells of the body where they are reesterified to form triglycerides for storage in adipose tissue. The endogenous cascade involves triglyceride-rich VLDL secreted by the ; triglycerides are synthesized in the liver from free fatty acids derived from plasma-free fatty acids and glyc- erol. Ingestion of glucose, carbohydrates, and alcohol stimulates the endogenous synthesis of triglyceride- rich VLDL. The hyperlipidemia responsible for xanthomas may be the result of a primary genetic defect that A yields defective apoproteins or may be secondary to an underlying systemic disorder such as diabetes mellitus, , or .4 Primary genetic defects include genetic deficiency of lipopro- tein lipase, familial deficiency of apolipoprotein C-II, familial lipase inhibitor, and endogenous familial hypertriglyceridemia.5 In 1965, Lees and Fredrickson6 published a system for classifying dis- orders of lipid metabolism based on electrophoretic migration of the serum lipoproteins present, which is used today in a modified form (Table).3 Eruptive xanthomas are associated with type I, IV, and V hyperlipoproteinemias. In its mildest form, endog- enous lipemia appears in a type IV pattern (increased B VLDL). However, when lipogenesis in the liver is CUTISmore marked, removal mechanisms are saturated and are unable to assimilate all of the additional lipids derived from the ; chylomicrons accumulate with VLDL giving a type V pattern. Impaired activity leads to the defective removal of the chylomicrons, chylomicron remnants, and the endog- enous VLDLs producing type I (chylomicrons) or Do Nottype V (chylomicronsCopy and VLDL) hyperlipoproteinemia. Certain diseases or drugs raise the triglyceride level either by increased production or removal defects. Examples of pertinent diseases or drugs include obe- sity, ,B chronic renal failure, hypothyroid- ism, corticosteroids, or estrogens. Patients with a primary defect also may have 1 of these contributing C secondary disorders. With this second insult, the lipo- Figure 1. Numerous yellowish red papules on the protein lipase system can become saturated and, as a forearm (A and B) and abdomen (C). result, can no longer handle dietary lipids. Secondary disorders applicable to this case include diabetes mel- chylomicrons that are secreted from the intestinal litus, obesity, and hypothyroidism, which contributed mucosa following the absorption of ingested animal to the hypertriglyceridemia. For example, whenever and vegetable fats (triglycerides) and exogenous insulin deficiency is present, an acquired lipoprotein cholesterol. Dietary triglycerides and cholesterol are lipase deficiency exists, which results in impaired packaged with apolipoprotein B-48, which forms a clearance of chylomicrons and VLDLs causing hyper- film surrounding the triglycerides in the core of the triglyceridemia.7 This scenario can lead to type I, IV, chylomicron. In the lymph and blood, chylomicrons or V hyperlipoproteinemia. Associated conditions acquire additional apoproteins, and these modified include pancreatitis (not noted in this patient), which chylomicrons interact with lipoprotein lipase bound can cause the hyperlipoproteinemia pattern because to the endothelial surface of blood capillaries. Lipo- of a transient state of insulin deficiency resulting in a protein lipase hydrolyzes the triglycerides to liberate decrease in the activity of lipoprotein lipase. Another

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A B C

Figure 2. Histology revealed collections of foamy histiocytes in the dermis abutting a thin (H&E; original magnifications 310 [A], 340 [B], and 3100 [C]). Photographs courtesy of Alun R. Wang, MD, PhD, New Orleans, Louisiana.

Important Hyperlipoproteinemias

Laboratory and Clinical Type Pathogenesis (Systemic) Findings Type I (familial LPL deficiency, Deficiency of LPL; production of Slow chylomicron clearance; familial hyperchylomicronemia) abnormal LPL; apo C-II deficiency reduced LDL and HDL levels; hypertriglyceridemia; no CUTISincreased risk of

Type II (familial LDL receptor defect; reduced Reduced LDL clearance; hypercholesterolemia or affinity of LDL for LDL receptor; accel- hypercholesterolemia; familial defective apo B-100) erated degradation of LDL receptor of peripheral and Do Notdue to missense PCSK9 mutations Copya coronary arteries Type III (familial Hepatic remnant clearance im- Elevated levels of chylomicron dysbetalipoproteinemia, paired due to apo E abnormality; remnants and IDLs; remnant removal disease, patients only express the apo E2 hypercholesterolemia; broad beta disease, apo E isoform that interacts poorly with hypertriglyceridemia; deficiency) the apo E receptor atherosclerosis of peripheral and coronary arteries Type IV (endogenous familial Elevated production of VLDL Increased VLDLs; hypertriglyceridemia) associated with glucose intol- hypertriglyceridemia; frequently erance and associated with type 2 non– insulin-dependent diabetes mellitus, obesity, alcoholism Type V Elevated chylomicrons and Decreased LDLs and HDLs; VLDLs due to unknown cause hypertriglyceridemia; diabetes mellitus Abbreviations: LPL, lipoprotein lipase; apo, apolipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PCSK9, proprotein convertase subtilisin kexin 9; IDL, intermediate-density lipoprotein; VLDL, very low-density lipoprotein. aAlmost exclusively in African-Americans.

This table was published in Bolognia et al,3 Copyright Elsevier (2008).

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contributing secondary disorder, obesity, can lead to lesions began resolving within 1 month of beginn- overproduction of triglyceride-rich VLDL in the liver. ing treatment. Finally, hypothyroidism retards cholesterol conver- sion to bile salts and results in hyperbetalipoprotein- Conclusion emia, hence hypertriglyceridemia. Our patient could be classified with type IV or type V Clinical Characteristics—Eruptive xanthomas most hyperlipoproteinemia. Her family history was remark- commonly arise over the extensor surfaces of the able for hypercholesterolemia; her secondary factors of extremities, the buttocks, and the shoulders. They hypothyroidism, diabetes mellitus, and obesity could appear suddenly as crops of small yellowish red pap- have easily saturated removal mechanisms resulting in ules 1 to 5 mm in diameter with waxy centers on an accumulation of chylomicrons and VLDL, which erythematous bases. Pruritus is a common symptom, subsequently led to marked hypertriglyceridemia. and the lesions may be slightly tender. The pruritus is believed to be associated with focal increased mass in REFERENCES the skin, effecting a stretching, which causes pruritus. 1. Mishriki Y. Puzzles in practice. eruptive xanthoma. An association between xanthomatosis and koebner- Postgrad Med. 2008;120:121-122. ization has been described.8 2. Parker F. Xanthomas and . J Am Acad Histologic Characteristics—Histologically, xantho- Dermatol. 1985;13:1-30. mas show characteristic collections of macrophages 3. Massengale WT, Nesbitt LT Jr. Xanthomas. In: Bolognia with foamy cytoplasm, an appearance that results JL, Jorizzo JL, Rapini RP, eds. . Vol 2. when lipid is extracted during routine fixation.9 There 2nd ed. London, England: Mosby Elsevier; 2008:1411-1419. are occasional Touton giant cells, small numbers of 4. Park JR, Jung TS, Jung JH, et al. A case of hypothyroid- lymphocytes or neutrophils in younger lesions, and ism and type 2 diabetes associated with type V hyperlipo- fibrosis or cholesterol clefts in older lesions.10 The proteinemia and eruptive xanthomas. J Korean Med Sci. triglyceride-containing lipoproteins apparently pass 2005;20:502-505. through vessel walls and accumulate in tissue macro- 5. James WD, Berger TG, Elston DM. Errors in metabolism. phages, which are seen as foam cells.11 In: James WD, Berger TG, Elston DM. Andrews’ Diseases Treatment—Diet and drugsCUTIS have had consid- of the Skin: Clinical Dermatology. 10th ed. Philadelphia, erable success in clearing eruptive xanthomas in PA: Saunders Elsevier; 2005:519-546. endogenous lipemias. As chylomicron and VLDL 6. Lees RS, Frederickson DS. The differentiation of exoge- concentrations are brought to normal, the erup- nous and endogenous hyperlipemia by paper electrophore- tive xanthomas resolve completely in several weeks. sis. J Clin Invest. 1965;44:1968-1977. Cited by: Massengale Dietary manipulation alone often is effective in WT, Nesbitt LT JR. Xanthomas. In: Bolognia JL, Jorizzo lowering blood lipid levels in most primary hyper- JL, Rapini RP, eds. Dermatology. Vol 2. 2nd ed. London, lipoproteinemias.Do When insulin Not deficiency is the cause England:Copy Mosby Elsevier; 2008:1411-1419. of decreased lipoprotein lipase activity, exogenous 7. Naik NS. Eruptive xanthomas. Dermatol Online J. insulin administration rapidly increases the 2001;7:11. activity. Avoiding alcohol is important because it 8. Miller DM, Brodell RT. Eruptive xanthomatosis with stimulates the synthesis of VLDL in the liver and linear koebnerization. J Am Acad Dermatol. 1995;33 subsequently increases triglycerides. (5, pt 1):834-835. Fibric acid derivatives such as , fenofi- 9. Bickley L. Yellow papules on a middle-aged woman. eruptive brate, and clofibrates are most useful for the treatment xanthomatosis (EX). Arch Dermatol. 1989:125:288-289, 291. of hypertriglyceridemia; they activate lipoprotein 10. Rapini RP. Noninfectious granulomas. In: Rapini RP. lipase in peripheral tissue and decrease VLDL synthe- Practical Dermatopathology. London, England: Elsevier sis by suppression of the endogenous lipid pathway. Mosby; 2005:99-112. Our patient was treated with a , a 11. Crowe MJ, Gross DJ. Eruptive xanthoma. Cutis. , levothyroxine, ezetimibe, and insulin. Her 1992;50:31-32.

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