Skin manifestations in familial heterozygous hypercholesterolemia

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Skin manifestations in familial heterozygous hypercholesterolemiaLetter to the editorFig. 1d. Multiplereddish-yellowdome-shaped 2 mmeruptive xanthomas.Additional eruptivesenile angiomas arean unrelated finding.Fig. 1b. Tuberousxanthoma over bothAchilles tendons.Fig. 1c. Intertriginousxanthomas in palmarcreases and along fingertendons.Figs. 1e–1f. Bilateral xanthelasma before andafter Erbium-YAG-Laser treatment.Lp(a) was 103 mg/dl (2.66 mmol/l) (normal below30 mg/dl, 0.78 mmol/l).Cardiological and angiological examinationshowed severe generalized atherosclerosis. Noother relevant pathologic finding was obtained.The noncompliant patient refused skin biopsy andany cardiological intervention. Erbium-YAG-Lasertreatment was performed for his xanthelasma withan excellent cosmetic result (Fig. 1f).DiscussionThe term hyperlipidemia or hyperlipoproteinemiais used when there is an elevation of serumlipid levels in the blood. The plasma lipids aretransported in lipoproteins. Electrophoresis andultracentrifugation of blood are used to differentiatefour principle fractions of plasma lipoproteins:chylomicrons, VLDLs, LDLs, and HDLs. On thebasis of the electrophoretic lipoprotein phenotype,Frederickson et al. (Table 1) classified primaryhyperlipoproteinemias into five major types (typesI–V) (1). Familial hypercholesterolemia (FH)is a hereditary autosomal dominant disorder oflipoprotein metabolism characterized by a defectin the low-density lipoprotein (LDL) receptor gene184(2), which leads to progressive increase of LDLcholesterol levels in the blood.Familial hypercholesterolemia is expressedat birth or in early childhood (3). Heterozygousand homozygous variants have been described.The heterozygous form has a prevalence ofapproximately 1 in 500 individuals in most parts ofthe world, whereas the homozygous form is veryrare (1 in 1,000,000) (4, 5). In the homozygous form,high levels of LDL 600–1000 mg/dl (15.5–25.84mmol/l) can be found between birth and 5 yearsof age (6); clinically, this is characterized by severexanthomatosis developing in the first few years oflife, multiple types of xanthomas can occur (7), andcoronary atherosclerosis usually develops earlier,before the teenage years (8). In the heterozygousform, the cholesterol levels are approximately twicenormal, with values usually in the 270–550 mg/dl (6.98–14.21 mmol/l) range (9); in this form thexanthomatous lesions develop during the third to sixthdecades. Familial homozygous hypercholesterolemiais a type II hyperlipoproteinemia; it is sub-classifiedinto types IIa and IIb on the basis of defects found:type IIa is characterized by LDL-receptor proteindeficiency with increased LDL, whereas type IIb,called combined hyperlipidemia, is characterized byActa Dermatoven APA Vol 18, 2009, No 4
Letter to the editorSkin manifestations in familial heterozygous hypercholesterolemiaFig. 1g. Arcus senilis between 4 and 12 o’clock.decreased LDL-receptor and increased ApoB withadditional tendency for elevated LDL and VLDLIn our patient, the lipid profile was suggestive ofheterozygous type IIa hyperlipoproteinemia, withmarkedly elevated LDL cholesterol levels andnormal VLDL and triglyceride levels. Intertriginous,tendinous, tuberous xanthomas and xanthelasmapalpebrarum are typical manifestations.Xanthoma (from Greek ξανθός ‘yellow’) is adeposition of yellowish material formed by lipidsin foam cells (10) (macrophages with phagocytosedlipid material) and collagen. There are differentxanthomas based on their clinical and morphologicalaspects.Various experiments have been conducted todefine the mechanism of lipid deposition in tendonxanthomas. LDL derived from plasma is trapped inthe collagen and glycosaminoglycans of the tendonmatrix and can be oxidized at these sites. Thereaction of LDL with macrophages or other cells ofthe tendon can explain the modification of LDL intooxLDL, which is taken up mainly by macrophages,thereby promoting the formation of foam cells (11,12), which extravasate through the vascular wallsand deposit in perivascular connective tissue.Tendon xanthomas are firm subcutaneousnodules, which may be hard due to fibrosis. Theyare usually skin colored and do not appear yellowbecause the cholesterol ester is deposited deep withinthe tendons. They are localized over the proximalfinger joints, the insertions of the patellar tendons,and the Achilles tendons (13). This disfiguringpathological state may interfere with function andcause achillodynia and, rarely, spontaneous tendonrupture (14). Tendonitis, peritendinitis or bursitis,trauma, nodules from rheumatic arthritis, or gouttophi are other frequent conditions that may lead toAchilles tendon (AT) thickening, and in such casesdifferential diagnosis from ATX (Achille tendonFig. 2. The hypoechoic area between the arrowscorresponds to tuberous xanthoma.xanthoma) may be difficult. Detailed family andmedical history, serum lipid analysis, and ultrasoundof the affected tendon may help in the differentialdiagnosis (15, 16). Ultrasound is the most importantimaging method used for evaluating ATX (16–18).The sonographic aspect, with 7.5 MHz linear arraytransducer, of our patient’s Achilles tendon wascharacterized by a focal hypoechoic lesion (Fig.2). The deposition of cholesterol in xanthomas issimilar to that in atherosclerotic lesions (19). Clinicaland imaging studies have suggested that a positivecorrelation exists between tendon xanthomaregression and improvement in atheroscleroticdisease (20), which is the main cause of death indyslipidemic patients.Xanthelasma palpebrarum is the mostimportant clinical manifestation visible around theeyes. According to many epidemiologic studies,xanthelasma is thought to be a determinant of anincreased risk of atherosclerosis (21).Very rare are intertriginous xanthomas, consistingof a yellow dermal plaque with corrugated surfacelocalized in the finger webs, palmar creases, axillae,buttocks, and antecubital and popliteal fossae (22,23). Other type of xanthomas are the eruptive formlocalized in the gluteal region, trunk, and extensorsurface of the extremities; these lesions are small, lightyellow, and usually surrounded by an inflammatoryhalo. An important sign is the corneal arcus orarcus senilis, which appears as a single grayish ringparallel to the limbus and is separated from it by a1 mm lucid interval of Vogt. It is typically localizedbetween 6 and 12 o’clock. It develops as a result oflipid deposition in the deep corneal stroma and thelimbal sclera, and its prevalence increases with age.Various techniques and methods have been describedin the literature to treat this condition, includingapplication of trichloroacetic acid (TCA), electriccautery, surgical excision, carbon dioxide laserActa Dermatoven APA Vol 18, 2009, No 4 185
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Skin manifestations in familial heterozygous hypercholesterolemia

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