Clinical report
Widespread xanthomas regression by personalized lipid lowering therapy in heterozygous familial hypercholesterolemia
Regresión generalizada de xantomas mediante terapia hipolipemiante personalizada en hipercolesterolemia familiar heterocigótica
Francesco Sbrana
, Beatrice Dal Pino, Federico Bigazzi, Tiziana Sampietro
Corresponding author
Lipoapheresis Unit – Reference Center for Diagnosis and Treatment of Inherited Dyslipidemias, Fondazione Toscana “Gabriele Monasterio”, Via Moruzzi 1, Pisa 56124, Italy
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Partial regression in xanthelasma (Panel C) and in cutaneous xanthomas hyperpigmentation (Panel D) obtained after six months of maximal lipid lowering therapy (rosuvastatin/ezetimibe 20/10<span class="elsevierStyleHsp" style=""></span>mg OD<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>evolocumab 140<span class="elsevierStyleHsp" style=""></span>mg s.c. every 14 days<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>lipoprotein apheresis).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Familial hypercholesterolemia (FH) is a genetic disease causing severe and premature atherosclerotic cardiovascular disease. “<span class="elsevierStyleItalic">The lower, the</span><span class="elsevierStyleItalic">better</span>” is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> as in the case of a 69-year-old woman referred to our Institute for her lipid profile [LDL-C 412<span class="elsevierStyleHsp" style=""></span>mg/dl, Lp(a) 119<span class="elsevierStyleHsp" style=""></span>mg/dl], bilateral xanthelasma and cutaneous xanthomas (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> Panels A and B). At the age of 47, she undergone to PTCA/stenting on left anterior descending artery for effort angina. In the following twenty-two years, the patient did not experience any further cardiac event while self-discontinuing lipid-lowering therapies (LLT).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The physical examination was positive for Achilles tendon xanthomas (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>); CT coronary angiography showed diffuse non-critical calcific atherosclerotic disease and a 40% stenosis at the carotid bulb bilaterally was revealed. Genetic test confirmed the diagnosis of heterozygous familial hypercholesterolemia (HeFH). LLT with rosuvastatin/ezetimibe (20/10<span class="elsevierStyleHsp" style=""></span>mg OD), evolocumab (140<span class="elsevierStyleHsp" style=""></span>mg s.c. every 14 days) and lipoprotein apheresis (LA) was started (Liposorber®-LA MA-03 systems; Kaneka, Osaka, Japan) achieving a median inter-aphaeretic concentration of LDL-C and Lp(a) of 34<span class="elsevierStyleHsp" style=""></span>mg/dl and 40<span class="elsevierStyleHsp" style=""></span>mg/dl respectively.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">With this maximized LLT, after six months, the patient showed an impressive regression in her cutaneous xanthomas (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> Panels C and D).</p><p id="par0020" class="elsevierStylePara elsevierViewall">Patients with HeFH with elevated lipoprotein(a) and previous cardiovascular events represent a comorbidity profile hard to manage and the current guidelines propose a more aggressive lowering in LDL-C and cholesterol-rich apolipoprotein B for their key role in the arterial wall atherogenesis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The singularity of the described case is represented by over-time stability of atherosclerotic disease in contrast of the widespread lipid deposits in the skin and tendons, even in the absence of LLT. The personalization of LLT becomes fundamental especially in patients affected by heterozygous FH and high Lp(a) in the light of their high cardiovascular risk.</p><p id="par0030" class="elsevierStylePara elsevierViewall">FH patients are often characterized by age-related fat deposition on the Achilles tendon, showing thickening and fragility, and also related with the severity of coronary artery disease.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">2,3</span></a> We know that short-term evolocumab is able to induce tendon xanthomas regression in a patient with homozygous FH,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">4</span></a> that in HeFH the addition of a PCSK9 inhibitor to backbone LLT resulted in tendon xanthomas regression after 3 years of treatment<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a> and that LA treatment allows the complete regression of lipid deposition<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">6</span></a> because accelerate the efficacy of LLT. In this case we combined all these therapies to maximize their effect.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Waiting for the new drugs on the way, as the antisense oligonucleotides against apolipoprotein (a), the first step is the personalization of the therapy safeguarding heterozygous FH patient's safety and quality of life, keeping in mind that the correct diagnosis<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> and therapeutic adherence<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a> are essential stages for patient's clinical management.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Authors’ contribution</span><p id="par0040" class="elsevierStylePara elsevierViewall">FS, BDP, FB and TS: contributed to conception or design, drafted and critically revised the manuscript. All authors read and approved the final version of the manuscript.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Authors’ approval</span><p id="par0045" class="elsevierStylePara elsevierViewall">All authors have seen and approved the study submitted.</p><p id="par0050" class="elsevierStylePara elsevierViewall">No part of the submitted work has been published or is under consideration for publication elsewhere.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Notes</span><p id="par0055" class="elsevierStylePara elsevierViewall">Data have not been presented at any congress.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Consent for publication</span><p id="par0060" class="elsevierStylePara elsevierViewall">The patient signed the informed consent from form for anonymous medical data usage in our paper.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Funding sources</span><p id="par0065" class="elsevierStylePara elsevierViewall">No financial support was received.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">No conflict of interest for each author.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres2088944" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1781366" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2088943" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1781365" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Authors’ contribution" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Authors’ approval" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Notes" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Consent for publication" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding sources" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "xack727716" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-10-11" "fechaAceptado" => "2023-11-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1781366" "palabras" => array:5 [ 0 => "Cutaneous xanthomas" 1 => "Heterozygous familial hypercholesterolemia" 2 => "Lipid lowering therapy" 3 => "Tendon xanthomas" 4 => "Xanthelasma" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1781365" "palabras" => array:5 [ 0 => "Xantomas cutáneos" 1 => "Hipercolesterolemia familiar heterocigótica" 2 => "Terapia hipolipemiante" 3 => "Xantomas tendinosos" 4 => "Xantelasma" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">“The lower, the better” is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412<span class="elsevierStyleHsp" style=""></span>mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">«Cuanto más bajo, mejor» es el enfoque recomendado en el tratamiento del colesterol LDL alto. Lamentablemente esto no siempre se logra como en el caso de una mujer de 69 años remitida a nuestro Instituto por su perfil lipídico (colesterol LDL 412 mg/dL), xantelasma bilateral y xantomas cutáneos. Con terapias hipolipemiantes maximizadas y personalizadas (rosuvastatina, ezetimiba, iPCSK9 y aféresis de lipoproteínas), después de solo seis meses, la paciente mostró una regresión impresionante en sus xantomas cutáneos.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 899 "Ancho" => 2340 "Tamanyo" => 366083 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Baseline bilateral xanthelasma (Panel A) and extensive cutaneous xanthomas localized at the trunk (Panel B). Partial regression in xanthelasma (Panel C) and in cutaneous xanthomas hyperpigmentation (Panel D) obtained after six months of maximal lipid lowering therapy (rosuvastatin/ezetimibe 20/10<span class="elsevierStyleHsp" style=""></span>mg OD<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>evolocumab 140<span class="elsevierStyleHsp" style=""></span>mg s.c. every 14 days<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>lipoprotein apheresis).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1340 "Ancho" => 1340 "Tamanyo" => 239833 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Panel A – Physical examination of Achilles tendon xanthomas (arrowhead). Panel B – Achilles tendon ultrasonography with increased thickness and irregular hypoechoic region (circle).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Mach" 1 => "C. Baigent" 2 => "A.L. Catapano" 3 => "K.C. Koskinas" 4 => "M. Casula" 5 => "L. 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