Homozygous Familial Hypercholesterolemia (HoFH) is a rare inherited disorder affecting 1 in 160,000 to 1 in  300,000 individuals and resulting in extremely elevated low-densitym lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease (ASCVD). Manifestations of ASCVD most notably include fatal and non-fatal myocardial infarction (MI) and occlusive vascular disease requiring surgical or percutaneous revascularization. Deposits of cholesterol in the skin or tendons, or both, called xanthomas, are the hallmark of the disease

Borghi C.

Bragagni A

Cicero AFG

Fogacci F

English

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

Vol.:(0123456789) Internal and Emergency Medicine (2023) 18:307–310 https://doi.org/10.1007/s11739-022-03106-6CE - MEDICAL ILLUSTRATIONShort‑term evolocumab‑induced tendon xanthomas regression in an elderly patient with homozygous familial hypercholesterolemiaArrigo F. G. Cicero1,2,3 · Federica Fogacci1,2,3  · Alessio Bragagni1,3 · Claudio Borghi1,2,3Received: 24 August 2022 / Accepted: 15 September 2022 / Published online: 6 October 2022 © The Author(s) 2022Homozygous Familial Hypercholesterolemia (HoFH) is a rare inherited disorder affecting 1 in 160,000 to 1 in 300,000 individuals and resulting in extremely elevated low-density lipoprotein cholesterol (LDL-C) levels and premature ath-erosclerotic cardiovascular disease (ASCVD) [1]. Manifes-tations of ASCVD most notably include fatal and non-fatal myocardial infarction (MI) and occlusive vascular disease requiring surgical or percutaneous revascularization.  Depos-its of cholesterol in the skin or tendons, or both, called xan-thomas, are the hallmark of the disease [1].Below, we present a patient case of tendon xanthomas regression after short-term treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab.A 72-year-old heavy-smoking Caucasian men with multi-district atherosclerotic disease presented to Lipid Clinic because of consistently high levels of LDL-C (272 mg/dL) despite intensive lipid-lowering therapy (LLT). He took every day 40 mg rosuvastatin, 10 mg ezetimibe, 100 mg acetyl salicylic acid, 40 mg pantoprazole, 300 mg allopu-rinol, 2.5 mg bisoprolol and 25 mg furosemide. However, he reported that he had never taken any medications before experiencing acute coronary syndrome and undergoing percutaneous transluminal coronary angioplasty (PTCA) and stenting, 5 years before. Subsequently, he had also been treated with carotid endarterectomy (CEA) for severe asymptomatic carotid stenosis.Physical examination was positive for arcus cornealis and bulky tendon xanthomas in the fingers, elbows and ankles, for which the patient had previously referred to an ortho-pedic clinic because causing movement limitation. Based on radiographic evidence, the orthopedic specialist had diagnosed gouty tophi and surgically removed the lesions without requesting any histological confirmation. After sur-gery, the patient had been started on allopurinol and advised to limit consumption of purine rich food. Serum uric acid (SUA) concentrations quickly reduced to < 2 mg/dL, but all nodules obviously relapsed after few weeks from surgery. However, the patient reported that he was not surprised, because he “had always had them” and stated that his brother and sister had also had them.Considering the remarkable family history for ASCVD (Fig. 1A) and the very high LDL-C despite maximal stand-ard LLT, the patient was clinically diagnosed with familial  * Arrigo F. G. Cicero  arrigo.cicero@unibo.it1 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy2 Hypertension and Cardiovascular Risk Factors Research Center, Medical and Surgical Sciences Department, Sant’Orsola-Malpighi University Hospital, 40138 Bologna, Italy, 3  Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Bologna, Italy308 Internal and Emergency Medicine (2023) 18:307–3101 3hypercholesterolemia (FH). Then, the sequence of LDLR gene revealed that he was homozygous for a single-nucleo-tide substitution (c.662A > G) in exon 4, resulting in glycine for aspartic acid conversion at position 221 (p.Asp221Gly) of LDL receptor. The further mutation screening of liv-ing relatives (performed by directly sequencing of exon 4) revealed that patient’s daughter and granddaughter were heterozygous for the same mutation (Fig. 1A), that in silico analysis predicted to be “pathogenic”.After being adequately informed of the benefits and risks, the patient refused to be treated with both lipoprotein apher-esis and lomitapide, and he was started on subcutaneous administration of 420 mg of evolocumab every 2 weeks. The LLT was effective and safe (Table 1). Tendon xanthomas regression in fingers, elbows and ankles began 6 months after starting treatment with iPCSK9 evolocumab and became more evident at 2-year follow-up, with the patient dropping two shoe sizes for the thinning of the Achilles tendons (Fig. 1B). Patient’s self-perceived quality of life improved too.According to previously published data, individuals affected by HoFH usually develop ASCVD early in life. Not-pharmacologically treated individuals with HoFH suf-fer from MI as young as 3 years of age, and most patients experience fatal events prior to the age of 30 even if under-going LLT [2]. However, reaching an advanced age without cardiovascular complications should not be considered an exclusion criterion neither for the diagnosis of HoFH nor for physician’s decision to start an intensive LLT, as the patient case shows. Actually, treatment with PCSK9i evolocumab was both effective and safe for our patient, with multiple implications. In effect, previous evidence shows that pres-ence of xanthomas increases the risk of ASCVD in patients with FH by as much as threefold, implying that xanthomas and atherosclerosis may share a certain etiology [3]. Then, it is likely that tendon xanthomas regression corresponds to a reduced ASCVD risk in our patient, who did not experi-ence neither other ASCVD events nor disease progression. Moreover, tendon xanthomas regression has been rarely observed in general and never observed in elderly patients with HoFH. In particular, our observations are unexpected since xanthomas regression resulted from a non-maximal reduction in LDL-C, and after the previous surgical lesions, removal is likely to have caused fibroblast deposition and scar tissue in the tendons. Finally, patient’s self-perceived quality of life improved after tendon xanthomas regression, and this is definitely crucial for optimizing patients’ adher-ence to LLT [4]. Of course, before any inference, further observations are needed to confirm ours.Fig. 1  Family tree (A). Evolocumab-induced tendon xanthomas regression in elbow (above), fingers (in the middle) and ankles (below) (B)309Internal and Emergency Medicine (2023) 18:307–310 1 3Funding Open access funding provided by Alma Mater Studiorum - Università di Bologna within the CRUI-CARE Agreement. This study did not receive external funding.Declarations Conflict of interest The authors declare that they have no conflict of interest.Consent The patient signed informed consent regarding publishing his data and photographs.Human and Animal rights The study was conducted according to the guidelines of theDeclaration of Helsinki and approved by the Institu-tional Review Board.Informed consent Informed consent was obtained from the patient to publish data andpictures.Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long Table 1  Evolocumab-related changes in laboratory and hemodynamic collected variablesALT Alanine transaminases, AST Aspartate transaminases, b.i.m. bis in month, eGFR estimated glomerular filtration rate, HDL High-density lipoprotein, LDL Low-density lipoproteinBaseline 2-year follow-upLipid-lowering treatment 40 mg rosuvastatin and ezetimibe40 mg rosuvastatin and ezetimibe + 420 mg evo-locumab b.i.mLaboratory parameters Total cholesterol (mg/dL) 340 288 HDL-cholesterol (mg/dL) 26 45 LDL-cholesterol (mg/dL) 272 220 Triglycerides (mg/dL) 132 117 Apolipoprotein B-100 (mg/dL) 177 135 Lipoprotein(a) (mg/dL) 1.9 1.5 Fasting plasma glucose (mg/dL)e 93 115 Uric acid (mg/dL) 2.5 6.5 eGFR (ml/min) 80 90 Creatinine phosphokinase (U/L) 60 152 AST (U/L) 26 33 ALT (U/L) 30 28 Gamma-GT (U/L) 23 48Hemodynamic parameters Heart rate (bpm) 69 79 Systolic blood pressure (mmHg) 163 136 Diastolic blood pressure (mmHg) 64 58 Pulse pressure (mmHg) 99 78 Mean arterial pressure (mmHg) 111 91 Aortic systolic blood pressure (mmHg) 162 136 Aortic diastolic blood pressure (mmHg) 64 60 Aortic pulse pressure (mmHg) 98 76 Augmentation pressure (mmHg) 28 19 Augmentation index (%) 29 24 Cardiac output (L/min) 13.13 9.87 Peripheral resistance (PRU) 0.50 0.55 Stroke volume (mL) 191 125 Pulse Wave velocity (m/s) 10.7 10.3 Ankle-brachial index—right 0.51 0.81 Ankle-brachial index—left 0.98 1.23310 Internal and Emergency Medicine (2023) 18:307–3101 3as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.References 1. Tromp TR, Hartgers ML, Hovingh GK, Vallejo-Vaz AJ, Ray KK, Soran H, Freiberger T, Bertolini S, Harada-Shiba M, Blom DJ, Raal FJ, Cuchel M (2022) Homozygous Familial Hypercholester-olaemia International Clinical Collaborators. Worldwide experi-ence of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet 399(10326):719–728 2. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ (2015) International Familial Hypercholester-olemia Foundation. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Eur J Prev Cardiol 22(7):849–854. https:// doi. org/ 10. 1177/ 20474 87314 533218 3. Civeira F, Castillo S, Alonso R, Meriño-Ibarra E, Cenarro A, Art-ied M, Martín-Fuentes P, Ros E, Pocoví M, Mata P (2005) Span-ish Familial Hypercholesterolemia Group. Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation. Arterioscler Thromb Vasc Biol 25(9):1960–1965 4. 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Short-term evolocumab-induced tendon xanthomas regression in an elderly patient with homozygous familial hypercholesterolemia

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Short-term evolocumab-induced tendon xanthomas regression in an elderly patient with homozygous familial hypercholesterolemia

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