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Bigolin, Paola (2018) Ipercolesterolemia familiare: dal genotipo al fenotipo ed implicazione terapeutiche dei nuovi farmaci biologici ipocolesterolemizzanti. [Ph.D. thesis]

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Abstract (italian or english)

AIMS: Familial Hypercholesterolemia (FH) is a frequent genetic cause of early coronary artery disease, and is still under-diagnosed and under-treated. With the advent of PCSK9 inhibitors as adjunctive therapy to maximal lipid-lowering therapy, a significant reduction in cholesterol levels of low-density lipoprotein (LDL-C) and cardiovascular events was observed, while maintaining a good safety and tolerance profile. Ultrasonography (US) detects Achilles tendon (AT) xanthomas in patients (pts) with FH. Given the recent introduction of new therapies, there are no studies in the literature that evaluate the efficacy and safety of this therapy over a period of more than 3 years.
We analysed the potential associations between FH genotype, clinical phenotype and ultrasonographic AT findings, evaluating the contribution of AT US to identify individuals with an FH-causing mutation. We also analysed the long-term efficacy and safety of additional therapy with PCSK9 inhibitors, comparing treatment with evolocumab and that with alirocumab.

SUBJECTS AND METHODS: Genetic screening, clinical and biochemical parameters in 194 pts with possible, probable or definite clinical diagnosis of FH according to the Dutch Lipid Clinic Network Score (DLCNS); 71 pts underwent bilateral AT US.

RESULTS: 43 pts carriers of null allele (NA) and 62 of defective (DEF) allele for LDL receptor while 33 pts with no known mutations (NM) for FH. Presence of xanthomas and gerontoxon, total and LDL-cholesterol (NA vs DEF vs NM: 326.5+97.7 mg/dl, 316.9+93.9 mg/dl, 211.1+76.3mg/dl, p<0.000) at diagnosis were significantly higher in NA pts than other subgroups. AT thickness was significantly different among the three groups (p< 0,005) and 78.2%, 72.4% and 31.6% had USX in NA, DEF and NM carriers respectively (p=0.002).
Among the 52 pts positive for FH-causing mutations, 16 pts had a clinical diagnosis either possible or probable and in nine pts the presence of USX was clinically undetected and thereby not considered for DLCNS calculation. Tendon ultrasound was able to show a prevalence of 51% of tendon xanthomas in comparison to the prevalence of alterations detected only by physical examination, which was 10,2%.
Following the addition of treatment with PCSK9 inhibitors, a mean reduction in LDL-C levels from 169 ± 30 mg / dl to 46 ± 16 was obtained, compared to the traditional maximal lipid-lowering treatment, ie in percentage terms a reduction of 72.4%. Compared to baseline LDL-C levels, this corresponds to an average reduction of 86.9%. There were no statistically significant differences between treatment with evolocumab and that with alirocumab in terms of reduction of LDL-C levels. In the course of traditional maximal lipid-lowering therapy, the goal of LDL cholesterol was obtained based on the personal level of cardiovascular risk in 0% of cases, while with the addition of PCSK9 inhibitors, 100% of subjects achieved therapeutic goal. No statistically significant differences were found following the introduction of PCSK9 inhibitor treatment with regard to CPK and transaminase levels. Over the years we have observed that LDL-C levels remained substantially stable.

CONCLUSIONS: Genotypic functional characterization is associated with different phenotypic clinical features, AT thickness and presence of US xanthomas. AT ultrasonography may help reclassifying as definite FH, patients with DLCN score of possible/probable FH. Achilles tendon ultrasound has a greater sensibility than standard physical exam. It discloses a noticeable higher prevalence of tendon xanthomas (51%) in comparison to clinical evaluation (10,2%). This exam allows to look in a more integrated way at the cardiovascular and tendon complications in everyeach patient. It also suggests, when xanthomas are found, the necessity to adopt a stronger lipid-lowering therapy.
In our study, in subjects with FH, it emerged that PCSK9 inhibitor therapy (evolocumab or alirocumab), in addition to maximal lipid-lowering therapy, results in a significant reduction of LDL-C levels, allowing the totality of patients to achieve the therapeutic goal of LDL-C related to its cardiovascular risk. Further studies are needed to confirm mainly the persistence of long-term efficacy and safety of PCSK9 inhibitor therapy and to evaluate on a larger scale whether there are differences between evolocumab and alirocumab in terms of efficacy in reducing LDL-C and cardiovascular risk.

Abstract (a different language)

INTRODUZIONE e SCOPI dello STUDIO: L’Ipercolesterolemia Familiare (FH) è un disordine del metabolismo lipidico su base genetica, rara in omozigosi (1/250000) ma coinvolgente 1 soggetto ogni 250 abitanti nella forma eterozigote. Il fenotipo lipidico è caratterizzato da livelli molto elevati di colesterolo delle lipoproteine a bassa densità (LDL) dalla nascita e da un rischio elevato di aterosclerosi che predispone ad eventi clinici cardiovascolari (CHD) precoci.
La FH è causata da mutazioni nei geni che codificano per proteine chiave coinvolte nelle vie metaboliche che riguardano il recettore delle LDL (LRL-R) e il suo ciclo metabolico, con conseguente diminuzione dell’uptake cellulare delle LDL e conseguente aumento delle concentrazioni plasmatiche del colesterolo LDL (LDL-C). Tra i geni coinvolti sono note mutazioni con perdita di funzione nel gene LDLR, mutazioni nel gene dell’apolipoproteina B (ApoB) che alterano il dominio di legame dell’ApoB con LDL-R, mutazioni con guadagno di funzione nel gene per la proteina convertasisubtilisina/kexina tipo 9 (PCSK9).
Tra le mutazioni del LDL-R si riconoscono cinque classi funzionali, una delle quali è chiamata allele nullo e normalmente determina un difetto nella sintesi del recettore con conseguente funzione recettoriale quasi completamente abolita (<5% rispetto alla norma). Le restanti sono legate un’alterata sintesi della proteina dovuta ad alterazioni della sequenza amminoacidica che comporta difetti nel trasporto del recettore, nel legame tra ligando e recettore, nella localizzazione dello stesso a livello della superficie cellulare e infine nel riciclaggio.
Allo scopo di stabilire una diagnosi clinica, sono raccomandati i criteri del Dutch Lipid Clinic Network (DLCN) che permettono di fare diagnosi di FH considerando cinque aspetti anamnestici, clinici e bioumorali.
La formazione precoce di gerontoxon, xantelasmi e xantomi sono markers clinici suggestivi per indirizzare verso la diagnosi di FH. L’utilizzo dell’ecografia consente di valutare con maggiore accuratezza lo spessore tendineo, aumentato nel caso in cui siano presenti accumuli lipidici. Dal momento che il tendine di Achille si è rivelato essere la più comune localizzazione per lo sviluppo di xantomi, la valutazione ecografica di questo distretto consente di aumentare notevolmente la sensibilità (fino al 75%) nella diagnosi di FH, a discapito di una relativa perdita di specificità nei confronti di altre forme di ipercolesterolemia.
Con l’avvento degli inibitori di PCSK9 come terapia aggiuntiva a una terapia ipolipemizzante massimale, si è osservata una riduzione significativa dei livelli di colesterolo delle lipoproteine a bassa densità (LDL-C) e degli eventi cardiovascolari, mantenendo un buon profilo di sicurezza e tolleranza.
In tale contesto si inserisce il nostro studio con la valutazione della mappatura genetica dell’Ipercolesterolemia Familiare in relazione al fenotipo clinico, l’approfondimento dell’utilità dell’impiego dell’ecografia dei tendini achillei come strumento di approfondimento diagnostico, l’analisi di dati di efficacia e sicurezza della terapia addizionale con inibitori di PCSK9.

SOGGETTI e METODI:194 soggetti con diagnosi possibile, probabile o certa di FH, in accordo con i criteri del DLCN, sono stati sottoposti a screening genetico e valutazione delle caratteristiche cliniche e bioumorali; di 168 pazienti (pz) ad ora è disponibile il risultato dello screening genetico; 101 pz sono stati sottoposti ad ecografia bilaterale dei tendini achillei; gli xantomi ecografici sono stati definiti come presenza di uno spessore tendineo >6,15 mm in almeno un tendine e/o presenza di formazioni ipoecogene; 20 pazienti con FH eterozigote in trattamento con nuovi farmaci biologici ipocolesterolemizzanti (inibitori PCSK9).
RISULTATI: Dei 168 pz con risultato dello screening genetico in particolare 105 pz presentavano mutazione del gene per il recettore delle LDL in forma eterozigote, di cui 43 portatori di allele nullo (NA) e 62 di allele difettivo (DEF); in 33 pz non sono state individuate mutazioni per FH (NM). La prevalenza di xantomi obiettivi e gerontoxon, insieme ai livelli di colesterolo totale e LDL basali sono risultati significativamente maggiori nei soggetti NA rispetto agli altri sottogruppi (xantomi obiettivi: NA vs DEF vs NM 71,4 vs 48,5 vs 30,7 %: p<0,001 Anova; LDL: NA vs DEF vs NM 326,5+97,7 vs 316,9+93,9 vs 211,1+76,3 mg/dl: p<0,001 Anova).
Dei 101 pazienti di cui si disponeva del risultato degli esami bioumorali e dell’ecografia tendinea la prevalenza di xantomi obiettivi e gerontoxon, insieme ai livelli di colesterolo totale e LDL basali sono risultati significativamente maggiori nei soggetti NA rispetto agli altri sottogruppi (xantomi obiettivi: NA vs DEF vs NM 26,1 vs 13,8 vs 0,0 %: p=0,054 Anova; LDL: NA vs DEF vs NM 316+117 vs 321+109 vs 199+44 mg/dl: p<0,001 Anova). Lo spessore dei tendini achillei è risultato significativamente diverso tra i tre gruppi (NA vs DEF vs NM 7,64±2,06 vs 7,65±4,02 vs 5,67±0,75 mm: p<0,005 Anova) e la prevalenza di xantomi ecografici era del 78,2%, 72,4% e 31,6% nei soggetti portatori di NA, DEF e NM rispettivamente (p=0,002). Il solo esame obiettivo rilevava la presenza di xantomi tendinei achillei nel 10,2% dei soggetti, mentre l’ecografia tendinea rivelava una prevalenza di lesioni tendinee pari al 51%.
Nell’ambito dei 74 pz sottoposti ad ecografia dei tendini achillei di cui si dispone attualmente del risultato dello screening genetico, sono stati considerati i 52 pz con mutazioni responsabili di FH; tra questi 36 pz avevano una diagnosi clinica certa di FH secondo i criteri DLCN (punteggio >8), mentre vi erano 16 pz con diagnosi possibile (punteggio tra 3 e 5) o probabile (punteggio tra 6 e 8). Di questi 16 pz 1 mostrava xantomi evidenziabili clinicamente mentre 10 presentavano lo xantoma ecografico.
Nel sottogruppo dei 20 pz trattati con PCSK9, in seguito all’aggiunta di trattamento con inibitori di PCSK9 si è ottenuta, rispetto al trattamento ipolipemizzante tradizionale massimale, una riduzione media dei livelli di LDL-C da 169 ± 30 mg/dl a 46 ± 16, ossia in termini percentuali una riduzione del 72,4% (valore minimo 41,5% e massimo 87,5%). Rispetto ai livelli basali di LDL-C, ciò corrisponde a una riduzione media pari all’86,9%. Non sono emerse differenze statisticamente significative tra il trattamento con evolocumab e quello con alirocumab in termini di riduzione dei livelli di LDL-C. In corso di terapia ipolipemizzante tradizionale massimale si otteneva l’obiettivo di colesterolo delle LDL previsto in base al personale livello di rischio cardiovascolare nello 0% dei casi, mentre con l’aggiunta della terapia con inibitori di PCSK9 il 100% dei soggetti raggiungeva l’obiettivo terapeutico. Non si sono dimostrate differenze statisticamente significative in seguito all’introduzione del trattamento con inibitori di PCSK9 per quanto riguarda i livelli di CPK e di transaminasi. Nel corso degli anni abbiamo osservato che i livelli di LDL-C si mantenevano sostanzialmente stabili.

CONCLUSIONI:
La caratterizzazione genotipica funzionale si conferma essere associata a fenotipi clinici diversi, anche in termini di spessori tendinei e prevalenza di xantomi ecografici, confermando come il paziente con allele nullo presenti una maggiore aggressività clinica della patologia.
L’ecografia del tendine di Achille risulta più sensibile rispetto all’esame obiettivo classico, rilevando una prevalenza di xantomi tendinei notevolmente maggiore rispetto a quella rilevata mediante il solo esame obiettivo. Tale esame consente di guardare in modo integrato alle complicanze tendinee e vascolari nel singolo paziente, suggerendo, ove siano presenti xantomi, un trattamento ipolipemizzante più intensivo.
I risultati preliminari di questo studio suggeriscono inoltre come l’ecografia dei tendini di Achille possa essere uno strumento da considerare nell’aiutare a riclassificare quei pazienti per in cui il DLCN score è compatibile con diagnosi possibile o probabile di FH. Tale strumento potrebbe inoltre rivelarsi un valido alleato per il clinico, aiutandolo nel raggiungimento di una diagnosi sempre più precoce, ed una garanzia per il paziente di ricevere quanto prima il trattamento farmacologico più adeguato alla sua fascia di rischio.
L’utilizzo degli anticorpi monoclonali anti-PCSK9, evolocumab ed alirocumab, rappresenta un approccio terapeutico innovativo, caratterizzato da elevato profilo di sicurezza ed altamente efficacie in associazione alla terapia massimale attualmente disponibile nei pazienti eterozigoti per FH. Ulteriori studi sono necessari per confermare principalmente la persistenza di efficacia e sicurezza a lungo termine della terapia con inibitori di PCSK9 e per valutare su larga scala se vi siano differenze tra evolocumab e alirocumab in termini di efficacia nella riduzione dei livelli di LDL-C e del rischio cardiovascolare.

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EPrint type:Ph.D. thesis
Tutor:Zambon, Alberto
Supervisor:Zambon, Sabina
Ph.D. course:Ciclo 31 > Corsi 31 > SCIENZE CLINICHE E SPERIMENTALI
Data di deposito della tesi:29 November 2018
Anno di Pubblicazione:29 November 2018
Key Words:FH, ipercolesterolemia familiare, anticorpi anti PCSK9, PCSK9 inhibitors
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:11490
Depositato il:08 Nov 2019 13:07
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