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Gioco, Francesca (2016) CYP11B2/CYP11B1 Immunophenotyping of 111 Adrenal Glands Excised from Primary Aldosteronism Patients leads to a Novel Classification of the Disease. [Tesi di dottorato]

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Abstract (inglese)

Background. Primary Aldosteronism (PA) is due to the presence of an Aldosterone-Producing Adenoma (APA) in almost two thirds of the cases. Due to the lack of a specific antibody for human aldosterone synthase (hCYP11B2), the functional identification of aldosterone-producing sites in the excised adrenal gland has not been possible thus far. To tackle this challenge we used novel monoclonal antibodies for hCYP11B2 and hCYP11B1 to immuno-phenotype a large series of adrenal glands excised from patients with PA, including APA that were diagnosed by the “four corners criteria” and genotyped for KCNJ5 mutations.
Aims. Our aims were to identify the CYP11B2 and CYP11B1 steroidogenic patterns of the PA adrenal glands and to investigate whether immunostaining predicts the biochemical profile and/or the outcome of the patients.
Design and Method. Double immunohistochemistry and immunofluorescence was used to detect CYP11B2 and CYP11B1 in the excised adrenals from PA patients. Quantification of CYP11B2 and CYP11B1 immuno-staining was performed using an observer-independent PC-assisted method specifically developed in our laboratory that takes into account the area fraction and the staining intensity of the markers. The staining intensity was reported as H-score value and evaluated for each potential aldosterone-producing structure, including CYP11B2 positive clusters, APA and nodules.
Results. Based on the CYP11B2/CYP11B1 immunostaining of 111 excised adrenal glands from PA patients we could identify 5 major steroidogenic patterns (the proportion of cases shown in parentheses): Pattern 1: adenoma with uniform CYP11B2 staining and CYP11B1 staining outside the adenoma (16%); Pattern 2: adenoma with diffuse CYP11B2 staining, scattered CYP11B1 staining and some cells co-expressing CYP11B2/CYP11B1 inside the adenoma (46%); Pattern 3: adenoma expressing CYP11B1 and clusters of cells CYP11B2 positive (2%); Pattern 4: no adenoma, multiple clusters of sub-capsular CYP11B2 cells (25%); Pattern 5: multi-nodular adrenal cortex, clusters of sub-capsular CYP11B2 cells (11%).
The rate of pattern 2 differed significantly between mutated and wild-type KCNJ5 tumors (p=.012) and gender (p=.005). CYP11B2 H-score in APAs reflects aldosterone production before surgery (r=0.388, p=.002); by contrast, CYP11B1 did not correlate with the cortisol production. After adrenalectomy, steroidogenic patterns and H-score did not predict different aldosterone values between the patients, but, pattern 3 was prevalently detected in patients who biochemically resolved the PA picture, but still present high blood pressure levels.
Conclusions. Analysis of the excised adrenal gland from patients who were deemed to have an unilateral excess aldosterone production, by using specific antibodies for human CYP11B2 and CYP11B1, unveiled the existence of 5 different steroidogenic patterns. The H-score based on immunophenotyping which takes into account all aldosterone producing sites in the gland, including APA, clusters and nodules, reflected the aldosterone synthesis in the adrenal gland.
Hence surgically-curable PA is far more heterogeneous than previously held, which challenges the classical notion that PA entails only APA or bilateral hyperplasia. CYP11B2 immuno-staining is a promising tool for gaining better understanding in the pathophysiology of PA disease.

Abstract (italiano)

Background. Nei centri di riferimento per l’ipertensione arteriosa più del 50% dei casi di iperaldosteronismo primario (PA) sono dovuti alla presenza di un Aldosterone-Producing Adenoma (APA). La surrenectomia determina la cura dall’ipertensione e la correzione del quadro biochimico di PA. La comprensione dei meccanismi che inducono lo sviluppo dell’APA è, pertanto, di fondamentale importanza clinica.
La diagnosi di APA ad oggi è basata sul riconoscimento, all’interno della ghiandola surrenalica, di un nodulo costituito da cellule chiare, senza che si abbiano informazioni funzionali sulla produzione di aldosterone. La diagnosi di APA nel surrene rimosso rimane, quindi, piuttosto incerta. Lo sviluppo recente degli anticorpi monoclonali per l’aldosterone sintetasi (CYP11B2) e l’11beta-idrossilasi (CYP11B1) potrebbero permettere di localizzare le cellule responsabili dell’eccessiva produzione di aldosterone.
Scopo. Lo scopo di questo studio è stato di identificare i patterns di espressione degli enzimi steroidogenici CYP11B2 e CYP11B1 nella ghiandola surrenalica da pazienti con PA e indagare se la caratterizzazione immuno-fenotipica possa predire il profilo biochimico e/o l’outcome pressorio di questi pazienti.
Metodi. I surreni rimossi da 111 pazienti operati per PA che al cateterismo delle vene surrenaliche avevano mostrato eccesso di secrezione unilaterale, sono stati studiati mediante immunoistochimica e immunofluorescenza per CYP11B2 e CYP11B1. L’intensità della reazione cromogenica di CYP11B2 e CYP11B1 è stata quantificata utilizzando una metodica sviluppata nel nostro laboratorio che permette di attribuire ad ogni marker analizzato, un valore numerico denominato H-score, che è direttamente proporzionale alla percentuale di area positiva allo staining nella ghiandola e all’intensità di colorazione. Tutte le strutture potenzialmente competenti alla produzione di aldosterone (cluster di cellule CYP11B2 positive, APA e noduli) sono state analizzate per il calcolo dell’ H-score corrispondente.
Risultati. L’analisi immunoistochimica nei pazienti PA ha permesso di identificare 5 patterns steroidogenici (la percentuale dei pazienti classificati nei patterns è espressa tra parentesi): pattern 1 comprendeva i surreni con un unico adenoma compatto e positivo per CYP11B2 e cellule positive per CYP11B1 nel tessuto adiacente all’adenoma (16%); nel pattern 2 sono stati classificati gli adenomi composti da cellule positive per CYP11B2 o CYP11B1 e alcune cellule che esprimevano contemporaneamente CYP11B2 e CYP11B1 (46%); i surreni classificati come pattern 3 presentavano un adenoma CYP11B1 positivo e alcuni cluster di cellule CYP11B2 positive (2%); nel pattern 4 non era presente un adenoma riconoscibile ma cluster di cellule CYP11B2 positive (25%); infine, i surreni del pattern 5 non mostravano alcun adenoma ma diversi noduli prevalentemente positivi per CYP11B1 e cluster di cellule CYP11B2 positive (11%).
Al baseline, il pattern 2 si distingueva dagli altri patterns per la maggiore prevalenza di pazienti con una mutazione al KCNJ5 (p=.012) e di genere femminile (p=.005). L’H-score per CYP11B2 negli APA era direttamente proporzionale alla concentrazione di aldosterone (r=0.388, p=.002), mentre l’H-score per CYP11B1 non era correlato con la concentrazione plasmatica di cortisolo. Dopo la surrenectomia, né la classificazione in patterns né l’H-score sono stati in grado di predirre l’outcome biochimico dei pazienti. Tuttavia, i pazienti che dopo surrenectomia mostravano correzione del quadro biochimico ma continuavano ad essere ipertesi erano classificati prevalentemente come pattern 3.
Conclusioni. Gli anticorpi specifici per CYP11B2 e CYP11B1 permettono di identificare cinque patterns immunofenotipici, molto variabili tra loro. La metodica sviluppata dal nostro gruppo per la quantificazione dell’H-score che tiene in considerazione tutte le strutture potenzialmente abili alla produzione dell’aldosterone, ovvero APA, clusters e noduli, fornisce informazioni accurate sulla produzione di aldosterone nei pazienti con PA.
In conclusione, i risultati di questo studio mostrano che le forme di PA siano molto più eterogenee di quanto precedentemente ipotizzato, suggerendo che accanto all’APA classico definito come nodulo iper-funzionante e all’iperplasia esistano altri fenotipi che includono clusters e/o cellule che esprimono entrambi gli enzimi steroidogenici CYP11B2 e CYP11B1.
L’immuno-staining dei surreni con hCYP11B2 sembra essere un promettente strumento non solo per la diagnostica ma anche per lo studio della fisiopatologia dell’iperaldosteronismo.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rossi, Gian Paolo
Correlatore:Seccia, Teresa Maria
Dottorato (corsi e scuole):Ciclo 28 > Corsi 28 > Ipertensione Arteriosa e Biologia Vascolare
Data di deposito della tesi:31 Gennaio 2016
Anno di Pubblicazione:01 Febbraio 2016
Parole chiave (italiano / inglese):Aldosterone-Producing Adenoma; Immunohistochemistry; Primary Aldosteronism; CYP11B2; CYP11B1
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:9481
Depositato il:07 Ott 2016 10:17
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