S-55-4: HISTOPATHOLOGY-GENOTYPE CORRELATION OF ALDOSTERONE- PRODUCING ADENOMAS
S-55-4: HISTOPATHOLOGY-GENOTYPE CORRELATION OF ALDOSTERONE- PRODUCING ADENOMAS
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S-55-4：产生醛固酮的腺瘤的组织病理学-基因型相关性
DOI：
10.1097/01.hjh.0000913932.53564.fe
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发表时间：
2023
影响因子：
4.9
通讯作者：
Azizan E
中科院分区：
文献类型：
--
作者：
Azizan E
原发性醛固酮增多症（PA）是继发性高血压的一个严重漏诊（< 1/500）的原因，其中醛固酮的产生相对于抑制的血浆肾素水平过高。这是一个主要问题，因为即使与匹配的原发性高血压患者相比，未经治疗的患者患心血管疾病、中风和其他合并症的风险也会增加。PA通常是由醛固酮产生腺瘤（APA）引起的，这些腺瘤在醛固酮驱动基因中携带体细胞突变。它可以占高血压病例的5%至10%，或占难治性高血压病例的10%至20%。目前推荐的治疗APA时，只有影响一个肾上腺是单侧肾上腺切除术。这使得切除的组织能够被广泛研究和表征。有趣的是，已发现APA与一系列细胞形态和临床表型一起发生。这种异质性似乎有遗传基础。KCNJ 5突变型APA是APA中最常见的基因型，具有类似束状细胞（ZF）的细胞形态并分泌杂合类固醇。它们通常很大，经常发生在年轻女性和东方患者中。而CACNA 1D突变型APA更小，更像球状（ZG）（即比ZF更紧凑），在黑人患者中更常见。值得注意的是，CACNA 1D也是产生醛固酮的微结节和老年患者中最常见的醛固酮驱动突变，其次是ATP 1A 1和ATP 2B 3中的醛固酮驱动突变。CTNNB 1突变型APA也含有GNA 11/GNAQ突变，其细胞似乎向肾上腺-性腺前体细胞类型去分化，因为它们表达的LH/HCG受体比其他突变型APA或甚至仅CTNNB 1突变型APA高10倍。这就解释了为什么双突变患者经常出现高LH/HCG的情况。这些独特的基因型特异性表型可用于PA的筛查和诊断。例如，混合类固醇测量可用于筛选KCNJ 5突变型APA;或者与妊娠后期的妊娠相关高血压相比，妊娠早期（HCG分泌高峰期）的高血压发作应提示考虑双突变型阿帕。此外，这些体细胞突变的鉴定已经导致了潜在的治疗方法。例如，化学筛选已经鉴定出选择性抑制突变体KCNJ 5的大环内酯。因此，APA的组织病理学基因型相关性为PA的筛查、诊断、管理和治疗提供了新的机会。进一步阐明与每种相关性相关的细胞机制将有助于确定病理和生理途径，从而确定新的治疗靶点。
Primary aldosteronism (PA) is a vastly underdiagnosed (< 1 in 500) cause of secondary hypertension in which aldosterone production is inappropriately high relative to suppressed plasma renin levels. This is of major concern as untreated patients are at increased risk for cardiovascular diseases, stroke, and other comorbidities even when compared to matched essential hypertension patients. PA is commonly caused sporadically by aldosterone producing adenomas (APAs) that harbors somatic mutations in aldosterone driver genes. It can account for up to 5 to 10% of hypertensive cases or up to 10 to 20% of resistant hypertensive cases. The current recommended treatment for APAs when only affecting one adrenal is a unilateral adrenalectomy. This has allowed the excised tissue to be extensively studied and characterized. Interestingly APAs have been found to occur with a spectrum of cell morphology and clinical phenotype. This heterogeneity seem to have a genetic basis. KCNJ5 mutant APAs, the most common genotype of APAs, have zona fasciculata (ZF) like cell morphology & secrete hybrid steroids. They commonly are large and frequently occur among young females and Oriental patients. Whereas CACNA1D mutant APAs are smaller, more zona glomerulosa (ZG) like (ie more compact than ZF), and more common in Black patients. To note, CACNA1D is also the most common aldosterone driver mutations in aldosterone producing micronodules and elderly patients, followed by aldosterone driver mutations in ATP1A1 and ATP2B3. CTNNB1 mutant APAs that also harbor GNA11/GNAQ mutations have cells that seem to dedifferentiate towards the adrenal-gonadal precursor cell type as they express the LH/HCG receptor ten fold more than other mutant APAs or even CTNNB1 mutant only APAs. This would explain why patients with the double mutations often present at times of high LH/HCG. These distinct genotype specific phenotypes could be used to facilitate screening and diagnosis of PA. For example, hybrid steroid measurements could be used for screening of KCNJ5 mutant APAs; or onset of hypertension in the first trimester (the period of peak HCG secretion), compared to pregnancy associated hypertension in later trimesters, should prompt consideration for a double mutant APA. Moreover, identification of these somatic mutations has already led to potential therapeutic treatments. For example, chemical screens have identified macrolides that selectively inhibit mutant KCNJ5. Thus, histopathology genotype correlation of APAs have provided new opportunities for the screening, diagnosis, management, and treatment of PA. Further elucidations of the cellular mechanisms associated with each correlation will help to identify the pathological and physiological pathways, and thus novel therapeutic targets.