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ETIOLOGY AND CLINICAL PRESENTATION- Adrenocortical adenoma (ACA). Mostlly nonsecretory, can produce ACTH independent cortisol or angiotensin independent aldosterone, more rarely, androgens or estrogens. Activation of cAMP-PKA, a downstream mediator of ACTH-G protein receptor pathway, is implicated in its pathogenesis.
- Cortisol-producing adenoma. Clinically variable. Usually ACTH-independent, sometimes G-protein receptor hyperfunction.
- Adrenocortical carcinoma (ACC).
- Rare, 1-2 /M/y. Peak age <5 and 40-60.
- Most sporadic. Genetic syndromes Li-Fraumeni (p53), MEN-1, Beckwith-Weidemann.
- 60% producers, 45% cortisol, half of them cortisol + androgens, 10% only androgens, <10% estrogens.
- 90% >4 cm
- 30% painful
- Mutations: beta-catenin leads to Wnt activation, GNAS gene mutation with Gs-alpha activation, and mutations affecting PKA: inhibition of regulatory subunit or activation of catalytic.
- Aldosterone-producing adenoma (APA) has mutations in K channel KCNJ5 in 40%.
- Bilateral nodules 10-15%. Most frequent metastasis, bilateral adenomas and primary bilateral macronodular adrenal hyperplasia (mutations in armadillo repeat containing 5 ARMC5), it can also be congenital adrenal hyperplasia, cushing's disease, ectopic ACTH, or bilateral pheochromocytoma.
- Pheochromocytoma.
- 0,8/100,000 /y
- 40% germline mutation, mostly SDHB, SDHD, NF1, RET (MEN2), VHL
- Sporadics: 2 types of mutations:
- Cluster A (hypoxia): SDH D, C, B, A, AF2, VHL and other. Usually extra-adrenal
- Cluster B (protein-kinases): NF1, RET, other. Mostly adrenal.
- NF1 and RET secrete more metanephrine, VHL and SDH more normetanephrine, VHL more methoxythyramine than SDH.
ENDOCRINE HYPERSECRETION EVALUATION
- Pheochromocytoma screening
- 90% hypertension, 90% headache, 50% sweating+headache+tachycardia
- 99% >10 HU on TC
- Screening recommended in all cases: plasma or 24h urinary metanephrines (LC MS/MS)
- Autonomous cortisol secretion (ACS)
- Frequently asymptomatic. For overt Cushing, recommended diagnostic tests are 24h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and 9h cortisol after 1 mg dexamethasone.
- ACS is a- or oligosymptimatic.
- Up to 20% of all AI.
- Associated to hypertension, diabetes, insulinresistance, obesity, and increased mortality.
- No gold-Standard, screening usually 1 mg DXM, <1.8 mcg/dL excludes ACS, 1.9-5 is suspicious, and >5 confirmatory.
- UFC has lower sensitivities 30-75%, and LNSC has mixed results for ACS.
- Clinical consequences:
- Hypertension is present in 40-90%
- Diabetes or prediabetes 10-70%
- CV events and mortality are clearly increased.
- Effect on bone are not so clear. Both trabecular and cortical bone loss as well as vertabral fractures are reported.
- Consequences of reversal
- No RCT have shown benefits from adrenalectomy in ACS (there are ongoing)
- As surgery is a risky procedure, recommendation is control of CV risk factors.
- Natural history
- Non-secreting adenomas NSA rarely develop ACS (5%)
- Both clinical Cushing and spontaneous regression are exceptional in ACS <0.1%
- CV risk factors increase prevalence in ACS more than in NSA
- Mortality was similar in ACS than in NSA (meta-analysis) (contradicting previous statements of this post).
- Recommendation is no follow-up in NSA and 5y follow up in ACS.
- Aldosterone secretion
- Current recommendation is measuring A/R ratios in case of hypertension or hypokalemia
- There may be subclinical suppressed renin cases who would develop future hypertension, but there are no clear data so far.
- Sex hormones
- Isolated estrogen or androgen secretion are very infrequent in adenomas and should raise suspiction for ACC.
