E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020
Conniption, Connundrum, Connfusion (#119)
Case report
We present the case of a 21 year old man referred for investigation of secondary causes of hypertension and found to have primary hyperaldosteronism with clear evidence of lateralisation on adrenal vein sampling, despite no radiological evidence of adrenal tumour or hyperplasia. He went on to have a laparoscopic adrenalectomy and remains normotensive six months post-operatively. Histopathology demonstrated micronodular adrenal disease.
Initial referral occurred after he presented to his General Practitioner with paroxysmal light-headedness, pre-syncopal symptoms and headache and was found to be persistently hypertensive. His medical history was significant for Systemic Lupus Erythematosus which had been diagnosed three years earlier after he presented with acute renal failure associated with joint pains and rash. His lupus was treated with hydroxychloroquine and methotrexate, and he had not had any flares since diagnosis. Renal function was normal. He had a mother with onset of hypertension before the age of 40 years. There was no other relevant family history.
Physical examination was unremarkable other than BP 147/88mmHg. Weight was 82.9kg Hypertension was confirmed by repeat testing, and home blood pressure monitoring showed systolic BP consistently 140-150mmHg.
Potassium level was normal at 4.3 mmol/L. A 24 hour Holter monitor had not shown any evidence of arrhythmia. Doppler Renal ultrasound was normal and in particular showed no evidence of renal artery stenosis, noting this did not exclude the diagnosis. Plasma metanephrines were normal.
The patient’s aldosterone to renin ratio was found to be elevated at 124.0 (<70) with renin 9.6 mIU/L (4.4-46.1) and aldosterone 1190 pmol/L. He went on to a saline suppression test which showed failure to suppress with aldosterone 447 pmol/L (>170) following IV infusion of 2L normal saline over four hours during a seated procedure. He went on to have a triple phase CT abdomen which did not detect any adrenal abnormality.
Adrenal vein sampling was done without cosyntropin stimulation, which demonstrated lateralisation to the right. Both adrenal veins were successfully cannulated with a ratio of adrenal vein cortisol to peripheral cortisol greater than 2. The lateralisation index was > 4. The left adrenal had aldosterone to cortisol ratios of 1.1, 0.7 and 1.1, which were all less than the peripheral ratios of 1.6, 1.4 and 1.3 respectively.
Figure 1: Adrenal Vein Sampling results
The patient then commenced antihypertensive treatment with olmesartan and was referred for surgical review. An elective laparoscopic right adrenalectomy was done. He had an uncomplicated admission and was discharged off all anti-hypertensive medication.
Macroscopically, the resected adrenal gland had generally normal size and appearance, measuring 60mm x 23mm x up to 5mm. Scattered subcapsular miniature nodules were visible.
Figure 2: Macroscopic appearance of right adrenal gland
Microscopically there were small nodules of histologically unremarkable adrenocortical tissue in a subcapsular location and focally protruding into adjacent adipose tissue. In some areas, these nodules were entirely within adipose tissue and completely separate to the adjacent adrenal gland. All of the nodules had diameter less than 5mm. There was no necrosis and no mitoses seen. The histopathologic diagnosis was reported as micronodular hyperplasia.
Figure 3: Microscopic appearance of right adrenal gland demonstrating micronodules
At clinic review four months post adrenalectomy the patient’s blood pressure was 130/98mmHg. He reported improvement in his symptoms of pre-syncope and headache. His systolic blood pressure was below 130mmHg consistently on home monitoring.
Discussion
Primary aldosteronism describes a group of disorders in which production of aldosterone is inappropriately high for sodium status, fails to suppress after a sodium load, and is relatively autonomous of the other major regulators of secretion (angiotensin II and plasma potassium). It was initially described by Jerome Conn in 1955 and is a potentially curable cause of hypertension.
Though historically though to be a rare condition in which hypokalaemia was considered a sine qua non for diagnosis, recent cross-sectional and prospective studies report primary aldosteronism in greater than 5% of hypertension patients both in general and specialty settings, with prevalence of hypokalaemia estimated to be far from ubiquitous with estimates varying between 9 and 37%2. These data suggest that hyperaldosteronism may be underdiagnosed. However widespread screening with aldosterone to renin ratio is fraught given the multiple factors that can affect results, and the cost and expertise needed for confirmatory testing including adrenal vein sampling. Factors affecting aldosterone to renin ratio include posture, potassium status, dietary sodium intake, other hormones including ACTH, cortisol, and oestrogen, renal impairment, and multiple antihypertensive medications. Current Endocrine Society guidelines for case detection suggest screening with aldosterone to renin ratio in patients with sustained elevation of blood pressure >150/100 mmHg, or at lesser levels if multiple antihypertensive agents are required to achieve control. Screening is also recommended if hypertension associated with hypokalaemia, adrenal incidentaloma, sleep apnoea, or a positive family history (hypertension or stroke at age less than 40 years, or known primary hyperaldosteronism)1.
Importantly, aldosterone excess has cardiovascular system effects at least partially independent of blood pressure effect. A 2018 meta-analysis of prospective and retrospective observational studies comparing patients with primary aldosteronism to those with essential hypertension found increased risk of stroke, coronary artery disease, atrial fibrillation, heart failure, diabetes, metabolic syndrome and left ventricular hypertrophy3. There was no difference demonstrated between patients with primary aldosteronism from unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Even after treatment with mineralocorticoid antagonist, patients with primary aldosteronism have been found to have significantly higher incidence of cardiovascular events and death compared to age matched patients with essential hypertension and comparable cardiovascular risk profiles and blood pressure control4. Duration of hypertension is also a negative predictor of outcome after unilateral adrenalectomy, suggesting if surgical management is contemplated it is better to intervene earlier in the disease course.
The pathogenesis of primary aldosteronism remains incompletely understood. The most common cause of unilateral primary aldosteronism as demonstrated in our patient is an aldosterone producing adenoma. However in our case there was no evidence of adenoma on CT, and after resection the adrenals demonstrated generally normal appearance other than micronodules with a maximum dimension of 4mm. Proposed models for development of hyperaldosteronism include a neoplastic process where non-functional adenomas or hyperplasia progresses to become secretory, or a process whereby non-neoplastic secretory aldosterone producing cell clusters (APCCs), found to be commonly present in post mortem specimens, progress to a more severe neoplastic lesion2.
It is unknown whether one, some or all of the micronodules present in our patient’s right adrenal gland were aldosterone secreting, and whether similar micronodules are present in his left adrenal gland. Though at this stage our patient remains well and normotensive, it remains to be seen whether his remission from primary aldosteronism will be sustained or he will develop further contralateral secretory lesions with age. However this case demonstrates the utility of adrenal vein sampling in identifying unilateral disease that is not radiologically detectable, with likely significant benefits for his cardiometabolic risk into the future given his young age.
Discussion points
- Primary aldosteronism is likely underdiagnosed in all healthcare settings.
- Cardiovascular morbidity and mortality are higher than for age and sex matched controls with essential hypertension.
- Surgical management can be curative, even in the absence of an obvious adrenal lesion radiologically.
- Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.
- Vaidya A, Mulatero P, Baudrand R, Adler GK. The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment.Endocr Rev. 2018;39(6):1057-1088.
- Monticone S, D'Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41-50.
- Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol. 2018;6(1):51-59.
- Mulatero P, Monticone S, Bertello C, et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab. 2013;98(12):4826-4833.