Case Report

Normotensive Primary Hyperaldosteronism: A Case of Unilateral Adrenal Hyperplasia with a Contralateral Nonfunctioning Adenoma

Bridget Sinnott
Medical College of Georgia, Endocrinology and Metabolism, Augusta, USA
*Corresponding author:

Associate Professor of Medicine, Medical College of Georgia, Division of Diabetes, Endocrinology and Metabolism, 1447 Harper St, HB-5025, Augusta, GA 30912, Phone: 706-721-2131; Email: bsinnott@augusta.edu

Keywords:

Primary hyperaldosteronism, Unilateral adrenal hyperplasia, Adrenal vein sampling

Primary hyperaldosteronism is characterized by difficult to control hypertension, an increase in aldosterone excretion, and suppression of the renin-angiotensin system. Hypertension is the hallmark feature of this disorder. We report a case of primary hyperaldosteronism in a 41-year-old woman without hypertension which was first suspected because of persistent symptomatic hypokalemia. An abdominal computerized tomography scan showed a left adrenal nodule however adrenal venous sampling demonstrated an elevated aldosterone : cortisol ratio on the right. A successful laparoscopic right adrenalectomy revealed micronodular hyperplasia and resulted in resolution of her hypokalemia. We recommend that clinicians consider hyperaldosteronism as a cause of normotensive hypokalemia and recommend adrenal vein sampling to lateralise the source of the hyperaldosteronism given the high prevalence of benign adrenal adenomas. Additionally, unilateral adrenal hyperplasia is an uncommon but increasingly recognized subtype of primary hyperaldosteronism.

Primary hyperaldosteronism (PA) is recognized as the most common cause of endocrine hypertension, accounting for 5-20% of all hypertensive cases [1-3]. Primary hyperaldosteronism is classically characterized by difficult to control hypertension, an increase in aldosterone excretion, and suppression of the renin-angiotensin system. Hypertension is the hallmark feature of this disorder, with hypokalemia being seen in 9-37% [2,4]. It is unusual for patients with PA to present with hypokalemia in the absence of hypertension, with less than 30 cases reported in the literature [5-8]. We present such a case of a 41 year old normotensive white female who presented with muscle cramps related to persistent hypokalemia and further investigation uncovered PA.

Primary hyperaldosteronism is usually caused by small aldosterone producing adenomas (50-70%), followed by bilateral hyperplasia, also known as idiopathic adrenal hyperplasia (30%) [9]. More rarely, PA can be caused by adrenocortical carcinoma or the increasingly recognized unilateral adrenal hyperplasiasubtype [10], as in our case. Unilateral primary hyperaldosteronism caused by adenomas or unilateral adrenal hyperplasia can be cured surgically, whereas bilateral adrenal hyperplasia is treated medically with aldosterone receptor antagonist.

Unilateral adrenal hyperplasia is represented histologically by small nodules throughout the adrenal cortex, which can range in size from 2-16mm, without the presence of a distinct adenoma or diffuse hyperplasia [10]. Given their small size, they are often difficult to identify on routine adrenal computerized tomography. Given the high prevalence of non-functional adrenal adenomas and the small size of both unilateral adrenal hyperplasia and aldosterone producing adenoma, it is important to perform adrenal vein samplingto lateralise the aldosterone producing source, to facilitate successful surgery, especially in adults over 40 years [11].

A review of the literature uncovered 2 prior cases of unilateral adrenal hyperplasia with coexisting contralateral non-functioning adenomas, also known as incidentalomas [12,13]; which are similar to the findings in our case.

A 41 year-old Caucasian female was referred to the Endocrinology clinic for a history of hypokalemia and a left adrenal mass. She was first diagnosed with hypokalemia 10 months prior to presentation. This coincided with the onset of cramping in her upper and lower extremities. She also reported frequent headaches, flushing of the head and neck, fatigue and chronic constipation. She denied polyuria, polydipsia, weakness, paralysis, chest pain or palpitations.

On further questioning, the patient reported that she was eating a high salt diet in order to mitigate the muscular cramps. She had never been on any anti-hypertensives, specifically no diuretics. She denied any licorice intake. She was started on potassium chloride 20mEq daily for hypokalemia by her referring physician and was not taking any other medications. Her past medical history was negative for hypertension and positive for generalized anxiety disorder and gastric reflux disease. Her father had hypertension however there was no family history of endocrinopathies. On physical examination she was found to have BP of 132/83 mmHg, which was normotensive but in the pre-hypertensive range, with heart rate 89 beats per minute. Systolic blood pressures taken in the clinic over a period of 9 weeks ranged from 132 to 145 mmHg. Her cardiac, respiratory, neurologic, abdominal and musculoskeletal examinations were unremarkable. She had no features concerning for MEN 2B, Neurofibromatosis type 1 or Cushings syndrome.

Initial investigations are shown in table 1.


Test

Result

Reference Range

Sodium

141

132-146mEq/L

Potassium (on KCl 20mEq daily)

3.5

3.5-5.5mEq/L

Chloride

105

99-109mEq/L

CO2

31

20-31mEq/L

BUN

11

9-23mEq/L

Creatinine

0.57

0.6-1.6mg/dL

Glucose

90

74-106mg/dL

Magnesium

1.9

1.3-2.7mg/dL

Calcium

9.4

8.7-10.4mg/dL

Plasma Aldosterone Concentration (PAC)

32

<21mg/dL

Plasma Renin Activity (PRA)

1.1

0.6-3.0ng/ml/hr

Aldosterone/Renin ratio

29

<20

Table 1. Laboratory work-up for Hyperaldosteronism.

Her aldosterone: renin ratio was >20 with an aldosterone level 32mg/dL, suggestive for primary hyperaldosteronism. A confirmatory salt suppression test was performed and yielded a 24 hour urine aldosterone of 48mcg (normal 2-20) with 24hr urine sodium 196mEq and a concomitant serum potassium 3.7 mEq/L. She subsequently underwent computerized tomography scan (CT) of her abdomen with and without contrast which revealed a left adrenal nodule and a normal appearing right adrenal gland (see figures 1 A & B). (A)

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Figure 1. Computed tomography (CT) of the abdomen. (A) CT abdomen with contrast showing a 1 cm left adrenal nodule which measured -10 Hounsfield units (HU) in minimal density on pre contrast imaging. (B) CT abdomen with contrast showing an adrenal nodule which measured 25 HU on portal venous phase imaging and 0 HU on delayed images, consistent with a left adrenal adenoma.

Given the high prevalence of benign adrenal adenomas and the small size of aldosterone producing adenomas or adrenal hyperplasia, she underwent adrenal vein sampling (AVS) with adrenocorticotropic hormone stimulation, which lateralized to the right adrenal gland (see table 2).

Test

Right Adrenal Vein

Left Adrenal Vein

Inferior Vena Cava

Aldosterone

5170 ng/dL

55 ng/dL

55ng/dL

Cortisol

1096.87 mcg/dL

1394.20 mcg/dL

30.08 mcg/dL

Aldosterone-to-Cortisol ratio

 4.71

0.04

1.83


Table 2. Adrenal vein sampling with results showing an elevated aldosterone to cortisol ratio on the right side and suppression on the left.

She underwent a successful laparoscopic right adrenalectomy as definitive treatment for her hyperaldosteronism and hypokalemia. Macroscopic examination revealed a flattened, elongated adrenal gland with no obvious adrenal mass noted. Pathology was remarkable for micronodular hyperplasia (See figures 2 A & B).

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Figure 2. Right adrenal hyperplasia. (A) Micronodular hyperplasia is present throughout the adrenal cortex in the form of numerous small nodules(blue arrows) of histologically unremarkable adrenocortical cells. (B) Numerous small nodules of adrenocortical cells with expansile pushing borders and compression of adjacent adrenal cortex (blue arrows).Following laparoscopic adrenalectomy, her serum potassium level returned to normal (4.2-4.4mEq/L) with a plasma aldosterone of 9.2 ng/dL on post-op day one, confirming cure. Her blood pressure remained normal. One year post op she remains normotensive and normokalemic, with resolution of her muscle cramps

We described a patient with normotensive hyperaldosteronism, related to unilateral adrenal hyperplasia (UAH), who initially presented with muscle cramps and hypokalemia. Our case highlights the need to consider a diagnosis of PA as a cause of hypokalemia, in the absence of hypertension and the need for AVS to accurately locate the source of aldosterone excess. Additionally, unilateral adrenal hyperplasia is an uncommon but increasingly recognized subtype of PA.

Primary hyperaldosteronism is the most common endocrine cause of secondary hypertension, representing 5-20% hypertensive patients [1-3]. The syndrome of PA which is characterized by hypertension, hypokalemia, hyperaldosteronism and suppressed renin levels was originally described by Dr Conn in 1955 [14]. Excessive plasma aldosterone is associated with sodium retention and fluid expansion which results in hypertension, as well as hypokalemia which is mediated by aldosterone induced urinary potassium loss in exchange for sodium. The majority of patients with PA have hypertension however only 9-37% develop hypokalemia [2,4]. If hypokalemia is profound, it may be associated with muscle cramps (as in our patient), muscle weakness and even paralysis. Additionally, aldosterone has known deleterious effects on the kidney and heart promoting fibrosis and therefore increasing cardiovascular morbidity and mortality [15].

The biochemical diagnosis of PA involves obtaining an elevated renin-aldosterone ratio, with a normal potassium level in the absence of interfering anti-hypertensive medications. Occasionally a salt loading test or other confirmatory test may be indicated to confirm PA however is not always indicated [1]. This is followed by adrenal imaging with the possible need for AVS to distinguish unilateral from bilateral disease. Several studies have concluded that standard CT imaging of the adrenal glands is insufficient for lateralization of PA, as it can’t reliably visualize micro-adenomas, UAH or distinguish nonfunctional adrenal incidentalomas from aldosterone producing adenomas with confidence [11,16]. Adrenal vein sampling is recognised by the Endocrine Society guidelines as the gold standard test for lateralization of aldosterone secretion prior to surgery [1]. In patients with aldosterone producing adenomas or UAH, there is a high concentration of aldosterone from the involved gland, with suppression of aldosterone from the contralateral gland. In our case, AVS identified the normal appearing adrenal gland on adrenal CT as the source of the hyperaldosteronism and identified the left adrenal nodule as an incidentaloma. The right adrenal gland pathology was remarkable for unilateral adrenal hyperplasia.

Unilateral adrenal hyperplasia was first described by EJ Ross in a 1965 case report [17]. This entity is increasingly recognized as a cause of PA. In one series of 35 patients who underwent unilateral adrenalectomy for PA following unequivocal AVS, 26 patients (74%) had either nodular or diffuse UAH [18]. In a swedish prospective screening study of a hypertensive population, the incidence of UAH was similar to that of aldosterone producing adenomas in PA patients with unilateral disease [19]. It has been suggested that unilateral hyperplasia may represent a precursor of adenoma formation, as both hyperplasia and adenomas can coexist together [10].

Brooks et al [20] reported the first case of normotensive hyperaldosteronismin 1972 related to an adrenocortical carcinoma. Since that time, there has been at least another 28 reports, mostly benign aldosterone producing adenomas and UAH but also adrenocortical carcinoma causing normotensive hyperaldosteronism [5-8]. Rossi et al [6] reviewed the cases of 26 such patients and found that 85% were of Eurasian descent (predominantly Japanese), and the majority were middle aged female, suggesting ethnic and sex related protective factors in response to excessive aldosterone excretion. Medeau et al compared 10 normotensive PA cases to hypertensive PA cases and found that the normotensive group had lower BMIs, more profound hypokalemia and larger adrenal adenomas, despite similar aldosterone and renin levels [5]. Their study and our case report would suggest that the development of hypokalemia in the normotensive hyperaldosteronism patient represents a protective mechanism against the development of hypertension.

Hypokalemia was a universal feature in all cases of normotensive hyperaldosteronism reported to date, similar to our case, suggesting that aldosterone in this population has a strong urine potassium wasting effect on the cortical collecting tubules in the kidney rather than the traditional pressor effect to increase blood pressure. This is in contrast to the hypertensive population with PA, which has a 10-40% prevalence of hypokalemia observed in a large multicenter series collected in 5 continents [2].

Normotensive hyperaldosteronism may be diagnosed as part of the work-up for hypokalemia or an incidentally discovered adrenal mass. Interestingly, it has been speculated that cases of normotensive hyperaldosteronism may represent a mild “subclinical hyperaldosteronism” state, which is an early phase of disease which may progress to overt hypertension [5,21,22]. Indeed, our patient had pre-hypertension on presentation. A study of normotensive subjects with PA and suppressed aldosterone levels were followed over a period of 5 years. At 5 years, a significantly higher proportion of subjects with PA developed hypertension compared to subjects with adequate aldosterone suppression, even after controlling for known risk factors associated with hypertension development [23]. Vasan et al [21] demonstrated that in the Framingham Offspring study, increased morning aldosterone levels within the physiologic range predisposed individuals to the development of hypertension 4 years later [21]. In an unselected Japanese population of 292 adults, the prevalence of PA among prehypertensive (120-139/80-89) and stage 1 (140-159/90-99) hypertensive subjects, was 6.8% and 3.3%, respectively [24]. This study suggests that a significant number of pre-hypertensive patients may have subclinical forms of PA, similar to our case. The prevalence of normotensive hyperaldosteronism is likely underestimated, as screening for PA is limited to hypertensive cases or an adrenal mass.

Limitations of our case report include the short duration of follow-up prior to adrenalectomy, as she had pre-hypertension which may have progressed to overt hypertension over time. An additional short fall was the absence of ambulatory blood pressure data.

This case highlights the unusual presentation of normotensive hyperaldosteronism in a patient presenting with hypokalemia, muscle cramps and an adrenal nodule. Our case is unique in the fact that she had normotensive hyperaldosteronism related to UAH and highlights the need for AVS to preclude an adrenal incidentaloma and correctly lateralise the source of the hyperaldosteronism, to enable a surgical cure.

None

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Figure 2. Right adrenal hyperplasia. (A) Micronodular hyperplasia is present throughout the adrenal cortex in the form of numerous small nodules(blue arrows) of histologically unremarkable adrenocortical cells. (B) Numerous small nodules of adrenocortical cells with expansile pushing borders and compression of adjacent adrenal cortex (blue arrows).Following laparoscopic adrenalectomy, her serum potassium level returned to normal (4.2-4.4mEq/L) with a plasma aldosterone of 9.2 ng/dL on post-op day one, confirming cure. Her blood pressure remained normal. One year post op she remains normotensive and normokalemic, with resolution of her muscle cramps

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Presented by Currie, 1968 [7], where BG is the background counts, t is the counting time, Eff is the efficiency of the gamma energy line and V is the sample volume. The MDAs were found to be 0.8 and 0.7 Bq/kg for 226 Ra and 228 Ra respectively.

Citation: Sinnott B (2018) Normotensive Primary Hyperaldosteronism: A Case of Unilateral Adrenal Hyperplasia with a Contralateral Nonfunctioning Adenoma. J Diabetes Care Endocrinol 1:008.

Published: 05 January 2018

Reviewed By : Dr. Christodoulos Monastiriotis,

Copyright:

© 2018 Sinnott. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.