Most cases of hypertension are essential or idiopathic (primary hypertension) although 5–10% of hypertensive patients present an identifiable cause (secondary hypertension) (1). Primary aldosteronism (PA) is a mineralocorticoid-induced hypertension due to an excess of aldosterone (ALD) production. PA is the most frequent endocrine cause of secondary high blood pressure (BP) (2) and the main clinical presentation includes hypertension of variable degree, but hypokalemia only in 9–37% of the cases (3). However, there are other less common non-ALD-dependent causes of mineralocorticoid hypertension with a clinical presentation similar to PA, due to overproduction of different mineralocorticoid precursors like 11-deoxycorticosterone (DOC) or other intermediate steroids (4). A small number of case reports on adrenal lesions (either adenoma, carcinoma or hyperplasia) producing mineralocorticoid intermediate metabolites have been reported, although some are probably overlooked, since intermediate measurements of steroids are not available in clinical practice in the majority of centers.

We present a case of DOC-producing adrenal hyperplasia with a life-threatening clinical presentation and a comprehensive review of DOC-producing adrenal lesions described in the literature. This review is intended to provide insights on the most relevant reported clinical, radiological and pathological features of DOC-producing adrenal lesions that might be useful for clinicians dealing with patients with rare causes of secondary hypertension with low or normal ALD levels.

A 53-year-old Caucasian woman without any previous history of hypertension consulted the Primary Care Emergency Department for a one-week history of self-measured high BP (up to 190/100 mmHg), muscle aches and stiffness. A blood test showed serum potassium (K⁺) of 1.73 mmol/L. When reviewing previous blood tests, K⁺ was in the normal range with the exception of the immediately preceding level five months before with a result of 3.18 mmol/L. An angiotensin-converting enzyme inhibitor (enalapril 20 mg/24 h orally) and K⁺ supplements (50 KCl mEq/24 h orally) were initiated. Nevertheless, during follow-up BP was not controlled, and K⁺ levels did not improve (2.13 mmol/L). Four weeks later, she was admitted to the Intensive Care Unit (ICU) for uncontrolled hypertension (BP of 200/120 mmHg), severe hypokalemia (1.80 mmol/L), metabolic alkalosis (pH 7.52, HCO3⁻ 43.5 mmol/L) ( Table 1 ) and changes in the electrocardiogram, namely, QT interval prolongation, a visible U wave and T wave flattening. In the ICU she required high doses of both intravenous and oral K⁺ (up to 176 mEq KCl/24 h). Because of initial difficulties in raising serum K⁺ levels despite high supplements, access to the bathroom was banned and a psychiatric consultation ruled out self-induced vomiting. Her BP was finally controlled with two oral drugs (the calcium channel blocker amlodipine 10 mg/24 h and the peripheral vasodilator hydralazine 25 mg/8 h) and serum K⁺ levels were maintained with in the lower limit of the normal range with oral 72 mEq/24 h of KCl.

After her hemodynamic and biochemical situation normalized, she was transferred to the hospitalization ward for diagnostic workup of suspected secondary hypertension. Her family history was irrelevant for hypertension or any other endocrine disease. Besides high BP, physical examination was normal with no signs of hypercortisolism, hirsutism or virilization. Biochemical and hormone data are shown in Table 1 . Plasma metanephrines, 1 mg overnight dexamethasone suppression test, thyroid function and the rest of biochemical and hematological findings were normal; PRA and ALD were undetectable. Adrenal computed tomography (CT) showed two calcifications in the right adrenal gland and two adrenal nodules suggestive of adenomas in the left adrenal gland, the largest of 12.3 × 10 × 14 mm. Both nodular adrenal lesions presented −2 (the largest) and 5.4 Hounsfield Units and absolute and relative percentages of washout at 15 min of 70% and 79%, suggestive of benign lesions. Abdominal and renal ultrasonography did not reveal any abnormal finding.

At follow-up in the Endocrinology Department after hospitalization, new blood tests after adjusting antihypertensive drugs and maintaining oral K⁺ supplementation showed serum K⁺ levels in the lower normal range (3.43 mmol/L), undetectable PRA (<0.20 µg/L/h; reference range 0.6–4.18 µg/L/h) and low ALD (81.94 pmol/L; reference range 187–930 pmol/L). Further testing evidenced elevated DOC (35.8 ng/dl; reference range 2–15 ng/dl) and normality of the rest of the hormonal profile ( Table 1 ). All other potential causes of non-ALD-dependent mineralocorticoid excess were excluded by clinical history, physical examination and/or biochemical results.

With the diagnostic suspicion of a functional adrenal mass due to non-ALD-dependent mineralocorticoid secretion, namely, excessive DOC production, a laparoscopic left adrenalectomy was performed. Macroscopy revealed a 6 × 2 × 2 cm left adrenal gland with cortical adenomatous hyperplasia and several soft and yellowish nodules, the largest being 12 × 12 mm and the rest were less than 1 cm and less defined ( Figure 1 ). On microscopic examination, the larger nodule had no capsule and its margins were not clear ( Figure 2A ). Two main types of cells were identified: large cells disposed in irregular nests with vacuolated cytoplasm and small, round nuclei with inconspicuous nucleoli and, among these nests, a second cell population of smaller cells with eosinophilic cytoplasm ( Figure 2B ). No atypia, mitosis or necrosis was detected and the Ki67 index was positive in less than 1% of cells ( Figure 2C ). Immunohistochemical analysis of steroidogenic enzymes, namely, CYP11B2 (cytochrome P450 family 11, subfamily B, member 2) immunostaining (11β-hydroxylase, 18-hydroxylase and 18-oxidase activities) and CYP11B1 (cytochrome P450 family 11, subfamily B, member 1) immunostaining (11β-hydroxylase activity) was performed ( Figure 3 ). In the zona glomerulosa of the adenomatous hyperplasia, there was a sparse expression of CYP11B2, highlighting only two isolated clusters of ALD-producing cells in the outer margin of the subcapsular area ( Figure 3A ). Immunoreactivity for CYP11B1 was fundamentally expressed in the zona fasciculata ( Figure 3B ) as expected. These findings suggested an overproduction of DOC by hyperplasic adrenal cells, leading to a suppression of ALD levels ( Figure 4 ). After surgery, K⁺ levels normalized, and K⁺ supplementation could be withdrawn immediately. BP remained elevated but to a lesser degree, suggestive of co-diagnosis of primary hypertension. She required hypotensive therapy (angiotensin II receptor antagonist losartan 25 mg/24 h) at hospital discharge achieving a satisfactory BP control. Postoperative serum PRA and ALD levels were normal, while postoperative serum DOC levels practically normalized ( Table 1 ).

To our knowledge, this is the forty-sixth DOC overproduction due to an adrenal lesion published so far worldwide. This case is remarkable for the rapid and severe clinical presentation, despite the relatively small size of the adenomatous adrenal hyperplasia (the largest nodule of 12 mm) and mildly elevated DOC levels compared to the majority of cases reported. Our literature review revealed a female predominance, average age of presentation in the fourth decade, a median tumor size of around 62 mm and a benign behavior in roughly half of the DOC-producing adrenal lesions (including adrenal adenomas and hyperplasia). This review adds knowledge in the limited body of literature on this extremely rare functional adrenocortical lesion and is intended to raise awareness of the possibility of a DOC-producing adrenal lesion in the presence of low serum ALD levels despite hypertension presumed to be due to excessive mineralocorticoid secretion.

Mineralocorticoids are, together with glucocorticoids and sex steroids, the three different adrenal steroid hormones produced in the adrenal cortex ( Figure 4 ). ALD is the final and most potent mineralocorticoid hormone, representing 90% of mineralocorticoid activity (48). However, other mineralocorticoid products have been isolated from the adrenal cortex (48). These are usually secreted in small amounts and have a weaker mineralocorticoid activity (48). Thus, it seems plausible that only high levels of mineralocorticoid precursors different from ALD could produce a clinically relevant hypermineralocorticoid state.

DOC is an ALD precursor with a 1/20 (38) to 1/30 (48) of the mineralocorticoid activity of ALD. It is synthesized from progesterone by the 21α-hydroxylase enzyme in the adrenal cortex and converted to corticosterone by the 11β-hydroxylase enzyme ( Figure 4 ). Four uncommon situations generate DOC excess with low ARP and ALD levels: congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase and 17α-hydroxylase deficiency, DOC-producing adrenal tumors, primary cortisol resistance and apparent mineralocorticoid excess (AME) syndrome due to acquired or genetic 11β-dehydrogenase type 2 dysfunction. An algorithm for the differential diagnosis of non-ALD-dependent mineralocorticoid hypertension (also known as pseudohyperaldosteronism) is shown in Figure 6 . An accurate diagnosis is crucial since appropriate treatment differs substantially among each clinical entity. In our case, CAH was rapidly ruled out since the patient did not have any sign or symptom of hirsutism or virilization, nor relevant family history or consanguinity and the 5th decade is not a common age of presentation for CAH. Genetic AME syndrome, an autosomal recessive inherited disease usually presents in childhood, was excluded and also acquired causes (i.e., liquorice root intake and Cushing’s syndrome). Moreover, DOC concentrations might increase in patients receiving 11 β-hydroxylase inhibitors such as metyrapone or mitotane, which was not the case. Furthermore, the CT scan revealed an adrenal mass, increasing suspicion of a DOC-producing adrenal lesion.

The first evidence of adrenal tumor DOC production emerged in the sixties (49, 50) and was published in 1965 by Marquezy et al. and Biglieri (6, 41). Overproduction of DOC was determined by an excess of DOC and its metabolite THDOC excreted in 24 h urine (6, 41) and by an increased content of DOC in adrenal tissue and adrenal venous plasma (41). Two main factors can mask the diagnosis and contribute to underestimating its incidence. On the one hand, DOC assay is not readily available in many routine clinical centers (40). On the other hand, some cases of PA might occur simultaneously with DOC overproduction (16, 39), implying that DOC is not searched for since ALD is not suppressed.

Our case report shows several singularities. One was the suddenness of the life-threatening clinical presentation that took the patient to the ICU in less than a month since high BP was detected, while most of the previously published cases presented months or years before diagnosis (16, 20, 31, 32, 34, 39, 40, 43). Additionally, initial serum hypokalemia was resistant despite high intravenous and oral K⁺ supplements, leading to the suspicion of an underlying psychiatric disorder despite not having any previous history of mental diseases. The combination of severe hypokalemia, metabolic alkalosis, critical hypertension and the presence of two left adrenal adenomas were highly suggestive of mineralocorticoid hypertension, yet ARP and ALD levels were repeatedly very low, excluding PA, while elevated serum DOC led to the diagnosis of a DOC-producing adrenal neoplasm ( Figure 6 ).

As reported, very high DOC plasma levels are to be expected, the highest published up to eighty times above the upper normal limit (18). However, in our case, DOC levels only doubled the normal range. Similarly, Matsumoto et al. (26) reported a case of weak mineralocorticoid-producing benign adrenal tumor with a doubling of serum DOC levels. The authors hypothesized that another mineralocorticoid intermediate different from DOC, 18-hydroxy-deoxycorticosterone (18-OH-DOC, a hydroxylated metabolite of DOC), that was above the normal value, might be responsible for the hypertensive state of that patient (26). In addition to 18-OH-DOC, other mineralocorticoid precursor related to DOC, such as 19-Nor-DOC, can cause overt hypertension (51), especially in patients with slightly elevated DOC levels. Unfortunately, we could not measure 18-OH-DOC or 19-Nor-DOC. Although in the presented patient postoperative hormone levels almost normalized, supporting the indubitable participation of DOC overproduction, it is possible that other metabolites of DOC with a known hypertensive and salt-retaining activity were also involved.

Regarding histological behavior, malignant DOC-producing adrenal lesions were larger (about 2.5 times more) and had higher DOC levels (about 3 times higher) in comparison to benign lesions; without differences in gender distribution, age and K⁺ levels. Thus, the benign behavior of our case with a relatively small tumor size and mildly elevated DOC levels could be expected based on the review of DOC-producing adrenal lesions published so far.

First physiopathological reports on the mechanisms involved in DOC-producing adrenal tumors showed a relative 11β-hydroxylation deficiency in an adrenal carcinoma tissue of a deceased patient (50). Since then, intratumoral analysis of steroidogenic enzymes ( Figure 4 ) revealed a reduced 11β-hydroxylase and 17α-hydroxylase enzyme activities in all instances (23, 27, 30, 32, 34, 38, 39 and our case), suggestive of an autonomous DOC overproduction by adrenal neoplastic cells.

Recently, LC–MS/MS metabolite steroid profiling in urine followed by machine learning analysis have evidenced a panel of nine steroids as a highly discriminative tool in differentiating adrenocortical carcinoma from adenoma (52), being tetra-hydro-11-deoxycortisol (a metabolite of 11-deoxycortisol) the most distinguishable biomarker. This panel also included THDOC, a metabolite of DOC, which was significantly increased in patients with adrenocortical carcinoma (52). Similarly, urine metabolite steroid profiling of DOC-producing adrenal tumors could permit to better differentiate the behavior of these lesions.

Some limitations need to be considered. Unfortunately, we were not able to measure DOC intermediate products. However, the PA-like clinical presentation, the biochemical and hormonal profile at diagnosis, the immunohistochemical analysis in the surgical specimen together with the marked clinical, biochemical and hormonal improvement after surgery, led to confirm the diagnosis of DOC overproduction due to unilateral adenomatous adrenal hyperplasia. We might have not identified all cases reported and cannot rule out the possibility that some unpublished cases of interest may have been missed. Nevertheless, we collected an important number of cases of this very rare disease to provide enough accurate data to summarize its main characteristics and increase the knowledge of DOC-producing adrenal lesions. Besides, we had limited access to case reports written in Japanese, but all cases found were computed and the scant information available was included.

In conclusion, DOC overproduction due to adrenal lesions mostly affects middle aged women with a PA-like presentation and time to diagnosis of several months. Nearly half of the cases demonstrated malignant behavior and adrenal hyperplasia was exceptional. Reduced 11β-hydroxylase and 17α-hydroxylase enzyme activities were the most frequent immunohistochemical findings.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AA planned the concept of this review. QA and HS carried out the literature research, manuscript selection and data extraction. AA performed the analysis. QA and AA drafted the manuscript. EU performed the laboratory analysis. EL provided the macroscopic and microscopic images and MR performed the immunohistochemical analysis. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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