Stress-induced severe transient hypercortisolism with reversible bilateral adrenal enlargement after cardiogenic shock

Background

Adrenal glands respond to physical stress through corticotrophin-releasing hormone-mediated increase in adrenocorticotrophic hormone (ACTH), resulting in cortisol elevation. In animal studies, very high serum cortisol and ACTH levels associated with significant bilateral adrenal gland enlargement have been reported during major stress events (1, 2). Only a few cases with detailed imaging, biochemistry, and management have been reported in humans upon literature search performed on PubMed (3). We describe a case of massive bilateral adrenal enlargement incidentally found on abdominal imaging during critical illness, which was associated with new-onset nonischemic cardiomyopathy with acute reduction in ejection fraction. These findings interestingly disappeared within 3 weeks after resolution of acute illness.

Case presentation

A 57-year-old female with a long-standing history of chronic congestive heart failure, postpartum cardiomyopathy, type 2 diabetes, and hypothyroidism was hospitalized for acute respiratory failure from cardiogenic shock with new-onset nonischemic cardiomyopathy with a left ventricular ejection fraction (LVEF) drop from 57% to 5%. During her prolonged hospitalization, she was noted to have worsening preexisting hypokalemia while on loop diuretics, despite being on spironolactone and losartan.

Investigation

Workup due to persistent hypokalemia revealed significantly elevated serum morning cortisol of 122.4 μg/dL (repeated: 75.7 μg/dL) (reference range (RR): 6.02–18.4) and ACTH of 181 pg/mL (repeated: 170 pg/mL) (RR: 7.2–63.3), with a low aldosterone/renin ratio (aldosterone: < 1.0 ng/dL, renin: 0.92 ng/mL/h). Twenty-four-hour free urine cortisol was also very high at 6100 μg/24 h (RR: 6–42). DHEA sulfate levels were 62.3 μg/dL (RR 29.4–220.5), Metanephrine plasma levels were <10 pg/mL (RR 0–62). CT abdomen (Fig. 1) showed symmetrical enlargement of both adrenal glands, with a maximum diameter of 7 cm on the right and 9 cm on the left. Pre-contrast Hounsfield units (HU) were 40–45, and postcontrast washout was about 40%. Endocrinology was consulted. On questioning, she denied recent weight gain, headaches, vision change, abdominal striae, proximal muscle weakness, hirsutism, acne, history of kidney stones, or steroid use. On physical examination, her blood pressure was within normal range, and she had no evidence of cushingoid features. Pituitary MRI revealed a normal pituitary gland. Transthoracic echocardiogram showed an LVEF of 5% (from baseline 57%), attributed to stress-induced cardiomyopathy per her cardiologist. Over a period of 3 weeks, her cardiac condition improved with medical management, including vasopressors and diuretics. A 3-week follow-up CT scan of the abdomen (Fig. 2) showed near resolution of adrenal enlargement. Follow-up laboratory investigation at the same time revealed normalization of morning cortisol (9.55 µg/dL), ACTH levels (8.3 pg/mL), and 24-h free urine cortisol 2 μg/24 h. Her potassium levels also normalized, with minimal need for potassium replacement which was similar to her baseline. Cardiac ultrasoung showed an improvement in LVEF from 5% to 10%.

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Initial CT abdomen with and without contrast. Bilateral symmetrically enlarged adrenal glands. Right adrenal measures 4.1 × 2.4 × 7.2 cm. In average 38–40 HU on pre-contrast scan, 105–107 HU postcontrast, and 61–63 HU on the delayed scan, with 65% absolute washout and 41% relative washout. Left adrenal gland measures 5.2 × 2.5 × 9.0 cm. In average 41–43 HU on the pre-contrast scan, 97–112 HU on the postcontrast scan, and 57–69 HU on the delayed images, with 69% absolute washout and 41% relative washout.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0329

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Follow-up of CT abdomen without contrast. A significant decrease in the size of bilateral adrenal glands thickening.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0329

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After being discharged from the hospital, the patient was lost to endocrinology follow-up. However, she had cortisol and ACTH checks within normal limits in four different opportunities, up to 6 weeks after discharge, with values of 6.42 µg/dL and 22.3 pg/mL, respectively.

The patient was readmitted 5 months later for septic shock due to pneumonia, worsening cardiac failure, subsequent liver failure, and gastrointestinal bleeding and unfortunately died. Her morning cortisol level was normal during this admission at 9.11 µg/dL, and no autopsy was completed.

Treatment

Over this period the patient was admitted to the intensive care unit, dobutamine 5 µg/kg/min, milrinone and diuresis with IV bumetamide was given. Once diuresis and cardiovascular stability were achieved, milrinone was weaned off, and the patient was transitioned to oral bumetamide.

Outcome and follow-up

Over a period of 3 weeks, her cardiac condition improved with medical management, which included vasopressors and diuretics. Adrenal enlargement significantly improved, and our patient had normalization in morning cortisol levels (9.55 µg/dL), ACTH levels (8.3 pg/mL), and 24-h free urine cortisol 2 μg/24 h.

Discussion

As part of the hypothalamic–pituitary–adrenal (HPA) axis, the adrenal gland is an essential stress-responsive organ and plays a major role in mediating the sympathy–adrenomedullary system (1). Adrenal gland enlargement after stress has been reported in several animal studies (3). Animal models evaluating the chronic administration of ACTH have demonstrated augmented adrenal functionality and increased adrenal weight and size, which have been suggested to be mediated by both cellular hypertrophy and hyperplasia in the zona fasciculata (2). Adrenal medullar cellular hypertrophy is also expected in rat models exposed to prolonged stress periods (2). Chronic stress has also been shown to cause increased adrenal responsiveness to ACTH in animal models, likely secondary to maximal ACTH output and increased sensitivity to ACTH (4). Acute stress, such as surgery, has been found to induce hyperplasia in the zona fasciculata of adrenal glands (5). Animal studies suggest that this enhanced responsiveness inducing adrenal enlargement can be mediated not only by increased ACTH production but also by increased sensitivity to ACTH, inducing increased cell size (hypertrophy) and/or increase in the number of cells (hyperplasia) (2); however, there are no human studies to elicit the mechanism and predisposing factors.

The HPA axis response to stressful conditions in humans is well known; however, the degree or extent of adrenal enlargement and its clinical impact is unclear. A retrospective study evaluating abdominal CT scans in patients with depression demonstrated that 12 out of 38 subjects had significantly increased adrenal volumes compared to normal controls (6). Non-functional reversible adrenal enlargement cases have been previously reported (7, 8), suggesting hematomas, cystic lesions, and infections of adrenal glands as possible etiologies. Functional differentials include Cushing's disease with cyclical ACTH production, stress-induced ACTH-dependent adrenal hyperplasia, and ectopic ACTH production. A CT density > 10 HU indicates a low lipid content adenoma and has been correlated with functional adrenal enlargement (9). In addition to our report, there was only one case in humans found in the literature reporting reversible adrenal enlargement with abnormal adrenal function and self-resolution after the acute illness resolved (3). In that case, bilateral adrenal gland enlargement with increased 24-h urine metanephrines levels was incidentally found during acute illness. Subsequently, after the resolution of acute illness, these findings resolved with normalization in metanephrines levels and adrenal volume. On 6 weeks follow-up, this patient had a suboptimal cosyntropin stimulation test with elevated ACTH levels, suggesting primary adrenal cortical deficiency, which was thought to be transient. On subsequent 3-month follow-up, cosyntropin stimulation test showed improvement in adrenal function, and CT scan documented resolution of adrenal enlargement.

Our patient had significantly elevated cortisol and ACTH levels in conjunction with incidental bilateral adrenal gland enlargement in the setting of cardiogenic shock and stress-induced cardiomyopathy, prompting endocrinology consultation. Very high cortisol levels can cross-react and activate aldosterone receptors, resulting in hypokalemia with low aldosterone/renin ratio in our patient. The normalization of cortisol, potassium, and ACTH levels and the reversal of adrenal enlargement following hemodynamic stability within 3 weeks suggest stress-induced etiology. Acute stressors in very sick patients can augment HPA axis stress response in certain cases, resulting in transient bilateral massive adrenal enlargement, as seen in our patient. Interestingly, our patient also had a prior history of postpartum cardiomyopathy following childbirth in her 30s.

Abdominal imaging is frequently performed in critically ill patients for diagnostic workup of various conditions, commonly detecting incidental adrenal findings. Radiomic analysis could be useful to differentiate adrenal lesions (10) but was not completed in our patient. Based on our clinical experience and literature search, critically ill patients are not typically found to have bilateral significant adrenal enlargement as an incidental finding. Therefore, certain individual factors, possibly genetic, could predispose to this condition in some patients and are worth studying. Our patient likely had a predisposing factor that led to the development of postpartum cardiomyopathy, stress-induced cardiomyopathy, and stress-induced adrenal hypertrophy or ‘ballooning’, as the condition reversed with the resolution of acute illness.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Every effort was made to contact the next of kin of the deceased patient to obtain consent but was unsuccessful.

Author contribution statement

All the authors participated actively in the elaboration and review of this manuscript.