Unmasking Adrenal Insufficiency in COVID-19: The Diagnostic Challenge of Concomitant Acute Kidney Injury and High Ileostomy Output

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the Coronaviridae family, is known to affect multiple organ systems beyond the respiratory tract. Increasing evidence suggests that SARS-CoV-2 can disrupt the hypothalamic-pituitary-adrenal axis, leading to adrenal insufficiency. Proposed mechanisms include direct viral cytopathic effects via angiotensin-converting enzyme 2 receptors expressed in the adrenal cortex, immune-mediated adrenalitis, vascular coagulopathy, and critical-illness-related corticosteroid insufficiency (CIRCI) [1,2].

Detection of adrenal insufficiency in the acute setting is difficult because its symptoms, such as hypotension, fever, and fatigue, can mimic sepsis and other critical conditions [3,4]. This diagnostic complexity increases in patients with preexisting renal disease. In such cases, hyperkalemia – a hallmark sign of mineralocorticoid deficiency – is often attributed solely to renal dysfunction or is artificially corrected by renal replacement therapy [5].

Here, we describe a patient with an ileostomy and coronavirus disease 2019 (COVID-19), in whom the diagnosis of adrenal insufficiency was initially obscured by concurrent acute kidney injury (AKI) and dialysis. We discuss the “masking and unmasking” phenomenon that delayed the diagnosis, as well as pathophysiologic mechanisms relevant to COVID-19.

Case Report

A 46-year-old man presented to the emergency department with 1 day of dyspnea, generalized myalgia, fatigue, dizziness, crampy abdominal pain, and increased ileostomy output of liquid stool (>2.5 L/day). He also reported several days of malaise and sore throat, as well as poor oral intake and decreased urine output for 1 day. He denied recent changes in medications or the ingestion of toxic substances. The patient had a history of chronic kidney disease stage IIIB (baseline creatinine approximately 2 mg/dL; its cause was unclear and not evaluated during this case), depression, bipolar disorder, and a previous suicide attempt involving an overdose of antihypertensive medications. He also exhibited ischemic bowel disease and had experienced intestinal perforation 22 years earlier, which required colectomy with ileostomy.

On physical examination, the patient appeared ill, was febrile, and had dry mucous membranes. The abdomen was tender without guarding. Vital signs showed hypotension. Laboratory results revealed AKI (creatinine 10.5 mg/dL) superimposed on chronic kidney disease, severe metabolic acidosis (pH <7.0), and pronounced electrolyte abnormalities, including hyperkalemia (7.1 mEq/L), hyperphosphatemia (10.8 mg/dL), and hyponatremia (130 mEq/L). A nasopharyngeal polymerase chain reaction respiratory panel revealed COVID-19 positivity. Urinalysis showed muddy brown casts consistent with acute tubular necrosis (Table 1). Initial imaging via noncontrast computed tomography scan of the abdomen and pelvis demonstrated nonspecific nodular thickening of the left adrenal gland (Figure 1).

The patient was admitted for management of AKI attributed to acute tubular necrosis, secondary to severe volume depletion from high ileostomy output. He underwent hemodialysis and began bicarbonate infusion. Hyperkalemia was initially treated with intravenous calcium gluconate, insulin, and dextrose. The patient also received a 3-day course of remdesivir for COVID-19. Initial hemodialysis sessions successfully corrected the hyperkalemia and acidosis. A right internal jugular vein thrombus at the catheter site was identified and treated with heparin; the catheter was relocated to the femoral vein. Given that the patient’s renal function improved and creatinine returned to baseline (2.5 mg/dL), dialysis was discontinued. He completed 2 hemodialysis sessions, both during the first 2 days of admission.

Clinical deterioration was evident despite renal recovery. The patient developed sustained orthostatic hypotension refractory to midodrine and recurrent hyperkalemia (5.5 mEq/L), regardless of treatment with sodium zirconium cyclosilicate (Figure 2). An episode of hypoglycemia (11 mg/dL) was also noted. His ileostomy output remained high (>3 L/day) despite maximal doses of loperamide. Aggressive intravenous replacement did not prevent persistent hypomagnesemia (1.3 mg/dL) and hypocalcemia (7.3 mg/dL). Polymerase chain reaction testing for Clostridioides difficile and enteric pathogens showed negative results. The recurrence of hyperkalemia in the context of renal recovery and high ileostomy output, which typically causes potassium wasting – together with new-onset hypoglycemia – led to suspicion of adrenal insufficiency.

For initial evaluation of adrenal insufficiency, 2 morning serum cortisol levels were measured; the levels were critically low on consecutive days (1.74 μg/dL and 1.65 μg/dL) (Table 2). These results were obtained in the absence of prior steroid treatment. An adrenocorticotropic hormone stimulation test performed 24 hours later showed a baseline cortisol level of 5.53 μg/dL, rising to 14.6 μg/dL at 30 minutes and 18.38 μg/dL at 60 minutes (Table 2). Although the 60-minute value was borderline, the blunted 30-minute response in the context of physiologic shock supported a diagnosis of adrenal insufficiency. Empiric intravenous hydrocortisone (50 mg every 6 hours) and oral fludrocortisone were administered. Upon initiation of steroid therapy, the hypotension resolved, dizziness improved, and potassium levels normalized without further use of potassium-binding resins. The patient was discharged on oral midodrine 15 mg 3 times daily and fludrocortisone 0.2 mg daily. Unfortunately, he was lost to follow-up after discharge.

Discussion

Adrenal insufficiency, a rare syndrome characterized by cortisol deficiency, affects fewer than 279 per 1 million individuals. Primary adrenal insufficiency typically results from autoimmune destruction of the adrenal cortex, leading to deficiency of all adrenocortical hormones. Common causes include autoimmune disease, congenital adrenal hyperplasia, drugs (eg, azole antifungal therapy), infection (eg, tuberculosis, fungal infections), or surgical removal of adrenal cortical tissue. Secondary adrenal insufficiency is caused by disorders affecting the pituitary gland, such as tumors, hemorrhage, inflammatory or infiltrative conditions (eg, hypophysitis, sarcoidosis, hemochromatosis), surgery, radiation therapy, or medications (eg, opioids) that suppress corticotropin production [6].

The present case illustrates a critical diagnostic pitfall: the masking of adrenal crisis by renal replacement therapy. Primary adrenal insufficiency typically presents with hyponatremia and hyperkalemia due to aldosterone deficiency [5]. In our patient, the initial hyperkalemia was attributed to AKI and was corrected by dialysis. After the “mask” of dialysis had been removed and renal function recovered, persistent hyperkalemia and shock allowed unmasking of the underlying adrenal etiology.

The pathophysiology of adrenal insufficiency in COVID-19 is multifactorial. SARS-CoV-2 may cause direct viral injury through angiotensin-converting enzyme 2 receptors, which are strongly expressed in adrenal tissue [1]. Autopsy studies have confirmed viral presence and necrosis in the adrenal glands of patients with severe COVID-19 [7]. Additionally, the patient’s jugular vein thrombosis suggested a hypercoagulable state, potentially producing microvascular adrenal thrombosis. Finally, the clinical picture is consistent with CIRCI [1,7,8]. Studies by Mao et al [9] revealed that 66.6% of critically ill patients with COVID-19 met criteria for CIRCI, characterized by cellular resistance to glucocorticoids and localized tissue inflammation despite circulating cortisol [8].

Symptoms of adrenal insufficiency are nonspecific and include fatigue (50–95%), nausea and vomiting (20–62%), and anorexia and weight loss (43%–73%), consistent with our patient’s presentation [6]. Diagnostic evaluation is indicated in patients who present with dehydration, sustained hypotension, hyponatremia, hyperkalemia, and hypoglycemia [3]. In the present case, the “unmasking” phase, characterized by recurrent hyperkalemia despite renal recovery, was the key clinical clue. A unique feature of this case was the patient’s ileostomy. High ileostomy output typically results in pronounced potassium loss, leading to hypokalemia. The presence of hyperkalemia in a patient with high ileostomy output is physiologically paradoxical and should have served as an earlier clue to mineralocorticoid deficiency.

Other potential causes of the patient’s sustained hypotension include dehydration secondary to high ileostomy output and diuretic misuse. However, the patient had no history of diuretic use; diuretics were not administered during hospitalization because they were not indicated in the context of ongoing volume losses and AKI. In contrast, the patient’s persistent hyperkalemia and hypotension support adrenal insufficiency, a diagnosis confirmed by low morning cortisol levels and an adrenocorticotropic hormone stimulation test. Moreover, hypotension caused by dehydration or diuretic use would likely be associated with hypokalemia, rather than hyperkalemia [10].

Bhattarai et al [11] described a 19-year-old woman who presented with generalized malaise, vomiting, decreased oral intake, hypotension, and cerebral edema; she was subsequently diagnosed with COVID-19 and adrenal insufficiency, then treated accordingly. Although their report is similar to the present case, the key difference lies in the presumed onset of adrenal insufficiency. Notably, Bhattarai et al described COVID-19-mediated unmasking of Addison disease, whereas we observed COVID-19-mediated development of adrenal insufficiency. This interpretation is supported by the initially normal cortisol level in our patient, which subsequently decreased during hospitalization.

Marques et al [12] described a 28-year-old man who presented with generalized malaise, fatigue, and epigastric pain after developing COVID-19. Similar to the present case, their patient exhibited hypotension, AKI, hyponatremia, hyperkalemia, and metabolic acidosis. However, our case is unique because it demonstrates a diagnostic dilemma caused by the masking and unmasking effects that AKI and renal recovery had on underlying metabolic abnormalities.

According to Endocrine Society guidelines, a diagnosis of adrenal insufficiency is confirmed by a corticotropin stimulation test [3]. Our patient’s blunted 30-minute response (14.6 μg/dL), combined with persistently low morning cortisol levels, confirmed the diagnosis.

Treatment for adrenal insufficiency focuses on prompt glucocorticoid and mineralocorticoid replacement. Hydrocortisone is the preferred glucocorticoid, whereas fludrocortisone is the drug of choice for mineralocorticoid replacement [6]. In the context of adrenal crisis, treatment should not be delayed for confirmatory testing [4]. In the present case, empiric therapy led to rapid resolution of shock and electrolyte abnormalities, serving as a diagnostic and therapeutic trial.

Limitations of this report include the inability to obtain adrenal autoantibodies (eg, 21-hydroxylase antibodies) that would definitively distinguish between preexisting autoimmune adrenalitis and de novo viral injury. Additionally, the patient was lost to follow-up, preventing repeat testing to clarify whether hypothalamic-pituitary-adrenal axis suppression was transient or permanent.

Conclusions

This report highlights the importance of prompt investigation and management of hypotension and hyperkalemia; it suggests an association between adrenal insufficiency and recent COVID-19. In patients with COVID-19 and concomitant AKI, classic electrolyte abnormalities of adrenal insufficiency may be temporarily corrected by dialysis, leading to delayed diagnosis. Clinicians should suspect adrenal insufficiency if hypotension and hyperkalemia recur despite recovery of renal function. Furthermore, a “normal” cortisol level during severe physiologic stress may indicate relative insufficiency requiring treatment.