A rare case of severe hypertension with hypokalemic metabolic alkalosis in a 14-year-old girl: Answers

Our patient had metabolic alkalosis, hypokalemia, high urinary chloride, and hypertension. This situation can be approached as depicted in Fig. 1. Since the urinary chloride was high, and she had severe hypertension with hypokalemic metabolic alkalosis in the presence of rounded facies, we clinically suspected Cushing syndrome (CS) as a possible etiology, and she underwent estimation of serum cortisol along with plasma adrenocorticotropic hormone (ACTH). The history was reviewed, and she denied any history of intake of steroids or medications containing steroids. The plasma renin activity (0.2 ng/mL/h) and plasma aldosterone level (3 ng/dL) were low (reference values: plasma renin activity 0.9–6.6 ng/mL/h, plasma aldosterone level 6.5–29.5 ng/dL). This led to a clinical suspicion of endogenous CS as a potential explanation for the constellation of clinical and laboratory findings encountered in this patient.

In view of a clinical suspicion of CS, she underwent estimation of serum cortisol (at 8 am) along with plasma adrenocorticotropic hormone (ACTH). The levels of these were found to be > 75 mcg/dL (reference value 4.3–22.4 mcg/dL) and 363 pg/mL (reference value 10–60 pg/mL) respectively. This led to a diagnosis of ACTH-dependent Cushing syndrome. MRI cranium showed no evidence of pituitary or hypothalamic lesions. A contrast-enhanced computed tomography of the thorax and abdomen was performed for further evaluation of the etiology of endogenous Cushing syndrome. This showed evidence of a tumor in the tail of the pancreas, para-aortic and coeliac lymphadenopathy, evidence of metastasis to the liver, and bilateral adrenal hyperplasia (Fig. 2). Subsequently, the patient underwent distal pancreatectomy, bilateral adrenalectomy with nodal sampling, and liver nodule excision biopsy. Histopathological examination of the excised pancreatic specimen showed monomorphic tumor cells arranged in nests and sheets which showed moderate cytoplasm, fine stippled chromatin, and moderate degree of nuclear atypia. These cells were diffusely positive for immunohistochemistry with synaptophysin and chromogranin. The Ki-67 index was 40%. Hence, the final histopathology was suggestive of a well-differentiated pancreatic neuroendocrine tumor (World Health Organization Grade 3) with metastasis to celiac lymph node and liver nodule (Fig. 3). To summarize, she had a pancreatic neuroendocrine tumor producing ACTH, leading to endogenous CS. Post-operatively, she requires amlodipine (being tapered) and hydrocortisone. Stress dose of hydrocortisone was initiated. After multidisciplinary tumor board discussion, oral capecitabine and temozolamide chemotherapy were initiated.

The mechanisms of hypertension in endogenous CS are multifactorial. The primary mechanism is the mineralocorticoid action exerted by supraphysiological levels of serum cortisol. Serum cortisol is known to bind to both glucocorticoid and mineralocorticoid receptors [1]. The plasma levels of cortisol in humans are 100–1000-fold higher than that of aldosterone which implies that mineralocorticoid receptor (MR) can be chiefly activated by cortisol. However, this is kept in check by 11β-hydroxy steroid dehydrogenase (11β-HSD) which modulates the effect of cortisol at the tissue level. There are two isoforms of 11β-HSD enzyme. The first isoform 11β-HSD1 catalyzes both dehydrogenation and reduction reactions and is responsible for the interconversion of cortisol and cortisone. In vivo, it predominantly functions as a reductase, converting inactive cortisone to active cortisol. It is abundantly expressed in the liver and adipose tissue. The second isoform 11β- HSD2 is active at very low cortisol concentrations and has mainly dehydrogenase activity which inactivates cortisol to cortisone. It is highly expressed in mineralocorticoid target tissues like renal cortex, colon, salivary, and sweat glands. This enzyme prevents cortisol from binding to MR in mineralocorticoid target tissues under physiological concentrations of cortisol. However, in cortisol excess states, the levels of cortisol would exceed the capacity of 11β-HSD to inactivate it to cortisone, thus making it available to bind to MR, mimicking excess aldosterone. This MR activation in turn results in increased renal tubular sodium reabsorption and intravascular volume expansion. Mineralocorticoid-induced hypertension is due to over activity of epithelial Na⁺ (ENac) [2] (Fig. 4). MR activity also leads to ROMK channel and H⁺K⁺ATPase stimulation in the distal nephron, leading to hypokalemia and metabolic alkalosis, respectively.