Abstract
Aldosterone-producing adenoma (APA), one of the most common causes of primary hyperaldosteronism, is clinically characterized by hypertension, increased sodium retention, increased potassium excretion and altered glucose metabolism. APA can also manifest in the form of hyperosmolar hyperglycaemic state (HHS), which is a life-threatening acute diabetic complication. Infection and inadequate fluid replacement are the common precipitating and predisposing factors for the occurrence of HHS. Here, we report a case of occult APA with the initial presentation of HHS, in which an unusually rapid correction of diabetes was observed after correct diagnosis and surgical resection of the APA. To our knowledge, this is the first case with such manifestations and outcome.
Introduction
Aldosterone-producing adenoma (APA), one of the most common causes of primary hyperaldosteronism (PHA), is an uncommon benign adrenal tumour that can present with hypertension, increased sodium retention, increased potassium excretion and altered glucose metabolism. 1 Aldosterone excess has detrimental metabolic effects on both insulin sensitivity and pancreatic insulin secretion, 2 and hence, may manifest as a specific form of diabetes. 3 Here, we report the case of a patient with hyperosmolar hyperglycaemic state (HHS) who responded to conventional treatment methodology; the diabetes in the patient was cured by the resection of the APA. We believe that the APA led to the occurrence of diabetes mellitus in this patient, and this diabetes manifested as HHS.
Case history
A 51-year-old man was presented to the emergency department with a month-long history of oral dryness, polyuria and weight loss (8 kg) and a week-long history of nausea, drowsiness and general weakness. He had no other complaints and no history of diabetes. His first- and second-degree relatives also did not have diabetes. He had not been taking any medications before admission. The results of the initial assessment were as follows: body temperature, 36.5°C; blood pressure, 165/95 mmHg; pulse rate, regular at 110 beats/min; weight, 78 kg and body mass index, 27 kg/m2. Physical examination indicated a debilitated, weakened appearance and signs of dehydration, including dryness of the mucous membranes and poor skin turgor. Abdominal tenderness was absent, and hypoactive bowel sounds were observed. Blood biochemistry was performed, and the results of the tests were as follows: plasma glucose concentration, 66 mmol/L; glycated haemoglobin, 77.0 mmol/mol; serum urea nitrogen concentration, 10 mmol/L (reference, 2.14–7.14 mmol/L); serum creatinine concentration, 0.1 mmol/L (reference, 0.061–0.106 mmol/L); plasma sodium concentration, 130 mmol/L (reference, 136–145 mmol/L); plasma potassium concentration, 3.2 mmol/L (reference, 3.5–5.1 mmol/L); and effective osmolality (2×Na [mmol/L] + glucose [mmol/L]), 326 mOsm/L. Ketone bodies were not detected in the urine and blood samples. Arterial blood gas analysis performed in room air yielded the following findings: pH, 7.48 (reference, 7.35–7.45); pCO2, 6.4 kPa (reference, 4.7–6.0 kPa); pO2, 13.1 kPa (reference, 10.0–13.3 kPa); and HCO3 −, 28.2 mmol/L. We diagnosed HHS in the patient on the basis of these findings.
The patient received continuous intravenous insulin infusion, potassium supplementation and a large volume of intravenous fluids. On the second day of hospitalization, the drowsiness and weakness in the patient reduced. After one week of hospitalization, the patient's diabetes was well under control with subcutaneous administration of a mixture of short- and intermediate-acting insulin two times a day. However, we did not observe any improvements in hypertension in spite of the administration of four different kinds of antihypertensive drugs, i.e. amlodipine (5 mg twice daily), olmesartan medoxomil (20 mg twice daily), doxazosin (4 mg once daily) and trichlormethiazide (2 mg once daily).
Investigations were then performed to determine the cause of secondary hypertension. 4 Renal artery stenosis was ruled out on the basis of the results of Doppler sonography. Cortisol and vanillylmandelic acid concentrations in a 24-h urine sample were observed to be normal. The plasma aldosterone concentration determined after two hours of ambulation was observed to be 1006 pmol/L (reference, 194–970 pmol/L), while the plasma renin activity was 0.13 ng mL−1 h−1 (reference, 1.31–3.95 ng mL−1 h−1). The plasma aldosterone/renin activity ratio was observed to be high (7738; normal value, <750). 5 The saline infusion test, which involves infusion of 2 L of normal saline within four hours, failed to induce aldosterone suppression (aldosterone concentration: 412 pmol/L; normal concentration: <139 pmol/L). 5 On the basis of these results and as per the guidelines proposed by The Endocrine Society, we diagnosed PHA. Abdominal magnetic resonance imaging revealed an adenoma (diameter, 1.5 cm) in the medial limb of the right adrenal gland. The adenoma was enucleated laparoscopically, and we observed that the histology of the adenoma was consistent with that of APA. Postoperative serum aldosterone concentrations and renin activity were within the normal limits. However, we observed a significant reduction in the plasma glucose concentrations of the patient during the follow-up examination performed one month after the operation. Therefore, his antidiabetic medications were gradually discontinued. An oral glucose tolerance test performed using 75 g of glucose showed a fasting plasma glucose concentration of 5.2 mmol/L and a two-hour glucose concentration of 7.7 mmol/L, which, as per the World Health Organization criteria, 6 is a normal response when no antidiabetic medications are being administered to the patient. Therefore, only medical nutrition therapy and one antihypertensive drug were prescribed to the patient for glycaemic control and blood pressure control, respectively.
Discussion
HHS is a potentially fatal acute metabolic complication of diabetes. The mortality rate in patients with HHS is 15–50%, and the rate increases with age and serum osmolality levels. 7 High mortality may also be associated with delayed diagnosis and failure to aggressively treat HHS. HHS is usually observed in patients with diabetes (mostly type 2 diabetes), and in 30–40% of the cases, it is the initial presentation of diabetes. 7 To our knowledge, this is the first report on HHS as the initial manifestation in a patient with APA.
APA, first described by Dr Conn more than 50 years ago, is one of the most common causes of PHA. Patients with APA show inappropriately high aldosterone production along with very low or suppressed renin activity. 5,8 This over-production of aldosterone results in a number of cardiovascular and metabolic disorders, such as hypertension, increased sodium retention, increased potassium excretion and disturbance in glucose metabolism. 1 Excessively high levels of aldosterone are known to negatively impact both insulin signalling and pancreatic β-cell function. 9 The report of the expert committee on the diagnosis and classification of diabetes mellitus also lists APA as a unique form of diabetes mellitus. 3 Multiple factors can cause aldosterone-induced glucose intolerance, including effects of hypokalaemia on pancreatic β-cell function, direct effects on insulin receptors and signalling, stimulation of hepatic gluconeogenesis, effects on sodium–glucose transport, fibrosis-induced dysfunction in insulin-producing tissues or insulin-sensitive tissues, and detrimental effects on β-cell structure and function due to the induction of inflammation in the islet cells. 2
In this case, the patient's medical and family histories were negative for type 1 or type 2 diabetes, and his glucose homeostasis was restored after the resection of the APA and normalization of aldosterone concentrations. Recent studies have shown that after undergoing adrenalectomy, patients with APA exhibit a significant reduction in blood pressure and plasma glucose concentrations, and normalization of the parameters indicating insulin resistance. 10,11 In our patient, physiological stress may have further reduced the effectiveness of circulating insulin 7 and exacerbated the disturbance in glucose homeostasis. Marked hyperglycaemia eventually leads to osmotic diuresis, glycosuria, dehydration and severe hyperosmolality. The altered mental status in our patient directly corresponds to hyperosmolality and may be associated with intracellular cerebral dehydration.
In our patient, who was middle-aged, the observation of treatment-resistant hypertension was the most important factor influencing the diagnosis and prompt treatment of the underlying disease. The American Heart Association recommends that patients with resistant hypertension should be evaluated for secondary causes of hypertension, including PHA, obstructive sleep apnoea, renal parenchymal disease, renal artery stenosis, pheochromocytoma and Cushing's syndrome. 4 PHA is common in patients with resistant hypertension (prevalence, approximately 17–23%). 4 Biochemical evaluation of PHA includes determination of the aldosterone–renin ratio for case detection and performing an oral sodium-loading test, saline infusion, a fludrocortisone suppression test or a captopril challenge test for confirmation of the condition. 5 After PHA is diagnosed, APA can be detected by performing adrenal imaging and bilateral adrenal venous sampling and can be optimally treated by laparoscopic adrenalectomy. 5
In summary, we have reported a case of occult APA with an initial presentation of HHS. This case demonstrates both a rare presentation of APA and an unusually rapid correction of diabetes after accurate diagnosis and surgical resection of the APA.
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