Rare but serious cause for hypokalaemia and hypertension

Abstract

Adrenocortical carcinoma is a rare tumour but hypertension conversely is very common. We present the case of a woman in her 30s, with poorly controlled hypertension on four antihypertensive agents. She was referred to the accident and emergency department with hypokalaemia. For a year, she had experienced oedema, weight gain, acne, hirsutism and oligomenorrhea. She had a classic Cushingoid appearance and marked striae. Cushing’s syndrome was confirmed biochemically with an abnormal overnight dexamethasone suppression test. She was diagnosed with metastatic adrenocortical carcinoma following CT imaging. This was resected via a right adrenalectomy, nephrectomy and cholecystectomy. She also received mitotane. Unfortunately, she has a terminal prognosis having experienced a recurrence. This case demonstrates the value of a thorough clinical assessment. More importantly, it highlights the need to refer earlier patients under 40 with resistant hypertension to a specialist. Finally, it encourages clinicians to investigate hypokalaemia in the context of hypertension.

Background

Adrenocortical carcinoma is a rare tumour, with an incidence of approximately 0.5–2 cases/million/year.¹ It has a poor prognosis and advanced tumour staging is one of the prognostic parameters.^{2 3} In patients with complete resection of European Network for the Study of Adrenal Tumours (ENSAT) stage 2, 5-year survival can be as high as 90% in comparison to a median survival of about 15 months in ENSAT stage 4.¹ Around 50% of patients present with hormone excess. The most common of these being hypercortisolism.³ Hypokalaemia and hypertension are commonly observed in these patients.^{3 4} Although this can mimic hyperaldosteronism.^5–7

Hypertension conversely is a very common disease affecting 30% of the population.⁸ A good history and examination would enable early differentiation of causes of secondary hypertension from essential hypertension. We hope this case will highlight the value of a thorough clinical assessment; prompting relevant investigations and subsequently leading to an earlier diagnosis and thereby potentially a better prognosis. But most importantly it will encourage clinicians to consider secondary causes of hypertension and referrals to specialists earlier, especially in those under 40⁹ with resistant hypertension accompanied by electrolyte abnormalities.

Case presentation

This case is about a woman in her 30s, who was referred by her general practitioner (GP) to the emergency department with hypokalaemia and deranged liver function tests. She had been diagnosed with hypertension 6 months previously. She was taking lercanidipine, furosemide, doxazosin and atenolol. However, her GP was still struggling to control her blood pressure.

Over the last year she had experienced bilateral leg swelling and gained three stone in weight. Her bilateral leg swelling had been investigated 6 months ago in ambulatory care. She had a normal chest X-ray, urea and electrolytes, urine dip and bilateral Doppler; thereby ruling out pulmonary oedema, nephrotic syndrome and deep vein thrombosis. During this attendance, she was noted to be hypokalaemic and commenced on a short course of potassium replacement. However, this had now recurred.

Furthermore, she experienced daily regular palpitations, which lasted a few minutes and were associated with shortness of breath. She had developed acne on her face and neck and stretch marks over her abdomen and upper legs. She had also noticed hirsutism along with easy bruising. Furthermore, she reported an excessive thirst, constant bloating and headaches at night. She had also felt lethargic during this time. She had been concerned about early menopause in light of a decreased libido and irregular periods. She had already taken a pregnancy test, which was negative. She also had no family history of adrenal cancer.

On examination she had acne and a flushed round face. Additionally, there was evidence of easy bruising on her limbs and bilateral oedema up to her knees. She looked Cushingoid with proximal muscle wasting, an enlarged supraclavicular fat pad and purple striae on her abdomen and thighs. Her blood pressure was 176/106 mm Hg. Her chest examination and heart sounds were normal and her pulse was regular at 70 beats per minute. Her abdomen was soft with some right upper quadrant tenderness and there was no aortic bruit.

Differential diagnosis

This woman had multiple symptoms; however, she had a typical clinical picture of Cushing’s syndrome. Her GP had additionally done a random cortisol which was raised at 959 nmol/L. We therefore investigated this further in ambulatory care. The main differentials for secondary hypertension, for example, pre-eclampsia, glomerulonephritis, chronic kidney disease, hyperparathyroidism and hyperthyroidism, had been ruled out by her GP. She had a negative pregnancy test, normal urinalysis and normal blood tests, that is, urea 3.9 mmol/L, creatinine 63 µmol/L, phosphate 0.97 mmol/L, calcium 2.38 mmol/L and thyroid stimulating hormone 1.1 mIU/L. In light of her bruising, her coagulation (prothrombin time 12.9 s, activated partial thromboplastin time 23.5 s, fibrinogen 3.8 g/L), platelets (265×10⁹/L) and erythrocyte sedimentation rate (16 mm/hour) were checked and were normal. Further blood tests were done to look for causes of her hypokalaemia, 2.8 mmol/L, in the context of hypertension, to confirm Cushing’s syndrome and check for any complications. Please refer to table 1 as a summary of blood tests.

Table 1.

The patient’s initial blood tests

Test	Patient’s results	Normal ranges	Test	Patient’s results	Normal ranges
White cell count	11.89×109/L	4–11×109/L	Random cortisol	959 nmol/L	170–540 nmol/L
Haemoglobin	144 g/L	115–161 g/L	Thyroid stimulating hormone	1.1 mIU/L	0.3–4.5 mIU/L
Platelets	265×109/L	140–400×109/L	Plasma normetanephrine	571 pmol/L	0–1180 pmol/L
Erythrocyte sedimentation rate	16 mm/hour	1–20 mm/hour	Plasma metanephrine	<100 pmol/L	0–510 pmol/L
Prothrombin time	12.9 s	12–15 s	Aldosterone/renin ratio	<4 pmol/mIU	<30 pmol/mIU
Activated partial thromboplastin time	23.5 s	24–35 s	Renin	33.1 mIU/L	Supine <59.7 mIU/L Erect 5.3–99.1 mIU/L
Fibrinogen	3.8 g/L	1.8–4.5 g/L	Aldosterone	<103 pmol/L	Supine 103–859 pmol/L Erect 103–1197 pmol/L
Sodium	142 mmol/L	133–146 mmol/L	Random testosterone	1.1 nmol/L	<1.7 nmol/L
Potassium	2.8 mmol/L	3.5–5.3 mmol/L	Sex hormone	52 nmol/L	26–110 nmol/L
Urea	3.9 mmol/L	2.5–7.8 mmol/L	17 hydroxyprogesterone	6.9 nmol/L	<6.8 nmol/L
Creatinine	63 μmol/L	49–90 μmol/L	Androstenedione	13 nmol/L	1.4–14.3 nmol/L
eGFR	>90 mL/min/1.73 m2	>90 mL/min/1.73 m2	Dehydroepiandrosterone sulfate	6.6 µmol/L	1.7–9.2 µmol/L
Bilirubin	7 µmol/L	<21 µmol/L	Beta-human chorionic gonadotropin	<1 IU/L	<5 IU/L
Alkaline phosphatase	281 U/L	30–130 U/L	Follicular stimulating hormone	4.4 IU/L	Follicular 2–10 IU/L Mid-cycle 5–28 IU/L Luteal 2–8 IU/L
Alanine aminotransferase	45 U/L	<40 U/L	Luteinising hormone	4.0 IU/L	Follicular 2–10 IU/L Mid-cycle 10–96 IU/L Luteal 2–11 IU/L
Albumin	36 g/L	35–50 g/L
Calcium	2.38 mmol/L	2.2–2.6 mmol/L	pH	7.52	7.35–7.45
Magnesium	0.87 mmol/L	0.7–1 mmol/L	pCO2	6.8 KPa	4.5–6.1 kPa
Phosphate	0.97 mmol/L	0.8–1.5 mmol/L	Bicarbonate	41.6 mmol/L	21–25 mmol/L
Glucose	6.8 mmol/L	3–10 mmol/L	Base excess	18.7 mmol/L	−3 to +3 mmol/L
Haemoglobin A1C	45 mmol/mol	20–42 mmol/mol

Bold values highlight results outside normal range.

eGFR, estimated glomerular filtration rate.

Her ECG showed normal sinus rhythm with a normal QT interval corrected for heart rate, ruling out common cardiac arrhythmias. All electrolytes were normal other than potassium (sodium 142 mmol/L, magnesium 0.87 mmol/L). Although she had palpitations and headaches, pheochromocytoma was ruled out with normal metanephrines: plasma normetanephrine 571 pmol/L, plasma metanephrine <100 pmol/L and 3 methoxytyramine <100 pmol/L. She was also screened for hyperaldosteronism, a known mimic, and had a normal aldosterone/renin ratio of <4: renin 33.1 mIU/L and aldosterone <103 pmol/L.

Imaging is needed to look for adrenal and renal causes for hypertension, such as polycystic kidney disease, renal artery stenosis and pyelonephritis. We therefore arranged for an ultrasound (figure 1) which showed a large mass superior to the right kidney. It was difficult to determine if this mass was extending from the right kidney or adrenal or was part of the liver. As it did demonstrate a mass effect within the internal liver parenchyma. The findings were suspicious of malignancy and clinical correlation and further imaging was advised. Therefore, a CT scan (figure 2) was performed, which showed a large right adrenal mass, potentially invading inferior vena cava. Adrenocortical carcinoma was felt to be most likely. The fact it was invading the inferior vena cava meant there was already extra-adrenal spread at the time of diagnosis. Therefore, her disease was likely to be incurable.

Figure 1.

The patient’s initial ultrasound demonstrating a mass superior to the right kidney.

Figure 2.

The patient’s initial CT scan demonstrating a large right adrenal mass.

She was reviewed by an endocrinologist on the same day. He felt she had signs and symptoms of Cushing’s syndrome due to excess cortisol from the adrenal tumour. Furthermore, this was likely malignant due to the size and appearance.

Cushing’s syndrome can be caused by pituitary, ectopic adrenocorticotropic hormone (ACTH) or adrenal disease. A 1 mg overnight dexamethasone suppression test (cortisol 836 nmol/L) and 24 hours urine cortisol were arranged to confirm Cushing’s syndrome. A low ACTH usually then rules out ACTH-dependent causes. However, she became poorly after 2 days and underwent urgent surgery at the tertiary centre. The diagnosis of adrenal carcinoma was very obvious clinically, radiologically and with available biochemistry by this point. Hence, they did not pursue ACTH and 24 hours urine cortisol.

Concurrent androgen with cortisol production is evident in adrenocortical carcinoma.² However, her androgen levels were normal (random testosterone 1.1 nmol/L, sex hormone 52 nmol/L, free androgen 2.0, 17 hydroxyprogesterone 6.9 nmol/L, androstenedione 13 nmol/L, dehydroepiandrosterone sulfate 6.6 μmol/L). Both luteinising hormone (LH) and follicle-stimulating hormone (FSH) may be suppressed with adrenal tumours (beta-human chorionic gonadotropin suppressed <1 IU/L, LH 4.0 IU/L, FSH 4.4 IU/L).

There were signs of high risk of developing diabetes (glucose 6.8 mmol/L, haemoglobin A1C 45 mmol/mol) secondary to Cushing’s syndrome. She also had consequently deranged liver function tests (alkaline phosphatase 281 U/L, alanine aminotransferase 45 U/L) with metabolic alkalosis (pH 7.52, bicarbonate 41.6 mmol/L, base excess 18.7 mmol/L, pCO₂ 6.8 kPa). But she had a normal bilirubin (7 μmol/L) and albumin (36 g/L).

Treatment

This woman was initially managed with potassium replacement and spironolactone for her hypokalaemia, leg oedema and hypertension. Following a multidisciplinary team discussion, she had a surgical resection. She underwent an open approach right adrenalectomy with right nephrectomy and cholecystectomy. Unfortunately, this was an R1 resection (figure 3). The tumour was confirmed to be an adrenocortical carcinoma (Ki67 23%, pT3 NX R1, ENSAT stage 3). Postoperatively she was commenced on maintenance hydrocortisone and mitotane to reduce her risk of recurrence.^{1 2}

Figure 3.

This is the resected specimen showing the tumour mass was 170 mm long.

Outcome and follow-up

In the following months she received ongoing follow-up at the tertiary endocrine clinic. She experienced ongoing fatigue with nausea and vomiting secondary to mitotane. Her blood pressure was initially satisfactory at 139/92 mm Hg. She started returning to normal life and had a normal initial 3-month surveillance CT scan. But she began to experience right-sided abdominal pain and unfortunately the 6-month CT scan showed a recurrence with peritoneal and liver metastases. Her hypertension along with hypokalaemia, palpitations, headaches and excess thirst returned. She was initially treated with palliative chemotherapy. Secondary to the chemotherapy she had an episode of haematemesis caused by candida oesophagitis and an oesophageal ulcer. She was commenced on a proton pump inhibitor for gastric protection. She then developed ascites requiring drainage. At this point she was rescanned and this showed further progression of her disease. Therefore, in light of her experiencing side effects and lack of clinical improvement, her chemotherapy was discontinued. Her prognosis is now terminal, 8 months on from diagnosis.

Discussion

There are similar published cases, however, usually in older patients above the age of 40.^{5 10 11} They demonstrate that the signs and symptoms experienced by our patient are very typical. However, these papers tend to focus more on the management and investigation of adrenocortical carcinoma rather than diagnosis. The most closely related case is of a 20-year-old woman who similarly presented with leg oedema.⁴ This case demonstrated again how there was delay in diagnosis. Although key Cushing’s signs and symptoms had been present in this athletic person, the diagnosis of adrenocortical carcinoma was only reached via imaging for her back pain, rather than investigating her hypertension associated with hypokalaemia.

National Institute for Health and Care Excellence recommends that the clinician ‘should consider’ seeking specialist evaluation of secondary causes of hypertension in adults under 40 with hypertension and also resistant hypertension.⁹ Our patient was not only less than 40 but also her blood pressure was poorly controlled on four drugs. She was a previously fit young woman who was suddenly experiencing multiple new symptoms. This therefore should have been investigated sooner. A systematic approach to investigating hypertension with hypokalaemia would have helped reach a diagnosis sooner. An earlier referral could have led to an earlier diagnosis of less advanced and potentially curable disease.

Furthermore, she had typical signs and symptoms of Cushing’s syndrome for a year. During this time, she was seen in ambulatory care as well as by her GP multiple times. There were ample opportunities to screen for secondary causes of hypertension by doing simple investigations such as blood tests. In this case, clinicians were more focused on controlling her blood pressure and treating hypokalaemia rather than considering the cause. Taking a look at the bigger picture would have revealed the classical picture of Cushing’s syndrome.

Patient’s perspective.

At the time of diagnosis, she was devastated. However, she had suspected something sinister as she had been very poorly for some time. She had been repeatedly told that her symptoms were secondary to stress and she even started to consider this. She was initially glad that there was treatment available but was worried about the short-term and long-term complications. She is understandably heartbroken with having a terminal diagnosis and the limited time left with her family. However, she has been trying to raise awareness in order to prevent this being missed in another person. She appreciates everything that has been done for her but wishes she had been investigated sooner.

Learning points.

• Patients with resistant hypertension under 40 should be referred early to a specialist to investigate for secondary causes of hypertension.

• Consider secondary causes in hypertension with electrolyte disturbances.

• Think about Cushing’s syndrome as a cause of bilateral leg oedema, hypokalaemia and hypertension.

• A good history and clinical examination would have aided reaching the diagnosis of Cushing’s syndrome.

• The most important secondary causes of hypertension include Cushing’s syndrome, hyperaldosteronism, pheochromocytoma, chronic kidney disease, hyperthyroidism, renal vein stenosis and sleep apnoea.