Rare but serious cause for hypokalaemia and hypertension
Hussun-Ara Shah , 1,2 Asgar Madathil,3 Charlotte Routh4
1Medical Education, Newcastle University, Newcastle upon Tyne, UK 2Respiratory Medicine, Northumbria Healthcare NHS Foundation Trust, Newcastle Upon Tyne, UK 3Diabetes and Endocrinology, Northumbria Healthcare NHS Foundation Trust, Newcastle Upon Tyne, UK 4Acute Medicine, Northumbria Healthcare NHS Foundation Trust, Newcastle Upon Tyne, UK
Correspondence to
Dr Hussun-Ara Shah; h.shah2@newcastle.ac.uk
Accepted 21 January 2021
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To cite: Shah H-A, Madathil A, Routh C. BMJ Case Rep 2021;14:e239955. doi:10.1136/bcr-2020- 239955
SUMMARY
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.23 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 hyper- cortisolism.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 hyperten- sion 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 accompa- nied 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 previ- ously. 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 electro- lytes, 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 supracla- vicular 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
BMJ
Case report
| 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 mlU/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 <59.7mIU/L Erect 5.3-99.1 mlU/L |
| Fibrinogen | 3.8 g/L | 1.8-4.5g/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 umol/L | 49-90 umol/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 umol/L | 1.7-9.2 umol/L |
| Bilirubin | 7 μmol/L | <21 umol/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.
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, glomer- ulonephritis, 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 umol/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 Cush- ing’s syndrome and check for any complications. Please refer to table 1 as a summary of blood tests.
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, pheochro- mocytoma 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 ultra- sound (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 correla- tion 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.
SAMSUNG PS80A
DI 120.19 mm
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 adre- nocorticotropic 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 umol/L). Both luteinising hormone (LH) and follicle-stimulating hormone (FSH) may be suppressed with adrenal tumours (beta- human chorionic gonadotropin suppressed <1IU/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 amino- transferase 45 U/L) with metabolic alkalosis (pH 7.52, bicar- bonate 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 hyper- tension. Following a multidisciplinary team discussion, she had a surgical resection. She underwent an open approach right adre- nalectomy with right nephrectomy and cholecystectomy. Unfor- tunately, 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
SHATTER RESISTANT
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 haemate- mesis 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 progres- sion 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 diag- nosis. The most closely related case is of a 20-year-old woman who similarly presented with leg oedema.4 This case demon- strated 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 recom- mends that the clinician ‘should consider’ seeking specialist eval- uation 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 hypokalemia
Case report
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.
would have helped reach a diagnosis sooner. An earlier referral could have led to an earlier diagnosis of less advanced and poten- tially curable disease.
Furthermore, she had typical signs and symptoms of Cushing’s syndrome for a year. During this time, she was seen in ambula- tory 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 clas- sical picture of Cushing’s syndrome.
Acknowledgements The authors would like to thank Simon Pearce, Professor of Endocrinology, Newcastle Hospitals, NHS foundation Trust, for his support.
Contributors H-AS is the first author of this case report and wrote up the case with feedback from CR and AM shaping the final version. All authors were involved in the patient’s care.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
ORCID İD Hussun-Ara Shah http://orcid.org/0000-0003-2876-4056
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