Diagnosis and Treatment > Investigation > Metanephrines (plasma)
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Summary
Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing’s syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR <0.71) and metanephrines of 0.69 nmol/L (NR <0.36). An adrenal CT showed a 3.8 cm right adrenal nodule, which was not MIBG-avid but was clinically and biochemically consistent with a phaeochromocytoma. He was started on alpha blockade and referred for right adrenalectomy. Four weeks later, on the day of admission for adrenalectomy, profound hypokalaemia was noted (serum potassium 2.0 mmol/L) with non-specific ST-segment ECG changes. He was also diagnosed with new-onset diabetes mellitus (capillary blood glucose of 28 mmol/L). He reported to have gained weight and his skin had become darker over the course of the last 4 weeks. Given these findings, he underwent overnight dexamethasone suppression testing, which showed a non-suppressed serum cortisol of 1099 nmol/L. Baseline serum ACTH was 273 ng/L. A preliminary diagnosis of ectopic ACTH secretion from the known right-sided phaeochromocytoma was made and he was started on metyrapone and insulin. Surgery was postponed for 4 weeks. Following uncomplicated laparoscopic adrenalectomy, the patient recovered with full resolution of symptoms.
Learning points:
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Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis.
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Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing’s syndrome, thus complicating tumour removal.
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Removal of the primary tumour often leads to full recovery.
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The limited literature suggests that the presence of ectopic Cushing’s syndrome does not appear to have any long-term prognostic implications.
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Summary
Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients.
Learning points:
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18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients.
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Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions.
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MEN1 is implicated in the tumorigenesis of PHEO in this patient.
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Summary
Although pheochromocytoma classically presents with headaches, palpitations and paroxysmal hypertension, atypical presentations such as cardiomyopathy, stroke and subarachnoid haemorrhage have been infrequently documented. We present in this case report, an uncommon presentation of pheochromocytoma with myocardial infarction with normal coronary arteries (MINOCA). A 79-year-old woman presented with central crushing chest pain radiating to left arm associated with headache, palpitations, sweating and difficulty in breathing. For 2 years, she experienced brief episodes of headache, tinnitus, dizziness, palpitations, and sweating that spontaneously resolved. Clinical examination was unremarkable except for high blood pressure (210/105 mmHg). Her electrocardiogram showed T wave inversions from V1 to V6 and elevated troponins (774 ng/L at baseline and 932 ng/L 3 h from baseline (normal <16 ng/L) in keeping with a diagnosis of non-ST elevated myocardial infarction. Coronary angiography showed normal coronary arteries. Patient was hence treated as myocardial infarction with normal coronaries (MINOCA). Despite appropriate treatment for MINOCA, she continued to experience episodic headaches, palpitations, dizziness and erratic blood pressures (particularly severe hypertension shortly after beta-blocker administration). Further investigations revealed raised urine noradrenaline of 4724 nmol/24 h (<554 nmol/24 h) and urine adrenaline of 92863 nmol/24 h (<77 nmol/24 h). Computerised tomography demonstrated a well-defined rounded mass in right adrenal gland morphological of pheochromocytoma. She underwent laparoscopic right adrenalectomy with histology confirming pheochromocytoma. This case highlights the importance of thorough investigation for the underlying cause for MINOCA. In patients with unexplained erratic blood pressure control, pheochromocytoma should be considered as a differential diagnosis.
Learning points:
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Pheochromocytoma is rare tumour that often presents with non-specific symptoms.
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It is important to investigate underlying cause of MINOCA.
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Thorough history is the key to diagnosis.
National University of Ireland, Galway, Ireland
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Summary
Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient’s SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient’s father’s paraganglioma.
Learning points:
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Pituitary adenomas may be the presenting and/or sole feature of SDHB mutation-related disease.
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SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.
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Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.
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Immunohistochemistry may not always predict the presence of SDHx mutations.
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Summary
Pheochromocytoma is a rare tumor of the adrenal gland. It often presents with the classic triad of headache, palpitations and generalized sweating. Although not described as a typical symptom of pheochromocytoma, anxiety is the fourth most common symptom reported by patients suffering of pheochromocytoma. We report the case of a 64 year old man who had severe anxiety and panic disorder as presenting symptoms of pheochromocytoma. After 13 years of psychiatric follow-up, the patient was diagnosed with malignant pheochromocytoma. After surgical resection of his pheochromocytoma and his hepatic metastases, the major panic attacks completely disappeared, the anxiety symptoms improved significantly and the psychiatric medications were stopped except for a very low maintenance dose of venlafaxine. We found in our cohort of 160 patients with pheochromocytoma 2 others cases of apparently benign tumors with severe anxiety that resolved after pheochromocytoma resection. These cases highlight that pheochromocytoma should be included in the differential diagnosis of refractory anxiety disorder.
Learning points:
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Anxiety and panic disorder may be the main presenting symptoms of pheochromocytoma.
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The diagnosis of pheochromocytoma should be excluded in cases of long-term panic disorder refractory to medications since the anxiety may be secondary to a catecholamine-secreting tumor.
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Surgical treatment of pheochromocytoma leads to significant improvement of anxiety disorders.
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Summary
We report a case of elderly Chinese lady with neurofibromatosis type-1 presenting with longstanding palpitation, paroxysmal hypertension and osteoporosis. Biochemical testing showed mild hypercalcaemia with non-suppressed parathyroid hormone level suggestive of primary hyperparathyroidism, and mildly elevated urinary fractionated normetanephrine and plasma-free normetanephrine pointing to a catecholamine-secreting pheochromocytoma/paraganglioma. Further scintigraphic investigation revealed evidence of a solitary parathyroid adenoma causing primary hyperparathyroidism and a left pheochromocytoma. Resection of the parathyroid adenoma and pheochromocytoma resulted in normalization of biochemical abnormalities and hypertension. The rare concurrence of primary hyperparathyroidism and pheochromocytoma in neurofibromatosis type-1 is discussed.
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Summary
A phaeochromocytoma (PC) is a rare, catecholamine-secreting neuroendocrine tumour arising from the adrenal medulla. Presenting symptoms of this rare tumour are highly variable but life-threatening multiorgan dysfunction can occur secondary to catecholamine-induced hypertension or hypotension and subsequent cardiovascular collapse. High levels of circulating catecholamines can induce an acute stress cardiomyopathy, also known as Takotsubo cardiomyopathy. Recent studies have focused on early diagnosis and estimation of the prevalence of acute stress cardiomyopathy in patients with PC, but very little is reported about management of these complex cases. Here, we report the case of a 38-year-old lady who presented with an acute Takotsubo or stress cardiomyopathy and catecholamine crisis, caused by an occult left-sided 5 cm PC. The initial presenting crisis manifested with symptoms of severe headache and abdominal pain, triggered by a respiratory tract infection. On admission to hospital, the patient rapidly deteriorated, developing respiratory failure, cardiogenic shock and subsequent cardiovascular collapse due to further exacerbation of the catecholamine crisis caused by a combination of opiates and intravenous corticosteroid. An echocardiogram revealed left ventricular apical hypokinesia and ballooning, with an estimated left ventricular ejection fraction of 10–15%. Herein, we outline the early stabilisation period, preoperative optimisation and intraoperative management, providing anecdotal guidance for the management of this rare life-threatening complication of PC.
Learning points:
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A diagnosis of phaeochromocytoma should be considered in patients presenting with acute cardiomyopathy or cardiogenic shock without a clear ischaemic or valvular aetiology.
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Catecholamine crisis is a life-threatening medical emergency that requires cross-disciplinary expertise and management to ensure the best clinical outcome.
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After initial resuscitation, treatment of acute catecholamine-induced stress cardiomyopathy requires careful introduction of alpha-blockade followed by beta-blockade if necessary to manage β-receptor-mediated tachycardia.
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Prolonged α-adrenergic receptor stimulation by high levels of circulating catecholamines precipitates arterial vasoconstriction and intravascular volume contraction, which can further exacerbate hypotension. Invasive pressure monitoring can aid management of intravascular volume in these complex patients.
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Summary
Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1–1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case.
Learning points:
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Pheochromocytomatosis is a very rare form of pheochromocytoma recurrence.
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Pheochromocytomatosis refers to new, multiple and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma.
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Tumor capsule rupture during adrenalectomy predisposes a patient to develop pheochromocytomatosis.
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Surgical resection of the multiple tumors of pheochromocytomatosis is recommended.
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Pheochromocytoma recurrence should prompt genetic testing for syndromic pheochromocytoma.
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University of Melbourne, Parkville, Victoria, Australia
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University of Melbourne, Parkville, Victoria, Australia
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University of Melbourne, Parkville, Victoria, Australia
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University of Melbourne, Parkville, Victoria, Australia
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Summary
ACTH-secreting phaeochromocytoma (ASP) is a rare cause of ACTH-dependent Cushing’s syndrome (CS). We report the case of a 63-year-old female presenting with CS secondary to an ASP complicated by bowel perforation. This case report highlights ASP as an uncommon but important cause of ectopic ACTH secretion (EAS). There have been 29 cases of ASP, all of which were unilateral and benign, but associated with significant complications. Patients presenting with ASP have the potential for cure with unilateral adrenalectomy. Given this promising prognosis if recognised, ASP should be considered in the diagnostic workup of ACTH-dependent CS. As this case demonstrates, gastrointestinal complications can arise from severe hypercortisolaemia associated with CS. Early medical and surgical intervention is imperative as mortality approaches 50% once bowel perforation occurs.
Learning points
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Consider phaeochromocytoma in the diagnostic workup of ACTH-dependent CS; screen with plasma metanephrines or urinary catecholamines.
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Serial screening may be required if ACTH-secreting phaeochromocytoma is suspected, as absolute levels can be misleading.
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Early catecholamine receptor blockade and adrenal synthesis blockade may avoid the need for rescue bilateral adrenalectomy in ACTH-secreting phaeochromocytoma.
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Consider early medical or surgical management when gastrointestinal features are present in patients with CS, as bowel perforation due to severe hypercortisolaemia can occur and is associated with significant mortality.
Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, Quebec, H4J 1C5, Canada
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Summary
In patients with primary aldosteronism (PA) undergoing adrenal venous sampling (AVS), cortisol levels are measured to assess lateralization of aldosterone overproduction. Concomitant adrenal autonomous cortisol and aldosterone secretion therefore have the potential to confound AVS results. We describe a case where metanephrine was measured during AVS to successfully circumvent this problem. A 55-year-old hypertensive male had raised plasma aldosterone/renin ratios and PA confirmed by fludrocortisone suppression testing. Failure of plasma cortisol to suppress overnight following dexamethasone and persistently suppressed corticotrophin were consistent with adrenal hypercortisolism. On AVS, comparison of adrenal and peripheral A/F ratios (left 5.7 vs peripheral 1.0; right 1.7 vs peripheral 1.1) suggested bilateral aldosterone production, with the left gland dominant but without contralateral suppression. However, using aldosterone/metanephrine ratios (left 9.7 vs peripheral 2.4; right 1.3 vs peripheral 2.5), aldosterone production lateralized to the left with good contralateral suppression. The patient underwent left laparoscopic adrenalectomy with peri-operative glucocorticoid supplementation to prevent adrenal insufficiency. Pathological examination revealed adrenal cortical adenomas producing both cortisol and aldosterone within a background of aldosterone-producing cell clusters. Hypertension improved and cured of PA and hypercortisolism were confirmed by negative post-operative fludrocortisone suppression and overnight 1 mg dexamethasone suppression testing. Routine dexamethasone suppression testing in patients with PA permits detection of concurrent hypercortisolism which can confound AVS results and cause unilateral PA to be misdiagnosed as bilateral with patients thereby denied potentially curative surgical treatment. In such patients, measurement of plasma metanephrine during AVS may overcome this issue.
Learning points
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Simultaneous autonomous overproduction of cortisol and aldosterone is increasingly recognised although still apparently uncommon.
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Because cortisol levels are used during AVS to correct for differences in dilution of adrenal with non-adrenal venous blood when assessing for lateralisation, unilateral cortisol overproduction with contralateral suppression could confound the interpretation of AVS results
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Measuring plasma metanephrine during AVS to calculate lateralisation ratios may circumvent this problem.
