E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Case 1

A 50-year-old male was admitted to the Footscray campus of the Western Hospital with pneumonia and acute decompensated heart failure. This occurred on a background of recently diagnosed human immunodeficiency virus, type 2 diabetes mellitus managed with metformin, and fortnightly recreational inhaled methamphetamine use. There was no history of excessive alcohol consumption. Transthoracic echocardiography demonstrated a dilated cardiomyopathy with severe global systolic dysfunction and a left ventricular ejection fraction (LVEF) of 15% (normal >50%). CT coronary angiography revealed no significant coronary artery disease, however a 41x42mm right-sided heterogeneous hyper-enhancing adrenal mass was incidentally detected. Adrenal function tests were sent and the patient was referred for outpatient endocrinology follow-up. Prior to endocrinology review the patient was prescribed carvedilol, ramipril and ivabradine. The plasma normetanephrine returned significantly elevated at 10743pmol/L (<900pmol/L) and remained elevated despite a period of abstinence from methamphetamine (Table 1) 

The patient attended endocrinology clinic and immediately commenced phenoxybenzamine 10mg BD for treatment of a noradrenaline-secreting phaeochromocytoma. Phenoxybenzamine was uptitrated over 4 months to 30mg BD. A pre-operative repeat echocardiogram showed myocardial recovery with an LVEF of 40-50% and mild global systolic dysfunction. He tolerated a high salt and fluid diet for 7 days pre-operatively and his phenoxybenzamine was withheld the morning of surgery. He underwent open adrenalectomy and did not require inotropic support post-operatively. Histopathology confirmed a completely resected phaeochromocytoma, with a Ki67 of <1% and marked nuclear pleomorphism (PASS score: 2). He has been referred for genetic testing.

Case 2

A 39-year-old female presented to the Royal Melbourne Hospital Emergency Department with a severe, sudden-onset headache associated with vomiting. Initial biochemical investigations and CT brain were unremarkable. She was treated for a migraine with morphine, metoclopramide, chlorpromazine, prochlorperazine and transferred to the Emergency Short Stay unit for observation. Nine hours later she had an episode of syncope and chest pain. Electrocardiography demonstrated ST elevation in leads I and aVL, with reciprocal ST depression in leads II, III, aVF, V1, V3 and V4. A high sensitivity troponin was 7920 ng/L (<16ng/L). Urgent coronary angiography was performed showing normal coronary arteries. The left ventriculogram (Figure 1) and subsequent transthoracic echocardiogram demonstrated akinesis of basal and mid segments with only apical contraction preserved, consistent with reverse-takotsubo cardiomyopathy. The ejection fraction was estimated to be 5-10% (normal >50%).

Post-coronary angiography, the patient became febrile, confused, and hypoxaemic. She was transferred to the intensive care unit with cardiogenic shock that proved refractory to inotropic support and was commenced on extracorporeal membrane oxygenation (ECMO). Her haemodynamics were difficult to manage, having periods of hypotension alternating with hypertension and tachycardia requiring periods of noradrenaline and glyceryl trinitrate respectively. An abdominal ultrasound was performed to investigate an ischaemic right lower limb that had complicated ECMO cannulation, which incidentally found an 8cm mass abutting the upper pole of the right kidney. Endocrinology was consulted and plasma metanephrines and chromogranin A were sent (Table 2). It was suspected that the patient had a secretory phaeochomocytoma and alpha-adrenal blockade with phentolamine infusion was commenced. The patient was transferred to another quaternary centre given the concern about potential requirement for a ventricular assist device or cardiac transplantation. There, the patient was transitioned to phenoxybenzamine 10mg BD via nasogastric tube, uptitrated to 40mg QID. Metoprolol 25mg BD was later commenced and uptitrated to 100mg TDS. On day 9 of admission the patient was decannulated from ECMO and extubated. She was transferred to the ward 5 days later and a transthoracic echocardiogram showed complete recovery of left ventricular function. A CT abdomen identified a 7.7cm left adrenal mass. A DOTATATE PET/CT showed a large DOTATATE avid left adrenal mass with no evidence of locoregional nodal or distant metastasis (Figure 2). She underwent an elective left adrenalectomy 6 weeks later with histopathology confirming a phaeochromocytoma, 67mm in maximum dimension, clear of margins, with a PASS score of 0, favouring a benign tumour. On follow-up genetic testing there was no germline mutation conferring increased risk for pheochromocytoma found.

Discussion

Acute catecholamine-mediated cardiomyopathy has been described in association with phaeochromocytoma, occurring in 11% of patients in one series¹. Catecholamines initially have a positive inotropic effect on the myocardium. States of excess, however, lead to massive concentrations of calcium in the myocardial sarcoplasmic reticulum, reducing mitochondrial energy production resulting in stunning of the myocardial fibres¹. Additionally, impaired myocardial oxygen supply due to coronary vasospasm leading to reduced perfusion has been hypothesised to contribute¹. The classic manifestation of this is a takotsubo cardiomyopathy characterised by left ventricular apical akinesis and ballooning with hyperkinesis of the basal segments^1,2. This cannot by differentiated from an acute coronary syndrome clinically, and the diagnosis of takotsubo cardiomyopathy is made at angiogram on the basis of patent coronary arteries and characteristic left ventriculogram appearance. In the second case, the intra-angiographic and echocardiographic appearance of apical myocardial contractility with basal stunning was the opposite of the classical pattern, hence the moniker of “reverse takotsubo” cardiomyopathy². 

The first case is remarkable due to the dual catecholaminergic insults of methamphetamine as well as noradrenaline hypersecretion from the phaeochromocytoma. Methamphetamine is a sympathomimetic drug, causing release of noradrenaline, dopamine and serotonin from storage vesicles due to its structural similarity to monoamines³. Use of methamphetamine is known to cause both catecholamine-mediated cardiomyopathy; as well as elevated urinary catecholamine and plasma metanephrines, in a pattern that can mimic a noradrenaline or dopamine secreting phaeochromocytoma^3,4. Methamphetamine can be detected in urine for up to 60 hours after use, making diagnosis of phaeochromocytoma in a person who uses methamphetamines challenging and reliant on a period of abstinence for reliable results as in our case³. Abstinence from methamphetamine and pharmacological alpha- and beta-adrenoceptor blockade lead to almost complete recovery of myocardial function.

The role that catecholamine excess played in the fulminant course of cardiac failure in the second case was multifactorial. Acute catecholamine excess, or “phaeo crisis”, potentially precipitated by medications including metoclopramide used to treat presumed migraine, lead to the aforementioned cardiomyopathy, severely reducing cardiac output. Additionally, the peripheral vasoconstriction associated with catecholamine agonism of alpha-adrenoceptors lead to an increase in peripheral resistance and a dramatic increase in afterload, further impairing cardiac output. This resulted in cardiac failure refractory to inotropic support and necessitated the use of extracorporeal membrane oxygenation (ECMO). ECMO lends itself as a solution to the unique haemodynamic challenges of providing alpha- and then beta-adrenoceptor blockade to a patient with cardiogenic shock⁵.

The mechanical and pharmacological offloading of the left ventricle achieved was seen in the second case to result in resolution of the cardiomyopathy. This is typical of catecholaminergic cardiomyopathy wherein the echocardiographic features are estimated to resolve within months of cessation of the insult². Prior to adrenalectomy it is imperative that all patients with phaeochromocytoma have adequate alpha and beta-adrenoceptor blockade to prevent life-threatening intra-operative cardiogenic shock.

Take home messages:

• Methamphetamines cause elevation of plasma noradrenaline and dopamine, which can lead to elevated plasma metanephrines and urinary catecholamines
• ECMO is potentially life-saving in the setting of a severe phaeochromocytoma crisis with acute catecholamine cardiomyopathy and peripheral vasoconstriction
• Alpha- and beta-adrenoceptor blockade improves myocardial recovery in patients with phaeochromocytoma and catecholamine-mediated cardiomyopathy prior to adrenalectomy
• Adequate alpha and beta-adrenoceptor blockade is required to prevent an intra-operative phaeochromocytoma crisis.