A case of catecholamine crisis induced by iatrogenic glucocorticoids: case report

doi:10.21203/rs.3.rs-3753606/v1

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Case Report

A case of catecholamine crisis induced by iatrogenic glucocorticoids: case report

https://doi.org/10.21203/rs.3.rs-3753606/v1

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Background: Pheochromocytoma is a rare neuroendocrine tumor originating from chromaffin cells in the adrenal medulla, and is a rare type of secondary hypertension. It mainly synthesizes and secretes excessive catecholamines, causing a series of clinical symptoms, such as headache, sweating, palpitations, and may be life-threatening in severe cases. In the current case report, we describe a rare case of a clinically manifesting pheochromocytoma with which landed in pheochromocytoma crisis.

Case presentation: The authors describe a rare case of a clinically manifesting pheochromocytoma with which landed in pheochromocytoma. A 19-year-old female was admitted with headache, recurrent nausea and vomiting, and fever. The patient's levels of troponin I and BNP increased after using glucocorticoids. And the patient continued to be treated with glucocorticoids due to misdiagnosis as myocarditis. Computerized tomography exposed a soft tissue density mass at the left adrenal gland.

Further evaluations revealed high levels of plasma catecholamines and 24-hour urine catecholamines and their metabolites. The patient was clinically diagnosed with pheochromocytoma and discontinued glucocorticoids. RET Cys634Arg mutation was found in this case. After 3 months of preparation, the patient underwent surgical. The patient was discharged from hospital without further medication. The patient was followed-up regularly after surgery and did not experience any of the above symptoms.

Conclusion: Glucocorticoids can induce crisis in pheochromocytoma. Therefore, before starting therapeutic glucocorticoids, any clinical signs or symptoms of a potential pheochromocytoma or adrenal accidental tumors should prompt reliable biochemical testing to rule out a pheochromocytoma.

Pheochromocytoma

Glucocorticoids

pheochromocytoma crisis

Case report

Pheochromocytoma is a rare neuroendocrine tumor originating from chromaffin cells in the adrenal medulla, and is a rare type of secondary hypertension[1]. It mainly synthesizes and secretes excessive catecholamines, causing a series of clinical symptoms, such as headache, sweating, palpitations, and may be life-threatening in severe cases[2]. It has an estimated annual incidence of 0.8 per 100,000 person-years[3]. Most cases of pheochromocytoma are sporadic and unilateral, but 10–25% of the cases possibly related to genetic syndrome which are mostly bilateral and multiple, such as multiple endocrine neoplasia 2, in which 50–80% of patients are bilateral[4]. In the current case report, we describe a rare case of a clinically manifesting pheochromocytoma with which landed in pheochromocytoma crisis. Pheochromocytoma crisis is a life-threatening complication that requires timely identification and the most challenging correct treatment.

A 19-year-old female presented to the emergency room of our hospital with the main reason for admission was “headache for 2 days, recurrent nausea and vomiting with fever for 1 day”. After poor treatment with glucocorticoids and antibiotics, the patient was admitted to the hospital and transferred to the intensive care unit. A year prior, she had experienced the same symptoms and diagnosed with "myocarditis". During the hospitalization, the patient had been diagnosed with hypertension and the doctor had prescribed antihypertensive drugs for her. After discharge, the patient did not follow the doctor's instructions to take medication and test her blood pressure regularly. His father died suddenly for an unknown reason.

On admission, physical examination revealed a body temperature of 39.1°C, a pulse rate of 148/min, a respiratory rate of 24/min, and blood pressure of 189/120 mmHg, The initial laboratory data is given in Table 1. The important laboratorys throughout the entire treatment process are detailed in Fig. 1. Computerized tomography exposed a soft tissue density mass of 43 mm ×36 mm at the left adrenal gland (Fig. 2). No abnormalities found on head and chest computerized tomography. The electrocardiogram showed sinus tachycardia with short PR interval, and high and sharp P-waves in leads II、III and avF. There was no significant finding on the transthoracic echocardiography.

Table 1

Laboratory tests results
Laboratory tests	Result		Reference value
Laboratory tests	Result in admission	Result before discharge	Reference value
Urine
Urinary free norepinephrine (nmol/24h)	> 12697.60		60.00-352
Urinary metanephrines (nmol/24h)	4078		< 216
Urinary normetanephrines (nmol/24h)	8312		< 312
Urinary vanillylmandelic acid (mg/24h)	58.1		≤ 12
Urinary free adrenaline (nmol/24h)	4368.89		4.31–61.60
Urinary dopamine (nmol/24h)	1802.74		750–2088
Blood
Cortisol (nmol/L)
8:00	> 1655.31	296.95	185–624
16:00	1095.63		< 276
24:00	961.98		< 50
ACTH (pg/mL)
8:00	95.07	30.98	6–48
16:00	21.73		3–30
24:00	31.9		< 20
Dopamin (pmol/L)	524.5		≤ 195.7
Norepinephrine (pmol/L)	83975		414-4435.5
Epinephrine (pmol/L)	10579.3		≤ 605.4
TT3 (nmol/L)	0.94		1.01–2.48
TT4 (nmol/L)	141.67		69.97-152.52
FT3 (pmol/L)	4.28		3.28–6.47
FT4 (pmol/L)	8.35		7.64–16.03
TSH (mU/L)	0.469		0.56–5.91
Tn I (ng/mL)	0.023	0.081	0.02–0.06
BNP (pg/mL)	30.23	501.63	0-37.3
PCT (ng/mL)	0.683		0-0.05
ESR (mm/h)	39		0–34
CRP (mg/L)	3.08		0–10
IL-6 (pg/mL)	4.588		0-6.6
WBC (×10^9/L)	14.77	14.01	3.5–9.5
NE%	91.8	79.3	40–75
NE (×10^9/L)	13.55	11.11	1.8–6.3
FBG (mmol/L)	7.74		3.9–6.1
HbA1c (%)	6		4–6
AST (U/L)	22	70	13–35
ALT (U/L)	24	85	7–40
BUN	7.61	4.85	2.6–7.5
Cr	105	49	41–73
PTH (pg/mL)	83.4		12–88
Calcitonin (pg/mL)	19.21		0–18
K (mmol/L)	4.57	4.47	3.5–5.3
Na (mmol/L)	141.4	138.7	137–147
Ca (mmol/L)	2.76	2.26	2.11–2.52
Venus blood gas analysis
pH	7.3		7.35–7.45
pCO2 (mmHg)	39.1		35–45
pO2 (mmHg)	123.8		80–100
Lac (mmol/L)	2.5		0.7–2.5
HCO3 (mmol/L)	18.9		21–28
ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; BNP, brain natriuretic peptide; CRP, C-reactive protein; FBG, fibrinogen; Lac, lactic acid; NE, neutrophils; pO2, oxygen partial pressure; pCO2, partial pressure of carbon dioxide; pH, potential of hydrogen; Cr, serum creatinine.TP, total protein; Tn I, troponin I; WBC, white blood cell;PTH, parathyroid Hormone༛HbA1c, glycosylated hemoglobin༛TSH, thyroid releasing hormone༛FT4, free thyroxine; TT4, total thyroxine; FT3, free triiodothyronine; TT3, total triiodothyronine; ESR, erythrocyte sedimentation rate; PCT, procalcitonin; ESR, erythrocyte sedimentation rate; IL-6, interleukin-6.

The cardiologist suggested a diagnosis of myocarditis of unknown etiology. Treatment with methylprednisolone (0.25g everyday), furosemide (20mg every 12 h), spironolactone (20mg every 12 h), perindopril amlodipine (10mg: 5mg everyday), metoprolol tartrate (25mg every 12 h), esmolol ( 0.2g/h intravenous infusion) was initiated. Because of concern for infection the patient was treated with moxifloxacin. Considering patients with adrenal masses and hypertension, endocrinologist suggested that aldosterone to renin ratio, plasma cortisol, plasma catecholamines, and 24-hour urinary catecholamines and their metabolites should be assessed. In recumbent position, the levels of plasma catecholamines, various urinary catecholamines and their metabolites rose significantly (Table 1), including plasma dopamine 524.5 pmol/L, norepinephrine 83975pmol/L, epinephrine 10579.3 pmol/L, 24-hour urinary free adrenaline 4368.89 nmol/24 hours, urinary free norepinephrine > 12697.60 nmol/24 hours, urinary normetanephrine 8312 nmol/24 hours, urinary metanephrines 4078 nmol/24 hours and urinary vanillylmandelic acid 58.1 mg/24 hours. The patient was clinically diagnosed with pheochromocytoma. Glucocorticoid therapy was discontinued and perindopril amlodipine was replaced to terazosin to control the patient’s blood pressure.

In addition, an enhanced abdominal CT scan (Fig. 2) confirmed the presence of a left adrenal mass, which was likely a pheochromocytoma. Moreover, whole-exome sequencing was performed on the patient after signing the informed consent form. A heterozygous missense mutation c.1900T > C: p. Cys634Arg was found in the RET gene of the subject, which resulted in a change in 634 codon of the RET gene from encoding cysteine to arginine. Considering the possibility of multiple endocrine adenoma syndrome, the thyroid and parathyroid were examined. Except a hypoechoic mass of 6 mm × 4 mm in the left thyroid by thyroid color Doppler ultrasound and mild increased in calcitonin levels, no other significant abnormalities were found.

As the condition gradually improved, plasma cortisol and ACTH levels decreased to normal. The patient was discharged and the following medications were prescribed to be taken at home: metoprolol tartrate (100mg every 12 h), ivabradine hydrochloride (5 mg every 12 h).

After three months, the patient’s condition stabilized, and left adrenal tumor resection was performed. The tumor diameter was 50 mm × 40 mm × 30 mm. Immunohistochemical results showed that Vim (+), CD56 (+), Syn (+), CgA (+), NSE (+), S-100 (sertoli cells +), CKpan (−), CD10 (−), MART-1/MenlanA (−), Melan-A (−), Ki67 (1%+). Since then, the patient was diagnosed with adrenal pheochromocytoma. The patient was discharged from hospital without further medication. The patient was followed-up regularly after surgery and did not experience any of the above symptoms. Three months after discharge, there were no significant changes in thyroid ultrasound, the 24-hour urinary vanillylmandelic acid, PTH and electrolyte levels were normal, and calcitonin remained slightly elevated.

Pheochromocytoma is a rare neuroendocrine tumor originating from the chromaffin tissue of the corona, accounting for only 0.5% of hypertensive patients. Pheochromocytoma located in the adrenal medulla can secrete catecholamines, leading to various clinical symptoms. Mild cases may manifest as silent, local occupying, or non-specific symptoms, while typical cases may manifest as paroxysmal hypertension accompanied by headache, palpitations, and sweating. Severe cases may cause hemodynamic instability and terminal organ damage or dysfunction, known as pheochromocytoma crisis. Pheochromocytoma can also cause cardiotoxic myocarditis, which was the main manifestation of the case we reported.

When the patient presented to the emergency department, the BNP and troponin I levels were normal, but on the second day of hospitalization, the BNP and troponin I levels significantly increased. We found that the patient had been treated with glucocorticoids before admission. In addition, considering acute myocarditis, the patient was treated with glucocorticoids for 5 days, and her BNP and troponin I levels peaked on the third day after admission, while troponin I levels dropped significantly on the fourth day, but the BNP and troponin levels were still higher than the reference range throughout the hospitalization. The increased in BNP and troponin I levels in patients may be induced by glucocorticoids. According to one literature review, in most cases of pheochromocytoma crisis caused by glucocorticoids, the tumor diameters were reported to be ≥ 30 mm, while the glucocorticoid dosages were equivalent to ≥ 60 mg/day of hydrocortisone[5]. In our case, the tumor diameter was 50 mm × 40 mm × 30 mm, and the dose of glucocorticoids was equivalent to hydrocortisone 1250 mg/day, which was much higher than 60 mg/day. High-dose glucocorticoids can lead to a life-threatening conditioncalled catecholamine crisis[5, 6]. Previous studies have shown that glucocorticoids can promote the synthesis and release of catecholamines. Steroids have been shown to stimulate the synthesis of catecholamines by inducing biosynthetic enzymes (phenylethanolamine-N-methyltransferase, tyrosine hydroxylase, and dopamine-b-hydroxylase)[7–9]. Previous study has shown that the release of catecholamines from perfused canine adrenal glands by corticosteroids[10]. Glucocorticoids have also been shown to increase catecholamine synthesis and storage in PC12 pheochromocytoma cell cultures[11].

The patient in our case had hypertension of 189/120mmHg at admission, and blood pressure was controlled to a safe range after treatment with antihypertensive drugs. However, the patient had persistent high fever and palpitations. After taking the medication to lower the heart rate, the patient's heart rate did not drop to 100 until 15 days after admission. The patient's body temperature dropped below 37.3℃ after 10 days of hospitalization. Throughout the entire hospitalization period, the patient's white blood cell and neutrophil levels were higher than normal. The sustained high levels of body temperature, heart rate, and white blood cell levels in patients may be related to the use of glucocorticoids.

During the hospitalization, the patient’s echocardiography has not shown any abnormalities. A study on 26 consecutive, unselected patients with pheochromocytoma over a 3-year period reported that the most common (80% of patients) echocardiographic pattern was normal left ventricular (LV) mass with normal or even increased systolic performance[12]. The patient's cortisol level increased significantly at admission, which may have been caused by stress. Additionally, there has been case reporting the presence of ACTH-secreting pheochromocytoma[13, 14]. After the patient's condition stabilized, we found the cortisol level returned to normal, suggesting that the increased cortisol level in patients is related to stress response.

An endocrine society clinical practice guideline of Pheochromocytoma and paraganglioma has suggested that all patients with pheochromocytoma should undergo genetic testing, as they may be sporadic or in the context of genetic syndromess[15]. RET Cys634Arg mutation was found in this case, which is related to Multiple endocrine neoplasia type 2A (MEN2A). A study with an average follow-up of 7 years found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism in Cys634Arg carriers than in Cys634Tyr carriers[16]. And the Cys634Arg mutation was an independent factor for persistent/recurrent of MEN2A[16].

During hospitalization and postoperative follow-up, the patient's calcitonin levels slightly increased, while electrolyte and parathyroid hormone levels remained normal. A study has shown that immunoreactive calcitonin in catecholamine storage vesicles of human pheochromocytoma[17]. Long-term follow-up is required for all patients with pheochromocytoma due to the possibility of recurrence[18]. For this patient, it is even more important to closely followed-up to detect and diagnose thyroid cancer, hyperparathyroidism and the recurrence of pheochromocytoma.

Pheochromocytoma is a rare disease with significant harm, and timely identification and diagnosis of pheochromocytoma are important. However, there are numerous medical personnel in China with varying levels of professional knowledge, and they are also limited by their expertise, making it difficult for everyone to identify pheochromocytoma in a timely manner. In addition to improve the overall level of medical personnel, what we need to consider is what simple and effective measures we should take to avoid the occurrence of such cases. For example, when prescribing glucocorticoids, the electronic system can pop up reminders to remind medical personnel whether the patient has the triad of pheochromocytoma (headaches, palpitations, and excessive sweating), and whether there is adrenal accidental tumor. Alternatively, exploring a scoring method for identifying pheochromocytoma.

Glucocorticoids can induce crisis in pheochromocytoma. Therefore, before starting therapeutic glucocorticoids, any clinical signs or symptoms of a potential pheochromocytoma or adrenal accidental tumors should prompt reliable biochemical testing to rule out a pheochromocytoma.

Ethics approval and consent to participate

This case report was approved by the patient and Institutional Review Board.

Consent for publication

The written informed consent was obtained from subjects for publication.

Availability of data and materials

All Data and material collected during this study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was funded by Taizhou People Hospital Teaching Research Project (General Project, JX-3-202302).

Authors’ contributions

Collected the data: Boliang Li, Bangkui Xu, Jing Zheng. Wrote the draft manuscript: Xue Wei, Qingqing Zhang. Revised and edited the final manuscript: Shufang Yang, Qingqing Zhang, Yu Lu. Approved the manuscript:Yucheng Wu. All authors read and approved the manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

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A case of catecholamine crisis induced by iatrogenic glucocorticoids: case report

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